DEVELOPMENT OF BIOSIMILAR PRODUCTS + + + + + PART 15 … · 2014. 10. 16. · PANEL MEMBER MALONEY: Diane Maloney, Associate Director for Policy, CBER. PANEL MEMBER MARCHAND: Hello

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FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

OFFICE OF MEDICAL POLICY

+ + + + +

DRAFT GUIDANCES RELATING TO THE

DEVELOPMENT OF BIOSIMILAR PRODUCTS

+ + + + +

PART 15 PUBLIC HEARING

+ + + + +

FRIDAY

MAY 11 2012

+ + + + +

The Hearing convened at the Food

and Drug Administration White Oak Campus

Building 31 Room 1503 10903 New Hampshire

Avenue Silver Spring Maryland at 830 am

Rachel Sherman Presiding Officer presiding

PANEL MEMBERS

RACHEL SHERMAN MD MPH Associate

Director for Medical Policy Center for Drug

Evaluation and Research Presiding Officer

LEAH CHRISTL PhD Associate Director for

Biosimilars Office of New Drugs Center for

Drug Evaluation and Research

DENISE ESPOSITO JD Deputy Director Office

of Regulatory Policy Center for Drug

Evaluation and Research

Neal R Gross amp Co Inc202-234-4433

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PANEL MEMBERS STEVEN KOZLOWSKI MD Director Office of Biotechnology Products Office of Pharmaceutical Science Center for DrugEvaluation and Research

DIANE MALONEY JD Associate Director for Policy Office of the Center Director Centerfor Biologics Evaluation and Research

HEIDI C MARCHAND PharmD Assistant Commissioner Office of Special Health IssuesOffice of the Commissioner

MARYLL TOUFANIAN JD Associate Chief Counsel for Drugs Office of the Chief Counsel Office of the Commissioner

ROBERT A YETTER PhD Associate Director for Review Management Center for BiologicsEvaluation and Research

PRESENTERS

ROBERT YAPUNDICH MD Alliance for Patient Access ANDREW R SPIEGEL ESQ Colon Cancer Alliance ALEXEY SALAMAKHA Global Healthy Living Foundation

MARCIA BOYLE Immune Deficiency Foundation

DOLPH CHIANCHIANO JD MPA National Kidney Foundation IncRENE CABRAL-DANIELS National Patient Advocate Foundation

AL CORS RetireSafe PRESENTERS


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RICHARD DOLINAR MD The Alliance for Safe Biologic Medicines

SHEIN-CHUNG CHOW PhD Duke University

School of Medicine

MARCIE BOUGH PharmD American Pharmacists

Association

EVERETT NEVILLE Express Scripts

KRISTIN BASS Pharmaceutical Care Management

Association

NEAL PARKER ESQ Abbott Laboratories

JOSEPH P MILETICH MD PhD Amgen Inc

MICHELLE ROHRER PhD Genentech a Member of

the Roche Group

SUMANT RAMACHANDRA MD PhD MBA

Hospira Inc

JAY P SIEGEL MD Janssen RampD Inc

JAMES ROACH MD Momenta Pharmaceuticals

Inc

PATRICK VINK Mylan Inc

JAMES C SHELAN Novo Nordisk Inc

F OWEN FIELDS PhD Pfizer

MARK MCCAMISH MD PhD Sandoz International GmbH a Novartis CompanyKARL HEINZ EMMERT PhD Teva Global Branded Products Merckle GmbH Teva Group Member

PRESENTERS


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RONALD A RADER Biotechnology Information Institute

MICHAEL STRAUSS PhD CBR International CorporationBRUCE BABBITT PhD PAREXEL International LLC

SARA RADCLIFFE Biotechnology IndustryOrganizationCORNELIA ULM European Generic Medicines Association

KRISTIN VAN GOOR PhD RAC Pharmaceutical Research amp Manufacturers of America

OPEN PUBLIC COMMENTERS

JAMES E SYKES MPH HealthHIV

ANDREW SPERLING JD National Alliance on Mental Illness KALYAN R ANUMULA PhD Therapeutic ProteinsInternational LLC

GREGORY DAVIS PhD Eli Lilly and Company

AHAVIAH DIANE GLASER JD Generic Pharmaceutical Association


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CONTENTS Presiding Officer Opening Remarks

Rachel Sherman MD MPH 8

PRESENTATIONS

Robert Yapundich MDAlliance for Patient Access 15

Andrew R Spiegel EsqColon Cancer Alliance 28

Alexey SalamakhaGlobal Healthy Living Foundation 40

Marcia BoyleImmune Deficiency Foundation 50

Dolph Chianchiano JD MPANational Kidney Foundation Inc

Rene Cabral-Daniels 64

National Patient Advocate Foundation 75

Al Cors RetireSafe 86

Richard Dolinar MD The Alliance for Safe BiologicMedicines 95

Shein-Chung Chow PhDDuke University School of Medicine 107

Marcie Bough PharmDAmerican Pharmacists Association 119

Everett Neville Express Scripts 135


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CONTENTS (Cont)

Kristin Bass

Pharmaceutical Care Management

Neal Parker Esq

Association 148

Abbott Laboratories 158

Joseph P Miletich MD PhD

Amgen Inc 174

Michelle Rohrer PhD

Genentech a Member of the Roche

Sumant Ramachandra MD PhD MBA

Group 188

Hospira Inc 204

Jay P Siegel MD

Janssen RampD Inc 216

James Roach MD

Momenta Pharmaceuticals Inc 232

Patrick Vink

Mylan Inc 246

James C Shehan

Novo Nordisk Inc 261

F Owen Fields PhD

Pfizer 271

Mark McCamish MD PhD

Sandoz International GmbH a

Karl Heinz Emmert PhD

Teva Global Branded Products

Novartis company 287

Merckle GmbH - Teva Group Member 302


CONTENTS (Cont)

Ronald A Rader

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Biotechnology Information

Institute 316

Jeanne Novak PhD and

Michael Strauss PhD

CBR International Corporation

Bruce Babbitt PhD

PAREXEL International LLC

324

333

Sara Radcliffe

Biotechnology Industry

Organization 347

Cornelia Ulm

European Generic Medicines

Association 360

Kristin Van Goor PhD RAC and

Sascha Haverfield PhD

Pharmaceutical Research amp

Manufacturers of America 367

Open Public Comments

Closing RemarksAdjournment

376

410


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P-R-O-C-E-E-D-I-N-G-S

(832 am)

PRESIDING OFFICER SHERMAN Good

morning We would like to welcome both the

attendees in the Conference Center and those

viewing the hearing through our live webcast

Welcome to the Part 15 hearing on the Draft

Guidances Related to the Development of

Biosimilar Products

I am Rachel Sherman Associate


Evaluation and Research at the FDA I will

serve as presiding officer for this hearing

And before I go on with the other

scripted announcements I will ask the

panelists to introduce themselves

PANEL MEMBER KOZLOWSKI Steven

Kozlowski Director of the Office of

Biotechnology Products in CDER

PANEL MEMBER ESPOSITO Denise

Esposito from the Office of Regulatory Policy

in CDER


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PANEL MEMBER CHRISTL Leah

Christl Associate Director for Biosimilars

Office of New Drugs CDER

PANEL MEMBER MALONEY Diane

Maloney Associate Director for Policy CBER

PANEL MEMBER MARCHAND Hello

Heidi Marchand Assistant Commissioner for the

Office of Special Health Issues of the Office

of the Commissioner

PANEL MEMBER TOUFANIAN Good

morning Im Maryll Toufanian Associate

Chief Counsel for Drugs in the Office of the

Chief Counsel

PANEL MEMBER YETTER Bob Yetter

Im the Associate Director for Review

Management in the Center for Biologics

PRESIDING OFFICER SHERMAN Before

we begin I will provide a few housekeeping

announcements

Please turn off any mobile

devices as they may interfere with the audio

in this room We ask that all attendees sign


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in The meeting is scheduled from 830 am

until 500 pm today and I will have another

comment on that in a moment

Restrooms are located in the lobby

to the left and the right hallways We are

planning for one 15-minute break during the

morning session and one 15-minute break during

the afternoon session Lunch break is from

1200 to 100 There will be sandwiches

salad and beverages available for purchase in

the lobby

The purpose of the hearing today

is to obtain broad stakeholder input on three

recently issues draft guidances relating to

the development of biosimilar products FDA

has issued the following draft guidances as

part of its initial implementation of the

Biologics Price Competition and Innovation Act

of 2009 the BPCI Act

The first is scientific

considerations in demonstration biosimilarity

to a reference product The second is


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questions and answers regarding implementation

of the BPCI The third is quality

considerations in demonstrating biosimilarity

to a reference protein product

FDA will consider the information

obtained from the public hearing in finalizing

these guidances In addition and this is

actually very crucial to us we are interested

in obtaining public input about the agencys

priorities for the development of future

policies surrounding biosimilars We

obviously have a limited number of resources

to devote to any one issue including

biosimilars

Turning to the speakers and the

agenda We have agenda speakers from about 30

organizations with scheduled slots In order

to keep the agenda as closely on time as

possible I will go over some ground rules

First this meeting is informal

The Rules of Evidence do not apply No

participant may interrupt the presentation of


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another participant Only FDA Panel Members

will be allowed to question a presenter

FDA may recall a presenter for

additional questions at the end of the day

assuming time allows and the presenter remains

available And this is actually quite useful

to us I believe Ms Esposito holds the

record for recalling three panelists at the

same time and having a very interesting

compared and contrast of views So if you are

able please do stay with us

Public hearings under Part 15 are

subject to FDAs policies and procedures for

electronic media coverage of FDAs public

administrative proceedings Representatives

of the electronic media may be permitted

subject to certain limitations to videotape

film or otherwise record FDAs public

administrative proceedings including the

presentations of the speakers today

This meeting will be transcribed

and copies of the transcript may be ordered


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through the docket or accessed on our website

approximately 30 days after this public

hearing

Each speaker has been given an

eight-minute time slot on the agenda with

five additional minutes allotted for the FDA

Panel Members to ask questions And that is

our only opportunity to question you We will

carefully scrutinize everything submitted to

the docket but the only opportunity we have to

ask you clarifying questions is today

So if any speaker goes over the

eight-minute slot the time allowed to

question will be reduced accordingly If a

speaker ends early we intend to go on to the

next speaker As I said if there are

additional questions at the end we would

recall the speaker

For those of you who did not

register to make an oral presentation but

would like to present your comments and we

did hear from a number of you after the


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registration period closed you may speak

during the open public comment period at the

conclusion of the hearing Those interested

in presenting during this open public comment

period but who have not expressed interest

please see Sandra Benton who is standing in

the back of the room you probably all know

her by now by the end of the first break to

be added to this list

And in the interest of

accommodating as many speakers as possible we

will extend this comment period longer if

needed Please recognize that that means that

we may well go beyond 500 pm And also

please recognize that with our apologies

there is one panelist who has a fixed prior

time commitment and will not be able to stay

past the allotted time and we apologize for

that

This hearing is not your last

chance to comment The docket will open until

May 25th and we strongly encourage all


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interested parties to comment Please see the

Federal Register notice for details and again

I emphasize the importance of this We

scrutinize these comments very closely They

are extremely helpful to us and I think those

of you that did comment and then read our

guidance can see that they certainly impact

what we say

Given the full agenda we again

request that each speaker keep the allotted

time so we will be able to keep to our very

tight time schedule We thank you for your

interest and your participation We look

forward to a very productive public hearing

We will now begin with

presentations The first speaker and I

apologize in advance if I butcher anybodys

name is Robert Yapundich MD Alliance for

Patient Access

DR YAPUNDICH I commend you on

pronouncing my name correctly Thank you

Good morning and I wish to thank


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the panel for allowing me to express comments

during this public comment period

I am here today actually wearing

two hats The first as a member and

representative of the Alliance for Patient

Access which I will refer to as AfPA

hereinafter And this is an organization

dedicated to the protection of patient access

to approve medical treatments

And my second hat is as a

neurologist in a small town in North Carolina

in private practice And I have experienced

the good and the bad of generic equivalents

And I strongly desire access to the most

effective and safe therapies for my patients

As the FDA formalizes by a similar

approval process the AfPA has a strong

interest in ensuring this is a safe and

balanced process We ask that you recognize

the unique complexities of each biologic

agent that you ensure patient safety through

rigorous testing and monitoring process of


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biologics and that also we ask that this

pathway be one that promotes access by

protecting and prescribing autonomy for all

practitioners

We recognize that the challenges

in perfecting a biosimilars pathway in many

ways is based on a biologic agents unique and

complex nature First of all the biological

molecules are often produced in cell cultures

And even small variations in how the cells

are grown can change the properties of the

protein produced For this reason any

comprehensive biosimilars pathway should

account for a variety of factors and I list

these up here They should be highly these

are highly sensitive in nature to the

biologics And because many of these

biologics are proteins they are significantly

larger than traditional pharmaceuticals

exceptionally sensitive to heat light and

being denatured by agitation

Also the dosing safety and


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efficacy is an important point determining and

ensuring these biologics and biosimilars is an

entirely different undertaking when compared

to the usual procedures for traditional small

molecule pharmaceuticals

And then finally the biological

therapies are costly The complexity inherent

in the manufacturing process of the biological

therapies results in high cost to patients as

well as the payers

Ultimately the ideal biosimilars

pathway should incorporate three main

elements One is patient safety it should be

affordable and again allow patient access

As the FDA moves forward in this

process the AfPA asks that the following

elements be incorporated into the approval

process of every biosimilar agent The first

is clinical trials These we feel should be

mandatory for each biosimilar product even if

it contains the same biologically active

component as a product that is already on the


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market

We feel that the FDA should

require animal toxicity in human clinical

trials evaluating the safety and efficacy as

these drugs carry the added risk of triggering

an immune response that can sometimes be life-

threatening

The second is the monitoring

aspect We feel that each step of the

manufacturing process must be monitored with

robust tracking system and includes unique

proprietary names and lot numbers And also a

comprehensive labeling system that must be

implemented to allow the precise tracking of

an individual dose of biological product to a

specific manufacturer Obviously if an

individual were to have an adverse event we

would want to be able to track exactly where

that may have come from

The third is the

interchangeability determinations These

should be made only after a biosimilar product


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has been fully investigated in the premarket

clinical trials and then been utilized in the

United States post-market in a sufficient

number of patients over a long enough period

of time to reflect its performance type in the

clinical practice

We feel that the pre- and the

post-market surveillance of these products is

very important Because of the diversity of

the biological products interchangeable

standards and determinations must be very

narrowly defined and there should be no

vagueness left in this for each specific class

of therapeutics

And then finally which is

important to me is the physician-patient

relationship and the physician clinical

decision-making process must be preserved

This is something I battle every day as a

practitioner Insurers and other third

parties must not be empowered to dictate what

therapies physicians can prescribe and what


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therapies patients can access

Only the physicians not the

insurers or other third parties have the

medical education and the understanding of

their patients needs that are necessary to

safely prescribe these very powerful

therapies

I am going to close and just share

a few disclosures about myself I have listed

up here my education my practice I do want

to mention that I have used biologics in my

practice in a variety of conditions I use

IVIG for myasthenia CIDP other conditions

botulinum toxins and interferons as well

At the bottom of my disclosures I

have served as a speaker as well as a

consultant for a variety of pharmaceutical

companies Some of these have used biologics

many of them do not

A little bit about the Alliance

for Patient Access We are a national network

of 400 physicians Our mission is to gain and


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protect patient access to approved medical

treatments including prescription

pharmaceuticals biologics and medical

devices This is our website

In 2011 we launched a group called

the National Physicians Biologics Working

Group And there is a white paper and web

video available at this website

In regards to our funding we are

funded by a variety of grants donations and

associate memberships These are the

financial supporters of AfPA listed here

Finally in summary many

individuals both patients and providers are

looking at the FDA to adhere to its core

mission of protecting the public health by

assuring the safety effectiveness and the

security of biological products To this end

we ask that you recognize the unique

complexities of each biologic agent that you

help ensure patient safety through rigorous

testing and monitoring the process of


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biologics And finally as I mentioned

previously help us protect in prescribing

autonomy for all practitioners

Thank you

PRESIDING OFFICER SHERMAN Thank

you and thank you for getting us off to a good

start and being ahead of schedule

I will turn to the panel now to

see who has questions

PANEL MEMBER TOUFANIAN Thank you

for your presentation I was hoping you could

elaborate a little more about your concerns

with respect to the insurers or third-party

role and how you see the Agency involved in

that consideration

DR YAPUNDICH This is something

I battle every day I am in a small town

Our practice is we have about eight providers

I have one full-time person in my practice

whose only role is to deal with

preauthorizations for products

So in other words as


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practitioners we may see a patient We

evaluate that patient We feel that the

product that we would work for best for that

patient we want to prescribe and then the

insurance companies deny that They deny it

and oftentimes it is very interesting here

they deny it and they want us they force our

hand to use an agent that is not FDA-approved

first before we can use the FDA-approved

agent Its crazy

And so this is what I mean a lot

by the prescribing autonomy This is

something every day that we battle and it is

getting worse and worse

PANEL MEMBER TOUFANIAN And in

terms of FDA considering those issues do you

foresee a role of FDA bringing it sort of at

this Part 15 hearing do you see FDA inserting

themselves into something like that

DR YAPUNDICH No I recognize

this may be out of the auspices of the FDA but

I think that again as the FDA goes through


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this biosimilars pathway anything you can do

to ensure that that agent that I may be forced

to utilize is as similar as possible to the

referenced product would be very much

appreciated

I very commonly on a weekly -- in

fact just this past Wednesday I was on-call

and I had a person show up to the emergency

room this actually happens almost every week

taking their agent This is not a biologic

agent This was another generic product for

seizures And they had seizures They are

taking their medicine and the patient didnt

know I didnt know that they had been

switched from their brand name to their

generic And this is a common problem that we

see You know the generics are very like I

said earlier in my presentation they are good

and they are bad I mean I have many

patients who wouldnt have their conditions

treated if it wasnt for the generic agents

but I have a number of patients whose


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condition actually gets worse because of the

switching that may occur without my knowledge

and without the patients knowledge

PANEL MEMBER KOZLOWSKI Dr

Yapundich in your presentation you mentioned

that there should be mandatory trials and you

also mentioned that there should be class-

specific standards that are narrowly defined

So I wondered whether analytical similarity

plays any role in your thoughts on those

bullets basically

DR YAPUNDICH Yes And I think

the analytical aspect of this is very

important but I think you cannot rely on that

totally We are talking again about a class

of agents that is very unique and not similar

-- not identical to the routine pharmaceutical

agents that we utilize So these are agents

that are obviously grown in cell cultures and

even a small variation can result in an agent

down the line that triggers and immune

response and a very different outcome


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So again I think the analytical

process is very important but I think you need

to go a step beyond that And again my

feeling the AfPAs feeling is that clinical

trials need to be done in every one of these

with every one of these products

PRESIDING OFFICER SHERMAN If I

could follow up on Dr Kozlowskis question

Clinical trial it is a very broad spectrum

For example you talked about

interchangeability and you talked about

immunogenicity Are you thinking beyond those

two settings

DR YAPUNDICH No I think that

would suffice

PRESIDING OFFICER SHERMAN Any

other questions Thank you very much for your

comments

DR YAPUNDICH Thank you very

much

PRESIDING OFFICER SHERMAN Our

next speaker is Andrew Spiegel Esquire Colon


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Cancer Alliance

MR SPIEGEL Good morning I

would like to thank the panel for providing me

an opportunity to give some remarks on this

important issue In terms of disclosures I

should say that the Colon Cancer Alliance is a

501(c)(3) non-profit organization and as a

non-profit we do rely in part upon the

generosity of industry to help bring our

program to patients In terms of full

disclosures I would say in 2011 we received

less than 10 percent of our budget from the

pharmaceutical industry So not significant

but I thought I should disclose that

So panel thank you for having me

My name is Andrew Spiegel I am the chief

executive officer of the Colon Cancer

Alliance And the Colon Cancer Alliance is

the largest national patient advocacy

organization in America dedicated to

colorectal cancer We are not only the

largest in America but we have recently


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launched a venture with our European

counterparts EuropaColon in launching an

international patient advocacy organization

called Global Colon Cancer Alliance So I

believe it is now safe to say that we are the

largest colorectal cancer patient advocacy

organization in the world representing the

12 million Americans who have this disease

and the more than five million people

worldwide who have colon cancer

I come here today to tell you that

I have a personal connection to cancer that I

want to tell you about In 1999 I lost my

mother to colon cancer two days after losing

my father to pancreatic cancer So I

certainly know the devastating effects that

cancer can have on a family I was 35-yearsshy

old at that time And at the time we are

going back about 12 13 years now there were

very few treatment options for colon cancer

patients as well as pancreatic cancer

patients That remains true today by the


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way There have been only -- there is only

about six or seven approved drugs for

colorectal cancer and there has not been a new

drug approved in six years

Many do not realize that colon

cancer is the second leading cause of cancer

deaths in America and worldwide when you

combine the sexes The second leading cause

of cancer death not only in America but

worldwide and this is responsible for 50000

deaths in America each year and more than

600000 deaths worldwide

Pancreatic cancer by the way is

one of the fastest growing cancers in this

country and worldwide and these two cancers

alone account for more than 20 billion dollars

a year in treatment costs

We know that in this country

cancer is an epidemic One out of every two

men will develop cancer in their lifetime

One out of every three women will get cancer

So one thing is clear there is a


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great need for safe and effective therapies

and we know this because as our population is

aging and people are living longer lives the

number of Americans getting cancer in the

future will be beyond our wildest current

imagination In fact when talking about

colon cancer a recent study by the Lance

Armstrong Foundation predicted that by the

year 2020 colon cancer will be the number one

cause of cancer death worldwide As more

developing countries become more westernized

and as people stop smoking and lung cancer

incidents go down they do expect colon cancer

to become the number one cause of cancer death

in only seven years

I came here today to thank the FDA

for the cautious approach that it is taking to

establish a pathway that will bring

biosimilars to patients in the United States

And it is clear from the draft guidance that

the administration is following in the

footsteps of the European counterparts in


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using a science-based approach that refuses to

compromise on patient safety And that is my

point today that these drugs have to be safe

To that end we are encouraged to

see that the FDAs progress in creating an

approval process for biosimilars in the US

and we view the Agencys draft guidelines as

another important step toward providing a safe

biosimilars marketplace for Americas

patients

As patient advocates our role is

to always try to get drugs cheaper We always

want to reduce costs and that is extremely

important for the patients that we represent

yet the number one concern is that patients

must be assured that these medications are not

only effective but that they are safe The

last thing a cancer patient needs to hear is

that a medication that they know works is not

working on them because of a problem with the

medication

So it is important the FDA


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recognize the inherent safety challenges

associated with biologic medicines and mandate

clinical testing of biosimilars to ensure

that they are as safe and as effective as the

approved products that are already on the

market

We also believe that the FDA

should place safeguards that will ensure

patients and physicians know what medications

that they are receiving and that are being

prescribed Patients have the right to know

exactly what is being put in their bodies

One way to do this would be a unique naming

system that includes nonproprietary names for

biologics and biosimilars so that physicians

patients and regulators can easily

differentiate products

Since physicians will know whether

they are prescribing a biologic or a

biosimilar and the physician will fully

understand their patients specific needs the

pharmacy should fill the doctors request as


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written or at a minimum at least notify the

physician within a reasonable period of time

that a substitution has occurred And I think

that sort of addresses I dont -- I cant

see your name here but I think you were

General Counsel I think that sort of

addresses your issue that you had asked about

The FDA does have an opportunity here to not

interfere with a patient physician

relationship and ensure that physicians are

notified promptly if a substitution does occur

or prevent the substitution from occurring to

begin with

Again patients have the right to

know that the drug they are getting is what

the doctor prescribed and only the doctors and

patients should decide what is best for them

not payers and not regulators

We understand that the legislative

language that granted the FDA the authority to

establish a pathway also gave the Agency the

ability to determine and approve biosimilar


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interchangeable with its referenced product

We greatly appreciate the Agencys signals in

the draft guidance to take this responsibility

seriously by indicating that more time is

needed to study the amount and the types of

clinical data that would be needed to deem a

biosimilar interchangeable

We have come a long way in

providing access to lifesaving drugs to colon

cancer and to all other cancer patients We

want to ensure that these efforts continue as

biosimilars are introduced and above all else

we want to ensure that patient safety and drug

efficacy is the priority for the FDA

I thank you for the opportunity to

speak here today and I am grateful that the

FDA has taken time to hear from all the

patient advocates who have come today like

the colon cancer alliance Thank you


you for your comments and also for remaining

on schedule


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Would anyone on the panel like to

ask a question

PANEL MEMBER KOZLOWSKI Mr

Spiegel you had talked about naming and

substitution issues Are there any other

comments on the guidances because they do not

deal with naming that you would like to make

for your organization Any other suggestions

MR SPIEGEL You want to know if

there are suggestions on that issue of the

naming of substitutions

PANEL MEMBER KOZLOWSKI On other

issues I mean you discussed that In other

words you mentioned that these guidances seem

to be heading in the right direction Are

there any other comments on what is in them

that you would like to make

MR SPIEGEL Well I think I

touched on the fact that we would ask that the

FDA take all necessary steps to make sure that

these drugs are safe which may require

clinical trials to some extent to ensure


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that these follow-on products are as safe and

as effective as the original product So

things along those lines are extremely

important to us But as patient advocates

what we are most concerned with is efficacy

and safety and then of course costs as well


could follow up on that Your comment was

mandate clinical testing yet your response to

Dr Kozlowski was not quite as -- well I dont

know if it was Could you expand a little bit

on mandate clinical testing Again you are

thinking about the interchangeability arena or

another arena

MR SPIEGEL No I think

mandating clinical testing is the way to

properly ensure that the follow-on product is

as safe and effective as the originator

product I cant think of another way that

you can possibly ensure that this follow-on

product will work as well and more importantly

be as safe or equally importantly be as safe


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as the original product other than clinical

testing

We recognize that that increases

costs but to not do that we think that the

downside risk is extremely high The last

thing a cancer patient wants to hear is that

they have hope from getting a drug that they

know works and then the drug gets substituted

and this one may not work

So I think that that is an

important opportunity for the FDA to address


other questions from the panel Ms Maloney

PANEL MEMBER MALONEY Thank you

for your comments I had a question with

regard to your comments about that patients

and physicians ought to decide what is best

for the patients and not the regulators I am

trying to understand how do you see FDA

potentially interfering with that

MR SPIEGEL Well weve heard

stories about how a patient will be prescribed


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a certain medication and they go to pick up

that medication from the pharmacy and they

receive a different medication And I dont

mean that they receive a generic medication of

the original chemical compound I mean that

they receive an entirely different medication

within the same class of drugs We worry that

if that is allowed to occur with biologics

that a doctor may write a prescription for a

biologic drug and that a different drug will

be substituted the patient will not know

about that and the doctor will never be told

that the drug they prescribed was not given to

the patient

And I think the FDA has the unique

role here of stopping that from happening

That in your guidance in your final rulings

you will be able to address that issue to

either require that no substitutions take

place or at least that doctors are notified

within a reasonable period of time that a

substitution has occurred to make sure that


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the doctors is okay with that and that the

patient is informed about that I think

patients have the right to know what drugs are

going into their bodies and certainly have the

right to know that if a drug was substituted

that that occurred

PRESIDING OFFICER SHERMAN Other

questions Thank you for your comments

MR SPIEGEL Thank you


next speaker is Alexey Salamakha

MR SALAMAKHA I have no

disclosures to make regarding my travel here

today The GHLF accepts grants and charitable

contributions from many pharmaceutical

companies as well as governments private

foundations and individuals

Good morning On behalf of the

Global Healthy Living Foundation I want to

thank this committee for allowing me to speak

GHLF is a 501(c)(3) patient advocacy group

that works to improve access to care for


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people with chronic disease often focusing on

those least likely to advocate for themselves

We represent more than 55000

members in our CreakyJoints arthritis

organization Approximately 70 percent have

rheumatoid arthritis and many safe biologics

Other groups we have created and nurtured

like CreakyBones for osteoporosis and

RedPatch for psoriasis Of course many

patients in these groups take biologics too

My name is Alexey Salamakha the

national program manager for the Global

Healthy Living Foundation I am speaking for

these patients as well as our president and

co-founder Seth Ginsberg who was diagnosed

with arthritis 17 years ago when he was 13

Seth regrets not being able to deliver our

remarks personally

Dr Sherman and members of the

Panel in sports there is a winner and a

loser Infrequently there is a tie We know

in medicine that it can be all three at the


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same time The clicheacute a level playing field

comes from sports because fairness is the

foundation that protects players and ensures a

credible outcome that each team respects win

lose or tie

In medicine we cant always have

clear winners or clear losers Sometimes

medications work and sometimes they dont

But we need to strive for the level playing

field so patients are protected and all

parties respect the process The Global

Healthy Living Foundation is asking the

committee to build a level playing field for

biosimilars so that all parties physicians

patients care givers insurers

pharmaceutical companies regulators and

advocacy groups like ours will respect the

process

We believe the committees current

guidance can become the foundation for the

level playing field our constituencies require

and we thank the committee for this important


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beginning Everyone is here today to help

guide the process and we would like to do this

in the following categories 1) the

biosimilars definition 2) clinical testing

issues 3) the physician-patient relationship

4) interchangeability and substitution 5)

pharmacovigilance in naming

Because biosimilars are comprised

of living unique and complex structures

they are not easily replicated Small changes

in the creation of biosimilars have the

potential to help or hurt a patient They are

not identical copies of the innovator drug and

we want to ensure that the populations we

serve understand this Therefore a

comprehensive definition is necessary

Because of the inherent difference

between the innovator drug and the biosimilar

we believe clinical trials are crucial There

are no shortcuts to safety or efficacy that

might be otherwise appropriate with

traditional small molecule drugs We support


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testing and post-approval monitoring

Physician organizations and the

innovator companies themselves recognize there

is an increased risk of infection with

biologics It is the physician who is charged

with mitigating the risk by monitoring

treatment and knowing patient history

Despite the fact that biologics are well-

tolerated and safe the physician is the

person most qualified to make the right

medical decision not a third-party that will

make the decision based on economics that

translate into profit

Medical decisions are not

arbitrary and neither are those that promise a

greater return to the payer As a society we

have to decide whether we want physician-based

or profit-based care The Global Healthy

Living Foundation recommends physician-based

care which prevents payer-initiated automatic

substitution and interchangeability

Our last request asks the


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committee to allow all constituencies to

readily tell the difference between

biosimilars and the original biologics We

have spoken with several people on both sides

of the biosimilars issue and we have not heard

a substantive reason for abandoning unique

biosimilars names and distinctive labels so

physicians can make informed decisions and

regulatory bodies can track any quality or

safety issues Our community deserves to know

what drug it has taken and that all drugs have

successfully passed safety and efficacy

trials

We believe a clear definition

stringent testing preserving the physician-

patient relationship eliminating substitution

interchangeability and the naming system that

provides a clear audit trail is imperative if

the committee is to continue to build on its

foundation of providing a level and healthy

playing field for all parties

When the analogy of a level


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playing field is applied to sports it means

all parties have an equal chance to pursue

victory When profit intrudes to the benefit

of one team it is illegal and it is called

game fixing When the level playing field

analogy applies to medicine it means all

parties enjoy the support of fair rules of

government and society so the patient and

physician can pursue an individualized

productive health and improved quality of life

strategy

We respectfully request that the

committee consider our point of view and

although I am standing in for Mr Ginsberg

today I can either answer your questions or I

can refer them to him so he can respond

directly

Thank you again for allowing us to

speak on this important issue


you for your comments Questions from the

panel


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Salamakha you mentioned education as one of

your first points So I was wondering Do

you have any thoughts on the right way of

educating various stakeholders and consumers

and physicians on biosimilars

MR SALAMAKHA I can only share

on my personal experience of working with the

Global Healthy Living Foundation for over six

years and putting together a wide variety of

education programs for patient community HCB

community and other stakeholders So we can

regularly apply this experience and our skills

in organizing those educational programs in a

format of seminars webinars phone talks and

live events so that the patient community is

well aware of all the issues and questions

concerning the biosimilars and biologic drugs


questions Okay so thank you

So each of the speakers so far

have mentioned payers And I dont believe we


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have any payers speaking today but what would

you say to them in addition to what you have

already said

MR SALAMAKHA Our position is

that the relationship between the physician

and the patient is sacred And when there is

a third-party who is not a physician is trying

to interfere in this relationship it will

lead to negative outcomes and a worse outcome

for the patients

So I am not ready to say anything

to the payers directly I wish that we can

all work together to make sure that we can

eliminate barriers to care and also try to

achieve the best care and best treatment

possible for the patient community

PRESIDING OFFICER SHERMAN

Maryll

PANEL MEMBER TOUFANIAN You

mentioned one important component of your

thinking is distinctive labeling Can you

elaborate a little bit more if your


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organization has specific ideas and what that

would constitute And I know that others

today are also going to be speaking on this

issue so I would encourage if anyone has sort

of specific ideas with respect to labeling to

share those as part of your presentation

within eight minutes

MR SALAMAKHA Sure but as far as

this question I will probably need to refer

to Seth Ginsberg and ask him to get back to

you

PRESIDING OFFICER SHERMAN We

would look forward to seeing those comments on

our docket That would be great

Other questions I cant resist

given the sports analogy that we are a

Washington-based organization and we did not

exclude Rangers fans from todays meeting If

anyone follows hockey you will understand

what I mean We do strive for a level playing

field Thank you for your comments

MR SALAMAKHA Thank you


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PRESIDING OFFICER SHERMAN The

next speaker is Marcia Boyle from the Immune

Deficiency Foundation

MS BOYLE Well thank you for

convening todays meeting I appreciate the

continued efforts of the FDA to ensure patient

safety while implementing a biosimilars

pathway and the opportunity to share the

perspective of the patients I represent

My name is Marcia Boyle and I am

the President and founder of a 501(c)(3)

organization the Immune Deficiency Foundation

or IDF Founded in 1980 IDF is the national

patient organization dedicated to improving

the diagnosis treatment and quality of life

of persons with primary immunodeficiency

diseases through advocacy education and

research I am also the mother of a now grown

son living with a primary immunodeficiency

disease Therefore I am here to talk to you

today about key issues for patients and

parents everywhere


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The patients we represent have an

enormous stake in the FDA regulatory framework

for biosimilars In IDFs testimony in

November 2010 to the FDA on the biosimilars

pathway we outlined our thinking on

biosimilarity interchangeability and

clinical trials as they relate to patient

safety especially for individuals with

primary immunodeficiency diseases

IDF is keenly interested in the

IDFs development of a regulatory framework

and guidance documents for biosimilar

manufacturers We believe the Agencys

foremost responsibility is to ensure the

biosimilars are manufactured and prescribed

safely

When thinking of our patient

population I urge you to think zebra Our

patients are unique the zebras of the medical

world In medical school physicians are told

to focus on the likeliest possibilities when

making a diagnosis They are told when you


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hear hoof beats think horses However for

our patients you must think zebras and look

for the unusual possibilities and

consequences

Primary immunodeficiency diseases

are a constellation of disorders disrupting

the immune system resulting in a spectrum of

illnesses There are more than 150 different

primary immunodeficiency diseases currently

recognized by the World Health Organization

The number of Americans now living with

primary immunodeficiency is estimated to be in

the range of 250000 with between 35000 and

55000 on immunoglobulin replacement therapy

Many patients diagnosed with primary

immunodeficiency require biologic medicines

for long-term management Specifically

antibody or immunoglobulin replacement therapy

is used to replace missing or incorrectly

functioning antibodies needed to fight

infection Without lifelong immunoglobulin

treatments individuals with primary


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immunodeficiency would be unable to fight off

even minor infections including the common

cold

Primary immunodeficiency is one of

the FDA-approved indications for

immunoglobulin replacement and represents a

major use of the immunoglobulin therapy in the

US Therapeutic immunoglobulins are complex

biologics available in intravenous and

subcutaneous modes of administration These

medicines are derived from human blood product

or plasma sourced from over a thousand

donors Manufacturing changes the composition

of donor pools and final formulations can

impact our patients tolerability the

infusion rate and potential efficacy and

safety of the product Currently the FDA

recognizes each immunoglobulin brand as unique

and requires each drug to develop and complete

an individual clinical trial protocol to

receive licensure even if it is from the same

manufacturer This reflects the many


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processing steps involved in plasma

fractionation purification stabilization

and virus inactivation or removal that yields

products that are distinct from one or

another

As biosimilars are developed and

approved in the US we urge the FDA to take

steps that uphold patient safety above all

else IDF patients face additional risks from

adverse reactions to biosimilars that have not

been adequately tested for safety and

efficacy The following measures should be

incorporated into the IDFs -- or excuse me -shy

the FDAs final biosimilar guidance documents

restrict immunoglobulin therapies from the

biosimilars pathway require clinical and non-

clinical trials for biosimilars track and

trace and automatic substitution policies must

reflect the safety of biosimilars and the

sensitivities of patients with primary

immunodeficiency diseases

Unlike small molecule drugs


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plasma therapies such as immunoglobulin are

natural proteins of the human body and can

differ in terms of processing and in

composition The fragility of this class of

medicines is demonstrated by the worldwide

voluntary withdrawal of an immunoglobulin

product in 2010 by a major manufacturer due to

increased reports of thromboembolic events

thought to be caused by a small change in the

manufacturing process approved by the FDA

The FDA should exempt immunoglobulin

properties from the biosimilars pathway until

the science advances significantly This

policy will be in keeping with the European

medicines agency which opted to exclude

immunoglobulin from its regulatory pathway for

biosimilars It will also ensure that the FDA

is appropriately focusing on international

harmonization

For patients with primary

immunodeficiency whose lives depend on

frequent antibody replacement antibody titers


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and diversity are extremely important in

ensuring protection against infections

In 2008 IDF performed a national

survey to examine treatment experiences and

preferences among patients with primary

immunodeficiency That survey highlighted

ongoing challenges to safety and efficacy of

this therapy Nearly half of subcutaneous

users and 37 percent of IVIG users reported

that they tolerate some immunoglobulin

products better than others And among

patients that are no longer being treated with

Ig therapy eight percent cited safety issues

or side effects as the reason for stopping

Given the divergent therapeutic

responses to FDA-approved products clinical

and analytical studies should be required to

establish the safety and efficacy of all

biologic and biosimilar products Clinical

data not animal studies are the best

indicator of patient responses from a new

biological product Physicians rely on


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clinical trial results when making informed

decisions about treatment options To

demonstrate the safety of these products for

vulnerable patient populations this

requirement should not be waived

And our treatment survey found

patients are at greater risk of adverse events

when switched to a new product Of the

patients who reported having side effects from

the immunoglobulin therapy 28 percent

reported having a serious side effect to

reaction when they tried a new Ig product for

the first time Twenty-four percent of

patients refused a particular product and 15

percent delayed their infusion due to concerns

about product tolerability

Current science cannot demonstrate

that two products will provide the exact same

clinical result in a large cohort of patients

or that switching patients from one product to

another will pose no additional risks It is

therefore necessary that the FDA require


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products to undergo clinical trials to

determine that a proposed interchangeable

biological product can be expected to produce

the same clinical result as the reference

product in any given patient Additional

post-marketing surveillance also is needed to

protect patients especially as new products

are made available

All products including

biosimilars should carry unique nonproprietary

names as well as brand and lot information to

quickly trace a product to an adverse event

Finally the FDA must take

concrete steps to prohibit automatic

substitution of a biosimilar with an original

biologic Unlike generic drugs biosimilars

can never be identical copies of a referenced

product The choice of products should not be

determined by a pharmacist regulator or

insurer but by a physician in consultation

with his or her patient

In summary all medicines must be


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thoroughly tested and meet the highest safety

standards set by the FDA Immunoglobulin

therapy should be exempt from the biosimilars

pathway until the science advances

significantly However at minimum given the

unique properties of biosimilars and

immunoglobulin therapies in particular the

focus should be on making sure that

biosimilars approval process meets the same

strict criteria required for current

manufacturers

On behalf of patients with primary

immunodeficiency diseases I want to thank

you for your consideration and look forward to

the final guidance documents that give

thoughtful deliberation to our patients

concerns

Thank you



panel



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Just a question on the survey You talked

about a number of the patients or users

reporting difficulty in tolerating

MS BOYLE Correct

PANEL MEMBER MALONEY And I guess

the question I have is do you have a sense of

how many of the patients are actually using or

switching now having been exposed to multiple

treatments

MS BOYLE Our patient surveys

are nationally distributed based on over a

thousand responses I dont remember the

exact data but lets say you know 50 to 60

percent had never changed Some patients have

in some surveys Later surveys patients have

changed more because we had in the last

decade there was a shortage so patients did

have to switch products

And essentially I have seen my

son collapse on the floor in having an

infusion of a new product going from a five

percent to a ten percent solution from the


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same manufacturer Patients report to our

organization frequently I indicated the

statistics as well that concerned when they

have to change products because they had some

products that they cannot tolerate such as

patients who have auto antibodies to IgA

And again going back to the

biosimilars discussion these are unique

products They are made from antibodies from

thousands of individuals They are

manufactured differently Patients will react

differently because they have different

bodies

PANEL MEMBER MALONEY Just as a

follow-up the survey is that something that

you would like to submit to the docket if you

think that would be helpful to us

MS BOYLE I would be delighted

to submit our surveys and we will do that


PANEL MEMBER KOZLOWSKI A

question for clarification So you had


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mentioned that to achieve interchangeability

there would need to be clinical trials But

later you also said that the Agency should

take steps to prohibit automatic substitution

So could you clarify that Because

interchangeability I think is defined in the

statute to mean substitution

MS BOYLE For immunoglobulin

products they are unique They have to

undergo clinical trials There cannot be any

substitution

I mean frankly what I am saying is

please do not consider immunoglobulin products

as a reference product and then biosimilars

They should be exempt from the biosimilar

pathway

All other as far as I am

concerned I agree with all of the other

comments made as far as biologics should be

viewed as unique with brand names and no

automatic substitution

PANEL MEMBER MARCHAND Ms Boyle


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thank you very much for your comments I

appreciate the thoughtfulness and the

thoroughness of them

I wanted to just focus on the

point that you make about asking for

additional post-marketing surveillance So

given what we currently have as our standard

post-marketing surveillance how would you

envision there to be something beyond what

currently exists for this particular scenario

in biosimilars

MS BOYLE I mean well even I can

really only speak for immunoglobulin But

even with immunoglobulin we are finding some

products have more thromboembolic events than

other products do and we do not feel and I

believe some people at the FDA agree they

would like to see more surveillance of the

experience of patients on individual products

and their reactions


you very much for your comments


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MS BOYLE Thank you very much


next speaker is Dolph Chianchiano from the

National Kidney Foundation

MR CHIANCHIANO Good morning and

thank you for your pronunciation

The National Kidney Foundation

with its 50000 patient and professional

members appreciates the opportunity to

summarize the response to the guidance

documents concerning a pathway proposed for

the approval of biosimilars The National

Kidney Foundation annual meeting is taking

place across the river at the Gaylord Hotel

and National Harbor and my travel expenses to

this hearing will be part of the cost of the

National Kidney Foundation annual meeting

In previous communications with

the Agency on this subject we have emphasized

and we will continue to focus on protecting

patient outcomes patient safety and

clinician discretion We also believe that


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the pathway for approval of biosimilars should

be constructed in such a way that innovation

is not stifled

Anemia is a common complication of

progressive loss of kidney function The

kidney community has had more experience

perhaps with biologics than any other

stakeholder group since there has been a

biologic erythropoiesis stimulating agent in

use in the United States to treat anemia

caused by chronic kidney disease since 1989

As other speakers have noted with

biosimilars even seemingly insignificant

changes in drug formulation manufacturing

processes packaging storage or handling can

result in severe health consequences and those

unintended consequences could be life-

threatening

For example a decade ago the Food

and Drug Administration collected information

on 82 patients worldwide who had developed

pure red cell aplasia as a result of changes


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in the manufacturing andor packaging of a

reference product ESA with the brand name of

EPREX Because of that experience the kidney

community has been especially cautious about

the development of an approved pathway for

biosimilars in general and regarding the

possibility of substituting or alternating

between reference drugs and biosimilars or

between biosimilars

There are approximately 400000

people on dialysis in the United States today

most of them receive treatment with a biologic

ESA for some period of time during the year

Moreover the annual rate of incidents in the

prevalent cases of kidney failure has ranged

between 19 percent and 24 percent since

2003 Finally there are an estimated 700000

Americans with Stage 4 kidney disease many of

them are candidates for ESA treatment These

data should suggest the magnitude of impact

should a problem with a biosimilars ESA

develop


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With respect to

interchangeability we have been concerned

that interchangeable products may be

substituted for the reference product without

the intervention of the prescribing healthcare

provider We recognize that that is a feature

of the legislation that created this pathway

that we are discussing here today And

therefore we support stringent standards for

interchangeability And we note that in the

draft guidance there is a statement that

clinical comparisons with non-US licensed

product would not provide an adequate basis to

support a determination of interchangeability

We support that statement However we note

that the guidances that we have seen so far

describe situations in which a finding of

interchangeability would not be appropriate

We understand and certainly expect that an

additional guidance may be forthcoming as to

the requirements that will be recommended to

prove interchangeability affirmatively And


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we look forward to the opportunity to provide

input on that supplementary guidance

In the meantime when approving a

biosimilar before an interchangeability

guidance is finalized we urge the Agency to

indicate that the approval does not constitute

a determination of interchangeability

With respect to packaging we urge

the Agency to reconsider the response in the

QampA document about packaging which states that

some design differences in the delivery device

or container closure with proposed biosimilar

product may be acceptable

As noted previously in regard to

the history of pure red cell aplasia organic

compounds leached by polysorbate 80 from the

rubber plungers used in prefilled syringes of

EPREX may have had a role in the ESAs

immunogenicity Another potential cause of

the increased immunogenicity might have been

the use of silicone oil as a lubricant in the

prefilled syringes


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In addition the answer in the QampA

would appear to be inconsistent with a

statement in the guidance for scientific

consideration in that the latter guidance

acknowledged that protein modification and

high order structure can be affected by

packaging materials container closure

systems and delivery and device materials

With respect to extrapolating

clinical data the following statement is not

clear The potential exists for the

biosimilar product to be licensed for one or

more additional conditions of use for which

the referenced product is licensed If the

referenced product receives a new indication

after the biosimilar has been approved how

will this affect the biosimilar Will a

biosimilar manufacturer need to file a

supplemental application for the new

indication

With regard to the totality of

evidence approach we question the principle


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that slight differences in rates of

occurrence of adverse events between two

products ordinarily would not be considered

clinically meaningful differences We do not

believe that this is a workable standard for

the approval of biosimilar and are concerned

that such a standard might also be applied in

post-marketing safety monitoring

As other speakers have urged

today we note that the draft guidances do not

describe how biosimilars should be named And

we maintain that the naming of biosimilars is

a quality consideration that the FDA should

address in the final guidance

The National Kidney Foundation has

maintained that each biosimilar product should

be given a unique nonproprietary name andor

identifier code This is important for

purposes of prescribing as well as for

identifying the specific product by a

manufacturer that a particular patient

receives In the event that said patient has


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a negative reaction to the medicine or there

is a quality control problem with the product

tracking through NDC codes will not capture

all cases because payers do not universally

use NDC codes and these codes are not

necessarily found in patient records

We call upon the FDA to include a

provision for naming in the final iteration of

the guidance for approval of biosimilars We

also as other speakers draw attention to the

issue of labeling The only direction that

the guidance provides is that the labeling of

a proposed product should include all the

information necessary for a health

professional to make prescribing decisions

We maintain that the package insert for a

biosimilar should provide testing information

including the number of studies the study

circumstances the number of study

participants and the duration of the study

both for the referenced product as well as

data provided for the purposes of establishing


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bioequivalence

Finally with respect to post-

marketing safety we hope that the brief

description of post-marketing safety

monitoring in the guidance does not represent

the totality of the Agencys plans in this

regard As previously noted or as previously

stated unintended consequences of biosimilars

could be life-threatening Even seemingly

insignificant changes in drug formulation

manufacturing process packaging storage or

handling can result in severe health

consequences For this reason NKF has

recommended that FDA track reports of

unintended consequences through MedWatch and

in an early communication with the Agency

with respect to pack rate for biosimilar

approval the National Kidney Foundation

called on the Agency to require that

biosimilar manufacturers conduct post-

marketing surveillance and that the Agency

enforce that requirement strictly


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In response to the current set of

guidances we are calling for as we said

earlier the unique names and identifiers for

biosimilar products so that adverse events can

be tracked and attributed with dispatch and

with least burden for patients and clinicians

Thank you very much for your

consideration of the reservations that the

National Kidney Foundation has expressed in

response to the guidance documents published

for public comment to this date


you for your comments

We have time for one or two

questions Dr Kozlowski

PANEL MEMBER KOZLOWSKI So you

mentioned that slight changes in delivery

devices and container closures can have

consequences And you also stated that even

slight differences potential differences in

adverse events should not be tolerated So do

you think that if an originator manufacturer


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makes a change in container closure or dosage

form that they would be required to do a study

large enough to detect rare adverse events

MR CHIANCHIANO Well I certainly

think that the Agency should be aware of any

changes in manufacturing process or dosage and

then within the Agencys discretion as to what

to do with that information


Another question

PANEL MEMBER TOUFANIAN To follow

up on Dr Kozlowskis question with respect to

your concern about the slight differences in

occurrence of adverse events you indicate a

concern that such a standard also might be

applied in the post-marketing surveillance

context Could you elaborate a little bit

more on that concern

MR CHIANCHIANO Well it has to

do with how the Agency tracks and monitors any

post-marketing problems that develop If in

fact slight differences will be tolerated


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then there would be no reason to recall a drug

or take any other action

We urge the Agency to consider

every instance in which there is an adverse

event as a unique problem with a biosimilar


you We appreciate in particular the

specificity of your comments and encourage

you to the extent possible where you believe

you have found inconsistencies or would like

to see revisions to be very specific in what

you would like to see

MR CHIANCHIANO Thank you We

will submit additional commentary


next speaker is Rene Cabral-Daniels

MS CABRAL-DANIELS Good morning

I would like to thank you for the opportunity

to present these comments on behalf of the

National Patient Advocate Foundation NPAF is

a non-profit organization dedicated to

improving patient access to healthcare


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services through both federal and state policy

reform Its mission is to be the voice for

patients who have sought care after a

diagnosis of a chronic debilitating or a

life-threatening illness NPAF has a 15-year

history of serving as the trusted patient

voice The advocacy activities of NPAF are

informed and influenced by the collective

experiences of patients who receive direct

sustained case management services from our

companion organization the Patient Advocate

Foundation Those experiences have been

quantified in the PAF patient data analysis

report which illustrates the data collected

across 260 variables by PAF senior case

managers

In 2011 PAF resolved 110000

patient cases and has received more than five

million additional inquiries from patients

nationwide PAFs ability to assist patients

confronting a wide spectrum of challenges

enables NPAF to competently serve as a patient


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voice

NPAF supports the promise of

improved patient care as a result of

biosimilar development and approval We are

keenly aware of the critical public health

benefit biosimilars and interchangeable

biologic products represent as well as the

resulting benefit to potentially offer a

lifesaving or a life altering therapies at

reduced cost to patients

Today NPAF will focus its comments

on the second component of FDAs meeting

notice the Agencys future policies and

priorities regarding biosimilars NPAF

believes that a critical component of FDAs

biosimilar policies should be patient and

consumer education The following passage of

the Biologics Price Competition and Innovative

Act of 2009 FDA posted a brief information for

consumers page on its website regarding

biosimilars As the panel certainly knows

the page essentially explains what a biologic


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product is what a biosimilar is and that some

biosimilars may be determined interchangeable

which would allow for pharmacy substitution

This page however could be

improved upon to educate patients about many

other important issues such as the risks and

benefits of biosimilars how the products

would be developed studied and approved for

marketing by FDA and which facts should be

considered when discussing the possible use of

a biosimilar with their physicians NPAF

believes that patients need complete

information about how biosimilars work and

have been tested in order to make fully

informed choices about their use

Consumer understanding of new

technology is critical to its uptake and

successful integration into the healthcare

system but it is highly unlikely that many

consumers currently have a good or any

understanding of biosimilars This situation

should be remedied as soon as possible even


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before the first biosimilar products are

approved for marketing

The experience of generic drug

marketing and consumer perception may prove

informative A recent GAO report on generic

drug use specifically pointed out the effect

consumer perceptions can have on the

utilization of the generic drugs The January

2012 report is entitled Drug Pricing

Research on Savings from Generic Drug Use In

it GAO noted that physicians pharmacists

consumers may have perceptions about the

safety and efficacy of generic drugs compared

to brand named drugs which in turn affect

what drugs they choose to use These

perceptions are based on a number of factors

including prior experience results of

relevant studies or advertising Negative

perceptions of generic drugs may be more

common where questions have been raised about

the medical appropriateness of generic or

therapeutic substitution


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The history of generic drug

acceptance by patients in the medical

community provides FDA with important

information about how to proceed with

implementing the nations biosimilar policy

Of course biosimilar products will need to be

approved before they can be utilized but once

they are available perceptions about safety

and efficacy of the products will be a

decisive factor in whether they are

prescribed dispensed and used As has been

the case with generic drugs patients and

healthcare professionals as well as health

plans must have a stake in the biosimilar

system if it is to be successful

Accordingly NPAF respectively

urges FDA to undertake a patient-focused

proactive educational campaign on biosimilars

that utilizes creative approaches to educate

consumers about these important issues and

more The educational materials that have

been developed on generic drugs are an


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excellent starting template FDA has made

available to the community slides brochures

pharmacy mats posters audio files and much

more on generic drugs The FDA website also

provides facts about generic drugs and

questions and answers about generic drugs in

consumer-friendly formats Public service

announcements and coverage on public radio and

television networks might also be beneficial

to teach consumers about biosimilars

NPAF encourages FDA to establish

public-private partnerships with non-profit

patient advocate community to assure its

patient education efforts are impactful

Patient ability to afford medical

care is a significant challenge for them The

recently released 2011 patient data analysis

reports reveals debt crisis and cost of living

issue category was the most frequently

reported and represents 31 percent of all

issues This is a 19 percent increase from

2009


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As we note from the recent GAO

report the retail price of a generic drug is

75 percent lower than a retail price of a

brand name drug Although it is unclear what

the cost-saving potential of biosimilars will

be given their complex manufacturing

processes there will certainly be some cost

savings for patients The Federal Trade

Commission estimated in 2009 that price

discounts for biosimilars may be 10 to 30

percent of the referenced product cost Many

biological products are used to treat very

expensive life-threatening diseases diseases

that all too often are responsible for debt

crisis issues and medical bankruptcies And

any decrease in cost for these expensive

treatments through the approval of

corresponding biosimilars may have a

significant impact on patient access

A significant number of cancer

treatments are injectable biological products

as are many current treatments for autoimmune


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diseases such as rheumatoid arthritis

multiple sclerosis and Crohns disease These

health conditions represent the majority of

patients assisted by PAF in 2011 Patients

with cancer were 69 percent of the population

and those with chronic and debilitating

conditions were 17 percent demonstrating the

impact of these chronic debilitating or life-

threatening diseases and the very expensive

treatments on the American consumer

As part of the patient-focused

educational campaign NPAF also believes that

FDA should consider preparing lay summaries of

the three current biosimilar guidances and any

future guidances The lay summaries could be

appended to the end of the technical guidances

in a way that medication guides for patients

are appended to the prescriber oriented

package inserts for prescription drugs These

efforts could help increase physician health

plan and consumer confidence in FDAs

approval process for biosimilars and


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consequently the acceptance of biosimilar

products by those critical stakeholders

As suggested above NPAF believes

a public-private partnership with the nonshy

profit community could result in lay summaries

that positively impact the patient community

by allowing them to make well-informed

decisions

Finally NPAF believes that these

consumer educational materials and campaigns

should be disseminated in other languages

besides English The selection of which

languages to translate various materials

should include the most recent census data

reflecting the nations multicultural

composition and limited English proficiency

as well as Centers for Disease Control and

prevention data on disease prevalence by race

andor ethnicity

Thank you again for the

opportunity to present these comments on

behalf of NPAF


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panel

PANEL MEMBER KOZLOWSKI So we

heard about education earlier and I think it

is really an important topic and you have

outlined some very specific suggestions So I

think if there were ways of even adding more

specificity to them it would be very useful

to us I mean I am particularly interested

in what the best structure of a public-private

partnership for this would be who it would

include and how it would be set up to make a

level playing field to use the term we heard

before And also the role of newer you know

you mentioned innovative approaches social

networks Are there other tools that will

help this work even better


I had a very similar thought Any

suggestions you have of any specific

organizations that would want to assist the


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Page 86

Agency or partner with the Agency in this

effort would be appreciated

Thank you So that constitutes

our patient panel So I will just ask the

panelists we have heard some repeating

themes if there is anyone you would like to

recall and ask a particular question

Oh we have one more Thank you

Thank you Denise for keeping me on track

All right we are -- that actually

does conclude for the moment our patient

panel We are missing a panelist

So I will go back Are there any

other patient-oriented questions from the

panel Okay

Then we will keep our break on

time and we will go -- Oh Im sorry Al Cors

from RetireSafe is here

MR CORS Thank you

PRESIDING OFFICER SHERMAN Youre

welcome

MR CORS Thank you very much


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Dr Sherman and thank you and your colleagues

for this hearing this morning And I am

certainly very honored to participate My

name is Al Cors and I serve as the Vice

President of Public Affairs for RetireSafe a

non-profit non-partisan organization that

educates and advocates on behalf of 400000

older Americans across the country

Our President Thair Phillips had

hoped to be here however he is in Denver

today participating in the Colorado

Generentological Societys 23rd Annual Salute

to Seniors So he is holding forth with a few

thousand seniors in the Denver Convention

Center right now So I am pleased to be here

to represent him and RetireSafe in this

important hearing this morning

I would like to first cite three

recent news events that just popped out at me

as I was preparing comments An April 21

2012 Wall Street Journal article In hundreds

of documented cases that undermine a broad


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swath of research cancer samples that were

supposed to be one type of tumor have turned

out to be another through either careless

laboratory handling mislabeling or other

mistakes That was one story

In that same edition of The Wall

Street Journal on April 21st is another story

about fake Avastin possible in 13 states It

cites reports an FDA warning to doctors and

medical practices in 13 states regarding the

fact that they may have purchased a fake

version of the cancer drug Avastin an

injectable biologic All told at least 76

physicians and medical practices have received

letters from FDA warning about using

counterfeited Avastin of one form or another

The story notes By purchasing

cheaper foreign drugs doctors can increase

their profits say investigators probing the

purchases If doctors buy cheaper-priced

controlled drugs from other countries but

bill managed care companies and government


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health programs for the full FDA-approved -shy

full price of FDA-approved drugs the

difference goes to their bottom line the

investigators say

And then finally three days later

on April 24th both The Wall Street Journal

and the Daily Mail had stories regarding an

Avastin Lucentis age-related macular

degeneration controversy Evidently the drug

company in the United Kingdom the drug

company Novartis has taken legal action to

stop a national health service effort to

encourage the use of the approved cancer drug

Avastin to treat wet age-related macular

degeneration or wet AMD rather than a more

expensive drug Lucentis a drug specifically

approved and licensed for use in the treatment

of AMD

The Daily Mail story noted that

the Royal College of Ophthalmologists supports

the continued use of Lucentis and also noted

that fears over side effects had led the US


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Department of Veterans Affairs to stop using

off-label Avastin for the treatment of AMD

Now I cite these three news items

I think they are important because they

highlight just how critical the FDA biosimilar

guidances for all Americans and especially for

seniors

Please remember that there are

roughly 10000 new retirees every day and that

older Americans will soon comprise 20 percent

of our population They will no doubt be

the largest users of biologics and

biosimilars We want them to be safe

In the first instance above

scientists made major mistakes in the lab

endangering both research and patients In

the second instance we know that fake

biologics of uncertain provenance are

enriching some greedy individuals while

putting perhaps thousands of cancer patients

at risk

In the third and final instance


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we know that governments on both sides of the

Atlantic Ocean have tried to favor the use of

one unapproved and unlicensed injectable

biologic for the treatment of AMD over the use

of an approved and licensed injectable

biologic designed to treat AMD just to save

money

In the last case we know that

infections and side effects have been reported

probably because of the substitution Our

point is there can be no shortcuts Both

original biologics and biosimilars must be

rigorously tested including full clinical

trials Biologics are complex organisms and

as we have seen even scientists can make

mistakes

Every drug destined for the market

must be fully proven to be safe with no

exceptions The biosimilar system must

absolutely guard against the use of cheaper

imported drugs that may bring the plague of

counterfeit foreign drugs here The complete


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Page 92

surveillance system for biosimilar manufacture

marketing and distribution must be in place

before a single patient is put at risk

Finally there could be no forced

government or third-party substitution because

one biologic drug is simply cheaper than

another The choice between two biologic

drugs should be a patient-physician decision

made after both drugs are fully approved to

treat the respective illness Biosimilar

drugs are not innovator drugs and must have a

large time and cost advantage over the

developers of new innovative treatments and

cures These drugs should certainly come to

market sooner and cost less but biosimilar

drugs are also not generics and they must all

be required to prove their safety and

effectiveness just as the reference drug to

which their similar did earlier

There should be no flexibility

intentionally introducing differences to the

molecule or the finished product allowed in


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the manufacture of biosimilars That would

clearly open the door to unintended or

unanticipated risk Biosimilar drugs should

be labeled distinctively and a strong track

and trade system for them should be fully in

place before they come to market That is

what patients want is guidance for this

important new class of drugs

Thank you for your consideration


you for your comments Questions for the

panel

I have one overarching question

for you or for anyone So you have all

emphasized the importance of maintaining our

standards of safety and efficacy or safety

purity and potency Is there anything in

what we have communicated so far that raises

in your mind a question that in fact we are

indicating otherwise in the guidance documents

we have provided

MR CORS No there is not And


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we have on several occasions submitted

comments essentially supporting what you are

doing and saying and urging the strongest

possible safeguards We are here today to do

that again to highlight the fact that there

are many concerns whether it be counterfeit

drugs whether it be mistakes in the lab all

of these concerns that we are all looking to

safeguard against every day and certainly you

more than anyone else So we appreciate what

you are doing And again we just want to

encourage the strongest possible safeguard

because -shy

And I just turned 65 earlier this

year so I can speak personally for seniors

across America We are a very vulnerable

population and we count on you to safeguard

our medications And this is going to be a

critical area in an era of cost controls

people looking to save the dollar wherever

they can This is going to be very important

So what you do with these guidelines will


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impact every one of those seniors across

America Thank you very much


questions Okay thank you very much

It is 1000 so we will take a 15shy

minute break And if everyone could be back

here at 1015 Thank you

(Whereupon the foregoing hearing went off the

record at 957 am and resumed at

1014 am)

PRESIDING OFFICER SHERMAN Okay

welcome back Our first speaker in this panel

is Dr Dolinar from the Alliance for Safe

Biologic Medicines Welcome

DR DOLINAR Dr Sherman and

panel members good morning Thank you for

giving me this opportunity to speak with you

today My name is Dr Richard Dolinar I am

a practicing physician I am an

endocrinologist I specialize primarily in

diabetes I am also chairman of the Alliance

for Safe Biologic Medicines


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The Alliance is a non-profit

organization composed of patients physicians

clinical researchers scientists and

innovative medical biotechnology companies

We have a slide here I can you show you some

of the -- Im pushing this and it is not

moving Oh there we go There we go

We are a diverse organization a

non-profit organization Our objective is to

ensure that patient safety is in the forefront

of the biosimilars policy To achieve this

goal the Alliance has been active in many

ways since the FDAs initial public hearing in

November 2010 We have put on webinars we

have also written op-eds And in fact just a

few weeks ago on the Hill we hosted a forum

on biosimilars and biologics that was well

attended

A list of our activities can be

found on our website safebiologicsorg I

would encourage all of you to review the

website I think you will find it very


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helpful

All of these activities are meant

to drive home our primary message that

patient safety must be the non-negotiable

priority in developing a framework for the

review and approval of biosimilar medicines

As you know biosimilars are quite

complex quite large molecules In contrast

to the small molecule standard drugs of the

past that are made chemically as you know

biologics are made with living cells We grow

them That is why I call it farming It is

actually farming at a molecular level We

call it molecular farming And as we know no

two biologics made from two different cell

lines or by different processes are identical

I just want to point out that small changes

or small differences in a molecule can have

major differences in how it impacts the body

If I can go to the next slide here

-- there we go

Notice how similar these molecules


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are These are actually three hormones and

you can see they are very similar Very minor

changes between them But look at the

difference when they are in the body You

know the one on the left testosterone that

makes boys Progesterone estradiol on the

right that makes girls A major difference

even with small changes in these molecules

So we recognize what an immense

task that you are undertaking to formalize a

regulatory pathway for biosimilars The

Alliance appreciates your ongoing efforts and

we appreciate that you have consulted with

stockholders -- stakeholders We strongly

support the work you are doing because you

know ultimately it is the patient who is

going to benefit And that is what we are all

about What is right for the patient is right

for everybody So we truly appreciate what

you are doing We strongly support the work

that you have done

We do have some suggestions for


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you as you continue in your work Clinical

studies have been mentioned repeatedly by

previous speakers So I will just go briefly

through this As you know immunogenicity is

an issue regarding not only biosimilars but

all biologic drugs And unfortunately our

ability to predict immunogenicity is limited

by our scientific knowledge We are learning

more each day Science is progressing each day

and we think analytic studies are very

important to analyze these molecules in an

attempt to determine immunogenicity but along

with that we think that clinical testing

plays a very important role

As a practicing physician I can

tell you this is the kind of information I

need to feel comfortable with a drug What

clinical tests were done What were the

results And I can tell you physicians if

they are not comfortable if they are not

confident in a drug they are not going to use

it Clinical testing will help provide that


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confidence and allow docs to use the drugs

with confidence

The next point I would like to

make is about foreign source reference

products The global biosimilars market is

expanding markedly and we believe steps must

be taken to monitor the global supply chain

and the manufacturing process

We believe that the FDA must

receive critical supporting information before

it can accept biosimilar clinical data that

would be used to seek approval in the US

This supporting information must be able to

demonstrate the following we believe We

believe the same company should manufacture

the reference drug both in the United States

and outside the United States We believe

that the non-US reference drug and US

reference drug should be analytically

indistinguishable from each other

We also believe that it should be

demonstrated that the product is filled and


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finished in fully representative strengths

formulations and containers An earlier

speaker from the Kidney Foundation pointed out

how a difference in the container made they

believe a difference in the effect of that

drug

And we believe that proof of

pharmacokinetic bioequivalence between the

biosimilar the US reference product and the

non-US reference product should be shown

And please note we are not suggesting that

foreign clinical trial data generated to

support the approval of a new biosimilar by

the FDA be limited We are basically saying

that it can be used as long as it conforms to

current standards That is all we ask there

Regarding track and trace and

naming provisions currently the post-approval

surveillance of biosimilar products is

impossible under the current system if

biosimilars use the same nonproprietary name

We think it is absolutely critical that


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different nonproprietary names be used for the

biologic and also for the biosimilar drugs

This we believe is one very helpful way to

help with track and tracing and in the end

will ensure that we are able to identify what

drugs the patient is taking when they were

taking them et cetera

The issue came up earlier about

packaging labeling and prescribing

information We believe that the drugs the

biologics and the biosimilars should be in

packages that are unique easily identifiable

The patient should know what drug they are

receiving from the doctor or from the

pharmacy We believe the package should list

the manufacturer the lot number directions

on how to use how to prescribe and unique

packaging would help identify that and it

could be easily identified

Interchangeability has come up

with the previous speakers I want to make a

few points regarding that At the present


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time little is known about switching a

patient from one drug to another drug from a

biologic to a biosimilar or perhaps from a

biosimilar to a different biosimilar or back

to the reference biologic We are still

beginning to understand that So in light of

that we strongly encourage clinical trials

once again We also would like to raise the

issue of drift As you know over time due to

manufacturing process or changes in storage or

whatever these biologics can tend to drift

from where they were initially And this will

need to be monitored Two drugs that were

initially thought to be similar with time

might drift apart and be different So

sometime a mechanism needs to be in place to

monitor for that

The lady earlier asked the

question about what can the FDA do regarding

biosimilars and biologics and I would like to

address that Like the earlier physician the

first speaker the neurologist in parts of


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the country pharmacists can change the drug

without notifying the doctor And we too in

our office have one person who just works

with the pharmacist all day working on prior

authorizations et cetera

We would suggest and we believe

that the doctor should be involved in the drug

substitution process He should be involved

in that decision And although this process

is available in some states we recommend that

this not be applied to the biologics and the

brand name biologic drugs

In conclusion we support what you

are doing As I said the work you are doing

will ultimately benefit the patient If there

is any way to help you we are happy to do it

Thank you



panel

PANEL MEMBER MARCHAND Thanks for

your comments I appreciate them I wanted


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to just explore this with regards to the

comment you made about before biosimilars are

sold there should be a robust surveillance

system So beyond what currently exist can

you talk a bit about what you might envision

beyond the current structure for biosimilars

that would be unique

DR DOLINAR As I pointed out I

think one of the main issues we think that the

biosimilar and the biologic should have

different nonproprietary names We think that

that is a critical issue and important so that

they can be differentiated so the doctor can

know exactly what medication the patient is on

and therapy So that would be main point

Ultimately it is all about

patient safety It is all about keeping good

notes What was the patient treated with

when See as a treating physician I cant

tell you how important it is to keep a good

chart good notes and to be very specific

PANEL MEMBER KOZLOWSKI I just


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want to follow up on the question of naming

and tracking and tracing

And so I think you stated that it

was impossible to be able to track and trace

without unique names And I sort of wonder

what is the data you have to support that

DR DOLINAR It is my clinical

experience working in hospitals and treating

patients et cetera

My concern is if the biosimilar

and the biologic have the same nonproprietary

name that is what is going to be written in

the chart We wont know which drug was

actually given to the patient I am trying to

keep things as clear as possible so that

people dont make mistakes


questions

I have one One concern we have

heard is that if you will the same product

the biosimilar and the reference product have

unique names there is a danger of inadvertent


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if you will dual prescribing Do you have any

comments on that

DR DOLINAR As a physician that

is your responsibility You are trained I

think that type of a problem for somebody who

is trained in working in that area I would

think it would be unlikely You know people

make errors I think anything is possible of

course My concern is that if they have the

same name we dont know which drug they are

getting and if there is a problem we cant

identify it

And I think that that is a major

consideration whereas your consideration I

think is possible but I think less so



DR DOLINAR Thank you


next speaker is Shein-Chung Chow from Duke

University

DR CHOW Thank you My name is


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Page 108

Shein-Chung Chow I am from Duke University

School of Medicine Before I get started

first I would like to congratulate the FDA for

the wonderful job that they have done in such

a short period of time And also I would like

to thank the panel for providing me the

opportunity to comment on the guidance

especially the one for the scientific

consideration

So in the next ten minutes or so I

will focus on the two key concepts for

assessment of biosimilarity proposed in the

guidance by the FDA Those two key concepts

include the stepwise approach and also

totality of the evidence Then I think that I

would like to provide my input regarding the

interchangeability intents of the definition

interpretation and the concept of the

alternating and the switching Then I think

that if I may I will probably propose some

possible use for study designs for tracing the

interchangeability by using the alternating


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and the switching indices

In the guidance the FDA proposed

the use of the stepwise approach This stepshy

by-step approach is understandable However

at each step it is not clear the way the one

size fits all criterion or the way that the

one size fits all criterion will be used and

how to determine how similar is considered

highly similar Those are not mentioned in

the draft guidance

And in addition to that I think

in my opinion I think in order to implement a

stepwise approach for assessment of

biosimilarity the fault in the scientific

issues should be addressed The first one is

how many steps is required How many steps

are there How many studies should be

required And the second is the order of the

steps that matter And the third should each

of the steps carry the same rate And finally

I think how to control the overall error rate

And now that the key concept


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Page 110

proposed by the FDA the so-called totality of

the evidence The concept of totality of the

evidence involves two concepts One is the

so-called local biosimilarity For example

in some specific domain you know a specific

domain or similar specific domains versus the

global biosimilarity across all domains And

it should be noted that the degree of the

biosimilarity may vary from domain to domain

and each domain may carry different weights

So I think that the face on this

concept I think we feel that FDA seem to

suggest a scoring system for measuring the

totality of the evidence Along this line

the ideas of the so-called Biosimilarity Index

proposed by Chow and others 2011 may be

useful These proposed Biosimilarity Index

will achieve the totality of the evidence

under different study designs andor the

biosimilarity criteria

In order to I mean before I

introduce the Totality Biosimilarity Index I


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think first I would like to propose the so-

called local Biosimilarity Index The so-

called Biosimilarity Index it is very

straightforward by following the steps

Step one I think that we can

assess the average biosimilarity based on a

given criterion For example the company

used the 80 100 and 125 based on long-

transformed data for the assessment of body

clearance

Step two we can then calculate a

reproducibility probability based on the

observed ratio and availability

Then step three we would claim

that the local biosimilarity if the 95 percent

confidence interval lower bound of the

reproducibility probability is larger than the

pre-specified number p0

Now you may ask I think how are we

going to determine the p0 The p0 actually

can be obtained based on some comparison of

the reference product to the reference


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product In other words we can calculate the

reproducibility probability when comparing the

reference to itself This probability is

expected to be very high because we compare

the reference to itself So the probability

should be high

Then in this case I think the p0

can be selected as 80 percent of the pRR the

reproducibility probability for comparison

between the reference and itself

For example if the pRR is 90

percent and we may choose the p0 as 80 percent

of the 90 percent which is 72 percent and the

p0 actually can reflect a degree of

biosimilarity that either I think they are

required by the regulatory agency or the

sponsor would like to achieve

Now totality biosimilarity across

the different domains I mean also follows a

similar idea We first obtained a pi pi is

the reproducibility probability or a local

Biosimilarity Index for the ith domain I


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Page 113

mean I goes from 1 to K and the K domains is

supposed And then we can define the Totality

Biosimilarity Index which is the weighted pi

So the Totality Biosimilarity Index could be

P In this case under step three we are

going to claim the biosimilarity if at a 95

percent confidence lower bound of the p is

greater than the pre-specified value of p0

Now I would like to provide some

of my input regarding the interchangeability

According to the BPCI Act the biologic

product is considered to be interchangeable

with the reference product if they satisfy the

following condition First the biologic

product is similar to the reference product

and then second it can be expected to

reproduce the same clinical results in any

given patient And then I think the Part B I

think the risk of alternating andor the

switching I mean between the use of the

biologic product and the reference is not

greater than the risk of using the reference


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product without such alternating andor

switching

Now based on this definition the

first we noticed that there is a clear

distinction between the biosimilarity and the

interchangeability And then the key concern

the major concern of this is that it is

possible to show the same clinical result in

any given patient I think that is would be

our major concern according to the definition

as described in the BPCI I think that in

practice is difficult if not impossible to

demonstrate the same clinical result in any

given patient However it could be possible

to demonstrate the same clinical result in any

given patient with a certain assurance

Now I would like to now talk a

little bit about the concept of the switching

and alternating Switching is referred to the

switch from one biologic product to another

So in our case I think it could be a switch

from the reference to test 7 to (T) or to


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switch from the (T) to 7 7 to 7 or (T) to

(T) And alternating is a switch from the one

biologic product to another and then switch to

another for example the original biologic

product So it could be I think start with

the reference product and then switch to the

test product and then switch back to the

reference product Or maybe we start with the

test product and to the reference product and

then back to the test product

Now in order to address this

switching and alternating the drug

interchangeability I think I would like to

propose that four impossible study designs

The first of the design in order to address

the switching that will be the four by two

balanced crossover design Four by two that

means it is a four sequence and a two (T)

rail In other words I think that the first

sequence with the test you will receive the

test product first after some original answer

was shown and then cross over to receive a


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test product

And then the second sequence would

be the (R)7 and then the third would be (T) 7

and the fourth sequence will be (R)(T)

In order to address the

alternating I think the two by three dual

design which is a (T)(R)(T) (R)(T)7 may be

useful And an alternative design could be

the actual reference design which is the

(T)(R)7 (R)(T)7 I mean the design has been

studied extensively in the literature

In order to address the switching

and the alternating altogether perhaps I think

the modified Balaams design like a (T)(T)

(R)7 (T)(R)(T) and (R)(T)7 may be useful

Of course there is some

alternative designs such as the extended and

modified Balaams design TDD RR TRT RTR

And another the alternative design could be

the TDD RR RTR RTD Im sorry RTD RTR So

this design currently has been studied by a

group of researchers to compare the relative


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advantage and the disadvantage for a

situation the potential switching and

alternating

So now I will like to conclude my

presentation by listing two remarks The

first the proposed Biosimilarity Index and the

Totality Biosimilarity Index across different

domains is useful in providing the totality of

the evidence for assessment of biosimilarity

describing the FDA guidance And a similar

concept can be used to address the issue of

the interchangeability by developing the

switching index alternating the index andor

the switching and alternating index under the

proposed possible useful study designs


consideration


you for your comments we have time for one

or two questions

PANEL MEMBER KOZLOWSKI So do you

envision this score including all aspects of


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the evaluation each of the analytical tests

with what their margins are whatever clinical

studies are performed animal studies all

integrated using the same score

DR CHOW Yes that is the idea

But the only thing that I think is different

I mean the studies for example if we want to

evaluate the quality attribute in the

manufacturing process of things like that I

think that we may have a different set of the

criteria for the biosimilarity So I think

the proposed scoring system the so-called

Totality Biosimilarity Index actually we take

that into consideration because I think the

calculation of the Biosimilarity Index or the

so-called reproducible probability is robust

to the design and also the selected the


PANEL MEMBER KOZLOWSKI But would

you weigh those different factors for each

product each analytical attribute

DR CHOW That is a very good


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question I think that is probably subject to

the discussions between the regulatory agency

and also the sponsor because the sponsor they

probably have a better idea in terms of what

kind of weight that you should carry forth

specific domain


you for your comments We hope you submit

them in detail to the docket

Our next speaker is Marcie Bough

from the American Pharmacists Association

DR BOUGH Good morning My name

is Marcie Bough Im a pharmacist with the

American Pharmacist Association APhA where I

serve as the Senior Director of Government

Affairs APhA is the first established and

largest professional association for

pharmacists and we represent members in -shy

over 62000 members practicing in all practice

settings including community pharmacies

hospitals long-term care facilities

community health centers managed care


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organizations hospice settings and the

uniformed services Thank you again for the

opportunity to provide comments today

APhA supports the development of

scientifically based safe and effective

processes to approve biological products

demonstrated to be biosimilar to or

interchangeable with FDA-licensed biologic

reference products We appreciate FDAs

efforts to develop the initial implementation

draft guidances to date and we look forward to

providing additional input in the future We

also appreciate that you are seeking public

input and support the stepwise approach as

development continues

Pharmacists are often considered

the most successful healthcare provider for

some patients or the medication use experts on

healthcare teams and play an important role in

helping patients manage their medications and

achieve optimal medication therapy outcomes

which will be including biosimilars in the


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future

Standard components of

pharmacists practice include recommending

generic alternatives for patients requesting a

generic or facing cost-related access

barriers complying with dispensing as

written or DAW orders on a prescriptions

complying with formulary management orders on

a prescription complying with formulary

management requirements set by a plan and

complying with other plan or state-based

generic utilization programs

Often we are in communication with

the prescriber and make adjustments to clarify

dosing and directions or make adjustments due

to formulary coverage issues Such processes

and actions for a prescription order

fulfillment and dispensing to a patient

translate to biosimilars

Pharmacists long-standing trust in

the FDA process for generic drug approval and

now for biosimilars focusing on safety


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effectiveness and evidence-based medicine is

a core component of pharmacists daily practice

in helping patients As FDA considers the

next steps in finalizing current draft

guidances and importantly considering future

draft guidances on biosimilars we recommend

that FDA consider the following key focus

areas

1) Processing prescriptions in

interchangeability As the abbreviated

license or pathway for biosimilars matures we

recommend additional guidance to the extent

possible on the logistics for handling

biosimilar prescriptions in the pharmacy For

example will pharmacists processing

prescription orders in any pharmacy need a

unique individual prescription by name for a

biosimilar andor for a biosimilar determined

to be interchangeable with that reference

product Do we need an individual

prescription for the biologic for the

biosimilar and the interchangeable And does


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that constitute a unique individual

prescription order for each processing of that

prescription

Recognizing that at this stage in

guidance and implementation it may be too

early for such switch in logistical aspects

for prescribing and dispensing of the

biologics but it is what we think about and we

will need more information as to how

physicians and other prescribers and

pharmacists are to manage prescription orders

for these products

In addition we support references

in the guidances to development of an FDA-

compiled interchangeable reference list

something similar to the current Orange Book

for generics to assist healthcare providers in

managing prescription orders

2) Labeling and naming of

biosimilars As outlined in the draft

guidance we support that a biosimilar product

label should clearly indicate approval of the


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biosimilar to a reference product as well as

labeling to indicate approval or lack thereof

of interchangeability with reference products

Such information will be critical for

pharmacists to have and will help guide

pharmacists in appropriate product selection

at the point of dispensing

In addition we support reference

in the draft guidances about similar

interchangeables used the same strength or

measurement as the reference product labeling

Furthermore we consider that the

variety of potential mechanisms for naming of

biosimilars we caution these with suffixes

If it is to be considered suffixes present

challenges for pharmacy operating systems and

in processing for fulfilling orders Suffixes

may not be included in the original electronic

or written prescription They may fall off

the electronic dropdown menu order form for

product selection and they may not fit into

the data field in the database However the


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naming is finalized we will need to provide

clear information to providers on the correct

use at the point of prescribing and

dispensing

Similarly information will be

needed on naming and tracking for the use in

adverse event reporting and post-market

surveillance activities to ensure standard

procedures are used that are applicable to

inpatient and outpatient settings and

consistent with current adverse event

reporting procedures

For example we believe it is

important for the adverse event tracking to

work in compliance with the existing formats

with MedWatch processes and the evolving

Sentinel Initiative

For another point on labeling if

a biosimilar is approved to be slightly

different in delivery design we recommend

that such variation be clearly indicated in

the label as providers and patients will need


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to know if it is a different form than the

reference product because additional or

different patient education may need to be

provided on use of the product or instruction

3) Education and outreach APhA

recognizes the need for education and training

for healthcare providers on the implementation

of biosimilars Education and outreach will

need to focus on but is not limited to

awareness identification of biosimilars and

interchangeability terminology processes

and logistics to prescribe and dispense

biologics and importantly those that are

determined to be interchangeable differences

from our current generic process and

necessary resources that are available to

healthcare providers and patients

Education for pharmacies should

also address the biosimilar information will

or will not be integrated into the pharmacy

operating system meaning product menu

selection safety edits interaction warnings


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et cetera that are currently in place and

uploaded into our pharmacy operating databases

and used for fulfilling those prescription

orders Such information will be important to

understand how prescribers will see the

information as they use electronic prescribing

order entry processes as well

There will be a learning curve

before during and after products complete

the biosimilar pathway to market We

understand that Again we do believe that

there will need to be education as we have

heard earlier today and awareness campaigns

for the entire healthcare system on how to

handle these products and the logistics for

prescribing and dispensing

APhA is willing to work with FDA

and the other stakeholders to help develop and

provide education to pharmacists through

vehicles such as continuing education

programs faculty and practice tool kits and

online communication tools and other outreach


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opportunities

4) State preparation for

biosimilars We recommend that FDA consider

future guidance to assist states as they

consider potential and if needed revisions

to their state substitution laws and

regulations to reflect biosimilars and

interchangeability or for what they may

require for their state programs Such

guidance could potentially help the states

forgo creating different interchangeability

standards for biosimilars

5) Totality of evidence We

support FDAs efforts to use the totality of

evidence support approach as it considers

biosimilars and applications that focus on

considerations of the complexity of the

proteins and manufacture process use of data

driven from non-US studies or licensed

products close market surveillance

monitoring and considerations in early

communications with those manufacturers


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potentially seeking to proceed through the

biosimilar pathway

In closing we need to ensure that

healthcare providers have education on how

biosimilars are being implemented what is

classified as and how to identify biologics

and biosimilars and what is the

interchangeable use and access to

interchangeable reference list and what needs

to happen to prescribe and dispense these

products

Pharmacists in the community

across the country will play an important role

in patients accessing biosimilars We look

forward to working with FDA and the other

stakeholders as additional information becomes

available and the future guidance is

developed

Thank you



panel Heidi


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PANEL MEMBER MARCHAND Thank you

Ms Bough -- Dr Bough we appreciate it very

much

I wonder if you could talk a

little bit about models that you have seen

with FDA interacting with regard to the

training So you have talked about some

specific things and I am particularly

interested in sort of the timing of

introducing that training

DR BOUGH Great question We

have often thought -- Well as we have gathered

feedback from our members and we have talked

internally people are not lacking of interest

but they are lacking of awareness of when

these are really hitting the market and what

are we going to have to do when when we start

seeing applications that have completed the

biosimilar pathways So in advance of the

products hitting the market we would want to

make sure that we have information out in the

hands of pharmacists and the other healthcare


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providers that know what it is they are

supposed to do when they receive that

prescription so that even if they are

processing a prescription for the first time

of one of those products they at least know

what to do when they are on the receiving end

of that or what reference material to go to in

search of that type of information

One example that we have done

through print and electronic kind of education

and awareness campaigns is inserting into our

publications or posting on the website simple

guides

One example that we have that

relates to the generic side is called the

Pharmacists Guide to Using the Orange Book for

Product Substitution and Decisions It is

branded under what we have as The One Minute

Counselor That is on the front side for the

pharmacist On the back side it is The

Patients Guide to Drug Product Substitutions

So with regard to the interchangeability of


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all of this that type of information just

some logistical information could be helpful

even if we dont know which product might hit

that landing spot in the future But it is

that type of awareness campaign that others

have mentioned today that we really want to

make sure we have already in place before we

start filling these prescription orders

But I think it is also important

as products become available on the market

that go through this pathway the material

about the new product just as with any new

product to clearly indicate that here may be

something different with filling these

prescriptions This is a biosimilar This is

interchangeable with X reference product

That type of information should clearly be

indicated not only in the labeling but the

information and awareness about that product

marketing materials as with normal new

prescription products

PANEL MEMBER KOZLOWSKI So thank


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you Dr Bough I thought you raised a number

of very important points I wanted to ask

that one particular thing you mentioned was

names and databases

So there are a variety of reasons

that there can be errors in leaving suffixes

or any changes you might have in a name Some

of them are database limitations Some of

them are human limitations in terms of data

entry So we would be curious if you could

supply in more detail to us more thoughts

about where those problems exist

And then on a related topic we

have heard reference to NDC codes And

certainly many outpatient pharmacies track

everything by NDC codes We would kind of be

interested in the APhA perspective on when

that is captured and when it is not and in

what context

DR BOUGH Okay We can

certainly provide some additional information

in our written comments And there is one


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variation on how NDCs are used whether it is

inpatient or outpatient So we wouldnt want

to create anything that is different from kind

of tracking that we can do now but make sure

it is integrated and not kind of siloed just

because these might potentially biosimilar

products

There is lots of improvements from

a technology perspective on better or

decreasing the option for potential for error

with order entries and transfer the

information from electronic platforms are

written but we will be happy to work with some

of our other pharmacy colleagues to provide

some additional information So thank you

PRESIDING OFFICER SHERMAN Ms

Esposito

PANEL MEMBER ESPOSITO Thank you

I will make it quick because I know we are

out of time

Following up on Dr Kozlowskis

comment I was going to ask a question related


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to naming Since it sounds like you will be

submitting additional information to the

docket if you have specific recommendations

for naming conventions that APhA thinks would

work for all of the different -- satisfying

all of the different factors we have

discussed including pharmacovigilance that

would be helpful

And also I dont think we have

your statement in the record so I would

encourage you to put your full statement in

the record so that we have it for reference

DR BOUGH Will do Thank you

PRESIDING OFFICER SHERMAN Thanks

for your comments

Our next speaker is Everett

Neville Express Scripts

MR NEVILLE Good morning and

thank you for the opportunity to present

today

My name is Everett Neville I am

the Chief Trade Relations Officer at Express


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Scripts I am a pharmacists by training I

spent the first ten years of my career in

hospital pharmacy and the last 14 years I have

been on the payer side

Express Scripts is a pharmacy

benefit manager We administer the pharmacy

benefits of approximately one hundred million

Americans So I guess I am here representing

the much maligned payer perspective today

Additionally we own specialty

pharmacies that are responsible for dispensing

about 30 percent of all retail biologics that

go through a pharmacy So we bring that

perspective or I bring that perspective as

well

When Congress passed the BPCI

certainly the purpose of that was to allow

pathway for biologics and inherent in that

were interchangeable biologics The rationale

for enacting this Act clearly had to do with

the cost of biologics In fact they submitted

to the CBO this Act and it was scored at about


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25 billion dollars over ten years

From the payer perspective we

have a real problem today with biologic costs

As you can see the overall trend for drug

costs is trending in the single digits

typically around three percent Biologics are

well into the double digits 17 percent last

year as much as 20 percent in some of the

recent years and we predict that will

continue for the foreseeable future This is

not just on new products by the way The

overall increase in existing biological

products was over ten percent last year for

products already on the market many of which

have been on the market for as much as a

decade

We dont look at cost though

strictly as -- this is not about how much

money the greedy payers can make Cost is

about affordable healthcare and affordable

healthcare is about access The best

medications in the world if they cannot be


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taken cannot be afforded by patients do not

benefit those patients So we believe this is

an extremely important healthcare issue

I want to spend a few moments on

interchangeability I am certainly not a

scientist but as a previous speaker addressed

earlier today the science of highly

analytically similar drugs is a science It

is well-known and can be attributed that way

We believe that with the use of that science

that the use or need for clinical trials can

be limited Where it is necessary it

certainly should be done but they should be

limited as a science directs We would like

to see guidelines that allow for flexibility

by the FDA depending on the molecule As you

know biologics are not universally complex

Some of them are much more complex than

others Some of them are much more larger

molecules than others

The level and the degree of

clinical studies should vary based on what the


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science dictates We dont want to see

clinical trials essentially as a barrier to

interchangeability

I would like to commend the panel

on the draft We found much that we liked

there Certainly and I am going to hit a few

points certainly we would have preferred to

see less than a 12-year marketing exclusivity

in the Act but we believe that is workable for

all sides It protects the innovators as well

as the cost side of the equation

We commend you on your indication

that you would allow the use of non-US data

as we believe that the quality of research

particularly in Europe is sound Also with

the use of foreign-source comparator products

We believe that is important in order to make

the clinical trials that will be required

cost-effective and not prohibitive

We also commend your allowance or

the indication that there may be some

allowance for the extrapolation of indications


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as these indications expand on the innovator

products

And lastly in what has certainly

been a focus today I wanted to discuss the

naming convention And Im sorry that is a

typo That should be IND We believe it is

absolutely imperative that the same

nonproprietary generic name be used If you

do not allow that you effectively have no

interchangeability in our healthcare system

So that would from our perspective make that

impossible to do

Today drugs essentially reach the

public in three ways in the American

healthcare system And with biologics

approximately half of them come through a

pharmacy Pharmacy dispensing requires and

uses an NDC which is more specific It even

tells you the package size The vast majority

of pharmacies by the state law actually even

track lot numbers I know in our pharmacies

we track it down to the lot number not just


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the NDC

The second pathway are through

hospitals Most hospitals also track those

drugs through NDCs and they certainly track it

from a purchasing point of view They dont

purchase multiple manufacturers in a time

They typically strike contracts and purchase

one manufacturers product as a time until

that is used and a new contract comes into

play Having worked in hospitals it is not

hard when you have an adverse event to track

it back to which product is used

That leaves the third alternative

which is that dispensed in a physicians

office or a buy and bill model I would posit

that if physicians dont know what they used

that is not going to be solved by giving it a

different name in convention That we may

want to have more robust tracking required at

the physicians offices but that would be the

change I would recommend not changing the

names Changing the names creates very


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difficult processes with changing in

interchangeability as was referenced by the

APhA pharmacists what prescription do you

use

Additionally there is a real risk

that a patient who is on one product gets a

prescription when they go into a teaching

hospital and is sent back to the community

feel that a separate pharmacy that that

pharmacist fills that product the patient

doesnt realize they are the taking the same

product twice because they have two different

names and that continues for some period of

time I think that is a real healthcare

risk not something to be minimized

Thank you



panel Ms Maloney


for your comments I had a question on the

naming and I think I heard you say you support


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the same name for interchangeable products but

Im not sure I heard you speak to the name

with regard to biosimilar products

MR NEVILLE For biosimilars I

would support the same naming convention for

the same reasons that the risk of prescribing

essentially the same medication twice the

difficulty in tracking and lining up adverse

drugs checking engines that also look for

those as well as just confusion within the

marketplace

But I think that if it does not

occur then interchangeability cant happen

So I would support it on both and I think it

is absolutely essential for an interchangeable

drug

The other problem you would have

if you dont use it on both if a product comes

out and it is not interchangeable because you

are requiring a different level of studies and

those are completed one or two years later

does the product change its name


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PANEL MEMBER MALONEY Just a

follow-up question Do you have concerns that

when the product is not interchangeable if the

same name is used that there might

substitutions

MR NEVILLE I do not because

that exists today I mean the filo of a 4C of

a 3C where there are products that are not

interchangeable They are not AB-rated and

they cant be interchanged today

So that exists today where you

have products with the same name that are not

interchangeable That has not proven to be a

problem within the system


Esposito


I have a follow-up question on the patient

safety issue that you perceive associated with

the potential for double prescriptions

I guess the first question is

whether you have any data that would suggest


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that that is a real risk and if so to what

extent Is there quantitative data to suggest

that this is a risk

MR NEVILLE I dont believe we

would have that because it doesnt exist

today So we dont have a situation where

drugs have the same two different names for

the same drug that I am aware of at the

nonproprietary level

So again my comment is that is

the way the system works today Why would we

change it

PANEL MEMBER ESPOSITO And are

you aware of any literature or social science

studies that looked at this issue even though

we dont have those on the market today

MR NEVILLE I am not


mentioned a variety of ways in which products

can be tracked through NDC codes et cetera

So there are adverse event reports but there

is a whole variety of other sources of data


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and Sentinel is an example and I think it was

mentioned earlier of using a variety of

databases claims databases medical records

that are electronic if they are available and

integrating them

And so I think the issue of

identifying products goes beyond necessarily

what gets submitted through MedWatch So I

was wondering if you could comment on whether

or not the strategies you mentioned would work

in that broader environment of surveillance

MR NEVILLE And I will tell you

I am not an expert on pharmacovigilance

Certainly I work within those systems But it

would be my understanding when those other

Sentinel and other indications show that there

is a potential problem there needs to be

considerable more investigation of potential

studies and evaluation after that And even

today were that to occur you wouldnt know if

that was a for example a problem related to

the packaging that contained one type of


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rubber in the top of the syringe or another

At some point in order to make that workable

and to issue a recall or to change warnings on

a package insert you still have today when we

have multiple products and package sizes in a

market have to get additional research and

have to get additional data But I am not an

expert in that area so I am not familiar with

any specific issues related to them


questions

I have one The only published

data we are aware of is Platt and colleagues

where they looked at the ability to trace this

type of product in a Sentinel type of

environment without a unique name And their

conclusion was that it was not possible And

we heard from previous speakers that the

ability to be able to identify which product

is causing a problem is very crucial So

perhaps your organization could look at the

published literature and other data you have


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and then put a response to dockets either

supporting your recommendation that the name

be the same or discussing how we have as an

agency might track and trace the problem

without that

MR NEVILLE I would be happy to

do that

PRESIDING OFFICER SHERMAN Great

Thank you

Our next speaker is Kristin Bass

from the Pharmaceutical Care Management

Association

MS BASS Good morning everybody

I am Kristin Bass I am the or PCMA

Senior Vice President for Policy and Federal

Affairs for the Pharmaceutical Care Management

Association or PCMA We represent the

pharmacy benefit managers again the much

maligned payers and are very pleased to be

here today

Our companies our member

companies cover the benefits for about 210


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million Americans who have coverage through

private payers through Medicare through

TRICARE essentially across the panoply of

health benefits Our members also operate

specialty pharmacies that focus on managing

high cost complex biological medications as

well as mail-service pharmacies that dispense

prescriptions to millions of Americans

We appreciate the opportunity

again as I said And we appreciate your

leadership in working through the pathway

PCMA strongly supported the pathway as it was

developed through the statute and is very

pleased that this is proceeding We believe

that with the pathway competition can enter

the market And we think that competition

will be crucially important to getting

medications that are life-saving and life-

altering to patients at a more affordable

cost

And we think that will benefit not

just the patients but obviously our whole


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healthcare system because if we constrain

costs in one area we have more money to spend

in other areas

While we really appreciate your

guidance documents wet think that they

represent an overly cautious approach that

doesnt build on the experiences and

guidelines of other highly regulated markets

that have approved biosimilars For instance

the experiences in Europe should be built on

to a greater extent than currently is

reflected in your guidance documents

We are concerned that the overall

effect of the draft documents will delay

development and approval of safe and effective

biosimilars mostly around the issue of

interchangeability We are disappointed that

the draft documents dont go further in

offering requirements for interchangeability

We urge the FDA to accelerate development of

guidance in this critical area We note that

the guidance basically said that you are


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Page 151

continuing to consider the type of information

sufficient to enable FDA to determine whether

a biological product is interchangeable with

a reference product and we saw a presentation

a little earlier suggesting ways to do it We

believe that the work that you have done

already on biosimilars as manufacturers have

changed their products in areas in which you

approved a change a manufacturing change and

designated that product as interchangeable

helps to pave the way for your development of

interchangeability with biosimilars

And we also think that you have

worked on interchangeability with respect to

distinct biologics in the case for instance

of the Omnitrope being the therapeutic

substitution for Genotropin in the growth

hormone market So we urge you to consider

all of the advice that you have been given and

put out some more specific guidance on this so

that you can accept applications and make a

determination more quickly than later


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We think that if you dont do that

there is going to be an unnecessary delay in

bringing lower cost equally safe and

effective crucial medications to patients We

think that access and affordability for

biologics cant be realized without

competition as I noted earlier And we think

that the abbreviated pathway will offer an

opportunity for competition

With the cost of biologic and

specialty medications increasing by double

digits each year as Everett pointed out

greater availability of lower cost actions

will be an enormous benefit to patients and

the entire healthcare system

By analogy an analysis for IMS

Institute for Healthcare Informatics shows

that the use of generic prescription drugs in

place of brand name counterparts and this is

on the small molecule side saved the US

healthcare system more than 931 billion

dollars in the decade between 2001 and 2010


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In 2010 alone generic use generated more than

150 billion dollars in savings

If the FDA approves even a few

biosimilars as interchangeable just one year

earlier than your currently overly cautious

approach would likely allow the savings for

patients employers and the system as a whole

will be millions of dollars We urge you to

create an environment of regulatory

predictability for biosimilars that encourages

sponsors to invest in their development and to

submit applications We look forward to

continuing to work with FDA and other

stakeholders to implement the rules for

biosimilar products in a way that doesnt

restrict patient access to medications

Thank you and we appreciate the

opportunity to be here at this meeting



panel



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for your comments I have a question You

mentioned or touched on in your opening

statement that you would encourage the FDA to

leverage the EU biosimilars experience Can

you elaborate on what you meant by that and

areas that you think work well that we should

be considering

MS BASS I would refer to Dr

Vink who is going to testify later on behalf

of Mylan and he will be able to answer that

question I dont claim to be a scientist but

we can get you some answers for the record


Maloney

PANEL MEMBER MALONEY Thanks

again for your comments I was trying to

understand if there was a biosimilar and not

an interchangeable product what activities or

actions might your organization take with

regard to that such an approval

MS BASS Can you ask the first

part If there was a biosimilar and not -shy


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Page 155

PANEL MEMBER MALONEY That was

not interchangeable Would that effect what

products you made available on your formulary

MS BASS So we are the trade

association for the PBMs Typically the way

therapeutic substitution currently works in

our member companies there is a difference as

you know between therapeutic substitutions and

generic substitutions Our understanding

would be that if there were

interchangeability it would act as generic

substitution currently acts If there were

not interchangeability then I think that our

PampT committees would be in a situation in

which they would think about therapeutic

substitution and would have to think about

formulary placement and tiering and those

sorts of things under that rubric And I am

sure Everett can elaborate on that if you

would like or if you would like him to


questions


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Page 156

PANEL MEMBER KOZLOWSKI So to

follow up on that you mentioned that

Omnitrope is part of the therapeutic

substitution program now So that is

something that has been initiated by what

group and is it being studied in some way

MS BASS So if there is a

substitution there my assumption is that it

is some combination of patients and physicians

probably working with their health plans on

what is most effective for the patients in the

context of what is also cost effective for the

plan

Are there studies on that I

dont know the answer to that

PANEL MEMBER KOZLOWSKI I think

that it is very useful as it has been

mentioned that sometimes products are switched

and may have occurred in Europe in sort of

data around those switches actually very

useful information And so if there are

programs to move from one product to the


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Page 157

other it would seem being able to at least

capture some surveillance data around that

would be useful

MS BASS Agreed Agreed We

mentioned that instance as an instance in

which we believe that you have the scientific

capability of judging biosimilarity and

interchangeability and we are just using that

as an example to encourage you to not be

overly cautious but to actually move forward

PRESIDING OFFICER SHERMAN I have

a question You emphasized interchangeability

quite a bit We have the guidances that we

have put out to date the three documents that

are under your consideration address

biosimilarity You did not talk about or I

think you seemed to imply that without

additional guidance on interchangeability the

pathway the biosimilarity was somehow either

not as clear or less attractive Am I reading

your comments correctly

MS BASS Our understanding from


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our member companies and again the way that we

put together our comments on this is to talk

to our member companies talk to the generic

manufacturers to get their perspective And

what we have been hearing from folks is that

given that lack of predictability they arent

sure that they will use the abbreviated

pathway

And so from our perspective what

was the point of establishing getting the

statute done and trying to establish a pathway

if folks dont think that it is going to be

useful to them to use

So we just threw that out there


thank you Thank you for your comments

Our next speaker is Neal Parker

from Abbott Laboratories

MR PARKER Good morning

everyone My name is Neal Parker I am an

attorney with Abbott a global broad-based

healthcare company headquartered in Abbott


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Page 159

Park Illinois And on behalf of Abbott I

would like to thank FDA for the opportunity to

present today

Abbott as a healthcare leader is

keenly interested that patient access to

innovative therapies long-term is maintained

If companies like Abbott dont keep on

discovering new therapies eventually there

wont be any new biologic treatments for

biosimilar companies to reference

FDA must therefore we believe

implement the BPCIA in a manner that both

increases access to biotherapies for a greater

number of patients but also preserves

incentives for companies like Abbott to

continue to discover study and get approved

new innovative biologic products

So today my remarks are going to

focus on two specific areas use of non-US

comparator products in biosimilar applications

and also protection of reference product

sponsor trade secrets during FDAs review of


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biosimilar applications

Now on the first issue FDA

discusses in I believe all three of the

guidance documents the drafts the potential

use of data comparing a proposed biosimilar

product to a non-US-licensed product in

order to demonstrate that the proposed

biosimilar is highly similar to the USshy

licensed product that has been identified as

the reference

We at Abbott are concerned that

the proposed approach in the draft guidances

may not comport with the Agencys statutory

authority Our position is that data from

studies involving a foreign comparator product

cannot be considered pivotal if the foreign

comparator is different than the US

reference product If the comparator product

is anything less than the same as the US

reference if it is just similar to the US

reference or if it is highly similar to the

US reference or if it is biosimilar to the


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Page 161

US reference then the utility of such data

has to be limited

The task of the biosimilar

applicant after all is to identify and

address residual uncertainties about

differences between its proposed biosimilar

and the US reference product But comparing

a proposed biosimilar to a foreign non-

licensed non-US reference product and then

trying to compare that non-licensed non-US

comparator product to the US reference by

adding a third and a different product into

the mix seems to us to just increase rather

than alleviate those residual uncertainties

Now under the statute and that is

what I have put up on this slide the

reference product has to be the single

biological product licensed under a US BLA

against which a proposed biosimilar is

evaluated If the proposed biosimilar

compares itself or to use the words of the

statute is evaluated against a non-USshy


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Page 162

licensed product and the resulting data

provides a basis for approval licensing of the

proposed biosimilar application then the non-

US-licensed product has either become the

reference product or else it has become a

second reference product and the statute

expressly forbids this

The second topic that Abbott would

like to raise is the need to adequately

protect reference product trade secrets during

FDAs review of biosimilar applications

Now just a note here There are

specific concerns related to the protection of

BLA data submitted to FDA prior to enactment

of the BPCIA and Abbott has raised these

issues separately in another form with the

Agency

Here today at this hearing I want

to emphasize that my remarks are limited and

focused on innovator data which is submitted

to FDA after the date of enactment of BPCIA

Now with respect to such data


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Page 163

nothing in the statute authorizes access to

the innovator BLA or direct use of the actual

trade secrets in the innovators application

by either the biosimilar applicant or the

Agency But we at Abbott are concerned that

the Agencys guidance omits any discussion or

reference to this important topic

Specifically we think safeguards are needed

to ensure that the Agency doesnt

unintentionally inadvertently but

nevertheless impermissibly use or disclose to

a biosimilar applicant an innovators trade

secrets

The major safeguard that we think

is needed is to prevent FDA reviewers who

worked on specific US-licensed innovator BLA

products from reviewing biosimilar

applications that reference those same

specific innovator BLAs We actually think

the law compels FDA to take this step

Our concern is rooted in the idea

and the concept of bias Now both law and


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Page 164

science recognize bias as something that needs

to be controlled So for example in clinical

investigations for example double-blinding

investigators to patients receiving placebo

versus study drug is done because it is

recognized that it is impossible to prevent

subconscious knowledge from impacting

behavior Likewise FDA has expressly

acknowledged that comparable concepts of bias

affect FDA reviewers

Here for example on this slide the

first quote on this slide is from a senior FDA

official testifying before Congress on the

biosimilars law I am going to read this

quote just because it is so directly on point

This was acting Commissioner Crawford I

believe said this Reviewers are sometimes

unavoidably conscious of information in a

prior application even without physically

consulting the application simply because they

recall the information from having worked on

the earlier review Now in the law likewise


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Page 165

they have a way of handling these situations

So for example lets say that you have an

employee of one company that has access to

trade secrets about a product and that

employee takes another job at another company

competitor who makes a similar product courts

will find in circumstances like this they will

find what is called inevitable disclosure In

other words they will find that the

likelihood that the employee in a situation

like this will inevitably use the trade

secrets from former employer is so apparent

that the courts will issue an injunction to

prevent that from happening

Now what I personally know to be

true from my 20-year plus career doing this

kind of work both in industry and my years at

FDA and in the government is that FDA

scientists and government employees almost

without exception strive to follow the law

and to protect innovator trade secrets I do

know that to be true But again to be clear


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Page 166

what Abbott is concerned about is subconscious

bias

So we have some potential

safeguards and we request that FDA consider

adopting these safeguards along the lines on

this slide to ensure that trade secrets in

reference product BLAs are not disclosed or

used during biosimilar product development

meetings or while reviewers are reviewing

applications

I am not going to read these to

save time They are up on the slide They

are also in our written comments But they

are generally guardrails to protect against

the source of trade secret violations that I

think we should all be concerned about

Again I want to thank you for

allowing Abbott to present today and if you

have any questions I am more than happy to

hear them




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Page 167

panel

Maryll

PANEL MEMBER TOUFANIAN You had

mentioned in the first component of your

comments the reference to the single

biological product It seems from your

comments that you werent objecting wholesale

to the use of non-US comparator data but not

using it as a pivotal mark It almost seems

like there was a tipping point after which you

think such reliance would be or such data

would be inappropriate Could you elaborate a

little bit more on that

MR PARKER Yes this is a key

question I would be happy to

We think words like supportive or

corroborative I actually dont think those

are very helpful There is a model here

essential to approval In the Hatch-Waxman

context FDA has 30 years of experience

assessing whether data submitted to FDA is

essential to approval for a condition of use


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Page 168

If it is you get three years There is case

law on this There is the Upjohn case on

Rogaine It involved a switch of a product

And there was a study done I think it was a

switching study And Bob Temple after the

fact wrote a memorandum on this and at issue

in the case was whether that study submitted

by the sponsor was essential to approval And

FDAs position and it is supported by the

preambles it is a but-for test What the

court did and what FDA does when looking at

these kinds of studies is but for this study

this bit of data could we approve the

biosimilar application

Now if the Agency answers that no

we needed this study otherwise the biosimilar

would not be approved then we believe that

the test has failed and that product has

become a reference product It is really a

but-for test


questions


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Page 169

I have one not being a lawyer I

can ask a clinical question So Europe

because they are ahead of us there is a large

randomized controlled trial of a thousand

patients and there is a very rich source of

data human experimentation What do we do

with that information How do we -- Are you

suggesting we put it on the shelf and try and

reproduce it

MR PARKER Well under what

conditions was the data gathered I mean

what product Was this data of a proposed

biosimilar to a European reference product

PRESIDING OFFICER SHERMAN Lets

say we are confident that the product in that

study was biosimilar not identical using -- I

dont know what identical means but not

identical -- but was biosimilar

MR PARKER Wasnt the same

stuff

PRESIDING OFFICER SHERMAN Wasnt

made in the same -- Well Steve would have to


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Page 170

comment on that but wasnt the same yes

MR PARKER Right Well we dont

believe that that data satisfies the statutory

standard to be allowed to be used as pivotal

for approval of a US biosimilar

PRESIDING OFFICER SHERMAN But it

could contribute to our thinking

MR PARKER It could -- What we

are talking about today it was the prior

question is the but-for test

Scientists and FDA reviewers need

to look at stuff They like data If someone

is going to present a body of data there is

no way we are going to say no you cant look

at it The question is to what extent can it

be used to approve the product And it is a

question a statutory question we believe that

there is a limit here There has got to be

one reference product and the studies to

support approval of a proposed biosimilar if

they are evaluated against the proposed

biosimilar evaluated against another product


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Page 171

it has got to be evaluated against the US

reference product

PRESIDING OFFICER SHERMAN And I

have two questions on this last slide The

first is do you have does Abbott have

concerns these types of concerns in other

environments other than biosimilars Because

I can tell you as a former reviewer I reviewed

many different it was on the drug side many

different applications from many different

manufacturers

MR PARKER Yes it is a good

question too You know so if you are not in

a follow on statutory context you are just in

the same division and you have got two

innovators the sensitivity to trade secrets I

believe isnt as acute because the subsequent

product still has to come up with a standalone

full package and it has got to stand by

itself And so the familiarity of one

reviewer with another product I dont think is

as acute there And so these questions dont


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arise in that context If you look at other

follow on product context I guess with ANDAs

and the 505(j) application because you have

the sameness standard again I dont think the

familiarity applies

Now in the (b)(2) context I think

there may be some crossover And frankly

FDA there have been instances where FDA has

run into issues regarding reviewer access on a

505(b)(2) to the reference product And it is

an area where there could be more transparency

on the part of the agency and some of these

issues may apply

PRESIDING OFFICER SHERMAN So

since we are out of time I could just ask

again as a former reviewer this has

logistical nightmare qualities to it But to

the extent in your submission to us you can

define significantly and so forth and really

talk about how you would want to see that

implemented would be very helpful to us

MR PARKER And if I can respond


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Page 173

I understand And what we are asking for as

Abbott is a rule of reason here Obviously

in a hierarchy of the Agency and I am quite

familiar with this someone has to sign off on

ultimately every approval Im not saying you

need different sign-off It is reviewers who

are significantly materially involved in the

review of one product that we think steps

should be taken to ensure that subconscious

bias does not affect those reviewers when they

are confronted with a biosimilar for that same

product


thank you for your comments

PANEL MEMBER KOZLOWSKI One quick

question

MR PARKER Sure

PANEL MEMBER KOZLOWSKI This

would also apply to reviewing multiple

biosimilar products So no reviewer could

review the same biosimilar products

MR PARKER Again you could keep


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Page 174

spinning this out and what we are asking for

is a rule of reason I think at some point if

the Agency could recognize the issue of trade

secrets and the issue of subconscious bias in

a way that certain safeguards could be set up

reasonable safeguards this is an area of

transparency where I think it would be

worthwhile to at least begin the discussion

towards ensuring that trade secrets wherever

they exist within the Agency are adequately

protected



Our next speaker is Joseph P

Miletich from Amgen

DR MILETICH Good morning

Thank you for the opportunity to comment

today My name is Dr Joe Miletich I am the

Senior Vice President of Research and

Development at Amgen one of the worlds

leading healthcare biotechnology companies

Since 1980 Amgen has been


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Page 175

discovering developing and delivering

innovative human therapeutics As a leading

provider of high-quality biologic medicines

we plan to use our expertise to produce

biosimilars as well Consequently we

understand both the challenges and the

opportunities biosimilars present

We at Amgen appreciate the FDAs

efforts on the guidelines and we encourage

adoption of a thorough review and approval

process However Amgen believes some changes

and additional clarity are needed to advance

patient safety and to promote confidence in

biosimilars marketed in the United States

We have provided detailed comments

in our submission but with the limited time I

have today I would like to focus on some

important points for the FDA to consider

Biotechnology is an evolving

field While much more is known today than 30

years ago FDA guidance documents should

candidly acknowledge that there are some


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things we still do not know today It is

important that the Agencys policies account

for this FDA is seen as the leading source

of expertise and the steps taken by FDA to

implement the biosimilar program will be

modeled around the world

As we have previously stated

patient safety must be a non-negotiable

priority both for the FDA and for

manufacturers However focus on safety does

not end with drug approval We believe that

it is essential that FDA first adopt policies

that facilitate the attribution of adverse

events and that foster manufacturer

accountability second conduct a

communication campaign about biologics and

biosimilars and third foster supply chain

stability

So first FDA policy should

facilitate attribution of adverse events and

foster manufacturer accountability Tracking

and tracing all biologics not just


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Page 177

biosimilars throughout the product lifecycle

is important We know from experience that

biologics can be highly sensitive to small

changes that could in turn lead to

unexpected clinical implications The

challenge and importance of accurate tracking

and tracing will increase significantly with

the arrival of biosimilars in the US

marketplace Today there is often only one

and certainly no more than acute products in

the class of biologics However when

multiple manufacturers are marketing different

versions of a medicine identification of

exactly which product a patient received will

be far more difficult We believe prompt

identification and resolution of product

problems will be facilitated by

distinguishable established names Whereas

products sharing the same name would

definitely confound the attribution of adverse

events

Amgen urges the FDA to implement a


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policy of biosimilars sharing a common root

with a reference product but requiring every

biologic to have a unique suffix possibly a

Greek letter or the manufacturers name For

example monoclonal mAb gamma or monoclonal

mAb Amgen Distinguishable product names

facilitate manufacturer accountability and

avoid incorrectly implying that the molecules

are identical

Second in addition to guidances

FDA communication to stakeholders will play an

essential role in the safety and success of

biosimilars The biosimilars approval pathway

is a new initiative in the US with many

scientific and administrative challenges and

nuances These could have important

implications for patients healthcare

providers states payers other federal

agencies and more as we seek to introduce

this new class of medicine into the healthcare

system

It will be essential for FDA to


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Page 179

clearly communicate to all stakeholders what

biosimilar products are and what they are not

For example there should be no perception

implied or otherwise that an FDA approved

biosimilar is somehow less effective or less

safe than the reference product However

biosimilars are not appropriate for automatic

substitution that is without the explicit

consent of the prescribing physician unless

deemed interchangeable by the FDA

This information is important not

only for patients but for all stakeholders

Doctors making prescribing decisions payers

implementing formularies state and federal

agencies putting policy in place all face

important decisions that will define the

success or failure of the introduction of

biosimilars into the healthcare system

FDA has a track record of

successful healthcare professional outreach

programs that have included public

presentations conference exhibits brochures


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and webinars We urge the FDA to execute such

a program for biosimilars

Among the first priorities for FDA

communication should be the message that

patient safety is a collective effort It is

important that healthcare providers are

prepared for the essential role they play in

the accurate attribution of adverse events in

light of the increased number of similar

products on the market Doctors and

pharmacists are on the front lines and will

often be the first recognize or to be alerted

when a problem is associated with a biologic

Accurate records will facilitate the correct

product identification

Third FDA policy should foster

supply chain stability Making biologic

medicines whether innovative or biosimilar is

neither straightforward nor easy Biologics

have complex manufacturing processes and today

require significant investment to deliver high

quality and reliable supply both critical to


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patient safety

Recent medicine shortages have

been an opportunity for some manufacturers to

suggest that FDA standards are overly

rigorous This is exactly wrong Complex

products require high standards It is by

maintaining appropriately robust GMP and

facility inspection standards that FDA assures

the public reliable supply of high-quality

products

Amgens vision is to produce high-

quality products more efficiently and at lower

cost We will achieve this through precision

and predictability not through lower

standards Pretending biologics manufacturing

is simple will not make it so To borrow a

quote all things are difficult before they

are easy In time the science of

biotechnology will evolve to where meeting the

necessarily robust standards set by the FDA

will be easier and less expensive Indeed in

ten years biotech manufacturing will look


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much different than it does today Between

now and then there is much hard work to do and

we are committed to it

In summary the biosimilar

approval pathway presents opportunities and

challenges Manufacturer accountability FDA

communication and supply chain stability all

play essential roles in advancing the safety

in biologics

Thank you for your time


you for your comments Questions

PANEL MEMBER MALONEY Thanks for

your comments I had a question on the first

point you made about attribution of adverse

events and fostering manufacturer

accountability And my question goes to the

latter the manufacturer accountability Are

you making a different point there Something

in addition -shy

DR MILETICH Im sorry I dont

understand your question


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PANEL MEMBER MALONEY The

question is when you talk about fostering

manufacturer accountability are you saying

something in addition to this notion of

attribution of adverse events

DR MILETICH The comment about

manufacturer accountability is that we believe

without distinguishable established names

that it is not possible to attribute adverse

events to the correct manufacturer And we

believe that any reputable reliable

manufacturer would want to know about the

adverse events that might be connected with a

product so that they could investigate and

correct a potential problem

PRESIDING OFFICER SHERMAN Heidi


very much for your comments One of your

points that you are making is that you would

suggest that FDA have a communication with

stakeholders The FDA recently has done a lot

of things such as using social media


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teleconferences webinars Can you talk a

little bit about how you might see that

campaign being effective and timing of it

DR MILETICH Regarding the

timeliness it would be great if it was ahead

of the introduction of biosimilars into the

marketplace of course

In terms of an example the bad ad

campaign was a particularly good example I

think of effectively reaching stakeholders and

making people aware of a problem and what they

should do and act And that is one that could

be emulated

I would also add that in terms of

influence where the FDA may not have actual

statutory authority for example around

substitution education campaigns directed at

those who do could be exceptionally helpful

such as toward state payers and other

influential individuals


questions


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PANEL MEMBER ESPOSITO You spoke

a little bit about naming in your support of a

distinguishable name and I think you made

reference of a suffix as an example And we

heard earlier today that there might be a

logistical problem with a suffix either not

being in the original prescription or database

limitations that might drop off a suffix

Have you thought about other naming

conventions that might be distinguishable and

can you speak a little bit to Amgens view on

that

DR MILETICH I think the reality

of our current situation is that it is not

really possible to come up with a perfect

solution I think the idea here is

redundancy The idea is that we want

everybody who could be involved in recognizing

and reporting an adverse event to have as many

chances as possible to be able to correctly

identify the manufacturer So there probably

isnt yet even though it is aspirational that


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we would like to get there There probably

isnt a single system that is going to catch

everything I think redundancy is the key

here

PANEL MEMBER CHRISTL In follow-

up to sort of the labeling naming conventions

that we are talking about you had made a

statement that biosimilars are not appropriate

for automatic substitution unless deemed

interchangeable by FDA and then had gone on to

discuss FDAs role in communication and

outreach in that Does Amgen have a position

in terms of other ways to be articulating that

a product is biosimilar and not

interchangeable either through naming or

labeling or other ways that that communication

would occur to separate that a product is

biosimilar and not deemed interchangeable or

when it is approved as an interchangeable

product or is it just through education

DR MILETICH I think that we

would strongly advocate that labeling be very


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clear and that labeling indicate certainly

whether a product is biosimilar or

interchangeable We agree with the FDAs

position that interchangeability is currently

a very high standard I personally think it

is going to be a very difficult thing to prove

interchangeability So I think the label

should be clear The label should also be

clear about the distinguishable name We also

would advocate for very clear labeling

particularly in regard to transparency around

the data that was derived from clinical trials

with a reference product versus the clinical

data that was derived from the use of the

biosimilar if such was done

We have made some recommendations

about consistent labeling for biosimilars and

we would be happy to go into more details with

the FDA on those suggestions


Thanks So to the extent that we have heard

specific suffix is a good example specific


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recommendations for and against the suffix to

the extent that you could submit state it to

the docket if you have not already done so

and the same comment for Dr Bough that would

help us to evaluate

Thank you for your comments

DR MILETICH Thank you we will

do that


next speaker is Michelle Rohrer from

Genentech a member of the Roche Group

DR ROHRER Good morning Im

Dr Michelle Rohrer Vice President of US

Regulatory Affairs at Genentech Roche

Overall Genentech supports the

FDAs approach as outlined in the guidances

that is a science-driven risk-based approach

to determine biosimilarity As written the

guidance has balanced the need to assure

safety and efficacy for biosimilars while

allowing for an abbreviated pathway for

follow-on biologics


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Within the guidances themselves

there are issues that could benefit from

additional FDA clarification particularly

with regard to more clearly stating certain

expectations so that in the global setting

these expectations are not misunderstood as

optional when the requirements are truly

expected

In this presentation I will not be

speaking to Genentechs extensive commentary

on the guidances as these can be found in our

submission to the docket My remarks today

will focus instead on the need for unique

naming as has been mentioned previously

certain labeling considerations including

data and promotion guidance for biosimilar and

interchangeable products

Biosimilars are similar to the

innovator product but not identical And

therefore a unique name is critical for clear

identification safe prescription and

dispensing of medicines to patients We see


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four categories of biologic products needing

unique names These are 1) the innovator

molecule 2) related biologic products

approved under a full BLA 3) biosimilars and

4) interchangeable biosimilars

The need for unique names has been

discussed extensively in other forums and

indeed today here with the chief benefit

being the ability to identify the exact

product prescribed for and received by the

patient Having unique names will avoid

unintended substitutions minimize risk of

medication errors allow for essential

elements of pharmacovigilance such as

traceability and follow-up of adverse drug

reactions as well as facilitate prescriber-

patient decision making

In this proposed naming system

biosimilars would be distinguished from the

innovator biologic product by use of a unique

nonproprietary name The nonproprietary name

would include the same distinct additional


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stem as the innovator but would have a unique

suffix for each biosimilar of the innovator

and a unique prefix for biosimilar approved

as interchangeable

Now certainly we have heard issues

with implementing that idea in the system I

dont have an alternate solution today but I

think the point is that we need a unique name

that is simple and that can track that

molecule through the healthcare system

As biosimilars enter the

healthcare system the ability to distinguish

products by the name is critical as I said

for clear identification safe prescription

and dispensing of products to patients as

well as accurate adverse drug reaction

reporting In order to avoid reporting errors

on adverse drug reaction reports we propose

that both the nonproprietary and brand name

would be required on the report

We request that FDA issue guidance

to address this issue of unique naming after


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considering input from stakeholders This

additional FDA guidance would serve to

proactively define the standardized naming

system which will distinguish biologic

products in the marketplace and link adverse

events to the appropriate product Early

action by FDA will also help provide clarity

so as to avoid confusion among providers and

patients as well as to facilitate

harmonization on global nomenclature a very

important topic

Moving on from unique names to my

next topic labeling considerations for

biologics It is Genentechs position that

all biologic product labeling should first

acknowledge that the label information is only

applicable to that specific biologic product

Second clarify the data source

especially as certain data may come from tests

involving only the reference innovator

product

Third state that substitution


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between similar biologics by a pharmacist or

payer should not be allowed without the

consent of a physician And finally labeling

should state that switching patients between

similar biologic products should be avoided

unless the biologic is approved as

interchangeable This point is especially

relevant for biologics that are indicated for

chronic use

To accomplish this clarity in

labeling guiding principles are necessary

which follow existing principles for drug

labeling and are expanded to include specifics

for biosimilar labeling These guiding

principles are necessary to set expectations

so that biosimilar labels are clear non-

misleading and contain essential information

specific to the product These principles

could play an additional role in that they

would serve to transition the healthcare

system out of generic drug label mindset where

the labels are essentially identical to the


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brand label and this will not be the case for

biosimilar labels

Moving from the broad topic of

guiding principles to more specific

requirements should specify that labeling

should clearly state whether a product is

biosimilar or interchangeable Additionally

labeling requirements should clarify that any

differences from the innovator and reference

product should be detailed in each section

The requirements should also require a

labeling statement that all differences might

not be known at this time

Continuing on from the prior

slide biosimilar labels should be required to

be clear about which indications are supported

by clinical trial data and which indications

were granted based on extrapolation from

solely the referenced product data

Biosimilar labels should also state that there

is a risk to switching or substituting The

label should acknowledge that there may be


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differences between biologic product and that

prescribing decisions should be based solely

on information in the labeling

Finally we ask FDA to consider

whether interchangeable biosimilar labels

should address the issue of drift

specifically whether the labeling should warn

that products may not always maintain

biosimilar status

With regard to biosimilar

promotion in advertising we see a need for

FDA guidance For example a question and

answer on promotion and advertising of

biosimilars could be added to the biosimilar

QampA guidance to address how biosimilars should

or should not be promoted relative to the

reference product

In summary the three biosimilar

guidance documents are comprehensive They

provide a science-driven risk-based framework

for the development of biosimilars Genentech

encourages FDA to extend the guidance further


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to define uniform naming requirements and to

work globally to harmonize these unique naming

requirements

To support patient safety we also

encourage FDA to provide further clarity on

labeling of biosimilar products to facilitate

treatment decisions and safe prescription and

dispensing of medicines to patients This

further clarity on labeling will limit

unintended substitution minimize medication

errors and enable robust pharmacovigilance

And then finally further guidance from FDA on

appropriate promotion and advertising of

biosimilar products would help to support

patient safety and appropriate treatment

sources

Thank you very much



panel

PANEL MEMBER KOZLOWSKI So the

previous speaker said that these products


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should not be substituted unless the Agency

deems them interchangeable stated that it

would be a high bar but nonetheless stated

that if the Agency did deem them

interchangeable they should be substituted

Do you agree or disagree Because it wasnt

clear from your presentation

DR ROHRER We think that the

should clearly outline when a biosimilar has

achieved the interchangeable status And if

it has that interchangeable status then it

could be substituted

PANEL MEMBER KOZLOWSKI Right

But would it require a physician Because

again I think we were sort of thinking about

pharmacy substitutions and I thought you had

stated that it would require a physician

Maybe I misheard

DR ROHRER Well we believe that

the best situation is when the physician is

involved in the decision-making around the

product choice In the case of an


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interchangeable the physician would not need

to be involved

PANEL MEMBER KOZLOWSKI Okay

And then another question to clarify You

mentioned started off by saying

interchangeable products when you brought up

the question of drift but your bullet point

says may not maintain biosimilarity So I

just want to clarify Do you consider drift

an issue for biosimilarity as well as

interchangeability

DR ROHRER I think there could

be both As you know when you are

manufacturing a product there are

manufacturing changes and the comparability is

based back to your original reference So

both that biosimilar product would be

comparing back to its original manufacturing

license the changes to it as the reference

product is also changing referencing back to

comparability of its original license

And so at some point the question


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becomes do you need to reestablish

biosimilarity as well as interchangeability as

these products drift

PANEL MEMBER KOZLOWSKI And I

think I wonder whether one views biosimilarity

as making a link to the clinical data that

supported the originator product and then that

product now has acquired that information and

then it maintains that information

independently through its own process which

is a little different than interchangeability

So just to clarify do you have concerns for

both And apparently you do

DR ROHRER Yes

PANEL MEMBER TOUFANIAN Excuse

me You mentioned your discussion of unique

naming that unique names would be required not

only for biosimilars and interchangeable

products but related biological products

Could you provide Genentechs definition or

criteria you would suggest FDA use to identify

those products


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DR ROHRER I think it is

important that products have unique names

And certainly there are the four different

types of products that could be possible today

that I mentioned in the talk You could have

related biologic products approved under a

full BLA I think we have that situation

today with the EPO products Those have

unique names


Dr Rohrer I have a question I appreciate

particularly your thoughtful comments on

labeling And you mentioned the following up

on the drift issue a recommendation that

labeling include the concept of drift and that

the product may drift away from the reference

product over time

The question I have for you is how

do you distinguish that from not having that

kind of labeling for any biological product

that may drift from its original license date

DR ROHRER I dont have a


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specific answer for you I think that this is

one of the issues that we wanted to put into

the melting pot here of ideas for us all to

think about how do we deal with this issue of

drift

PRESIDING OFFICER SHERMAN Dr

Marchand


your comments I wanted to get your sense if

you thought about what would be a labeling for

biosimilars to the extent that the current

rule or regulations for labeling that exist

the PLR and just wanted to get your thoughts

if they have been developed to the point of

thinking about information relative to the

analytic data the reference product clinical

trials or data as well as the originator

DR ROHRER Are you asking if we

have specific ideas on those

PANEL MEMBER MARCHAND Yes As

you are thinking about what might be in

labeling So as we are thinking about how


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labels for biosimilars might look have you

thought through levels of detail as to the

kind of information that might be there like

the analytic data information with regard to

clinical trials for the reference product

originator

DR ROHRER I think we can take

that back and perhaps provide to you more

granular thinking At the moment we are

thinking quite broadly specifically around

the clinical trial data just would be helpful

to understand for example if the reference

product is being leveraged then how is the

comparison portrayed in the clinical data

section That some verbiage that would guide

biosimilar manufacturers as to how that would

look and then also that would inform the

marketplace what to expect And it is not

clear how differences would be described You

can look at adverse event tables today in the

current labeling situation and that is always

a case-by-case basis But for example if you


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look at adverse events how would differences

in adverse events between the reference

product and the biosimilar product be

described And we just think that some more

granularity guiding sponsors would be helpful


additional questions Okay thank you for

your thoughtful comments

We now have lunch Ala carte

items are available for purchase outside And

if we could reconvene at one oclock Thank

you

(Whereupon at 1158 am a lunch recess was

taken)


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A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

(104 pm)


Welcome back I hope everyone had a good

lunch

So I am back trying not to butcher

peoples names Our first speaker of the

afternoon is Sumant Ramachandra

DR RAMACHANDRA Thats perfect


we are off to a good start

DR RAMACHANDRA Thank you So

good afternoon to the FDA panel and to the

guests here for the public hearing Thank you

for the opportunity to speak to the FDA today

My name is Sumant Ramachandra and I am the

Chief Scientific Officer and Head of Research

Development in Regulatory and Medical Affairs

for a Lake Forest Illinois-based company

called Hospira

Hospira is a global leader in

biosimilars and is the only US-based company


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with biosimilars on the market in Europe and

Australia Our biosimilar EPO also known as

Retacrit is the leading product in the EU and

our biosimilar filgrastim known as Nivestim is

the only biosimilar competitor in the

Australian market as well as being available

in Europe

Hospira therefore has solid

experience in the biosimilar space that we

believe will allow us to intelligently pursue

the US market with scientific and clinical

integrity and thoughtfully contribute to the

regulatory guidance process Hospira is

pleased that the FDA has issued guidance

thereby demonstrating its commitment to making

this important class of medicines available to

US patients and we look forward to

continuing to partner with the FDA on the

development and implementations of the

guidance documents

To begin I would like to share

some of our general impressions of the


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guidance documents as published then

highlight some of the aspects we value and

want to see maintained in the final guidances

and then briefly mention specific areas we see

require clarification or modification to

facilitate effective implementation

It was clear that the FDA had

heeded the input of key stakeholders and

Hospira is proud to have been an active

participant in this process thus far both

through our input offered in public comment

forums and in our individual product-specific

consultations with the agency We are pleased

that FDAs published guidance documents are

generally consistent with our development

approach and that it provides a reasonable

framework within which biosimilar companies

can operate This framework describes a

scientifically rigorous approach and bases the

approval of biosimilars on the totality of

evidence put forth in a stepwise approach

The stepwise approach makes sense


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but Hospira would caution that this does not

always mean that everything needs to be done

purely in a sequential manner That is some

activities should be allowed to be conducted

in parallel to ensure efficiency in the

development process To that end Hospira

welcomes the Agencys invitation to seek

consultation early and often to ensure proper

alignment between the FDA reviewer

expectations and industry sponsors The broad

nature of guidances necessitates such

interactions to calibrate all parties on the

right approach that takes advantage of the

flexibilities afforded yet maintains the

discipline to rigorous signs and the

progressive reduction of uncertainty

Hospira is pleased with several

aspects of the guidance documents that support

an efficient and effective approach to

biosimilar development and would like to see

these aspects maintained in the final version

of the guidances Specifically Hospira


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values use of a non-US reference product

with appropriate scientific data bridging

ability to reduce the preclinical and clinical

requirements using bioanalytical

characterization extrapolation with

scientific justification and the ability to

incorporate product differentiation that does

not affect clinical safety or efficacy These

aspects of the guidance will enable biosimilar

development in a cost-effective and timely

manner without compromising quality or safety

There are however aspects of the

guidance that Hospira believes needs to be

clarified to facilitate the consistent

interpretation of the guidances and remove

ambiguity that could result in inefficiencies

in the development process To that end we

have submitted specific written suggestions to

the FDA based around the three guidance

documents quality documents the scientific

documents and the question and answer

documents And a summary of these suggestions


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are captured here

From a quality considerations

perspective Hospira has three primary

recommendations First FDA mentions extra

crystallography and multidimensional NMR

methods to assess three-dimensional structure

but other methods for example vibration

circular dichroism hydrogen exchange Raman

spectroscopy and Fourier transform infrared

spectroscopy can also be considered based on

the molecule being studied The emphasis

should be placed on using the correct method

as appropriate for the molecule

Second FDA should clarify how the

variability of reference product loss observed

over time should be used to set biosimilar

specifications When reference products lots

vary widely and we have seen they do in the

market sometimes then the applicant may

choose to define a narrower acceptance range

if scientifically justified

Third Hospira would like the FDA


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to clarify the degree to which impurity levels

need to be similar in order to realize relief

of pharmacological and toxicological

requirements The term similar levels used in

the guidance document is ambiguous and

difficult to interpret practically

From a scientific considerations

perspective Hospira has four primary

recommendations First we suggest that we

conduct toxicity studies in only one gender

if the data suggests no gender effect

Second we suggest rewording to clarify the

requirements of a clinical immunogenicity

assessment Third regarding clinical study

design Hospira suggests that the FDA

recommend a non-inferiority design in cancer

studies with an appropriate surrogate

endpoint provided that the safety profile is

not significantly different between the

biosimilar and the reference product

Finally in regards to

extrapolation biosimilar sponsors should be


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required to provide scientific data to

demonstrate that the mechanism of actions are

similar across extrapolated indications

Hospira applauds the FDA on the

incorporation of the QampA section of the

guidance documents This information is very

helpful to clarify FDAs position on aspects

of the guidance documents and we hope will

evolve over time to incorporate further topics

and clarifications Even with the QampA

section however Hospira would like

clarification on some areas that remain

ambiguous

With interchangeability the

guidance does not define the requirements for

interchangeability Hospira would like to see

the requirements defined ensuring that there

is only one standard that is the highly

similar standard for biosimilars and

interchangeable biologics With pediatric

requirements a waiver is allowed for

interchangeable biosimilars but what about the


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biosimilar that is not pursuing this

designation Hospira believes that pediatric

assessment should not be a requirement for

biosimilar development if the active

ingredient is already known and shown to be

highly similar to the originator

And in the area of immunogenicity

testing the guidance could be interpreted as

required to require a sequential approach to

immunogenicity assessment in accordance with

the stepwise philosophy This approach

however could protract biosimilar

development Hospira recommends the Agency

clarify that this assessment can be done in

parallel or combined with safety and efficacy

studies

In closing I again would like to

thank the FDA for the opportunity to

participate in this process and in this forum

We are generally pleased with the guidances

that have been issued and would appreciate

clarification of some areas of the guidance


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and have articulated these in our written

feedback While the guidance documents

provide a good framework and starting point

they are relatively broad and subject to

interpretation by the Agency and biosimilar

sponsors In some instances we believe that

clarification is necessary to tighten the

language and decrease the chance of divergent

interpretations between the FDA and industry

In other instances the flexibility will

serve to more efficiently advance these

important development programs We look

forward to working with the FDA to achieve the

proper balance while maintaining a commitment

to scientific rigor in the implementation of

these guidances Thank you



panel


commented about including more methods in the

guidance So I think often when guidances


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talk about methods they are examples They

are not necessarily all-inclusive lists And

too much specificity has its own challenges

but we certainly invite you and your comments

if they are not already there to describe

what other things you think might be useful

for us to talk about

You also mentioned sort of

appropriate boundaries and variability of what

you are aiming to do So I think that the

challenge of statistics is a very difficult

one There may be different numbers of lots

and different situations So again we

welcome any input you might have on general

approaches to doing that

I think one comment you made and

this on the scientific consideration document

is reword the approach to the clinical

immunogenicity assessment So I wondered what

exactly you were referring to

DR RAMACHANDRA There is -- the

way the document is written it sounds like


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immunogenicity follows safety studies PK

studies and before potentially efficacy

studies As you know this sequential

approach will just prolong development And

the reality is that immunogenicity you can

actually maybe test for it in your preapproval

trials but it is measured over time

Sometimes the size you need to actually detect

rare events actually is really in the post-

market setting And I think what has to be

done is that you have to really ensure that

the preclinical data is very solid as well as

you have the appropriate measures within your

clinical trials whether they be phase 1 or

pivotal trials to measure for this knowing

that the statistical chance of finding

immunogenicity unless you have done something

very wrong with your product is very low So

that is what we mean by that



DR RAMACHANDRA Thank you


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next speaker is Jay P Siegel from Janssen

RampD

DR SIEGEL Good afternoon I am

Jay Sigel Chief Biotechnology Officer and

head of Global Regulatory Affairs for Janssen

the pharmaceutical companies of Johnson amp

Johnson

I want to thank the FDA and this

panel for holding this hearing and for

creating an inclusive and transparent and

science-driven process for developing a

biosimilars pathway

Janssen has submitted extensive

comments on the document When I say

extensive I should say we find the guidance

to be in general very strong but extensive

comments of areas for additional

consideration guidance or perhaps

redirection of which I would like to highlight

three selected areas in the time available

One regarding the biosimilarity standard one


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regarding interchangeability and one

regarding extrapolation of indications

With regard to the biosimilarity

standard I specifically want to talk about

avoidable differences The guidance

contemplates in a number of places differences

that are not necessary It speaks about

differences between products introduced by

design It speaks about package and

container and formulation and N amp C terminal

differences that one would presume are

intentional and are avoidable

The fundamental drive for

biosimilars pathway is that there are

differences that cannot be avoided or at

least cannot be avoided with reasonable

practicality If that werent the case we

would have generic biologics But given that

we cant avoid differences and we recognize

that those differences carry certain risks of

potential clinical difference we have created

a biosimilars pathway and we require FDA


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requires and other regulatory bodies a high

degree of similarity and has provided draft

guidance now as to how to control and minimize

those risks what testing is necessary But

to allow extensively avoidable reasonably

avoidable differences is to expose patients to

avoidable risk

Not all the implications of

differences can be predicted All sorts of

differences certainly to the product but also

excipients impurities containers can have

unpredictable implications An interesting

example was the removal of albumen since that

is an example in the guidance document of what

was considered a minor difference and

therefore acceptable Removal of albumen from

erythropoietin formulations which was

requested by European regulators but

specifically not allowed by FDA because of

concerns about what it might to do the product

was a proximal cause of the emergence of pure

red cell aplasia in 2002 and 2003 or of an


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increased incidence including some fatal cases

in Europe and around the world but without any

change in the US because of the FDA approach

on this issue And I ask that you contemplate

that in thinking about whether removal of

albumen is really a minor issue and whether

that sort of avoidable change is something

that you risk that you want to -- because that

would not have been excluded by testing short

of testing tens of thousands of patients

So with regard to the draft

guidance we would urge the FDA to indicate

that reasonably avoidable differences in the

active pharmaceutical ingredient must be

avoided and that other reasonably avoidable

differences should be avoided that HSA

removal is not a good example of a minor

difference It should not meet the legal

standard of a minor difference so it

shouldnt be given as an example of the type

of differences that could be justified

And also why are such differences


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made Well one of the concerns would be that

one might make differences in the product that

have an implicit claim of superiority And in

fact some differences may lead to

superiority But there is of course already

a novel product pathway through BLA for

products that are intended to be different or

superior And so there should be clear it

should be made very clear that the

biosimilars pathway is not appropriate for

intentionally improved products and that

claims of superiority would not be permitted

under this pathway

With regard to interchangeability

much has already been said It is important

to note that even after you have a well-

qualified highly similar safe and effective

biosimilar there are additional risks that

could occur in patients who are switched from

the innovator to the biosimilar They could

get additive immunogenicity risk higher than

on either one alone They may not have -shy


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They might require dosing adjustments that are

not well studied and there are other issues as

well And so the legal standard which we

think is an appropriate one speaks to both

demonstrating that the products would have the

same effect in any given patient and that

switching would not expose patients to risks

or outcomes different from taking either

product or We believe that is an appropriate

standard and we agree with the guidance that

it would be difficult as a scientific matter

to establish interchangeability in an original

351(k) application given the statutory

standard We believe it would be difficult in

a follow-on application and we urge the FDA

as it considers this area and it promotes

guidance that it uphold the legal

interchangeable standard with appropriate

scientific rigor And other speakers have

spoken at length to ensure that naming and

packaging minimize -- maximize the ability to

trace events And I would add also to the


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extent possible minimize the likelihood that

switching will occur except where it has been

appropriately tested

The final area that I would like

to mention is the extrapolation of clinical

data from one indication to another In the

stepwise approach that I think is very well

described and we would support very well

described by the Agency the purpose of

clinical testing is to exclude the possibility

or address the remaining concerns or risks

that exist after all the prior testing non-

clinical preclinical laboratory testing has

occurred

And the fundamental concern

regarding extrapolation is the possibility

that there could be differences between the

biosimilar and reference products differences

that havent been excluded non-clinically that

may not manifest in the first indication

studied but might be clinically meaningful in

another indication


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And we would hold forth that the

basic scientific principles that should be

guiding this consideration and in fact a

basic generalizable scientific and regulatory

principle is that when you do clinical testing

to exclude differences it should be done in a

setting that is sensitive to such differences

This is something Bob Temple often likes to

refer to with regard to non-inferiority as

assay sensitivity

But it is an important principles

and it is principle that is indirectly alluded

to in the discussion of this issue when the

Agency wrote in the guidance consideration of

whether the tested condition of use is the

most sensitive one in detecting clinically

meaningful differences But that wording

suggests that there is a most sensitive one

whereas I think the appropriate and what

needs clarification is that it is really a

difference by difference issue

So what are the residual


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differences If they are in immunogenicity

is the group you studied sensitive to

immunogenicity If they are differences that

might lead to liver toxicity is the group you

studied on the right medications or have the

right risk factors If they are differences

that might influence biodistribution

penetration into the brain may be one

indication that is more important than the

other So those need to be looked

scientifically

Mechanism of action that the

previous speaker spoke to is important

Arguably when mechanisms of action are

different when you require new or different

mechanism of action then probably it is the

case that the different mechanism of action

study is not sensitive to differences that

might influence that new mechanism of action

So I would ask or we would ask

that the Agency consider that principle and

provide a broader clarification of the


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criticality of addressing sensitivity to

various risks in its guidance

And with that I will conclude my

remarks and once again thank you for your time

and attention and express our companys

interest in continuing to work in this process

toward a science-driven pathway for

biosimilars in the United States



panel

PANEL MEMBER KOZLOWSKI So on

your comment about avoidable differences so

when an originator changes their delivery

system or formulation they are also taking an

avoidable risk and what are the sizes of

studies they do to confirm that those risks

are mitigated

DR SIEGEL Well that is

something that of course you as a regulatory

body and other regulatory bodies determine

with an innovator And that is appropriate


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and that needs to be looked at and innovators

are innovating

I would suggest that though to

add that sort or risk on top of the risks or

uncertainties of a biosimilar the goal of a

biosimilar is not to improve a product It is

to make something as similar as possible So

there is not a reason to make a product

different

Now there may be reasons It may

be impractical There may be impediments to

making it the same Thats why I am not

trying to raise barriers that are

unachievable I am just suggesting it

shouldnt be conceived as part of the pathway

that oh well we can make a better product

We wont say it is better but people will know

it is better because it has a gentler

formulation it is purer or it is whatever

Those things can be misleading I can give

you other examples of ways that purer products

have run into problems


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PANEL MEMBER KOZLOWSKI And then

another question So when you talk about the

most sensitive indication you point you that

you can have very different things you are

looking at and sensitivity can vary

And so I would ask do you envision

that if one is very very comfortable with the

analytical similarity or a high-level the

fingerprint-like that is discussed in the

guidance that at some point the burden is not

to reduce any uncertainty in any possible

situation but to confirm in a more general

way

DR SIEGEL Well that is part of

the testing I agree You could never totally

exclude all uncertainty and there is some role

for some broad general but there are certain

areas I would argue even with fingerprinting

that immunogenicity is an area where there

will always be residual risk So many things

can influence immunogenicity

And you know there is discussion


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Im pretty sure there is discussion in the FDA

guidance for example that speaks about

cancer patients perhaps as immunosuppressed

being less sensitive for immunogenicity than

arthritis or rheumatology patients or

autoimmune patients But you know autoimmune

patients may be receiving methotrexate or 6shy

mercaptopurine or steroids or other drugs that

suppress immunogenicity And so they are

usually I think -- Yes there is general

confirmation but there usually are specific

and important questions that remain Does the

product get to get the right place at the

right -- you know will it -- Are there

toxicities Are there potential differences

It just has to be looked at product by

product

What are the possible differences

that cant be excluded by testing I would

argue there always are some with regard to

immunogenicity Usually there are others

And then how do you adequately test it


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clinically

So frankly general Im not sure

If you really could exclude all differences

I think you could make a strong case for not

doing clinical testing So when you say you

need clinical testing you are saying there

are differences that need to be assessed But

then the question is how do you adequately

assess them


your comments I had one question On one of

your slides you say you urge FDA to ensure

that naming and packaging maximize the ability

to trace events to specific products

So can you expand on what you are

referring to when you are talking about

packaging to maximize tracing

DR SIEGEL I dont have the

expertise in this area I say that the

concern comes from the fact that I know that

often when one gets safety reports they are

originated from the patient And the patient


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doesnt necessarily know or report and it

isnt always readily accessible you know

what is the chemical name what is the lot

number or whatever

So the concept there although I

dont have a great deal of expertise is just

to do this in a way that people know what they

are getting and that the reports maximize the

likelihood that it is traceable

PANEL MEMBER TOUFANIAN Just to

follow up on Dianes point You referenced in

your discussion of interchangeability a

specific concern with tracing problems And I

wasnt sure if you are using that in the same

context as you were below And if you could

explain that and if it is in fact tracking

with respect to pharmacovigilance tracking if

you could explain that a little bit more or if

it is in a different context

DR SIEGEL I dont recall

specifically -- oh yes So I have that in a

bullet there yes Well I think that when


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patients -- So we have had company experience

for example trying to track down cases of PRCA

in Thailand where sometimes it is very

difficult there are a number of biosimilars

to erythropoietins are available Sometimes

we dont have clear record about what

information which products the patient got

Sometimes we know they have gotten a number a

products I think although the Agency can

only go so far in limiting this the switching

will per se make tracing to which product

may have given rise to a problem difficult if

you discover that the patient has been on more

than one product And so except where it has

been well-validated or studied that sort of

switching should be discouraged or avoided


we are out of time so I cant ask my question

But I hope in your comments to the docket you

will help us grapple what you mean by

reasonably avoidable because one can probably

spend some time on that Thank you for your


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comments

DR SIEGEL Youre welcome


next speaker is James Roach from Momenta

Pharmaceuticals

DR ROACH Good afternoon Im

Jim Roach the Senior Vice President of

Development and Chief Medical Officer at

Momenta Pharmaceuticals

Momenta is an innovative

biotechnology company that is focused on the

development of analytical tools and methods to

advance the science of thorough product

characterization and knowledge Our

technology has enabled the development of

generic versions of complex drugs such as

enoxaparin approved almost two years ago now

and glatiramer acetate currently under review

by FDA

We have extended our technology

and scientific approach to develop biosimilar

and potentially interchangeable products and


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are very interested in utilizing the 351(k)

pathway

We fully support the emphasis that

the draft guidance documents place on quality

by design and the recognition of the

fundamental importance of thoroughly

characterizing products structurally and

functionally in a stepwise manner

We believe that by following this

rigorous approach it is will be possible to

realize the potential efficiencies in

development that the abbreviated pathway may

allow

Momenta supports and agrees with

the foundation laid by the Agency in the

guidance documents with respect to retaining

scientific discretion to review each

application on a case by case basis without

mandating a priori requirements considering a

risk-based totality of the evidence approach

and lastly proceeding with development in a

stepwise fashion allowing for the science to


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dictate additional requirements if any

following review of structural and functional

characterization data

We request that the final guidance

documents continue to reflect these concepts

and approaches and retain flexibility to

assure that each company is able to find the

best means available to them to demonstrate

biosimilarity as well as the possibility of

interchangeability

And we do have some specific

comments With respect to the determination

of interchangeability in the original

application I will be flipping through the

questions quickly We really believe that the

experience with enoxaparin is very relevant to

consider here We certainly understand that

it will be difficult as a scientific matter

for an applicant to establish

interchangeability in an original 351(k)

application and the bar should be high

But again this experience is


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relevant And we noted with interest the

Agencys recent publication in the New England

Journal last August entitled Developing the

Nations Biosimilar Program authored by

several folks from FDA including some of our

panel members And in this article the

Agency commented on how the scientific

principles applied in reviewing generic

enoxaparin could be applied to the review of

biosimilar products And I wont read this

whole quote but to hit the highlights such a

totality of the evidence approach can also be

applied to assessing biosimilars And there

may be strategies that allow a fingerprint-

like identification to very similar patterns

in two different products Although

additional animal and clinical studies will

generally be needed the scope and extent of

such studies may be reduced further if more

extensive fingerprint-like characterization is

used

I bring this up and think this


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context is important because many in the

scientific regulatory and innovator

communities believed it would not only be

difficult rather it would be impossible to

replicate this complex drug and many now state

that it is impossible to replicate biologics

We do not underestimate the complexity of

this task but do believe that achieving this

goal is possible and ask simply that the

Agency remain open to the possibility of

granting interchangeable status based on the

data presented in the original application

We note that high-quality high-

resolution structural and functional data may

actually be a much more robust and sensitive

means to be able to detect differences between

products should they exist than data

obtained in clinical trials

With respect to the question on

whether the use of comparative animal or

clinical data with a non-US-licensed product

can be utilized to support a demonstration of


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biosimiliarity we certainly support allowance

of non-US-licensed product data to support

biosimilarity with appropriate bridging data

and believe that this is in fact critical if

the goal is to implement a global development

program that is feasible to conduct

We also believe that the same

scientific principles applied whether

comparing non-US reference product to US

reference product or comparing either of these

to a proposed biosimilar And I will make

further comments on the PKPD aspect of that

question shortly


the applicability of ICH Q5E it is a

demonstration of biosimilarity we agree that

some of the scientific principles in ICH Q5E

are certainly applicable to the demonstration

of biosimilarity Much more data utilizing a

lens which provides a much higher degree of

resolution than has been historically utilized

in the industry may be required to establish


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biosimilarity as well as interchangeability

and in particular if this same structural and

functional characterization set is serving as

the primary justification or reducing or even

potentially eliminating clinical trial

requirements

Moving on to the question

regarding human PK andor PD study

requirement I note that the answer to this

question states for example but we are unclear

based on the wording and the use of the word

must and at least in this answer as to

whether the Agencys intent was to actually

mandate a requirement for a clinical PK andor

PD study to support the demonstration of

biosimilarity and request that the Agency

provide further clarification

If the intent was in fact to

mandate this requirement we believe that this

is inconsistent with the clear discretion

afforded the agency in determining

requirements for approval based on review of


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the data and request that the Agency continue

to consider the totality of the evidence and

stepwise approach outlined in the guidances

From our perspective as a

scientific matter we actually believe it is

premature to mandate any particular

requirement or approach without first

evaluating the data presented The science of

comparative assessment of complex products

both structurally an functionally continues to

evolve

Others will be and have commented

on the clinical study section And it is

clear that the Agency has given significant

consideration to the design of the different

types and stages of clinical studies that may

be required to address residual uncertainties

that may remain following the completion of

preceding trials The progression of clinical

studies that is outlined in the guidance

document certainly is logical However as

the Agency begins to implement the 351(k)


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pathway we believe it will also be important

to continue to emphasize a concept articulated

elsewhere in this guidance namely that the

purpose of the biosimilar development program

is to support a demonstration of biosimilarity

between a proposed product and a referenced

product including an assessment of the

effects of any observed differences between

the products but very importantly it is not

to independently establish the safety and

effectiveness of the proposed product And we

believe it is important to not lose sight of

this as this is implemented

For the pathway to actually be

utilized and to ensure that the benefits to

patients in the healthcare system are fully

realized it is imperative that the Agency

truly takes a risk-based totality of the

evidence approach and considers the

feasibility of study design and conduct when

providing guidance

Clinical trials should be designed


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and conducted to provide supportive evidence

to the existing structural and functional data

set rather than to be conducted to

independently establish safety and efficacy

We only have one key point

regarding future guidance development We

believe that less is more in this regard The

state of the science with respect to the

enhancement of product understanding continues

to evolve and is progressing rapidly We

encourage the Agency to continue to set and

implement policy that is flexible enough to

allow the Agency to consider scientific

advancements on an ongoing and real-time

basis

In conclusion patient access to

biologics continues to be limited by high

costs and growing demand Many emphasize the

potential risks to patients if we rush too

quickly to bring biosimilars to the market

However equal emphasis should be placed on

the potential benefits to patients by


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implementing the pathway in a way that ensures

the introduction of safe and effective

biosimilars including interchangeable

biologics into the marketplace in a timely

manner

And I will close by quoting

another statement from the August 2011 New

England Journal article Evaluating

biosimilarity with a risk-based approach is

scientifically appropriate and familiar to

FDA whose decisions are commonly based on

reducing residual uncertainty to an acceptable

level in any given clinical setting

There is a very big difference

between defining and implementing policies

that will reduce uncertainty to an acceptable

level versus policies implemented with the

goal of reducing uncertainty to zero which is

an impossible task

Striking the right balance for

regulatory perspective will certainly not be

easy and nor will it be easy to develop


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biosimilar and potentially interchangeable

products that merit a significant reduction

for elimination in clinical trial requirements

but I believe the biotechnology industry has

historically thrived on challenges such as

this and I think we both share the

responsibility to ensure that the 351(k)

pathway is successfully implemented

Thank you very much for your time

and attention



panel

PANEL MEMBER KOZLOWSKI So in

your question about the interpretation of

whether a PK study is required So you know

you are stating a view that with the right

characterization you think even a

pharmacokinetic clinical study would not be

necessary

DR ROACH You know I am

sitting I guess from a conceptual level that


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I am not sure that should be mandated It

certainly wouldnt be the end of the world if

at the end of the completion of a very

rigorous structural and functional

characterization data set there was a

suggestion or a requirement to conduct a PK

study but it struck me conceptually that if

the intent was to proceed in a stepwise

fashion and we have truly demonstrated through

our very rigorous analytical and structural

characterization -- sorry structural and

functional characterization package that the

two drugs are truly indistinguishable from

each other at a level of satisfaction that

first we have to convince ourselves of and

then you then arguably there should be no

further requirement

PANEL MEMBER KOZLOWSKI And one

other question You mentioned that obviously

one cant reduce the residual uncertainty to

zero So earlier we had comments in the

morning session about our definition of


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clinically meaningful differences and it was

challenged from the other side that it is too

close to zero or too far from zero

And I guess what I am asking is do

you have a specific comment on that

definition based on this view

DR ROACH You know I wish I did

because that is really to me where the rubber

hits the road if you will in trying to

define using scientific judgment where one

draws that line But what I will say is that

it is clear that through your decades of

experience in reviewing biologics and

reviewing even comparability packages that

companies are putting forth to you when they

make their own manufacturing changes you are

making these kinds of assessments every day

And I think the same kind of judgment that you

are apply in those situations also apply as

you are reviewing a biosimilar program


questions


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I have just a follow-up one on

Steves You pointed out correctly there are

a couple of places that we speculated that it

would be likely that we would want to see

human data PK and obviously

interchangeability Can you envision a

biosimilar development program where there

would be licensure with a product never having

been introduced into a human

DR ROACH Can I envision that

We envision a lot of things at Momenta So I

would say yes I think we can envision that

We appreciate that there may well be some

question about residual uncertainty still at

the end where you may want to see some human

PK data



All right our next speaker is

Patrick Vink from Mylan

MR VINK Good afternoon My

name is Patrick Vink I am the Senior Vice


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President of the Global Institutional and

Biologic Business at Mylan

I first want to thank the FDA for

organizing this meeting today I think it is

a great venue for everybody to listen to what

all stakeholders have to say I also want to

thank the panel for their continued attendance

and interest in all of the presentations

during this whole day

Mylan is the worlds first largest

generic company and we are the largest

generics company with headquarters in the US

Today already one out of 11 prescriptions

dispensed in the US either brand or generic

comes from us and we have a commitment from

over 15 years to help patients get access to

high-quality affordable generics And we take

that commitment that we have for 15 years now

also to the market of biogenerics

As I say as part of that

commitment we are going to take a leading

role in development of this new class of drugs


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for the US marketplace We are actively

pursuing a number of development programs and

we look forward to the ongoing interactions

with the Agency on those product-specific

discussions

We want to express our full

support to the effort of FDA to put in place

this guidance or potentially as mandated by

the implementation of the BPCIA We applaud

this first step that has been made and a

number of elements that are in that we very

much support And as was already mentioned

during today the stepwise approach the

recognition of the totality of evidence and

especially the key role the Agency sees in the

fact that state of the art analytical tools

that are currently available and as are

currently still evolving play a key role in

establishing that high similarity level that

we need to have products approved

We also see moving forward that a

dedicated office of biogenerics would help the


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transparency in terms of funding and the focus

of implementation could help like it did for

generic drugs in the past

My presentation focuses on four

key areas that can be condensed out of our

written comments that we have submitted

already to the docket of the FDA So it

doesnt cover all of our comments but a

number of them

The first one is the issue of

interchangeability We have learned with

small molecule generics that the way to create

an efficient pathway for cost-saving of

quality drugs is interchangeability And we

say over 15 years we have seen already that

the appliance of the highly similar standard

to a diverse array of biological products

regulated under PHSA has worked FDA has

significant experience in this area in order

to assess all these complex drugs We see

that the very same similar standards can be

applied directly to biogenerics We see that


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that is an important issue The present

available state of the art analytical tools

enable direct application of these same

standards to biogenerics when making these

determinations

We also want to emphasize that

actually in the past the evolvement of those

analytical data already allow us to know far

more about the compounds than at the time that

they were originally approved All elements

will actually lead to a very vigorous exercise

that can be done by the applicant of


So what we see is that highly

similar standards is a standard for

interchangeability and it has enabled

switching of biologics for more than 15 years

especially when manufacturing changes that

were done that highly similar standards that

was applied helped determining

interchangeability

We see actually the important


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issue is that there is one standard for highly

similarity Once you apply that to have a

biosimilar determination you are also

interchangeable Different standards of the

brand versus the biosimilar drug dont see any

good scientific rationale to do that

The second point which goes handshy

in-hand with interchangeability is the naming

of these drugs We saw already that in 2006

the debate at WHO was there about INN naming

In 2006 the FDA helped persuade the global

regulatory payers that we should continue to

apply to biogenerics to 50-year-old

international naming system

The other thing what FDA in 2006

already concluded is that it shouldnt be used

to different shaped products with the same

active ingredient when credible scientific

data demonstrated no pharmacological relevant

differences exist

The second point is that we

believe that pharmacovigilance doesnt provide


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the rationale to do it different because it is

routinely accomplished for biologics and

drugs even within the Sentinel pilot that

using other measures than NDC codes works

You dont need to differentiate INNs

The last point is also that INNs

have not been an issue implicated in

pharmacovigilance in other situations like the

myriad of biologic drugs when you compare

brands to other brands You dont need it

when you have to differentiate drug products

brand-brand versus brand-generic And

actually those show share identical INNs dont

-- it makes no difference And we see from

biogenetics there is no rationale to do

anything different than we did in the past for

other things

And the last point is we also

believe that if we would have distinctive

biogeneric names that could in itself create

public health issues like mis-dosing

overdosing and were of confusion about


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relative safety efficacy profiles

Important to underline is that the

issue interchangeability and INN naming are

very mis-linked in our perspective given the

way how products are distributed and dispensed

in the US system

The third point which we believe

is extremely important is the application of

foreign data foreign comparator data in the

application of a drug Global development

programs for biologics are routinely used for

foreign-sourced comparator products in pivotal

trials It is not at all unusual the global

development program for pivotal clinical

trials have support from foreign-sourced

comparator product trials It is all driven

by the fact that we believe that unnecessary

trials should not be mandated by regulatory

authorities And FDA has a sound and long-

standing policy of approving products based on

such pivotal data

The second point is we dont see


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a scientific basis for discrimination against

global development programs for biogenerics

that similarly used foreign comparator

products

The available information

reflecting the biologic approved overseas is

highly similar to its licensed brand biologic

counterpart and it should enable a biogeneric

global development program to proceed without

generating new data on the similarity to the

US or foreign counterparts Again avoiding

unnecessary data that is not mandated by the

science

The burden of proof should be

consistent with the product facts For

example the minimal public information for a

product with the same brand and generic names

and manufacturing facility and moderately

more for such a product with a different

manufacturing facility

The last point that I want to make

here is once US and foreign-brand


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counterparts are shown to be highly similar

this study requiring study arms to generate

new comparator data is really not warranted

in our opinion and would create only situation

where unnecessary trials would be mandated

The last point I want to make here

is about the exemption for pediatric

development We believe that the biogeneric

must meet the same highly similar standard as

we said before Like the obstacle of carrying

a heavier regulatory burden and like its brand

counterpart should be equally interchangeable

and exempt from pediatric development

We discussed already from the

beginning that that highly similar standard is

the same one that the FDA has been applying to

modify brands since 1996 And the effect of

meeting that standard should be the same for

all biologics being interchangeable in a

marketplace and exempt from pediatric

development

Therefore we say mandating


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pediatric development for those highly similar

biogenetics is not really consistent with the

current and sound science The BPCI Act

exempts interchangeable biogenerics from

pediatric development and that should be

applied to every biogeneric that has met the

highly similar standards Otherwise we would

say pediatric testing would result in

unnecessary duplication of repetitive studies

In conclusion I want to say that

we believe the draft guidance is a great step

in the right direction What is very

important is that all the lessons we have

learned in the past from the Hatch-Waxman

implementation and from 15 to 20 years of

experience of characterization of biologics

should not be lost but used in implementing a

pathway that leads to highly safe and

effective drugs leading to cost savings for

the American population

Thank you Any questions



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panel

PANEL MEMBER KOZLOWSKI So just

to clarify the position So the view would be

that you could take US reference products

do an analytical comparison to the candidate

biosimilar product and then based on knowing

it is from the same manufacturer you never

use the US reference product in any clinical

studies

MR VINK No What we say is we

believe we have to establish the compatibility

of the highly similar standard between the

drugs US and foreign reference products

based our own product Then we are open to

dong a PKPD comparison three-armed because we

believe that the pivotal clinical endpoint

study usually requires to establish

biosimilarity and the interchangeability to be

done versus one global reference product

PANEL MEMBER KOZLOWSKI If you

could comment on how that differs from the QampA


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that we have And one of the other things you

state is that highly similar and

interchangeability are effectively the same

standard

MR VINK Yes

PANEL MEMBER KOZLOWSKI They are

clearly not the same standard in the law we

have I wondered if you wanted to comment a

little more about that

MR VINK Yes What we say is

that we support fully that the FDA mandates

the highly similar standard to establish

biosimilarity We wouldnt like to compromise

on that because we believe the highly similar

standard is the standard one needs to apply to

approve a product to the market based on the

reference to an originator drug But what we

say is once we meet that highly similar

standard it needs to be collapsed with

interchangeable standard And we believe that

the statute as such doesnt mandate the FDA to

do additional things We say once you reach


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that highly similar standard that is enough

for an innovator who does a manufacturing

change to get interchangeability We

shouldnt apply a different standard for a


PRESIDING OFFICER SHERMAN Diane

PANEL MEMBER MALONEY Okay

Thanks for your comments I had a question on

the naming And you talked about if the names

were different they might result in mis-dosing

or overdosing Can you just say a little bit

more about how you see that coming about

MR VINK Well there are

different situations where if one prescribes

one product and a different product has a

somewhat different INN name gets dispensed

then people say hey that product does not

dispense and it gets dispensed another time

The confusion that could exist once you would

have different INN names for what is basically

the same product in different clinical

settings can lead to mis-dosing


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PANEL MEMBER MALONEY So just to

follow up is the possible concern that the

physician might be unaware about the products

but the earlier product that was used

MR VINK There are in different

clinical settings examples when a product is

prescribed by one generic name with a

different INN suffix or a different INN naming

that another product is substituted for that

that then it gets dosed one more time We

believe that having for the same compound

different INN namings could lead to confusion

in different clinical settings and we can

supply some more information on that in our

submission how that has happened and what

other experience has been there

PRESIDING OFFICER SHERMAN Yes

if you could do that that would be great

And also the comment I made this morning to

another speaker the one article published

thus far by Platt and his colleagues comes to

a slightly different conclusion So if you


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could address that in your written comments

that would be great Thank you for your

comments

Our next speaker is James C

Shehan from Novo Nordisk

MR SHEHAN Good afternoon I am

Jim Shehan I am a Corporate Vice President

at Novo Nordisk and once upon a time an FDA

employee

On behalf of Novo Nordisk thank

you for the hearing Novo Nordisk is a

pioneer and world leader in biotechnology and

diabetes care with about 24 million people

using our products worldwide last year

Almost all of those products are proteins

produced by recombinant means and injected via

our own proprietary delivery devices

We believe that product safety

must be paramount in implementation of this

law and we therefore applaud the draft

guidance science-based and patient protective

approach


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There are four areas however

where we think the guidance could use revision

or clarification and I am going to go through

those

The first is the definition of

protein The second is what products are

eligible for the biosimilar pathway The

third is delivery devices and their treatment

and the fourth is transitional products

The first on protein definition

We believe that your proposed definition of

protein excludes alpha amino acid polymers

that are less than 40 amino acids in length

and we believe that this definition is in

conflict with the statute

The statute defines a biological

product as to include any proteins and in

parentheses except for any chemically

synthesized polypeptide and then another

parentheses The way that is phrased the

parentheses and the use of the word except

show that at least for purposes of this law


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all polypeptides are proteins If they were

not there would be no need to carve out the

chemically synthesized polypeptides We

therefore disagree that you can exclude the

alpha amino acid polypeptides

Second it appears that your

proposed definition would result in

inconsistent treatment of scientifically

similar products Although FDA states that

the scientific literature supports the

proposed 40 amino acid cutoff there is no

literature to support that point In fact

there are no fundamental scientific

differences between polypeptides with 40 amino

acids and those with 41 For this reason key

ICH quality guidance documents which FDA has

adopted apply to products based on their

method of manufacture and scientific features

not on an arbitrary size cutoff

Therefore Novo Nordisk urges FDA

to instead define protein by reference to

primary method of manufacture Specifically


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FDA should interpret protein to mean any

alpha amino acid polymer that is produced by

means of living cells biological source

material and a unique cell bank Not only

would this definition accord with the wording

of the statute and with those ICH guidances

it would create a bright line test for protein

status and therefore provide the

administrative clarity and predictability that

FDA wants

Next eligible biosimilars We

also recommend that FDA revise this guidance

I first address the situation where an

applicant cannot adequately characterize

either the proposed biosimilar or its

reference product For both legal and

scientific reasons a biosimilar application

would be inappropriate in that situation If

the applicant cannot adequately characterize

the structural and functional features of

either product it cannot show the product is

highly similar to the reference product Yet


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this showing is legally required for approval

of a biosimilar It is also a scientific

imperative given the importance of protein

structure to product function

For example as the draft guidance

recognizes some aspects of a proteins three-

dimensional conformation may be absolutely

required for functional activity For these

reasons European regulators have stated that

the success of a biosimilar program will

depend on the ability to characterize the

product We agree and believe that the

guidance should state that full applications

are necessary for inadequately characterized

products

Second the guidance should state

that a biosimilar must have the same amino

acid sequence as the reference product

without exception This is because any

difference in amino acid sequence can have

major safety implications Novo Nordisks

experience in developing a fast-acting insulin


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analog demonstrates this fact We had two

compounds that differed by one amino acid

Both products were equally effective however

one showed significantly elevated tumor

potential while the other one is today

marketed as NovoLog To guard against safety

problems then a biosimilar should have the

same primary structure as the reference

product

The third topic is device delivery

changes Novo Nordisk believes that FDA

should take a more cautious approach to

changes to delivery devices that are found in

the guidance To protect patients then the

guidance should more clearly call for robust

data packages to support delivery device

changes This would include compatibility

testing performance testing and

comprehensive human factor testing

The last point I am going to touch

on is transitional products We offer two

suggestions in this area First the guidance


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documents should state that their scientific

principles that apply to follow-on

transitional products such as follow-on

insulin products have to be identical

Although the transitional products will be

approved under the Food Drug and Cosmetic

Act until 2020 thereafter they will be deemed

approved under the Public Health Service Act

Applying the guidances scientific principles

to all proteins now will ease that transition

It is also appropriate as a scientific

matter

FDCA proteins raise the same

scientific issues as PHSA proteins and CDER

Director Janet Woodcock has previously

recognized that FDA should apply a consistent

scientific approach across these products

Second we ask that FDA confirm

that the sponsor of an innovative transitional

product may file either an NDA or BLA at its

option during the transition period By

innovative transitional product we mean a


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product that requires a full application and

is subject to the BPCIAs transition

provisions We believe that the statute

requires this approach It generally requires

BLAs for proteins but also states that

applications for innovative transitional

products may be submitted under the FDCA

during the transition period

Thank you



panel

PANEL MEMBER KOZLOWSKI So

regarding your comments on product class So

you state that you dont want homologous

proteins to fall into two different product

classes Yet if there is an option to

choose then whatever criteria you use they

could fall into two different classes up

until the point of the final transition So

how would that remedy You know how would

your suggestion remedy that problem


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MR SHEHAN You are talking about

the transitional products

PANEL MEMBER KOZLOWSKI Yes

Your statement that you dont want homologous

products to fall into two different classes

MR SHEHAN But the statute would

seem to require that you can either go the BLA

or the NDA route


But I am saying if the option -shy

MR SHEHAN Scientifically you

would -shy

PANEL MEMBER KOZLOWSKI -- if the

option remains then what the definition is

you could still end up with the choice I

mean again maybe that needs more

clarification

PRESIDING OFFICER SHERMAN Can I

try I think what Steve is asking is on the

one hand you are suggesting we try and create

a consistent system which we try to do On

the other hand you are saying but if a


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sponsor can come in as an NDA or BLA thereby

being regulated under different parts of the

statute that doesnt seem consistent

MR SHEHAN I think you would

have the option whether it is an NDA or a BLA

to apply consistent scientific principles to

how you review and approve those products We

are just pointing out what the statute seems

to say

PANEL MEMBER KOZLOWSKI And

another question So I would ask you if you

had a dipeptide that was made in cells what

would you classify that as

MR SHEHAN Again as a legal

matter what the law says not necessarily

scientifically that is a polymer That is a

protein


So that would be far smaller than many

antibiotics that would be grown

MR SHEHAN It would be far

smaller But again that is what the law


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says

PANEL MEMBER KOZLOWSKI One

interpret


ation of the law

Other

questions from the panel Thank you for your

comments

Our next speaker is F Owen Fields

from Pfizer

DR FIELDS Good afternoon I am

Owen Fields from Pfizer and I am in regulatory

strategy there

By way of outline Pfizer agrees

with the large majority of the content of the

draft guidance documents Our comments are

largely intended today to supplement rather

than to replace elements of the draft

documents We will not generally comment on

elements that we agree with or are not

otherwise controversial

I will progress through this

presentation in the rough order of stepwise

development considerations and biosimilar


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development I will start with the topic that

was just discussed What is the scope

Namely what is a protein I will then talk

about quality assessment considerations I

will then talk about what level of

extrapolation is appropriate I will talk

about the choice of comparator and the

implications of the choice of comparator I

will talk about some study design

considerations and then I will end with naming

the product

All right so first of all what

is in scope And namely what is a protein

versus a peptide FDA has proposed a bright

line approach of 40 to 41 amino acids for

biosynthetic products We appreciate the

value of the simple approach like this as

applied generally However in our written

document comments we made the point that

there are structures less than 41 amino acids

that present regulatory science issues that

are more similar to biologically synthesized


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proteins than they are to chemically

synthesized peptides based on two elements

either their structural or their synthetic

complexity and obviously those two elements

are often interrelated

We provided some examples of

natural peptides that would best be treated as

proteins in our docket submission and we note

that some of these could become substrates for

new drug development The one example I have

shown here is actually approved by FDA as a

food preservative that is only 37 amino acids

but its post-translational modifications and

structure is vastly complicated and it really

has characteristics more similar to a protein

for those reasons

So given that we think that

polypeptides less than 41 amino acids should

be considered on a case by case basis as

determined by their structural and synthetic

complexity And we note that the FDA may

eventually need to adopt something like the


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RFD process the request for designation

process for borderline products because the

characterization or the classification rather

affects exclusivity fairly meaningfully

Second some quality comments We

agree with the majority of the recommendations

in the draft guidance However given the

wide range of fact patterns presented by

various development scenarios we note that

CMC development requires flexibility

Accordingly we believe that the quality

considerations guidance should begin with an

outline of high level principles and recommend

that highly specific requirements are best

addressed on a case by case basis in

discussions between the applicant and FDA

based on each products unique fact pattern

and context

Any highly prescriptive elements

on the final guidance should be presented in

the context of product examples by

illustrating specific situations


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All right turning to

extrapolation we support FDAs overall

criteria and again our comments are intended

to supplement rather than replace We

believe that the concept of totality of

evidence should be added as a foundation of

the section because the degree of similarity

should affect extrapolation requirements

Overall obviously the tone of the FDA

guidances makes this plain but the concept

should probably be added explicitly to this

section

We agree as the guidance noted

that the most sensitive population for

detecting differences should generally be

studied We note that extrapolation between

populations within an indication should

generally be acceptable Pediatrics are one

example of this that was noted in the QampA

There are some exceptions There are cases in

which pediatric pathophysiology is notably

different from that in adults and those should


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be considered as exceptions obviously

Obviously again differences in

background immunosuppression should be

considered

Regarding in contrast

extrapolation between very different and

unrelated indications should be used more

cautiously Decisions in this area should be

based on the criteria FDA outlined in the

draft guidance Again differences background

immunosuppression should be considered

When there are a wide range of

indications approved for the reference

product and there are more and more drugs

that are in this situation we suggest that

two different approaches might be applied

The first is a so-called

orthogonal approach in which you study two

reasonably different indications For

example one might be an indication that has a

high level of immunosuppression and the other

lower level of immunosuppression The other


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approach would be a bracketing approach And

this involves studying indications on what we

call the outer bounds of the indication range

This might be more appropriate when more

conservatism is called for For example

based on mechanistic uncertainty or structural

differences that we are aware of

Regarding the comparator

discussion Pfizer supports the draft guidance

concepts on bridging two non-US-licensed

comparators We note that it is the drug

substance that has activity in the body and

given those differences if any between the

US and foreign drug substances should be the

largest concern There should be concerns

with the effect of the drug product on the

drug substance for example with regard to

aggregation but this will sometimes be

addressable by analytical characterization

However if supported data from a

non-US-licensed product is relied upon then

the bridging exercise between the two products


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will need to be considered pivotal and it must

be rigorous In other words it must pass the

but-for test The EU has recently signaled a

move towards increased flexibility in allowing

bridging data although the specific data

requirements are yet to be defined And it is

hoped that eventually that bridging if it is

successful and if it is rigorous can support

global programs with locally-sourced

comparators

Regarding statistical design

again we support the content of the draft

guidance but there has been a lot of

discussion on the requirement for equivalence

design versus non-inferiority versus

asymmetric equivalence bounds We note that

in practice most biological products fall into

one of two classes Those that have a clear

dose response on both sides of the approved

dose or dose range cytokines are a good

example of this class And for these

products equivalents should be the standard


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clinical trial design The second class are

those that saturate the target and are used at

or near the maximum level of effect Many

anticytokine antibodies are in this class

For these products either asymmetric

equivalence bounds or an extreme version of

that non-inferiority design should be

justifiable because pharmacodynamic activity

above the level the reference product is

considered highly unlikely

We believe this policy as it was

stated in the draft guidance is consistent

with the concept of rational regulation which

calls for focusing your testing on what is

rational

All right finally naming What

to call the product We believe that

differential labeling and unique names are

both well-established mechanisms for

distinguishing products and distinguishing

different levels of evidence We think both

of those are material here We believe that


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each subsequent entry product should have its

own unique trade name This could either be a

traditional trade name it could for example

be the use and name followed by the

manufacturers name This might be used by

companies that dont want the burden of

registering a new trade name globally and I

can assure you that is a very difficult thing

these days

We think that prominent labeling

statements and labels regarding

interchangeability or biosimilarity status for

each indication are appropriate

In closing we are a major

innovator of biological products We know

that these are complicated drugs for

complicated patients We never thought that

entering this product class should or would be

easy In fact we have always thought it

would be hard but we always felt it should be

hard in a scientifically valid way and

consistent with the principles of rational


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regulation And in our view the draft FDA

guidance documents generally strike the right

balance and we welcome the issuance of the

final document



panel

PANEL MEMBER KOZLOWSKI So your

comments on protein definition So you point

out a bright line is useful but that it is

very very difficult for any bright line to

coincide with an exact scientific gap

DR FIELDS Thats right

PANEL MEMBER KOZLOWSKI So I

would ask you this So there are two issues

There is the scientific continuum which

proteins larger than 40 or 100 amino acids

there may be relatively simple nonshy

glycosylated ones and there may be very large

more complex ones And the science is a

continuum even within that regulatory

framework


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DR FIELDS Right

PANEL MEMBER KOZLOWSKI So as a

prior speaker pointed out you know we can

apply the scientific principle in these

guidances to products even if they arent

under this particular regulatory framework

So is that a good enough response that

basically the science will be great as a

continuum and we will use the scientific

principles in a clear way We have regulated

proteins as NDAs And we have approved the

biosimilar-like protein under NDA with many of

these same principles So the science can be

a continuum

But for the regulatory framework

things like exclusivity we may think a bright

line is necessary and still maintain the

proper scientific rigor at any given molecule

So what I would ask you is does that address

your question

DR FIELDS I dont think

changing the -- or the bright line approach


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actually changes the level of scientific

rigor We have to think back to the

fundamental regulatory construct in the US

and I am not an attorney but there are two

constructs There was one that was largely

designed for small molecules There is

another that was designed for biosynthetic

molecules The one designed for biosynthetic

molecules for a number of reasons part of it

having to do with the massive investment that

is needed in manufacturing and

characterization for products that have to

made in biological systems provided a

different level of exclusivity And that was

for a specific reason

So our point is we are aware that

companies could game this because of the

differential exclusivity We are happy with

the bright line approach that is applied most

of the time but we want to point out there are

exceptions and there are smaller molecules

that have every bit as much manufacturing and


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structural complexity as larger molecules So

biologically there is not a bright line

So we are aware that you want to

avoid gaming We are also aware as you noted

in the guidance that companies could

literally extend the length of the product to

fall on one side of the bight line and that

could have a negative public health

implication

So we think a more flexible -- you

know a general bright line as a starting

point but if a company can make a case that

they are not gaming the system and that the

product has to be made in biological system

then we think that should be treated as

appropriate

Does that make sense

PRESIDING OFFICER SHERMAN Does

anyone else have questions

Let me ask you this Take the

flip side What would be the downside If a

bright line provides clarity whatever bright


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line you want 40 45 50 55 and provides

clarity and avoids -shy

DR FIELDS It may stimulate

gaming actually

PRESIDING OFFICER SHERMAN Well

no avoids unnecessary temptation to -shy

DR FIELDS Yes thats true

PRESIDING OFFICER SHERMAN -shy

accuse the Agency of being arbitrary

capricious What is the downside to

bright line if we all agree that searching

and

the

this carefully searching the scientific

literature there is not one right answer

DR FIELDS The main downside is

the one I have already noted that is the

products from a regulatory science and

development perspective have more in common

with biological products Congress has

maintained and extended the system for

biological products and they did so because of

the additional manufacturing complexity

PANEL MEMBER KOZLOWSKI But


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again no system is perfect That is why you

look for a bright line

So I would have this suggestion

Is that if you have a set of clear criteria

that would not end up leading to a battle over

what they mean each time for how one could

define what is appropriate in these cases of

something near the line we are very happy to

look at that I think the idea of we think

this looks more like a protein because it

does would create a lot of uncertainty So

if there are if there is a very clear

algorithm that could be proposed we would be

very happy to look at it

DR FIELDS Okay we previously

provided some suggestions in front of the

December 2010 and we can recycle those and

provide those to the docket again

PRESIDING OFFICER SHERMAN That

would be great and we would invite everyone on

the panel to do the same Thank you for your

comments


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DR FIELDS Thank you


next speaker is Mark McCamish from Sandoz a

Novartis company

DR McCAMISH Its my pleasure to

be here today representing the Novartis group

of companies and to provide my seven minutes

and 59 seconds of comments on the guidances

PRESIDING OFFICER SHERMAN Oh

no You get the full eight minutes

DR McCAMISH Okay good On

that in general we are very supportive of

the guidances that you all have put forth We

do believe it provides a scientific basis It

provides for a stepwise case by case approach

It provides for the potential of

extrapolation potential for

interchangeability potential for using a non-

US reference product We have provided

extensive comments to the docket So today I

have a few comments and then I will try to

address some of the issues that came up during


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the meeting itself

Overall we feel that patient

access to biologics is increasingly limited by

high costs and increasing demand that high

quality clinically-proven biosimilars can

fulfill this unmet need and I have got some

data on that And to fully realize the impact

of biosimilars we need a science-based

standard for comparing all biologics And FDA

has the experience it may not have the

resources but has the experience to approve

safe and effective biosimilars and I will talk

a little bit about that resource issue

In general we have a lot of

experience with biologics at Novartis and we

do both novel as well as biosimilar biologics

And with that we have 50 million patient

days experience in 50 countries with

biosimilars So a fair amount of experience

in the area And with that we file both pre-

IND meetings and filings with novels as well

as with biosimilars


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Just a point of note on this in

terms of having scientific and regulatory

consistency applied by the FDA fairly and

irrespective of the sponsor when we file for

a pre-IND meeting for novel biologic we get

it in 60 days When we file for a pre-IND

meeting for biosimilar six months The last

one just last week seven months from the

request to the meeting There is five months

difference a five months delay for us in

just the first meeting So I would urge you

to really assign resources necessary that will

not inhibit the review of these programs

because they are critical to address the

patient access This slide documents the

patient access we are already able to do

outside of the US wherein we have about 35

percent more patients receiving appropriate

primary prophylaxis with G-CSF by introducing

a lower cost biosimilar

In addition there are things that

we have learned in Europe and EMA has learned


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in Europe And on this you have asked what

additional guidances you should create I

think what EMA has learned is that this

information and misunderstanding are key

problems for biosimilars It has

unsubstantiated fears that have been talked

about safety issues et cetera and that has

led to some of the misunderstandings So

having a consistent approach as you have

outlined in general in the biosimilar

guidances the draft guidances would be very

helpful

On the product-specific technical

guidelines they do exist in the EMA and I

would suggest that you not spend a lot of time

in reworking these We suggest that you focus

on areas where you can really add value and

that is an interchangeability area So

guidance and interchangeability is key And

also on potentially working with EMA on

establishing a legitimate scientific approach

to using a non-US or non-EU reference


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product would be very helpful from a guidance

perspective

I think this slide illustrates

some of the things that EMA is doing

consistently to try to really share with the

outside world about this biosimilar concept

including biosimilars being intended to use

the same doses same dosing regimens as the

reference product The focus is on

demonstration of biosimilarity not patient

benefit per se extensive comparability

exercises to ensure the similar quality

safety and efficacy and scientific principles

underlying the comparability exercise required

for changes in the manufacturing process of a

given biological product and the development

of a biosimilar are the same Their words

not mine And that similar physicochemical

characteristics are prerequisite for reduction

for non-clinical and clinical data

requirements That is really a key and has

been a challenge for us when we do all of the


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work in terms of all the analytical

characterization to be able to negotiate a

reduced clinical trial is really key based on

the similarity that we have established

This slide just simply shares that

there are savings and even additional savings

Hausler et al recently published a

projected savings of up to 33 billion dollars

in the use of biosimilars in eight European

countries in the future Similarly from the

US perspective 25 billion dollars of

savings were projected over four years ago by

the CBO so an older estimate

These savings will actually

encourage innovation and also free up

healthcare dollars to purchase the new

innovative products And so this is something

that we have learned in Europe with our

experience Now one science-based standard

for comparing all biologics is what we

recommend highly similar as you have

outlined that the standards must be


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consistent Data will always be case by case

Highly similar quality attributes is really

the established standard for both

manufacturing changes and highly similar is

the biosimilar statutory standard The data

bridge is always back to the original clinical

studies in which the original product was

approved And biosimilar clinical studies are

really only confirmatory that you do a lot of

work in terms of showing the analytical and

biologic comparability of the biosimilar to a

reference product and the clinical studies

then become confirmatory to that

To this I will jump over to three

issues that have come up today That is

naming extrapolation and interchangeability

Comparability is really the extrapolation

interchangeability standard applied by FDA to

currently approve biologics when a

manufacturing change is undertaken

So on naming we have always

suggested or supported the use of the same


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INN But let me straighten out what may have

been a confusion to you and others When we

have stated that we have not suggested that

we would brand our products with the INN

What we suggest is a novel proprietary name

and this is what we do in Europe Then the

INN then the additional information such as

in DC et cetera So we have never marketed

a product under the INN And if you want to

suggest something or have a rule it should be

that a biosimilar should have a unique

proprietary name not a modified INN That is

where the confusion comes in If you have the

unique proprietary name the same INN in DC

then it is tracked dealt with marketed

followed the same way as all biologics

From an extrapolation perspective

extrapolation between indications always

occurs when a manufacturing change has been

approved using comparability mechanisms of

action does not come into the issue with that

Here we think extrapolation should also


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follow the science in terms of all the work

that you have done from a comparability

perspective should also apply

Interchangeability is inevitable

when a manufacturing change has been approved

using comparability And interchangeability

is critical for us It matters for biosimilar

access to be facilitated And that can follow

along with the same science-based approach

And let me show you if I can in

the backup slide a data slide on this And if

you look at the graph on the left-hand side of

this it plots a fucosylation versus ADCC

And in this situation all we are showing is

that there is a structure-function

relationship to this The red circle

illustrates the variability of the originator

product and that becomes our goalpost We are

shooting for that for our degree of

fucosylation and ADCC If you vary outside of

that whether you are the originator or the

biosimilar that would not be deemed as highly


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similar It is a small goalpost to meet If

you do vary outside of it that is

justification for a different name It is

justification for not having extrapolation

justification for not having

interchangeability They all fall together

So this just gives you a database around how

this can be applied to these areas

Lastly from a drift perspective

this keeps coming in that we are going to be

drifting This is a critical quality

attribute It is followed It is measured

It is a release spec This is not going to

drift outside of that particular area And if

it does the Agency will know about it And

the biosimilar company if it drifts out

should also know about it and there will not

be problems in dealing with that

Finally you asked about label I

think the label should say that it is a

biosimilar It should talk about the

reference product that is a biosimilar to It


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should include the indications for the

reference product and the data around that

reference product

If you want to include information

about the data done to show biosimilarity

what we would suggest is that the reference

product also show data around manufacturing

changes What did they do to justify the

comparability of those manufacturing changes

for a label That is really transparency and

that is one issue that we run into

With that I will be happy to take

any questions Thank you



panel

PANEL MEMBER KOZLOWSKI Your

comment about having a unique proprietary name

being sufficient for surveillance so as you

have had these products out in Europe for a

while do you have any data about how often

adverse event reports are categorized by brand


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name Is there uncertainty in certain

databases because brand names are not part of

what is entered

DR McCAMISH Yes And I

mentioned brand name I didnt mean to say

that that is sufficient I said brand name

along with the other information so INN as

well as NDC things of that nature But from

our perspective we use the same

pharmacovigilance programs tools database

following for all biosimilars through Novartis

and Sandoz and we get these ADRs reported on a

routine basis and follow up on them We have

not been aware of a problem and there has been

switching throughout that we are aware of and

when a safety event comes up you also have to

look at which product they were on at the

point in time that it is there But we

havent had a problem in terms of a mix-up of

our product with other products on the market

utilizing those characteristics



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questions

PANEL MEMBER ESPOSITO Could you

speak a little bit more about your vision of

establishing biosimilarity throughout the life

cycle of the product and whether you

anticipate that being on an annual basis or on

an ongoing basis and what test you would

envision being involved there

DR McCAMISH So give me an idea

in terms of your question Are you concerned

that over the lifetime of the biosimilar that

the goalpost or these things will change over

time Or when you say a new biosimilar comes

in do you have to redefine it Which

question are you dealing with

PANEL MEMBER ESPOSITO Thats a

good question I was focusing on your slide

on highly similar being for the lifetime of

the product and how you disagree with the

statement in the guidance that require

maintenance of biosimilarity over time would

inhibit manufacturing quality improvements


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DR McCAMISH Right

PANEL MEMBER ESPOSITO So I was

wondering exactly what you were envisioning in

terms of establishing the highly similar

standard after approval even though it was

already established in approval dealing with

direct improvements in those issues

DR McCAMISH Yes so the highly

similar standard refers back to the originator

product and you have described the information

variability around the originator product and

that gives you a quality a characteristic

that you can define And the originator will

then have to justify any additional

manufacturing changes and the biosimilar

company will have to justify any additional

manufacturing changes to that And so it is

going back to that original configuration the

critical quality attributes that were defined

And so a biosimilar or the

manufacturer is not going to create a product

that has clinically relevant differences that


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are there otherwise it will not be approved

with the same label with the same indications

And that knowledge base coming back to that

original critical quality attributes that were

defined within the original manufacturing and

the changes to that original manufacturing are

what define that design space

PANEL MEMBER MARCHAND Just one

question On your slide five you describe

that there is misinformation was identified as

a leading problem for biosimilars How do you

think this experience in Europe then would

translate for us to be prepared to be

responsive in advance of misinformation What

would you suggest

DR McCAMISH I think it is

really key It becomes we all have to have an

educational process going forward And there

is misunderstanding not only about biosimilars

but about biologics by clinicians that are

there And so what I gave you is an example

of Martina Weiss who is out speaking


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continually at programs to educate So it is

an educational program regarding what is the

biosimilar concept What is expected by a

biosimilar sponsor How close is it to the

originator What are the concepts around it

So that is what I am saying is that they have

done that and it has helped them in terms of

being able to drag this biosimilar

understanding further into the clinicians

use



Our next speaker is Karl Heinz

Emmert from Teva

DR EMMERT Good afternoon I am

Karl Heinz Emmert I am head of biosimilar

development of Teva Teva has been working on

the development of follow-on biologics and

biosimilars in Europe for more than a decade

We have clinical experience in development of

biosimilars for about ten years and we have

two products on the markets already for four


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years I just wanted to state here that so

far we have not experienced adverse events or

immunogenic findings going beyond what is

observed for the referenced products

Teva welcomes FDA publishing the

draft guidances as a key milestone

facilitating development of biosimilars in the

US The draft guidance has acknowledged that

the approach is for the development of new

biosimilars and biologics are significantly

different But for a new biologic the

characteristics have to be explored and

clinical efficacy and safety have to be

proven The development of biosimilar is

focused to demonstrate similarity to the

reference product

You discussed with Mark about the

misunderstanding of the biosimilar concept I

think this is an essential example for the

misunderstanding We are not trying to prove

the efficacy and safety of our product as

such We are trying to demonstrate that our


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products behave the same way as the reference

product does And therefore the development

of a biosimilar is not an abridged one It is

rather a tailored one where we tried to

address those questions which are necessary

to establish the similarity

I also want to highlight the

development of a biosimilar is based on sound

scientific principles and that the same

quality requirements of life for the

development of a biosimilar as for the

development of a new biologic molecule does

relate to the technologies This relates to

the method of analytics This relates to

clinical studies

Applying these principles the

high quality of the biosimilar products is

assured We assure a high degree of

similarity in terms of physical chemical

properties and functional activities And at

the end we demonstrate that there will be no

clinical meaningful differences to the


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reference product both in efficacy and safety

These principles are reflected to

our understanding in the guidances in the

draft guidances presented by the FDA and by

accepting that some clinical studies be

conducted in comparison to non-US sourced

reference product FDA encourages the global

development of biosimilars

Teva supports the position of the

European Generic Associations as it will be

presented later today here Teva wants only

to highlight some points which Teva believes

warrants greater discussion

One thing is the extrapolation

across indications Extrapolation across

indications is dependent more on the degree of

similarity than on the mechanism of action

There is no scientific rationale to assume

that the post receptor intercellular

biological effects introduced by a biosimilar

are different by those introduced by the

reference product in different indications


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So if high similarity is

demonstrated it is demonstrated If it is

demonstrated that the product is distributed

comparably in the body and that it is binding

to the same receptors and exerting the same

effects at the receptor levels there is no

question about extrapolation of indication

Therefore Teva encourages FDA to base the

justification of the extrapolation of

indication on the degree of similarity and the

totality of evidence rather than on a

detailed analysis of the mechanism of action

which may not even be known for the reference

product

Teva does not agree with the

consideration of a biosimilar product as a new

active ingredient for the purpose of PREA

Assuming that a reference product has been

tested in pediatric population If

biosimilarity is established it should be

extrapolated to the pediatric population

since again the biologic ethics are


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dependent on degree of similarity Therefore

it is unnecessary to repeat clinical studies

in reasonable pediatric population

Immunogenicity is a relevant

matter for all biologics However the

intrinsic immunogenicity of the compound is

less of a concern for a biosimilar as has

already been established for the reference

product

Immunogenicity due to impurities

aggregates and excipients has been reported

for biologics also for new biological

molecules And they are dependent on the

details of the specific manufacturing

processes the formulations that contain a

close assistance

These specific risks based on

these factors are different from product to

product Therefore Teva encourages FDA to

adopt a case by case risk-based approach for

the assessment of immunogenicity of each

biosimilar product rather than defining a


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large immunogenicity study as being necessary

There are some burning issues with

regards to the guideline For instance in

the draft quality consideration guidance in

line 142 it states to meet the higher standard

of interchangeability the term higher

standard should be avoided as it implies that

a noninterchangeable biosimilar is of lower

quality which is and must not be the case

So we encourage FDA to rephrase the sentence

and to make sure that in the guidance no such

implication of full quality of biosimilars is

provided

Regarding naming conventions Teva

encourages FDA to apply the USAN respectively

the INN of the reference product across all

biosimilar products if they meet the criteria

of high biosimilarity

The use of common name is a long-

standing acceptable principle in the

prescribing community in the US It

eliminates unnecessary confusion and probably


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reflects the nature and the medical utility of

this product

On the other hand Teva definitely

acknowledges the importance of traceability in

the area of adverse events and in case of

quality issues However these events require

that we go back to the batch and identify what

is happening Therefore Teva encourages FDA

to accept a traceabilities through assignment

of a unique NDC code and the latter

identifiers for every tracked product in every

batch rather than some different USANs

Finally for the purpose of global

surveillance and pharmacovigilance global

common names are essential to maintain

continuity of information cross jurisdiction

In summary Teva appreciates the

thoughtful approach FDA has taken in issuing

these guidances The draft guidances

accommodate the unique approach incumbent in

the development of biosimilars in general

Teva trusts that the same scientific spirit


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will apply while the guidance are completed

and as the Agency is called to provide

product-specific guidances going forward

Thanks



panel


for your comments My question is about your

discussion of the immunogenicity assessment

And you are advocating if I am understanding

it right a case by case basis but I wasnt

clear whether your position was that in some

cases no clinical immunogenicity would be

required

DR EMMERT We think that

depending on the risk and depending on the

product as such and depending on the risk

associated with immunogenicity of the molecule

as such there may be no need for specific

studies and all the immunogenicity can be

assessed in the ongoing clinical works lets


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say in the clinical efficacy or safety study

or in the PKPD study

PANEL MEMBER ESPOSITO I see So

you were suggesting that it could be done in

parallel of another study not that there

would be no human clinical study

DR EMMERT Yes


your comments I am referring to your slide

five in which you are suggesting that

biosimilarity can be extrapolated to a

pediatric population and would be unnecessary

to require clinical studies Can you talk in

terms of any data that you have that might

suggest or support that

DR EMMERT Actually we have not

been conducting clinical studies in pediatric

populations so far Again if receptor

binding is the same if distribution is the

same it is hard to imagine that there will be

differences

Where we will gain information is


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strong is from some lets say follow-on

molecules which are not biosimilars where we

have to conduct pediatric populations studies

in pediatric populations there we will gain

experience but so far we dont have the data


your discussion of mechanism of action and its

role in extrapolation you mentioned that you

know the molecule binds the same receptor So

to some extent you were already hinting at

some mechanistic knowledge in saying you dont

need it So I was kind of wondering what you

think is appropriate to know to extrapolate

indications

DR EMMERT Definitely receptor

binding Definitely distribution which means

pharmacokinetics and comparable

physicochemical properties and functional

activities I think those three parameters

state it fine whether or not a product is

highly similar and is a biosimilar and the

additional work like if clinical efficacy and


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safety studies they are just potentially

confirming what is established already


one question What would you do for those

pharmacovigilance What would you do for

those products not billed by NDC codes but

rather billed by CPT code How would you -shy

DR EMMERT Pardon

PRESIDING OFFICER SHERMAN How

would you track and trace those

DR EMMERT Pardon I havent

got it

PRESIDING OFFICER SHERMAN You

said you were relying on the NDC codes but

some of these products are not billed by NDC

codes rather they are billed by CPT codes

They are more like diagnosis codes at least

in this country How might you suggest we

approach that

DR EMMERT I think that it is in

all countries usually the systems rely on the

name of the products which is a brand name


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And again for a biosimilar or even for every

biologic this is not enough because in most

cases adverse events are related to

manufacturing issues and you have to go to

batch and identify what has happened to that

batch

PRESIDING OFFICER SHERMAN Are

there any question from the panel for anyone

any of the speakers

I have one question for Mr Vink

just as a point of clarification You

referred to the biogenerics pathway

throughout Is that just out of habit or were

you sending us a message if I might ask

MR VINK I was sending message

yes No I think we believe as I always

said in the perspective that in order to

create a pathway that does what it is

intended to do which is creating a market

that is based on substitution of equally

effective and safe drugs we say what we have

learned after Hatch-Waxman which pertained to


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a generics pathway we should take those

lessons forward to this pathway And that is

why we refer to biogenerics as interchangeable

drugs

PRESIDING OFFICER SHERMAN And do

you have any thoughts about why the US

Congress chose a different name I know it is

difficult to speculate on what the Congress is

thinking

MR VINK Exactly I wont do

that

PRESIDING OFFICER SHERMAN Fair

enough We will take a 15-minute break now

and please be back at five after Thank you


record at 248 pm and resumed at

304 pm)


first speaker for this session is Ronald A

Rader from BIO

MR RADER Okay we have got it

now Yes my name is Ron Rader I am


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president of the Biotechnology Information

Institute

PRESIDING OFFICER SHERMAN Im

sorry Can I -- Yes not the usual use of the

word Bio Sorry

MR RADER Yes I am President

of the Biotechnology Information Institute

which I am unique in terms of presenters today

that I only represent myself Mine is a one-

person company

My background is I am an author

and publisher particularly in the

biopharmaceutical area My main product

service is biopharma currently It used to be

a book Now it is an online database at

biopharmacom It is the only reference or

information resource of any type specializing

in biopharmaceutical products And obviously

it is at biopharmacom It is now in its 11th

year

I also have an embryonic database

excuse me an embryonic website at


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biosimilarscom and that I envision as being

an information portal and such primarily

serving the biopharmaceutical industry In

other industry-grade high quality information

technical information

I am also author of an upcoming

biosimilars pipeline study hopefully coming

out within the next month and I expect that to

be the most comprehensive pipeline study to

date There is further information about that

at biosimilarscom And I also am proposing

Ill obviously get to this later what I am

calling the US Biopharmacopeia Registry of

Biopharmaceutical Products And this is a

proposed project to propose a nomenclature and

develop a public reference for names and

nomenclature

Now this slide just shows a

breakdown of the product entries in my

upcoming biosimilars pipeline study As you

can see already it is rather early on

tracking over 425 biosimilar products in


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development and along with that over 360

what you know misnomer really called

biobetters And this is only covering the

recombinant proteins It ignores all vaccines

and conventional blood products

So total now when we are talking

about nomenclature we cant just talk about

biosimilars alone You definitely also have

to consider the biobetter products because in

many cases they are going to contain exactly

the same or very subtle variations in the

activations

Now here again from the upcoming

study just showing biosimilars not also the

biobetters in development you can see from

many of the top selling products those listed

first there are many products in development

But with many of those molecule antibodies

those are coming later in terms of being

approvable So it is really early to look at

those

But if you look at some of the


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products such as epoetin and filgrastim

Neupoegen and EpogenProcrit products you

already have already over 40 50 whatever

products known to be in the pipeline

Now this just shows my own crude

estimates of the launchability of the

biosimilars and biobetters that will cover as

being in the pipeline As you can see there

are a large number that will be hitting FDA

likely within the next few years And then

another wave including monoclonal antibodies

later in the decade

Okay so as we can see biosimilars

and also biogenerics and biobetters are

coming This raises a number of issues that

must be resolved concerning how to define the

most aspects in nomenclature that is the

naming of these and other biopharmaceutical

products What are we giving names to That

is a very good question that FDA will need to

resolve Are we giving names to products

active agents or what What is a distinct


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biosimilar product Again a related question

What names or identifiers are needed for

biosimilar active agents and products for

different uses and different user communities

What differences or changes in active agents

and finished products require or considering

these to be new or different products or

versions of products perhaps requiring new

names or identifiers

For example the FDA assigned

nonproprietary names established names

assigned by FDA are used for marketing and

prescription purposes in the US Well these

are the first names the first whatever

regarding biosimilar products that consumers

and also even physicians and professionals

healthcare professionals will encounter So

the names will very much control the

preconceptions and conceptions perceptions of

these products

Now FDA will surely require unique

names for biosimilars Whether these are used


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or not as the official names is a good

question But should these names be fully or

partially unique and should they be indicative

of biosimilarity or not If they are

indicative of biosimilarity how is this done

What type of relationships in other words

whether structure or product class

indications relationship or not to reference

products what type of relationships might or

should be implied in biosimilar names

Should these names be based on

science In other words the product and

active agent in other words be entity-based

Should they be based on approvals you know

BLAs if a product gets a new BLA does it get

a new name Or do you go by more fluid and

probably not worthwhile market or real world

considerations about how these products are

defined or viewed

Now will the same nomenclature

system also apply to innovator and reference

products Who will develop and control agent


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and product definitions nomenclature and

information dissemination Now these are

difficult issues with broad ramifications

Now regarding what needs to be

named obviously unique names are required but

again you know are you going to use assign

the same or other names for the active agents

or the finished products

Okay now currently FDA

established names for biopharmaceuticals I

would characterize it as total chaos where you

are basically relying on the status quo for a

long time has been reliance on INN USANs To

me they are totally useless for

biopharmaceuticals They are totally useless

There is no consistency They were never

designed for biopharmaceuticals

Now in this context I am

proposing what I am calling the US

Biopharamcopeia Registry of Biopharmaceutical

Products This would ideally be funded by

industry andor FDA perhaps a public-private


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collaboration Now this would be an informal

group that proposes both unique and biosimilar

or generic names for both active agents and

products That is four different kinds of

names for selective adoption or not by FDA

other regulators worldwide publishers

formularies public use and such

Now as a model for this I would

site the CTFA the cosmetic industries what

they call a dictionary where since 1970s the

cosmetic industry committee has been proposing

the names have almost always been accepted by

FDA for purposes of cosmetic product labeling

And also as part of this

biopharmacopeia or registry I am proposing a

public online product registry that would

provide authoritative names and associated

description needed descriptive information

about marketed products

Now for further information I

would just like to cite I have authored an

article entitled Nomenclature of Biosimilars


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Will Be Highly Controversial This was

published in BioProcess International earlier

this year and that and much other information

is online at biosimilarscom and also

biopharmacopeiacom Thank you


you for your remarks Any questions from the

panel No Thank you


next speakers are Jean Novak and Michael

Strauss from CBR International Corporation

DR STRAUSS Okay thank you I

wanted to thank you on behalf of myself and my

coauthors for the opportunity to speak today

CBR International Corporation is a

biopharmaceutical development consulting firm

located in Boulder Colorado founded by Dr

Jeanne Novak For over ten years we have

assisted our clients on scientific and

regulatory issues related to product

development with an emphasis on biologic

products Due to the breadth of the companies


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in our clients programs we are experienced

in scientific quality and clinical issues

surrounding development of biologic products

relevant to todays discussion on the

biosimilar product guidances

During this presentation I will

be highlighting some important points that we

thought were key inclusions within the

guidances suggesting some other areas of

clarification within the three documents And

then if time allows suggesting further

guidance documents that will be helpful to

support development of biosimilar products

Our first comment is on the

contents of the scientific considerations

guidance CBR applauds the Agencys

recognition that for certain products a robust

PK andor PKPD endpoint may provide adequate

data to demonstrate biosimilarity as defined

in the act We would encourage the Agency to

provide more clarity on the types of products

or circumstances where this type of


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development approach might be considered

As described in this QampA guidance

page seven CBR finds the potential use of

non-US-licensed product extremely important

in light of the global development of

biosimilars We appreciate the Agencys

initiatives to work with its European

counterparts to develop a unified approach to

this issue CBR and industry look forward to

additional guidance from the Agency regarding

what is adequate bridging data

During the next portion of my

presentation I will be discussing

clarifications or additional detail we

recommend in the final versions of the three

guidance documents On page seven of the

scientific considerations guidance the

stepwise approach is mentioned Is the

stepwise approach to clinical development

required or recommended Will conducting

clinical trials in parallel rather than

stepwise jeopardize development if the sponsor


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is willing to assume the development risk and

FDAs informed For example would FDA permit

studies to be conducted under an IND in

parallel ie concurrently that were

intended to demonstrate comparability of PK

and efficacy in separate populations

On the subject of clinical

development the scientific considerations

guidance provides direction on the clinical

studies required to demonstrate biosimilarity

but does not specify any requirements for such

studies to be conducted in the US

Specifically please provide guidance on

whether a certain number of US subjects or

US trials are needed Additionally please

clarify certain types of trials that we

require to be conducted in the US

Within the scientific

considerations guidance emphasis is placed on

clinical relevance as well as sensitivity of

study endpoints Please clarify whether most

sensitive or clinically relevant study


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endpoints are valued more for the

demonstration of biosimilarity as seen on

page 17 and 21 For example when is it

appropriate to choose a clinically-relevant

dose versus a lesser dose in the steepest

portion of the dose response curve

CBR recommends that in the next

version of the guidance to provide

clarification regarding the use of non-

approved indications for clinical studies

Specifically can a non-approved indication

for the reference product be the basis of

comparative clinical studies if the study

endpoints are more sensitive for comparison

for example PD or efficacy

On the subject of immunogenicity

CBR has the following suggestions Please

provide additional guidance on the preapproval

of immunogenicity database size when a low

incidence of immunogenicity has been

demonstrated in the reference product Can

post-marketing commitments to assess


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immunogenicity reduce requirements for IND

studies or the size of preapproval database to

support licensure CBR recommends clarifying

the guidance of the pre- and post-approval

immunogenicity database sizes under a number

of common scenarios for example high and low

incidence of seropositives

In the Act reference and

biosimilar product are required to have the

same mechanism of action In the final

guidance please clarify FDAs expectations

for demonstrating mechanism of action of a

biosimilar especially when it is poorly

understood in the reference product For

example it would be helpful to clarify how

extrapolation of clinical indications is

assessed if the mechanism of action for the

reference product in certain indications is

unknown or incompletely understood

I will now shift focus to the

quality considerations guidance We will

request that FDA clarify the requirements for


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validated versus qualified assays at each

major development milestone For example

early phase pivotal or BLA for each category

of testing as you see here on the slide

FDA has stressed the use of

orthogonal methods in numerous instances

within this guidance See pages 11 and eight

of the quality considerations guidance and one

of the passages I have highlighted here CBR

recommends broadening the language regarding

the comparative analytical exercise methods to

account for adequate scientific rigor without

implying orthogonal methods are required in

all cases

One page nine the guidance refers

to N or C terminal truncations that will not

have an effect on safety or purity Please

clarify this text to include N or C terminal

changes such as amino acid modifications or

additions as the FDA sees appropriate

Most of our comments on the QampA

guidance were addressed previously but we have


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one additional suggestion for this guidance

One area we suggest clarification is if the

QampA suggests that you should wait to meet with

FDA until you have preliminary analytical

comparison data Furthermore the guidance

states that such data could influence the

type and amount of animal and clinical data

needed Could the next version of the

guidance clarify how a sponsor can get

feedback on the design methods and number of

lots of reference product in the analytical

exercise before it is initiated and before

filing of the IND We feel such early

feedback would be useful to ensure that the

analytical package will be adequate for

discussion with FDA at a pre-IND meeting

We have provided some suggestions

and further useful guidance documents similar

to those seen in Europe including clinical

and preclinical guidances product class

guidances and individual product guidances

when a suitable amount experience is


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accumulated on a product Furthermore we

would suggest a guidance on interchangeability

which may already be planned and one on the

regulatory process for development of

biosimilars The latter could specify

development milestones and recommended

meetings with the FDA

Thank you so much for your time

and attention and the opportunity to provide

the feedback



panel None You are aware that everyone is

wearing us out I guess

I have one On slide ten I

didnt quite understand what you were asking

us when you said can non-approved indication

You meant for a US-licensed reference

product

DR STRAUSS Yes So for

instance something may have been approved on

an indication that is not approved in the US


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but is approved elsewhere and there is data to

show that that is a very sensitive endpoint

Would that be an alternative that could be

considered


you for the clarification

Okay our next speaker is Bruce

Babbitt from PAREXEL International LLC

DR BABBITT On behalf of PAREXEL

International a global biopharmaceutical

services organization currently extensively

involved in biosimilar development I would

like to thank the FDA for the opportunity to

present our thoughts regarding the draft

biosimilar guidances My name is Bruce

Babbitt and the ideas that I am presenting

today have been developed in collaboration

with my colleague Cecil Nick

For todays meeting I will focus

my comments on the assessment of clinical

immunogenicity We recognize the importance

of rigorously evaluating the relative


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immunogenicity of a proposed biosimilar

product head-to-head against the reference

product and to do so in an adequately

sensitive patient population

From our perspective the

following is some of the more important points

related to clinical immunogenicity assessments

included in the scientific considerations

guidance The overall goal is to establish

that there is no clinically meaningful

differences in immune response between a

proposed protein product and the reference

product Generally at least one head-to-head

clinical immunogenicity assessment will be

required A one-sided design demonstrating

that the immunogenicity of a proposed product

is not increased relative to the reference

product will ordinarily be adequate This

implies the need to establish a non-

inferiority margin

Immunogenicity should be assessed

in a sensitive patient population in using the


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treatment regimen most likely to result in the

generation of antidrug antibodies with a

negative effect on safety or efficacy And a

risk-based approach will dictate the amount

and timing of the clinical immunogenicity

required For example if antibodies for the

reference product are rare or are of no

clinical consequence than a premarket study

power to detect major differences followed by

a larger post-market study designed to detect

more subtle differences might suffice

Related to these points I would

like to make the following comments

Regarding the circumstances under which a

stand-alone comparative clinical

immunogenicity assessment might be required as

part of a given biosimilar development

program we envision that only a minority of

biosimilar products fall under this category

and in most cases that immunogenicity data

can be generated from therapeutic equivalence

trials Exceptions include cases in which


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comparative efficacy can be established based

solely on short-term PD studies or the

selected clinical efficacy population does not

take into account factors known to impact

immunogenicity for example subcu

administration exposure to immunosuppressive

agents and underlying pathology This is most

important for biosimilars that mimic critical

endogenous proteins or for which antibodies

are known to have a negative effect on safety

Regarding determination of a non-

inferiority margin for comparative clinical

immunogenicity assessments the draft

guidelines state that it is generally only

important to demonstrate that the

immunogenicity of the proposed product is not

increased So a one-sided design would

ordinarily be adequate to compare clinical

immunogenicity of a proposed product and

reference product This implies that

generally a non-inferiority margin needs to be

set although we are not sure that this is the


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intention We assume that a two-sided

equivalence design for assessment of clinical

immunogenicity would not be required under any

or most circumstances

We consider that if there were to

be a general requirement to set a non-

inferiority margin for immunogenicity

assessments that this could be highly

problematic given that current antidrug

antibody assays are typically more sensitive

than those previously used for assessment of

the reference product immunogenicity

Therefore historical data could be of very

limited value in serving as a relevant point

of reference for setting a formal margin non-

inferiority margin

This situation is exacerbated by

the fact that the clinical relevance of

antidrug antibodies detected using state of

the art assays would not be fully understood

prior to completion of a trial which makes

prospective clinical justification of any non-


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inferiority margin unfeasible

As a result of these

considerations large clinical immunogenicity

studies could be deemed necessary although

FDA has pointed out that they would take a

risk-based approach when determining the

relative amounts of required pre- versus post-

marketing comparative immunogenicity data

Overall it is our position that

for the majority of biosimilar development

programs immunogenicity assessments can be

monitored as a secondary endpoint as part of

pivotal phase 3 therapeutic equivalence

trials without the need for a formal non-

inferiority limit to be set

The draft guidelines also state

that establishing that there are no clinically

meaningful differences in immune response

between the proposed product and the reference

product is a key element in the demonstration

of biosimilarity It is our view that any

determination of clinically meaningful


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differences should be based on the totality of

the data In other words is there reduced

efficacy or safety associated with a

difference in the antidrug antibody incidents

Regarding the potential to

extrapolate comparative clinical

immunogenicity results to other approved

indications the draft guidelines state that

if the sponsor is seeking to extrapolate

immunogenicity findings for one indication to

other indications the sponsor should consider

using the study population and treatment

regimen that are the most sensitive for

detecting a difference in immune responses

However selection of the most

sensitive patient population in which to

perform this assessment is sometimes not so

straightforward For example although

patient with rheumatoid arthritis receiving

methotrexate plus anti-TNF biologics typically

have lower immunogenicity rates than similar

patients on monotherapy These patients in


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general are also potentially more susceptible

to generating antidrug antibodies compared to

various other patient populations for whom the

anti-TNF products are approved

Again also for anti-TNF products

first approved for rheumatoid arthritis it is

possible that higher incidences of antidrug

antibody responses in subsequently approved

indications are due to the introduction of

more sensitive immunoassay methods rather

than being a true population effect

PAREXEL considers that the

selection of the most sensitive patient

population in which to perform the comparative

clinical immunogenicity assessment needs to

take the following factors into careful

consideration Overall incidents in time

course for generation of antidrug antibodies

presence of neutralizing antibodies effects

of antidrug antibodies on established PK

parameters potential negative effects of

antibodies on safety or efficacy relative use


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of the reference product across all approved

indications in other words relative size of

the safety databases historical development

of the reference product and any knowledge of

immunogenicity assay design and performance

for example the format the sensitivity the

specificity that is known to the biosimilar

developer And it is understood that these

data may not all be in the public domain and

therefore it may not be possible to

rigorously define the most sensitive

population At least that is the challenge

Finally given that many

biosimilar clinical development programs will

likely include a single pivotal phase 3

therapeutic equivalence trial with efficacy as

the primary endpoint and comparative

immunogenicity as the secondary endpoint with

the goal to extrapolate results cross other

approved indications supported by a shared

mechanism of action it is very important for

biosimilar developers to meet with FDA to


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present the various pros and cons that went

into their selection of a patient population

and condition of use considered adequately

sensitive to assess both efficacy and

immunogenicity

That concludes my presentation

Again I would like to thank the FDA for this

opportunity to share our thoughts focused on

comparative clinical immunogenicity

assessments for biosimilars



panel


mentioned that increased assay sensitivity may

be problematic So that was in the context of

looking at historical data to design studies

and that may be the case But if an

immunogenicity study is a comparative one

then that increased sensitivity applies to

both arms of the study And in fact one

might argue that would reduce your study size


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because measuring a difference between a one

percent incidence of immunogenicity is

probably much harder or much more challenging

in terms of numbers than ruling out a

difference in a five or ten percent So it

may be that better assays actually make it

easier I throw that out not harder

And I think your comment about

does one-sided apply a pre-specified non-

inferiority margin is a good comment if you

havent already to send to us because we need

to consider exactly the best way of expressing

what we think is a reasonable approach

DR BABBITT Yes I dont

disagree at all with what you said about the

potential advantage of an increased

sensitivity of the current assays and actually

with I think industry working with FDA to

design and validate immunogenicity-related

assays very well I have been part of that

many times with clients and with FDA It was

just in terms of the challenge of knowing


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what kind of margin that you are really

dealing with ahead of time Even as we

started to look at trying to define the most

sensitive patient population either for

efficacy assessments andor for immunogenicity

assessments with biosimilar programs we are

involved with we notice that as you look over

time with the same product approved for one

indication and then a period of time later

another indication and another indication I

have noticed that there would be apparent

increases in the immunogenicity levels when it

didnt make sense to me And I also noticed

in some of the reviews written by the FDA that

the comment was well in one case these phase 2

and 3 datasets were analyzed with a low

antigen density coated plate and to keep that

in mind because this other set of information

in the higher incidences apparent incidence

was based on a higher density of antigen

coated plates So that is a challenge

And also what we might find very


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interesting over time is that what we might be

picking up would be these improved assays

might be just a low titer responses that were

missed before So on the one hand it looks

like you have an apparently higher rate of

incidence for both the reference product and

the biosimilar but you might not really have

that And whether either one will translate

into any clinically meaningful affect you

wont know that until you assess it also

PANEL MEMBER KOZLOWSKI And you

commented on the clinically meaningful

differences in immunogenicity and said

obviously that there should be some clinical

link to a difference in antibody incidence

So I would ask you say you had a difference

where you went from three percent at low titer

to 50 percent at high titer and in the

duration of the study you didnt see a

clinical effect would you be concerned about

that

DR BABBITT Honestly I would


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That would I guess I dont know whether I

should use the word concerned but it would

clearly catch my attention It would catch my

attention and what I would think is therefore

I would want to -- it wouldnt necessarily

convince me that I didnt still have the

chance for having a biosimilar but at the very

least I would want to monitor in more detail

and maybe across more patient types whether

that difference maintained itself what that

difference meant in terms of clinical outcome

Yes and of course I would also

look at whether or not those higher titer

antibodies that higher percent were also

neutralizing or not and then look at the

history of the reference product to see

whether that was a new outcome or not and I

would have to make lots of comparisons


questions No Thank you for your comments

Our next speaker is Sara Radcliffe

from Biotechnology Industry Organization


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usually known as BIO

MS RADCLIFFE Thank you Good

afternoon My name is Sara Radcliffe and I am

the Executive Vice President for Health at the

Biotechnology Industry Organization or BIO

On behalf of BIO and our members I would like

to thank FDA for the opportunity to present

today

BIO represents more than 1100

biotechnology companies academic

institutions state biotechnology centers and

related organizations across the US and in

more than 30 other nations The

implementation of the Biologics Price

Competition and Innovation Act of 2009 BPCIA

is of significant importance to BIO members

and we commend FDAs efforts in developing

draft guidance to illustrate the Agencys

current thinking on certain aspects of the

biosimilars approval pathway BIO has

previously commented on biosimilars issues and

appreciates FDAs consideration of our


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comments

BIO recognizes that the issuance

of the three draft guidances in February is an

important initial step in implementing BPCIA

We have submitted written comments to the

docket regarding each of the three draft

guidances Today I would like to highlight

several key issues listed on this slide that

BIO believes merit particular consideration by

FDA as the Agency moves forward to develop the

regulatory framework for the biosimilars

approval pathway

First interchangeability an area

where FDA guidance would be extremely useful

In developing guidance it is important that

a number of factors be considered including

those shown here BIO appreciates FDAs

recognition that the approval criteria for

interchangeability are more difficult to

achieve than biosimilarity and we look forward

to the opportunity to comment on proposed

guidance


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Page 349

Second I would like to address

naming and labeling BIO believes that

identification of the exact product received

by the patient is essential to recognizing

safety issues quickly and limiting risks to

patients Therefore both a unique brand name

and distinguishable nonproprietary name for

each product are essential Use of the same

nonproprietary name for a reference biologic

and any biosimilar versions could be taken to

imply that these products are

pharmacologically the same when they are not

Use of distinct nonproprietary names will

also enable tracking of an adverse event to

the exact product administered

BIO requests that FDA issue

guidance on naming A lack of guidance on

uniform naming requirements to distinguish

among innovator biologics biosimilars and

interchangeable biologics mainly to multiple

approaches taken by sponsors and result in

confusion among healthcare providers and


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Page 350

patients We also encourage FDA to work with

other health authorities to harmonize distinct

nonproprietary naming requirements globally

BIO supports FDAs proposed

labeling statements as outlined in the draft

guidance for industry on scientific

considerations as a means of clearly and

factually stating the indications for which a

biosimilar has been approved and how the

product differs from the reference product

However we encourage FDA to address in

separate guidance the other components of

biosimilar labeling ie what would be

included

clinical

section

in the highlights section the

study section and the warning

As discussed in our comments the

labeling should include information such as a

warning regarding the risks of substituting or

alternating innovator and biosimilar products

that have not been approved as

interchangeable the nature of the clinical


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Page 351

studies that were conducted for approval the

essential clinical data that served as the

basis of the licensure decision and what if

any indications have been granted based on

data extrapolation any observed differences

in incidence or type of adverse event compared

to the reference product and any other

essential scientific information specific to

the biosimilar product

BIO appreciates that FDA has begun

to address confidentiality That is FDAs

draft QampA addresses what portions of a BLA may

be considered public information However two

related issues warrant guidance as well

Assuring that nonpublic BLA information is not

released to the public and assurance that

confidential BLA information is protected in

the context of the FDA review process for

351(k) applications

BPCIA directs the biosimilar

applicant to include public information

related to the reference product in its


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application and limits FDAs review to the

information presented in the biosimilar

application BPCIA does not authorize FDA to

consider or rely upon confidential trade

secret information in an innovators BLA in

product development meetings with biosimilar

applicants or in review of a 351(k)

application In short a 351(k) application

must stand on its own

In the draft QampA FDA sets forth a

number of proposed regulatory and scientific

factors to be considered in determining when

and whether data comparing a prospective

biosimilar to a non-US-licensed comparator

product may be useful in supporting a 351(k)

application BIO appreciates FDAs

recognition of a number of the factors

proposed in BIOs 2010 comments as these are

reflected in the draft QampA

We reiterate here that the use of

non-US-licensed comparator data in a

biosimilar application raises fundamental


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concerns from both a legal and scientific

perspective First BPCIA mandates that a

biosimilar be evaluated against only one USshy

licensed reference product Therefore data

comparing to a non-US-licensed product

should only be accepted as support for an

application And such data should only be

accepted when both the US-licensed and non-

US-licensed product are released by the same

license holder or manufacturer

We ask that FDA describe more

fully the type of bridging studies and

associated confidence intervals that could

support biosimilar approval and note the

scientific bridge should generally include all

of the bridging information listed in the

draft QampA and the draft guidance for industry

on quality considerations

Finally we note that use of a

non-US-licensed comparator generally would

not be appropriate for particularly complex

biological products


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FDA has an important role in

assuring full compliance with patent

certification requirements in BPCIA to

maintain the balance of interests established

by the law BPCIA requires that the 351(k)

applicant provide a copy of its application

and manufacturing process information to the

reference BLA holder within 20 days of the

application being accepted for review We ask

that FDA require 351(k) applicants to certify

that they will provide this information to the

reference BLA holder and that FDA refused to

file a 351(k) application without a

certification Absent such requirements the

innovator may not know that an application has

been filed until the FDA approves it The

result would undermine the preapproval dispute

resolution process established in BPCIA and

could lead to FDA unnecessarily expending

review resources on products that are subject

to patent disputes post-approval as well as

leading to disruption in product availability


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to patients and providers

For transition products BIO

requests that FDA address the time frame for

and clarify the process for implementation of

the provision deeming a biologic approved

under Section 505 of the FFDCA to have an

approved BLA in 2019 In addition we note

that any biosimilar guidance should be applied

to follow-on proteins for transition products

with the same scientific requirements for

assessment of biosimilarity and

interchangeability for FFDCA and PHSA

products

In summary BIO requests that FDA

issue additional guidance on the topics listed

on this slide We also request that FDA

provide additional QampAs on the topics on this

slide factors FDA will consider in

determining whether an application submitted

under 351(a) is not a full BLA and FDAs

refusal to file policy the process for

assuring 351(k) applicant compliance with


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BPCIAs patent provisions in the forms to be

used for 351(k) submission the procedures to

be employed to assure that non-public BLA

information is not accessed for purposes of

351(k) approval

In conclusion BIO-member

companies have pioneered innovative and

lifesaving treatments for patients worldwide

using biotechnology processes These

therapeutic and diagnostic products have led

to significant improvements in the care of

patients with serious diseases In many

cases the first approved treatment for a

condition BIO supported the passage of

legislation to enable FDA to approve

biosimilars so that patients living with unmet

medical needs will have expanded access to

safe and effective therapies at lower cost

We look forward to continuing to work with FDA

on implementation of the law

Thank you for the opportunity to

present today and for your attention


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you for your comments Questions Maryll

PANEL MEMBER TOUFANIAN With

respect to your request for the Agency to

require notice of the patent certification

issue does that stem from BIOs experience in

noncompliance with statutory requirements of

applicants in other context or is this more of

a belt and suspenders desire to make sure that

the statutory requirements are complied with

by the biosimilar applicant

MS RADCLIFFE I would think more

the latter The law was constructed in the

way that it was to ensure that patent disputes

would be resolved prior to launch And so

without the sponsor knowing that an

application has been filed and receiving the

information to which it is entitled to balance

interest that was established under the laws

disrupted and as I said could lead to fairly

severe consequences in terms of disruption of

the availability of the product to patients


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as well as potential unnecessary use of

resources by FDA itself as well as sponsors

PANEL MEMBER KOZLOWSKI Weve

heard a number of comments about concern about

trade secrets And I think that is an

important concern At a recent biologics

conference an innovator spoke about

attempting to better characterize their older

products because now the companies making

biosimilars are characterizing their products

better than they have and understand them

better

And so I would wonder whether 12

years down the line in fact will there not be

that much value in knowing what the originator

did That basically getting the right samples

and using the current 12 years or more down

the road state of the art analytics will in

fact be much more informative than this

information Again not that it is not

important to protect but I just ask There is

a lot of concern about it Is that really


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what the information that is going to be very

important in moving these products forward

MS RADCLIFFE So science moves

on and that is a wonderful thing It is true

that 12 years is a very long time in drug

development

In addition biological products

are very complicated and that is one reason

why the information that was in the

applications for biologics have been treated

differently from that for drugs and we have

requested that the Agency ensure technical

changes made so that it is very clear that

that information in fact is protected So in

short the answer to your question I think

will sometimes be emphatically yes in those

cases where science has moved on The

information that is contained in the

innovators application in any event should be

protected but may not be relevant to the

comparison exercise that needs to take place

with respect to establishing biosimilarity


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That is something that has to take place and

stand on its own as I said in my

presentation


questions Thank you for your remarks

Our next speaker is Cornelia Ulm

from the European Generic Medicines

Association

MS ULM My name is Cornelia Ulm

and it is my pleasure to present the EGA

perspective on the FDA draft biosimilar

guidance documents

First of all the EGA appreciates

the fact that the draft guidance has been

published by FDA We think that it is a big

step forward to global biosimilar development

as it now allows sponsors to obtain coherent

advice globally The guidance documents have

been prepared on sound science with focus on

high similarity to ensure high product

quality

EGA especially values the focus on


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similarity and the totality of evidence the

acceptance of non-US-licensed reference

product if adequately justified the

possibility of extrapolation of indications

and the acknowledgment of the powerfulness of

human PKPD studies to demonstrate

biosimilarity Furthermore the EGA values

the possibility to waive preclinical studies

if justified We also value the fact that

clinically irrelevant differences in

formulations and containerclosure systems may

be acceptable if justified So treating

biosimilars like any other biological product

And we finally acknowledge -shy

value the acknowledgment regarding post-

marketing safety monitoring

Now I would like to address points

where EGA suggests that further clarification

may be needed First the requirement for

interchangeability needs to be defined to

allow sponsors working towards that target

We also suggest to reconsider the requirement


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to select doses in the steepest part of the

doseresponse curve as this may not always be

possible EGA suggests to add that

extrapolation of indications should not only

be justified by the mode of action but rather

the totality of data

We also suggest to reconsider

review on the active substance and to follow

the EMA approach that biosimilars have well-

known active substance as they are designed to

match the reference product Consequently

there should not be the need to perform

pediatric studies and the same nonproprietary

name should be used for biosimilars and

reference products regardless of the

interchangeability status

EGA also suggests clarifying that

a stepwise approach does not necessarily mean

to perform development strictly sequentially

Running part of the development program in

parallel should be acceptable We would also

suggest to clarify more clearly that


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immunogenicity is not more but less of a

concern for a biosimilar as the immunogenic

profile per se has already been established

with a reference product EGA suggests to

clarify that immunogenicity studies may

sufficient in certain circumstances

Furthermore EGA suggests to

clarify more clearly in the guidance that the

scientific principles which apply for

comparability hold also true in the same way

for biosimilarity assessment and FDA has

gained a lot of experience with comparability

exercises over the last years and can easily

rely on this experience

EGA suggests to reconsider the

definition of strength to phrase it more

flexible as scientifically it doesnt make

any difference if the same dose is delivered

in a different volume provided the entire

container content is administered

The approach to process-related

impurities is identical between biologics and


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biosimilar products That is reference to the

relevant ICH guideline seems sufficient and no

further details are needed to be provided in

the guidance document EGA also would suggest

to clarify the role of fingerprinting more

clearly in the guidance documents

To summarize EGA thanks FDA for

issuing the scientific-based guidance

documents We also appreciate the opportunity

to comment and contribute today EGA is

confident that the remaining discussion points

will be addressed adequately by the FDA

And I would like to add one

additional point as that was a question this

morning At the EGA biosimilar conference in

April there have been two physicians

providing information on post-marketing

studies which have been carried out when

switching from the originator product to

biosimilar products One was a prospective

study in Sweden switching to a growth hormone

The other one was a retrospective study


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switching to or using a biosimilar filberstin

products and that was a retrospective study

because the physicians in the hospital werent

even aware that the hospital had purchased a

biosimilar product So in those studies it

has been demonstrated that there were no

differences in safety and efficacy So this

is just to provide you some information that

there is no data around generated by day to

day use in clinical practice

Thank you




shared a comment with several of your

colleagues that have spoken today It was on

your slide 14 or I guess slide number six

The notion that there should be one standard

high similarity for both biosimilar and

interchangeable biologics And I note in the

statute that the standards for biosimilar and

interchangeable products are facially not the


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same So I was wondering if you could explain

your statement that one standard the high

similarity standard should be applied for both

types of products both interchangeable and

biosimilar products

MS ULM Yes thank you I think

the experience so far gained in Europe over

the last five years has shown that the current

requirements which are demanding for a high-

quality product are sufficient to guarantee

that there are no differences when switching

from originator products to reference

products

As it has been said by speakers

before pharmacovigilance data generated has

not indicated any new adverse events or any

safety concerns with biosimilar products

approved on the market So that is why we are

of the opinion that the same standard of the

standard which is currently already in place

is adequate to also allow for

interchangeability and that not artificially a


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different standard should be created Because

currently the fact is that for originator

companies when the manufacturing process

change has happened that there is automatic

interchangeability granted means that products

with different product quality attribute are

interchangeable on the market because how the

authorities have assumed or assessed that

there is no difference in efficacy and safety


questions Okay thank you for your comments

The last speakers on this panel

are Kristin Van Goor and Sascha Haverfield

from PhRMA

DR VAN GOOR Thank you Im

Kristin Van Goor The Pharmaceutical Research

and Manufacturers of America or PhRMA

appreciates the opportunity to participate in

this public meeting and share our views on the

draft guidances on biosimilar development

PhRMA supported enactment of the



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of 2009 BPCIA which in our view struck an

appropriate balance between creating an

abbreviated pathway for biosimilar

interchangeable products while still

preserving adequate incentive to encourage

innovation of new biologicals PhRMA has been

highly supportive of ongoing efforts by the

FDA to implement BPCIA and welcomes the

Agencys decision to seek public input on the

draft guidances

PhRMA has submitted detailed

written comments on each of the three draft

guidances FDA has issued with specific

recommendations for the Agency to consider

prior to finalization PhRMAs comments today

will focus on the broad scientific principles

that should guide FDA as it implements BPCIA

both with respect to the three draft

guidances as well as future guidances

presently under consideration

PhRMA believes the concern for

patient safety must be paramount when


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evaluating proposed biosimilar products The

FDAs biosimilar guidances should therefore

be based on the statutory requirements of

BPCIA and sound science That is an

abbreviated licensure pathway is appropriate

only when a biological product has been

demonstrated to be highly similar to and

devoid of any clinically meaningful

differences from a single FDA-approved

reference product

Given the size and complexity of

biologics and the use of living systems for

their production seemingly small changes to a

products structure or means of production may

have unintended consequences that may be

difficult to predict especially in the

absence of extensive manufacturing experience

with biological products as a clear

scientifically rigorous approach to the

evaluation of potential differences between

proposed biosimilars and a reference product

is essential to ensure for patients the


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quality safety and efficacy of biosimilars

To minimize the potential for

unintended or unanticipated differences

between a proposed biosimilar and the

reference product FDA should recommend that

biosimilar applicants minimize controllable

differences to the extent possible

recognizing that the feasibility of utilizing

the biosimilar pathway is diminished by the

intentional introduction of differences

PhRMA believes that evaluation of

biosimilars to demonstrate the absence of the

clinically meaningful differences should

include comparative molecular evaluations of

physical chemical and functional properties

as well as preclinical and clinical testing

As such PhRMA firmly supports the need for

multiple sophisticated and sensitive

analytical procedures to identify and evaluate

potential small differences between a proposed

biosimilar and a reference product since

seemingly minor structural differences may


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have significant clinical consequence

It must be recognized however

that even state of the art technology may not

identify all differences between a proposed

biosimilar and the reference product that are

potentially clinically meaningful

Understanding the limitations of their

analytical program will be essential to the

appropriate design of preclinical and clinical

studies

While there may be challenges

associated with the relevance of animal

studies in predicting immunogenic responses in

humans PhRMA believes preclinical testing

plays an important role notably as a means to

protect patients PhRMA recommends that the

size and scope of preclinical testing should

be based on sound science and aligned with

relevant ICH guidelines

PhRMA believes that clinical

testing is essential to satisfy the statutory

requirement that there be no clinically


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meaningful differences between a biosimilar

product and the reference product It is

PhRMAs view that the primary concern should

be for patient well-being which will

necessitate clinical immunogenicity testing

as well as at least one comparative clinical

trial of adequate size and with appropriate

endpoints to detect small differences in

safety and efficacy

Unless strong scientific

justification for extrapolation is provided

PhRMA believes that clinical data will be

needed for each indication for which a

biosimilar applicant is seeking approval For

example FDA should recommend that applicants

seeking to extrapolate data across populations

within an indication study the patient

populations most sensitive to differences

recognizing that the most sensitive patient

population may not be the same when evaluating

safety efficacy or immunogenicity

FDA has also asked for public


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input on future guidance development and PhRMA

has identified two topics for prioritization

one being reference product exclusivity and

the other being the naming of biosimilar

products

The statute provides for 12 years

of exclusivity subject to a very narrow

exception for any biological product that is

the subject of a 351(a) application During

this exclusivity period a biosimilar to the

reference product cannot be approved PhRMA

considers this provision for exclusivity to be

a necessary measure to protect and encourage

innovation as it the basis for investment

decisions made by biopharmaceutical companies

PhRMA further believes it is

incumbent upon FDA to clarify as soon as

possible and in plain language the biological

products that are the subject of 351(a)

applications are presumptively eligible for 12

years of exclusivity Any modification to the

structure of a biological product with a


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change to safety purity or potency should

result in a 12-year exclusivity period for the

new application

An application is a very narrow

exception known as the first licensure

provision The supplement or subsequent

application should be protected for any

remaining period of exclusivity applicable to

the first licensed product to which it is

related

With respect to naming of

biosimilar products PhRMA believes that

distinct nonproprietary names that

differentiate a biosimilar product from the

reference product and other biosimilar

products will be essential for post-market

safety monitoring Unique names will also

ensure that patient and physician decisions

regarding treatment choices are respected as

well to help prevent errors in the

prescribing dispensing and administration of

biologics


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Finally as FDA continues to

implement BPCIA and in particular as the

Agency further develops the scientific

standards governing biosimilarity PhRMA

encourages an open transparent and public

process Drawing on the experience and

knowledge offered by a broad range of

stakeholders including innovators will help

ensure patient access to biosimilar products

that are safe and effective


you for your comments Questions None


Any questions from any other

member of the panel No All right You

guys are really beating us down here

We will go into the open public

comment period Our first speaker is James

Sykes from HealthHIV

MR SYKES Im impressed Thats

nice

Good afternoon Dr Sherman and


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your fellow colleagues My name is James

Sykes I am the advocacy manager for

HealthHIV And HealthHIV is a HRSA-funded

national center for HIV care in minority

communities We provide capacity building

assistance for physicians in community health

centers for people with HIVAIDS And I

really appreciate the opportunity to come and

talk to you today and present these comments

And these are not for good looks These are

for health So maybe for use here

I appreciate that the FDA is

taking the time to understand the concerns and

issues that we in the patient community can

provide We applaud the FDA for their effort

to keep the patient at the center of its

process that will enable the safe introduction

of biosimilars into the US drug market

As a leader in the effort to

ensure that patients with HIV and AIDS are

informed of the risk and benefits of available

treatment options HealthHIV works to provide


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education assistance and support health

research for people living with or at risk for

HIVAIDS And additionally we seek to

improve the lives of patients and provide them

with the best and most effective treatment

information

Having worked as a patient

advocate for many years I have witnessed the

positive effect that biologics can have on

patients with chronic diseases including HIV

and AIDS However as life changing as these

drugs are HealthHIV believes that there are

still several patient concerns that must be

addressed as the FDA moves forward developing

a pathway to introduce biosimilars in the US

As you know biosimilars are

distinct from generics which are made from

chemically produced drugs I am reiterating

what many folks have said before but that is

because they are made from living systems and

so that they have highly complex structures

that are neither completely understood nor


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easily reproduced As a result any time a

manufacturer attempts to copy a biologic the

process does not yield to an exact replica

contained in the same structure or raw

material but only a similar version of the

innovator product as we understand it And

with biologic medicines small difference can

present several safety challenges beyond that

of a chemically produced drug

To safeguard patients the FDA

must implement clinical trials that test the

safety and efficacy of all biologic and

biosimilar medicines In addition HealthHIV

recommends that the FDA institute the

following safeguards And these are again

reiterating what has been heard before today

a new naming system that distinguishes each

biosimilar from the biologic it seeks to

replicate and easy to understand product

labels and lot numbers for product

traceability in the event of an adverse

reaction Because we all know that most of


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these are going -- this is postmarket

surveillance for patients And so a way to

get some feedback after patients have started

on these treatments

Further establishing the pathway

we must also leverage what we know and adopt a

science-based approach For example it is

currently impossible to determine that two or

more biologic products can be interchangeable

and remain so over time as I have heard here

today and regulators must recognize that gap

as it formulates its final

biologicbiosimilars guidance HealthHIV

believes that the additional time needed to

fully understand the dynamics of biosimilars

justifies an extended period of data

exclusivity And naturally even when the

guidance is finished the doctor-patient

relationship must be maintained in order to

ensure patient choice access to and safety

of all biologic and biosimilar medicines

HealthHIV views the draft guidance


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as an important first step to enable lower

cost biosimilars entering into the US

market while not compromising patient safety

But we would also like to take this

opportunity to encourage the FDA to begin a

process or encourage a process that supports

research of biologics a more extensive

research of biologics efficacy and safety in

biosimilars in children

And I stand here I am the person

known as the uncle of a 13-year-old young lady

with Crohns disease who in 2010 spent four

months in the hospital with nothing by mouth

so she can have the surgical resection and

that is 2010 In 2011 she is back at school

Last week she had a colonoscopy that showed

that the ulceration has returned The doctor

is considering Remicade as a treatment

As a lay person as her uncle as

the brother of her grandmother as the uncle

of her mother we are concerned We dont

know a lot And we are scared and we dont


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know how to lead her So we as lay people

depend on the FDA When you say it is safe

we believe you And so in the final analysis

it all comes down to what the effect is on

patients and we ask that you always keep the

patient in mind and front and center in what

you do Thank you very much


you for your comments Any questions from the

panel Thank you

Our next speaker is Andrew

Sperling from the National Alliance on Mental

Illness

MR SPERLING Thank you for this

opportunity to offer public comment on the

draft guidances on biosimilars product

development I am Andrew Sperling Director

of Legislative Advocacy for NAMI the national

Alliance on Mental Illness NAMI is the

nations largest advocacy organization

representing people living with serious mental

illness in their families


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We have always placed the highest

priority on expanding access to new and more

effective treatments for disorders such as

schizophrenia bipolar disorder major

depression and severe anxiety disorders We

need both breakthrough therapies that get

beyond the current generational treatments and

incremental improvements in the medications we

have Improving side effect profiles can do a

lot to enhance treatment adherence and move us

forward in advancing treatment These

incremental improvements can also help in a

number of ways to advance treatment for those

who were struggling with side effects today

So we urge advances in treatment both

breakthrough therapies and incremental

treatments

We are pleased to go on record in

support of the major components of the FDAs

draft guidance We know that there are

inherent challenges associated with regulating

biologic medicines due to their large size


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complexity and immunogenic properties As

has been stated over and over again today at

this day-long meeting biosimilars are similar

to but not exact copies of biologics and so

small differences can have unexpected or

harmful clinical outcomes for patients

Ill make four quick points in

response to the guidance Number one NAMI

feels strongly that clinical studies are

important and a comprehensive way to test for

immunogenicity in biosimilarity prior to

biosimilar products being approved We have

to FDA has to effectively examine the full

range of possible outcomes Shortcuts in the

approval process can ultimately risk patient

safety

Number two it is important to

recognize that there remains uncertainty about

how biologic medicines can act NAMI

recommends caution with respect to

interchangeability standards for biosimilars

Number three since biosimilars


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are only similar to and not identical to their

reference product NAMI would welcome the use

of unique nonproprietary names labels and

distinct packaging for biosimilars A unique

naming system leverages what we know about

patients specifically that many take more

than one product and confuse details such as

product names

And finally number four NAMI

urges the FDA to put in place requirements to

ensure that biological products are traceable

This is absolutely critical as a result of

gaps in treatment a lack of coordinated care

that are commonplace particularly for people

with serious mental illness in the treatment

system It is particularly important that

physicians be consulted prior to a patients

medicine being switched from one product to

another This is a critical protection the

patients need

We dont have biologic products

right now for most major serious mental


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illnesses but we are hopeful that the research

that is being done can result in breakthrough

therapy So we support the guidance and urge

the FDA to move forward Thank you



panel

Our next speaker is Kalyan R

Anumula from the Therapeutic Proteins

International

DR ANUMULA Good afternoon

everyone And Dr Niazi could not be here and

he asked me to present our comments this

afternoon And I am a glycobiologist and I

am the head of analytical at TPI

So I would like to thank the panel

for providing this opportunity to comment

And by way of introduction to biosimilarity

here is an oxymoronic combination of words

What I mean by that bio inherently means that

something not similar We are variables In

fact we are all variables we are similar


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and life is variable on a philosophical basis

And if you look at it in a big picture

actually the innovators produced the first

biosimilar product to be endogenous proteins

Physiochemical footprint inevitably is

variable It is likely But it will be

highly similar and will have the same

function at least in a small molecular area

where the bioequivalence is done chemically

chemical analysis and most of the time no

clinical studies are required

So why cant we do the same thing

for biologics So knowing that we know the

molecule very well when you come to

biosimilar molecules We have plenty of

history in terms of not only clinical -- not

only in terms of molecular structure but also

in terms of clinical experience by the time

the biosimilar industry tries to develop

biosimilar molecules

So we can in fact define a

molecule structure extremely well in great


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detail And also we can develop analytical

strategy in which where if we have defined any

differences can be really nailed down and

examined in great detail And certainly we

can have animal toxicity in PKPD and in situ

immunogenicity and obviously this

responsibility depends on the sponsor

Our view is that a simple human

immunogenicity study in healthy subjects is

sufficient for demand stating immunogenicity

of the biosimilar under review

So if you take the clinical side

of things it is not that plain either And

pitfalls of clinical trials may be The

clinical trials have so much variability there

may be a situation in where actually the

biosimilar may be giving the wrong answers

It maybe may not be similar to what you

expect

The number of human subjects

required is also much higher in order to prove

clinical equivalency to the reference


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material On the other hand if we

characterize the molecule of using current

analytical methods et cetera we can prove

at least chemicals means that it is highly

similar and very likely to show clinically

equivalent performance

On the other hand if you go on

the route of clinical trials then you would

be exposing the drug unnecessarily to human

beings which I am not so sure it is a good

way of doing things However clinical trials

may add value where substantial history of

refractory clinical failures exist and ADRs

are known Also it adds kind of productively

a significant cost to the development and also

time

So in our view the guidelines

should say all applicant on a case by case

basis should provide evidence of totality

And phase 2 phase 3 trials required only

where the need is established by FDA after

reviewing after reviewing the submission


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except the evidence of immunogenicity and

levels of antibodies in human beings will be

provided We ask that FDA should increase the

use of novel characterization methods not so

much so clinical trials

Our experience so far what we are

doing here at TPI in Chicago is we manufacture

biosimilars and it is our opinion if we

establish the lowest impurities in our product

and characterize the molecule using highly

sophisticated analytical technologies over

time and compare stability profiles and

establish comparable safety in terms of PK and

PD and also establish equal or lower

immunogenicity in healthy individuals should

be sufficient for approval

And thank you very much



panel

PANEL MEMBER KOZLOWSKI So on the

list of the development program you suggested


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you didnt have any human pharmacokinetics or

pharmacodynamics I wondered if that was an

intentional omission

DR ANUMULA I thought we did I

thought we put in a PKPD

PANEL MEMBER KOZLOWSKI Well you

had comparable safety in PKPD in animals

DR ANUMULA Oh no Sorry

That probably our oversight on that aspect

PANEL MEMBER KOZLOWSKI All

right Just clarifying

DR ANUMULA Yes okay


questions

Our next speaker is Gregory Davis

from Eli Lilly

DR DAVIS Good afternoon My

name is Greg Davis and I am a Senior Principle

Fellow in Global Regulatory Affairs with Eli

Lilly and Company in Indianapolis

Lilly has been a leader in

biopharmaceuticals since 1922 when the company


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was the first to make and market insulin

Today Lilly is one of the largest

biotechnology companies in the world Biotech

medicines accounted for approximately one-

quarter of Lillys 2011 sales and biotech

medicines today represent roughly half of the

companys drug pipeline

I appreciate the opportunity to

speak with you today about biosimilars Lilly

supports the biosimilar policy that allows

patients to have access to biosimilars that

are safe and effective that maintains

incentives for innovation that is in all

respects science-driven We join other

stakeholders in applauding the FDA for

issuing the three draft guidances which

contain a great deal of helpful information on

biosimilar development While there are many

issues worthy of discussion for the sake of

time I would like to focus on a single issue

today that being the issue of conducting

trials with non-US-licensed comparator


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products

Before commenting on this issue

directly though I will make two framing

comments First this issue takes on added

importance because purely as a scientific

matter FDA standards for acceptance of

comparator data derived in part from non-US

sourced biological products impacts not only

biosimilar trials but also trials of

originator biologics This could be the case

if for example those innovator trials are

global and include an active comparator arm

Sponsors of these kinds of an innovator global

trials are increasingly being asked by the

Agency to justify use of locally-sourced

active comparator We believe that this is

based on the types of bridging data that is

being discussed in the draft biosimilar

guidances

The second framing comment is that

we recognize the issue of non-US comparators

in biosimilar trials is not purely a


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scientific issue As has been pointed out

the US law requires that a biosimilar

product be evaluated against a US-licensed

reference product But whether or not the law

permits including nonclinical or clinical

evaluations against a non-US comparator as

part of the package is a question that I

intend to leave to legal counsel

The point I want to make about

that is to the extent this law impacts the

analysis FDA should clarify how it is so

impacted and should clearly distinguish any

combined legal-scientific analysis of this

issue from the purely scientific analysis

The reason is that there will be situations

such as biologics in active comparator trials

or biosimilar trials of transition products

that will not be impacted by the legal part of

this analysis In fact we propose there is

an urgent need to know the extent to which the

advice contained in the draft guidance on this

topic also applied to these other non-351(k)


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situations

To the extent FDA policy outside

the biosimilar realm is impacted or evolving

based on biosimilar policy it creates

significant uncertainty for sponsors and

guidance on those situations is badly needed

With that framing I would like to

concisely address the appropriate scientific

standard for non-US comparator products in

biosimilar trials as discussed in the FDA

scientific and QampA draft guidances To begin

with Lilly agrees with FDA that if done

correctly it is consistent with good science

to include comparisons with a non-USshy

licensed product in addition to direct

comparisons with the US reference product as

part of the required approval package We do

not believe that such comparative data must be

categorically excluded from the pivotal data

package but rather that good science should

dictate whether including the non-US

comparator data are justified This would of


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course be determined in part by evaluating

the sufficiency of data from studies directly

comparing the proposed biological product to

the US comparator as well as bridging data

between the US and non-US comparators

Again particularly in light of the broader

potential implications of this issue we

joined other stakeholders in requesting more

certainty and predictability of this critical

issue

Finally I would like to make a

related point about the important distinction

between the scientific concepts of similarity

and comparability We appreciate and very

much support FDAs discussion of this

distinction and Section 4(b) of the draft

scientific guidance which is consistent with

FDA existing comparability guidance In this

draft guidance FDA reiterates that

manufacturers who have made changes to their

own process will have extensive knowledge and

information about its product and existing


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processes and that the disparity and knowledge

differentiates the biosimilarity exercise from

the comparability exercise

Now this framework that you

describe might be helpful in setting the

starting point for the analysis of non-US

comparators If comparability between the

US and the OUS versions has already been

determined by the reference product sponsors

then the bridging analysis by the third party

wanting to use both versions might be more

straightforward On the other hand if the

reference product manufacturer has determined

the two to be non-comparable perhaps doing

global trials is not even an option for any

party In order to be used and available to

third parties of course these findings

regarding comparability must have been made

public by the manufacturer or have become a

matter of public record in support of a

regulatory determination previously made by

the FDA


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So this concludes my comments

Again I very much appreciate the time to

address the Agency today and I would be glad

to take any questions



panel

PANEL MEMBER KOZLOWSKI Just to

clarify Initially you had mentioned that you

thought some of the concepts being applied to

non-US comparators for biosimilarity were

being applied to active comparators that were

non-US for other purposes or in other

trials Can you comment a little more on

that

DR DAVIS Well yes We have

our companies and other companies we have

talked to have been asked to provide what

looks to be right out of the biosimilar

guidance data regarding bridging studies for

doing active comparator trials across the

globe So if we were doing a study in the


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US and we are using the US source

comparator we are buying the same drug that

is approved comparator drug in the EU We

are being asked to do extensive studies

demonstrating essentially comparability

between the comparators

PANEL MEMBER KOZLOWSKI And was

this to justify the non-inferiority margin or

for another purpose

DR DAVIS Basically it is to

justify the use of non-locally sourced

material



DR DAVIS Thank you I

appreciate it


last speaker is Ahaviah Glaser from GPhA

MS GLASER Good afternoon and

thank you so much for allowing us time to

speak today on this important subject

I actually think it is a good


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idea but especially as the final speaker to

take just a second to reflect on what it is

that brings us here which is that biologic

drugs have really revolutionized modern

medicine and created a range of treatments for

very severe conditions The issue however

of access and affordability remains a barrier

in some instances which is why the Biologics

Price Competition and Innovation Act was such

an extraordinary step forward And we very

much welcome the FDA guidances to move us

forward on the implementation of this

important legislation

In particular we feel that the

Act is geared towards allowing for the

approval of both biosimilars and

interchangeable biosimilars and ensuring that

a competitive market is created for these

vital medicines We have worked and will

continue to work with you to ensure that the

twin goals both have enhanced patient access

and improvements in patient health outcomes


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Page 400

are achieved With the application of best in

class scientific standards and always the most

appropriate methodologies which we trust FDA

to identify while avoiding artificial barriers

to market entry

First and foremost GPhA promotes

safe effective and affordable medications

We represent many of the companies that you

have already heard from today including GPhA

members that are already manufacturing safe

quality wonderful biosimilars that are under

use around the world Our members make high

quality biologics available elsewhere in the

world just as they have done already for

generics here and elsewhere The savings that

can be recognized as a result of this

competitive market really cannot be

understated But as some of our members have

already suggested ensuring that this kind of

marketplace occurs really requires that

implementation be done in a very evenhanded

and fair way


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Page 401

Good science is really the key and

we feel it is important that the FDA have the

discretion to determine scientific

requirements and to do so on a case by case

basis to ensure safety and efficacy at all

times In seeking reduced nonclinical or

clinical testing the burden rests with the

applicant seeking the reduction to submit

data to show sufficient similarity under the

statutorily defined highly similar standard

Analytical testing is really the foundation

of biosimilarity and some of our members have

spoken to various analytical methodologies and

their importance in this evaluation moving

forward

Certainly as has also been

mentioned by some prior speakers we wish to

avoid scientifically unnecessary clinical

testing both to avoid unnecessary subjects to

these tests and in any way inappropriately

delay access to vital medicines once they have

already been established as safe and effective


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Page 402

by other methods satisfactory to the FDA

We have talked quite a bit too

about the flexible approach that the FDA is

taking the totality of the evidence the

stepwise approach to moving applications

forward It was lovely to have our colleague

here from the European Generic Association

sort of recognizing that this sort of

admiration for this approach Ultimately as

these draft guidances move forward it is

essential to ensure that the FDA can consider

scientific enhancements on a real-time basis

as I think has also -- thats the problem with

being the final speaker -- I think it is also

has been mentioned by a few folks today

What we know today the tests that

area available the manufacturing methods that

are available today are very different than

they were ten years ago are very different

than they may be ten years from now 20 years

from now and having the flexibility built in

so that the FDA can evaluate things as they


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Page 403

present themselves at the moment is truly

essential

Similarly we feel it is important

that data from other countries on both

originator and biosimilar products when

scientifically appropriate may comprise the

full existing product knowledge dataset

Always always always it is about

quality safety purity and potency that

these standards need to be maintained And

really only when biosimilars raise unique

issues should currently regulatory approaches

be changed And then those changes should be

made across the board with respect to all

biologic drugs The issue of immunogenicity

has already been discussed as has naming

although I will of course discuss that a bit

further on

But at the end of the day we just

need to remember that all stakeholders can

trust the FDA approval One of my

predecessors said it best If you say it is


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Page 404

safe we know it is safe And I think the FDA

has really been the gold standard on that If

the FDA commits to applying the same science-

based and data-driven standards across the

board to all biologics consistently and fairly

going forward we think that will continue to

be the case

Lets see Back to the access and

affordability issue It is important really

to have quality and safety be first and

foremost and to make sure that any data

requirements any study requirements that are

brought in are all for pieces of information

that are necessary to FDA reaching

conclusions We feel strongly that analytical

studies that demonstrate high similarity are

standards with which FDA has extensive

experience and oftentimes these studies can in

fact be more revealing than clinical trials

about what can be anticipated from the

molecule at issue That is clinical trials

should only be required and conducted when


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Page 405

that data will contribute meaningful

additional information

Extrapolation between indications

in interchangeability should be science-based

for biosimilars just as it is for the

biologics already on the market

On the tracking issue I would say

that we will certainly make an effort in our

comments on May 25th to more directly address

this but we feel that there is an existing and

robust track and trace system and rather than

create a new system outside of the NDC

approach that it might be more worthwhile to

make sure that that approach is being used as

fully as possible And we do wish to ensure

that any safety concerns are promptly

identified and addressed but that a unique

name or a unique nonproprietary name is by no

means necessary to making that possible and

to the contrary may in fact create safety

concerns and also interfere with the sort of

competitive marketplace that the BPCIA was


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Page 406

designed to create

The World Health Organization

system really must be maintained with naming

conventions used to advise physicians

worldwide of the active ingredients in

medicines Since 1952 the International

Nonproprietary Name has applied to the active

ingredient of every medicine and not to the

product Ideally the USAN should continue to

match the INN to maintain the integrity and

pliability of the global system

Back in September of 2006 before

the World Health Organization the FDA made

the following statement Specifically INNs

should not be used to imply pharmacologic

interchangeability of products with the same

active ingredients when no credible scientific

data exists that demonstrates such Likewise

INNs should not be used to differentiate

products with the same active ingredients when

credible scientific data demonstrate that no

pharmacologically relevant differences exist


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Page 407

And I think staying true to that is essential

to moving the biosimilar access issue forward

Im sorry my slides are in a

different order than they are here

Further on the issue of using the

same INN we are joined by a number of

consumer groups with a concern that using a

different INN could impede genuine market

competition potentially precluding

interchangeability at the state level even

when interchangeability designation has been

granted by the FDA and also likely requiring

the sort of full marketing campaign that is

similar to what is used with a new biologic

with the likely result of increasing cost to

patients

Different INNs would in many ways

decouple existing medical knowledge of

biosimilars including safety information that

is important to prescribers in understanding

characteristics of the underlying molecule

And it is our understanding based on


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Page 408

discussions with providers and pharmacists and

dispensers that the different INN could

increase medical errors for a number of

reasons including existing computer systems

and drop-down menus So taking a closer look

at what those implications are we believe it

is important

As is quite clear from the number

of international companies here today as well

as folks of many different backgrounds

testifying before you this is very much an

international market and an international

place for innovation And we welcome the

FDAs approach to foreign reference products

GPhA supports quality data for all biologics

being recognized by FDA the appropriate use

of data generated in head to head studies with

foreign sourced comparator product as long as

it is scientifically justified no unnecessary

repetition of any studies

GPhA supports a transparent and

public process for the finalization of these


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Page 409

and any future guidances in this area which

will allow our companies to make competitive

high quality biosimilars available to American

patients just as they already do in other

highly regulated markets

I do want to close we can go into

more detail on this in our May 25th comments

but we share concerns about protecting

intellectual property in totality So thank

you very much again for having us today


you for your comments We have ten seconds

for any questions that anyone might have

PANEL MEMBER TOUFANIAN I would

just offer a request for information You had

alluded to the intersection of naming and

potential naming conventions and current

technologies that are used either in the

tracking or dispensing of these products As

part of your submission on May 25th if you

could identify those technologies more

precisely that would be educational for us


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Page 410

MS GLASER I would be delighted

to share with you what we know Our

investigation is ongoing and we are happy to

talk to you about that as well Thank you



On behalf of the FDA panel and the

larger group tasked with implementing the

BPCIA that we represent first we would like

to thank the policy staff that staged

organized and ran todays meeting Jennifer

Hymiller Kayla Garvin Marcia Holloman

Nicole Silva Tomeka Arnett Connie Wisner

Lauren Myers and a special thank you to Sandy

Benton who keeps all things biosimilar running

smoothly I think one speaker this morning

mentioned that we seemed to get guidance out

rather rapidly That is in large part due to

Sandy

I would like to thank everyone who

joined us whether it was by webcast or in

person and in particular we would like to


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Page 411

thank the speakers for their time and effort

not just in traveling here but in the thought

and the analysis that was evident in your

comments generally very concise So we

appreciate that as well

I would be remiss if I did not

once again remind you to please submit

everything that you have said everything that

we have questioned you on and anything else

you would like us to think about into the

docket The docket will remain open until May

25th We take this very seriously The last

docket was extremely helpful to us And as we

move forward in creating what we all want

which is a clear transparent science-drive

pathway your thoughts your comments your

data are extremely important to us as we move

forward and try and implement the BPCIA in the

way that best serves the public

So we have had a very full and

interesting day Todays meeting is concluded

and we thank you for your participation Have


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a good weekend

(Whereupon at 444 pm the foregoing

hearing was concluded)


Page 413

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acceptance 802 841 20920 3612 3926

accepted 32312 35368 3549

accepting 3055 accepts 4014 access 214 55

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accountability 1761521 1787 18261718 1833 1837

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achieved 19710 4001

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acknowledge 17522 19216 19422 36114

acknowledged 695 1649 3038

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acting 16416 action 752 8911

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adding 858 16112 addition 117 482

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Neal R Gross amp Co IncNeal R Gross amp Co Inc202-234-4433202-234-4433

Page 414

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advocates 3211 3518 374 877

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affirmatively 6722 afford 8115 affordability 1525

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afforded 1381 20714 23821

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AfPAs 274 afternoon 108

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agents 177

age-related 89814 aggregates 30711 aggregation 27718 aging 313 agitation 1721 ago 4116 6519

9616 17521 23217 29212 40219

agree 6218 6317 1873 1976 22110 22715 23716 26512 27118 2746 27513 28511 30615

Agreed 15744 agrees 23314

27112 39412 Ahaviah 416

39818 ahead 237 1693

1845 3442 AIDS 37620

37711 aiming 21410 al 221 514 8617

874 2927 Ala 2039 albumen 2181316

2196 alerted 18012 Alexey 216 57

4011 4111 algorithm 28613 aligned 37118 alignment 2079 alleviate 16114 alliance 21315 31

412 55616 1518 165 2120 28161818 294 3519 951321 96112 9812 3811219

allotted 136 1418 1510

allow 1814 1914 451 783 1001 13617 13815 13913 1409 1536 19013 20510 2185 23313 23514 24113 2508 36121 36621 4092

allowance 13920 13922 2371

allowed 122 1313 398 9222 1704 1932 2074 21121 21819

allowing 161 4020 4618 847 16618 18821 23322 2784 39820 39915

allows 125 32511 36017 39110

alluded 22312 40916

all-inclusive 2142 alpha 26212 2635

2642 altering 779

14919 alternate 1917 alternating 667

1081922 11319 114119 115212 116613 117313 11714 35020

alternative 1168 1161719 14113 3333

alternatives 1214 altogether 11613 ambiguity 20816 ambiguous 2105

21113 AMD 891518

902 9146 America 49 713


Page 415

282022 3079 3011 9416 952 36717

American 34 519 8310 1191114 14014 25620 4093

Americans 298 314 5211 6618 878 90610 1368 14918

Americas 329 Amgen 39 66

174152022 175811 17722 1786 18612

Amgens 18111 18511

amino 2621213 26351114 2642 2651720 2662 2721520 27312 27318 28117 33019

amount 355 28819 331722 3354

amounts 3387 analog 2661 analogy 4522 466

4916 15216 analysis 7613

8117 15216 30612 3813 38610 3931113 3931419 3966 39610 4113

analytic 9910 20116 2024

analytical 26913 271 5617 1181 11821 2278 23212 24410 24816 25028 2576 27719 2921 29310 33011 331411

33115 37019 3718 38515 3871 3883 38911 4011113 40415

analytically 10019 1388

analytics 30414 35818

analyze 9911 analyzed 34416 ANDAs 1722 Andrew 215 412

56 2722 2816 3811117

andor 661 7017 8419 11019 11319 1141 11713 12218 238814 32222 32518 3445

anemia 65410 animal 193 5620

1183 23517 23620 3317 37112 3875

animals 3907 announcements

815 919 818 annual 641317

6614 8712 2996 answer 4615 691

11521 15410 15615 19513 2011 20821 238912 28513 35915

answers 111 816 15412 16815 38717

antibiotics 27020 antibodies 5220

6169 2794 31818 31911 33526 3369 33719 340218 340192022

34614 3892 antibody 5218

552222 33710 3394 3408 34515

anticipate 2996 anticipated 40420 anticytokine 2794 antidrug 3352

337919 3394 340271820

antigen 3441720 anti-TNF 33920

34045 Anumula 414

385911 39048 39012

anxiety 3825 anybodys 1517 apart 10315 APhA 1191416

1204 1265 12717 13317 1354 1423

aplasia 6522 6815 21822

apologies 1415 apologize 1418

1517 apparent 16512

3441119 apparently 19913

3455 appear 692 appears 2636 appended 831618 applaud 2489

26120 37615 applauding 39115 applauds 2114

32516 appliance 24916 applicability

23715 applicable 1259

19217 23718 3748

applicant 1614 163412 20919 23419 25012 2641419 27416 35121 3546 35522 35711 37214 38818 4018

applicants 3527 35410 3578 3706 37215

application 6919 1623 1633 1641920 16814 1723 2211315 23318 2341421 23612 250313 253810 2595 26417 2681 35213881622 3537 3546913 35415 35519 35717 35919 3739 374347 4001

applications 12816 13018 15121 15312 15920 1601 16211 16318 16610 17110 26513 2686 35119 35910 37320 4025

applied 461 707 7416 10411 2358913 2378 24922 25020 2566 27218 27616 28319 2893 29318 2968 3558 3663 39322 3971012 4067

applies 466 1725 34220

apply 1121 4713

17213 17319 2451919 2512 25113 25815 2594 26317 267216 2706 2824 2953 30815 3101 32121 3439 3639

applying 25516 2679 30416 4043

appreciate 352 505 632 757 9410 981319 10422 120913 1302 149910 1504 15317 1758 20011 21221 24613 27216 3266 3649 376812 3918 39514 3972 39816 4115

appreciated 255 862

appreciates 649 9812 30917 34722 34817 35110 35216 36013 36718

approach 3117 321 6922 10814 1093413 12014 12815 1506 1536 16012 1881617 20616 206192122 2071319 2129 21211 21418 2154 2193 2227 23221 2331020 23512 23937 24019 2429 24813 26122 26612 26717


Page 416

2684 2721517 27618 27711 28222 28319 28715 290921 2959 3039 30720 3091820 31319 3261818 32619 3354 3386 34313 362918 36321 36919 3797 402359 40513 40514 40814

approaches 8019 8516 21415 2346 27616 34921 40312

appropriate 4321 6718 1246 1797 1868 1926 1961315 2082 20913 21017 2149 21513 22010 2214918 22319 22522 2373 24210 26711 2726 2774 28013 28416 2867 28918 31213 3284 33020 35321 3682 3695 3719 3727 3948 4003 4036 40816

appropriately 5518 1817 2223

appropriateness 7921

approvable 31820 approval 1617

1817 326 599 6412 651 686 706 719 7218 774 8217 8322 976 10012 10113 12121

12322 1242 15015 15420 1622 1671922 1688 170520 1735 17510 17611 17813 1825 20620 23822 2651 30056 34720 3481218 3511 35314 3565 37214 38315 38916 39417 39916 40321

approvals 32114 approve 169 3422

1206 16813 17016 25816 2707 28811 29319 35615

approved 221 302 304 335 547 5510 665 6916 788 792 807 891317 915 929 12519 1509 1519 15916 16817 1794 18619 1904 1913 1936 2006 23217 24820 25010 2546 26768 27311 27613 27819 28211 2938 29420 2955 3011 32810 3322122 3331 3397 340468 341120 3448 350921 35557 35613 36618 37311 38312 3983

approves 1533 35416

approving 683

25320 approximately

132 415 6610 1367 14016 3914

April 8720 887 896 36416

arbitrary 4415 26319 2859

area 9419 1076 1478 150221 17211 1746 2127 22116 2224 22719 22919 24919 26622 2768 28820 29018 29614 3095 31613 3312 34813 3868 40217 4091

areas 1228 1503 1518 1546 15919 2064 21112 21222 2161821 22718 2495 2621 29017 2968 3259

arena 371314 arguably 22414

24416 argue 22718

22820 34222 arm 39212 arms 2552 34221 Armstrong 318 Arnett 41013 array 24917 arrival 1778 art 24816 2502

33720 35818 3713

arthritis 414616 831 2285 33919 3406

article 8721 2356

2428 26020 32322

articulated 2131 2402

articulating 18613 artificial 4004 artificially 36622 asked 347 10318

2901 29619 37222 38513 39214 39718 3984

asking 4212 635 1731 1741 20118 2454 26919 33216

asks 1816 4422 aspect 199 2613

23712 3909 aspects 11722

1236 2062 2071821 2089 20812 2117 2656 31917 34719

aspirational 18522 assay 22310 3415

34215 assays 3301

3371020 3436 3431720 3452

assess 1116 2096 2299 24920 32822 3424 34510

assessed 2297 31022 32917 33421 3678

assessing 16721 23513

assessment 10812 10913 1119 1179 21014 21231014 21419 2399 2407 2724 30721 31010

33320 33414 33516 337211 33917 34015 35511 36311

assessments 24517 3347 33613 3378 33811 34210 34456

assign 28912 3226

assigned 3201012 assignment 3099 assist 7620 8522

12317 1284 assistance 30716

3766 3771 Assistant 26 97 assisted 834

32419 associate 11517

24810 810 92 951115 2211

associated 332 14419 18013 31019 32317 3393 35313 37112 38221

association 347 4717 519 63 710 119111417 1481217 1555 3608 4027

Associations 30510

assume 30518 3271 3371

assumed 3678 assuming 125

30618 assumption 1568 assurance 11416

35116 assure 8113

18819 2347 2808 30418 3563

assured 3216


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30418 assures 1818 assuring 2217

35115 3542 35522

asymmetric 27816 2795

Atlantic 912 attempt 9912 attempting 3588 attempts 3782 attendance 2477 attended 9618 attendees 85 922 attention 7110

2255 24310 3329 34634 35622

attorney 15821 2834

attractive 15720 attribute 118821

1839 29612 3676

attributed 735 1389

attributes 2932 30019 3014

attribution 17613 17620 17720 1808 18215 1835

audio 921 813 audit 4518 August 2353 2427 auspices 2421 Australia 2052 Australian 2056 author 31611

3176 authored 2354

32321 authoritative

32317 authorities 25319

3502 3678 authority 3420

16014 18416 authorizations

1045 authorize 3523 authorizes 1631 auto 616 autoimmune 8222

22866 automatic 4420

5418 5814 624 6221 1797 1869 3674

autonomy 173 233 2412

availability 11113 15213 35422 35722

available 1010 126 228 539 588 808 812 10410 12616 12917 13210 1464 1553 20310 205616 21621 2315 2348 24817 2502 2545 37621 39616 40013 4021718 4093

Avastin 8881216 89814 902

Avenue 112 average 1116 avoid 1788 19011

19117 1928 21719 2844 4011819

avoidable 217512 218567 2197 2191315 22513 22516 23121

avoided 1935 2171516 21915 21916 23116 3087

avoiding 25411

4004 avoids 28526 aware 4717 745

775 145814 14713 18411 2777 28316 28434 2981415 33213 3654

awareness 12610 12713 13015 13111 132519

A-F-T-E-R-N-O- 2041

am 112 82 101 95910 20313

Bb 11318 1726 Babbitt 44 76

3338916 34314 34522

back 147 2919 4910 617 8613 95612 1034 115710 13120 14112 14281981618202028 204462832 2936 3009 30018 30133097 3151438015 404840612

background 276327610 31611

backgrounds40810

backup 29511bad 1613 2519

1848badly 3946Balaams 11614

11618balance 21314

24220 28133544 357183682

balanced 1619 11517 18819

bank 2644 bankruptcies 8215 bar 1973 23421 barrier 1392

3997 barriers 4814

1216 22613 4004

base 3013 3068 based 177 4412

6011 7916 1116 11181221 1143 1205 13822 19418 1952 19816 20422 20819 20910 23611 2381122 24211 2456 25320 257715 25816 26317 2732 27417 2769 2776 2923 3048 30717 31420 3211114 3361 3391 34420 3514 3693 37118 39217 3944 4044 40722

bases 20619 basic 22324 basically 2611

10114 15022 25920 2828 32212 35816 39810

basis 6713 1622 20222 23318 24115 2541 27319 27415 28714 29813 29967 31012 32812 3513 37314 3861 38819 4015

40212 Bass 36 62 14810

1481314 1548 15421 1554 1567 157422

batch 309712 31456

battle 2019 2317 2413 2865

beating 37516 beats 521 beginning 431

1036 25515 begins 23922 begun 35110 behalf 4018 5912

7519 8422 877 1549 1591 26110 32413 3339 3476 4107

behave 3041 behavior 1648 beings 38810

3892 believe 127 295

337 4219 4319 4514 4722 5113 6317 6422 705 759 100691410015172110157 102310 10215 1046 12513 12711 138210 139914 13917 1406 1454 14914 1516 1576 15911 1603 16417 16817 170317 17117 17611 17715 183711 19719 20510 2136 221914 2339 23415 2368 23747 23819 2395 240112


Page 418

2417 2434 25122 25219 253717 2558 25611 2571217 2581420 26011 26118 2621114 26512 2683 27411 2755 279111722 28714 31416 3813 39216 39418 4086

believed 2363 believes 7715

7812 8312 843 849 17511 20813 2122 26611 30512 3489 3492 36821 37011 3711420 37212 37316 37412 37712 37914

belt 3579 beneficial 819 benefit 463 7768

9817 10415 1366 1382 14818 14921 15214 1892 1908 29111

benefits 787 1367 14822 1494 24015 24122 37621

Benton 146 41015 best 243 3417

3817 481515 5620 8511 13721 19720 2348 2737 27414 34312 3775 4001 40322 41119

better 5611 8518 1194 1349 226161718

3436 35881112 beverages 1010 beyond 1414 273

2712 315 639 10546 1467 3033 3788 3827

bias 16322 16419 1662 17310 1744

big 24214 36015 3862

bight 2847 bill 8822 14115 billed 3136715

31316 billion 3016 1371

15221 1532 292811

binding 3064 31119 31216

binds 3129 bio 31520 3165

34715691620 3482917 3492 34916 3504 35110 35216 355214 35614 38520

bioanalytical 2084 biobetter 3189 biobetters 318315

319714 biodistribution

2247 bioequivalence

721 1018 3869 biogeneric 25220

2548 2558 2566 biogenerics 24719

24822 24922 2504 25113 2542 2564 31412 3153 31914

biogenetics 25215 2562

biologic 31 516

1620 177 2220 2510 33219 3910 4718 5216 5619 5816 659 6612 77722 8813 9146 926 927 951422 996 1022 1033 1035 10412 10510 10611 113111421 11420 11534 1208 12221 1373 15210 159917 1753 1783 1801317 1901320 1924 1921517 19356 1951 2006 2472 2529 25467 2895 29311 30311 30412 30622 3142 32421 3253 3499 3555 3782 37871218 3799 37921 38222 38319 38421 3993 40315 40714

biological 178 1868 1915 2010 2218 5622 583 821221 1206 13712 1496 1513 16118 1676 19919 20020 24917 26216 2643 27817 28015 28313 28414 2851820 29116 30520 30712 35322 3597 36113 369618 373818 37322 38411

3928 3953 biologically 1821

27222 2842 biologicals 3686 biologics 2511

916 1018 171 171718 182 211118 2236 231 3315 398 41610 4458 453 539 6219 657 7718 9012 9018 911214 9617 971115 10211 1031120 10411 1238 12613 1296 13612181921 1376 13817 14015 15115 1526 1761622 177311 18019 18115 1829 18822 19214 19318 21120 21718 2366 24117 2424 24513 25017 2522 25311 25519 25616 288391516 29220 29319 29416 30120 30218 30310 307512 33920 34714 3491920 3586 35910 36322 36520 36722 36912 37422 3779 38078 3834 38613 39210 39316 3998 40013 4045 4056 40815

biologicbiosimil 37913

Biopharamcopeia 32220

biopharma 31614 biopharmaceutical

3161318 3173 31714 31918 32220 32416 33310 37315

biopharmaceutic 322101517 39022

biopharmacopeia 31713 32315

biopharmacopei 3245

biopharmacom 3161619

BioProcess 3242 biosimilar 14 89

1015 181820 1922 3320 3422 357 4318 5112 5414 5619 5815 6215 68412 6912161718 70616 7117 721720 734 755 77416 781 7811 791 8056 8014 8314 841 905 9119 921 921015 933 976 10011 1019 1011319 1022 103344 10510 1061021 1207 12214181822 12321 1241 12519 12619 12710 1292 13019 13215 1346 1433 15315 1541722 1591020 16015 160822 16136 16181920 1623 16211 163412


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16317 1668 1681416 16913 1691618 1705 1702022 17311 1732021 1765 17925 18018 1824 1861418 187215 18916 19123 1931416 194271520 19559101418 196614 1979 19817 20216 2033 2052459 20617 20720 2089 20916 2102022 21214 21212 2135 2201820 22218 22656 23221 235410 23711 2404 2431 24520 2467 25013 25135 2577 2595 2627 2641517 2652 2651017 2667 27122 28816 289720 29010 291617 29358 29311 29411 295722 29616 2962122 29911 29913 3001520 30234816 3031418 30438 3041117 30520 30616 307722 308817 31221 3141 31722 3201315 32110 3232 325513 329913 33312 33315 3341 3351719 33810 34171422 3446 3457 3467

34910 350913 35020 351920 352261422 353314 3558 35711 3601116 3632 36411520 365151921 366517 36720 3683 36912 37046921 3715 372114 373410 37412 3741415 3759 3781318 37921 38312 386415 3861920 38711 38717 3911018 39291822 3932 39317 3943410 39719 4035 4072 41015

biosimilarity 1021 113 516 10812 10914 110479 11015172022 11123615 112151822 113346 1145 117679 11811 118131518 15771619 18818 198810 19925 21622 2173 2349 2373 2371619 2381 23816 2405 2429 25719 25813 28012 29110 2975 299421 30620 30818 31111 32145 32519 32710 3282 33821 34820 35511 35922 3617 36311 3754 38311

38518 3962 39711 40112

biosimilars 117 92 111114 176 1713 18211 251 3119 3269 33315 3512 4214 434811 45357 47618 507 513415 54610161719 551217 581016 59369 618 6214 6311 6412 65113 66689 6621 701112 719 728 77614 7721 782713 7821 8018 8110 8251018 8322 9013 9112 931 961117 977 9811 995 1005 10121 10211 10320 10526 12022 1211922 122611 12320 12414 126810 128371216 1295714 1434 150916 151712 153410 1544 16414 1717 1755714 17617 17718 178113 17813 179718 1802 1846 1868 18717 18820 18918 1904519 19111 1951415 19521 19918 20111 2021 20422 2051 20620 2111922 21613 2171422 22010 2258 2314 23513

24120 2423 26411 2885812 2881922 2905 2917 2929 29811 3011119 3021921 3037 30310 3058 30812 30921 3122 317720 318814 319713 32022 32322 3266 3325 3368 34210 3472021 34811 34919 35616 35810 36113 362914 36921 370112 37618 3771516 37915 38029 38116 383321 38322 3844 3898 391911 3991617 40011 40311 4055 40719 4093

biosimilarscom 317111 3244

biosimilar-like 28212

biosimiliarity 2371

biosynthetic 27216 28378

biotech 18122 39135

biotechnology 22 415 728 819 964 17421 17519 18119 2165 23211 2434 26112 31617 34622 34751011 3569 3913

biotherapies 15913

BIOs 35218 3576

BIO-member 3566

bipolar 3824 bit 2120 3711

4822 7417 1055 11418 1305 15713 16713 16813 1842 185211 23018 25911 28322 28813 2993 4022 40317

BLA 16118 16214 163216 1904 2007 2206 26720 2697 27015 32115 3303 3511215 35117 3525 354812 355720 3563

BLAs 16319 1667 2685 32115

blood 5311 3185 board 40314 4045 Bob 914 1685

2238 bodies 3312 404

459 6113 2181 22521

body 552 9719 984 1119 17013 22521 27712 3064

book 12316 13116 31615

borderline 2742 borrow 18116 bottom 2115 893 botulinum 2114 Bough 34 519

119101213 1302211 1331 13320 13513 1884

Boulder 32417 bound 11116


Page 420

1137 boundaries 2149 bounds 2773

27816 2796 Boyle 217 59 502

50410 60410 6118 62822 6312 641

boys 986 BPCI 1019 112

11311 11411 13616 2563

BPCIA 15912 1621521 2489 34715 3484 35120 3523 3532 3543518 3681817 3694 3752 40522 4109 41118

BPCIAs 2682 3561

bracketing 2771 brain 2248 brand 2515 5318

5811 6220 662 7914 824 10412 15219 19119 1941 24714 2515 254717 25511 2944 29722 298256 31322 3496

branded 320 620 13118

brands 2521010 25517

brand-brand 25212

brand-generic 25212

breadth 32422 break 10678 148

8616 956 31513 breakdown 31719 breakthrough

382616 3852

bridge 2936 35315

bridging 2082 2373 2771022 27857 32611 3531216 39217 3954 39610 39720

brief 723 7719 briefly 993 2064 bright 2647

27214 2811011 2821622 28319 2842112222 28511 2862

bring 289 3118 9121 1361314 23522 24120

bringing 2417 1523

brings 3993 broad 1013 279

8722 1943 20710 2134 22717 3223 36816 3757

broadening 33010 broader 14611

22422 3956 broadly 20210 broad-based

15821 brochures 812

17922 brother 38020 brought 1986

40413 Bruce 44 76 3337

33315 budget 2812 build 4213 4519

1507 building 112 3765 built 15010 40221 bullet 1987 23022 bullets 2611 burden 736

22710 25414 25511 2806 4017

burning 3082 Business 2472 butcher 1517

2046 but-for 1681020

17010 2783 buy 8820 14115 buying 3982 by-step 1094

CC 26 316 615

21710 26143301618

Cabral-Daniels220 512 7516 7517

calculate 111111121

calculation 11815calibrate 20712call 717 971214

26615 277327917 32310

called 225 294 464 7219 1112 1113 131151658 204202775 3102 3182

calling 732 31713 32219

calls 27914campaign 8018

8312 132517616 1843940713

campaigns 841012713 1311118417

Campus 111cancer 215 56

281617182129461012142915172021

3036691319 302021 31479 3110121314 3218 35101019 386 8220 835 88112 8913 9020 21016 2283

cancers 301415 candidate 2576 candidates 6619 candidly 17522 capability 1577 capacity 3765 capricious 28510 capture 713 1572 captured 13318

2091 care 36 62 4022

4215 441820 481415 763 773 8116 8822 1192122 14811 14816 26113 35611 3764 38413

career 1362 16516

careful 34016 carefully 139

28512 careless 883 Carolina 1611 carried 36418 carry 195 5810

10920 11010 1195 21720

carrying 25510 carte 2039 carve 2632 case 761015 8012

918 1127 1135 11421 15115 168127 1941 19722 21717 22417 2294 2331818 27319

27319 2741515 28412 2871515 29311 3072020 3089 3095 3101212 34218 34415 3881818 39210 40144 4047

cases 6615 714 7618 8722 2191 2312 27520 2867 31014 3143 31810 33014 335202235613 35917

case-by-case20222

catch 1862 34633 categorically

39419 categories 433

1901 categorized 29722 category 8119

3303 33519 cause 3068 3110

3114 6819 21821

caused 559 6511 causing 14720 caution 12414

2071 38320 cautious 3117 664

1506 1535 15710 26612

cautiously 2768 CBER 95 CBO 13622

29213 CBR 42 75

3241115 32516 32639 328717 3293 3309

CDER 81922 93 26714

Cecil 33318 cell 179 2619


Page 421

6522 6815 9715 21822 2644

cells 1710 9711 2643 27012

census 8414 center 11151719

235511 8511 916 8715 3764 37616 3816

centers 8417 11922 34711 3767

certain 1217 391 11416 1745 189415 19219 21720 22717 2981 32517 3271416 32918 34719 3636

certainly 157 2916 404 6719 744 7721 827 873 9214 949 1331521 13617 138513 13967 1403 1414 14614 17710 1871 1915 2003 2144 21810 23417 237118 23921 24221 2442 3874 40116 4058

certainty 3959 certification 3543

35414 3575 certify 35410 cetera 1027 1045

1069 1271 14520 2907 2948 3883

chain 1007 17617 18017 1827

chairman 9521 challenge 8116

1776 21411 29122 34112

34322 34421 challenged 2452 challenges 175

331 567 7621 12416 1756 17815 1826 2143 2435 37111 3788 38221

challenging 3433 chance 1421 462

2138 21516 3467

chances 18520 change 1711 559

614 741 1041 14121 14322 14512 1473 15199 21937 2593 29320 29419 2955 29912 3674 3741

changed 601416 1518 40313

changes 4310 5313 651422 7210 7317 746 9717 9838 10310 1337 17511 1774 1981519 22514 24516 25018 266111317 2831 29115 2934 29789 3001517 3016 3205 33019 35913 36913 39520 40313

changing 14121 14122 1421 19820 28222 37711

chaos 32211 characteristic

30012

characteristics 27315 29119 29821 30312 40721

characterization 2085 23214 2343 23520 2383 24318 24451112 25616 2743 27719 28312 2922 3894

characterize 2641419 26511 32211 3588 3882 38910

characterized 26514

characterizing 2337 35810

charged 445 charitable 4014 chart 10521

10613 cheaper 3212

8818 9120 926 cheaper-priced

8820 checking 1439 chemical 395

2303 30419 37015 38610

chemically 9710 26218 2633 2731 37718 3789 3869

chemicals 3884 Chianchiano 218

510 6435 744 7419 7513

Chicago 3897 chief 289 91213

2816 13522 1908 20417 2165 2328

children 3809 choice 5818 927

19722 26915 27278 37920

choices 7815 37419

choose 7915 11212 20920 26818 3284

chose 3157 Chow 32 517

1072022 1081 11016 118522

Christl 117 912 1865

chronic 411 6511 764 8368 1939 37710

CIDP 2113 circle 29516 circular 2098 circumstances

7119 1657 32522 33514 3374 3636

cite 8718 903 32321

cited 5613 cites 889 claim 11114 1136

15411 2203 claims 1463

22012 clarification 6122

1893 2065 21112 21222 2137 22320 22422 23817 2623 26917 31411 32510 3289 3312 3336 36118

clarifications 21110 32614

clarified 20814 clarify 625 12114

19218 1948 19849 19912 20914 210112

2117 21214 2574 3271621 329111522 33018 3319 3554 36222 36358 3645 37317 39311 3979

clarifying 1311 3293 36217 39011

clarity 17512 1927 19310 19659 2649 28422 2852 32521

class 2013 26715 397 554 938 17711 17820 20516 24722 26814 27821 27914 28018 3217 33120 4002

classes 2681719 2695 27818

classification 2743 classified 1296 classify 27013 clear 3022 3120

4277 451418 6911 10615 1095 1144 1252 15720 16522 18718910 18920 19114 19316 19416 1977 20219 2067 22089 2316 23820 23914 24512 27818 28210 286412 31013 35913 36918 4088 41115

clearance 11110 clearly 932 12322


Page 422

12521 1321317 13620 1791 1894 1946 1979 2587 26615 3463 3507 36222 3638 3646 39312

clicheacute 421 clients 32419

3251 34321 clinical 1819 193

202617 2749 333 356 3622 3791216 381 43419 517 5320 541617 561619 57119 5814 62210 6712 6910 9113 963 9911318 9922 10011 10112 1037 1067 11317 11481315 1182 1381122 1392 13918 1642 1692 1775 1871213 19417 1996 20116 20251114 20511 20838 2101314 21418 21514 21721 22251013 2235 22956 23517 2361821 2385 23814 2391316 23919 24022 24213 243319 25314 257917 25921 260613 2791 29120 2923 2936812 30220 30313 3041522 3055 3072 3101422 311161317

31222 3252 3261921 32779 32720 3281013 32916 331719 33320 334714 3355815 3363 3361218 3372 3371822 3383 3396 34015 34114 3429 3451420 34611 3501522 3512 36510 37016 3711920 3725 372612 37811 38369 3861116 38618 3871214 3871522 3888 3881113 3895 3935 401718 4041921

clinically 704 22221 22316 2291 2451 30022 32722 33410 3381722 345912 36110 3698 37013 371622 3885

clinically-proven 2885

clinically-relevant 3284

clinician 6422 clinicians 736

30120 clinicians 3029 close 218 12820

2426 2453 3024 30716 4096

closed 141 closely 1118 154 closer 4085 closing 715 1293

21217 28014 closure 6812 697

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coherent 36017 cohort 5719 coincide 28112 cold 533 collaboration

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collected 6520 7614

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colorectal 2821 296 303

combination 1569 38519

combine 308 combined 21215

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comes 422 1419 14318 22920 24715 26021 29413 29816 29913 3814

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commend 1520 13941220 34717

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comparability 1981521 24514 2911114 29311 29317 29420 29526 2979 3275 3631012 3951418 39637 39618 3985

comparable 1649 31217 38913 3907

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Page 424

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Page 427

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Page 429

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drifting 29611 drifts 29616 drive 973 21713 driven 12819

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duplication 2569 duration 7120

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efficacy 181 194


Page 430

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Page 431

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Page 435

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goal 9612 2265 2369 2375 24218 3349 34119

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Page 436

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Page 437

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Page 438

identification 12610 1771316 18015 18921 19114 23515 3493

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identifier 7018 identifiers 733

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IDF 501313 5110 549 563

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Ig 5613 5712 IgA 616 ignores 3184 illegal 464 Illinois 1591 Illinois-based

20419 illness 413 765

9210 3811319 38122 38415

illnesses 528 3851 illustrate 34718 illustrates 7614

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196 2621 502 5012 527 33411 33818 33914

immunoassay 34010

immunodeficiency 501619 519 52591216 531 534 5421 5521 566 5913

immunogenic 3033 3632 37113 3831

immunogenicity 2712 681920 994712 21013 212710 21419 2151517 22021 22413 2271921 2284921 3074 30761021 3081 31010141921 328161920 32915 33321 33417141621 33551620 3365 336131619 3373712 3383 338811 339710 33921 34015 341518 34259 34219 3432 344512 34513 36315 372521 38311 3876910 389115 40315

immunogenicity- 34319

immunoglobulin 52141821 536 53718 5415 55161116 5610 5710 592 597 62813 631314

immunoglobulins 538

immunosuppress 2283

immunosuppress

2763112122 immunosuppress

3366 impact 157 5315

6620 8219 838 846 951 2887 3364

impacted 39312 39318 3943

impactful 8114 impacting 1647 impacts 9719

3928 39310 impede 4078 impediments

22611 imperative 4518

1407 24017 2653

impermissibly 16311

implement 10912 15314 15912 1765 17722 2375 23922 24112 3688 3752 37811 41118

implementation 1017 111 12010 1235 1267 2066 21315 2489 2492 25615 26119 34714 3554 35620 39912 40021

implementations 20519

implemented 1914 1295 17221 24013 24217 2438

implementing 507 805 17914 1916 242115 25617 3484 4108

implements 36817

implicated 2527 implication 2849

30812 implications 1775

17817 218812 26521 2728 3957 4086

implicit 2203 implied 1794

32110 implies 3087

33419 33620 imply 15717

34911 40615 implying 1788

33013 importance 153

9315 1776 2336 2653 3094 33321 34716 3925 40114

important 181 20916 2614 272 285 32814 3222 374 3811 4222 4619 4820 561 7018 786 80320 856 8717 904 938 9421 991114 1051220 12019 12514 1274 12913 1329 1332 1383 13917 14917 1637 17518 1762 1772 17816 1791116 1806 19211 2002 20516 21312 22015 22311 224913 22812 2361 240112 250122 25328 25613 3257 3264 3346 336815 34121

348415 3541 358621 3592 37115 3801 3831017 38416 39512 39821 39913 4012 4033 4049 40720 4087 41117

importantly 3721 3722 1225 12613 2409

imported 9121 impossible 10120

1064 11412 11514 14012 1646 23646 24219 3798

impractical 22611 impressed 37520 impressions 20522 improve 4022

2266 3774 improved 4610

773 785 22011 3452

improvements 1348 29922 3007 35611 382812 39922

improving 5014 7522 3829

impurities 21811 30710 36322 3899

impurity 2101 IMS 15216 inactivation 543 inadequately

26514 inadvertent 10622 inadvertently

16310 inappropriate

16712 26418 inappropriately

40120


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incentive 3685 incentives 15915

39113 incidence 2191

32820 3297 3432 34419 345615 3516

incidences 3407 34419

incidents 3113 6614 3394 34017

include 71713 8414 8513 10814 1213 19022 19313 20015 26217 26617 29714 33018 33522 34115 35018 35121 35315 37014 39212 39414

included 12418 17921 3348 35014

includes 1911 3314

including 1113 1219 222 532 589 7118 7917 9113 11722 11920 12022 1357 18915 21321 2191 2355 2407 2423 2917 31911 33119 34816 3758 37710 3935 39421 4009 40719 4084

inclusions 3258 inclusive 21611 incompletely

32919 inconsistencies

7510 inconsistent 692

23820 2638 incorporate 1812

2087 2119 incorporated 1817

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increased 444 558 6820 1809 2191 2784 33417 33617 3421520 34316

increases 383 15913 34412

increasing 15211 2884 40715

increasingly 2883 39214

incremental 3828 3821216

incumbent 30920 37317

IND 1406 28821 3273 3291 33113

independently 19910 24010 2414

index 110151722 11123 11222 11334 11767 117131314 1181315

Indianapolis 39020

indicate 686 7414 12322 1242 13213 1871 21912

indicated 612 12521 13218 1938 36616

indicating 354 9320

indication 691520 1391221 2226 2222022 2249 2273 27517 27620 2773 28013 306710 32811 3321722 33910 344910 34410 3721317

indications 535 13922 1401 14616 1941617 2113 2172 2767 2761319 2772 29418 2971 3012 3051516 30522 31214 3218 32810 3291618 3398 33911 3409 341220 3508 3514 3614 3624 4053

indicative 32135 indicator 5621 indices 1091 indirectly 22312 indistinguishable

10020 24413 individual 191517

5320 6319 1221720 1231 20612 33121

individualized 469 individuals 2214

4017 518 5222 6110 9019 18420 38915

industries 3239 industry 45 78

28913 16517 20710 2139

23722 2434 3173 32222 32311 3269 34318 34622 3475 3506 35317 38619

industry-grade 3174

inefficiencies 20816

inevitable 1658 2954

inevitably 16511 3865

infection 444 5221

infections 532 562 919

inferiority 33420 33612 337716 338115 34310

influence 18415 224719 22721 3316

influenced 768 influential 18420 inform 20217 informal 1120

3231 Informatics 15217 information 41

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informative 795 35819

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infrared 2099 Infrequently 4121 infusion 5316

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ingredients 4065 4061720

inherent 187 331 4317 13618 38221

inherently 38520 inhibit 28913

29922 initial 1017 9613

12010 3484 initially 1031214

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17814 initiatives 3267 injectable 8221

8813 9135 injected 26116 injunction 16513 INN 25110 2533

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innovative 7718 8516 9213 964 159617 1752 18018 23210 2671922 2686 29217 3567

innovator 431318 443 9211 1401 16220 163216 16319 16521 18919 190220 19112 19220 1949 22020 22522 2362 2592 28015 32121 34919 35020 35415 3587 3786 3921113

innovators 13910 17116 2261 3758 3863

innovators 1633 16312 3525 35919

INNs 2525613 4061419 40717

inpatient 12510 1342

input 1013 119 682 10816 11310 1201214 1921 206811 21414 3689 3731

inquiries 7619 insert 7116 1474 inserting 2418

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7210 inspection 1818 instance 754 9014

901722 1509 15115 15755 3083 33221

instances 1728 213610 3306 3998

institute 41 73 15217 31627 37814

Institutional 2471 institutions 34711 instruction 1264 insulin 26522

2674 3911 insurance 245 insurer 5820 insurers 2020 213

2313 4215 integrated 1184

12620 1345 integrating 1465 integration 7818 integrity 20512

40610 intellectual 4099 intelligently 20510 intend 1315 3938 intended 2207

27115 2753 2917 31419

3275 intent 2381318

2448 intention 3371 intentional 21712

37010 3903 intentionally 9221

22011 intents 10817 interacting 1306 interaction 12622 interactions 20712

2483 intercellular

30519 interchangeability

1921 2711 3713 436 4421 4517 516 6216 672 6710141822 6847 10220 1081722 11310 1146 11513 11712 12210 1243 12611 128811 13122 1385 1393 14010 1422 14313 1501719 1511214 15511 15513 157812 15718 18747 19811 199211 2111416 2171 22014 22112 23012 2341013 23420 2381 2466 2491114 2501621 2518 2533 25719 2583 2593 28012 28718 2901819 29316 29318 29546 2966 3086 3322 3481319 35512 36120 36216

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interchangeables 12410

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interest 14510 1513 1618 13014 2256 2351 2478 35719

interested 118 143 151 5110 8510 1309 13317 1595 2331

interesting 129 246 21812 3451 41121

interests 3544

interfere 921 349 488 40521

interfering 3820 interferons 2114 internally 13014 international 319

42414 618 75 76 293 5518 25114 324211 32415 333810 38510 4066 40891212

interpret 2106 2641

interpretation 10818 20815 2135 24315 2713

interpretations 2139

interpreted 2128 interrelated 2735 interrupt 1122 intersection 40916 interval 11116 intervals 35313 intervention 675 intravenous 539 intrinsic 3076 introduce 816

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introduction 17917 1846 2422 3409 37010 37617 38518

intrudes 463 invest 15311 investigate 18314 investigated 201 investigation


Page 441

14618 4103 investigations

1643 investigators 8819

894 1644 investment 18021

28310 37314 invitation 2077 invite 2144 28620 involved 2314

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issuing 30918 3648 39116

items 903 20310 iteration 718 ith 11222 IVIG 2113 569 ie 3274 35013

JJames 31416 411

61215 2324 2614 37518 3761

Janet 26715 Janssen 313 611

2162614 January 798 Jay 313 610 2162

2165 JD 510 Jean 32410 Jeanne 74 32418

Jennifer 41011 jeopardize 32622 Jim 2327 2617 job 1084 1655 Joe 17418 Johnson 21678 join 39114 joined 3958 4076

41021 Joseph 39 65

17414 Journal 8721 887

896 2353 2428 judging 1577 judgment 24510

24518 jump 29314 jurisdiction 30916 justifiable 2798 justification 2086

2384 296345 3069 33722 37211

justified 20921 21921 3613912 3625 39422 40819

justifies 37916 justify 2978

3001416 39215 398811

JD 119 24818 41216

KK 11311Kalyan 414 3858 Karl 320 620

3021316Kayla 41012keenly 5110 775

1595keep 1118 1510

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3815 keeping 5514 869

10517 keeps 29610

41015 key 5021 10811

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kidney 219 511 64471317 655 65611 66315 6618 7015 7218 739 1013

kind 9916 1195 13110 13316 13435 16517 20020 2023 24518 31212 3441 38814 40019

kinds 16812 24517 3234 39213

Kingdom 8910 kits 12721 know 147 251414

2517 2916 3018 312 3219 339 331118 3415 369 3711 388 3911 4035 4121 4510 492 6013 8515 9017 9118 9771014 98516 994 10213 1039 10514 10613 107710 1105 1261 13115

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knowing 447 21515 2577 34322 35716 35815 38613

knowledge 2623 998 1647 23214 3013 31211 3414 3757 39521 3961 4037 40718

known 1031 17520 19413 20524 2125 30613 3194 336410 3417 3471 36210 3745 38011 38814

knows 7721 Kozlowski 22 817

818 264 36312 3710 471 6121


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Kozlowskis 278 7412 13421

Kristin 36 48 62 711 1481014 3671316

L lab 9015 947 label 12322 12522

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labels 457 19316 19322 194215 19420 1955 2021 28011 37820 3843

Laboratories 38 64 15818

laboratory 884 22213

lack 1242 1586 34917 38413

lacking 1301415 lady 10318 38011 laid 23315 Lake 20419 Lance 317 landing 1324 language 3420

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languages 841113 large 5719 743

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larger 1719 11117 13819 28117 2841 33510 4108

largest 281922 296 9012 11917 2471011 27715 38120 3912

lastly 1403 23321 2969

launch 35715 launchability 3196 launched 225 291 launching 292 Lauren 41014 law 14020 16320

16322 1641422 16520 1682 2587 26120

26222 2701522 2713 3545 35620 35713 3932410

laws 1286 35719 lawyer 1691 lay 831315 845

38019 3811 leached 6816 lead 489 1774

2204 2244 25011 25922 26012 35419 35720 3811

leader 1594 20421 26112 37619 39021

leadership 14911 leading 3068

17421 1752 1763 2053 24721 25619 2865 30111 35422

leads 25618 Leah 117 91 learned 24911

25614 2892222 2903 29218 31422

learning 998 1278 leave 3938 leaves 14113 leaving 1336 led 8922 2908

35610 left 105 2013 985 left-hand 29512 legal 8911 21918

221317 26416 27014 3531 393818

legally 2651 legal-scientific

39313 legislation 677

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legislative 3419 38118

legitimate 29021 length 22120

26213 2846 lens 23720 lesser 3285 lessons 25613

3152 letter 1784 letters 8815 lets 6013 1652

16914 31022 3121 4048

level 42191321 452022 465 4920 8514 9713 13821 14320 1459 2421317 24322 24414 24819 2725 27413 2762122 27939 283114 40710

levels 2022 21014 27921 3066 34412 3892

leverage 1544 3796

leveraged 20213 leverages 3845 license 12211

1981921 20021 35310

licensed 6712 691214 8917 915 12819 1606 1609 161918 16214 16316 23621 2372 2547 2771021 3264 33218 3521421 35345 3538920 3612 3749 39122 3933 39415

licensing 1622

licensure 5321 2468 3293 3513 3695 3745

life 196 4610 5015 6517 779 838 14918 2994 30410 37711 3861

lifecycle 1771 lifelong 5221 lifesaving 359 779

3568 lifetime 3020

2991118 life-saving 14918 life-threatening

729 765 8213 light 1720 1036

1809 3265 3956 liked 1395 likeliest 5121 likelihood 16510

2221 2309 likes 2238 likewise 164822

40618 Lilly 415 39016

3902021 39129 39412

Lillys 3915 limit 17018 1969

33815 limitations 1217

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limiting 23110 3495

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Page 443

2811011 28217 28222 28319 284271122 285111 28628 3085 35814

lines 373 9716 1665 18011

lining 1438 link 1925 1996

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listen 2475 listing 1175 lists 2142 literally 2846 literature 11611

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live 86 4716 liver 2244 lives 313 5521

3774 living 216 58 313

4019 4113 4212 439 4419 479 5019 5211 8118 9711 2643 35616 36912 377220 38121

LLC 4414 76 3338

lobby 10411

local 1104 1112 11115 11221

locally-sourced 2789 39215

located 104 32417 logical 23921 logistical 1236

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logistics 12213 12612 12715

long 204 358 10115 1118 25319 30819 32213 3595 40818

longer 1412 313 5612

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looked 14515 14714 22410 2261 22816

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looks 28610 3454 37610 39719

lose 425 24012 loser 4121

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lovely 4026 low 21518 32819

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lower 823 11116 1137 152313 1811214 27622 28920 3088 33921 35618 3801 38914

lowest 3899 lubricant 6821 Lucentis 89816

8921 lunch 108 2039

20313 2045 lung 3112

MmAb 17856macular 89814magnitude 6620Mail 89719mail-service 1497main 1812 1059

10515 2851431613

maintain 70127116 1958 1988 28217 309153544 40610

maintained 7016 1596 2063 20721 28519 34610 37919 40310 4063

maintaining 9315 1817 21314

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maintenance 29921

major 537 557 9015 9719 987 10713 114710 16314 26521 28014 3302 3359 382419 38422

majority 833 14019 27113 2746 33810

making 5122 571 598 17913 18017 18219 18319 18411 19017 1996 20515 22612 24517 2504 3589 40519

maligned 1369 14819

Maloney 24 945 381314 5922 605 611420 1421920 1441 1541415 1551 18213 1831 22910 2597 2601

manage 12020 12311

managed 8822 11922

management 211 36 62 916 5217 7610 1218 12110 1481116

manager 4112 1366 3762

managers 7616 14818

managing 12318 1495

mandate 332 379 3712 2381419 2396 25821

mandated 2441 2488 25318 25412 2555

mandates 25811 3532

mandating 3716 23319 25522

mandatory 1820 266

manifest 22220 manner 15912

2073 20811 2338 2425

manufacture 921 931 10015 12818 2631822 3897

manufactured 5115 6111

manufacturer 1916 5322 557 611 6918 7021 7322 10216 1761421 1787 18261618 1833 1837101218521 2578 30021 35310 3782 3961319

manufacturers 49 713 5113 5911 7220 12822 1416 1517 1584 17111 17610 17712 1813 20216 36717 39520

manufacturers


Page 444

1418 1784 2805 manufacturing

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Marchand 26 96 97 6222 10421 1301 18317 2017820 3018 3118

Marcia 217 59 50210 41012

Marcie 34 519 1191013

margin 33420 3361221 3377 3371516 3381 34310 3441 3988

margins 1182 mark 318 618

1679 2873 30317

markedly 1006 market 191 336

9117 9215 936 1005 12710 12820 1301620 13210 1371415 14516 1476 14916 15118 18010 2051611

20919 21510 24120 24719 25816 29820 31419 32117 36618 3677 37618 3803 3911 39918 400517 4056 4078 40812

marketed 17514 2666 294815 32319

marketing 72321 789 7924 922 13220 1398 17712 32012 3388 36116 40713

marketplace 329 14311 1779 1847 1925 20218 2424 2481 25520 40020 40522

markets 1508 30222 4095

Martina 30122 Maryland 112 Maryll 28 911

4818 1672 3572 36513

massive 28310 match 36211

40610 material 1317

13211 2644 27922 3785 3881 39812

materially 1737 materials 6978

8021 841013 13220

mats 813 matter 10919

22111 23418 2395 26712 27015 3075

3926 39620 matters 2957 matures 12211 maximize 22121

2291317 2308 maximum 2793 MBA 69 McCamish 318

618 2873511 2984 2999 3001 3008 30116

MD 612 mean 2411 2519

3613 3945 4920 62712 6312 8510 11021 11219 113120 11610 1187 1447 16911 2072 21519 23120 2641 26722 26916 2866 2985 36218 38520

meaning 12621 meaningful 704

22221 22317 2451 30422 33410 3381822 345912 3698 37013 3716 3721 4051

meaningfully 2744 means 1413 4616

11518 16917 2348 23616 26116 2643 31216 3507 3675 36914 37115 38520 3884 40519

meant 972 1545 33218 34611

measure 21515 37313

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21513 2524 measuring 11013

3431 mechanism 10316

2112 2241216 2241719 30517 30612 3127 329101217 34121

mechanisms 12413 22414 27919 29420

mechanistic 2776 31211

media 121416 18322

medical 1215 811 169 214 2213 441114 511920 7921 802 8115 8215 881014 964 1463 20418 2328 3091 35617 40718 4083

Medicare 1492 medication 3219

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medications 3216 339 428 9418 12020 13722 149618 152411 15316 2245 3828 4007

medicine 33 518 2513 4122 426 466 711 1082 1221 17713 17820 1812 38418 3995

4068 medicines 31 47

516 710 332 5216 5311 555 5515 5822 9514 9522 976 1753 18018 18922 1968 20516 3607 378713 37921 38222 38319 39146 39919 40121 4066

MedWatch 7215 12516 1468

meet 591 21918 2559 25818 2961 308517 3313 34122

meeting 101 1120 1221 4918 505 641317 7712 15318 18119 2474 25518 2881 289579 28911 33116 33319 36719 3833 41011 41121

meetings 1669 28821 3327 3526

meets 599 melting 2013 member 31020

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Page 445

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members 114 21 121 137 41419 649 9516 11918 11919 13013 1494 2356 3476 34716 4001012 40018 40112

memberships 2211

memorandum 1686

men 3020 mental 413 38112

3811921 38415 38422

mention 2111 2064 2225

mentioned 231 2657 3614 472 4722 4820 621

7317 8516 992 1099 1326 1333 14519 146210 1542 156218 1575 1674 18914 1985 19916 200513 2148 24419 24812 2985 3128 32618 34215 3979 40117 40215 41017

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12621 menus 4085 mercaptopurine

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3141415 met 2566 method 20912

2631822 30414 methodologies

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21321 2141 23212 330611 33013 33110 34010 3883 3894 402117

methotrexate 2287 33920

Michael 42 74 32410

Michelle 310 67 1881013

milestone 3036 3302

milestones 3326 Miletich 39 65

174151618 18221 1836 1844 18513

18621 1887 million 2989

7619 1367 1491 26113 28817

millions 1498 1538

mimic 3368 mind 9319 34418

3816 mindset 19321 mine 29118 3169 minimal 25416 minimize 19012

19610 2183 22121 2221 37026

minimized 14215 minimum 341

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21815 219617 21919 37022

minority 33518 3764

minute 956 13118 minutes 136 497

10810 287710 misheard 19718 misinformation

3011014 mislabeling 884 misleading 19317

22620 misnomer 3182 missed 3454 missing 5219

8612 mission 2122

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16718 3238 modeled 1766 models 1305 moderately 25418 modern 3994 modes 5310 modification 695

2065 37321 modifications

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molecules 179 97822 988 9911 13820 1788 283689 28321 2841 30713 3122 3861520

moment 103 8611 2029 4031

Momenta 314 612 2324910 23314 24611

moments 1384 money 917 13719

1502 monitor 1007

10317 3468 monitored 1910

10313 33812 monitoring 1622

198 2222 4416 708 725 12821 36116 37417

monitors 7420 monoclonal 1785

1785 31911 monotherapy

33922 month 3178 months 289789

28910 38013 morning 84 911

107 1522 282 4018 645 7517 87217 9516 11912 13518 14813 15819 17416 18812 24422 26019 36415 41016

mother 2914 5018 38021

mouth 38013 move 15622

15710 2784 38210 3854 39911 40210 4111417

moved 35917 moves 1815

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moving 967 19212 1943 2387 24821 3592 40114


Page 446

4025 4072 MPA 510 MPH 52 multicultural

8415 multidimensional

2095 multiple 608 832

1416 1475 17319 17712 34920 37018

myasthenia 2113 Myers 41014 Mylan 315 614

15410 24620 247210

myriad 2529 MBA 311 MD 115 2213

31911131418 52415 65910 618 1518

MPA 218 MPH 115 411

N N 21710 3301618 nailed 3873 name 151821

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2607 2802345 2807 29451214 2963 29718 298156 30819 3132222 3157 31522 32116 33315 3473 349679 3609 36214 3761 39018 4051818 4067

named 7011 7914 3225

names 1912 3314 457 5811 6220 733 1021 10511 106522 1334 1412222 14213 1457 17718 1786 1838 1902 190611 19212 19917 20029 2047 25220 25417 259920 27918 2982 30915 31716 3191921 32029 32011111418 32022 3211210 32111 3225710 323351217 34913 3741317 38438

NAMI 3811819 383819 38429

naming 3313 364 36711 437 4517 7012 718 10118 1061 12319 12413 12516 13514 1405 14222 1435 18529 186615 18914 19018 19122 1923 19612 19917 22120

22913 251810 25114 2533 2599 2608 27210 27916 2931621 30814 31918 349217 34918 3503 3734 37411 37817 3845 40316 4063 4091617

namings 26012 narrow 3737

3744 narrower 20920 narrowly 2012

268 national 21820

412 51112 2121 226 2819 4112 5013 563 6447121517 7015 7218 739 7520 8912 3764 3811218

nationally 6011 nations 34713 nationwide 7620 nations 805 8415

2354 38120 natural 552 2737 naturally 37917 nature 17816

20711 2988 3091 35022

NDA 26720 2698 27015 28212

NDAs 28211 NDC 7135 13314

13316 14018 1411 14520 2524 2988 30910 313614 31315 40512

NDCs 1341 1414 Neal 38 64 15817

15820

near 2793 2868 Nearly 568 necessarily 716

1467 18120 2142 2301 27015 3465 36218

necessary 215 3620 4316 5722 7114 12616 13812 1931115 2137 2177 2184 24320 26514 28217 28912 3045 3081 3384 37313 40414 40519

necessitate 3725 necessitates 20711 need 2725 311

429 499 622 6918 7812 806 9917 10313 1221620 1239 125122 12636 1269 12712 1293 13811 1629 17011 1736 18819 18913 1906 1918 19511 1981 1991 2102 2158 22410 22967 24820 252510 2632 27322 2781 28868 31020 31212 31920 33419 33814 34311 36212 37017 3826 38420 38821 39320 4031020

needed 1413 355 356 5220 586 1256 1285 1638 16315 16816

17512 23518 28311 3202 32318 32715 3318 36119 3643 37213 37914 3946

needing 1901 needs 215 3218

3321 10316 1299 14617 1641 2072 20813 22320 2261 2581519 26916 3224 33621 34015 35617 35921 36120

negative 489 711 7918 2848 3353 33610 34021

negotiate 2922 neither 4415

18019 37722 network 2121 networks 819

8517 Neupoegen 3192 neurologist 1611

10322 neutralizing

34019 34615 never 3912 5817

6014 22715 2468 2578 28017 2948 32216

nevertheless 16311

Neville 35 520 1351718211434 1446 1454 14517 14612 1486

new 11217 93 303 5621 578 5712 587 6021 691519 7816


Page 447

909 9213 938 10113 1321212 13220 13711 1419 1598917 1781420 22415 22419 2352 2427 24722 25410 2553 27310 2807 29216 29913 303911 30412 30616 30712 32078 3211516 34617 36616 3686 3743 37817 3822 40512 40714

newer 8515 news 8719 903 Niazi 38512 nice 37521 Nick 33318 Nicole 41013 nightmare 17217 nine 33015 Nivestim 2054 NKF 7213 NMR 2095 nomenclature

19210 3171517 3187 31917 32120 3221 32322

non 5416 844 1618 1623 19316 22212 28118 28718 3289 33419 33611 337615 33722 33814 3439 3538

nonclinical 3935 4016

noncompliance 3577

noninterchangea 3088

nonproprietary 3314 5810 7017 10121 1021 10511 10611 1408 1459 1902121 19119 32011 3497913 3503 36213 37413 3843 40518 4067

nonpublic 35115 non-approved

32811 33217 non-clinical 29120 non-clinically

22219 non-comparable

39614 non-EU 29022 non-inferiority

21016 2239 27815 2797 33621 3988

non-licensed 16110

non-locally 39811 non-negotiable

974 1768 non-partisan 876 non-profit 2878

7521 8112 876 9619

non-public 3563 non-US 6712 non-US 10018

10110 12819 13913 15919 1606 16191022 1678 2081 23621 23729 2771021 29022 3056 3264 3521421 3535 35320 3612 39122 392721 3936 39491421 3955 3966

3971113 non-351(k) 39322 Nordisk 316 615

261581011 26320 26611

Nordisks 26521 normal 13220 North 1611 notably 27521

37115 note 671015 7010

821 10111 15021 16212 22016 23613 2389 273821 2749 27516 27711 27816 2891 3531419 3557 36520

noted 6512 6814 727 7911 8919 8921 1108 1527 2351 2751319 2844 28515

notes 8817 10518 10521

notice 152 7713 9722 3447 3575

noticed 1144 3441113

notified 3411 3920

notify 341 notifying 1042 notion 1834

36518 Novak 74 32410

32418 Novartis 319 619

8911 28746 28815 29811

novel 2206 28816 2895 2945 3894

novels 28821 November 514

9614 Novo 316 615

261581011 26320 26521 26611

NovoLog 2666 NPAF 7520 7657

7622 7721114 7811 8016 8111 8312 843922

nuances 17816 number 1112

1322 204 2522 314914 3215 5211 602 7118 7119 7916 8220 10216 11118 1331 14022 15914 1809 2176 2304 2314 2318 248211 2499 2839 3199 31915 32714 3295 33110 34816 3521117 3584 36517 38213 383817 38322 3849 38720 4076 40838

numbers 1912 14021 21412 3434 37820

numerous 3306 nurtured 417

OOak 111objecting 1677objective 969observed 11113

20915 24083034 3515

obstacle 25510obtain 1013

36017obtained 116

11121 1122023618

obtaining 119 obviously 1112

1916 2619 14922 1732 24419 2465 2734 2759 2761 2762 31618 31712 3225 34514 3876

occasions 941 occur 262 3411

398 14313 14620 18617 22019 2222

occurred 343 3922 406 15619 22214

occurrence 702 7414

occurring 3412 occurs 29419

40020 Ocean 912 offer 778 1528

26621 38115 40915

offered 20611 3757

offering 15019 office 121719 22

2257799 818 821 938812 1043 14115 24822

officer 11316 52 8313 917 235 2771621 2817 3520 377 3812 40710 4620 4719 4817 4912 501 5919 6321 642 7312 749 75615 85119 8620 9310 953 9511 10418 10617 107161911718 1197


Page 448

12920 13416 1351422 14217 14415 14710 1488 15319 15413 15521 15711 15815 16621 16821 1691421 1706 1713 17214 17313 17412 18211 18316 18421 18720 1889 19618 2016 2036 2043 2041017 21317 21520 21615 2259 23117 23238 24311 24521 24617 25622 2596 26017 26810 26918 2714 2815 28418 28558 28619 28729 29714 29822 30211 3105 3133913 3147 31551218 3163 32469 33211 3335 34211 34619 3571 3604 36512 36710 37511 3818 3855 38918 39013 3975 3981317 40911 4105

offices 14120 official 16413

3211 off-label 902 oftentimes 246

40418 oh 86817 967

22616 23021 2879 3908

oil 6821 okay 401 4720

8615 95411 13320 15815 17313 1983 2037 20410 23117 2597 28615 28711 31521 31913 3229 32412 3337 36711 39012

old 2918 older 878 9010

29213 3588 omission 3903 omits 1636 Omnitrope 15116

1563 once 807 1038

2254 2512 25422 2581822 25919 2618 40121 4117

ones 2811920 one-sided 33415

33617 3439 ongoing 567 9812

24114 2483 2997 31022 3687 4103

online 12722 31615 32316 3244

on-call 257 open 410 714 142

14421 932 23610 25715 375517 41111

opening 52 1542 operate 1494

20618 operating 12416

12621 1272 Ophthalmologists

8920 opinion 10912

2554 36619 3898

opportunities 1281 1757 1825

opportunity 138 1310 284 348 3515 3811 508 649 681 7518 8421 9517 1087 1203 13519 1499 1529 15318 1592 17417 1813 20415 21218 32414 3329 33313 3428 3477 34821 35621 3649 36718 3768 3805 38115 38517 3918

opted 5515 optimal 12021 option 13410

26721 26817 2691014 2705 39615

optional 1897 options 2920 572

37622 op-eds 9615 oral 1320 Orange 12316

13116 order 1117 696

7814 1091218 11021 1151115 116512 12117 1232 12420 1277 13411 13917 1472 1607 19117 2102 24919 27121 31417 37919 38721 39616 4074

ordered 1222

orders 12178 12216 1231118 12417 1274 1328

ordinarily 703 33418 33618

organic 6815 organisms 9114 organization 46

78 167 28720 2937 368 415 49117 501214 5210 612 7521 7611 876 9628 969 14721 15419 33311 34622 3475 38120 406213

organizations 1117 442 8522 1201 34712

organized 41011 organizing 4714

2474 oriented 8318 original 372 381

395 453 5815 9112 115421 12418 1857 198161821 20021 22112 2341320 23612 29367 30018 301456

originally 25010 originated 22922 originator 3718

7322 1997 20117 2026 2126 22514 25817 2951721 30091113 3025 35815 36419 36612 3672 39210 4035

orthogonal 27618 330613

osteoporosis 418 ought 3817 OUS 3968 outcome 2622

424 489 34611 34617

outcomes 489 6421 12021 2218 383614 39922

outer 2773 outline 1979

27112 27413 outlined 515 857

12320 18816 239320 2769 29010 29222 3505

outpatient 12510 13315 1342

outreach 12658 12722 17920 18612

outside 10017 20310 28917 2916 29520 296214 3942 40512

overall 10921 137412 15013 18815 27529 2882 3349 3389 34017

overarching 9313 overdosing 25222

25911 overly 1506 1535

15710 1814 overseas 2546 oversight 3909 Owen 317 616

271710 oxymoronic 38519 oclock 20311

Pp 3913 6510


Page 449

11357 17414 2162

pack 7217 package 7116

8319 10215 14019 14745 17119 2179 24412 33115 3937 3941720

packages 10212 24514 26616

packaging 6515 661 68810 697 7211 102918 14622 22121 2291317 3844

PAF 76131517 834

PAFs 7620 page 772022 784

326316 3283 33015

pages 3307 pancreatic 2915

2921 3013 panel 114 21 817

820 91461014 121 137 161 23810 2415 264 28315 361 36312 381314 4120 4622 471 4819 592122 605 61142021 6222 7316 7411 7721 8534 864 861215 9312 951216 10420 10421 10522 1086 11721 11819 12922 1301 13222 13418 1394 1421920 1441 14417 1451318 1532122 15415 1551 156116

16713 1731518 18213 183117 1851 1865 1962021 19713 1983 199415 20010 201820 20413 2131920 21610 2251112 2271 22910 23010 2356 2431314 24418 2477 2572321 2586 2597 2601 2681213 26939 26913 2701018 27125 28178 28114 2822 28522 28621 2971617 2992 29916 3002 3018 31078 31138 3126 3148 3248 33213 3421314 34511 3573 3583 36514 36712 37515 38110 385716 3892021 3906 39010 39778 3987 40914 4107

panelist 1416 8612

panelists 816 128 865

panoply 1493 paper 227 parallel 2075

21215 3115 32621 3274 36221

parameters 31219 34021

paramount 26119 36822

Pardon 313811

parentheses 26218 2622021

parents 5022 PAREXEL 44 76

33389 34012 Park 1591 Parker 38 64

158171920 16714 1691019 17028 17112 17222 1731722

part 16 87 1017 1212 2418 288 496 6416 8311 11318 15422 1563 17212 22615 22714 24720 2839 2982 32314 33517 33812 34320 362120 3927 393718 39417 3951 40920 41018

partially 3213 participant 1122

121 20610 participants 7120 participate 873

21219 36718 participating 8711 participation 1513

41122 particular 5714

597 6310 7021 757 867 1333 2382 2396 2826 29614 3489 3752 39914 41022

particularly 8510 1308 13915 1849 18711 1893 20012 31612 35321 3841416 3956

parties 151 2021

213 421114 4521 4627 20712 39617

partner 861 20518

partnership 844 8512

partnerships 8112 parts 10322 2702 party 3961016 pass 2782 passage 7717

35614 passages 3309 passed 4512

13616 patent 354221

3561 357514 pathology 3367 pathophysiology

27521 pathway 172613

1812 251 3118 3421 508 515 5416 551216 594 6216 6411 651 665 677 9811 12211 12710 1292 13211 13618 1412 1491112 14915 1528 15719 158811 17813 1825 18821 21613 2171422 2206 2201013 2257 22615 233212 240114 2421 2438 24913 25618 2627 3141218 31512 34720 34812 3683 3695 3709 37715 3795 41116

pathways 13019

patient 21320 55 512 1519 1658 1621 181314 2121 22121 24124 2513 2819 2936 322 321118 349 351318 374 38622 391114 40221 4312 447 4516 468 471116 48616 50614 51717 548 5621 574 58521 6010 6482121 7021 7022 716 7520 7522 7661113 761822 77316 8113141517 8219 846 864 8611 923 9610 974 981618 102613 1032 10415 1051417 10518 10614 11318 114914 11416 12118 1263 142610 14418 15316 1595 17513 1768 17714 1805 1811 1901117 1964 19615 2216 2292222 2317 23113 24116 26121 288217 2891516 29110 334422 33916 33919 340313 3422 3444 3469 3494 36822 37241719 37418 3759 3761416 3777 37713 37920


Page 450

3803 3816 38315 3992122

patients 1615 189 204 2115 2214 252022 2810 292122 3119 32101415 339 331116 341417 3510 381618 403 411014 421015 4810 50921 51119 52215 5315 54920 5520 56512 577914 571920 587 591216 6027 60141517 611 61611 6319 6521 736 7639 761920 7710 78512 80212 828 834417 901620 937 962 1069 12018 12020 1214 1223 12522 12617 12914 13812 1491922 152414 1537 156911 15914 1644 1695 17817 17912 18922 19115 1929 1934 1968 20517 2186 21910 22019 2217 2283567 2311 24016 2411922 24716 26614 28017 28918 3392222 3496 3501 3551 35681216 35722 36922 37116 37620 377410 37810

37923 3815 3836 384620 39111 40716 4094

patients 263 3321 13121 38417

patient-focused 8017 8311

patient-oriented 8614

patient-physician 928

Patrick 315 613 2462022

pattern 27417 patterns 23515

2748 pave 15111 payer 4416 1364

1369 1372 1932 payers 1810 3418

4722 48112 714 13719 14819 1492 17818 17913 18419 25112

payer-initiated 4420

PBMs 1555 PCMA 1481417

14912 PD 238815 32815

3362 38914 pediatric 21120

2122 25571320 256158 27521 3061921 3073 3111217 31234 36213

Pediatrics 27518 penetration 2248 people 299 31312

411 454 6317 6611 9420 10616 1077 13014 18411

22617 2307 25917 26113 3767 3772 3811 38121 38414

peoples 2047 peptide 27214 peptides 27327 perceive 14419 percent 2812 415

56913 571013 5715 60142222 661616 812021 82311 8357 9010 11115 112812121313 1137 13612 13767813 28918 34325 3451718 34614

perception 794 1793

perceptions 797 79121619 808 32019

perfect 18515 2049 2861

perfecting 176 perform 33917

34014 3621219 performance 205

26618 3415 3886

performed 563 1183

period 1412512 162 204 342 3921 6613 1085 14213 26721 2688 3449 37310 37428 37518 37916

permit 3272 permits 3935 permitted 1216

22012 person 2319 258

4410 1043

31610 3801019 41022

personal 2912 478

personally 4118 9415 16515 1875

persons 5016 perspective 509

13317 1349 13691414 1372 14011 15849 2093 2108 2394 24221 2534 28517 2912 29211 29417 2953 2969 2989 31417 3345 3532 36011

persuade 25111 pertained 31422 Pfizer 317 617

27181012 2779 pharmaceutical

23 36 4917 62 712 2117 2617 2813 4015 4216 1481116 2167 21914 36716

pharmaceuticals 314 612 1719 185 223 23259

pharmacies 11920 12618 13315 13611 1402021 14957

pharmacist 5819 1044 1191314 13120 14210 1931

pharmacists 34 519 7911 1041 1191118 12016 121320 122215 12311 12456 12719 12912 13022 13116

1361 1423 18011 4081

pharmacodynamic 2798

pharmacodynam 3902

pharmacokinetic 1018 24319

pharmacokinetics 31217 3901

pharmacologic 40615

pharmacological 2103 25119

pharmacologically 34912 40622

pharmacovigilan 437 1357 14613 19014 19611 23017 25122 2528 29810 30914 3135 36615

pharmacy 3322 392 783 813 10215 1221416 12416 12620 1272 13414 13635613 1401717 1429 14818 19716

PharmD 519 PharmD 26 34 phase 21514 3303

33813 34115 34415 3882020

Phillips 879 philosophical

3861 philosophy 21211 phone 4715 phrase 36316 phrased 26220 PhRMA 3671417

36721 368611 36821 3701117 371141620


Page 451

37212 373111 37316 37412 3754

PhRMAs 36815 3723

PHSA 24918 26714 35512

physical 30419 37015

physically 16419 physician 2017

3320 3429 442 4459 4515 469 4857 5820 8320 9519 9915 10321 10519 1073 1799 1933 197141720 1981 2603 37418

physicians 2022 21222 226 339 331518 3410 3817 4214 458 476 5120 5622 7811 7911 8814 962 9919 12310 1411620 1569 32016 36416 3653 3766 38417 4064

physicians 14114 physician-based

441719 physician-patient

2016 435 physicochemical

29118 31218 Physiochemical

3865 PhD 117 210 32

3910111718 320 42481415 517 65791618 620 74461112

pi 1122020 1133 pick 391

picking 3452 picture 3862 pieces 40413 pilot 2523 pioneer 26112 pioneered 3567 pipeline 3177920

31948 3917 pitfalls 38714 pivotal 16016

1679 1704 21515 2531214 25321 25717 2781 3303 33813 34115 39419

PK 2151 238814 24316 2446 246516 32518 3275 34020 38913

PKPD 23712 25716 3112 32518 3616 3875 39057

place 338 3920 6414 922 936 10316 1271 1327 15219 17915 22813 2334 2487 35921 3601 36620 38410 40813

placebo 1644 placed 20912

24121 32719 3821

placement 15517 places 2176 2463 plague 9121 plain 27510

37318 38713 plan 8321 12110

12111 15613 1754

planned 3323

planning 106 plans 726 8014

15610 plasma 5312 541

551 plate 34417 plates 34421 platforms 13412 Platt 14713 26021 play 12019 12913

14110 17811 1807 1828 19319 24818

players 423 playing 421913

4221 4521 461 465 4920 8514

plays 2610 9914 37115

please 920 1211 1461315 151 6213 908 10111 31514 3271315 32721 32817 32911 33017 4117

pleased 8715 14819 14914 20514 20613 20717 21220 38218

pleasure 2875 36010

plenty 38615 pliability 40611 plots 29513 PLR 20113 plungers 6817 plus 16516 33920 point 181 323

4613 635 9111 9717 1003 10515 1247 125318 1415 1472 15810 16415 16710 1742 1821519

1918 1937 1987 19822 20114 2133 227310 23011 2415 251721 252618 253722 25421 2556 26312 26620 26820 27219 2819 2831620 28412 2891 29818 31411 33714 36414 3939 39512 3966

pointed 796 1013 1058 15212 2462 2823 3385 3931

pointing 2708 points 473 10222

1332 1397 17518 18319 30512 3257 3346 33512 36117 36411 3837

policies 1111 1213 5418 7713 7716 176212 2421517

policy 121519 25 81121 95 5514 761 805 9611 14815 17619 1781 17915 18016 24112 25320 27911 35521 39110 39424 41010

polymer 2642 27016

polymers 26212 polypeptide 26219 polypeptides 2631

2633514 27318 polysorbate 6816 pools 5314

poorly 32913 popped 8719 population 312

5118 835 9011 9417 25620 27514 3061921 3073 31112 334422 3363 3391216 34011 34014 34112 3422 3444 37220

populations 4314 574 27517 31118 31234 3276 3403 3721618

portal 3172 portion 32612

3286 portions 35112 portrayed 20214 pose 5721 posit 14115 position 484

16014 1689 18612 1874 19214 2117 2574 3059 31013 3389

positive 3779 positively 846 possibilities 5121

523 possibility 667

2221016 2349 23610 36148

possible 1119 1411 253 4816 759 781022 888 94412 10615 107815 10821 114814 11715 12213 14717 1839 1851520 2004 2221 2267


Page 452

22711 22818 23310 2369 2602 3407 34110 3623 3707 37318 38314 4051519

possibly 3720 1783

post 72220 2159 30519 3387 36115

posted 7719 posters 813 posting 13112 postmarket 3791 post-approval 441

10118 3294 35421

post-market 2038 1257 33510 37416

post-marketing 586 6368 708 724 741621 32822 36417

post-translational 27313

pot 2013 potency 9317

3741 4039 potential 4312

5316 6819 6911 7320 825 1172 12413 1285 13410 14420 1461718 1604 1663 18315 21721 22815 23311 2411922 2665 2871617 28718 3263 3395 34021 34316 3581 36920 370220 3957 40917

potentially 3820 778 12810 1291

1346 2152 23222 2385 2431 2488 29020 3131 3401 3716 4079

power 3359 powerful 216 powerfulness 3615 practicality 21717 practically 2106 practice 1612 206

211012 231819 11412 11919 1213 1222 12721 27817 36510

practices 881014 practicing 9519

9915 11919 practitioner 2020 practitioners 174

233 241 PRCA 2312 pre 207 28820

3294 3387 PREA 30617 preambles 16810 preapproval 2156

32818 3292 35417

preauthorizations 2321

preceding 23919 precise 1914 precisely 40922 precision 18113 preclinical 2083

21512 22213 33120 3618 37016 371914 37117

precluding 4079 preconceptions

32019 predecessors

40322 predict 997 1379

36916 predictability

15310 1586 18114 2649 3959

predicted 318 2189

predicting 37113 preferences 565 preferred 1397 prefilled 681722 prefix 1913 preliminary 3314 premarket 201

3358 premature 2396 preparation 1282 prepared 1807

30113 36019 preparing 8313

8720 prerequisite

29119 prescribe 2022

216 244 10217 12612 12910

prescribed 3311 3416 3822 3913 5115 8011 19010 2607

prescriber 8318 12114 19016

prescribers 12310 1275 40720

prescribes 25914 prescribing 173

232 2412 3319 675 7019 7115 1029 1071 1237 1253 127616 1436 179913 1952 30821 37421

prescription 222 399 8319 1219 12117 1221617 12221 1232311

12318 12419 1273 13134 132821 14237 15218 1857 18921 19114 1967 32013

prescriptions 1217 122914 13215 14420 1498 24713

prescriptive 27419 presence 34019 present 1321

7519 8421 10222 12415 13519 1593 16618 17013 1757 2501 27221 33314 3421 3477 35622 36010 3769 3788 38513 4031

presentation 1122 1320 2311 2518 265 496 1175 1514 1899 1977 2494 27121 3256 32613 3426 3603

presentations 53 1220 1516 17922 2478

presented 23612 2398 274820 305411 3522

presenter 12235 presenters 21222

322 3168 presenting 144

33316 presently 36820 presents 1825 preservative

27312 preserved 2018 preserves 15914

preserving 4515 3685

president 4114 5011 8759 14815 17419 18813 2327 2471 2617 3161 3166 3474

presiding 11313 116 52 8313 917 235 27716 2721 3520 377 3812 40710 4620 4719 4817 4912 501 5919 6321 642 7312 749 75615 851 8519 8620 9310 95311 10418 10617 1071619 11718 1197 12920 13416 13514 14217 14415 14710 1488 15319 15413 15521 15711 15815 16621 16821 1691421 1706 1713 17214 17313 17412 18211 18316 18421 18720 1889 19618 2016 2036 2043 20410 21317 21520 2161 2259 23117 2323 24311 24521 24617 25622 2596 26017 26810 26918 2714 2815 28418 28558 28619 28729 29714 29822 30211


Page 453

3105 3133913 3147 31551218 3163 32469 33211 3335 34211 34619 3571 3604 36512 36710 37511 3818 3855 38918 39013 3975 3981317 40911 4105

presume 21711 presumptively

37320 Pretending 18115 pretty 2281 prevalence 8418 prevalent 6615 prevent 3412

16315 1646 16514 37420

prevention 8418 prevents 4420 previous 6418

993 10221 1386 14718 19622 22413

previously 232 6814 7277 1767 18914 26715 28615 33022 33711 34721 39621

pre-IND 28956 33116

pre-specified 11118 1138 3439

price 1018 7718 82239 892 34714 36722 3999

Pricing 799 primarily 9520

3172 primary 501619

519 52591215 5222 534 5420 5520 565 5912 973 2093 2108 2384 26322 2668 28919 34117 3723

principle 6922 223512 22421 2824 30820 39018

principles 19311 193121518 1944 223211 2358 237817 26729 2706 27413 28022 2821013 29113 304916 3052 3639 36816

print 13110 prior 1416 7917

1044 16214 16419 1709 19414 22212 2823 33721 35715 36815 38311 38417 40117

priori 23319 priorities 1110

7714 1803 prioritization

3732 priority 3514 975

1769 3822 private 1612 4016

1492 proactive 8018 proactively 1923 probability 11112

11117 112235 112921 11816

probably 147 499 9110 10820 11914 15610 18521 1861

22416 23121 27511 30822 32117 3433 3909

probing 8819 problem 2516

3220 6621 712 755 107511 1373 14317 14414 1461721 14720 1484 18013 18315 18411 1856 23112 26822 2981419 30111 40213

problematic 3379 34216

problems 7421 13312 17717 22622 23013 2667 2905 29618

procedures 1213 184 125912 3562 37019

proceed 804 1291 2448 2549

proceeding 14914 23321

proceedings 1215 1219

process 161719 1622 1881618 1910 2018 2222 272 326 4211 4218 432 5510 599 7211 746 8322 1008 10310 10489 1189 12121 12615 12818 17511 19910 20513 20610 2076 20817 21219 21612 2256 27412

29115 30118 3324 35118 354718 355421 3673 3756 37617 3783 38066 38315 39521 40822

processes 6515 827 9716 1206 12116 12516 12611 1277 1421 18020 30715 3569 3961

processing 541 553 122915 1232 12417 1314

process-related 36321

produce 583 1754 18111

produced 17912 26116 2642 37718 3789 3863

product 1022 114 182022 191522 243 25411 351 372171921 381 531117 557 5622 578 5712141620 58351218 6021 6214 662 67413 6813 69121415 7016 7020 7121321 781 8211 9222 10022 101910 1062021 11122 1121 1131213 113151521 114120 11535 1156789910 11521 1161 11821 12220

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52 8310 917 235 2771621 3520 377 3812 40710 4119 4620 4719 4817 4912 501 5919 6321 642 7312 749 75615 851 8519 8620 871 9310 9531115 10418 10617 1071619 11718 1197 12920 13416 13514 14217 14415 14710 1488 15319 15413 15521 15711 15815 16621 16821 1691421 1706 1713 17214 17313 17412 18211 18316 18421 18720 1889 19618 2016 2036 204310 21317 21520 2161 2259 23117 2323 24311 24521 24617 25622 2596 26017

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shift 32920 shooting 29519 short 1085 2199

3528 35915 shortage 6017 shortages 1812 shortcuts 4320

9111 38314 shortly 23713 short-term 3362 show 258 965

1148 14616 25213 26222 26421 29510 29757 3332 3885 4019

showed 2664 38016

showing 2651 29310 29514 31814

shown 10110 11522 2125 2551 27311 34817 3668

shows 15217 31718 3195

side 5614 57911 8922 919 13115 1311920 1364


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13911 15220 1719 2452 2847 28421 29512 382914 38712

sides 454 911 13910 27819

Siegel 313 610 21624 22519 22714 22918 23020 2322

Sigel 2165 sight 24012 sign 922 1734 signaled 2783 signals 352 significant 2813

8116 821920 18021 23914 2432 24919 34716 35611 3711 38815 3945

significantly 1718 5513 595 17219 1737 1777 21019 2664 30310

signs 20715 sign-off 1736 silicone 6821 siloed 1345 Silva 41013 Silver 112 similar 1616 253

2616 8520 9219 9722 982 10314 10989 1106 11220 11315 11710 12316 1249 1388 1608 1602021 1656 1809 18918 19315 21024 211319 2126 22017 2267 23515 2491621 2501519 2547

2551915 2561 2567 25713 2582121418 2591 2639 26422 27222 27315 2911218 29221 29324 2961 29918 30049 31221 33118 33921 3697 3785 3833 3841 3852122 3867 38718 3885 40110 40714

similarity 269 2182 2278 24819 2512 25410 2757 2924 30315 304619 30517 306110 3071 36020 3611 36519 3663 39513 4019 40416

similarly 1255 2543 29210 4033

simple 13112 18116 1919 27217 28118 3878

simply 926 16420 2369 2925

single 923 1375 16117 1675 1862 34115 3699 39120

site 3239 sitting 24322 situ 3875 situation 7821

1172 1456 15514 16510 18514 19720 2007 20221

22712 2554 2641318 27615 29514 33717 38716

situations 6717 1651 21413 24519 2528 25914 27422 39315 39416

six 3024 479 2897 36517

size 10967 14019 2158 26319 32819 3292 3412 34222 36911 37117 3727 38222

sizes 1475 22516 3295

skills 4713 slide 965 9720

16116 1641112 166612 1714 19415 28915 2913 2925 2951111 29917 3019 3119 31718 3304 33215 3488 3551618 36517 36517

slides 812 22912 4073

slight 701 731720 741322

slightly 12519 26022

slot 13513 slots 1117 small 1611 1710

184 2317 2620 431022 5422 559 9791718 988 15220 1773 24912 2836 2961 36913 37020 3728

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28321 smoking 3112 smoothly 41016 social 8516 14514

18322 society 4416 468 Societys 8712 sold 1053 solely 19419 1952

3362 solid 2058 21512 solution 6022

18516 1917 solved 14117 somebody 1075 somewhat 25916 son 5019 6020 soon 7822 9010

37317 sooner 9215 sophisticated

37018 38911 sorry 8617 11620

1405 18221 24411 31645 3908 4073

sort 2417 3446 494 1065 1309 15619 1866 19715 2148 2197 2264 23115 40288 40521 40713

sorts 15518 2189 sought 763 sound 13915

25319 2563 3048 36019 3694 37118

sounds 1351 21422

source 1004 16615 1695 1763 19218 2643 3981

sourced 5312 3056 3928 39811 40818

sources 14522 19616

so-called 11014 11015 1181216 27617

space 2059 3017 speak 141 3516

4020 4619 6313 9415 9517 1432 18511 20415 2993 32414 3919 39821

speaker 1341215 131618 151016 2116 2722 4011 502 643 7516 9512 1013 10322 10720 11910 13516 1386 14810 15817 17414 18810 19622 2047 2162 22413 2324 24619 26020 2614 2717 2823 2873 30213 31519 3337 34621 3606 37518 38111 3858 39015 39818 3991 40214 41016

speakers 111516 1220 1411 4721 6512 709 7110 993 10221 14718 22119 3149 32410 36614 36712 40117 4111

speaking 4113 481 493 18910 30122


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speaks 21779 2214 2282

spec 29613 special 27 98

41014 specialize 9520 specializing 31617 specialty 13610

1495 15211 specific 1916

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specifically 5217 796 8916 1638 1957 20210 20722 2174 21819 23021 26322 32713 32811 3846 40614

specifications 20917

specificity 758 859 2143 3417

specifics 19313 specify 1945

32711 3325 spectroscopy 2099

20910 spectrum 279 527

7621

speculate 3158 speculated 2463 spend 1384 1502

23122 29015 spent 1362 38012 Sperling 412

381121417 Spiegel 215 56

2722 28216 364918 3715 3821 409

spinning 1741 spirit 30922 spoke 1851 22413

3587 spoken 454 22120

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sponsors 15311 2035 20710 21022 2136 34921 3582 36017 36121 39213 3945 3969

sports 4120 422 461 4916

spot 1324 Spring 112 stability 17618

18017 1827 38912

stabilization 542 staff 41010 stage 6618 1234 staged 41010 stages 23916 stake 512 8014 stakeholder 1013

658 stakeholders 475

4712 842 9814 12718 12916 15314 17811 179112 18321 18410 1921 2068 2476 3758 39115 3958 40320

stand 17119 3529 3602 38010

standalone 17118 standard 637 705

707 7415 979 1212 1258 1704 1724 1875 2111819 21622 2174 21919 2213101418 24916 25015 2511 25591518 25713 2584712 25815151920 25914 27822 2889 29219 2933518 3005 3009 30857 36518 3662319 36620 3671 3949 40110 4042

standardized 1923 standards 2011

268 592 679 9316 10116 12812 181468 1811520 24921 25041519 2514 2567 29222 36521 3754 38321 3926 4002 40310 404417

standing 146 4614 25320 30820

stand-alone 33515 start 237 11558

13017 1328 20411 2721

started 1082 1985 3443 3793

starting 811 2133 28411 3966

state 761 128269 14020 17914 18419 1882 19222 1934 194620 2365 2418 24816 2502 2582 2651316 2671 26815 3031 31220 33614 33719 33816 3398 34711 35818 3713 40710

stated 728 7319 1063 1767 1972 197317 2659 27912 2943 3832

statement 671115 69310 1351011 1543 1868 19412 2427 2694 29920 3662 40614

statements 28011 3505

states 203 3119 6510 6611 6810 88810 1001617 10410 128410 17514 17818 2258 23810 2639 2685 3085 3316

state-based 12111 stating 1894

24317 3508 38710

statistical 21516 27811

statistics 613 21411

status 1959 19710 19711 23611 2648 28012 32212 36216

statute 627 14913 15811 1611522 1626 1631 25821 2621516 2646 2683 2696 27038 36521 3736

statutorily 40110 statutory 16013

170317 17114 18416 22113 2935 357710 3693 37121

stay 1211 1417 staying 4071 steepest 3285

3621 stem 1911 3576 step 199 273 328

10935 111511 11114 1135 16320 24810 25611 3484 36016 3801 39910

steps 3620 5418 5814 624 1006 10916161920 1114 1224 1738 1764

stepwise 10814 109313 12014 2062122 21211 2227 233822 2393 2448 24813 27121 28715 3261819 32622 36218 4025

steroids 2288 Steve 16922


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26919 Steven 22 817 Steves 2462 stifled 653 stimulate 2853 stimulating 659 stockholders 9814 stop 3112 8912

901 stopping 3916

5614 storage 6515

7211 10310 stories 3822 897 story 885717

8919 straighten 2941 straightforward

1114 18019 33918 39612

strategies 14610 23514

strategy 4611 27111 3872

Strauss 42 74 3241112 33220

Street 8721 887 896

strength 12410 36316

strengths 1011 stressed 3305 strict 5910 strictly 7222

13718 36219 strike 1417 2812 Striking 24220 stringent 4515

679 strive 429 4920

16520 strong 1617 934

21617 2294 3121 37210

strongest 94312 strongly 1422

1614 981420

1037 14912 18622 3839 40415

struck 2447 3681 structural 2342

23614 2382 2412 24441011 26420 273320 2776 2841 37022

structurally 2337 23910

structure 696 8511 1056 2096 2654 2668 27314 3217 36914 37322 3784 3861722

structures 439 27220 37721

structure-function 29515

struggling 38214 studied 788

1161121 1566 20911 2212 22221 22425 23115 27516

studies 561720 7118 7918 992 9910 10917 118337 12819 13822 14320 14515 14619 15614 16015 16812 17019 2101017 21216 215123 22517 2351719 23916 23920 2569 25710 2937812 30415 3055 3072 31021 3111317 3123 3131 32731012 3281013 3292 3362 3384

34217 3511 35312 36168 36213 3635 36418 3655 3711013 3839 38611 3952 39720 3984 4041618 40817 40820

study 317 355 71181920 742 10821 11019 11514 11715 15916 1645 1684571216 16916 21014 22418 238815 23913 24020 2431619 2447 25522 25718 2729 27618 3081 3111256 3177920 31814 3272122 32813 335810 33912 342192122 34519 35015 3642122 3652 37217 3879 39722 40412

studying 2772 stuff 16920 17012 subconscious 1647

1661 1739 1744 subcu 3365 subcutaneous

5310 568 subject 121317

6419 1191 2134 2682 3277 32816 35420 3737919 39821

subjects 32714 387920 40119

submission 17218 17516 18912 26015 2738

3562 38822 40920

submit 611619 7514 1198 15312 1882 4018 4117

submitted 139 941 13621 1468 1621420 16721 1687 20818 21614 2496 2687 3485 35519 36811

submitting 1352 subsequent 17117

2801 3746 subsequently 3408 substance 27712

27717 362810 substances 27714 substantial 38812 substantive 456 substituted 388

3911 405 674 1971512 2609

substituting 667 19421 35019

substitution 343 341112 365 3922 436 4421 4516 5418 5815 62471121 783 7922 9110 925 1048 1286 13117 15117 15561216 1564 1568 1798 18417 1869 19222 19610 31420

substitutions 3611 3919 13121 1445 15589 19012 19716

substrates 2739 subtle 31811

33511

success 17812 17917 26510

successful 7818 8015 12017 17920 2788

successfully 4512 2438

suffice 2715 33511

sufficiency 3952 sufficient 203

1512 29719 2986 3636 3642 36610 38710 38916 4019

suffix 1783 1854 18568 18722 1881 1912 2608

suffixes 1241415 12417 1336

suggest 6620 1046 11013 14422 1452 1814 18320 19921 210912 2263 27615 2901516 2945 29410 2976 30115 31115 31318 3312 3322 36122 362722 3644

suggested 843 29322 2943 38922 40019

suggesting 10111 1515 1698 22614 26920 311410 325911

suggestion 2446 26822 2863 3311

suggestions 36810 85721 9822 18719 2081822 26622 28616 32817 33117


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suggests 2101115 22318 3313 36118 362317 3634715

suitable 33122 Sumant 311 69

204816 summaries 8313

8315 845 summarize 6410

3647 summary 2213

5822 1824 19518 20822 30917 35514

superior 2208 superiority 22035

22012 supplement 27115

2754 3746 supplemental

6919 supplementary

682 supply 1007

13311 17617 1801722 1819 1827 26014

support 4322 467 6791415 9815 9820 10113 10413 1066 12014 1231321 1248 1281415 14222 143514 17020 1852 196414 20718 2228 2333 23622 23712 23815 2405 248712 25315 25811 26312 26616 2752 278812 31115 32513 3293 353614 3771 38219 3853

39515 39620 supported 14912

1689 19416 1997 27720 29322 34120 35614 36721

supporters 2212 supporting 942

1001013 1482 35215

supportive 16716 2411 28712 3687

supports 772 8920 1204 18815 23314 26310 2779 3059 3504 37017 3806 39110 4081521

supposed 882 1132 1312

suppress 2289 sure 3620 3922

4813 498 598 13021 1327 1344 1432 15519 1587 17317 2281 2292 23014 2441 30811 33622 3579 38810 40411 40514

surely 32021 surgical 38014 surrogate 21017 surrounding 1111

3253 surveillance 208

586 636818 7221 7416 921 10119 1053 1258 12820 14611 1572 29719 30914 3792

survey 5646 576 601 6115

surveys 601015 6015 6119

susceptible 3401 suspenders 3579 sustained 7610 swath 881 Sweden 36421 switch 6018

1142021 11512 115367 1236 1683

switched 2515 578 15618 22019 38418

switches 15620 switching 262

5720 608 1031 10819 1091 11320 114218 11419 1151216 11612 117213 11714 1685 1934 19421 2217 2222 2311016 25017 29815 3641921 3651 36611

Sykes 411 37519 37520 3762

synthesized 26219 2633 27222 2732

synthetic 273320 syringe 1471 syringes 681722 system 191113

3314 4517 527 7819 8015 9119 921 935 10120 1054 11013 11812 12621 12714 1401015 14414 14511 1501 1521521 1537 17821

17918 1862 19018 191610 19112 1924 19321 22515 24016 25114 2536 26921 2841314 28519 2861 32121 37817 384516 4051112 4063 40611

systems 698 12416 14614 28313 31321 36111 36912 37720 4084

S-E-S-S-I-O-N 2041

T T 11422 115112

11518 116347 116710141415 11615

tables 20220 tailored 3044 take 353 3620

3919 4110 547 5813 624 752 955 11813 15419 16320 2027 2471721 2575 26612 28420 29712 315113 3364 3385 34016 35921 3601 3804 3846 38712 3974 3992 41112

taken 3517 4511 8911 1007 1381 1739 1764 20314 30918 3491021

takes 1655 20713 24018 3924

talk 5020 1055 11417 1304 15716 15823 17220 1832 1841 2005 2141 2147 2174 2272 2723569 28812 29621 31113 3187 3769 4104

talked 271011 364 601 1307 13013 2599 2906 39718 4022

talking 2615 316 1709 1867 22916 2691 3186

talks 4715 target 2792 36121 task 9810 1613

2368 24219 tasked 4108 TDD 1161820 teach 8110 teaching 1427 team 424 464 teams 12019 technical 8316

29013 3175 35912

technologies 30413 38911 4091821

technology 7817 1349 2321520 3713

teleconferences 1841

television 819 tell 291113 452

991619 10520 14612 1718

tells 14019 template 811 Temple 1685


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2238 temptation 2856 ten 6022 10810

1362 137113 18122 30221 32418 33215 3435 4021920 40912

tend 10311 tens 21910 term 8514 2104

3086 terminal 21710

3301618 terminology

12611 terms 2416 285

2810 553 1194 1339 184814 18613 2491 2892 2921 29310 2951 29819 29910 3004 3027 30419 31114 3168 31819 343422 34611 35721 3861617 38618 38913

test 11422 11579 115102021 1161 1681018 16820 17010 2156 22822 2647 2783 2997 37811 38310

tested 5411 591 7814 9113 2223 22315 30619

testify 1549 testifying 16413

40811 testimony 513 testing 1622 2222

333 3791216 382 434 441 4515 7117 9913

9922 2128 2184 219910 22210 2221213 2235 22715 22819 22956 2568 266181819 27914 3304 37016 3711417 37121 3725 40171119

testosterone 985 tests 9918 1181

19219 40120 40216

Teva 32020 620 621 302141717 3035 30591112 306815 30719 30814 3093817 30922

text 33018 Thailand 2313 Thair 879 thank 15122122

2345610 2717 2719 28315 3116 35151920 3814 408920 4222 461820 4720 492122 504 59131819 5922 6120 631 6321 6416 737 7312 7561318 8420 851 8638 8691922 871 93910 95247 9516 1041718 107161822 1086 1171618 1197 1202 1291920 1301 13222 1341518 1351319 14216 1421720 14417 1489 1531719 15322 1581616

1592 1661721 17314 1741217 1821011 18317 18867 1961718 20010 203711 2041214 21218 2131617 21521 21522 2169 22549 23122 243911 24617 24737 2562122 261210 268910 2715 2815 28621 2871 2971314 30211 31058 31514 3245681213 332811 333513 342711 34620 34727 35621 3571 3605 3651112 3666 3671115 37511 37513 3817810 38114 3854516 3891718 3975 398141520 409911 41045 410101420 411122

thanks 10421 13514 15415 18213 18721 2018 22910 2598 3104 3118 3647

themes 866 therapeutic 414

538 5615 7922 15116 1556815 1563 33521 33813 34116 35610 3859

therapeutics 2014 1752

therapies 1615 1879 2022 211

217 311 5415 551 597 779 15968 35618 382616

therapy 521418 537 56813 5710 593 10515 12021 3853

thereof 1242 thing 3022 3218

386 1186 1333 1876 25115 2808 30514 3594 38612

things 373 10615 1189 1308 15518 1761 18117 18322 2146 22620 227420 24611 25217 258122 28216 28921 2914 2988 29912 38713 38811 40222 41015

think 155 2422 261214 2712 2714 34356 3618 371519 38410 3915 402 5118 5212 6117 626 7322 745 8558 904 9622 991013 10122 1059911 1063 107578 107131515 1081519 10911 1091221 11011 11012 1111519 112715 11318 11319 114911 11421 115513 11519 116613 1186101114 1191 1238 1329

1359 1421422 1431214 14616 1491621 1505 15113 152157 1546 1551315 15516 15616 15717 15812 16381419 16616 1671116 16717 1684 17121 17246 1738 17427 18410 185313 18516 186321 18757 1918 197815 19812 1995 20017 20114 2027 2034 21322 21461016 21510 2214 2227 22319 22810 2294 23022 2319 23522 243618 24518 24612 2474 2622 26919 2704 27317 27921 28010 2821621 2832 2841015 28699 2903 2913 29422 29620 3011216 30319 31016 3121319 31320 31416 343813 34318 3464 35712 3585 35915 36015 3666 39822 4021314 40416 4071 41016 41110

thinking 2712 3713 4821 515 5117 1707


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19715 2011521 20122 202910 2195 3159 34719

thinks 1354 third 112 1920

2020 213 9022 10919 1163 14113 16112 17617 18016 19222 20922 21014 2537 2628 26610 3961017

third-party 2313 4411 487 925

thorough 17510 23213

thoroughly 591 2336

thoroughness 633 thought 2814 559

8520 10314 13012 1331 1859 19716 20110 2022 2801719 3258 39045 39710 4112

thoughtful 5916 20012 2038 30918

thoughtfully 20512

thoughtfulness 632

thoughts 2610 474 13311 20113 3156 33314 3428 41116

thousand 5312 6012 8714 1694

thousands 6110 9020 21910

threatening 197 6518 839

three 1013 128 1812 3021 4122 8314 8718 895 903 981 11114 1135 1166 1376 14014 15714 1603 1681 19518 20819 2093 21621 2656 29314 31219 32510 32615 34517 34836 3681218 38322 39116

three-armed 25716

three-dimensional 2096

threw 15814 thrived 2435 thromboembolic

558 6315 throw 3437 tie 4121 425 tiering 15517 tight 1512 tighten 2137 time 1118 1259

13513 141718 151112 205 291818 342 35417 3921 421 5713 6613 7314 8617 9212 1031914 1085 11719 1314 13420 14168 14214 16612 17215 17516 18118 18210 19413 20017 20916 2119 2157 21621 2254 2311822 2439 2509 25918 26010 2618 28320

2866 29015 29818 2991321 32213 32511 3328 34017 344289 3451 3553 3595 37613 3781 3791014 38610 38618 38816 38912 39120 3972 39820 4111

timeliness 1845 timely 20810

2424 times 34321 4016 timing 1309 1843

3355 tipping 16710 titer 34531718

34613 titers 5522 today 10212

1220 1311 163 291122 3116 323 351618 4014 431 4615 481 493 5021 6611 678 7010 7711 8711 944 9518 1203 12713 1326 13520 1369 1373 1387 1404 14013 144710 14411 145611 14516 14620 1474 14820 159318 16218 16618 1709 17418 1751720 1761 1779 18020 1821 1855 18912 1908 1917 2004 2008 20220 20415 247413

24813 2665 27115 287620 29315 30511 3168 32414 33317 3478 3487 35622 36410 36516 36815 3769 37816 37911 38214 3832 39126921 3973 39821 4009 4021516 40218 4089 40910

todays 4918 505 3254 33319 41011 41121

told 3912 512022 8813

tolerability 5315 5716

tolerate 5610 615 tolerated 449

7321 7422 tolerating 603 Tomeka 41013 tone 2759 tool 12721 tools 8517 12722

23212 24816 2502 29810

top 1471 2264 31816

topic 856 13313 1628 1637 1921113 1943 26610 2721 39322

topics 2119 35515 35517 3732

total 3186 32211 totality 6921 726

10815 1101214 1101822 11218 11324 11778 11813 1281314

20620 23320 23512 2392 24018 24814 2755 30611 3391 3611 3626 38819 4024 4099

totally 2615 22715 3221415

touch 26620 touched 3619

1542 Toufanian 28 910

911 2310 2415 4819 7411 1673 19915 23010 3573 36514 40914

town 1611 2317 toxicities 22815 toxicity 193

21010 2244 3875

toxicological 2103 toxins 2114 TPI 38515 3897 trace 5418 5812

10117 1064 14714 1484 22122 22914 31310 40511

traceabilities 3099 traceability 19015

3094 37821 traceable 2309

38411 tracing 1024 1062

10821 17622 1777 22917 23013 23111

track 1918 459 5417 7214 869 934 10117 1024 1064 13315 1402122 14134 14111 1484 17919 1919


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2312 31310 40511

tracked 735 14520 29415 30911

tracking 191114 713 1062 1256 12514 1344 14119 1438 17621 1776 2301617 31722 34914 4057 40919

tracks 7420 trade 828 935

13522 1554 15922 16210 163312 165411 16521 166615 17116 17439 280237 3524 3585

traditional 1719 184 4322 2803

trail 4518 trained 10746 training 1266

130710 1361 transcribed 1221 transcript 1222 transfer 13411 transform 2099 transformed 1119 transition 19320

2671021 26828 26820 35529 39317

transitional 2629 26621 2673519 26722 2686 2692

translate 4413 8413 12119 30113 3458

transparency 17211 1747 18711 2491

29710 transparent 21611

3755 40821 41115

travel 4013 6415 traveling 4112 treat 6510 8212

8914 916 9210 treated 2521 5612

10518 2737 28415 35910

treating 10519 1068 36112

treatment 2920 3017 447 4815 5015 564 5726 661219 8917 902 914 1967 19615 2628 2638 3351 33912 35613 37419 37622 3775 38018 38210111315 3841315

treatments 169 222 5222 609 82172122 8310 9213 1599 3568 3794 3823717 3995

trend 1374 trending 1375 trial 279 5320

571 10112 1694 19417 20211 2385 2433 2791 2923 33721 34116 3727

trials 1819 194 202 266 275 3622 4319 4513 517 5417 581 62210 9114 1037 13811 139218 18712 20117 2025

21571415 23618 23919 24022 2531315 2531618 2555 32621 3271516 33522 33814 37811 3871415 38881120 3895 39122 3929911 3921422 39316 39317 39410 39615 3971421 4041921

TRICARE 1493 tried 5712 912

3044 tries 38619 triggering 195 triggers 2621 TRT 11618 true 2922 16516

16522 2857 34011 3594 36310 4071

truly 9819 1897 24018 244913 4031

truncations 33016 trust 12120 4003

40321 trusted 766 trusts 30922 try 3212 4814

1698 2691920 26921 28721 2915 41118

trying 3819 487 10614 15416 15811 16110 2046 22613 2312 2459 3032022 3443

tumor 882 2664 turn 920 238

7914 1774 turned 882 9414 turning 1115

2751 Twenty-four 5713 twice 14212 1437 twin 39921 two 164 2713

2914 301519 5718 702 7314 927 971515 10313 1081113 1103 11111 115161718 1166 117520 14212 14321 1457 15919 171415 23217 23516 24413 266121 26816 26819 2695 27324 2761618 2771022 27818 28115 2834 30222 35113 36416 3732 3798 38317 3923 39614

two-sided 3371 type 205 882

1075 1318 1321 132517 14622 1471515 1511 21920 31617 32169 32522 3317 3516 35312

types 355 1716 2004 23916 32521 32716 3469 3664 39217

typically 1376 1417 1555 33710 33920

typo 1406 T)7 11671015

Uulceration 38017

Ulm 47 79 3606 36099 3666

ultimately 1811 9816 10415 10516 1735 38315 4029

unable 531 unachievable

22614 unanticipated 933

3703 unapproved 913 unavoidably

16418 unaware 2603 uncertain 9018 uncertainties 1615

16114 2265 23917

uncertainty 20716 2271116 24212 2421618 24420 24614 2776 28611 2981 38318 3945

uncle 380111920 unclear 824

23810 underestimate

2367 undergo 581 6210 underline 2532 underlying 29114

3367 40721 undermine 8722

35417 understand 3321

3419 3819 4315 4919 6719 1036 127511 15417 1731 1756 18222 20212 23417 33216 35811 37613 378619 37915

understandable 1094


Page 469

understanding 214 781621 14615 1559 15722 2419 3029 3053 31011 3717 4072022

understated 40018 understood 32914

32919 33720 3418 37722

undertake 8017 undertaken 29320 undertaking 183

9810 unexpected 1775

3835 unfeasible 3381 unfortunately 996 unified 3268 uniform 1961

34918 uniformed 1202 unintended 6517

72815 932 19012 19610 36915 3703

unintentionally 16310

unique 1620 177 1911 2219 2616 3313 3915 439 456 5119 5318 5810 596 618 62920 7017 733 755 10212 10217 1057 106522 12217 1231 14716 1783 1891320 190261120 19113822 19212 1962 1991617 20029 2644 27417 27918 2802 2941114 29718

3091020 3168 32021 3213 3225 3232 3496 37417 38434 40311 4051718

United 203 3119 6510 6611 8910 1001617 17514 2258

universally 714 13817

University 32 518 10721 1081

unknown 32919 unlicensed 913 unmet 2886

35616 unnecessarily

35419 3889 unnecessary 1522

25317 25412 2555 2569 2856 3072 30822 31112 3581 4011819 40819

unpredictable 21812

unrelated 2767 unsubstantiated

2906 unusual 523

25313 upcoming 317620

31813 uphold 548 22117 Upjohn 1682 uploaded 1272 uptake 7817 urge 5118 547

6858 753 15020 15118 1538 1801 21912 22115 22912 28911 38215 3853

urged 709 urgent 39320

urges 8017 17722 26320 38410

urging 943 USAN 30815

4069 USANs 30912

32213 use 2112 2489

537 6510 6821 6913 715 7810 7815 7961015 8514 89131721 912420 9921 1001 10121 10217 10821 1093 11320 12018 12536 1264 1276 1281418 1298 1381011 13913 13916 1424 14318 15218 1531 158713 15919 1605 16121 163211 16511 167822 1754 18714 19020 1939 19921 2081 22315 23620 23811 2579 262221 26818 2804 2829 2917 2929 29322 2989 30210 30819 3164 3226 3237 3263 3289 3305 34022 3423 3462 349813 35220 35319 3581 36510 36912 37611 3842 3894 39215 39611 39811 40012 40816

useful 126 859 11017 116815 117815 15617 15621 1573 15813 2146 28110 3311418 34814 35215

useless 3221415 user 3204 users 5699 602

9012 uses 14018 3204 usual 184 3164 usually 2281011

22821 25718 31321 3471

utility 1611 3091 utilization 798

12112 utilize 253 2618 utilized 202 807

23622 23721 24015

utilizes 8019 utilizing 2331

23719 29821 3708

US 326 538 547 8922 1001218 1019 15220 160817192022 161171118 1624 16316 1705 1711 1778 17814 18813 20422 2051117 2193 2379 2471214 2481 2536 2541122 2575914 27714 2833 28719 28917 29211 3038 30821 3156 31713 32013 32219 32712141517 3321822 34712

353389 37618 37715 3802 39323 39416 39545 3968 39811

Vvaccines 3184 vagueness 2013valid 28021 validate 34319 validated 3301 value 1138 2062

27217 2901733714 35815361915 38812

valued 3281 values 2081

36022 3617Van 48 711

367131516variability 20915

2149 2951730011 38715

variable 38616 variables 7615

3852122 variation 2620

12521 1341variations 1710

31811variety 1714 2112

2117 2210 4710 12413 1335 1451922 1462

various 475 8413 2252 2749 3403 3421 40113

vary 1109 13822 20918 227529520 2962

vast 14019 vastly 27314 vehicles 12720 venture 291 venue 2475 verbiage 20215


Page 470

version 8812 20721 2796 3288 3318 3785

versions 17713 23216 3208 32615 34910 396811

versus 1106 1645 18713 24217 2515 25212 25720 27214 2781515 29513 3285 3301 3387

Veterans 901 vibration 2097 Vice 874 14815

17419 18813 2327 24622 2617 3474

victory 463 video 228 videotape 1217 view 327 4613

1415 18511 24317 2456 2574 2811 33821 3681 3723 3878 38817

viewed 6220 32119

viewing 86 views 1210 1995

36719 37922 vigorous 25011 Vink 315 613

1549 2462021 24622 25711 258510 25913 2605 3141015 31510

violations 16615 virus 543 vision 18111 2993 vital 39919 40121 voice 7627 771 volume 36319

voluntary 556 vulnerable 574

9416

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896want 1918 2110

2447 2913 3213 351113369 4019 4314 4417 5913 8522 9013 937 9411 9717 102211061 118713020 13261342 1384 1391 14119 1621816617 1722018312 185171989 2063 2169 2174 2198 2464 24615 247362486 250625421 255625610 268152694 280628320 28432851 2949 2974 3047 346583939 409641114

wanted 634 10422 1332 1404 2012 201913 2588 3031 32413

wanting 39611wants 386 26410

30511warn 1957warning 88915

3501519warnings 12622

1473 warrant 35114 warranted 2553 warrants 30513 Washington-based

4917 wasnt 2521

1691921 1701 1976 23014 31012

wave 31911 way 30113 3313

358 371619 474 652 8317 1023 10416 10956 13711 1389 14511 15111 15315 1555 1566 1581 1651 17014 1745 21422 22713 2307 2421 24912 2535 26220 27112 28021 28210 29416 3041 34312 35714 36310 3792 38310 38518 38811 40022 40120 41119

ways 177 858 9613 14014 14519 1515 1861316 22621 38213 40717

wearing 163 33214

web 227 webcast 86 41021 webinars 4715

9614 1801 1841 website 131 2248

7720 814 9620 9622 13112 31622

Wednesday 257 week 259 2898

38016 weekend 4121 weekly 256 weeks 9616 weigh 11820 weight 1195 weighted 1133 weights 11010 Weiss 30122 welcome 847

8621 951214 2044 21414 2322 2813 3842 39911 40813

welcomes 2077 3035 3688

well-being 3724 well-established

27919 well-informed 847 well-known 1389 well-validated

23115 went 958 31515

3421 34517 werent 1677

21717 3653 westernized 3111 wet 891415 1505 weve 3821 3583 white 111 227 wholesale 1677 wide 4710 7621

2748 27612 widely 20918 wildest 315 willing 12717

3271 win 424 winner 4120 winners 427 wish 1522 4812

2457 40117 40515

Wisner 41013

withdrawal 556 witnessed 3778 women 3021 wonder 1065

1304 1995 35813

wondered 269 21419 2588 3902

wonderful 1084 3594 40011

wondering 473 1469 3003 31212 3661

Woodcock 26715 word 23811

26221 3165 3462

wording 22317 23811 2645

words 2322 3614 1121 11519 16121 1659 16716 2782 29117 32161232113 3392 3412 38519

work 243 3721 389 428 4813 7813 8518 9815 9820 991 10414 12515 12717 13413 1355 1461014 1516 15313 1546 16517 1822 1962 2256 2921 29310 2951 31222 3267 3501 35619 39920

workable 705 1399 1472

worked 14110 15114 16316 16421 24918 3777 39919


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working 226 3220 478 1044 1068 1076 12915 14911 15610 21313 29020 30217 34318 36121

works 3219 388 4022 1043 14511 1556 2524 31022 37622

world 297 5120 5210 13722 1766 2192 2442 26112 2916 32117 3913 4001214 4062 40613

worldwide 2910 307101215 3110 555 6521 26114 3236 3568 4065

worlds 17420 24710

worry 397 worse 241414

261 489 worthwhile 1748

32117 40513 worthy 39119 wouldnt 2520

1342 14620 2442 25813 3465

write 399 written 341 9615

10612 1217 12419 13322 13413 16613 18818 20818 2131 21422 2496 2611 27218 34414 3485 36812

wrong 1815

21518 38717 wrote 1686 22314

XX 13216

Y Yapundich 213

54 151820 2316 2420 265 2612 271419

year 301117 319 6613 9415 1378 13713 15212 1534 26114 31620 3243

years 2919 304 3115 4116 4710 13623 13719 14321 16517 16720 1681 17521 18122 23217 2471618 24915 25017 25615 29212 30221 3031 31910 32418 3581417 3595 36313 3668 373621 3778 402192020

Yetter 210 91414 yield 3783 yields 543 young 38011

Z zebra 5118 zebras 5119 522 zero 24218 24421

24533

1 1 433 1131 1229

1902 21514 1100 3479 12 298 19 6616

14 36517 100 109 104 2042 10 2812 8210 10000 909 1000 955 1014 9510 1015 957100 1118 28117 107 51810903 112 11 19 24713 3307 11th 316191158 20313110000 7617119 519 12 2919 3581317

3595 37362012-year 1398

37421200 109125 111813 2919 4116 888

881013-year-old 38011135 52114 1363142 3085148 6315 16 55 87 1212

2418 5714 955 2471618 24915 25017 25615

15-minute 1067 31513

15-year 765150 528 1532 1503 112158 64 17 4116 837 1377

3283 174 66188 6819 81211922 390221952 40661970s 32310

1980 5013 17422 1989 6511 1996 25517 1999 2913

22 434 12319 1726

1903 3441538820

24 6616 248 31516 20 3016 9010

1378 25615 3548 40220

20-year 16516 2001 15222 2002 21822 2003 6617 21822 2006 25191115

40612 2008 563 2009 1019 7719

8122 829 34715 3681

2010 514 557 9614 15222 1531 28617 35218 3801215

2011 225 2811 7617 8117 834 11016 2427 38015 3915

2012 19 799 8721 2019 3557 2020 319 2677 204 69 21 8720 3283 21st 887 210 14822 216 61123rd 8712232 61224 2611324th 896246 61425 1371 29211 25th 1422 4059

409720 41112 250000 5213 260 7615 261 615 271 617 28 56 5710 287 619

33 435 1265 1904

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13612 1672017520 34713

302 62131 112 8120 316 73324 7533 2928333 76347 7835 2891735000 521335-years 2917351(a) 35520

373919351(k) 22113

2331 2342023922 243735119 35278153545101335522 35625

360 710 3181 367 71337 569 27312 376 714

44 436 6618 1282

19054C 14474(b) 39516444 412240 58 26213

2631114 27215


Page 472

28117 2851 3193

400 2122 400000 6610 877 41 26315 27215

27220 27318 410 715 425 31722 45 2851

5 5 436 12813 500 102 1414 50 59 6013 2851

2881718 3193 34518

50000 3010 648 50-year-old 25113 501(c)(3) 287

4021 5011 505 3556 505(b)(2) 17210 505(j) 1723 55 2851 55000 413 5214 59 2878

6 6 2287 60 6013 2896 600000 3012 62000 11919 64 511 65 9414 69 835

7 7 11422 115111

1163 70 415 700000 6617 72 11213 75 513 823 76 8813

8 8 52 830 112 101

832 82 80 6816 1118

112812 82 6521 86 514

9957 959 90 1121113931 15221 95 516 11115

1136


473

C E R T I F I C A T E

This is to certify that the foregoing transcript

In the matter of Development of Biosimilar Products

Before FDA

Date 05-11-12

Place Silver Spring MD

was duly recorded and accurately transcribed under

my direction further that said transcript is a

true and accurate record of the proceedings

-----------------------Court Reporter

NEAL R GROSS COURT REPORTERS AND TRANSCRIBERS

1323 RHODE ISLAND AVE NW (202) 234-4433 WASHINGTON DC 20005-3701 wwwnealrgrosscom

Page 2

PANEL MEMBERS STEVEN KOZLOWSKI MD Director Office of Biotechnology Products Office of Pharmaceutical Science Center for DrugEvaluation and Research

DIANE MALONEY JD Associate Director for Policy Office of the Center Director Centerfor Biologics Evaluation and Research

HEIDI C MARCHAND PharmD Assistant Commissioner Office of Special Health IssuesOffice of the Commissioner

MARYLL TOUFANIAN JD Associate Chief Counsel for Drugs Office of the Chief Counsel Office of the Commissioner

ROBERT A YETTER PhD Associate Director for Review Management Center for BiologicsEvaluation and Research

PRESENTERS

ROBERT YAPUNDICH MD Alliance for Patient Access ANDREW R SPIEGEL ESQ Colon Cancer Alliance ALEXEY SALAMAKHA Global Healthy Living Foundation

MARCIA BOYLE Immune Deficiency Foundation

DOLPH CHIANCHIANO JD MPA National Kidney Foundation IncRENE CABRAL-DANIELS National Patient Advocate Foundation

AL CORS RetireSafe PRESENTERS


Page 3



School of Medicine


Association



Association




the Roche Group


Hospira Inc



Inc





PRESENTERS


Page 4











Page 5



PRESENTATIONS














Page 6

CONTENTS (Cont)

Kristin Bass


Neal Parker Esq

Association 148



Amgen Inc 174

Michelle Rohrer PhD



Group 188

Hospira Inc 204

Jay P Siegel MD


James Roach MD


Patrick Vink

Mylan Inc 246

James C Shehan


F Owen Fields PhD

Pfizer 271








CONTENTS (Cont)

Ronald A Rader

Page 7


Institute 316


Michael Strauss PhD


Bruce Babbitt PhD


324

333

Sara Radcliffe


Organization 347

Cornelia Ulm


Association 360







376

410


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(832 am)







Biosimilar Products













in CDER


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of the Commissioner




Chief Counsel






announcements





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the lobby













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biosimilars










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hearing















recall the speaker






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that





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what we say











Patient Access





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practitioners




















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well as the payers














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market






threatening













The third is the




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clinical practice








of therapeutics










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therapies












many of them do not





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Thank you











that consideration









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agent Its crazy














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appreciated



















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bullets basically













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two settings


would suffice



comments


much




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Cancer Alliance























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in only seven years









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patients











medication



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market


















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begin with











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on schedule


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ask a question






















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another arena










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testing






















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the patient










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that that occurred


















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remarks personally






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lose or tie













process






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trials











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strategy






directly





panel


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already said







for the patients








Maryll






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you













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parents everywhere


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safely








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consequences




















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cold





















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another



















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harmonization





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are made available
















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manufacturers






concerns

Thank you



panel



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Page 60




MS BOYLE Correct





treatments















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bodies











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substitution





pathway








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in biosimilars









and their reactions




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is not stifled















threatening






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between biosimilars













develop


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With respect to























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prefilled syringes


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indication




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bioequivalence























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Another question














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managers








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voice























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2009


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decisions











andor ethnicity



behalf of NPAF


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panel





















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panel Okay




MR CORS Thank you


welcome



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investigators say














of AMD






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seniors














at risk



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money









mistakes








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panel









we have provided



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because -shy











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1014 am)














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attended






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helpful




















-- there we go



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that you have done



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with confidence






















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drug


















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Page 103

















monitor for that







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Thank you



panel




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patients et cetera









questions






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comments on that










identify it









University



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consideration















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the draft guidance














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clearance














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should be high


















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switching






















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test product























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alternating














consideration



or two questions




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specific domain


















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future























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areas
















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prescription









for these products












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dispensing













Sentinel Initiative







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opportunities























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biosimilar pathway









products







developed

Thank you



panel Heidi


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much





















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guides











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names and databases















what context





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products










Esposito



out of time




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Page 135








would be helpful







for your comments





today




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well









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decade








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interchangeability





















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products










impossible to do












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the NDC























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use












Thank you



panel Ms Maloney





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marketplace





drug








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substitutions











Esposito








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that this is a risk









change it





MR NEVILLE I am not







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Page 146





integrating them



















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questions













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Page 148





without that


do that


Thank you



Association








here today




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Page 149




















cost




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Page 150



in other areas





















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panel



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be considering







Maloney










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questions


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Page 156













plan











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Page 157



would be useful





















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Page 158








pathway
















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Page 159



present today





















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Page 160










the reference














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Page 161


has to be limited






















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Page 162

















Agency







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Page 163













secrets











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Page 165
























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Page 166


bias








applications










hear them




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Page 167

panel

Maryll






















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Page 168




















but-for test


questions


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Page 169









reproduce it











stuff




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Page 171


reference product









manufacturers













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Page 172





familiarity applies








issues may apply











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Page 173












product




question

MR PARKER Sure







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Page 174











protected




Miletich from Amgen









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stability






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Page 177





















events



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Page 178









are identical












system



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Page 179
























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Page 180
























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Page 181

patient safety









products














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Page 182









in biologics











in addition -shy




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Page 183
























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Page 184













be emulated









questions


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Page 185












that












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Page 186




here




















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Page 187
























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Page 188





help us to evaluate



do that














follow-on biologics


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Page 189








expected
















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Page 190
























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Page 191




as interchangeable




















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Page 192











important topic










product



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Page 193









chronic use















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Page 194


biosimilar labels






















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Page 195









biosimilar status








reference product







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Page 196



requirements













sources

Thank you very much



panel




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Page 197


















Maybe I misheard






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Page 198


to be involved









interchangeability













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Page 199














DR ROHRER Yes








those products


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Page 200









unique names








product over time







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Page 201





drift


Marchand

















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Page 202






originator


















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Page 203












you


taken)


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Page 204


(104 pm)



lunch















called Hospira




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Page 205







in Europe













guidance documents




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Page 209

are captured here























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Page 210
























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Page 211













ambiguous











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Page 212
















studies








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Page 213



















panel





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Page 214
























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Page 215
























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Page 216



RampD





Johnson





biosimilars pathway











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Page 217
























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Page 218







avoidable risk

















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Page 219
























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Page 220













under this pathway











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Page 222














occurred








another indication


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Page 223










assay sensitivity














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Page 224











scientifically













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Page 225











panel







are mitigated






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Page 226


are innovating







different















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Page 227













way











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Page 228

















product







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Page 229

clinically








assess them















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Page 230




number or whatever




















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Page 231
























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Page 232

comments




Pharmaceuticals














by FDA





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Page 233


pathway











allow











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Page 234










interchangeability














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Page 235





















used



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Page 236
























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Page 237













question shortly











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Page 238






requirements


















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Page 239











evolve













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Page 240





















providing guidance



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Page 241















basis









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Page 242





manner














an impossible task





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Page 243










and attention



panel







necessary




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Page 244

















further requirement







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Page 245






















questions


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Page 246
















PK data








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Page 247
























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Page 248





discussions



















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Page 249









number of them















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Page 250





determinations
















interchangeability



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Page 251




















differences exist




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Page 252

















other things







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Page 253






in the US system















such pivotal data



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Page 254




products









science











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Page 255





















development



1

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Page 256
























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Page 257


panel








studies














1

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Page 258




standard

MR VINK Yes



















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Page 259
























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Page 260
























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Page 261



comments






employee













approach


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Page 262




those




















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Page 263
























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Page 264










FDA wants














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Page 265















products









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Page 266









product















1

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Page 267












matter












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Page 268









Thank you



panel












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Page 269








or the NDA route




would -shy





clarification







1

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Page 270









to say








protein







1

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Page 271

says


interpret


ation of the law

Other


comments


from Pfizer



strategy there













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Page 272











the product













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Page 273
















for those reasons








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Page 274


















and context






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Page 275












section












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Page 276




considered




















1

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Page 277
























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Page 278










comparators














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Page 279















rational









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Page 280









these days















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Page 281




final document



panel















framework


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Page 282

DR FIELDS Right













a continuum






your question




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Page 283
























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Page 284









implication







appropriate








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Page 285




gaming actually








and

the













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Page 286






















comments


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Page 287

DR FIELDS Thank you



Novartis company




















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Page 288

the meeting itself





















as with biosimilars


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Page 289
























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Page 290












helpful












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Page 291


perspective






















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Page 297



reference product













panel








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Page 298



what is entered





















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Page 299

questions























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Page 300

DR McCAMISH Right























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Page 301















would you suggest









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Page 302










use




Emmert from Teva










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Page 303
















reference product








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Page 304















clinical studies









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Page 305
























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Page 306














product










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Page 307









product







close assistance








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Page 308













provided











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Page 309


this product






















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Page 310




Thanks



panel








required









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Page 311







DR EMMERT Yes














differences



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Page 312














indications










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Page 313








DR EMMERT Pardon




got it







approach that





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Page 314






batch



any of the speakers















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Page 315




drugs





thinking


that






304 pm)



Rader from BIO




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Page 316


Institute



word Bio Sorry





person company










year




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Page 317

















nomenclature







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Page 318












activations









those



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Page 319












later in the decade












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Page 320




















these products




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Page 321



















defined or viewed





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Page 324








panel No Thank you
















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Page 330














all cases










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Page 332










the feedback









product





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Page 333




considered




















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Page 334




















inferiority margin




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Page 337
















inferiority margin








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Page 342





immunogenicity








panel











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Page 345





















that



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Page 347








today
















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Page 348

comments











approval pathway










guidance


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Page 350














included

clinical

section










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Page 351



















351(k) applications





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biological products


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Page 355













products











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Page 356





351(k) approval



















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Page 357
























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Page 358












better












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Page 359






development


















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Page 360



presentation





Association




guidance documents









quality



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Page 365











Thank you













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Page 366





biosimilar products








products











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Page 367














from PhRMA










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draft guidances














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Page 369










reference product














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Page 370
























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Page 371










studies














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Page 372









safety and efficacy















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Page 373





products



















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Page 374



new application







related












biologics


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nice



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Page 377






information


















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Page 379




on these treatments




















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Page 380
























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Page 381










panel Thank you



Illness











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Page 382

















treatments







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Page 383
















safety








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Page 384








product names












patients need




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Page 385







panel



International














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expect





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time








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panel




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DR ANUMULA Yes okay


questions


from Eli Lilly








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products


















guidances





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situations























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issue














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the FDA


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panel








that









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for another purpose



material




appreciate it








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to market entry

















and fair way


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forward









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essential
















further on






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be the case

















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designed to create























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patients








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is important

















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Sandy





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a good weekend




Page 413


158182122 15914715 16011 162815 1635 166118 1715 1732

abbreviated 12210 1528 1587 18821 23312 3683 3695

ability 3422 7620 8115 997 14714 14719 1909 19112 20836 22121 22913 26511

able 1211 1417 1511 1918 3918 4117 10013 1025 1064 14719 15410 1571 18520 2347 23616 28916 2922 3028



10122 1407 14315 2657 38412


15121 3099 acceptable 6813

21816 2421216 27518 30820 36112 36221

acceptance 802 841 20920 3612 3926

accepted 32312 35368 3549


1519 166814 172 1814 211 2121 221 359 4022 7522 8219 1215 1298 13721 1525 15316 159513 1631 1653 1729 24116 24716 2883 2891516 2958 35617 3759 37920 3822 39111 399721 40121 4048 4072

accessed 131 3564


30920 accommodating



3016 1762 33012 3364

accountability 1761521 1787 18261718 1833 1837



9611 11018

11217 12021 18113 21313 34820

achieved 19710 4001


26311 2642 2651820 2662 33019

acids 26213 26315 2721520 2731218 28117

acknowledge 17522 19216 19422 36114


acknowledges 3094


acquired 1998 act 101819 7719

11311 1362022 1399 15511 18412 2563 26778 32520 3298 34715 36722 38319 399915


1927 2241214 224161719 29421 30517 30612 3127 329101217 34121 3625

actions 12117 15213 15419 2112


2069 2124 21914 25118 30617 31922

32035 32113 3227 3233 3628 36210 3921216 39316 3971221 406571720


9619 972 1258 15418 2074 30420 31219

activity 2658 27712 2798

acts 15512 actual 1169 1632

18415 acute 1711722

17710 ad 1848 ADCC 2951320 add 18414 22122

2264 29017 3623 36413 38812

added 149 195 19514 275611 3924


691 10911 12313 1248 17810 18220 1834 28921 3557 3597 37813 39415

additional 124 13617 549 5721 585 636 6720 6913 7514 7619 12012 12212 1262 12916 13321 13415 1352 14767 15718 17512 1893 19022 1922 19319 2037 21618 22018

2341 2351725822 285212902 2926 29473001416 312223261014 328183311 355151736414 379144052

additionally 136101425 194732715 3773


3918 701410321 1151115116512 1171112619 157151615 19122195615 2221123917 261126413 2821928722 289143045 349135011 351113553 361173948 3973 4059


1386 2741533022 3641237714 40517

addresses 344735112


32518 3261133012 3311533418 3361836621 36853727

adequately 54111629 1741022822 22982641419 33433423 3613


Page 414




111 3121 5310 6520 3366 37421



27322 30720 3796


3235 ADRs 29812


13019 17512 21311 23213 30114 38213

advancements 24114

advances 5513 594 38215


advantage 9212 1171 20713 34316

adverse 1917 5410 577 5812 702 73421 743 7414 754 1257 1251114 14111 1438 14521 1761320 17720 1808 18215

1835913 18519 19015 1911618 1925 20220 20312 29722 3032 3095 3143 34914 3516 36616 37821

advertising 7918 1951113 19613

advice 15119 36018 39321


2936 4021 4217 5017 767 3762 3811820

advocate 220 512 412 7520 7611 8113 18622 18710 3778

advocates 3211 3518 374 877


11916 14816 18814 20418 2166 39019

affect 6917 7914 16410 17310 2088 2758 3459



1372020 14919 24717 4007

afforded 1381 20714 23821

AfPA 16617 1816 2212


204813 2164 2326 24621 2616 2719 30215 3473

37522 3851114 39017 39819


agency 2314 3421 5515 623 6419 6859 721619 7221 74520 753 8611 11216 1192 1484 16217 16359 16815 17212 1733 174310 19714 20613 21213 2135 2229 22314 22421 2319 23315 2357 23610 2381621 2391 2391422 24017 2411113 2484 24815 2859 29615 3102 32520 32610 34810 3574 35912 36814 3753 39215 3973

agencys 119 327 352 5113 726 747 7713 16013 1636 1762 2077 2352 23813 32516 3266 34718 3689

agenda 11161618 135 159

agent 1621 1818 2220 24810 2521011 2620 659 3211322

agents 2521 2616 261818 31922 32035 3227 3233 3367

agents 177


9616 17521 23217 29212 40219

agree 6218 6317 1873 1976 22110 22715 23716 26512 27118 2746 27513 28511 30615


27112 39412 Ahaviah 416

39818 ahead 237 1693

1845 3442 AIDS 37620

37711 aiming 21410 al 221 514 8617

874 2927 Ala 2039 albumen 2181316



412 55616 1518 165 2120 28161818 294 3519 951321 96112 9812 3811219

allotted 136 1418 1510

allow 1814 1914 451 783 1001 13617 13815 13913 1409 1536 19013 20510 2185 23313 23514 24113 2508 36121 36621 4092

allowance 13920 13922 2371

allowed 122 1313 398 9222 1704 1932 2074 21121 21819

allowing 161 4020 4618 847 16618 18821 23322 2784 39820 39915

allows 125 32511 36017 39110

alluded 22312 40916


2642 altering 779


1081922 11319 114119 115212 116613 117313 11714 35020

alternative 1168 1161719 14113 3333


21113 AMD 891518

902 9146 America 49 713


Page 415

282022 3079 3011 9416 952 36717

American 34 519 8310 1191114 14014 25620 4093

Americans 298 314 5211 6618 878 90610 1368 14918


174152022 175811 17722 1786 18612

Amgens 18111 18511

amino 2621213 26351114 2642 2651720 2662 2721520 27312 27318 28117 33019

amount 355 28819 331722 3354


4916 15216 analysis 7613

8117 15216 30612 3813 38610 3931113 3931419 3966 39610 4113

analytic 9910 20116 2024

analytical 26913 271 5617 1181 11821 2278 23212 24410 24816 25028 2576 27719 2921 29310 33011 331411

33115 37019 3718 38515 3871 3883 38911 4011113 40415




56 2722 2816 3811117

andor 661 7017 8419 11019 11319 1141 11713 12218 238814 32222 32518 3445


1183 23517 23620 3317 37112 3875


815 919 818 annual 641317

6614 8712 2996 answer 4615 691

11521 15410 15615 19513 2011 20821 238912 28513 35915

answers 111 816 15412 16815 38717


6169 2794 31818 31911 33526 3369 33719 340218 340192022

34614 3892 antibody 5218

552222 33710 3394 3408 34515


337919 3394 340271820


34045 Anumula 414

385911 39048 39012


1204 1265 12717 13317 1354 1423

aplasia 6522 6815 21822


1517 apparent 16512






19217 23718 3748

applicant 1614 163412 20919 23419 25012 2641419 27416 35121 3546 35522 35711 37214 38818 4018

applicants 3527 35410 3578 3706 37215

application 6919 1623 1633 1641920 16814 1723 2211315 23318 2341421 23612 250313 253810 2595 26417 2681 35213881622 3537 3546913 35415 35519 35717 35919 3739 374347 4001

applications 12816 13018 15121 15312 15920 1601 16211 16318 16610 17110 26513 2686 35119 35910 37320 4025

applied 461 707 7416 10411 2358913 2378 24922 25020 2566 27218 27616 28319 2893 29318 2968 3558 3663 39322 3971012 4067

applies 466 1725 34220

apply 1121 4713

17213 17319 2451919 2512 25113 25815 2594 26317 267216 2706 2824 2953 30815 3101 32121 3439 3639

applying 25516 2679 30416 4043

appreciate 352 505 632 757 9410 981319 10422 120913 1302 149910 1504 15317 1758 20011 21221 24613 27216 3266 3649 376812 3918 39514 3972 39816 4115

appreciated 255 862

appreciates 649 9812 30917 34722 34817 35110 35216 36013 36718

approach 3117 321 6922 10814 1093413 12014 12815 1506 1536 16012 1881617 20616 206192122 2071319 2129 21211 21418 2154 2193 2227 23221 2331020 23512 23937 24019 2429 24813 26122 26612 26717


Page 416

2684 2721517 27618 27711 28222 28319 28715 290921 2959 3039 30720 3091820 31319 3261818 32619 3354 3386 34313 362918 36321 36919 3797 402359 40513 40514 40814

approaches 8019 8516 21415 2346 27616 34921 40312

appropriate 4321 6718 1246 1797 1868 1926 1961315 2082 20913 21017 2149 21513 22010 2214918 22319 22522 2373 24210 26711 2726 2774 28013 28416 2867 28918 31213 3284 33020 35321 3682 3695 3719 3727 3948 4003 4036 40816




1817 326 599 6412 651 686 706 719 7218 774 8217 8322 976 10012 10113 12121

12322 1242 15015 15420 1622 1671922 1688 170520 1735 17510 17611 17813 1825 20620 23822 2651 30056 34720 3481218 3511 35314 3565 37214 38315 38916 39417 39916 40321


1206 16813 17016 25816 2707 28811 29319 35615

approved 221 302 304 335 547 5510 665 6916 788 792 807 891317 915 929 12519 1509 1519 15916 16817 1794 18619 1904 1913 1936 2006 23217 24820 25010 2546 26768 27311 27613 27819 28211 2938 29420 2955 3011 32810 3322122 3331 3397 340468 341120 3448 350921 35557 35613 36618 37311 38312 3983

approves 1533 35416

approving 683

25320 approximately

132 415 6610 1367 14016 3914

April 8720 887 896 36416

arbitrary 4415 26319 2859

area 9419 1076 1478 150221 17211 1746 2127 22116 2224 22719 22919 24919 26622 2768 28820 29018 29614 3095 31613 3312 34813 3868 40217 4091

areas 1228 1503 1518 1546 15919 2064 21112 21222 2161821 22718 2495 2621 29017 2968 3259


24416 argue 22718


33720 35818 3713

arthritis 414616 831 2285 33919 3406

article 8721 2356

2428 26020 32322



2901 29619 37222 38513 39214 39718 3984

asking 4212 635 1731 1741 20118 2454 26919 33216

asks 1816 4422 aspect 199 2613

23712 3909 aspects 11722

1236 2062 2071821 2089 20812 2117 2656 31917 34719


34215 assays 3301

3371020 3436 3431720 3452

assess 1116 2096 2299 24920 32822 3424 34510

assessed 2297 31022 32917 33421 3678


assessment 10812 10913 1119 1179 21014 21231014 21419 2399 2407 2724 30721 31010

33320 33414 33516 337211 33917 34015 35511 36311

assessments 24517 3347 33613 3378 33811 34210 34456

assign 28912 3226


12317 1284 assistance 30716



24810 810 92 951115 2211

associated 332 14419 18013 31019 32317 3393 35313 37112 38221

association 347 4717 519 63 710 119111417 1481217 1555 3608 4027

Associations 30510

assume 30518 3271 3371



35116 assure 8113

18819 2347 2808 30418 3563

assured 3216


Page 417


35115 3542 35522



2255 24310 3329 34634 35622

attorney 15821 2834


1839 29612 3676

attributed 735 1389

attributes 2932 30019 3014

attribution 17613 17620 17720 1808 18215 1835


3176 authored 2354

32321 authoritative


3502 3678 authority 3420




5418 5814 624 6221 1797 1869 3674

autonomy 173 233 2412

availability 11113 15213 35422 35722

available 1010 126 228 539 588 808 812 10410 12616 12917 13210 1464 1553 20310 205616 21621 2315 2348 24817 2502 2545 37621 39616 40013 4021718 4093

Avastin 8881216 89814 902


19117 1928 21719 2844 4011819

avoidable 217512 218567 2197 2191315 22513 22516 23121

avoided 1935 2171516 21915 21916 23116 3087

avoiding 25411

4004 avoids 28526 aware 4717 745

775 145814 14713 18411 2777 28316 28434 2981415 33213 3654

awareness 12610 12713 13015 13111 132519

A-F-T-E-R-N-O- 2041

am 112 82 101 95910 20313

Bb 11318 1726 Babbitt 44 76

3338916 34314 34522

back 147 2919 4910 617 8613 95612 1034 115710 13120 14112 14281981618202028 204462832 2936 3009 30018 30133097 3151438015 404840612

background 276327610 31611

backgrounds40810

backup 29511bad 1613 2519


11618balance 21314

24220 28133544 357183682

balanced 1619 11517 18819


3997 barriers 4814

1216 22613 4004

base 3013 3068 based 177 4412

6011 7916 1116 11181221 1143 1205 13822 19418 1952 19816 20422 20819 20910 23611 2381122 24211 2456 25320 257715 25816 26317 2732 27417 2769 2776 2923 3048 30717 31420 3211114 3361 3391 34420 3514 3693 37118 39217 3944 4044 40722


10114 15022 25920 2828 32212 35816 39810

basis 6713 1622 20222 23318 24115 2541 27319 27415 28714 29813 29967 31012 32812 3513 37314 3861 38819 4015

40212 Bass 36 62 14810

1481314 1548 15421 1554 1567 157422

batch 309712 31456

battle 2019 2317 2413 2865



7519 8422 877 1549 1591 26110 32413 3339 3476 4107


3892 believe 127 295

337 4219 4319 4514 4722 5113 6317 6422 705 759 100691410015172110157 102310 10215 1046 12513 12711 138210 139914 13917 1406 1454 14914 1516 1576 15911 1603 16417 16817 170317 17117 17611 17715 183711 19719 20510 2136 221914 2339 23415 2368 23747 23819 2395 240112


Page 418

2417 2434 25122 25219 253717 2558 25611 2571217 2581420 26011 26118 2621114 26512 2683 27411 2755 279111722 28714 31416 3813 39216 39418 4086


7812 8312 843 849 17511 20813 2122 26611 30512 3489 3492 36821 37011 3711420 37212 37316 37412 37712 37914


9817 10415 1366 1382 14818 14921 15214 1892 1908 29111

benefits 787 1367 14822 1494 24015 24122 37621

Benton 146 41015 best 243 3417

3817 481515 5620 8511 13721 19720 2348 2737 27414 34312 3775 4001 40322 41119

better 5611 8518 1194 1349 226161718


2712 315 639 10546 1467 3033 3788 3827

bias 16322 16419 1662 17310 1744

big 24214 36015 3862


31316 billion 3016 1371

15221 1532 292811

binding 3064 31119 31216

binds 3129 bio 31520 3165

34715691620 3482917 3492 34916 3504 35110 35216 355214 35614 38520



2247 bioequivalence

721 1018 3869 biogeneric 25220

2548 2558 2566 biogenerics 24719

24822 24922 2504 25113 2542 2564 31412 3153 31914


biologic 31 516

1620 177 2220 2510 33219 3910 4718 5216 5619 5816 659 6612 77722 8813 9146 926 927 951422 996 1022 1033 1035 10412 10510 10611 113111421 11420 11534 1208 12221 1373 15210 159917 1753 1783 1801317 1901320 1924 1921517 19356 1951 2006 2472 2529 25467 2895 29311 30311 30412 30622 3142 32421 3253 3499 3555 3782 37871218 3799 37921 38222 38319 38421 3993 40315 40714

biological 178 1868 1915 2010 2218 5622 583 821221 1206 13712 1496 1513 16118 1676 19919 20020 24917 26216 2643 27817 28015 28313 28414 2851820 29116 30520 30712 35322 3597 36113 369618 373818 37322 38411



916 1018 171 171718 182 211118 2236 231 3315 398 41610 4458 453 539 6219 657 7718 9012 9018 911214 9617 971115 10211 1031120 10411 1238 12613 1296 13612181921 1376 13817 14015 15115 1526 1761622 177311 18019 18115 1829 18822 19214 19318 21120 21718 2366 24117 2424 24513 25017 2522 25311 25519 25616 288391516 29220 29319 29416 30120 30218 30310 307512 33920 34714 3491920 3586 35910 36322 36520 36722 36912 37422 3779 38078 3834 38613 39210 39316 3998 40013 4045 4056 40815




3161318 3173 31714 31918 32220 32416 33310 37315



biopharmacopei 3245



1015 181820 1922 3320 3422 357 4318 5112 5414 5619 5815 6215 68412 6912161718 70616 7117 721720 734 755 77416 781 7811 791 8056 8014 8314 841 905 9119 921 921015 933 976 10011 1019 1011319 1022 103344 10510 1061021 1207 12214181822 12321 1241 12519 12619 12710 1292 13019 13215 1346 1433 15315 1541722 1591020 16015 160822 16136 16181920 1623 16211 163412


Page 419

16317 1668 1681416 16913 1691618 1705 1702022 17311 1732021 1765 17925 18018 1824 1861418 187215 18916 19123 1931416 194271520 19559101418 196614 1979 19817 20216 2033 2052459 20617 20720 2089 20916 2102022 21214 21212 2135 2201820 22218 22656 23221 235410 23711 2404 2431 24520 2467 25013 25135 2577 2595 2627 2641517 2652 2651017 2667 27122 28816 289720 29010 291617 29358 29311 29411 295722 29616 2962122 29911 29913 3001520 30234816 3031418 30438 3041117 30520 30616 307722 308817 31221 3141 31722 3201315 32110 3232 325513 329913 33312 33315 3341 3351719 33810 34171422 3446 3457 3467

34910 350913 35020 351920 352261422 353314 3558 35711 3601116 3632 36411520 365151921 366517 36720 3683 36912 37046921 3715 372114 373410 37412 3741415 3759 3781318 37921 38312 386415 3861920 38711 38717 3911018 39291822 3932 39317 3943410 39719 4035 4072 41015

biosimilarity 1021 113 516 10812 10914 110479 11015172022 11123615 112151822 113346 1145 117679 11811 118131518 15771619 18818 198810 19925 21622 2173 2349 2373 2371619 2381 23816 2405 2429 25719 25813 28012 29110 2975 299421 30620 30818 31111 32145 32519 32710 3282 33821 34820 35511 35922 3617 36311 3754 38311

38518 3962 39711 40112

biosimilars 117 92 111114 176 1713 18211 251 3119 3269 33315 3512 4214 434811 45357 47618 507 513415 54610161719 551217 581016 59369 618 6214 6311 6412 65113 66689 6621 701112 719 728 77614 7721 782713 7821 8018 8110 8251018 8322 9013 9112 931 961117 977 9811 995 1005 10121 10211 10320 10526 12022 1211922 122611 12320 12414 126810 128371216 1295714 1434 150916 151712 153410 1544 16414 1717 1755714 17617 17718 178113 17813 179718 1802 1846 1868 18717 18820 18918 1904519 19111 1951415 19521 19918 20111 2021 20422 2051 20620 2111922 21613 2171422 22010 2258 2314 23513

24120 2423 26411 2885812 2881922 2905 2917 2929 29811 3011119 3021921 3037 30310 3058 30812 30921 3122 317720 318814 319713 32022 32322 3266 3325 3368 34210 3472021 34811 34919 35616 35810 36113 362914 36921 370112 37618 3771516 37915 38029 38116 383321 38322 3844 3898 391911 3991617 40011 40311 4055 40719 4093



biosimiliarity 2371


biotech 18122 39135

biotechnology 22 415 728 819 964 17421 17519 18119 2165 23211 2434 26112 31617 34622 34751011 3569 3913

biotherapies 15913

BIOs 35218 3576

BIO-member 3566

bipolar 3824 bit 2120 3711

4822 7417 1055 11418 1305 15713 16713 16813 1842 185211 23018 25911 28322 28813 2993 4022 40317

BLA 16118 16214 163216 1904 2007 2206 26720 2697 27015 32115 3303 3511215 35117 3525 354812 355720 3563

BLAs 16319 1667 2685 32115

blood 5311 3185 board 40314 4045 Bob 914 1685

2238 bodies 3312 404

459 6113 2181 22521

body 552 9719 984 1119 17013 22521 27712 3064

book 12316 13116 31615


119101213 1302211 1331 13320 13513 1884



Page 420


27816 2796 Boyle 217 59 502

50410 60410 6118 62822 6312 641

boys 986 BPCI 1019 112

11311 11411 13616 2563

BPCIA 15912 1621521 2489 34715 3484 35120 3523 3532 3543518 3681817 3694 3752 40522 4109 41118

BPCIAs 2682 3561


5811 6220 662 7914 824 10412 15219 19119 1941 24714 2515 254717 25511 2944 29722 298256 31322 3496

branded 320 620 13118

brands 2521010 25517

brand-brand 25212

brand-generic 25212



382616 3852

bridge 2936 35315

bridging 2082 2373 2771022 27857 32611 3531216 39217 3954 39610 39720


27214 2811011 2821622 28319 2842112222 28511 2862

bring 289 3118 9121 1361314 23522 24120

bringing 2417 1523


8722 1943 20710 2134 22717 3223 36816 3757



15821 brochures 812


40413 Bruce 44 76 3337

33315 budget 2812 build 4213 4519


22710 25414 25511 2806 4017


2046 but-for 1681020


CC 26 316 615

21710 26143301618


calculate 111111121


26615 277327917 32310

called 225 294 464 7219 1112 1113 131151658 204202775 3102 3182

calling 732 31713 32219


8312 132517616 1843940713

campaigns 841012713 1311118417


281617182129461012142915172021

3036691319 302021 31479 3110121314 3218 35101019 386 8220 835 88112 8913 9020 21016 2283


2091 care 36 62 4022

4215 441820 481415 763 773 8116 8822 1192122 14811 14816 26113 35611 3764 38413

career 1362 16516



10920 11010 1195 21720


918 1127 1135 11421 15115 168127 1941 19722 21717 22417 2294 2331818 27319

27319 2741515 28412 2871515 29311 3072020 3089 3095 3101212 34218 34415 3881818 39210 40144 4047

cases 6615 714 7618 8722 2191 2312 27520 2867 31014 3143 31810 33014 335202235613 35917

case-by-case20222




3303 33519 cause 3068 3110

3114 6819 21821


2071 38320 cautious 3117 664

1506 1535 15710 26612


29213 CBR 42 75

3241115 32516 32639 328717 3293 3309

CDER 81922 93 26714

Cecil 33318 cell 179 2619


Page 421

6522 6815 9715 21822 2644

cells 1710 9711 2643 27012


235511 8511 916 8715 3764 37616 3816

centers 8417 11922 34711 3767

certain 1217 391 11416 1745 189415 19219 21720 22717 2981 32517 3271416 32918 34719 3636

certainly 157 2916 404 6719 744 7721 827 873 9214 949 1331521 13617 138513 13967 1403 1414 14614 17710 1871 1915 2003 2144 21810 23417 237118 23921 24221 2442 3874 40116 4058


35414 3575 certify 35410 cetera 1027 1045

1069 1271 14520 2907 2948 3883

chain 1007 17617 18017 1827


1776 21411 29122 34112


331 567 7621 12416 1756 17815 1826 2143 2435 37111 3788 38221


2138 21516 3467


614 741 1041 14121 14322 14512 1473 15199 21937 2593 29320 29419 2955 29912 3674 3741

changed 601416 1518 40313

changes 4310 5313 651422 7210 7317 746 9717 9838 10310 1337 17511 1774 1981519 22514 24516 25018 266111317 2831 29115 2934 29789 3001517 3016 3205 33019 35913 36913 39520 40313

changing 14121 14122 1421 19820 28222 37711


30012



characterize 2641419 26511 32211 3588 3882 38910

characterized 26514



10613 cheaper 3212



2303 30419 37015 38610

chemically 9710 26218 2633 2731 37718 3789 3869


510 6435 744 7419 7513


2816 13522 1908 20417 2165 2328


19722 26915 27278 37920

choices 7815 37419

choose 7915 11212 20920 26818 3284


1072022 1081 11016 118522

Christl 117 912 1865

chronic 411 6511 764 8368 1939 37710


7119 1657 32522 33514 3374 3636

cite 8718 903 32321


15411 2203 claims 1463


1893 2065 21112 21222 2137 22320 22422 23817 2623 26917 31411 32510 3289 3312 3336 36118



19218 1948 19849 19912 20914 210112

2117 21214 2574 3271621 329111522 33018 3319 3554 36222 36358 3645 37317 39311 3979

clarifying 1311 3293 36217 39011

clarity 17512 1927 19310 19659 2649 28422 2852 32521

class 2013 26715 397 554 938 17711 17820 20516 24722 26814 27821 27914 28018 3217 33120 4002

classes 2681719 2695 27818


4277 451418 6911 10615 1095 1144 1252 15720 16522 18718910 18920 19114 19316 19416 1977 20219 2067 22089 2316 23820 23914 24512 27818 28210 286412 31013 35913 36918 4088 41115



Page 422

12521 1321317 13620 1791 1894 1946 1979 2587 26615 3463 3507 36222 3638 3646 39312


3251 34321 clinical 1819 193

202617 2749 333 356 3622 3791216 381 43419 517 5320 541617 561619 57119 5814 62210 6712 6910 9113 963 9911318 9922 10011 10112 1037 1067 11317 11481315 1182 1381122 1392 13918 1642 1692 1775 1871213 19417 1996 20116 20251114 20511 20838 2101314 21418 21514 21721 22251013 2235 22956 23517 2361821 2385 23814 2391316 23919 24022 24213 243319 25314 257917 25921 260613 2791 29120 2923 2936812 30220 30313 3041522 3055 3072 3101422 311161317

31222 3252 3261921 32779 32720 3281013 32916 331719 33320 334714 3355815 3363 3361218 3372 3371822 3383 3396 34015 34114 3429 3451420 34611 3501522 3512 36510 37016 3711920 3725 372612 37811 38369 3861116 38618 3871214 3871522 3888 3881113 3895 3935 401718 4041921

clinically 704 22221 22316 2291 2451 30022 32722 33410 3381722 345912 36110 3698 37013 371622 3885





2426 2453 3024 30716 4096


21217 28014 closure 6812 697

741


3137 codes 71355

1331416 14520 2524 31361416 3131617



4026 colleagues 871

13414 14713 26021 36516 3761

collected 6520 7614

collective 768 1805


2722 2861718 294101420 305 317913 35919

colonoscopy 38016

Colorado 8711 32417




39313 come 1919 2911

35818 9214

936 10220 14016 17118 18515 19219 2701 29315 29421 3768 38614

comes 422 1419 14318 22920 24715 26021 29413 29816 29913 3814


coming 25912 29610 3013 3177 31819 31915

commend 1520 13941220 34717

comment 103 142 1441221 1516 162 378 7311 1052 1087 13422 14510 1469 1701 17417 1836 1884 20611 21416 22513 2455 25722 2588 26019 27117 29718 32514 343810 34415 34821 36410 36515 37518 38115 38517 39220 39714


commented 21321 2357 23912 34512 34721

COMMENTERS 410


1321 154 161 2718 3521 366 3616 381516 408 4621 4913 4921 5920 6219 63122 7313 75819 7711 8421 852 8720 9311 942 10419 10422 107217 11719 1198 1203 12921 13322 13515 1421821 15320 154116 15721 158216 16613 16622 16757 17314 17413 17515 1821214 18318 1886 19619 20012 2019 2038 21318 2144 21521 2161518 22510 22911 23119 2321 23412 23712 24312 24421 24618 24968 2571 2598 2611 2613 2681114 271614 27219 2745 2753 2816 2819 28622 28782021 29715 30212 31069 3119 33021 33212 33320 33513 34212 34620 34815 35017 35218 3572 3584 36513 36711 3681215 3751213 3769 3819 385613 38919 3924


Page 423

39716 39814 4059 409712 4106 411416


279 979 16416 commitment 1417

20515 21314 247151821

commitments 32822


421322 45119 4613 32311


532 654 7920 1781 28517 30819 30915 3296

commonly 256 24211

commonplace 38414

communicate 1791

communicated 9318

communication 7216 12113 12722 17616 17811 1804 1827 18320 1861116



community 4510 47111216 4816 656 664 803 81213 8456 1192022 12912 1428 30821


245 4016 4216 443 8822 964 1482122 1557 15813 159710 15915 17421 20617 2167 24515 2806 28317 2845 2877 32422 34710 3567 3589 3673 37315 3913 3971717 4008 4089 4092


619 891011 10015 1117 15822 16535 2041922 2311 23211 2347 2471112 28412 2874 29616 30016 31610 3902022

companys 2255 3917

comparability 1981521 24514 2911114 29311 29317 29420 29526 2979 3275 3631012 3951418 39637 39618 3985

comparable 1649 31217 38913 3907


23620 2399 32813 33011 33515 336112 3388 3396 34014 34117

342919 37014 3726 39418

comparator 13916 15920 1601517 16018 16111 1678 25391216 2543 2553 2727 2728 2778 3521421 35320 39122 392712 39216 393616 394922 3954 39721 39823 40818

comparators 27711 27810 39221 3955 3967 3971112 3986

compare 1124 11622 16110 2529 33618 38912

compared 1210 183 7913 3402 3516


1605 1617 19818 237910 2889 29220 35213 3535 3953

comparison 11121 1129 20214 257616 3056 32814 3315 35921

comparisons 6712 34618 3941416



7718 1491516 15279 34715

36722 3999 4079

competitive 39918 40017 40522 4092



7812 9122 1279 completed 13018


2443 33721 complex 178 439

538 826 9114 978 1381718 1496 18020 1815 23216 2365 2399 24920 28120 35321 37721


complexity 187 12817 2367 273421 2841 28521 36911 3831

compliance 12515 3542 35522

complicated 27314 2801617 3598



4820 771215 1222 1674

components 1212 35012 38219


554 8416 compound 395

26011 3076 compounds 6816


1713 1913 4316 19519 26619 3179 38310

comprise 9010 4036


25813 compromising


10922 110212 11418 11711 16322 20015 2305 2402 2755 27510 27913 2916 3023 30318


1103 1649 2345 27710 3025 39513 39710


74131518 1061019 1079 1146710 16321 22215 22920 23013 2602 27715 3077 3584622 3632 36821 3723 4077

concerned 375 613 6218 672 706 15013 16011 1635


Page 424

166116 29910 34520 3462 38021

concerning 4718 6411 31916

concerns 2312 5715 5917 946 948 1442 16213 17166 19912 21820 2201 22211 27715 3531 36617 37613 37713 4051621 4098


1174 2253 concluded 25116

41121 4123 concludes 3426

3971 conclusion 143

10413 14717 24116 25610 26022 3566


11314 16722 22315 3423 35614

conditions 2112 2113 2520 6913 8337 16911 3996

conduct 7220 17615 21010 2376 24020 2446 3123

conducted 2074 24113 3056 32731217 3511 40422

conducting 31117


17922 3587 36415

confidence 8321 10012 11116 1137 17513 35313

confident 9921 16915 36411



configuration 30018

confirm 22517 22712 26718

confirmation 22811

confirmatory 293913



1928 25222 25919 26012 294213 30822 34922


16413 28518 31578


1933


consequences 524 651617 72813 7215 7319 35721 36915



4613 6213 753 8313 1227 12412 12835 151118 1664 17518 1954 1989 22421 23417 2392 24113 3189 3375 33911 34312 3524 35518 36814 40211

considerable 14618

consideration 2315 5914 694 7013 738 939 1071414 1089 11717 11814 15715 21417 21619 223314 23915 30616 3084 34017 34722 3489 36820

considerations 1021 113 12817 12821 18915 19213 2092 2107 27122 272410 27412 32118 32515 32617 327819 32921 3308 3348 3383 3507 35318

considered 703

7810 1098 11312 12016 12415 16016 20910 21815 27319 2761411 2781 27910 3261 3334 3423 34816 35113 35212

considering 2416 1225 1547 1921 23319 3206 38018

considers 1223 12815 22116 24019 34012 37312


consistent 12511 18717 20615 20814 25415 2562 26716 26921 27036 27912 28022 2909 2931 39413 39517






2078 consultations


38417


consumer 7717 7816 7947 831021 8410 4077

consumers 475 7720 7820 7912 8020 8110 32015


contain 19317 30715 31810 39117

contained 14622 35918 3784 39321

container 6812 697 7318 741 1014 21710 36320




27812 36320 contents 51 61 71

32515 context 7417

13319 15612 16720 17114 172126 23015 23019 2361 2741821 32218 34216 35118 3578


4519 6420 991 13710 15916 2345 2391 2402 24111 25112


Page 425

39920 4046 4069

continued 506 8921 2477

continues 12015 14213 23910 241917 3751

continuing 12720 1511 15313 19414 20518 2256 35619




20512 36410 4051

contributions 4015

control 712 8417 10921 2183 32018 32122




1405 14118 1435


18510 1866 30814 4064 40917

convince 24415 3466

Cont 61 71




75 3241115 correct 604 1252

18014 1831015 20912

correctly 1521 15721 18520 2462 39413

corresponding 8218

corroborative 16717

Cors 221 514 86171922 874 9322

cosmetic 2676 32391113

cost 189 6416 7710 8118 827 821116 921215 9419 13621 1371719 13911 149620 152310 15213 15612 18113 25619 28920 35618 3802 38815 40715


376 384 13735 1502 24118 2884



24913 counsel 299 912


946 counterfeited



3122 15219 25411 2551 3268

countries 3111 8821 28818 29210 31321 4034

country 301518 878 1041 12913 31318


806 1079 11616 1847 2205 22520 34018 34612 3951 39617 40317


3197 coverage 1214


24912 25220 2554 2647 26920 28611 2902 30021 31418 4051220 4061

created 417 677 21721 3671 399518

creates 14122 3944

creating 325 12811 21611 31419 3682 41114


25118 4061721 crisis 8118 8215 criteria 5910

11020 1181118 19921 26818 2753 2769 2864 30817 34818


critical 77515 7817 842 905 9419 10010 10122 10512 1244 15021 18022 18920 19113 2374 28914 2957 29611 30019 3014 3368 3841219 3959


38012 cross 11522

30916 34119 crossover 11517

1727 crucial 118 4319


2095 CTFA 3239 cultures 179 2619


5717 5910 731 8222 8314 1011620 1056 1224 12316 12511 12615 18514 20111 20221 2563 3379 34317 34719 35817 3668 3827 3882 40917

currently 529 5317 63710 7820 10118 1054 11621 1271 15011 1535 155612 1874 23218 2481718 29319 31614 3229 33311 36620 3672 3798 40312

curve 1278 3286 3622



6013 6620 6910 7122 7613148117 84141810011 101121066 111912422 128181339 1391314422 145222 14771322 15620 1572 160514 1611


Page 426

1621142022 16781121 16813 169611 16912 170312 17013 1871214 18916 1921819 1941719 1996 2011617 2024 2021114 2082 21011 2111 21512 2226 2343 2361214 2361721 23723 23719 23918 2412 2445 2465 24616 2508 25119 2539921 2541012 2553 26616 27720 27855 2887 29120 29315 29511 297257 29721 31114 3125 32519 32611 331567 3331 33520 33713 3388 3392 3419 34217 35125 3521321 35347 3626 3659 36615 3721216 37916 392717 394181922 39524 39720 4019 4034 40411 4051 4061821 40815 40817 41117

database 12422 1338 1857 2967 29810 3161521 32819 32925

databases 1272 1334 14633 2982 3413

dataset 4037


15714 16221 20021 31710

Davis 415 39015 3901718 39716 3981015

DAW 1217 day 124 2019

2317 2413 909 949 9999 1044 24517 2479 365910 40319 41121

days 132 2914 895 2809 28818 2896 3548


2014 2306 39117

dealing 29618 29915 3006 3442

dealt 29415 death 309 3110


8368 debt 8118 8214 decade 6017 6519

13716 15222 30219 31912



928 1049 19017 3513 3689

decisions 4414 458 572 7115 848 13117 1791316 1952

1967 24211 2768 37315 37418




2820 5014 7521 24822

deem 356 1974 deemed 17910

186918 2677 29522 3384


50312 define 1132

17219 17916 1923 1961 20920 21115 24510 26321 2867 30013 3017 31916 34111 3443 38621

defined 2012 268 626 21117 2786 30019 3015 32119 32519 36120 3872 40110



3093 3121516 3188

definition 43416 4514 10817 114310 19920 24422 2456 2625101114

2637 2645 26914 2819 36316


8915 degree 1108

11214 13821 2101 2182 23720 2757 29519 30418 30516 30610 3071

delay 15014 1522 28910 40121


4101 deliver 4117


7317 12520 22514 26117 2628 2661013 26616

demand 24118 2884 38710


5717 10014 1141315 1607 2112 2348 3031522 30421 32519 327510 33615 3616 37012 40416 40621

demonstrated 555 10022 1207 2449 25119 306223 32821 3656 3697


demonstrating 113 837 20515 2215 32912 33415 3985

demonstration 1021 23622 2371618 23815 2405 29110 3282 33820



26511 3812 dependent 30516



1871214 3927 describe 6717

7011 2145 3019 35311 3965

described 11411 20219 2034 22289 30010 3262



1151517 11678 116910141819 11621 11817 12520 2101516 2179 2335 23915 24020


Page 427

2729 2781115 27917 3017 33110 33415 33617 3372 3415 34217 34319 3719


2741 40711 designed 916

24022 283678 32217 33510 36210 4061

designs 10821 11019 11514 11617 11715


2022 32614 3468 38714 4097

detailed 17515 19410 30612 36811

details 152 18718 30714 3643 3847

detect 743 2158 23616 335910 3728



6714 687 15122 23412 2513 33611 33822 39621


determine 3422 582 9912 1098 11120 1512 18818 22521 3798 4013

determined 5819 782 12218 12614 27320 3951 396913

determining 181 23821 25020 3386 35212 35519


5319 6622 7421 12010 12718 23221 24222 31716 32122 3268 34810 38619 3871

developed 546 6521 788 8022 12918 14913 20114 33317



975 11712 1751 21612 2353 26522 34717 34815 37714

development 14 88 1015 1110 5111 665 774 120415 12314 1501520 15111 15311 1668 17420 19521 20418 20519 20615 207620 2081017 2124 21213 21312 2154 23281215 2331221 2375 2404 2416 2467 24722 2482 2531014 25429 25581321 2561 2565 27122 2721 27310

274910 28517 29116 3021718 30220 3037914 304281112 3058 30921 31811517 3241621 3253 32513 3261519 32622 32718 3302 33246 33312 33517 33810 341314 3526 3596 36016 3621920 36720 3731 38117 38815 38922 39118


2661016 devices 921 224

7318 26117 2628 26613



5215 diagnosis 5015




452 893 9847 10145 1557 21721 21815

2191819 22321 22321 24214 25214 26520 28910 339414 34315 3451516 3461011 36318 3679 3787

differences 6811 7014 732020 741322 9221 971819 12614 1616 194912 1951 20219 2031 217568 21711151920 2186910 21913 219162122 22024 2221718 2236717 2241 2243618 22513 2281518 22937 23616 2408 2451 25120 26314 27515 276210 277713 30022 30422 31121 3205 33411 335911 33818 3391 34513 3515 36110 3657 36611 369920 37037101320 37022 3714 3721818 3835 3873 40622

different 183 2622 393610 528 6112 9715 9716 1021 1034 10315 10511 1101019 11219 1177 11861020 12520 12613 12811 13214 1343 13556 14118 14212

14320 1457 16017 16112 17191010 1736 17712 182119 19911 2003 21019 2141213 2207 2218 224151517 2269 2274 23019 23516 23915 251417 252116 25419 259410141516 2592021 26058 2608121322 2681619 2695 2702 27522 27661619 27921 28314 2963 30311 3052122 30718 30912 3157 320447 3234 36319 36716 4021819 40748 40717 408210


differentiate 3317 252511 37414 40619


differentiates 3962



differs 25722 35010

difficult 11412 1421 17715 18117 1876 2106 21411 2211114 2314 23112 23418


Page 428

2364 2808 28111 3158 3223 34819 36916

difficulty 603 1438

digits 13757 15212


2503 3007 39415


7111 25612 3279


directly 4617 4812 16415 24922 3923 3952 4059

Director 1151719 224510 81118 92515 11915 26715 38117

directs 13814 35120


2634 29919 34315

disappointed 15017







747 23317 23820 4013

discrimination 2541

discuss 1404 18611 40317

discussed 3613 1357 1907 2279 25514 2722 30317 35017 39218 39410 40316


7810 1483 32613

discussion 618 1636 1748 19916 22313 22722 2281 23012 2779 27814 30513 31010 3127 3254 33116 36411 39119 39515

discussions 1192 2485 27416 4081

disease 298 411 5020 6511 6618 832 841718 38012

diseases 5017 519 5259 5421 5913 821313 8319 35612 37710



dispense 12612 12910 1497 25918

dispensed 8011 14114 24714 2535 2591618


12118 1237 1247 1254 12716 13611 14017 18922 19115 1968 37421 40919




3222 distinct 544

15115 19022 31922 34913 3502 37413 37717 3844




1924 20019 34918 39312


distinguished 19019

distinguishes 37817




divergent 5615 2138


1421 4914 6116 1199 1353 1883 18912 23119 2497 2738 28618 28720 3486 4111111 41113


3912 10214 10427 10513 38017

doctors 3416 3920 401 889 881820 17913 18010


37918 document 6810

2105 2141722 21615 21814 23921 27219 2814 3644


5414 5915 6411 7310 9320 1505 150121418 15714 1604 17521 19519 20520 206114 20718 2082020 2082122 21168 2132 233416 2345 26316

2671 2711417 2812 28915 3251012 32616 33118 3601218 36469

doing 94311 981520 10414 10414 16516 21415 2295 2914 38811 3897 39614 3972122

Dolinar 31 515 95131518 1058 1067 107318


15222 15328 29281116

Dolph 218 510 643

domain 1105699 11010 11222 1196 3419

domains 11067 11219 1131 1178


2782020 32855 3286 36318


3622 dosing 1722

12115 2211 2918

double 1377 14420 15211



Page 429


28421 2851014 Dr 1520 2316

2420 26412 2781419 3710 4119 7315 7412 871 95131515 9518 1058 1067 10731822 1185 11822 11912 130211 133120 13421 13513 1548 1741618 18221 1836 1844 18513 18621 1884712 18813 197819 19812 19914 20011122 2016 20118 2027 204912 21421 21522 2164 22519 22714 22918 23020 23226 24321 2457 24610 2719 28113 282121 28537 28514 28615 2871511 2984 2999 30018 30116 30215 31016 311716 31215 313811 31320 3241217 33220 3339 34314 34522 36715 37522 3851112 39048 3901217 39716 3981015

draft 14 87 1014 1016 3120 327 353 6711 7010 10910 12011 12246 12320

1249 1395 1501418 16012 2182 21911 2334 25611 26120 2655 2711416 2747 27610 2779 27812 27912 2811 29011 30368 3054 3084 30919 33314 33613 33816 3398 34718 34836 3505 35112 3521019 35317 35317 3601114 36720 3681012 36818 37922 38116 38220 39116 39218 39321 39411 3951619 40210


1956 19879 1993 2001415 2001621 2015 296914



119 23 811 304 3415 3513 3878 391010 3913 405 4313 4318 4511 5319

651420 7210 751 7936910 801 8224 8812 89910131616 9117 92618 991721 10016 1001819 1016 10213 10322 10417 10613 10710 11512 12121 13121 1374 14316 1458 1645 1719 17611 19015 1911618 19312 19321 2365 2515 25211 25310 25817 2676 27310 27711141617 3595 37618 3789 3889 3917 39823

drugs 117 29 93 912 195 302 32312 359 3621 397 403 4322 4511 4718 5422 5816 668 79813141519 801222 81456 8319 881821 892 912122 9289111114 9216 9338 947 979 996 1001 1022610 10313 10412 1388 14013 1414 1439 1457 15218 2288 23216 24413 24722 249314 24920 2519 25239 25619 25714 27614 28016 31421

3154 35911 3771218 3994 40315

dual 1071 1166 due 557 5715

1039 12115 30710 32422 3409 38222 41018

Duke 32 518 10720 1081


34519 dynamics 37915 DC 294814


855 9219 9414 1012 10281031821 12713 1387 1462 1515 1527 153516422 185524421 26043242

early 1315 7216 1236 128211926 207831721 318203303 33113


1021219 36313 3781

easy 18019 18118 2422222 28019 37819


3021educates 877


47211 5017 7717 8114 855 126356818 127121920 1294 13110 18417 18620 3771

educational 4714 801821 8312 8410 30118 3022 40922

effect 5711 796 1015 15014 1552 21011 2216 25517 27716 2793 33017 3353 33610 34011 34520 3779 3814 3829

effective 1615 311 3217 334 372 3718 1205 15015 1524 1561112 1795 1843 2066 20719 22017 2422 25619 2663 28812 31421 35618 37510 3775 3823 39112 4007 40122

effectively 1409 18410 2583 38313

effectiveness 2217 9218 1221 24011

effects 2916 5614 579 8922 919 2408 30520 3066 340192138214

efficacy 181 194


Page 430

3514 375 4320 4512 5316 5412 56718 7913 809 9316 18820 2088 21215 2152 2414 2531 29113 3031321 3051 3111 31222 3276 32815 3353 33613 3393 34022 34116 3424 3445 3657 3679 3701 3729 37221 37812 3808 4015



21311 effort 862 8912

1805 2487 3761519 4058 4111

efforts 3511 506 8114 8320 9812 12010 12814 1759 34717 3687

EGA 360101322 361718 362317 3634715 3644 36471015

eight 2318 497 5613 28710 2929 3307


either 3919 4615 883 11215 1481 15719 1624 1634 1856 18615 22022 2218 23710 24714 2641521

26720 2697 2733 2795 2802 3444 3458 38713 40918

elaborate 2312 4822 7417 1545 15519 16712

electronic 121416 1241820 1276 13110 13412 1464


19014 24811 25010 2711618 27324 27419



2385 elimination 2433 EMA 28922 2903

2901420 2914 3629



302141516 31016 311716 31215 313811 31320

emphasis 20911 2333 24121 32421 32719

emphasize 153 16219 2402 24118 2506

emphasized 6419 9315 15712

emphatically 35916



19611 2089 2503 2548 34914 35615 37617 3801

enabled 23215 25016



494 758 8913 9412 9621 1037 13511 1543 1579 1759 1965 24111 29215 30810 32520 350111 3685 37313 38056


15310 19522 3057 3068 30719 30815 3098 3755



3864 endpoint 21018

25717 32518 3332 33812 3411718

endpoints 32721 328114 3728

ends 1315



2419 enhancements




252 3338 3410 351113 3622 371720 4314 506 5114 5517 9610 1025 1258 1293 1639 1666 1739 20758 21511 22120 22912 24015 2437 29112 33114 35714 35912 36020 36922 37418 3759 37620 37920 38411 39920 4015 40211 40515


182 562 1749 21117 39917 40019

enter 14915 19111


3802 entire 12714

15215 36319



32113 entries 13411

31719 entry 1277 13310


14611 14716 1539

environments 1717

envision 639 1055 11722 2276 2466101112 2998 3171 33518


3192 EPREX 663 6818 equal 462 24121

38914 equally 3722

1523 25512 2663 31420


27816 2796 33521 3372 33813 34116


27822 era 9419 error 10921

13410 errors 1078 1336

19013 19117 19611 37420 4083


Page 431




587 664 906 1088 19219 1937 24815 25018 32913 36022 36916 3991

Esposito 119 820 821 127 13417 13418 1441617 14513 15322 1851 20010 299216 3002 3108 3113

Esq 215 38 56 64


1671922 1688 17612 1781222 1807 1828 19013 19317 30319 30915 34948 35128 36922 371821 37416 40211 4032 4071

essentially 6019 7722 942 1392 14013 1437 1493 19322 3985

establish 3118 3421 5618 8111 15811 22112 23419 23722 24010 2414 2571218 25812 3046 334919 38991314

established 11916 17718 1838 2924 2933 3006 30620 3078 3132 32011 32210 3361 34020 354418 35719 3633 38821 40122

establishing 7122 15810 24819 29021 2994 3004 33817 35922 3795



1069 1271 14520 2907 2927 2948 3883



15010 15619 1692 20517 2192 28922 2901 29218 2946 29720 30112 30219 33119 3667

European 47 710 291 3122 5514 16913 21818 2659 2929 30510 3267 3607 4027

evaluate 242 1188 1885 37019 40222

evaluated 16120 16122 1702122

1711 3533 3933 evaluating 194

2398 2428 33322 3691 37220 3951

evaluation 1116 11820 23511 812 1181 14619 36920 37011 40114



7022 755 1257 1251114 14111 14521 18519 20220 29722 29816 34914 3516 35919 37821

events 4716 558 577 6315 702 73421 74314 8719 1761420 17721 1808 18216 183510 18313 1926 20312 2159 22122 22914 3032 30956 3143 36616

eventually 1598 27322 2787

Everett 35 520 1351621 15212 15519

everybody 9819 14813 18518 2475

evidence 1121 6922 10815 110231418 1179 1281315 20621 23320 23512 2392 24019 2411

24814 2756 27921 30611 3611 38819 3891 4024

evidence-based 1221


2119 23911 24110


17519 24818 3943

exacerbated 33717

exact 5718 6013 1909 28112 349315 3783 3834

exactly 1918 3312 10514 17714 1815 21420 3003 31510 31810 34312

examine 564 38313


6519 1104 1117 11211 1154 1187 12215 12513 131914 146121 1579 1642311 1652 1785 1793 1848 184916 1854 18722 19512 2021222 2097 2181314 21917 21920 2282 2312 23810 25416 2655 27310 27519 27620 277517 27821 2803

30121 30319 32010 3272 328315 329615 3302 3356 3365 33918 3416 37215 3797 39211

examples 2141 22621 2606 2736 27421


26519 3738 3745


exceptions 9119 27520 2761 28321 33522


30711 exclude 4918

5515 22210 2236 22716 2293 2634

excluded 2199 22219 22819 39419


2744 28216 2831418 37337 373101221 37428 37917

excuse 5413 19915 31622


3474 exempt 5511 593


27722 29114 33011 33112


Page 432

35921 39623 exercises 29112


1455 17410 20112 22212 23617 25120 25919 29014 38813 40622

existing 12515 13712 19312 2412 3951822 4037 40510 40718 4084

exists 6310 6911 144711 40618

expand 3711 1401 22915


expanding 1006 3822

expect 3113 6719 20218 3178 38719

expectations 1895 1896 19315 20710 32911

expected 583 1124 11316 1898 3023


839 8916 18121 experience 47813

6319 656 663 79317 1068 1544 16720 1772 2059 2311 2341622 24513 24919 25616 26016 26522 28810111518 28819 29219

30112 30220 3125 33122 3576 3631214 3667 36917 3756 38618 3896 40418


experiences 564 76912 150710


expert 14613 1478

expertise 1754 1764 22919 2306



161 1351722 1365 2255 2486

expressed 145 739


1648 extend 1412

19522 2846 extended 11617

23220 28519 37916

extensive 18910 216141617 23520 28720 29111 36917 3807 39521

3984 40417 extensively 11611

1907 2185 33311

extent 3622 759 12212 1452 15011 17015 17218 18721 1882 20111 2221 23518 31210 3707 3931020 3942



33969 34119 37216



13922 19418 2085 21022 2172 222516 2726 2752816 2766 28717 2931617 29417 2941822 2964 3051415 30679 3128 32916 3515 3614 3624 37211 4053


3213 373 385 561 1383 2538 3264 34814 38622 4111317

FF 317 616 2717 face 549 11011


1787 18014

19016 1929 1966 2066 20814



2541820 facing 1215 fact 257 316

3619 448 7422 8811 9319 945 9615 13621 1686 2204 2233 22920 23016 2374 23818 24816 25317 26312 2661 274817 28019 33718 34221 3581419 35914 36014 3619 3672 38522 38621 39319 40419 40520

factor 8010 26619 factors 1714 7916

11820 1356 2246 30718 3364 34016 34816 3521217 35518

facts 789 815 25415


17917 failures 38813 fair 467 28819

31512 40022 fairly 2744 2893

35720 4045 fairness 422 fake 88811 9017

fall 12419 26816 26819 2695 27817 2847 2966 33519

familiar 1478 1734 24210



621719 6716 9318 17715 20610 23110 2453 2508 26021 2701921 3032 31118 3125 3667 3896

farming 971213 9714

fashion 23322 2449


115 1213 136 1616 1815 192 2215 24161718 242122 3116 3222 337 348 3420 351417 3620 381119 3915 506 5124 5317 547 5510 551117 5722 5813 592 6317 7013 717 7214 7719 789 803 8017 8114118313 88915905 1009 10114 10319 108313


Page 433

1092 110112 11710 12121 12237 12314 12717 1283 12915 1306 13816 15020 1512 153313 1543 159211 1602 1621421 1631520 1648 1641012 16518 16518 1664 1672021 16811 17011 17288 1751821 17634 17691219 17722 1781122 17941019 1801 180316 18148 18120 1826 1832021 18415 18610 18719 1893 19121 19227 195412 19522 196512 19921 2041315 2051418 2067 2079 20819 20941422 21015 2114 21218 213913 2169 21722 21819 219312 22115 2281 22912 23219 2355 24211 2473 2487 2497 24918 2511115 25319 25516 2581121 2618 26391620 2641 2641012 26611 2671618 27214 2731121 27416 2759 2769 2811 2889 2893 29318 3035

30547 3068 30719 3081015 309818 319920 320101221 322922 323513 3272 32922 330520 331416 3327 33313 3385 34122 3427 3431821 34414 3477 3481014 34916 350111 35110 35118 352310 35311 354110 354121619 3553141618 3561519 3582 3601115 36311 364712 368813 36817 3705 3721522 37317 3751 3761215 37714 3781014 3805 3812 38313 38410 3854 38821 3893 39115 3926 39311 39421012 3951819 39622 39911 4003 4012 4021311 40222 40321 404131417 40613 40712 40816 4107

FDAs 12131418 325 5414 7712 7715 8321 9613 1209 12814 15922 16211 1689 1758 18611 1873 18816 20614 2117 2752 3272 32911 3471722

34817 3504 35111 352116 35520 3692 38219 39515 40814

FDA-approved 2489 535 5616 8912 3699

FDA-licensed 1208

FDCA 26713 2687




828 14815 17818 17914

feedback 13013 2132 3311014 33210 3793

feel 1819 1929 207 242 6316 9917 11012 1429 2882 33113 39914 4012 4033 40415 40510


4521 4615 4921 8514 12422 17520

Fields 317 616 2717910 28113 282121 28537 28514 28615 2871


28820 28946 35413 35521



5414 5915 7014 718 9022 2063 20721 2224 2344 26820 27420 2814 32615 32910 37912 3813 3991 40214


finalized 685 1251

finalizing 116 1224

finally 186 2015 2213 231 5813 6617 722 849 895 924 10920 1933 1954 19612 21021 27916 29619 30913 34113 35319 36114 3751 3849 39511


1659 21616 2347 34422

finding 6314 6717 21516

findings 3033 33910 39617



2279 23520 finished 9222

1011 3206 3228 37918


148 1516 164 178 1818 249 473 5713 791 8718 9014 9512 10322 1083 10915 1111 11220 11314 1144 1151519 11521 1176 11916 1314 1362 14421 15421 1602 16412 1674 1715 1761219 180312 18214 19215 2047 2094 2109 22220 2397 24415 247310 24810 24910 262510 26413 26622 27212 27617 28911 31519 31817 3201414 32514 3406 34813 3532 35613 36013 36119 37459 37518 3801 3863 3911


Page 434

3924 4006 40410 4109

fit 12421 fits 10967 five 136 299 6021

7618 289910 3019 31110 31514 3435 3668


13815 21310 2346 27410 2784 40221

flexible 24112 28410 36317 4023


634 6420 7711 10811 1227 1269 12816 1404 1495 15919 17517 17610 18913 2491 29016 2919 32920 33319 3601922 36816 39120

focused 16220 23211 30315 3428


12122 27914 29917

folks 158512 2355 37719 40215 40810

follow 278 378 7411 1061 1562 16520 17114

1722 1865 19312 23011 2602 29518 29813 3628

followed 2804 29416 29612 3359

following 1016 1816 3121 433 5412 6910 7717 10014 1114 11314 1227 13421 20013 2339 2342 23918 29811 32817 3346 33513 34016 37815 40614

follows 4919 11219 2151

follow-on 37117 3720 18822 22115 26723 30218 3121 3559

follow-up 6115 144218 19015 2461

food 1111 6519 2676 27312


31515 4122 foreign 8818 9122

1004 10112 1601516 1618 25399 254311 25714 27714 4081418

foreign-brand 25422

foreign-source


2531215 foremost 5114


12420 1261 16216

formal 33715 33814


12515 former 16512




7210 21710 22515 22619

formulations 5314 1012 21817 30715 36111

forth 8713 1195 17219 20621 2231 24515 28713 35210


21219 forums 1907

20612 forward 1514

1815 4913 5914 681 12011 12915 15312 15710 20517

21313 248321 30118 3103 3152 3269 3481020 35619 3592 36016 37714 38211 3854 3991012 40115 402610 4046 4072 4111418

foster 176141721 18016


found 576 716 7510 9620 1395 18911 26613

foundation 21617 21920 58911 513 318 4019 4113 4231220 4419 4520 479 50312 644713 6417 7015 7218 739 7520 7612 1013 23315 2756 40111


32417 founder 5011 four 115141617

11518 1901 2003 2108 2494 2621 29212 30222 3234 38012 3837 3849


975 19520 2061718 2133 28122 282615

34811 3964 framing 392320

3947 frankly 6212



18011 28616 3816




892 9113 13511 17119 1904 2007 2486 26513 2681 28710 30812 3542 35520 38313 4037 40713 41120

fully 201 3320 7814 9118 929 935 1011 2333 24016 25811 2887 3212 33720 35312 37915 40515



23614 2383 2412 244412 26420 2658 30420 31218 37015


functioning 5220


Page 435

fundamental 21713 22215 2336 26313 2833 35222

funded 2210 32221


19522 1965912 2119 23519 23712 23817 24417 3029 31710 32320 32511 33118 36118 3643 37316 3753 3795 40318 4075

Furthermore 12412 3315 3321 3617 3637

future 1110 315 7713 8315 12012 1211 1225 1284 12917 1324 13710 2416 29210 36819 3731 4091

G gain 2122 31122

3124 gained 36312

3667 game 465 28317 gaming 284413




188111415 19521

Genentechs 18910 19214 19920

general 346 666 20522 21414 21617 2271217 22810 2292 28411 28712 28814 29010 30921 3376 3401

generalizable 2234

generally 16614 20615 21220 23518 2684 27117 27218 2751518 2812 33413 3361421 3531520 4114


1531 33521 3659 36615 40817




8712 generic 4716 710

1613 25111621 394 5816 7935 79810131921 8011222 8145 816 822 12145 1211221 12615 13115 1408 15218 1531 155911 1583 19321 21718

23216 2358 2471114 2493 25417 2607 30510 3233 3607 4027

generics 2517 9216 12317 2471217 24912 3151 37717 40015


314 3415 387 10711 14917 15810 2308 35816


4614 4910 girls 987 give 284 5915

22620 2999 given 134 159

3913 4916 5615 585 595 637 7017 826 10614 1117 11318 11491416 15119 1586 21718 21920 221613 23112 23914 24213 2534 2653 27317 2747 27713 28218 29116 33517 3379 34113 36911


14117 3191921 38717

glad 3973

Glaser 416 39818 39819 4101


58 620 294 4019 4112 4211 4418 479 1005 1007 1107 15821 1895 19210 20421 2166 2375 2471 25111 2531013 25429 25720 2789 3057 3091314 3265 33310 36016 39019 3921213 39615 40611

globally 1962 2807 3503 36018


38514 glycosylated

28119 GmbH 31920

61821 GMP 1817 go 814 1119 1315

1414 273 3113 391 861317 9677 972021 993 1317 13211 13613 1427 15018 18718 23110 2623 2697 3097 3144 32116 37517 38218 3887 4096

goal 9612 2265 2369 2375 24218 3349 34119

goalpost 29518 2961 29912

goals 39921 goes 1312 2422

893 1131 1467 18217 2517

going 218 2919 404 493 6021 617 941821 9817 9921 10612 11120 1136 13017 13422 1396 14117 1522 1549 15812 15918 16414 16611 1701314 1862 1876 24721 2623 26620 2961013 3001821 30118 3033 3103 31810 3226 3591 3791 4046

gold 4042 good 83 910 1522

1613 236 2518 282 4018 645 7517 7820 9516 105172021 11822 11912 13518 14813 15819 17112 17416 1849 18722 18812 20441113 2133 2164 21917 2326 24621 2516 2616 2719 27820 2827 28711 29917 30215 31920 3211 34310 3472 37522 37610 38511 38810 39017 3941320 39819 39822 4011 4121


Page 436

Goor 48 711 367131516


8822 925 11915 1651819


GPhA 39818 40069 4081521

grandmother 38020

granted 3420 19418 3514 3675 40712


13011 1488 1845 2306 2475 25611 26018 2612 2828 28620 38622 3874 39117

greater 4416 577 113822 15011 15213 15913 30513



39015 ground 1119 group 31020 68

621 2257 4021 658 11622 1566 18811 22424 2876 3232 4108

groups 41710 4217 4077


24118 grown 1711 2619

5018 27020 growth 15117


14421 1722 24322 2454 33214 3461 36517


3120 353 3917 4220 5112 5414 5915 6410 6711 6720 6825 693 694 7014 719 7112 725 7310 93720 108713 109210 11710 12212 123521 128410 12917 1505122122 15120 15718 1604 1636 17521 18819 18916 19121 1922 1951215 1951922 19612 205131420 206114 20718 20891319 2105 2116815 2128 21222 213222 2161619 2175 218314 21912 2211017 22314 2252 22710 2282 233416 2344 23920

240321 2416 2488 25611 26121 2622 26316 26412 26551316 266141522 27114 274712 27420 27513 27610 2779 27813 27912 2812 2845 29019 2911 29920 3038 308411 3101 3251216 3262 326101617 32791319 3288 32818 329411 32921 3307815 33022 331159 33118 3322 3349 34718 348141522 3491717 3506 35012 35114 35317 355815 360121418 3638 364468 3731 3791318 37922 38220 3838 3853 39321 3946 395171819 39720 41017

guidances 14 88 101416 117 36614 6716 7010 732 8314 831516 906 12011 12256 12314 1249 15713 16012 17810 18816 189111 2063 2071122 20815 21220 2131622 2393 2646 2679

27510 2825 287813 290211 29011 3036 30534 3091919 3103 32559 331202121 33315 34837 36720 3681013 3681919 3692 38116 39116 39219 39411 39911 40210 4091

guide 432 1245 1311621 20215 36817

guideline 3083 3642

guidelines 327 9422 13815 1508 1759 29014 33614 33816 3398 37119 38817

guides 8317 13113

guiding 1931114 1944 2035 2233

guys 37516 G-CSF 28919

Hhabit 31413half 568 14016


2692022 3093 3454 3881739612


7212 884 12213 1651



3145 3674 happening 3916

16514 3098 happens 259 happy 10416

13413 1486 16619 16715 18718 28318 286814 29712 4103

Harbor 6415 hard 14111 1822


5519 19210 harmonize 1962


16719 25614 31422


36713 HCB 4711 head 20417 2166

30216 38515 4081717


15822 headquarters


33413 health 27 98

2216 4610 5210 6516 7114 7212 775 8013 833 8320 8911211922 1494 15610 25221


Page 437

2678 2848 3474 3502 376611 3771 39922 406213

healthcare 675 7522 7818 8013 1201719 12317 126717 12714 1294 13022 1372021 1383 1401015 14214 1501 1521517 15221 15822 1594 17421 1781720 17918 17920 1806 1911012 19320 24016 29216 32017 34922

HealthHIV 411 37519 3763322 37712 37813 3791322

healthy 216 58 4019 4113 4212 4418 4520 479 3879 38915

hear 1322 3218 3517 386 521 16620

heard 3821 455 85514 865 10620 12713 13314 14222 1432 14718 1855 18721 1915 3584 37816 37910 4009

hearing 1611 86 8713 1012 116 133 14320 1514 2418 6416 87217 958 9613 1585 16218 20414 21610 26111


12922 18316 Heinz 320 620

3021316 Hello 96 help 2221 232

289 43112 8320 8518 9922 102418 10416 1245 12718 12810 1885 1927 19614 23120 24716 24822 2492 37420 3758 38212

helped 25020 25111 3027

helpful 155 6117 971 1023 1322 1358 16718 17221 18418 20211 2035 2117 29012 2911 32512 32915 39117 3965 41113

helping 12020 1223


11246 1496 18021 181611 1875 1973 2181 23421 23613 24117 24819 27413 27621 28844 3041718 3061 30818

3174 3296 34518 3602020 36519 36629 40012 40416 4093

higher 22021 23720 30856 3407 3441920 3455 3461314 38721


2062 21620 3047 30512 3487



35014 highly 171516

7819 1099 1387 1508 160821 1773 21118 2126 22017 24916 2501419 2511 2547 2551 255915 25617 25618 25713 2582121418 2591 26422 2741419 27910 29221 29324 29522 29918 30048 31221 3241 3378 3687 3697 37721 3867 3884 38910 40110 4095


1819 23613 24717



2435 history 447 6815

766 801 34616 38616 38812

hit 1323 1396 23511


3199 HIV 376420

37710 HIVAIDS 3767


354812 holding 8713



1198 2044 2118 23119



2042021 2058 20513 2069 207161722 20813 209322 210815 211411

21116 212213 hospital 1363

1428 36534 38013

hospitals 1068 11921 1413310


3763 HSA 21916 human 193 5311

552 1339 1696 1752 2388 2465 246915 26619 3116 3616 3878 38720 3889 3892 3901


IICH 2371517

26316 26463642 37119

idea 11220 1185 1194 16321 1851617 1916 2869 2999 3991


4069ideas 4915 11015

201319 33316 identical 2617

4313 5817 9716 1691617181789 1891919322 252132674 363223841

identifiable 10212


Page 438

identification 12610 1771316 18015 18921 19114 23515 3493

identified 10219 1609 30110 3732 40517


30911 32029 identify 102518

10712 1296 14719 1614 18521 1909 19921 3097 3145 37019 3714 4004 40921


IDF 501313 5110 549 563

IDFs 51311 5413


20419 illness 413 765

9210 3811319 38122 38415



196 2621 502 5012 527 33411 33818 33914

immunoassay 34010


immunogenic 3033 3632 37113 3831

immunogenicity 2712 681920 994712 21013 212710 21419 2151517 22021 22413 2271921 2284921 3074 30761021 3081 31010141921 328161920 32915 33321 33417141621 33551620 3365 336131619 3373712 3383 338811 339710 33921 34015 341518 34259 34219 3432 344512 34513 36315 372521 38311 3876910 389115 40315


immunoglobulin 52141821 536 53718 5415 55161116 5610 5710 592 597 62813 631314

immunoglobulins 538

immunosuppress 2283

immunosuppress


3366 impact 157 5315

6620 8219 838 846 951 2887 3364

impacted 39312 39318 3943




1407 24017 2653

impermissibly 16311

implement 10912 15314 15912 1765 17722 2375 23922 24112 3688 3752 37811 41118

implementation 1017 111 12010 1235 1267 2066 21315 2489 2492 25615 26119 34714 3554 35620 39912 40021


implemented 1914 1295 17221 24013 24217 2438

implementing 507 805 17914 1916 242115 25617 3484 4108

implements 36817



17817 218812 26521 2728 3957 4086


32110 implies 3087

33419 33620 imply 15717

34911 40615 implying 1788


9315 1776 2336 2653 3094 33321 34716 3925 40114

important 181 20916 2614 272 285 32814 3222 374 3811 4222 4619 4820 561 7018 786 80320 856 8717 904 938 9421 991114 1051220 12019 12514 1274 12913 1329 1332 1383 13917 14917 1637 17518 1762 1772 17816 1791116 1806 19211 2002 20516 21312 22015 22311 224913 22812 2361 240112 250122 25328 25613 3257 3264 3346 336815 34121

348415 3541 358621 3592 37115 3801 3831017 38416 39512 39821 39913 4012 4033 4049 40720 4087 41117

importantly 3721 3722 1225 12613 2409


1064 11412 11514 14012 1646 23646 24219 3798


2266 3774 improved 4610

773 785 22011 3452

improvements 1348 29922 3007 35611 382812 39922

improving 5014 7522 3829

impurities 21811 30710 36322 3899



16310 inappropriate


40120


Page 439



32820 3297 3432 34419 345615 3516


incidents 3113 6614 3394 34017

include 71713 8414 8513 10814 1213 19022 19313 20015 26217 26617 29714 33018 33522 34115 35018 35121 35315 37014 39212 39414

included 12418 17921 3348 35014

includes 1911 3314

including 1113 1219 222 532 589 7118 7917 9113 11722 11920 12022 1357 18915 21321 2191 2355 2407 2423 2917 31911 33119 34816 3758 37710 3935 39421 4009 40719 4084






5413 incorporation


1788 increase 8121

8320 8818 13712 16113 1777 3893 4083

increased 444 558 6820 1809 2191 2784 33417 33617 3421520 34316

increases 383 15913 34412

increasing 15211 2884 40715




IND 1406 28821 3273 3291 33113


index 110151722 11123 11222 11334 11767 117131314 1181315

Indianapolis 39020

indicate 686 7414 12322 1242 13213 1871 21912

indicated 612 12521 13218 1938 36616

indicating 354 9320

indication 691520 1391221 2226 2222022 2249 2273 27517 27620 2773 28013 306710 32811 3321722 33910 344910 34410 3721317

indications 535 13922 1401 14616 1941617 2113 2172 2767 2761319 2772 29418 2971 3012 3051516 30522 31214 3218 32810 3291618 3398 33911 3409 341220 3508 3514 3614 3624 4053


10020 24413 individual 191517

5320 6319 1221720 1231 20612 33121


4017 518 5222 6110 9019 18420 38915


28913 16517 20710 2139

23722 2434 3173 32222 32311 3269 34318 34622 3475 3506 35317 38619

industry-grade 3174




infection 444 5221


inferiority 33420 33612 337716 338115 34310

influence 18415 224719 22721 3316



72 115 5811 6520 711417 748 7719 7813 804 9916 10010 10013 10210 1239 1244 1252 1255 12619 12746 12916 13021 1318 132121719 13321 1341215 1352 1511 15621 1641821 1697 17911 19216 19317 1953 19989

20115 20234 2116 2317 2545 25416 26014 2904 2947 2974 2987 30010 30916 31122 3161717 3172 3174510 3222 3231820 3243 34418 35018 351813151721 35225 35316 354711 3564 35718 35820 359191418 36417 3658 3776 39117 39522 40413 4052 40719 40915


informed 402 458 571 768 7815 3272 37621



21914 25118 30617 4068


inherent 187 331 4317 13618 38221


29922 initial 1017 9613

12010 3484 initially 1031214

3979 initiated 1565



Page 440



2591620 26088 26012 294147 29491214 2987 30816 32213 40610 40768 4082


652 29215 34715 36722 3686 37314 39113 3999 40813

innovative 7718 8516 9213 964 159617 1752 18018 23210 2671922 2686 29217 3567

innovator 431318 443 9211 1401 16220 163216 16319 16521 18919 190220 19112 19220 1949 22020 22522 2362 2592 28015 32121 34919 35020 35415 3587 3786 3921113

innovators 13910 17116 2261 3758 3863

innovators 1633 16312 3525 35919

INNs 2525613 4061419 40717


input 1013 119 682 10816 11310 1201214 1921 206811 21414 3689 3731




901722 1509 15115 15755 3083 33221

instances 1728 213610 3306 3998

institute 41 73 15217 31627 37814






27115 2753 2917 31419

3275 intent 2381318




2483 intercellular


1921 2711 3713 436 4421 4517 516 6216 672 6710141822 6847 10220 1081722 11310 1146 11513 11712 12210 1243 12611 128811 13122 1385 1393 14010 1422 14313 1501719 1511214 15511 15513 157812 15718 18747 19811 199211 2111416 2171 22014 22112 23012 2341013 23420 2381 2466 2491114 2501621 2518 2533 25719 2583 2593 28012 28718 2901819 29316 29318 29546 2966 3086 3322 3481319 35512 36120 36216

36622 3675 38321 4054 40616 4071011



interchanged 14410

interest 14510 1513 1618 13014 2256 2351 2478 35719

interested 118 143 151 5110 8510 1309 13317 1595 2331

interesting 129 246 21812 3451 41121

interests 3544

interfere 921 349 488 40521


42414 618 75 76 293 5518 25114 324211 32415 333810 38510 4066 40891212

interpret 2106 2641

interpretation 10818 20815 2135 24315 2713



11022 17819 37715

introduced 3512 2178 2469 3052021

introducing 9221 13010 28919

introduction 17917 1846 2422 3409 37010 37617 38518



Page 441





541 10478 1683 1737 18518 19721 1982 2998 33312 3447

involves 1103 2772



3482 issue 1113 285

347 3610 3918 455 4619 494 7111 8119 995 1028 1039 10512 11711 1383 14419 14515 1466 1473 15016 1602 16513 1686 17434 1912122 1956 19810 20014 2014 21946 2231321 24910 2501 2511 2527 2533 28813 29421 29711 3269 34916 35515 3576 3912021 39224 39221 393114 395710 3996

40315 404921 4057 40725

issued 1016 20514 21221 36813

issues 27 98 1014 2416 36513 435 4510 4717 5021 5613 786 8020 8121 8215 1059 10915 12116 1479 16216 172913 1892 1915 2012 2212 25221 26714 27221 28115 28722 2907 29315 3007 3082 3096 3144 31915 3223 32420 3252 34721 3488 3495 35114 37614 39119 40312

issuing 30918 3648 39116


JJames 31416 411

61215 2324 2614 37518 3761


2162614 January 798 Jay 313 610 2162

2165 JD 510 Jean 32410 Jeanne 74 32418


41021 Joseph 39 65

17414 Journal 8721 887



2384 296345 3069 33722 37211

justified 20921 21921 3613912 3625 39422 40819


3001416 39215 398811

JD 119 24818 41216

KK 11311Kalyan 414 3858 Karl 320 620

3021316Kayla 41012keenly 5110 775

1595keep 1118 1510

1511 861610520 106151597 1732234417 37616

3815 keeping 5514 869

10517 keeps 29610

41015 key 5021 10811

10813 10922 1146 1227 16714 1863 2068 2415 2481518 2495 26315 290419 29121 2923 30117 3036 3258 33820 3488 4011

kidney 219 511 64471317 655 65611 66315 6618 7015 7218 739 1013

kind 9916 1195 13110 13316 13435 16517 20020 2023 24518 31212 3441 38814 40019

kinds 16812 24517 3234 39213


2517 2916 3018 312 3219 339 331118 3415 369 3711 388 3911 4035 4121 4510 492 6013 8515 9017 9118 9771014 98516 994 10213 1039 10514 10613 107710 1105 1261 13115

1323 13419 13817 14021 14116 14620 1558 15615 1651522 16917 17113 1761 1772 18312 19813 2153 22617 22722 228614 22920 230127 2318 2431621 2457 2508 26821 28015 2823 28411 2961517 312913 3157 3182 32114 3226 34510 3461 35415 37716 37822 3796 38022 3811 38220 3845 38613 39320 40216 4041 4102

knowing 447 21515 2577 34322 35716 35815 38613

knowledge 2623 998 1647 23214 3013 31211 3414 3757 39521 3961 4037 40718

known 1031 17520 19413 20524 2125 30613 3194 336410 3417 3471 36210 3745 38011 38814


818 264 36312 3710 471 6121


Page 442

10522 11721 11819 13222 14518 156116 1731518 19621 19713 1983 1994 21320 22512 2271 24314 24418 257321 2586 26813 2693913 2701018 2712 281814 2822 28522 29717 3126 34214 34511 3583 38921 390610 3978 3987


Kristin 36 48 62 711 1481014 3671316

L lab 9015 947 label 12322 12522

18778 19216 19321 194122 2961920 29710 3012


4821 495 7111 7112 1029 12319 124211 12518 13218 18661622 1871 1871017 18915 1921315 1933 193111314 1945812 1953 1957 19669 200131520 201101222 20221 27918 28010 32313 3492 35051318

labels 457 19316 19322 194215 19420 1955 2021 28011 37820 3843



lack 1242 1586 34917 38413


2138 33010 37318


9212 978 1693 27113 28119 3081 3199 3383 38222 41018

largely 27115 2835

larger 1719 11117 13819 28117 2841 33510 4108

largest 281922 296 9012 11917 2471011 27715 38120 3912

lastly 1403 23321 2969


16322 1641422 16520 1682 2587 26120

26222 2701522 2713 3545 35620 35713 3932410

laws 1286 35719 lawyer 1691 lay 831315 845

38019 3811 leached 6816 lead 489 1774

2204 2244 25011 25922 26012 35419 35720 3811

leader 1594 20421 26112 37619 39021


17421 1752 1763 2053 24721 25619 2865 30111 35422


25614 2892222 2903 29218 31422



221317 26416 27014 3531 393818



35615 39913





16914 31022 3121 4048

level 42191321 452022 465 4920 8514 9713 13821 14320 1459 2421317 24322 24414 24819 2725 27413 2762122 27939 283114 40710

levels 2022 21014 27921 3066 34412 3892

leverage 1544 3796


1981921 20021 35310

licensed 6712 691214 8917 915 12819 1606 1609 161918 16214 16316 23621 2372 2547 2771021 3264 33218 3521421 35345 3538920 3612 3749 39122 3933 39415

licensing 1622

licensure 5321 2468 3293 3513 3695 3745

life 196 4610 5015 6517 779 838 14918 2994 30410 37711 3861


3568 lifetime 3020


729 765 8213 light 1720 1036


2221 2309 likes 2238 likewise 164822

40618 Lilly 415 39016

3902021 39129 39412

Lillys 3915 limit 17018 1969


13389 1858 3717

limited 1112 8416 997 10114 1269 1381214 1612 16219 17516 24117 2883 33714

limiting 23110 3495


11014 24511 2647 27215


Page 443

2811011 28217 28222 28319 284271122 285111 28628 3085 35814

lines 373 9716 1665 18011

lining 1438 link 1925 1996

34515 list 149 1714

9619 10215 12315 1299 38922

listed 219 2212 31816 3488 35316 35515


14514 14722 2631012 28513

little 2120 2312 3711 4822 7417 1031 11418 1305 1515 16713 1842 185211 19911 23018 2589 25911 28813 2993 39714

live 86 4716 liver 2244 lives 313 5521

3774 living 216 58 313

4019 4113 4212 439 4419 479 5019 5211 8118 9711 2643 35616 36912 377220 38121

LLC 4414 76 3338

lobby 10411

local 1104 1112 11115 11221



1322 17217 1856

logistics 12213 12612 12715

long 204 358 10115 1118 25319 30819 32213 3595 40818

longer 1412 313 5612

long-standing 12120

long-term 5217 11921 1596

look 1513 4913 522 5914 681 983 12011 12914 13717 1439 14721 15312 1701214 1721 18122 20211720 2031 20517 21312 2483 2862914 29512 29817 3182022 3269 34437 3461315 34820 35619 3862 4085

looked 14515 14714 22410 2261 22816

looking 2215 948 9420 16811 2275 34217

looks 28610 3454 37610 39719

lose 425 24012 loser 4121


5811 10216 1402122 18321 2303 24611 27813 28611 28814 29015 2939 35822 36312 37820 38022 38210

lots 1348 20917 21412 33111 34618

lovely 4026 low 21518 32819

3296 34416 345317

lower 823 11116 1137 152313 1811214 27622 28920 3088 33921 35618 3801 38914


8921 lunch 108 2039

20313 2045 lung 3112


10515 2851431613

maintain 70127116 1958 1988 28217 309153544 40610

maintained 7016 1596 2063 20721 28519 34610 37919 40310 4063


maintains 1999 20714 39112

maintenance 29921

major 537 557 9015 9719 987 10713 114710 16314 26521 28014 3302 3359 382419 38422

majority 833 14019 27113 2746 33810

making 5122 571 598 17913 18017 18219 18319 18411 19017 1996 20515 22612 24517 2504 3589 40519

maligned 1369 14819

Maloney 24 945 381314 5922 605 611420 1421920 1441 1541415 1551 18213 1831 22910 2597 2601

manage 12020 12311

managed 8822 11922

management 211 36 62 916 5217 7610 1218 12110 1481116

manager 4112 1366 3762

managers 7616 14818

managing 12318 1495

mandate 332 379 3712 2381419 2396 25821

mandated 2441 2488 25318 25412 2555

mandates 25811 3532

mandating 3716 23319 25522

mandatory 1820 266


2073 20811 2338 2425

manufacture 921 931 10015 12818 2631822 3897


manufacturer 1916 5322 557 611 6918 7021 7322 10216 1761421 1787 18261618 1833 1837101218521 2578 30021 35310 3782 3961319

manufacturers 49 713 5113 5911 7220 12822 1416 1517 1584 17111 17610 17712 1813 20216 36717 39520

manufacturers


Page 444


188 1910 5313 5510 6514 661 7211 746 826 1008 10310 1189 1519 18020 1811522 198141518 24516 25018 2541820 2592 2831122 28521 29115 293420 29419 2955 29779 29922 3001517 30156 30714 3144 3547 3673 36917 40010 40217

Marchand 26 96 97 6222 10421 1301 18317 2017820 3018 3118

Marcia 217 59 50210 41012

Marcie 34 519 1191013

margin 33420 3361221 3377 3371516 3381 34310 3441 3988


1679 2873 30317


9117 9215 936 1005 12710 12820 1301620 13210 1371415 14516 1476 14916 15118 18010 2051611

20919 21510 24120 24719 25816 29820 31419 32117 36618 3677 37618 3803 3911 39918 400517 4056 4078 40812

marketed 17514 2666 294815 32319

marketing 72321 789 7924 922 13220 1398 17712 32012 3388 36116 40713

marketplace 329 14311 1779 1847 1925 20218 2424 2481 25520 40020 40522

markets 1508 30222 4095


4818 1672 3572 36513


40610 material 1317

13211 2644 27922 3785 3881 39812


8021 841013 13220


22111 23418 2395 26712 27015 3075



618 2873511 2984 2999 3001 3008 30116

MD 612 mean 2411 2519

3613 3945 4920 62712 6312 8510 11021 11219 113120 11610 1187 1447 16911 2072 21519 23120 2641 26722 26916 2866 2985 36218 38520


22221 22317 2451 30422 33410 3381822 345912 3698 37013 3716 3721 4051


11518 16917 2348 23616 26116 2643 31216 3507 3675 36914 37115 38520 3884 40519

meant 972 1545 33218 34611

measure 21515 37313

measured 2157

29612 measurement

12411 measures 5412

21513 2524 measuring 11013


2112 2241216 2241719 30517 30612 3127 329101217 34121

mechanisms 12413 22414 27919 29420


media 121416 18322

medical 1215 811 169 214 2213 441114 511920 7921 802 8115 8215 881014 964 1463 20418 2328 3091 35617 40718 4083


3221 3912346 8317 10514 1201821 1437 19013 19610

medications 3216 339 428 9418 12020 13722 149618 152411 15316 2245 3828 4007

medicine 33 518 2513 4122 426 466 711 1082 1221 17713 17820 1812 38418 3995


516 710 332 5216 5311 555 5515 5822 9514 9522 976 1753 18018 18922 1968 20516 3607 378713 37921 38222 38319 39146 39919 40121 4066

MedWatch 7215 12516 1468

meet 591 21918 2559 25818 2961 308517 3313 34122

meeting 101 1120 1221 4918 505 641317 7712 15318 18119 2474 25518 2881 289579 28911 33116 33319 36719 3833 41011 41121

meetings 1669 28821 3327 3526


6721 81720 91 9461014 164 2310 2415 264 36312 3814 471 4819 5922 605 61142021 6222 7316 7411 854 10421 10522 11721 11819 1301 13222 13418 14220 144117


Page 445

15322 15415 15517 156116 15813 1673 1731518 18213 183117 1851 1865 18811 19621 19713 1983 199415 20010 201820 21320 22512 2271 22910 23010 24314 24418 257321 2586 2597 2601 26813 2693913 2701018 2712 281814 2822 28522 29717 299216 3002 3018 3108 3113 3118 3126 34214 34511 3573 3583 36514 37515 38921 390610 3978 3987 40914

members 114 21 121 137 41419 649 9516 11918 11919 13013 1494 2356 3476 34716 4001012 40018 40112

memberships 2211

memorandum 1686

men 3020 mental 413 38112

3811921 38415 38422

mention 2111 2064 2225

mentioned 231 2657 3614 472 4722 4820 621

7317 8516 992 1099 1326 1333 14519 146210 1542 156218 1575 1674 18914 1985 19916 200513 2148 24419 24812 2985 3128 32618 34215 3979 40117 40215 41017




3141415 met 2566 method 20912


4003 40113 methods 20967

21321 2141 23212 330611 33013 33110 34010 3883 3894 402117


Michael 42 74 32410

Michelle 310 67 1881013

milestone 3036 3302


174151618 18221 1836 1844 18513

18621 1887 million 2989

7619 1367 1491 26113 28817

millions 1498 1538

mimic 3368 mind 9319 34418


19610 2183 22121 2221 37026


595 minor 532 982

21815 219617 21919 37022

minority 33518 3764





8612 mission 2122

2216 762 mistakes 885

9015 9116 947 10616



misunderstood 1896

mis-dosing 25221 2591022




27313 33019 modified 1161418


37014 386817 molecule 185

4322 5422 9222 97918 13816 15220 1903 19110 2091113 24912 28218 30412 31019 3129 31818 3861422 3882 38910 40421 40721

molecules 179 97822 988 9911 13820 1788 283689 28321 2841 30713 3122 3861520

moment 103 8611 2029 4031

Momenta 314 612 2324910 23314 24611


1502 monitor 1007

10317 3468 monitored 1910

10313 33812 monitoring 1622

198 2222 4416 708 725 12821 36116 37417



33922 month 3178 months 289789

28910 38013 morning 84 911

107 1522 282 4018 645 7517 87217 9516 11912 13518 14813 15819 17416 18812 24422 26019 36415 41016

mother 2914 5018 38021


15710 2784 38210 3854 39911 40210 4111417


34810 3593 37714

moving 967 19212 1943 2387 24821 3592 40114


Page 446



2095 multiple 608 832

1416 1475 17319 17712 34920 37018


15410 24620 247210

myriad 2529 MBA 311 MD 115 2213

31911131418 52415 65910 618 1518

MPA 218 MPH 115 411

N N 21710 3301618 nailed 3873 name 151821

2515 2816 345 4111 5010 662 7017 824 874 9518 10121 10412 10612 1071022 11912 12217 1337 13521 1408 14118 1431222 144412 14716 1482 15219 15820 17418 17719 1784 1853 1879 18920 1902121 19181319 20416 2303 24622 25916

2607 2802345 2807 29451214 2963 29718 298156 30819 3132222 3157 31522 32116 33315 3473 349679 3609 36214 3761 39018 4051818 4067

named 7011 7914 3225

names 1912 3314 457 5811 6220 733 1021 10511 106522 1334 1412222 14213 1457 17718 1786 1838 1902 190611 19212 19917 20029 2047 25220 25417 259920 27918 2982 30915 31716 3191921 32029 32011111418 32022 3211210 32111 3225710 323351217 34913 3741317 38438

NAMI 3811819 383819 38429

naming 3313 364 36711 437 4517 7012 718 10118 1061 12319 12413 12516 13514 1405 14222 1435 18529 186615 18914 19018 19122 1923 19612 19917 22120

22913 251810 25114 2533 2599 2608 27210 27916 2931621 30814 31918 349217 34918 3503 3734 37411 37817 3845 40316 4063 4091617



268 national 21820

412 51112 2121 226 2819 4112 5013 563 6447121517 7015 7218 739 7520 8912 3764 3811218



20711 2988 3091 35022

NDA 26720 2698 27015 28212

NDAs 28211 NDC 7135 13314

13316 14018 1411 14520 2524 2988 30910 313614 31315 40512

NDCs 1341 1414 Neal 38 64 15817

15820


1467 18120 2142 2301 27015 3465 36218

necessary 215 3620 4316 5722 7114 12616 13812 1931115 2137 2177 2184 24320 26514 28217 28912 3045 3081 3384 37313 40414 40519


429 499 622 6918 7812 806 9917 10313 1221620 1239 125122 12636 1269 12712 1293 13811 1629 17011 1736 18819 18913 1906 1918 19511 1981 1991 2102 2158 22410 22967 24820 252510 2632 27322 2781 28868 31020 31212 31920 33419 33814 34311 36212 37017 3826 38420 38821 39320 4031020

needed 1413 355 356 5220 586 1256 1285 1638 16315 16816

17512 23518 28311 3202 32318 32715 3318 36119 3643 37213 37914 3946


3321 10316 1299 14617 1641 2072 20813 22320 2261 2581519 26916 3224 33621 34015 35617 35921 36120

negative 489 711 7918 2848 3353 33610 34021




10322 neutralizing

34019 34615 never 3912 5817

6014 22715 2468 2578 28017 2948 32216

nevertheless 16311

Neville 35 520 1351718211434 1446 1454 14517 14612 1486

new 11217 93 303 5621 578 5712 587 6021 691519 7816


Page 447

909 9213 938 10113 1321212 13220 13711 1419 1598917 1781420 22415 22419 2352 2427 24722 25410 2553 27310 2807 29216 29913 303911 30412 30616 30712 32078 3211516 34617 36616 3686 3743 37817 3822 40512 40714


19210 3171517 3187 31917 32120 3221 32322

non 5416 844 1618 1623 19316 22212 28118 28718 3289 33419 33611 337615 33722 33814 3439 3538


noncompliance 3577


nonproprietary 3314 5810 7017 10121 1021 10511 10611 1408 1459 1902121 19119 32011 3497913 3503 36213 37413 3843 40518 4067





21016 2239 27815 2797 33621 3988

non-licensed 16110



7521 8112 876 9619


10110 12819 13913 15919 1606 16191022 1678 2081 23621 23729 2771021 29022 3056 3264 3521421 3535 35320 3612 39122 392721 3936 39491421 3955 3966

3971113 non-351(k) 39322 Nordisk 316 615

261581011 26320 26611


37115 note 671015 7010

821 10111 15021 16212 22016 23613 2389 273821 2749 27516 27711 27816 2891 3531419 3557 36520

noted 6512 6814 727 7911 8919 8921 1108 1527 2351 2751319 2844 28515

notes 8817 10518 10521

notice 152 7713 9722 3447 3575

noticed 1144 3441113

notified 3411 3920


36518 Novak 74 32410

32418 Novartis 319 619

8911 28746 28815 29811

novel 2206 28816 2895 2945 3894


9614 Novo 316 615

261581011 26320 26521 26611


7622 7721114 7811 8016 8111 8312 843922


1322 204 2522 314914 3215 5211 602 7118 7119 7916 8220 10216 11118 1331 14022 15914 1809 2176 2304 2314 2318 248211 2499 2839 3199 31915 32714 3295 33110 34816 3521117 3584 36517 38213 383817 38322 3849 38720 4076 40838

numbers 1912 14021 21412 3434 37820



20915 24083034 3515


36017obtained 116

11121 1122023618


1916 2619 14922 1732 24419 2465 2734 2759 2761 2762 31618 31712 3225 34514 3876


398 14313 14620 18617 22019 2222

occurred 343 3922 406 15619 22214

occurrence 702 7414


40020 Ocean 912 offer 778 1528

26621 38115 40915

offered 20611 3757


2257799 818 821 938812 1043 14115 24822

officer 11316 52 8313 917 235 2771621 2817 3520 377 3812 40710 4620 4719 4817 4912 501 5919 6321 642 7312 749 75615 85119 8620 9310 953 9511 10418 10617 107161911718 1197


Page 448

12920 13416 1351422 14217 14415 14710 1488 15319 15413 15521 15711 15815 16621 16821 1691421 1706 1713 17214 17313 17412 18211 18316 18421 18720 1889 19618 2016 2036 2043 2041017 21317 21520 21615 2259 23117 23238 24311 24521 24617 25622 2596 26017 26810 26918 2714 2815 28418 28558 28619 28729 29714 29822 30211 3105 3133913 3147 31551218 3163 32469 33211 3335 34211 34619 3571 3604 36512 36710 37511 3818 3855 38918 39013 3975 3981317 40911 4105



40418 oh 86817 967

22616 23021 2879 3908

oil 6821 okay 401 4720

8615 95411 13320 15815 17313 1983 2037 20410 23117 2597 28615 28711 31521 31913 3229 32412 3337 36711 39012

old 2918 older 878 9010


1563 once 807 1038

2254 2512 25422 2581822 25919 2618 40121 4117


33617 3439 ongoing 567 9812

24114 2483 2997 31022 3687 4103

online 12722 31615 32316 3244

on-call 257 open 410 714 142

14421 932 23610 25715 375517 41111




8920 opinion 10912

2554 36619 3898


opportunity 138 1310 284 348 3515 3811 508 649 681 7518 8421 9517 1087 1203 13519 1499 1529 15318 1592 17417 1813 20415 21218 32414 3329 33313 3428 3477 34821 35621 3649 36718 3768 3805 38115 38517 3918


26721 26817 2691014 2705 39615



13116 order 1117 696

7814 1091218 11021 1151115 116512 12117 1232 12420 1277 13411 13917 1472 1607 19117 2102 24919 27121 31417 37919 38721 39616 4074

ordered 1222

orders 12178 12216 1231118 12417 1274 1328

ordinarily 703 33418 33618


78 167 28720 2937 368 415 49117 501214 5210 612 7521 7611 876 9628 969 14721 15419 33311 34622 3475 38120 406213

organizations 1117 442 8522 1201 34712



395 453 5815 9112 115421 12418 1857 198161821 20021 22112 2341320 23612 29367 30018 301456


7322 1997 20117 2026 2126 22514 25817 2951721 30091113 3025 35815 36419 36612 3672 39210 4035



424 489 34611 34617

outcomes 489 6421 12021 2218 383614 39922


27112 27413 outlined 515 857

12320 18816 239320 2769 29010 29222 3505

outpatient 12510 13315 1342

outreach 12658 12722 17920 18612

outside 10017 20310 28917 2916 29520 296214 3942 40512

overall 10921 137412 15013 18815 27529 2882 3349 3389 34017


25911 overly 1506 1535



Pp 3913 6510


Page 449

11357 17414 2162


8319 10215 14019 14745 17119 2179 24412 33115 3937 3941720

packages 10212 24514 26616

packaging 6515 661 68810 697 7211 102918 14622 22121 2291317 3844

PAF 76131517 834

PAFs 7620 page 772022 784

326316 3283 33015


2921 3013 panel 114 21 817

820 91461014 121 137 161 23810 2415 264 28315 361 36312 381314 4120 4622 471 4819 592122 605 61142021 6222 7316 7411 7721 8534 864 861215 9312 951216 10420 10421 10522 1086 11721 11819 12922 1301 13222 13418 1394 1421920 1441 14417 1451318 1532122 15415 1551 156116

16713 1731518 18213 183117 1851 1865 1962021 19713 1983 199415 20010 201820 20413 2131920 21610 2251112 2271 22910 23010 2356 2431314 24418 2477 2572321 2586 2597 2601 2681213 26939 26913 2701018 27125 28178 28114 2822 28522 28621 2971617 2992 29916 3002 3018 31078 31138 3126 3148 3248 33213 3421314 34511 3573 3583 36514 36712 37515 38110 385716 3892021 3906 39010 39778 3987 40914 4107

panelist 1416 8612



21215 3115 32621 3274 36221



Pardon 313811



33389 34012 Park 1591 Parker 38 64

158171920 16714 1691019 17028 17112 17222 1731722

part 16 87 1017 1212 2418 288 496 6416 8311 11318 15422 1563 17212 22615 22714 24720 2839 2982 32314 33517 33812 34320 362120 3927 393718 39417 3951 40920 41018





597 6310 7021 757 867 1333 2382 2396 2826 29614 3489 3752 39914 41022

particularly 8510 1308 13915 1849 18711 1893 20012 31612 35321 3841416 3956

parties 151 2021

213 421114 4521 4627 20712 39617

partner 861 20518




13616 patent 354221


27521 pathway 172613

1812 251 3118 3421 508 515 5416 551216 594 6216 6411 651 665 677 9811 12211 12710 1292 13211 13618 1412 1491112 14915 1528 15719 158811 17813 1825 18821 21613 2171422 2206 2201013 2257 22615 233212 240114 2421 2438 24913 25618 2627 3141218 31512 34720 34812 3683 3695 3709 37715 3795 41116

pathways 13019

patient 21320 55 512 1519 1658 1621 181314 2121 22121 24124 2513 2819 2936 322 321118 349 351318 374 38622 391114 40221 4312 447 4516 468 471116 48616 50614 51717 548 5621 574 58521 6010 6482121 7021 7022 716 7520 7522 7661113 761822 77316 8113141517 8219 846 864 8611 923 9610 974 981618 102613 1032 10415 1051417 10518 10614 11318 114914 11416 12118 1263 142610 14418 15316 1595 17513 1768 17714 1805 1811 1901117 1964 19615 2216 2292222 2317 23113 24116 26121 288217 2891516 29110 334422 33916 33919 340313 3422 3444 3469 3494 36822 37241719 37418 3759 3761416 3777 37713 37920


Page 450

3803 3816 38315 3992122

patients 1615 189 204 2115 2214 252022 2810 292122 3119 32101415 339 331116 341417 3510 381618 403 411014 421015 4810 50921 51119 52215 5315 54920 5520 56512 577914 571920 587 591216 6027 60141517 611 61611 6319 6521 736 7639 761920 7710 78512 80212 828 834417 901620 937 962 1069 12018 12020 1214 1223 12522 12617 12914 13812 1491922 152414 1537 156911 15914 1644 1695 17817 17912 18922 19115 1929 1934 1968 20517 2186 21910 22019 2217 2283567 2311 24016 2411922 24716 26614 28017 28918 3392222 3496 3501 3551 35681216 35722 36922 37116 37620 377410 37810

37923 3815 3836 384620 39111 40716 4094

patients 263 3321 13121 38417




Patrick 315 613 2462022


2748 pave 15111 payer 4416 1364

1369 1372 1932 payers 1810 3418

4722 48112 714 13719 14819 1492 17818 17913 18419 25112


PBMs 1555 PCMA 1481417

14912 PD 238815 32815

3362 38914 pediatric 21120

2122 25571320 256158 27521 3061921 3073 3111217 31234 36213


411 454 6317 6611 9420 10616 1077 13014 18411

22617 2307 25917 26113 3767 3772 3811 38121 38414


56913 571013 5715 60142222 661616 812021 82311 8357 9010 11115 112812121313 1137 13612 13767813 28918 34325 3451718 34614

perception 794 1793

perceptions 797 79121619 808 32019

perfect 18515 2049 2861


34014 3621219 performance 205

26618 3415 3886

performed 563 1183

period 1412512 162 204 342 3921 6613 1085 14213 26721 2688 3449 37310 37428 37518 37916


22012 person 2319 258

4410 1043

31610 3801019 41022

personal 2912 478

personally 4118 9415 16515 1875


13317 1349 13691414 1372 14011 15849 2093 2108 2394 24221 2534 28517 2912 29211 29417 2953 2969 2989 31417 3345 3532 36011



23 36 4917 62 712 2117 2617 2813 4015 4216 1481116 2167 21914 36716


pharmacies 11920 12618 13315 13611 1402021 14957

pharmacist 5819 1044 1191314 13120 14210 1931

pharmacists 34 519 7911 1041 1191118 12016 121320 122215 12311 12456 12719 12912 13022 13116

1361 1423 18011 4081


pharmacodynam 3902



pharmacologic 40615




pharmacy 3322 392 783 813 10215 1221416 12416 12620 1272 13414 13635613 1401717 1429 14818 19716


33813 34115 34415 3882020



36721 368611 36821 3701117 371141620


Page 451

37212 373111 37316 37412 3754

PhRMAs 36815 3723

PHSA 24918 26714 35512



3320 3429 442 4459 4515 469 4857 5820 8320 9519 9915 10321 10519 1073 1799 1933 197141720 1981 2603 37418

physicians 2022 21222 226 339 331518 3410 3817 4214 458 476 5120 5622 7811 7911 8814 962 9919 12310 1411620 1569 32016 36416 3653 3766 38417 4064





3865 PhD 117 210 32

3910111718 320 42481415 517 65791618 620 74461112

pi 1122020 1133 pick 391



1679 1704 21515 2531214 25321 25717 2781 3303 33813 34115 39419

PK 2151 238814 24316 2446 246516 32518 3275 34020 38913

PKPD 23712 25716 3112 32518 3616 3875 39057

place 338 3920 6414 922 936 10316 1271 1327 15219 17915 22813 2334 2487 35921 3601 36620 38410 40813


24121 32719 3821


37318 38713 plan 8321 12110

12111 15613 1754

planned 3323


15610 plasma 5312 541


14110 17811 1807 1828 19319 24818


4221 4521 461 465 4920 8514

plays 2610 9914 37115

please 920 1211 1461315 151 6213 908 10111 31514 3271315 32721 32817 32911 33017 4117

pleased 8715 14819 14914 20514 20613 20717 21220 38218

pleasure 2875 36010


4613 635 9111 9717 1003 10515 1247 125318 1415 1472 15810 16415 16710 1742 1821519

1918 1937 1987 19822 20114 2133 227310 23011 2415 251721 252618 253722 25421 2556 26312 26620 26820 27219 2819 2831620 28412 2891 29818 31411 33714 36414 3939 39512 3966

pointed 796 1013 1058 15212 2462 2823 3385 3931


1332 1397 17518 18319 30512 3257 3346 33512 36117 36411 3837

policies 1111 1213 5418 7713 7716 176212 2421517

policy 121519 25 81121 95 5514 761 805 9611 14815 17619 1781 17915 18016 24112 25320 27911 35521 39110 39424 41010

polymer 2642 27016




5118 835 9011 9417 25620 27514 3061921 3073 31112 334422 3363 3391216 34011 34014 34112 3422 3444 37220

populations 4314 574 27517 31118 31234 3276 3403 3721618



16014 1689 18612 1874 19214 2117 2574 3059 31013 3389


523 possibility 667

2221016 2349 23610 36148

possible 1119 1411 253 4816 759 781022 888 94412 10615 107815 10821 114814 11715 12213 14717 1839 1851520 2004 2221 2267


Page 452

22711 22818 23310 2369 2602 3407 34110 3623 3707 37318 38314 4051519

possibly 3720 1783

post 72220 2159 30519 3387 36115


10118 3294 35421

post-market 2038 1257 33510 37416

post-marketing 586 6368 708 724 741621 32822 36417



3741 4039 potential 4312

5316 6819 6911 7320 825 1172 12413 1285 13410 14420 1461718 1604 1663 18315 21721 22815 23311 2411922 2665 2871617 28718 3263 3395 34021 34316 3581 36920 370220 3957 40917

potentially 3820 778 12810 1291

1346 2152 23222 2385 2431 2488 29020 3131 3401 3716 4079


211012 231819 11412 11919 1213 1222 12721 27817 36510



233 241 PRCA 2312 pre 207 28820


32818 3292 35417



21512 22213 33120 3618 37016 371914 37117


32019 predecessors

40322 predict 997 1379


15310 1586 18114 2649 3959

predicted 318 2189



30113 36019 preparing 8313

8720 prerequisite


216 244 10217 12612 12910

prescribed 3311 3416 3822 3913 5115 8011 19010 2607

prescriber 8318 12114 19016

prescribers 12310 1275 40720


232 2412 3319 675 7019 7115 1029 1071 1237 1253 127616 1436 179913 1952 30821 37421

prescription 222 399 8319 1219 12117 1221617 12221 1232311

12318 12419 1273 13134 132821 14237 15218 1857 18921 19114 1967 32013

prescriptions 1217 122914 13215 14420 1498 24713


7519 8421 10222 12415 13519 1593 16618 17013 1757 2501 27221 33314 3421 3477 35622 36010 3769 3788 38513 4031

presentation 1122 1320 2311 2518 265 496 1175 1514 1899 1977 2494 27121 3256 32613 3426 3603

presentations 53 1220 1516 17922 2478

presented 23612 2398 274820 305411 3522






president 4114 5011 8759 14815 17419 18813 2327 2471 2617 3161 3166 3474

presiding 11313 116 52 8313 917 235 27716 2721 3520 377 3812 40710 4620 4719 4817 4912 501 5919 6321 642 7312 749 75615 851 8519 8620 9310 95311 10418 10617 1071619 11718 1197 12920 13416 13514 14217 14415 14710 1488 15319 15413 15521 15711 15815 16621 16821 1691421 1706 1713 17214 17313 17412 18211 18316 18421 18720 1889 19618 2016 2036 2043 20410 21317 21520 2161 2259 23117 2323 24311 24521 24617 25622 2596 26017 26810 26918 2714 2815 28418 28558 28619 28729 29714 29822 30211


Page 453

3105 3133913 3147 31551218 3163 32469 33211 3335 34211 34619 3571 3604 36512 36710 37511 3818 3855 38918 39013 3975 3981317 40911 4105



16315 1646 16514 37420


993 10221 1386 14718 19622 22413

previously 232 6814 7277 1767 18914 26715 28615 33022 33711 34721 39621

pre-IND 28956 33116


price 1018 7718 82239 892 34714 36722 3999


3172 primary 501619

519 52591215 5222 534 5420 5520 565 5912 973 2093 2108 2384 26322 2668 28919 34117 3723

principle 6922 223512 22421 2824 30820 39018

principles 19311 193121518 1944 223211 2358 237817 26729 2706 27413 28022 2821013 29113 304916 3052 3639 36816

print 13110 prior 1416 7917

1044 16214 16419 1709 19414 22212 2823 33721 35715 36815 38311 38417 40117



3732 priority 3514 975

1769 3822 private 1612 4016


11117 112235 112921 11816

probably 147 499 9110 10820 11914 15610 18521 1861

22416 23121 27511 30822 32117 3433 3909


3220 6621 712 755 107511 1373 14317 14414 1461721 14720 1484 18013 18315 18411 1856 23112 26822 2981419 30111 40213


problems 7421 13312 17717 22622 23013 2667 2905 29618

procedures 1213 184 125912 3562 37019

proceed 804 1291 2448 2549



process 161719 1622 1881618 1910 2018 2222 272 326 4211 4218 432 5510 599 7211 746 8322 1008 10310 10489 1189 12121 12615 12818 17511 19910 20513 20610 2076 20817 21219 21612 2256 27412

29115 30118 3324 35118 354718 355421 3673 3756 37617 3783 38066 38315 39521 40822

processes 6515 827 9716 1206 12116 12516 12611 1277 1421 18020 30715 3569 3961

processing 541 553 122915 1232 12417 1314


produce 583 1754 18111

produced 17912 26116 2642 37718 3789 3863

product 1022 114 182022 191522 243 25411 351 372171921 381 531117 557 5622 578 5712141620 58351218 6021 6214 662 67413 6813 69121415 7016 7020 7121321 781 8211 9222 10022 101910 1062021 11122 1121 1131213 113151521 114120 11535 1156789910 11521 1161 11821 12220

12321 1241611 12421 1262421 1311721 1323 13212131619 141812 142610 14212 1431822 1443 1471519 1513410 15418 15622 15921 1606691518 16018 1617911 161121718 162145610 16546 16678 1676 16831819 169121315 170161922 17121821 1722 17210 173812 17711416 1782 1786 1796 18015 18314 186141720 187213 18919 1901020 1926 192151721 19318 194610 19419 195117 19722 1981417 19820 19978 200161720 20116 202513 20333 2053 20817 20915 21020 21518 2181020 22026 2219 2266816 228131617 2311114 23213 23621 2372910 2406711 2419 2468 25316 254151719 257791520 25816 2591515 2591721 26046 2609 26118


Page 454

26217 2641621 2642122 2654 2651218 2669 2672022 2681 2681416 27211 27421 27614 2771621 2799 27917 280118 284614 28719 2911916 2937 29312 2949 29518 29622 297237 29817 29820 299519 300101121 3031621 3042 3051722 3063 306141618 3079181922 30816 309211 31018 31220 31613 31719 3201 32171215 3221 3231316 32420 3255 3264 3281221 32991418 331112021 332119 33423 33412131618 3357 3361619 33620 33712 3381920 34114 3448 3456 34616 3493815 3501010 35179 35122 352615 353459 35422 35722 36020 361313 36211 3634 36419 3655 36610 3676 36961021 370521 3715 37222 37338 3731122 3749 3741415 3786

3781920 38116 38427818 3864 3899 3933 3934 3941516 395322 396913 4037 4069 40818



productively 38814

products 14 22 320 620 8919 1015 20810 2218 2321 276 33517 371 544 56111619 573 5718 5817918 6018 61459 62913 631516 6319 673 703 734 777 787 791 8069 8212 8221 842 1005 10119 12069 12312 1243 127915 12820 12911 13020 1315 1321021 1347 1371113 13714 13916 1402 14313 144812 14519 1467 1475 1518 15315 1553 15618 1591720 16317 1732021 1771019 1792 18010 181610 18112 18917 19013 1911315 1925 1935 1958 19661422 1986 1993191922 2002468

20917 2178 220711 2215 22218 22621 22914 23179 23222 2337 2351016 23617 2399 2409 2432 24820 24917 25117 25211 25351220 2544 257514 2603 2611415 26269 263917 26515 266321 26734 267517 2687 26925 2707 27216 2742 27722 2781722 279520 28015 2825 28312 285161820 29217 2944 29720 29820 30222 3034 304117 30817 31361522 31618 3171422 318591617 3191241921 32036781520 32191822 3228 32221 323419 32422 325313 3251721 33519 34045 34911 35020 35322 35420 3552913 35610 358910 35927 36215 364120 365222 36645121317 3675 3684 3691 36918 373519 3741216 3759 3799 38312 3841121 39218 39317 3949

4035 4061620 40814 40919



professional 648 7115 11917 17920



3633 profiles 2531

3829 38912 profit 4413 463


4112 1564 1765 1802 2354 2376 2404 24520 2467 25314 2549 26510 3022 33518 36220 3718 38922

programs 471114 891 12112 12721 1289 15622 17921 21312 2482 25311 2542 2789 28913 29810 3021 3251 33811 34114 3446

progress 325 27120




22116 4006 promotion 18916

1951113 19613 prompt 17715 promptly 3411



5512 596 30420 31218 37015 3831


1111 11514 19118 31715 39319

proposed 582 6411 6812 7113 10812 1092 11011617 1176 11715 11812 1605712 1616 16181920 1623 16912 1702021 19018 23711 240611 26211 263711 26415 27214 28613 31715 334112 33416 3361619


Page 455

33819 34821 3504 3521118 369121 370420 3714 3953


32219 3231115 proprietary 1912

26117 294512 29414 29718


35213 36420 protect 221 232

587 16210 16521 16614 26614 35821 37116 37313

protected 4210 17411 35117 3591420 3747

protecting 173 2216 6420 4098

protection 168 562 15921 16213 38419


13910 protein 114 1712

695 26261012 26321 26417 2653 27017 272313 27315 2819 28212 28610 33412

proteins 414 1718 552 12818 26115 26217 2631 2671013 26714 268516 27318 28117 28211 3184 3369 3559 3859 3864



9217 1876 30320 38721 3883

proven 9118 14413 30314


6713 681 7117 9922 10816 1139 1203 1251 12719 13321 13414 1927 19520 1965 19920 2028 2111 2133 22422 23817 2411 25122 2648 28618 2877 3102 32317 3251821 32713 328818 3329 354611 35517 3658 37651522 3774 38819 39718

provided 7122 9321 1264 17515 21018 2182 2736 28313 28616 28719 30813 33117 36319 3643 37211 3893

provider 676 12017 1753

providers 2214 2318 12317 125222 126717 1294 1311 17818 1806 1928 34922 3551 4081

provides 4518

7112 803 815 1622 20616 23720 28422 2851 2871415 28716 3279 3736

providing 283 328 359 4520 1086 1178 12012 24021 36417 38517

provision 718 3555 37312 3746

provisions 10118 2683 3561


714 1169 1212 121418 132 1424 1514 162 2216 7311 775 8178 875 9613 12013 14014 17921 1819 20414 20611 25221 25416 2678 2848 31716 323716 3419 3511316 35121 36719 3689 37222 375517 38115 3961920 40822 41119



8112 844 8511 32222

published 7310 1471222 2061 20614 26020 2927 3242


14167 20310 29216

purchased 8811 3654


1415 pure 6522 6815

21821 purely 2073 3925


33017 3741 4039

purpose 1012 13617 2229 2404 30617 30913 3989

purposes 7019 7122 26222 32013 32313 3564 39713

pursue 4629 20510

pursuing 2121 2482


9614 13511 1481 15120 15714 1582 16116 1698 2012 20621 2487 28713 38410 3905

putting 4710 9020 17915 24515


81 pm 102 1414

2042 3151617 4122

p0 111182020 11271214 1138

Q qualified 4410


4610 5015 7013 712 1188 13914 18022 18112 2081120 2092 2334 24914 26316 2724 274511 2885 29112 2932 29611 29922 3001219 3014 3041017 30849 30812 3096 3174 3252 32921 3308 35318 36021 36610 3676 3701 4001113 4039 40410 40815 4093


1314 278 362 3815 499 6016 6122 6922 7410 7412 867 9313 9319 10319 1061 1191 13011 13422 14221 144218 14421 154111 15712 16715 1692 1701015 1701717 17113


Page 456

17316 1821417 18222 1832 19512 1984722 2001118 20821 2272 229811 23118 23619 2371314 2387 23810 24315 24419 24614 2598 27011 28220 2991015 29917 3019 3067 3109 3134 314810 31920 3201 3212 35915 36414 3937


1371117 239 2717 3813 408 461521 471720 4915 5920 7315 7920 816 852 8614 9311 954 10419 10618 11720 12921 14218 14711 15320 15522 1661922 16822 171422 18212 18422 19619 2037 21318 21521 22510 22812 23415 24312 24522 25621 2571 26811 2715 2816 28419 2971315 2991 3045 3106 3247 33212 34212 34620 3572 3605 36513 36711 3751214 3819 3856 38919 39014

39746 39814 40913

quick 13419 17315 3837

quickly 5812 15122 23415 24120 3495

quite 126 3710 9778 15713 1733 20210 33216 4022 4088

quo 32212 quote 1641215

18117 23511 quoting 2426 QampA 6810 691

19515 211510 25722 27519 3262 33021 3313 35112 3521019 35317 39411

QampAs 35517 Q5E 2371517

R R 215 414 56

1164771015 11615 3858

RAC 711 race 8418 Rachel 11315 52

810 Radcliffe 45 77

34621 34723 35712 3593

Rader 41 72 315202122 3166

radio 818 rail 11519 raise 1038 1629

22613 26713 40311

raised 7920 1331 16215

raises 9318 31915 35222

Ramachandra 311 69 204891216 21421 21522



2748 27612 2773 27820 3757 38314 3995


41018 rare 743 2159

3357 rate 5316 6614

7217 1092021 3455



2516 252115 30518



40414 react 6111 reaction 5712 711

1911618 37822 reactions 5410

6320 19016 read 156 16414


1451 32117 reality 18513

2155 realize 305 14211

2102 23311 2887

realized 1526 24017

really 6313 856 13016 1326 1504 16819 17219 18515 215911 2196 22320 2293 23415 2458 2553 2562 27314 28912 29017 291521 2923 2932917 29710 30117 318220 3441 3457 35822 37516 3768 3873 3994 4001720 4011 40111 40311 40429 4063


40212 reason 1712 456

5614 7213 751 1732 1742 2268 26315 28315 3598 39315

reasonable 342 3921 1746 20616 21716 3073 34313

reasonably 2185 2191315 23121 27619

reasons 1335 1436 22610 26417 2659 27316 2839 4084

recall 123 1318 751 867 1473 16421 23020


5321 6612 769 10010 1152022 1312

received 2811 7618 8814 17714 19010 3493

receives 6915 7022

receiving 3310 10214 1316 1644 2287 28918 33919 35717

receptor 30519 3066 31118 312915


24814 32517 34818 35217

recognize 141315 1619 175 2219 2420 331 383 443 676 989 1641 1743 18012 21719 33321 37911 38318 39221

recognized 5210 1646 26716 3712 40016 40816

recognizes 5318 1266 2656 3482

recognizing 1234 18518 3494 3708 37219 4028



Page 457

recommend 10410 122612 12520 1283 14121 21016 26412 27413 29221 32615 3705 37215



recommended 6721 7214 32620 3326

recommending 1213

recommends 4419 21213 3287 3293 33010 37116 37814 38320

reconsider 689 36122 3627 36315


1351012 15412 17919 2316 31516 38218 39620

records 716 1463 18014

recycle 28617 red 6522 6815


22711 24216 24420 3291 34222

reduced 1314 7710 23519 2923 3392 4016

reducing 2384 2421218

reduction 20716 2432 29119 4018



499 1548 2239 3153

reference 1022 114 584 6214 6628 674 9218 1004161819 101910 1035 10621 1112222 1123510 11313 113152122 11422 115689 1169 1209 12219 12315 12413811 1262 1299 1317 13216 13314 13512 1514 1591021 16010 16018202122 1611791117 1625610 1637 16318 1667 1675 16819 16913 17019 1712 17210 1782 1796 1854 18713 19220 1949 19517 1981619 20016 20116 202512 2032 2081 2091517 21020 22218 237910 257591420 25817 26321 2641622 26518 2668 27613 2799 28719

29022 2919 29312 29622 297236 30316 3041 3051722 3061318 3078 30816 31616 31716 321821 3281221 3298 3291418 33111 33218 334212 33417 3357 33620 3371215 33819 34114 3456 34616 3499 35010 351722 3534 354812 3612 3621115 3634 3641 36612 3691021 3705 37021 3715 3722 373311 37415 3842 38722 3934 39416 396913 40814

referenced 254 351 5817 6914 6915 7121 8211 1422 19419 23011 2406 3034



22916 3119 refers 3009 33015 reflect 205 5419

11214 1287 2345 3992

reflected 15012 3052 35219


reflects 5322


35412 refuses 321 regard 3816 6814

6921 727 1306 13122 1433 15420 18711 1894 19510 2024 2173 21911 22014 2239 22820 2417 27717

regarding 111 4013 666 7714 7720 8810 897 995 10117 10222 10319 10816 11310 1729 1844 21014 21622 21712 22216 2388 2416 26814 2765 2778 27811 28011 3022 30814 32015 3224 32610 3289 33010 33314 33514 33611 3395 3486 35019 36115 37419 39618 39720


21021 3083 regimen 3351



24918 2702 28210 4095




3418 3818 4216 21818 2659 3236 37911

regulatory 119 821 459 51211 5516 9811 11216 1192 1539 18814 20418 20513 2166 2181 2234 2252021 2362 24221 25112 25318 25511 27110 27221 28121 282615 2833 28516 2892 32420 3324 34811 35211 39019 39621 40312


37816 relate 517 30413 related 88 13313

13422 14621 1479 16213 1903 19919 2006 3143 3201 32420 3347 33512 34712 3511422 37410 39512


Page 458

relates 13115 3041314


3410 435 4516 4858 29516 3218 37919


relative 11622 19516 20115 2531 33322 33417 3387 34022 3412



35116 3539 relevance 32720

33718 37112 relevant 7918

1938 23416 2351 25119 30022 3074 3254 32722 33714 35920 3642 37119 40622

reliable 18022 1819 18311



5622 31321 3524 36314

relying 31314 32212

remain 21112 22812 23610 23918 37910 41111

remaining 3521 22211 36411

3748 remains 125 2922

26914 38318 3997

remarks 52 284 4118 1175 15918 16219 18912 2254 3247 3605

RemarksAdjour 715



2181316 2195 21917






7959 822 19120 2301

reported 569 579 5711 8120 919 29812 30711

reporting 603 125712 18519 1911717

reports 558 7214 8118 889 14521 19118 22921 2308 29722

represent 3214 413 509 511 725 777 833 8716 11918 14817 1506 3169 3916 4008 4109



representing 297 1368 2876 38121




1111217 11229 11221

reproducible 11816


3322 4422 4612 1664 19121 2344 23816 2391 2741 2899 32922 35516 3574 40915



requests 34916 355314

require 193 3621 3919 4221 5216 5416 5722 7219 1289 18021 1816 19411

1971417 2065 2129 21722 2211 22415 2697 29920 3096 31113 320621 32717 35410 3575

required 5617 5910 742 9217 1091618 11216 13918 14119 19120 19415 19917 2111 2129 23722 23917 24316 26518 29114 31015 3225 32620 32710 3299 33013 33415 335616 3373 3387 38611 38721 38820 39417 40422

requirement 575 7222 2123 2389 2381419 2397 244617 27814 3376 3611922 37122

requirements 6721 12110 15019 1897 1945811 1961 1963 2084 2104 21013 2111517 21121 23319 2341 238622 2433 27414 2758 2786 29121 30410 32711 329122 34918 3503 354314 35510 357710 3669 3693 38410 4014 4041212

requires 5319 14017 2181 25718 268144 27410 3545 3932 40020

requiring 14320 1782 2552 3208 40712

research 111618 120 23511 49 712 812 5018 7910 881 9016 13914 1476 17419 20417 36716 3772 38078 3851



22322 22720 23917 24212 24420 24614


23614 23721 35418


31916 35715 resource 28813


12616 28811 28912 35420 3582

respect 2313 4211 4217 495 671 688 699 72217 7412 15114 16222 23017 23316 23412 23619 23714 2418 3574 35922 36818 37411 38320


Page 459


30815 respects 424

39114 respond 4616

17222 response 196

2622 379 6410 689 73110 1481 27819 2827 3286 33411 33818 3838

responses 561621 6012 33914 3408 3453 37113

responsibility 353 5114 1074 2437 3877




584 651622 7212 773 845 11481315 20816 2568 25910 2637 3351 3382 34921 35417 3742 3781 38412 3852 40016 40715


results 189 571 7917 9919 11317 3397

34119 resumed 959


514 8618 875 8716



9621 976 15922 16211 16422 173821 17510 23218 23317 2342 2359 23822 2707 28913 35118 35217 354920 3628 38711


172916 17320 2079

reviewers 16315 1641017 1669 17011 173610

reviewing 16317 1669 17319 2358 2451314 24520 3882222


1285 revolutionized




2285 rich 1695 Richard 31 515

9518 right 105 3311

3414 3615 403 405 4410 474 8610 8715 987 981818 1702 19713 20713 22456 2281314 24220 24317 24619 25612 2699 27018 27212 2751 27916 281213 2821 28513 3001 31012 35816 37515 38422 39011 39719

rigor 21315 22119 28218 2832 33012

rigorous 1622 2221 1815 20619 20715 23310 244410 27828 36919

rigorously 9113 33322 34111

rise 23112 risk 195 385 444

446 577 9021 923 933 11319 11322 142515 1436 14513 19012 19421 2187 2198 22021 2246 22516 2264 22720 3101718

3271 37621 3772 38315

risks 549 5721 786 21720 2184 22018 2217 22211 225217 2264 24119 30717 3495 35019

risk-based 18817 19520 23320 24018 2429 30720 3354 3386


232467 24321 2457 24610

road 2459 35818 Robert 21013 54

1518 robust 1911 1053

11816 14119 181720 19611 23615 26615 32517 40511

Roche 310 67 1881114


188101213 197819 19812 19914 200111 20022 20118 2027

role 231420 2417 2610 3211 3916 6818 8515 9914 12019 12913 17812 1807 18611 19319 22716 24722 2481518 3128 3541 3645 37115


Ronald 41 72 31519

room 112 922 147 259




2458 rubric 15518 rule 1732 1742

20112 29410 rules 111921 467


29711 running 36220

41015 rush 24119 RampD 313 611

2163 R)7 11631015 RAC 48

Ssacred 486 safe 31 516 1615

1618 295 311 323817 334 3621 37118223722 416 449 9013 9118 9513 9522 120515015 15231796 18921


Page 460

19114 1967 22017 2422 25618 28812 31421 35618 37510 37617 3812 39112 400710 40122 40411


safeguard 94912 9417 16314 37810

safeguards 338 944 1638 1664 1665 17456 37815

safely 216 5116 safety 1621 1722

1813 194 2217 2221 322 331 3513 376 4320 451012 507 518 5317 548 541119 56713 5618 573 591 6421 708 7234 7913 808 9217 931616 9610 974 10517 12122 12622 14419 17513 176810 17812 1805 1811 1828 18820 196415 208811 21018 21215 2151 22921 24010 2414 2531 26118 26521 2666 2907 29113 29816 3031321 3051 3111 3131 33017 3353 33610 3393 34022 3413

3495 36116 3657 36617 3679 36822 3701 372921 374117 378812 37920 38038 38316 38913 3907 4015 4039 40410 4051620 40719


57 401112 4111 4727 484 49822


35816 Sandoz 318 618




16612 saved 15220 savings 7910 828

15326 25619 2926681214 40015

saw 1514 2519 saying 6212 943

10114 1735 1833 1985 2296

2691022 3026 31211

says 1988 27015 2711


3296 schedule 1512


1117 schizophrenia

3824 school 33 518

5120 1082 38015

science 23 5513 5717 594 999 138781014 1391 14514 1641 18118 23213 23322 2398 2418 25413 2563 27221 28120 282813 28516 2951 32112 359317 36019 3694 37118 3941320 4011 4043

science-based 321 26121 2888 29219 2959 3797 4054

science-drive 41115

science-driven 18817 19520 21612 2257 39114

scientific 1020 693 998 1088 10914 1576 17815 20417 20511 2082620

2107 2111 21315 21417 2211119 22324 23221 23317 23418 2357 2362 237817 2395 24113 24510 251618 2541 2631013 26318 26417 2652 2671911 2671417 2706 2811216 28249 28218 2831 28512 28714 2892 29021 29113 3049 30518 30922 32419 325215 32617 327818 33012 3348 3506 3518 35211 353115 35510 3639 36816 37210 3753 3925 3931 39314 394811 3951317 4002 4013 40212 4061721

scientifically 1205 20619 20921 22411 24210 2638 26911 27016 28021 36317 36919 40118 4036 40819



scientists 9015 9115 963 16519 17011




13517 13615 scrutinize 139

154 se 23111 29111


28512 second 1022 1610

198 3068 7712 9017 10918 11316 1162 1412 16268 17615 17810 19218 20914 21012 251721 25322 2626 2636 26516 26718 2745 2791 3491 39220 3992


seconds 2878 40912


16210 163313 16541221 1666 17116 17449 3585

section 19410 20215 211511 23913 275712 350141516 3556 39516

security 2218 see 146 1517 239

2314 24118 2517 325 345


Page 461

3819 6318 7511 7512 982 10519 1275 1374 13815 13918 17220 1842 18922 19511 20634 20720 21116 246415 24821 2492022 2501422 2515 25214 25322 25912 3113 31721 31815 319813 33047 34519 34616 4048

seeing 4913 13018

seek 10012 17819 2077 3689 3773

seeking 12013 1291 3399 3721416 40168


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seen 6019 6716 9115 1305 1763 20918 24915 3282 33119


11817 21621 3363

selection 8412 124621 12622 33915 34013 3422


11915 14815 16412 17419 2327 24622 39018

seniors 871314 907 9415 951

sense 606 2019 20622 28417 34413

sensitive 171620 1773 22371618 224218 2273 2284 23615 27514 32722 32814 3332 334422 33710 3391316 34010 34013 34111 3424 3444 37018 3721819


22310 2251 2275 32720 3416 3421520 34317


146116 14715 2523

separate 1429 18617 3276 35012


11624 2651820 sequential 2073


35612 38121 3841522

seriously 354 41112

seropositives 3297

serve 813 4315 7622 874 11915 1922 19320 21311


2678 31614 services 76110

1202 33311 serving 766 2383

3173 33714 session 1078

24422 31519 set 592 731 8513

11810 12110 1745 18120 19315 20916 2383 241311 2445 2864 33622 3376 33815 34418

Seth 411517 4910


21510 2237 24213 33715 3965

settings 2713 11920 1201 12510 25922 260613

seven 302 3115 2877 2898 3263 32616

severe 6516 7212 35721 3825 3996


496 508 20521 2436 25213 2915 3428 36719 4098 4102

shared 34120 36515


1781 Shehan 615 2615

26167 26916 26911 270414 27021

Shein-Chung 32 517 10720 1081


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26810 26918 2714 2815 28418 28558 28619 28729 29714 29822 30211 3105 3133913 3147 31551218 3163 32469 33211 3335 34211 34619 3571 3604 36512 36710 3751122 3818 3855 38918 39013 3975 3981317 40911 4105




1148 14616 25213 26222 26421 29510 29757 3332 3885 4019

showed 2664 38016

showing 2651 29310 29514 31814

shown 10110 11522 2125 2551 27311 34817 3668

shows 15217 31718 3195

side 5614 57911 8922 919 13115 1311920 1364


Page 462

13911 15220 1719 2452 2847 28421 29512 382914 38712

sides 454 911 13910 27819

Siegel 313 610 21624 22519 22714 22918 23020 2322


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significantly 1718 5513 595 17219 1737 1777 21019 2664 30310


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similarity 269 2182 2278 24819 2512 25410 2757 2924 30315 304619 30517 306110 3071 36020 3611 36519 3663 39513 4019 40416

similarly 1255 2543 29210 4033

simple 13112 18116 1919 27217 28118 3878

simply 926 16420 2369 2925

single 923 1375 16117 1675 1862 34115 3699 39120


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22712 2554 2641318 27615 29514 33717 38716

situations 6717 1651 21413 24519 2528 25914 27422 39315 39416

six 3024 479 2897 36517

size 10967 14019 2158 26319 32819 3292 3412 34222 36911 37117 3727 38222

sizes 1475 22516 3295


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slides 812 22912 4073

slight 701 731720 741322


slot 13513 slots 1117 small 1611 1710

184 2317 2620 431022 5422 559 9791718 988 15220 1773 24912 2836 2961 36913 37020 3728

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sounds 1351 21422

source 1004 16615 1695 1763 19218 2643 3981

sourced 5312 3056 3928 39811 40818

sources 14522 19616

so-called 11014 11015 1181216 27617

space 2059 3017 speak 141 3516

4020 4619 6313 9415 9517 1432 18511 20415 2993 32414 3919 39821

speaker 1341215 131618 151016 2116 2722 4011 502 643 7516 9512 1013 10322 10720 11910 13516 1386 14810 15817 17414 18810 19622 2047 2162 22413 2324 24619 26020 2614 2717 2823 2873 30213 31519 3337 34621 3606 37518 38111 3858 39015 39818 3991 40214 41016

speakers 111516 1220 1411 4721 6512 709 7110 993 10221 14718 22119 3149 32410 36614 36712 40117 4111

speaking 4113 481 493 18910 30122


Page 463

speaks 21779 2214 2282



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specificity 758 859 2143 3417



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sports 4120 422 461 4916


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stand 17119 3529 3602 38010


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standing 146 4614 25320 30820


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started 1082 1985 3443 3793

starting 811 2133 28411 3966

state 761 128269 14020 17914 18419 1882 19222 1934 194620 2365 2418 24816 2502 2582 2651316 2671 26815 3031 31220 33614 33719 33816 3398 34711 35818 3713 40710

stated 728 7319 1063 1767 1972 197317 2659 27912 2943 3832

statement 671115 69310 1351011 1543 1868 19412 2427 2694 29920 3662 40614


states 203 3119 6510 6611 6810 88810 1001617 10410 128410 17514 17818 2258 23810 2639 2685 3085 3316


24317 3508 38710



status 1959 19710 19711 23611 2648 28012 32212 36216

statute 627 14913 15811 1611522 1626 1631 25821 2621516 2646 2683 2696 27038 36521 3736


170317 17114 18416 22113 2935 357710 3693 37121


3621 stem 1911 3576 step 199 273 328

10935 111511 11114 1135 16320 24810 25611 3484 36016 3801 39910

steps 3620 5418 5814 624 1006 10916161920 1114 1224 1738 1764

stepwise 10814 109313 12014 2062122 21211 2227 233822 2393 2448 24813 27121 28715 3261819 32622 36218 4025



Page 464


901 stopping 3916

5614 storage 6515

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1114 18019 33918 39612


strategy 4611 27111 3872

Strauss 42 74 3241112 33220

Street 8721 887 896




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21617 2294 3121 37210


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structure 696 8511 1056 2096 2654 2668 27314 3217 36914 37322 3784 3861722

structures 439 27220 37721



1161121 1566 20911 2212 22221 22425 23115 27516

studies 561720 7118 7918 992 9910 10917 118337 12819 13822 14320 14515 14619 15614 16015 16812 17019 2101017 21216 215123 22517 2351719 23916 23920 2569 25710 2937812 30415 3055 3072 31021 3111317 3123 3131 32731012 3281013 3292 3362 3384

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5310 568 subject 121317

6419 1191 2134 2682 3277 32816 35420 3737919 39821

subjects 32714 387920 40119

submission 17218 17516 18912 26015 2738

3562 38822 40920

submit 611619 7514 1198 15312 1882 4018 4117

submitted 139 941 13621 1468 1621420 16721 1687 20818 21614 2496 2687 3485 35519 36811




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substitution 343 341112 365 3922 436 4421 4516 5418 5815 62471121 783 7922 9110 925 1048 1286 13117 15117 15561216 1564 1568 1798 18417 1869 19222 19610 31420

substitutions 3611 3919 13121 1445 15589 19012 19716


33511

success 17812 17917 26510

successful 7818 8015 12017 17920 2788


suffice 2715 33511


1512 29719 2986 3636 3642 36610 38710 38916 4019

suffix 1783 1854 18568 18722 1881 1912 2608

suffixes 1241415 12417 1336

suggest 6620 1046 11013 14422 1452 1814 18320 19921 210912 2263 27615 2901516 2945 29410 2976 30115 31115 31318 3312 3322 36122 362722 3644

suggested 843 29322 2943 38922 40019

suggesting 10111 1515 1698 22614 26920 311410 325911

suggestion 2446 26822 2863 3311

suggestions 36810 85721 9822 18719 2081822 26622 28616 32817 33117


Page 465

suggests 2101115 22318 3313 36118 362317 3634715



8315 845 summarize 6410

3647 summary 2213

5822 1824 19518 20822 30917 35514




6919 supplementary

682 supply 1007

13311 17617 1801722 1819 1827 26014

support 4322 467 6791415 9815 9820 10113 10413 1066 12014 1231321 1248 1281415 14222 143514 17020 1852 196414 20718 2228 2333 23622 23712 23815 2405 248712 25315 25811 26312 26616 2752 278812 31115 32513 3293 353614 3771 38219 3853

39515 39620 supported 14912

1689 19416 1997 27720 29322 34120 35614 36721


1001013 1482 35215

supportive 16716 2411 28712 3687

supports 772 8920 1204 18815 23314 26310 2779 3059 3504 37017 3806 39110 4081521

supposed 882 1132 1312


4813 498 598 13021 1327 1344 1432 15519 1587 17317 2281 2292 23014 2441 30811 33622 3579 38810 40411 40514



586 636818 7221 7416 921 10119 1053 1258 12820 14611 1572 29719 30914 3792

survey 5646 576 601 6115

surveys 601015 6015 6119


1142021 11512 115367 1236 1683

switched 2515 578 15618 22019 38418


5720 608 1031 10819 1091 11320 114218 11419 1151216 11612 117213 11714 1685 1934 19421 2217 2222 2311016 25017 29815 3641921 3651 36611

Sykes 411 37519 37520 3762

synthesized 26219 2633 27222 2732


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17918 1862 19018 191610 19112 1924 19321 22515 24016 25114 2536 26921 2841314 28519 2861 32121 37817 384516 4051112 4063 40611

systems 698 12416 14614 28313 31321 36111 36912 37720 4084

S-E-S-S-I-O-N 2041

T T 11422 115112

11518 116347 116710141415 11615


3919 4110 547 5813 624 752 955 11813 15419 16320 2027 2471721 2575 26612 28420 29712 315113 3364 3385 34016 35921 3601 3804 3846 38712 3974 3992 41112

taken 3517 4511 8911 1007 1381 1739 1764 20314 30918 3491021

takes 1655 20713 24018 3924

talk 5020 1055 11417 1304 15716 15823 17220 1832 1841 2005 2141 2147 2174 2272 2723569 28812 29621 31113 3187 3769 4104

talked 271011 364 601 1307 13013 2599 2906 39718 4022

talking 2615 316 1709 1867 22916 2691 3186



29013 3175 35912

technologies 30413 38911 4091821

technology 7817 1349 2321520 3713



991619 10520 14612 1718



Page 466

2238 temptation 2856 ten 6022 10810

1362 137113 18122 30221 32418 33215 3435 4021920 40912

tend 10311 tens 21910 term 8514 2104

3086 terminal 21710

3301618 terminology

12611 terms 2416 285

2810 553 1194 1339 184814 18613 2491 2892 2921 29310 2951 29819 29910 3004 3027 30419 31114 3168 31819 343422 34611 35721 3861617 38618 38913

test 11422 11579 115102021 1161 1681018 16820 17010 2156 22822 2647 2783 2997 37811 38310

tested 5411 591 7814 9113 2223 22315 30619



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9922 2128 2184 219910 22210 2221213 2235 22715 22819 22956 2568 266181819 27914 3304 37016 3711417 37121 3725 40171119


19219 40120 40216

Teva 32020 620 621 302141717 3035 30591112 306815 30719 30814 3093817 30922


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1592 1661721 17314 1741217 1821011 18317 18867 1961718 20010 203711 2041214 21218 2131617 21521 21522 2169 22549 23122 243911 24617 24737 2562122 261210 268910 2715 2815 28621 2871 2971314 30211 31058 31514 3245681213 332811 333513 342711 34620 34727 35621 3571 3605 3651112 3666 3671115 37511 37513 3817810 38114 3854516 3891718 3975 398141520 409911 41045 410101420 411122

thanks 10421 13514 15415 18213 18721 2018 22910 2598 3104 3118 3647


538 5615 7922 15116 1556815 1563 33521 33813 34116 35610 3859


therapies 1615 1879 2022 211

217 311 5415 551 597 779 15968 35618 382616

therapy 521418 537 56813 5710 593 10515 12021 3853


386 1186 1333 1876 25115 2808 30514 3594 38612

things 373 10615 1189 1308 15518 1761 18117 18322 2146 22620 227420 24611 25217 258122 28216 28921 2914 2988 29912 38713 38811 40222 41015

think 155 2422 261214 2712 2714 34356 3618 371519 38410 3915 402 5118 5212 6117 626 7322 745 8558 904 9622 991013 10122 1059911 1063 107578 107131515 1081519 10911 1091221 11011 11012 1111519 112715 11318 11319 114911 11421 115513 11519 116613 1186101114 1191 1238 1329

1359 1421422 1431214 14616 1491621 1505 15113 152157 1546 1551315 15516 15616 15717 15812 16381419 16616 1671116 16717 1684 17121 17246 1738 17427 18410 185313 18516 186321 18757 1918 197815 19812 1995 20017 20114 2027 2034 21322 21461016 21510 2214 2227 22319 22810 2294 23022 2319 23522 243618 24518 24612 2474 2622 26919 2704 27317 27921 28010 2821621 2832 2841015 28699 2903 2913 29422 29620 3011216 30319 31016 3121319 31320 31416 343813 34318 3464 35712 3585 35915 36015 3666 39822 4021314 40416 4071 41016 41110

thinking 2712 3713 4821 515 5117 1707


Page 467

19715 2011521 20122 202910 2195 3159 34719


2020 213 9022 10919 1163 14113 16112 17617 18016 19222 20922 21014 2537 2628 26610 3961017

third-party 2313 4411 487 925


thoroughly 591 2336


8520 10314 13012 1331 1859 19716 20110 2022 2801719 3258 39045 39710 4112

thoughtful 5916 20012 2038 30918

thoughtfully 20512

thoughtfulness 632

thoughts 2610 474 13311 20113 3156 33314 3428 41116

thousand 5312 6012 8714 1694

thousands 6110 9020 21910


three 1013 128 1812 3021 4122 8314 8718 895 903 981 11114 1135 1166 1376 14014 15714 1603 1681 19518 20819 2093 21621 2656 29314 31219 32510 32615 34517 34836 3681218 38322 39116

three-armed 25716




13513 141718 151112 205 291818 342 35417 3921 421 5713 6613 7314 8617 9212 1031914 1085 11719 1314 13420 14168 14214 16612 17215 17516 18118 18210 19413 20017 20916 2119 2157 21621 2254 2311822 2439 2509 25918 26010 2618 28320

2866 29015 29818 2991321 32213 32511 3328 34017 344289 3451 3553 3595 37613 3781 3791014 38610 38618 38816 38912 39120 3972 39820 4111


2424 times 34321 4016 timing 1309 1843

3355 tipping 16710 titer 34531718

34613 titers 5522 today 10212

1220 1311 163 291122 3116 323 351618 4014 431 4615 481 493 5021 6611 678 7010 7711 8711 944 9518 1203 12713 1326 13520 1369 1373 1387 1404 14013 144710 14411 145611 14516 14620 1474 14820 159318 16218 16618 1709 17418 1751720 1761 1779 18020 1821 1855 18912 1908 1917 2004 2008 20220 20415 247413

24813 2665 27115 287620 29315 30511 3168 32414 33317 3478 3487 35622 36410 36516 36815 3769 37816 37911 38214 3832 39126921 3973 39821 4009 4021516 40218 4089 40910

todays 4918 505 3254 33319 41011 41121

told 3912 512022 8813




23212 24816 2502 29810

top 1471 2264 31816

topic 856 13313 1628 1637 1921113 1943 26610 2721 39322

topics 2119 35515 35517 3732

total 3186 32211 totality 6921 726

10815 1101214 1101822 11218 11324 11778 11813 1281314

20620 23320 23512 2392 24018 24814 2755 30611 3391 3611 3626 38819 4024 4099

totally 2615 22715 3221415



911 2310 2415 4819 7411 1673 19915 23010 3573 36514 40914


21010 2244 3875


10117 1064 14714 1484 22122 22914 31310 40511


3094 37821 traceable 2309

38411 tracing 1024 1062

10821 17622 1777 22917 23013 23111

track 1918 459 5417 7214 869 934 10117 1024 1064 13315 1402122 14134 14111 1484 17919 1919


Page 468

2312 31310 40511

tracked 735 14520 29415 30911

tracking 191114 713 1062 1256 12514 1344 14119 1438 17621 1776 2301617 31722 34914 4057 40919


13522 1554 15922 16210 163312 165411 16521 166615 17116 17439 280237 3524 3585

traditional 1719 184 4322 2803



2671021 26828 26820 35529 39317

transitional 2629 26621 2673519 26722 2686 2692

translate 4413 8413 12119 30113 3458

transparency 17211 1747 18711 2491


3755 40821 41115


8914 916 9210 treated 2521 5612

10518 2737 28415 35910

treating 10519 1068 36112

treatment 2920 3017 447 4815 5015 564 5726 661219 8917 902 914 1967 19615 2628 2638 3351 33912 35613 37419 37622 3775 38018 38210111315 3841315

treatments 169 222 5222 609 82172122 8310 9213 1599 3568 3794 3823717 3995


571 10112 1694 19417 20211 2385 2433 2791 2923 33721 34116 3727

trials 1819 194 202 266 275 3622 4319 4513 517 5417 581 62210 9114 1037 13811 139218 18712 20117 2025

21571415 23618 23919 24022 2531315 2531618 2555 32621 3271516 33522 33814 37811 3871415 38881120 3895 39122 3929911 3921422 39316 39317 39410 39615 3971421 4041921



16522 2857 34011 3594 36310 4071

truly 9819 1897 24018 244913 4031



1698 2691920 26921 28721 2915 41118

trying 3819 487 10614 15416 15811 16110 2046 22613 2312 2459 3032022 3443

tumor 882 2664 turn 920 238

7914 1774 turned 882 9414 turning 1115


2914 301519 5718 702 7314 927 971515 10313 1081113 1103 11111 115161718 1166 117520 14212 14321 1457 15919 171415 23217 23516 24413 266121 26816 26819 2695 27324 2761618 2771022 27818 28115 2834 30222 35113 36416 3732 3798 38317 3923 39614


1075 1318 1321 132517 14622 1471515 1511 21920 31617 32169 32522 3317 3516 35312

types 355 1716 2004 23916 32521 32716 3469 3664 39217

typically 1376 1417 1555 33710 33920

typo 1406 T)7 11671015

Uulceration 38017

Ulm 47 79 3606 36099 3666

ultimately 1811 9816 10415 10516 1735 38315 4029





16114 2265 23917

uncertainty 20716 2271116 24212 2421618 24420 24614 2776 28611 2981 38318 3945


23810 underestimate


3367 40721 undermine 8722


3419 3819 4315 4919 6719 1036 127511 15417 1731 1756 18222 20212 23417 33216 35811 37613 378619 37915

understandable 1094


Page 469

understanding 214 781621 14615 1559 15722 2419 3029 3053 31011 3717 4072022


32919 33720 3418 37722





72815 932 19012 19610 36915 3703


unique 1620 177 1911 2219 2616 3313 3915 439 456 5119 5318 5810 596 618 62920 7017 733 755 10212 10217 1057 106522 12217 1231 14716 1783 1891320 190261120 19113822 19212 1962 1991617 20029 2644 27417 27918 2802 2941114 29718

3091020 3168 32021 3213 3225 3232 3496 37417 38434 40311 4051718

United 203 3119 6510 6611 8910 1001617 17514 2258


University 32 518 10721 1081


35616 unnecessarily


25317 25412 2555 2569 2856 3072 30822 31112 3581 4011819 40819

unpredictable 21812


2906 unusual 523

25313 upcoming 317620


6858 753 15020 15118 1538 1801 21912 22115 22912 28911 38215 3853


urges 8017 17722 26320 38410


4069 USANs 30912

32213 use 2112 2489

537 6510 6821 6913 715 7810 7815 7961015 8514 89131721 912420 9921 1001 10121 10217 10821 1093 11320 12018 12536 1264 1276 1281418 1298 1381011 13913 13916 1424 14318 15218 1531 158713 15919 1605 16121 163211 16511 167822 1754 18714 19020 1939 19921 2081 22315 23620 23811 2579 262221 26818 2804 2829 2917 2929 29322 2989 30210 30819 3164 3226 3237 3263 3289 3305 34022 3423 3462 349813 35220 35319 3581 36510 36912 37611 3842 3894 39215 39611 39811 40012 40816

useful 126 859 11017 116815 117815 15617 15621 1573 15813 2146 28110 3311418 34814 35215



22821 25718 31321 3471



23622 23721 24015


23719 29821 3708

US 326 538 547 8922 1001218 1019 15220 160817192022 161171118 1624 16316 1705 1711 1778 17814 18813 20422 2051117 2193 2379 2471214 2481 2536 2541122 2575914 27714 2833 28719 28917 29211 3038 30821 3156 31713 32013 32219 32712141517 3321822 34712

353389 37618 37715 3802 39323 39416 39545 3968 39811


27217 2901733714 35815361915 38812


36022 3617Van 48 711


2149 2951730011 38715




31811variety 1714 2112

2117 2210 4710 12413 1335 1451922 1462

various 475 8413 2252 2749 3403 3421 40113

vary 1109 13822 20918 227529520 2962



Page 470

version 8812 20721 2796 3288 3318 3785

versions 17713 23216 3208 32615 34910 396811

versus 1106 1645 18713 24217 2515 25212 25720 27214 2781515 29513 3285 3301 3387


17419 18813 2327 24622 2617 3474


1415 18511 24317 2456 2574 2811 33821 3681 3723 3878 38817

viewed 6220 32119


36719 37922 vigorous 25011 Vink 315 613

1549 2462021 24622 25711 258510 25913 2605 3141015 31510



9416


896want 1918 2110

2447 2913 3213 351113369 4019 4314 4417 5913 8522 9013 937 9411 9717 102211061 118713020 13261342 1384 1391 14119 1621816617 1722018312 185171989 2063 2169 2174 2198 2464 24615 247362486 250625421 255625610 268152694 280628320 28432851 2949 2974 3047 346583939 409641114

wanted 634 10422 1332 1404 2012 201913 2588 3031 32413



3501519warnings 12622


4917 wasnt 2521

1691921 1701 1976 23014 31012

wave 31911 way 30113 3313

358 371619 474 652 8317 1023 10416 10956 13711 1389 14511 15111 15315 1555 1566 1581 1651 17014 1745 21422 22713 2307 2421 24912 2535 26220 27112 28021 28210 29416 3041 34312 35714 36310 3792 38310 38518 38811 40022 40120 41119

ways 177 858 9613 14014 14519 1515 1861316 22621 38213 40717

wearing 163 33214


9614 1801 1841 website 131 2248

7720 814 9620 9622 13112 31622



8621 951214 2044 21414 2322 2813 3842 39911 40813

welcomes 2077 3035 3688



23115 went 958 31515

3421 34517 werent 1677




2457 40117 40515

Wisner 41013


1304 1995 35813

wondered 269 21419 2588 3902

wonderful 1084 3594 40011

wondering 473 1469 3003 31212 3661


26221 3165 3462

wording 22317 23811 2645

words 2322 3614 1121 11519 16121 1659 16716 2782 29117 32161232113 3392 3412 38519

work 243 3721 389 428 4813 7813 8518 9815 9820 991 10414 12515 12717 13413 1355 1461014 1516 15313 1546 16517 1822 1962 2256 2921 29310 2951 31222 3267 3501 35619 39920

workable 705 1399 1472

worked 14110 15114 16316 16421 24918 3777 39919


Page 471

working 226 3220 478 1044 1068 1076 12915 14911 15610 21313 29020 30217 34318 36121

works 3219 388 4022 1043 14511 1556 2524 31022 37622

world 297 5120 5210 13722 1766 2192 2442 26112 2916 32117 3913 4001214 4062 40613

worldwide 2910 307101215 3110 555 6521 26114 3236 3568 4065

worlds 17420 24710



32117 40513 worthy 39119 wouldnt 2520

1342 14620 2442 25813 3465


10612 1217 12419 13322 13413 16613 18818 20818 2131 21422 2496 2611 27218 34414 3485 36812

wrong 1815

21518 38717 wrote 1686 22314

XX 13216

Y Yapundich 213

54 151820 2316 2420 265 2612 271419

year 301117 319 6613 9415 1378 13713 15212 1534 26114 31620 3243

years 2919 304 3115 4116 4710 13623 13719 14321 16517 16720 1681 17521 18122 23217 2471618 24915 25017 25615 29212 30221 3031 31910 32418 3581417 3595 36313 3668 373621 3778 402192020



24533

1 1 433 1131 1229

1902 21514 1100 3479 12 298 19 6616

14 36517 100 109 104 2042 10 2812 8210 10000 909 1000 955 1014 9510 1015 957100 1118 28117 107 51810903 112 11 19 24713 3307 11th 316191158 20313110000 7617119 519 12 2919 3581317

3595 37362012-year 1398

37421200 109125 111813 2919 4116 888

881013-year-old 38011135 52114 1363142 3085148 6315 16 55 87 1212

2418 5714 955 2471618 24915 25017 25615

15-minute 1067 31513

15-year 765150 528 1532 1503 112158 64 17 4116 837 1377

3283 174 66188 6819 81211922 390221952 40661970s 32310

1980 5013 17422 1989 6511 1996 25517 1999 2913

22 434 12319 1726

1903 3441538820

24 6616 248 31516 20 3016 9010

1378 25615 3548 40220

20-year 16516 2001 15222 2002 21822 2003 6617 21822 2006 25191115

40612 2008 563 2009 1019 7719

8122 829 34715 3681

2010 514 557 9614 15222 1531 28617 35218 3801215

2011 225 2811 7617 8117 834 11016 2427 38015 3915

2012 19 799 8721 2019 3557 2020 319 2677 204 69 21 8720 3283 21st 887 210 14822 216 61123rd 8712232 61224 2611324th 896246 61425 1371 29211 25th 1422 4059

409720 41112 250000 5213 260 7615 261 615 271 617 28 56 5710 287 619

33 435 1265 1904

33813 3411534416 38820

3C 1448304 3151730 1116 132 8210

13612 1672017520 34713

302 62131 112 8120 316 73324 7533 2928333 76347 7835 2891735000 521335-years 2917351(a) 35520

373919351(k) 22113

2331 2342023922 243735119 35278153545101335522 35625

360 710 3181 367 71337 569 27312 376 714

44 436 6618 1282

19054C 14474(b) 39516444 412240 58 26213

2631114 27215


Page 472

28117 2851 3193

400 2122 400000 6610 877 41 26315 27215

27220 27318 410 715 425 31722 45 2851

5 5 436 12813 500 102 1414 50 59 6013 2851

2881718 3193 34518

50000 3010 648 50-year-old 25113 501(c)(3) 287

4021 5011 505 3556 505(b)(2) 17210 505(j) 1723 55 2851 55000 413 5214 59 2878

6 6 2287 60 6013 2896 600000 3012 62000 11919 64 511 65 9414 69 835

7 7 11422 115111

1163 70 415 700000 6617 72 11213 75 513 823 76 8813

8 8 52 830 112 101

832 82 80 6816 1118

112812 82 6521 86 514

9957 959 90 1121113931 15221 95 516 11115

1136


473




Before FDA

Date 05-11-12





-----------------------Court Reporter



Page 3



School of Medicine


Association



Association




the Roche Group


Hospira Inc



Inc





PRESENTERS


Page 4











Page 5



PRESENTATIONS














Page 6

CONTENTS (Cont)

Kristin Bass


Neal Parker Esq

Association 148



Amgen Inc 174

Michelle Rohrer PhD



Group 188

Hospira Inc 204

Jay P Siegel MD


James Roach MD


Patrick Vink

Mylan Inc 246

James C Shehan


F Owen Fields PhD

Pfizer 271








CONTENTS (Cont)

Ronald A Rader

Page 7


Institute 316


Michael Strauss PhD


Bruce Babbitt PhD


324

333

Sara Radcliffe


Organization 347

Cornelia Ulm


Association 360







376

410


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(832 am)







Biosimilar Products













in CDER


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of the Commissioner




Chief Counsel






announcements





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the lobby













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biosimilars










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hearing















recall the speaker






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that





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what we say











Patient Access





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practitioners




















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well as the payers














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Page 19

market






threatening













The third is the




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clinical practice








of therapeutics










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therapies












many of them do not





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Page 23




Thank you











that consideration









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Page 24










agent Its crazy














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Page 25





appreciated



















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bullets basically













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Page 27













two settings


would suffice



comments


much




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Page 28

Cancer Alliance























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in only seven years









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Page 32










patients











medication



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Page 33






market


















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Page 34













begin with











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on schedule


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Page 36


ask a question






















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Page 37














another arena










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Page 38


testing






















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Page 39














the patient










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Page 40






that that occurred


















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remarks personally






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Page 42





lose or tie













process






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Page 45













trials











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Page 46











strategy






directly





panel


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Page 48



already said







for the patients








Maryll






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you













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parents everywhere


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Page 51
















safely








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Page 52




consequences




















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cold





















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Page 54





another



















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harmonization





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Page 58








are made available
















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manufacturers






concerns

Thank you



panel



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Page 60




MS BOYLE Correct





treatments















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bodies











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Page 62











substitution





pathway








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Page 63











in biosimilars









and their reactions




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is not stifled















threatening






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between biosimilars













develop


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With respect to























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prefilled syringes


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indication




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bioequivalence























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Another question














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managers








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voice























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2009


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decisions











andor ethnicity



behalf of NPAF


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Page 85



panel





















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panel Okay




MR CORS Thank you


welcome



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investigators say














of AMD






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Page 90







seniors














at risk



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Page 91







money









mistakes








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panel









we have provided



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because -shy











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1014 am)














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attended






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helpful




















-- there we go



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that you have done



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with confidence






















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drug


















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monitor for that







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Thank you



panel




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patients et cetera









questions






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comments on that










identify it









University



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consideration















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the draft guidance














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clearance














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should be high


















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switching






















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test product























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alternating














consideration



or two questions




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specific domain


















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future























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areas
















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prescription









for these products












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dispensing













Sentinel Initiative







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opportunities























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biosimilar pathway









products







developed

Thank you



panel Heidi


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much





















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guides











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names and databases















what context





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products










Esposito



out of time




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Page 135








would be helpful







for your comments





today




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well









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decade








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interchangeability





















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products










impossible to do












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the NDC























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use












Thank you



panel Ms Maloney





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marketplace





drug








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substitutions











Esposito








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that this is a risk









change it





MR NEVILLE I am not







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integrating them



















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questions













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without that


do that


Thank you



Association








here today




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cost




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in other areas





















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panel



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be considering







Maloney










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questions


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plan











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would be useful





















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pathway
















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present today





















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the reference














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has to be limited






















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Page 162

















Agency







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secrets











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bias








applications










hear them




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panel

Maryll






















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but-for test


questions


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reproduce it











stuff




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reference product









manufacturers













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familiarity applies








issues may apply











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product




question

MR PARKER Sure







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protected




Miletich from Amgen









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stability






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events



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Page 178









are identical












system



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patient safety









products














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Page 182









in biologics











in addition -shy




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be emulated









questions


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that












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Page 186




here




















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help us to evaluate



do that














follow-on biologics


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expected
















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as interchangeable




















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Page 192











important topic










product



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chronic use















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biosimilar labels






















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biosimilar status








reference product







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Page 196



requirements













sources

Thank you very much



panel




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Page 197


















Maybe I misheard






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to be involved









interchangeability













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Page 199














DR ROHRER Yes








those products


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Page 200









unique names








product over time







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Page 201





drift


Marchand

















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Page 202






originator


















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Page 203












you


taken)


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Page 204


(104 pm)



lunch















called Hospira




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Page 205







in Europe













guidance documents




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Page 209

are captured here























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Page 210
























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Page 211













ambiguous











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Page 212
















studies








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Page 213



















panel





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Page 214
























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Page 215
























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Page 216



RampD





Johnson





biosimilars pathway











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Page 217
























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Page 218







avoidable risk

















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Page 220













under this pathway











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Page 221
























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Page 222














occurred








another indication


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Page 223










assay sensitivity














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Page 224











scientifically













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Page 225











panel







are mitigated






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Page 226


are innovating







different















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Page 227













way











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Page 228

















product







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Page 229

clinically








assess them















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Page 230




number or whatever




















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Page 231
























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Page 232

comments




Pharmaceuticals














by FDA





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Page 233


pathway











allow











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Page 234










interchangeability














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Page 235





















used



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Page 236
























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Page 237













question shortly











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Page 238






requirements


















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Page 239











evolve













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Page 240





















providing guidance



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Page 241















basis









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Page 242





manner














an impossible task





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Page 243










and attention



panel







necessary




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Page 244

















further requirement







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Page 245






















questions


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Page 246
















PK data








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Page 247
























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Page 248





discussions



















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Page 249









number of them















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Page 250





determinations
















interchangeability



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Page 251




















differences exist




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Page 252

















other things







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Page 253






in the US system















such pivotal data



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Page 254




products









science











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Page 255





















development



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Page 256
























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Page 257


panel








studies














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Page 258




standard

MR VINK Yes



















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Page 259
























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Page 260
























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Page 261



comments






employee













approach


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Page 262




those




















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Page 263
























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Page 264










FDA wants














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Page 265















products









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Page 266









product















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Page 267












matter












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Page 268









Thank you



panel












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Page 269








or the NDA route




would -shy





clarification







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Page 270









to say








protein







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Page 271

says


interpret


ation of the law

Other


comments


from Pfizer



strategy there













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Page 272











the product













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Page 273
















for those reasons








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Page 274


















and context






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Page 275












section












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Page 276




considered




















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Page 277
























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Page 278










comparators














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Page 279















rational









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Page 280









these days















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Page 281




final document



panel















framework


1

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Page 282

DR FIELDS Right













a continuum






your question




1

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Page 283
























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Page 284









implication







appropriate








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Page 285




gaming actually








and

the













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Page 286






















comments


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Page 287

DR FIELDS Thank you



Novartis company




















1

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Page 288

the meeting itself





















as with biosimilars


1

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Page 289
























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Page 290












helpful












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Page 291


perspective






















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Page 292
























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Page 293
























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Page 294
























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Page 295
























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Page 296
























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Page 297



reference product













panel








1

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Page 298



what is entered





















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Page 299

questions























1

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Page 300

DR McCAMISH Right























1

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Page 301















would you suggest









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Page 302










use




Emmert from Teva










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Page 303
















reference product








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clinical studies









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product










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product







close assistance








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provided











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Page 309


this product






















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Thanks



panel








required









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DR EMMERT Yes














differences



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indications










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DR EMMERT Pardon




got it







approach that





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batch



any of the speakers















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Page 315




drugs





thinking


that






304 pm)



Rader from BIO




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Institute



word Bio Sorry





person company










year




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nomenclature







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Page 318












activations









those



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later in the decade












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these products




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defined or viewed





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panel No Thank you
















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all cases










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the feedback









product





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considered




















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inferiority margin




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inferiority margin








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immunogenicity








panel











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that



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Page 347








today
















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comments











approval pathway










guidance


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included

clinical

section










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351(k) applications





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biological products


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products











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351(k) approval



















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better












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development


















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Page 360



presentation





Association




guidance documents









quality



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Thank you













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biosimilar products








products











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from PhRMA










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draft guidances














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reference product














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studies














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safety and efficacy















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products



















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new application







related












biologics


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nice



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information


















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on these treatments




















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panel Thank you



Illness











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treatments







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safety








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product names












patients need




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panel



International














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expect





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time








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panel




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DR ANUMULA Yes okay


questions


from Eli Lilly








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products


















guidances





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situations























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issue














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the FDA


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panel








that









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Page 398









for another purpose



material




appreciate it








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Page 400





to market entry

















and fair way


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forward









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Page 403


essential
















further on






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Page 404







be the case

















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designed to create























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patients








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is important

















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Sandy





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a good weekend




Page 413


158182122 15914715 16011 162815 1635 166118 1715 1732

abbreviated 12210 1528 1587 18821 23312 3683 3695

ability 3422 7620 8115 997 14714 14719 1909 19112 20836 22121 22913 26511

able 1211 1417 1511 1918 3918 4117 10013 1025 1064 14719 15410 1571 18520 2347 23616 28916 2922 3028



10122 1407 14315 2657 38412


15121 3099 acceptable 6813

21816 2421216 27518 30820 36112 36221

acceptance 802 841 20920 3612 3926

accepted 32312 35368 3549


1519 166814 172 1814 211 2121 221 359 4022 7522 8219 1215 1298 13721 1525 15316 159513 1631 1653 1729 24116 24716 2883 2891516 2958 35617 3759 37920 3822 39111 399721 40121 4048 4072

accessed 131 3564


30920 accommodating



3016 1762 33012 3364

accountability 1761521 1787 18261718 1833 1837



9611 11018

11217 12021 18113 21313 34820

achieved 19710 4001


26311 2642 2651820 2662 33019

acids 26213 26315 2721520 2731218 28117

acknowledge 17522 19216 19422 36114


acknowledges 3094


acquired 1998 act 101819 7719

11311 1362022 1399 15511 18412 2563 26778 32520 3298 34715 36722 38319 399915


1927 2241214 224161719 29421 30517 30612 3127 329101217 34121 3625

actions 12117 15213 15419 2112


2069 2124 21914 25118 30617 31922

32035 32113 3227 3233 3628 36210 3921216 39316 3971221 406571720


9619 972 1258 15418 2074 30420 31219

activity 2658 27712 2798

acts 15512 actual 1169 1632

18415 acute 1711722

17710 ad 1848 ADCC 2951320 add 18414 22122

2264 29017 3623 36413 38812

added 149 195 19514 275611 3924


691 10911 12313 1248 17810 18220 1834 28921 3557 3597 37813 39415

additional 124 13617 549 5721 585 636 6720 6913 7514 7619 12012 12212 1262 12916 13321 13415 1352 14767 15718 17512 1893 19022 1922 19319 2037 21618 22018

2341 2351725822 285212902 2926 29473001416 312223261014 328183311 355151736414 379144052

additionally 136101425 194732715 3773


3918 701410321 1151115116512 1171112619 157151615 19122195615 2221123917 261126413 2821928722 289143045 349135011 351113553 361173948 3973 4059


1386 2741533022 3641237714 40517

addresses 344735112


32518 3261133012 3311533418 3361836621 36853727

adequately 54111629 1741022822 22982641419 33433423 3613


Page 414




111 3121 5310 6520 3366 37421



27322 30720 3796


3235 ADRs 29812


13019 17512 21311 23213 30114 38213

advancements 24114

advances 5513 594 38215


advantage 9212 1171 20713 34316

adverse 1917 5410 577 5812 702 73421 743 7414 754 1257 1251114 14111 1438 14521 1761320 17720 1808 18215

1835913 18519 19015 1911618 1925 20220 20312 29722 3032 3095 3143 34914 3516 36616 37821

advertising 7918 1951113 19613

advice 15119 36018 39321


2936 4021 4217 5017 767 3762 3811820

advocate 220 512 412 7520 7611 8113 18622 18710 3778

advocates 3211 3518 374 877


11916 14816 18814 20418 2166 39019

affect 6917 7914 16410 17310 2088 2758 3459



1372020 14919 24717 4007

afforded 1381 20714 23821

AfPA 16617 1816 2212


204813 2164 2326 24621 2616 2719 30215 3473

37522 3851114 39017 39819


agency 2314 3421 5515 623 6419 6859 721619 7221 74520 753 8611 11216 1192 1484 16217 16359 16815 17212 1733 174310 19714 20613 21213 2135 2229 22314 22421 2319 23315 2357 23610 2381621 2391 2391422 24017 2411113 2484 24815 2859 29615 3102 32520 32610 34810 3574 35912 36814 3753 39215 3973

agencys 119 327 352 5113 726 747 7713 16013 1636 1762 2077 2352 23813 32516 3266 34718 3689

agenda 11161618 135 159

agent 1621 1818 2220 24810 2521011 2620 659 3211322

agents 2521 2616 261818 31922 32035 3227 3233 3367

agents 177


9616 17521 23217 29212 40219

agree 6218 6317 1873 1976 22110 22715 23716 26512 27118 2746 27513 28511 30615


27112 39412 Ahaviah 416

39818 ahead 237 1693

1845 3442 AIDS 37620

37711 aiming 21410 al 221 514 8617

874 2927 Ala 2039 albumen 2181316



412 55616 1518 165 2120 28161818 294 3519 951321 96112 9812 3811219

allotted 136 1418 1510

allow 1814 1914 451 783 1001 13617 13815 13913 1409 1536 19013 20510 2185 23313 23514 24113 2508 36121 36621 4092

allowance 13920 13922 2371

allowed 122 1313 398 9222 1704 1932 2074 21121 21819

allowing 161 4020 4618 847 16618 18821 23322 2784 39820 39915

allows 125 32511 36017 39110

alluded 22312 40916


2642 altering 779


1081922 11319 114119 115212 116613 117313 11714 35020

alternative 1168 1161719 14113 3333


21113 AMD 891518

902 9146 America 49 713


Page 415

282022 3079 3011 9416 952 36717

American 34 519 8310 1191114 14014 25620 4093

Americans 298 314 5211 6618 878 90610 1368 14918


174152022 175811 17722 1786 18612

Amgens 18111 18511

amino 2621213 26351114 2642 2651720 2662 2721520 27312 27318 28117 33019

amount 355 28819 331722 3354


4916 15216 analysis 7613

8117 15216 30612 3813 38610 3931113 3931419 3966 39610 4113

analytic 9910 20116 2024

analytical 26913 271 5617 1181 11821 2278 23212 24410 24816 25028 2576 27719 2921 29310 33011 331411

33115 37019 3718 38515 3871 3883 38911 4011113 40415




56 2722 2816 3811117

andor 661 7017 8419 11019 11319 1141 11713 12218 238814 32222 32518 3445


1183 23517 23620 3317 37112 3875


815 919 818 annual 641317

6614 8712 2996 answer 4615 691

11521 15410 15615 19513 2011 20821 238912 28513 35915

answers 111 816 15412 16815 38717


6169 2794 31818 31911 33526 3369 33719 340218 340192022

34614 3892 antibody 5218

552222 33710 3394 3408 34515


337919 3394 340271820


34045 Anumula 414

385911 39048 39012


1204 1265 12717 13317 1354 1423

aplasia 6522 6815 21822


1517 apparent 16512






19217 23718 3748

applicant 1614 163412 20919 23419 25012 2641419 27416 35121 3546 35522 35711 37214 38818 4018

applicants 3527 35410 3578 3706 37215

application 6919 1623 1633 1641920 16814 1723 2211315 23318 2341421 23612 250313 253810 2595 26417 2681 35213881622 3537 3546913 35415 35519 35717 35919 3739 374347 4001

applications 12816 13018 15121 15312 15920 1601 16211 16318 16610 17110 26513 2686 35119 35910 37320 4025

applied 461 707 7416 10411 2358913 2378 24922 25020 2566 27218 27616 28319 2893 29318 2968 3558 3663 39322 3971012 4067

applies 466 1725 34220

apply 1121 4713

17213 17319 2451919 2512 25113 25815 2594 26317 267216 2706 2824 2953 30815 3101 32121 3439 3639

applying 25516 2679 30416 4043

appreciate 352 505 632 757 9410 981319 10422 120913 1302 149910 1504 15317 1758 20011 21221 24613 27216 3266 3649 376812 3918 39514 3972 39816 4115

appreciated 255 862

appreciates 649 9812 30917 34722 34817 35110 35216 36013 36718

approach 3117 321 6922 10814 1093413 12014 12815 1506 1536 16012 1881617 20616 206192122 2071319 2129 21211 21418 2154 2193 2227 23221 2331020 23512 23937 24019 2429 24813 26122 26612 26717


Page 416

2684 2721517 27618 27711 28222 28319 28715 290921 2959 3039 30720 3091820 31319 3261818 32619 3354 3386 34313 362918 36321 36919 3797 402359 40513 40514 40814

approaches 8019 8516 21415 2346 27616 34921 40312

appropriate 4321 6718 1246 1797 1868 1926 1961315 2082 20913 21017 2149 21513 22010 2214918 22319 22522 2373 24210 26711 2726 2774 28013 28416 2867 28918 31213 3284 33020 35321 3682 3695 3719 3727 3948 4003 4036 40816




1817 326 599 6412 651 686 706 719 7218 774 8217 8322 976 10012 10113 12121

12322 1242 15015 15420 1622 1671922 1688 170520 1735 17510 17611 17813 1825 20620 23822 2651 30056 34720 3481218 3511 35314 3565 37214 38315 38916 39417 39916 40321


1206 16813 17016 25816 2707 28811 29319 35615

approved 221 302 304 335 547 5510 665 6916 788 792 807 891317 915 929 12519 1509 1519 15916 16817 1794 18619 1904 1913 1936 2006 23217 24820 25010 2546 26768 27311 27613 27819 28211 2938 29420 2955 3011 32810 3322122 3331 3397 340468 341120 3448 350921 35557 35613 36618 37311 38312 3983

approves 1533 35416

approving 683

25320 approximately

132 415 6610 1367 14016 3914

April 8720 887 896 36416

arbitrary 4415 26319 2859

area 9419 1076 1478 150221 17211 1746 2127 22116 2224 22719 22919 24919 26622 2768 28820 29018 29614 3095 31613 3312 34813 3868 40217 4091

areas 1228 1503 1518 1546 15919 2064 21112 21222 2161821 22718 2495 2621 29017 2968 3259


24416 argue 22718


33720 35818 3713

arthritis 414616 831 2285 33919 3406

article 8721 2356

2428 26020 32322



2901 29619 37222 38513 39214 39718 3984

asking 4212 635 1731 1741 20118 2454 26919 33216

asks 1816 4422 aspect 199 2613

23712 3909 aspects 11722

1236 2062 2071821 2089 20812 2117 2656 31917 34719


34215 assays 3301

3371020 3436 3431720 3452

assess 1116 2096 2299 24920 32822 3424 34510

assessed 2297 31022 32917 33421 3678


assessment 10812 10913 1119 1179 21014 21231014 21419 2399 2407 2724 30721 31010

33320 33414 33516 337211 33917 34015 35511 36311

assessments 24517 3347 33613 3378 33811 34210 34456

assign 28912 3226


12317 1284 assistance 30716



24810 810 92 951115 2211

associated 332 14419 18013 31019 32317 3393 35313 37112 38221

association 347 4717 519 63 710 119111417 1481217 1555 3608 4027

Associations 30510

assume 30518 3271 3371



35116 assure 8113

18819 2347 2808 30418 3563

assured 3216


Page 417


35115 3542 35522



2255 24310 3329 34634 35622

attorney 15821 2834


1839 29612 3676

attributed 735 1389

attributes 2932 30019 3014

attribution 17613 17620 17720 1808 18215 1835


3176 authored 2354

32321 authoritative


3502 3678 authority 3420




5418 5814 624 6221 1797 1869 3674

autonomy 173 233 2412

availability 11113 15213 35422 35722

available 1010 126 228 539 588 808 812 10410 12616 12917 13210 1464 1553 20310 205616 21621 2315 2348 24817 2502 2545 37621 39616 40013 4021718 4093

Avastin 8881216 89814 902


19117 1928 21719 2844 4011819

avoidable 217512 218567 2197 2191315 22513 22516 23121

avoided 1935 2171516 21915 21916 23116 3087

avoiding 25411

4004 avoids 28526 aware 4717 745

775 145814 14713 18411 2777 28316 28434 2981415 33213 3654

awareness 12610 12713 13015 13111 132519

A-F-T-E-R-N-O- 2041

am 112 82 101 95910 20313

Bb 11318 1726 Babbitt 44 76

3338916 34314 34522

back 147 2919 4910 617 8613 95612 1034 115710 13120 14112 14281981618202028 204462832 2936 3009 30018 30133097 3151438015 404840612

background 276327610 31611

backgrounds40810

backup 29511bad 1613 2519


11618balance 21314

24220 28133544 357183682

balanced 1619 11517 18819


3997 barriers 4814

1216 22613 4004

base 3013 3068 based 177 4412

6011 7916 1116 11181221 1143 1205 13822 19418 1952 19816 20422 20819 20910 23611 2381122 24211 2456 25320 257715 25816 26317 2732 27417 2769 2776 2923 3048 30717 31420 3211114 3361 3391 34420 3514 3693 37118 39217 3944 4044 40722


10114 15022 25920 2828 32212 35816 39810

basis 6713 1622 20222 23318 24115 2541 27319 27415 28714 29813 29967 31012 32812 3513 37314 3861 38819 4015

40212 Bass 36 62 14810

1481314 1548 15421 1554 1567 157422

batch 309712 31456

battle 2019 2317 2413 2865



7519 8422 877 1549 1591 26110 32413 3339 3476 4107


3892 believe 127 295

337 4219 4319 4514 4722 5113 6317 6422 705 759 100691410015172110157 102310 10215 1046 12513 12711 138210 139914 13917 1406 1454 14914 1516 1576 15911 1603 16417 16817 170317 17117 17611 17715 183711 19719 20510 2136 221914 2339 23415 2368 23747 23819 2395 240112


Page 418

2417 2434 25122 25219 253717 2558 25611 2571217 2581420 26011 26118 2621114 26512 2683 27411 2755 279111722 28714 31416 3813 39216 39418 4086


7812 8312 843 849 17511 20813 2122 26611 30512 3489 3492 36821 37011 3711420 37212 37316 37412 37712 37914


9817 10415 1366 1382 14818 14921 15214 1892 1908 29111

benefits 787 1367 14822 1494 24015 24122 37621

Benton 146 41015 best 243 3417

3817 481515 5620 8511 13721 19720 2348 2737 27414 34312 3775 4001 40322 41119

better 5611 8518 1194 1349 226161718


2712 315 639 10546 1467 3033 3788 3827

bias 16322 16419 1662 17310 1744

big 24214 36015 3862


31316 billion 3016 1371

15221 1532 292811

binding 3064 31119 31216

binds 3129 bio 31520 3165

34715691620 3482917 3492 34916 3504 35110 35216 355214 35614 38520



2247 bioequivalence

721 1018 3869 biogeneric 25220

2548 2558 2566 biogenerics 24719

24822 24922 2504 25113 2542 2564 31412 3153 31914


biologic 31 516

1620 177 2220 2510 33219 3910 4718 5216 5619 5816 659 6612 77722 8813 9146 926 927 951422 996 1022 1033 1035 10412 10510 10611 113111421 11420 11534 1208 12221 1373 15210 159917 1753 1783 1801317 1901320 1924 1921517 19356 1951 2006 2472 2529 25467 2895 29311 30311 30412 30622 3142 32421 3253 3499 3555 3782 37871218 3799 37921 38222 38319 38421 3993 40315 40714

biological 178 1868 1915 2010 2218 5622 583 821221 1206 13712 1496 1513 16118 1676 19919 20020 24917 26216 2643 27817 28015 28313 28414 2851820 29116 30520 30712 35322 3597 36113 369618 373818 37322 38411



916 1018 171 171718 182 211118 2236 231 3315 398 41610 4458 453 539 6219 657 7718 9012 9018 911214 9617 971115 10211 1031120 10411 1238 12613 1296 13612181921 1376 13817 14015 15115 1526 1761622 177311 18019 18115 1829 18822 19214 19318 21120 21718 2366 24117 2424 24513 25017 2522 25311 25519 25616 288391516 29220 29319 29416 30120 30218 30310 307512 33920 34714 3491920 3586 35910 36322 36520 36722 36912 37422 3779 38078 3834 38613 39210 39316 3998 40013 4045 4056 40815




3161318 3173 31714 31918 32220 32416 33310 37315



biopharmacopei 3245



1015 181820 1922 3320 3422 357 4318 5112 5414 5619 5815 6215 68412 6912161718 70616 7117 721720 734 755 77416 781 7811 791 8056 8014 8314 841 905 9119 921 921015 933 976 10011 1019 1011319 1022 103344 10510 1061021 1207 12214181822 12321 1241 12519 12619 12710 1292 13019 13215 1346 1433 15315 1541722 1591020 16015 160822 16136 16181920 1623 16211 163412


Page 419

16317 1668 1681416 16913 1691618 1705 1702022 17311 1732021 1765 17925 18018 1824 1861418 187215 18916 19123 1931416 194271520 19559101418 196614 1979 19817 20216 2033 2052459 20617 20720 2089 20916 2102022 21214 21212 2135 2201820 22218 22656 23221 235410 23711 2404 2431 24520 2467 25013 25135 2577 2595 2627 2641517 2652 2651017 2667 27122 28816 289720 29010 291617 29358 29311 29411 295722 29616 2962122 29911 29913 3001520 30234816 3031418 30438 3041117 30520 30616 307722 308817 31221 3141 31722 3201315 32110 3232 325513 329913 33312 33315 3341 3351719 33810 34171422 3446 3457 3467

34910 350913 35020 351920 352261422 353314 3558 35711 3601116 3632 36411520 365151921 366517 36720 3683 36912 37046921 3715 372114 373410 37412 3741415 3759 3781318 37921 38312 386415 3861920 38711 38717 3911018 39291822 3932 39317 3943410 39719 4035 4072 41015

biosimilarity 1021 113 516 10812 10914 110479 11015172022 11123615 112151822 113346 1145 117679 11811 118131518 15771619 18818 198810 19925 21622 2173 2349 2373 2371619 2381 23816 2405 2429 25719 25813 28012 29110 2975 299421 30620 30818 31111 32145 32519 32710 3282 33821 34820 35511 35922 3617 36311 3754 38311

38518 3962 39711 40112

biosimilars 117 92 111114 176 1713 18211 251 3119 3269 33315 3512 4214 434811 45357 47618 507 513415 54610161719 551217 581016 59369 618 6214 6311 6412 65113 66689 6621 701112 719 728 77614 7721 782713 7821 8018 8110 8251018 8322 9013 9112 931 961117 977 9811 995 1005 10121 10211 10320 10526 12022 1211922 122611 12320 12414 126810 128371216 1295714 1434 150916 151712 153410 1544 16414 1717 1755714 17617 17718 178113 17813 179718 1802 1846 1868 18717 18820 18918 1904519 19111 1951415 19521 19918 20111 2021 20422 2051 20620 2111922 21613 2171422 22010 2258 2314 23513

24120 2423 26411 2885812 2881922 2905 2917 2929 29811 3011119 3021921 3037 30310 3058 30812 30921 3122 317720 318814 319713 32022 32322 3266 3325 3368 34210 3472021 34811 34919 35616 35810 36113 362914 36921 370112 37618 3771516 37915 38029 38116 383321 38322 3844 3898 391911 3991617 40011 40311 4055 40719 4093



biosimiliarity 2371


biotech 18122 39135

biotechnology 22 415 728 819 964 17421 17519 18119 2165 23211 2434 26112 31617 34622 34751011 3569 3913

biotherapies 15913

BIOs 35218 3576

BIO-member 3566

bipolar 3824 bit 2120 3711

4822 7417 1055 11418 1305 15713 16713 16813 1842 185211 23018 25911 28322 28813 2993 4022 40317

BLA 16118 16214 163216 1904 2007 2206 26720 2697 27015 32115 3303 3511215 35117 3525 354812 355720 3563

BLAs 16319 1667 2685 32115

blood 5311 3185 board 40314 4045 Bob 914 1685

2238 bodies 3312 404

459 6113 2181 22521

body 552 9719 984 1119 17013 22521 27712 3064

book 12316 13116 31615


119101213 1302211 1331 13320 13513 1884



Page 420


27816 2796 Boyle 217 59 502

50410 60410 6118 62822 6312 641

boys 986 BPCI 1019 112

11311 11411 13616 2563

BPCIA 15912 1621521 2489 34715 3484 35120 3523 3532 3543518 3681817 3694 3752 40522 4109 41118

BPCIAs 2682 3561


5811 6220 662 7914 824 10412 15219 19119 1941 24714 2515 254717 25511 2944 29722 298256 31322 3496

branded 320 620 13118

brands 2521010 25517

brand-brand 25212

brand-generic 25212



382616 3852

bridge 2936 35315

bridging 2082 2373 2771022 27857 32611 3531216 39217 3954 39610 39720


27214 2811011 2821622 28319 2842112222 28511 2862

bring 289 3118 9121 1361314 23522 24120

bringing 2417 1523


8722 1943 20710 2134 22717 3223 36816 3757



15821 brochures 812


40413 Bruce 44 76 3337

33315 budget 2812 build 4213 4519


22710 25414 25511 2806 4017


2046 but-for 1681020


CC 26 316 615

21710 26143301618


calculate 111111121


26615 277327917 32310

called 225 294 464 7219 1112 1113 131151658 204202775 3102 3182

calling 732 31713 32219


8312 132517616 1843940713

campaigns 841012713 1311118417


281617182129461012142915172021

3036691319 302021 31479 3110121314 3218 35101019 386 8220 835 88112 8913 9020 21016 2283


2091 care 36 62 4022

4215 441820 481415 763 773 8116 8822 1192122 14811 14816 26113 35611 3764 38413

career 1362 16516



10920 11010 1195 21720


918 1127 1135 11421 15115 168127 1941 19722 21717 22417 2294 2331818 27319

27319 2741515 28412 2871515 29311 3072020 3089 3095 3101212 34218 34415 3881818 39210 40144 4047

cases 6615 714 7618 8722 2191 2312 27520 2867 31014 3143 31810 33014 335202235613 35917

case-by-case20222




3303 33519 cause 3068 3110

3114 6819 21821


2071 38320 cautious 3117 664

1506 1535 15710 26612


29213 CBR 42 75

3241115 32516 32639 328717 3293 3309

CDER 81922 93 26714

Cecil 33318 cell 179 2619


Page 421

6522 6815 9715 21822 2644

cells 1710 9711 2643 27012


235511 8511 916 8715 3764 37616 3816

centers 8417 11922 34711 3767

certain 1217 391 11416 1745 189415 19219 21720 22717 2981 32517 3271416 32918 34719 3636

certainly 157 2916 404 6719 744 7721 827 873 9214 949 1331521 13617 138513 13967 1403 1414 14614 17710 1871 1915 2003 2144 21810 23417 237118 23921 24221 2442 3874 40116 4058


35414 3575 certify 35410 cetera 1027 1045

1069 1271 14520 2907 2948 3883

chain 1007 17617 18017 1827


1776 21411 29122 34112


331 567 7621 12416 1756 17815 1826 2143 2435 37111 3788 38221


2138 21516 3467


614 741 1041 14121 14322 14512 1473 15199 21937 2593 29320 29419 2955 29912 3674 3741

changed 601416 1518 40313

changes 4310 5313 651422 7210 7317 746 9717 9838 10310 1337 17511 1774 1981519 22514 24516 25018 266111317 2831 29115 2934 29789 3001517 3016 3205 33019 35913 36913 39520 40313

changing 14121 14122 1421 19820 28222 37711


30012



characterize 2641419 26511 32211 3588 3882 38910

characterized 26514



10613 cheaper 3212



2303 30419 37015 38610

chemically 9710 26218 2633 2731 37718 3789 3869


510 6435 744 7419 7513


2816 13522 1908 20417 2165 2328


19722 26915 27278 37920

choices 7815 37419

choose 7915 11212 20920 26818 3284


1072022 1081 11016 118522

Christl 117 912 1865

chronic 411 6511 764 8368 1939 37710


7119 1657 32522 33514 3374 3636

cite 8718 903 32321


15411 2203 claims 1463


1893 2065 21112 21222 2137 22320 22422 23817 2623 26917 31411 32510 3289 3312 3336 36118



19218 1948 19849 19912 20914 210112

2117 21214 2574 3271621 329111522 33018 3319 3554 36222 36358 3645 37317 39311 3979

clarifying 1311 3293 36217 39011

clarity 17512 1927 19310 19659 2649 28422 2852 32521

class 2013 26715 397 554 938 17711 17820 20516 24722 26814 27821 27914 28018 3217 33120 4002

classes 2681719 2695 27818


4277 451418 6911 10615 1095 1144 1252 15720 16522 18718910 18920 19114 19316 19416 1977 20219 2067 22089 2316 23820 23914 24512 27818 28210 286412 31013 35913 36918 4088 41115



Page 422

12521 1321317 13620 1791 1894 1946 1979 2587 26615 3463 3507 36222 3638 3646 39312


3251 34321 clinical 1819 193

202617 2749 333 356 3622 3791216 381 43419 517 5320 541617 561619 57119 5814 62210 6712 6910 9113 963 9911318 9922 10011 10112 1037 1067 11317 11481315 1182 1381122 1392 13918 1642 1692 1775 1871213 19417 1996 20116 20251114 20511 20838 2101314 21418 21514 21721 22251013 2235 22956 23517 2361821 2385 23814 2391316 23919 24022 24213 243319 25314 257917 25921 260613 2791 29120 2923 2936812 30220 30313 3041522 3055 3072 3101422 311161317

31222 3252 3261921 32779 32720 3281013 32916 331719 33320 334714 3355815 3363 3361218 3372 3371822 3383 3396 34015 34114 3429 3451420 34611 3501522 3512 36510 37016 3711920 3725 372612 37811 38369 3861116 38618 3871214 3871522 3888 3881113 3895 3935 401718 4041921

clinically 704 22221 22316 2291 2451 30022 32722 33410 3381722 345912 36110 3698 37013 371622 3885





2426 2453 3024 30716 4096


21217 28014 closure 6812 697

741


3137 codes 71355

1331416 14520 2524 31361416 3131617



4026 colleagues 871

13414 14713 26021 36516 3761

collected 6520 7614

collective 768 1805


2722 2861718 294101420 305 317913 35919

colonoscopy 38016

Colorado 8711 32417




39313 come 1919 2911

35818 9214

936 10220 14016 17118 18515 19219 2701 29315 29421 3768 38614

comes 422 1419 14318 22920 24715 26021 29413 29816 29913 3814


coming 25912 29610 3013 3177 31819 31915

commend 1520 13941220 34717

comment 103 142 1441221 1516 162 378 7311 1052 1087 13422 14510 1469 1701 17417 1836 1884 20611 21416 22513 2455 25722 2588 26019 27117 29718 32514 343810 34415 34821 36410 36515 37518 38115 38517 39220 39714


commented 21321 2357 23912 34512 34721

COMMENTERS 410


1321 154 161 2718 3521 366 3616 381516 408 4621 4913 4921 5920 6219 63122 7313 75819 7711 8421 852 8720 9311 942 10419 10422 107217 11719 1198 1203 12921 13322 13515 1421821 15320 154116 15721 158216 16613 16622 16757 17314 17413 17515 1821214 18318 1886 19619 20012 2019 2038 21318 2144 21521 2161518 22510 22911 23119 2321 23412 23712 24312 24421 24618 24968 2571 2598 2611 2613 2681114 271614 27219 2745 2753 2816 2819 28622 28782021 29715 30212 31069 3119 33021 33212 33320 33513 34212 34620 34815 35017 35218 3572 3584 36513 36711 3681215 3751213 3769 3819 385613 38919 3924


Page 423

39716 39814 4059 409712 4106 411416


279 979 16416 commitment 1417

20515 21314 247151821

commitments 32822


421322 45119 4613 32311


532 654 7920 1781 28517 30819 30915 3296

commonly 256 24211

commonplace 38414

communicate 1791

communicated 9318

communication 7216 12113 12722 17616 17811 1804 1827 18320 1861116



community 4510 47111216 4816 656 664 803 81213 8456 1192022 12912 1428 30821


245 4016 4216 443 8822 964 1482122 1557 15813 159710 15915 17421 20617 2167 24515 2806 28317 2845 2877 32422 34710 3567 3589 3673 37315 3913 3971717 4008 4089 4092


619 891011 10015 1117 15822 16535 2041922 2311 23211 2347 2471112 28412 2874 29616 30016 31610 3902022

companys 2255 3917

comparability 1981521 24514 2911114 29311 29317 29420 29526 2979 3275 3631012 3951418 39637 39618 3985

comparable 1649 31217 38913 3907


23620 2399 32813 33011 33515 336112 3388 3396 34014 34117

342919 37014 3726 39418

comparator 13916 15920 1601517 16018 16111 1678 25391216 2543 2553 2727 2728 2778 3521421 35320 39122 392712 39216 393616 394922 3954 39721 39823 40818

comparators 27711 27810 39221 3955 3967 3971112 3986

compare 1124 11622 16110 2529 33618 38912

compared 1210 183 7913 3402 3516


1605 1617 19818 237910 2889 29220 35213 3535 3953

comparison 11121 1129 20214 257616 3056 32814 3315 35921

comparisons 6712 34618 3941416



7718 1491516 15279 34715

36722 3999 4079

competitive 39918 40017 40522 4092



7812 9122 1279 completed 13018


2443 33721 complex 178 439

538 826 9114 978 1381718 1496 18020 1815 23216 2365 2399 24920 28120 35321 37721


complexity 187 12817 2367 273421 2841 28521 36911 3831

compliance 12515 3542 35522

complicated 27314 2801617 3598



4820 771215 1222 1674

components 1212 35012 38219


554 8416 compound 395

26011 3076 compounds 6816


1713 1913 4316 19519 26619 3179 38310

comprise 9010 4036


25813 compromising


10922 110212 11418 11711 16322 20015 2305 2402 2755 27510 27913 2916 3023 30318


1103 1649 2345 27710 3025 39513 39710


74131518 1061019 1079 1146710 16321 22215 22920 23013 2602 27715 3077 3584622 3632 36821 3723 4077

concerned 375 613 6218 672 706 15013 16011 1635


Page 424

166116 29910 34520 3462 38021

concerning 4718 6411 31916

concerns 2312 5715 5917 946 948 1442 16213 17166 19912 21820 2201 22211 27715 3531 36617 37613 37713 4051621 4098


1174 2253 concluded 25116

41121 4123 concludes 3426

3971 conclusion 143

10413 14717 24116 25610 26022 3566


11314 16722 22315 3423 35614

conditions 2112 2113 2520 6913 8337 16911 3996

conduct 7220 17615 21010 2376 24020 2446 3123

conducted 2074 24113 3056 32731217 3511 40422

conducting 31117


17922 3587 36415

confidence 8321 10012 11116 1137 17513 35313

confident 9921 16915 36411



configuration 30018

confirm 22517 22712 26718

confirmation 22811

confirmatory 293913



1928 25222 25919 26012 294213 30822 34922


16413 28518 31578


1933


consequences 524 651617 72813 7215 7319 35721 36915



4613 6213 753 8313 1227 12412 12835 151118 1664 17518 1954 1989 22421 23417 2392 24113 3189 3375 33911 34312 3524 35518 36814 40211

considerable 14618

consideration 2315 5914 694 7013 738 939 1071414 1089 11717 11814 15715 21417 21619 223314 23915 30616 3084 34017 34722 3489 36820

considerations 1021 113 12817 12821 18915 19213 2092 2107 27122 272410 27412 32118 32515 32617 327819 32921 3308 3348 3383 3507 35318

considered 703

7810 1098 11312 12016 12415 16016 20910 21815 27319 2761411 2781 27910 3261 3334 3423 34816 35113 35212

considering 2416 1225 1547 1921 23319 3206 38018

considers 1223 12815 22116 24019 34012 37312


consistent 12511 18717 20615 20814 25415 2562 26716 26921 27036 27912 28022 2909 2931 39413 39517






2078 consultations


38417


consumer 7717 7816 7947 831021 8410 4077

consumers 475 7720 7820 7912 8020 8110 32015


contain 19317 30715 31810 39117

contained 14622 35918 3784 39321

container 6812 697 7318 741 1014 21710 36320




27812 36320 contents 51 61 71

32515 context 7417

13319 15612 16720 17114 172126 23015 23019 2361 2741821 32218 34216 35118 3578


4519 6420 991 13710 15916 2345 2391 2402 24111 25112


Page 425

39920 4046 4069

continued 506 8921 2477

continues 12015 14213 23910 241917 3751

continuing 12720 1511 15313 19414 20518 2256 35619




20512 36410 4051

contributions 4015

control 712 8417 10921 2183 32018 32122




1405 14118 1435


18510 1866 30814 4064 40917

convince 24415 3466

Cont 61 71




75 3241115 correct 604 1252

18014 1831015 20912

correctly 1521 15721 18520 2462 39413

corresponding 8218

corroborative 16717

Cors 221 514 86171922 874 9322

cosmetic 2676 32391113

cost 189 6416 7710 8118 827 821116 921215 9419 13621 1371719 13911 149620 152310 15213 15612 18113 25619 28920 35618 3802 38815 40715


376 384 13735 1502 24118 2884



24913 counsel 299 912


946 counterfeited



3122 15219 25411 2551 3268

countries 3111 8821 28818 29210 31321 4034

country 301518 878 1041 12913 31318


806 1079 11616 1847 2205 22520 34018 34612 3951 39617 40317


3197 coverage 1214


24912 25220 2554 2647 26920 28611 2902 30021 31418 4051220 4061

created 417 677 21721 3671 399518

creates 14122 3944

creating 325 12811 21611 31419 3682 41114


25118 4061721 crisis 8118 8215 criteria 5910

11020 1181118 19921 26818 2753 2769 2864 30817 34818


critical 77515 7817 842 905 9419 10010 10122 10512 1244 15021 18022 18920 19113 2374 28914 2957 29611 30019 3014 3368 3841219 3959


38012 cross 11522

30916 34119 crossover 11517

1727 crucial 118 4319


2095 CTFA 3239 cultures 179 2619


5717 5910 731 8222 8314 1011620 1056 1224 12316 12511 12615 18514 20111 20221 2563 3379 34317 34719 35817 3668 3827 3882 40917

currently 529 5317 63710 7820 10118 1054 11621 1271 15011 1535 155612 1874 23218 2481718 29319 31614 3229 33311 36620 3672 3798 40312

curve 1278 3286 3622



6013 6620 6910 7122 7613148117 84141810011 101121066 111912422 128181339 1391314422 145222 14771322 15620 1572 160514 1611


Page 426

1621142022 16781121 16813 169611 16912 170312 17013 1871214 18916 1921819 1941719 1996 2011617 2024 2021114 2082 21011 2111 21512 2226 2343 2361214 2361721 23723 23719 23918 2412 2445 2465 24616 2508 25119 2539921 2541012 2553 26616 27720 27855 2887 29120 29315 29511 297257 29721 31114 3125 32519 32611 331567 3331 33520 33713 3388 3392 3419 34217 35125 3521321 35347 3626 3659 36615 3721216 37916 392717 394181922 39524 39720 4019 4034 40411 4051 4061821 40815 40817 41117

database 12422 1338 1857 2967 29810 3161521 32819 32925

databases 1272 1334 14633 2982 3413

dataset 4037


15714 16221 20021 31710

Davis 415 39015 3901718 39716 3981015

DAW 1217 day 124 2019

2317 2413 909 949 9999 1044 24517 2479 365910 40319 41121

days 132 2914 895 2809 28818 2896 3548


2014 2306 39117

dealing 29618 29915 3006 3442

dealt 29415 death 309 3110


8368 debt 8118 8214 decade 6017 6519

13716 15222 30219 31912



928 1049 19017 3513 3689

decisions 4414 458 572 7115 848 13117 1791316 1952

1967 24211 2768 37315 37418




2820 5014 7521 24822

deem 356 1974 deemed 17910

186918 2677 29522 3384


50312 define 1132

17219 17916 1923 1961 20920 21115 24510 26321 2867 30013 3017 31916 34111 3443 38621

defined 2012 268 626 21117 2786 30019 3015 32119 32519 36120 3872 40110



3093 3121516 3188

definition 43416 4514 10817 114310 19920 24422 2456 2625101114

2637 2645 26914 2819 36316


8915 degree 1108

11214 13821 2101 2182 23720 2757 29519 30418 30516 30610 3071

delay 15014 1522 28910 40121


4101 deliver 4117


7317 12520 22514 26117 2628 2661013 26616

demand 24118 2884 38710


5717 10014 1141315 1607 2112 2348 3031522 30421 32519 327510 33615 3616 37012 40416 40621

demonstrated 555 10022 1207 2449 25119 306223 32821 3656 3697


demonstrating 113 837 20515 2215 32912 33415 3985

demonstration 1021 23622 2371618 23815 2405 29110 3282 33820



26511 3812 dependent 30516



1871214 3927 describe 6717

7011 2145 3019 35311 3965

described 11411 20219 2034 22289 30010 3262



1151517 11678 116910141819 11621 11817 12520 2101516 2179 2335 23915 24020


Page 427

2729 2781115 27917 3017 33110 33415 33617 3372 3415 34217 34319 3719


2741 40711 designed 916

24022 283678 32217 33510 36210 4061

designs 10821 11019 11514 11617 11715


2022 32614 3468 38714 4097

detailed 17515 19410 30612 36811

details 152 18718 30714 3643 3847

detect 743 2158 23616 335910 3728



6714 687 15122 23412 2513 33611 33822 39621


determine 3422 582 9912 1098 11120 1512 18818 22521 3798 4013

determined 5819 782 12218 12614 27320 3951 396913

determining 181 23821 25020 3386 35212 35519


5319 6622 7421 12010 12718 23221 24222 31716 32122 3268 34810 38619 3871

developed 546 6521 788 8022 12918 14913 20114 33317



975 11712 1751 21612 2353 26522 34717 34815 37714

development 14 88 1015 1110 5111 665 774 120415 12314 1501520 15111 15311 1668 17420 19521 20418 20519 20615 207620 2081017 2124 21213 21312 2154 23281215 2331221 2375 2404 2416 2467 24722 2482 2531014 25429 25581321 2561 2565 27122 2721 27310

274910 28517 29116 3021718 30220 3037914 304281112 3058 30921 31811517 3241621 3253 32513 3261519 32622 32718 3302 33246 33312 33517 33810 341314 3526 3596 36016 3621920 36720 3731 38117 38815 38922 39118


2661016 devices 921 224

7318 26117 2628 26613



5215 diagnosis 5015




452 893 9847 10145 1557 21721 21815

2191819 22321 22321 24214 25214 26520 28910 339414 34315 3451516 3461011 36318 3679 3787

differences 6811 7014 732020 741322 9221 971819 12614 1616 194912 1951 20219 2031 217568 21711151920 2186910 21913 219162122 22024 2221718 2236717 2241 2243618 22513 2281518 22937 23616 2408 2451 25120 26314 27515 276210 277713 30022 30422 31121 3205 33411 335911 33818 3391 34513 3515 36110 3657 36611 369920 37037101320 37022 3714 3721818 3835 3873 40622

different 183 2622 393610 528 6112 9715 9716 1021 1034 10315 10511 1101019 11219 1177 11861020 12520 12613 12811 13214 1343 13556 14118 14212

14320 1457 16017 16112 17191010 1736 17712 182119 19911 2003 21019 2141213 2207 2218 224151517 2269 2274 23019 23516 23915 251417 252116 25419 259410141516 2592021 26058 2608121322 2681619 2695 2702 27522 27661619 27921 28314 2963 30311 3052122 30718 30912 3157 320447 3234 36319 36716 4021819 40748 40717 408210


differentiate 3317 252511 37414 40619


differentiates 3962



differs 25722 35010

difficult 11412 1421 17715 18117 1876 2106 21411 2211114 2314 23112 23418


Page 428

2364 2808 28111 3158 3223 34819 36916

difficulty 603 1438

digits 13757 15212


2503 3007 39415


7111 25612 3279


directly 4617 4812 16415 24922 3923 3952 4059

Director 1151719 224510 81118 92515 11915 26715 38117

directs 13814 35120


2634 29919 34315

disappointed 15017







747 23317 23820 4013

discrimination 2541

discuss 1404 18611 40317

discussed 3613 1357 1907 2279 25514 2722 30317 35017 39218 39410 40316


7810 1483 32613

discussion 618 1636 1748 19916 22313 22722 2281 23012 2779 27814 30513 31010 3127 3254 33116 36411 39119 39515

discussions 1192 2485 27416 4081

disease 298 411 5020 6511 6618 832 841718 38012

diseases 5017 519 5259 5421 5913 821313 8319 35612 37710



dispense 12612 12910 1497 25918

dispensed 8011 14114 24714 2535 2591618


12118 1237 1247 1254 12716 13611 14017 18922 19115 1968 37421 40919




3222 distinct 544

15115 19022 31922 34913 3502 37413 37717 3844




1924 20019 34918 39312


distinguished 19019

distinguishes 37817




divergent 5615 2138


1421 4914 6116 1199 1353 1883 18912 23119 2497 2738 28618 28720 3486 4111111 41113


3912 10214 10427 10513 38017

doctors 3416 3920 401 889 881820 17913 18010


37918 document 6810

2105 2141722 21615 21814 23921 27219 2814 3644


5414 5915 6411 7310 9320 1505 150121418 15714 1604 17521 19519 20520 206114 20718 2082020 2082122 21168 2132 233416 2345 26316

2671 2711417 2812 28915 3251012 32616 33118 3601218 36469

doing 94311 981520 10414 10414 16516 21415 2295 2914 38811 3897 39614 3972122

Dolinar 31 515 95131518 1058 1067 107318


15222 15328 29281116

Dolph 218 510 643

domain 1105699 11010 11222 1196 3419

domains 11067 11219 1131 1178


2782020 32855 3286 36318


3622 dosing 1722

12115 2211 2918

double 1377 14420 15211



Page 429


28421 2851014 Dr 1520 2316

2420 26412 2781419 3710 4119 7315 7412 871 95131515 9518 1058 1067 10731822 1185 11822 11912 130211 133120 13421 13513 1548 1741618 18221 1836 1844 18513 18621 1884712 18813 197819 19812 19914 20011122 2016 20118 2027 204912 21421 21522 2164 22519 22714 22918 23020 23226 24321 2457 24610 2719 28113 282121 28537 28514 28615 2871511 2984 2999 30018 30116 30215 31016 311716 31215 313811 31320 3241217 33220 3339 34314 34522 36715 37522 3851112 39048 3901217 39716 3981015

draft 14 87 1014 1016 3120 327 353 6711 7010 10910 12011 12246 12320

1249 1395 1501418 16012 2182 21911 2334 25611 26120 2655 2711416 2747 27610 2779 27812 27912 2811 29011 30368 3054 3084 30919 33314 33613 33816 3398 34718 34836 3505 35112 3521019 35317 35317 3601114 36720 3681012 36818 37922 38116 38220 39116 39218 39321 39411 3951619 40210


1956 19879 1993 2001415 2001621 2015 296914



119 23 811 304 3415 3513 3878 391010 3913 405 4313 4318 4511 5319

651420 7210 751 7936910 801 8224 8812 89910131616 9117 92618 991721 10016 1001819 1016 10213 10322 10417 10613 10710 11512 12121 13121 1374 14316 1458 1645 1719 17611 19015 1911618 19312 19321 2365 2515 25211 25310 25817 2676 27310 27711141617 3595 37618 3789 3889 3917 39823

drugs 117 29 93 912 195 302 32312 359 3621 397 403 4322 4511 4718 5422 5816 668 79813141519 801222 81456 8319 881821 892 912122 9289111114 9216 9338 947 979 996 1001 1022610 10313 10412 1388 14013 1414 1439 1457 15218 2288 23216 24413 24722 249314 24920 2519 25239 25619 25714 27614 28016 31421

3154 35911 3771218 3994 40315

dual 1071 1166 due 557 5715

1039 12115 30710 32422 3409 38222 41018

Duke 32 518 10720 1081


34519 dynamics 37915 DC 294814


855 9219 9414 1012 10281031821 12713 1387 1462 1515 1527 153516422 185524421 26043242

early 1315 7216 1236 128211926 207831721 318203303 33113


1021219 36313 3781

easy 18019 18118 2422222 28019 37819


3021educates 877


47211 5017 7717 8114 855 126356818 127121920 1294 13110 18417 18620 3771

educational 4714 801821 8312 8410 30118 3022 40922

effect 5711 796 1015 15014 1552 21011 2216 25517 27716 2793 33017 3353 33610 34011 34520 3779 3814 3829

effective 1615 311 3217 334 372 3718 1205 15015 1524 1561112 1795 1843 2066 20719 22017 2422 25619 2663 28812 31421 35618 37510 3775 3823 39112 4007 40122

effectively 1409 18410 2583 38313

effectiveness 2217 9218 1221 24011

effects 2916 5614 579 8922 919 2408 30520 3066 340192138214

efficacy 181 194


Page 430

3514 375 4320 4512 5316 5412 56718 7913 809 9316 18820 2088 21215 2152 2414 2531 29113 3031321 3051 3111 31222 3276 32815 3353 33613 3393 34022 34116 3424 3445 3657 3679 3701 3729 37221 37812 3808 4015



21311 effort 862 8912

1805 2487 3761519 4058 4111

efforts 3511 506 8114 8320 9812 12010 12814 1759 34717 3687

EGA 360101322 361718 362317 3634715 3644 36471015

eight 2318 497 5613 28710 2929 3307


either 3919 4615 883 11215 1481 15719 1624 1634 1856 18615 22022 2218 23710 24714 2641521

26720 2697 2733 2795 2802 3444 3458 38713 40918

elaborate 2312 4822 7417 1545 15519 16712

electronic 121416 1241820 1276 13110 13412 1464


19014 24811 25010 2711618 27324 27419



2385 elimination 2433 EMA 28922 2903

2901420 2914 3629



302141516 31016 311716 31215 313811 31320

emphasis 20911 2333 24121 32421 32719

emphasize 153 16219 2402 24118 2506

emphasized 6419 9315 15712

emphatically 35916



19611 2089 2503 2548 34914 35615 37617 3801

enabled 23215 25016



494 758 8913 9412 9621 1037 13511 1543 1579 1759 1965 24111 29215 30810 32520 350111 3685 37313 38056


15310 19522 3057 3068 30719 30815 3098 3755



3864 endpoint 21018

25717 32518 3332 33812 3411718

endpoints 32721 328114 3728

ends 1315



2419 enhancements




252 3338 3410 351113 3622 371720 4314 506 5114 5517 9610 1025 1258 1293 1639 1666 1739 20758 21511 22120 22912 24015 2437 29112 33114 35714 35912 36020 36922 37418 3759 37620 37920 38411 39920 4015 40211 40515


182 562 1749 21117 39917 40019

enter 14915 19111


3802 entire 12714

15215 36319



32113 entries 13411

31719 entry 1277 13310


14611 14716 1539

environments 1717

envision 639 1055 11722 2276 2466101112 2998 3171 33518


3192 EPREX 663 6818 equal 462 24121

38914 equally 3722

1523 25512 2663 31420


27816 2796 33521 3372 33813 34116


27822 era 9419 error 10921

13410 errors 1078 1336

19013 19117 19611 37420 4083


Page 431




587 664 906 1088 19219 1937 24815 25018 32913 36022 36916 3991

Esposito 119 820 821 127 13417 13418 1441617 14513 15322 1851 20010 299216 3002 3108 3113

Esq 215 38 56 64


1671922 1688 17612 1781222 1807 1828 19013 19317 30319 30915 34948 35128 36922 371821 37416 40211 4032 4071

essentially 6019 7722 942 1392 14013 1437 1493 19322 3985

establish 3118 3421 5618 8111 15811 22112 23419 23722 24010 2414 2571218 25812 3046 334919 38991314

established 11916 17718 1838 2924 2933 3006 30620 3078 3132 32011 32210 3361 34020 354418 35719 3633 38821 40122

establishing 7122 15810 24819 29021 2994 3004 33817 35922 3795



1069 1271 14520 2907 2927 2948 3883



15010 15619 1692 20517 2192 28922 2901 29218 2946 29720 30112 30219 33119 3667

European 47 710 291 3122 5514 16913 21818 2659 2929 30510 3267 3607 4027

evaluate 242 1188 1885 37019 40222

evaluated 16120 16122 1702122

1711 3533 3933 evaluating 194

2398 2428 33322 3691 37220 3951

evaluation 1116 11820 23511 812 1181 14619 36920 37011 40114



7022 755 1257 1251114 14111 14521 18519 20220 29722 29816 34914 3516 35919 37821

events 4716 558 577 6315 702 73421 74314 8719 1761420 17721 1808 18216 183510 18313 1926 20312 2159 22122 22914 3032 30956 3143 36616

eventually 1598 27322 2787

Everett 35 520 1351621 15212 15519

everybody 9819 14813 18518 2475

evidence 1121 6922 10815 110231418 1179 1281315 20621 23320 23512 2392 24019 2411

24814 2756 27921 30611 3611 38819 3891 4024

evidence-based 1221


2119 23911 24110


17519 24818 3943

exacerbated 33717

exact 5718 6013 1909 28112 349315 3783 3834

exactly 1918 3312 10514 17714 1815 21420 3003 31510 31810 34312

examine 564 38313


6519 1104 1117 11211 1154 1187 12215 12513 131914 146121 1579 1642311 1652 1785 1793 1848 184916 1854 18722 19512 2021222 2097 2181314 21917 21920 2282 2312 23810 25416 2655 27310 27519 27620 277517 27821 2803

30121 30319 32010 3272 328315 329615 3302 3356 3365 33918 3416 37215 3797 39211

examples 2141 22621 2606 2736 27421


26519 3738 3745


exceptions 9119 27520 2761 28321 33522


30711 exclude 4918

5515 22210 2236 22716 2293 2634

excluded 2199 22219 22819 39419


2744 28216 2831418 37337 373101221 37428 37917

excuse 5413 19915 31622


3474 exempt 5511 593


27722 29114 33011 33112


Page 432

35921 39623 exercises 29112


1455 17410 20112 22212 23617 25120 25919 29014 38813 40622

existing 12515 13712 19312 2412 3951822 4037 40510 40718 4084

exists 6310 6911 144711 40618

expand 3711 1401 22915


expanding 1006 3822

expect 3113 6719 20218 3178 38719

expectations 1895 1896 19315 20710 32911

expected 583 1124 11316 1898 3023


839 8916 18121 experience 47813

6319 656 663 79317 1068 1544 16720 1772 2059 2311 2341622 24513 24919 25616 26016 26522 28810111518 28819 29219

30112 30220 3125 33122 3576 3631214 3667 36917 3756 38618 3896 40418


experiences 564 76912 150710


expert 14613 1478

expertise 1754 1764 22919 2306



161 1351722 1365 2255 2486

expressed 145 739


1648 extend 1412

19522 2846 extended 11617

23220 28519 37916

extensive 18910 216141617 23520 28720 29111 36917 3807 39521

3984 40417 extensively 11611

1907 2185 33311

extent 3622 759 12212 1452 15011 17015 17218 18721 1882 20111 2221 23518 31210 3707 3931020 3942



33969 34119 37216



13922 19418 2085 21022 2172 222516 2726 2752816 2766 28717 2931617 29417 2941822 2964 3051415 30679 3128 32916 3515 3614 3624 37211 4053


3213 373 385 561 1383 2538 3264 34814 38622 4111317

FF 317 616 2717 face 549 11011


1787 18014

19016 1929 1966 2066 20814



2541820 facing 1215 fact 257 316

3619 448 7422 8811 9319 945 9615 13621 1686 2204 2233 22920 23016 2374 23818 24816 25317 26312 2661 274817 28019 33718 34221 3581419 35914 36014 3619 3672 38522 38621 39319 40419 40520

factor 8010 26619 factors 1714 7916

11820 1356 2246 30718 3364 34016 34816 3521217 35518

facts 789 815 25415


17917 failures 38813 fair 467 28819

31512 40022 fairly 2744 2893

35720 4045 fairness 422 fake 88811 9017

fall 12419 26816 26819 2695 27817 2847 2966 33519

familiar 1478 1734 24210



621719 6716 9318 17715 20610 23110 2453 2508 26021 2701921 3032 31118 3125 3667 3896

farming 971213 9714

fashion 23322 2449


115 1213 136 1616 1815 192 2215 24161718 242122 3116 3222 337 348 3420 351417 3620 381119 3915 506 5124 5317 547 5510 551117 5722 5813 592 6317 7013 717 7214 7719 789 803 8017 8114118313 88915905 1009 10114 10319 108313


Page 433

1092 110112 11710 12121 12237 12314 12717 1283 12915 1306 13816 15020 1512 153313 1543 159211 1602 1621421 1631520 1648 1641012 16518 16518 1664 1672021 16811 17011 17288 1751821 17634 17691219 17722 1781122 17941019 1801 180316 18148 18120 1826 1832021 18415 18610 18719 1893 19121 19227 195412 19522 196512 19921 2041315 2051418 2067 2079 20819 20941422 21015 2114 21218 213913 2169 21722 21819 219312 22115 2281 22912 23219 2355 24211 2473 2487 2497 24918 2511115 25319 25516 2581121 2618 26391620 2641 2641012 26611 2671618 27214 2731121 27416 2759 2769 2811 2889 2893 29318 3035

30547 3068 30719 3081015 309818 319920 320101221 322922 323513 3272 32922 330520 331416 3327 33313 3385 34122 3427 3431821 34414 3477 3481014 34916 350111 35110 35118 352310 35311 354110 354121619 3553141618 3561519 3582 3601115 36311 364712 368813 36817 3705 3721522 37317 3751 3761215 37714 3781014 3805 3812 38313 38410 3854 38821 3893 39115 3926 39311 39421012 3951819 39622 39911 4003 4012 4021311 40222 40321 404131417 40613 40712 40816 4107

FDAs 12131418 325 5414 7712 7715 8321 9613 1209 12814 15922 16211 1689 1758 18611 1873 18816 20614 2117 2752 3272 32911 3471722

34817 3504 35111 352116 35520 3692 38219 39515 40814

FDA-approved 2489 535 5616 8912 3699

FDA-licensed 1208

FDCA 26713 2687




828 14815 17818 17914

feedback 13013 2132 3311014 33210 3793

feel 1819 1929 207 242 6316 9917 11012 1429 2882 33113 39914 4012 4033 40415 40510


4521 4615 4921 8514 12422 17520

Fields 317 616 2717910 28113 282121 28537 28514 28615 2871


28820 28946 35413 35521



5414 5915 7014 718 9022 2063 20721 2224 2344 26820 27420 2814 32615 32910 37912 3813 3991 40214


finalized 685 1251

finalizing 116 1224

finally 186 2015 2213 231 5813 6617 722 849 895 924 10920 1933 1954 19612 21021 27916 29619 30913 34113 35319 36114 3751 3849 39511


1659 21616 2347 34422

finding 6314 6717 21516

findings 3033 33910 39617



2279 23520 finished 9222

1011 3206 3228 37918


148 1516 164 178 1818 249 473 5713 791 8718 9014 9512 10322 1083 10915 1111 11220 11314 1144 1151519 11521 1176 11916 1314 1362 14421 15421 1602 16412 1674 1715 1761219 180312 18214 19215 2047 2094 2109 22220 2397 24415 247310 24810 24910 262510 26413 26622 27212 27617 28911 31519 31817 3201414 32514 3406 34813 3532 35613 36013 36119 37459 37518 3801 3863 3911


Page 434

3924 4006 40410 4109

fit 12421 fits 10967 five 136 299 6021

7618 289910 3019 31110 31514 3435 3668


13815 21310 2346 27410 2784 40221

flexible 24112 28410 36317 4023


634 6420 7711 10811 1227 1269 12816 1404 1495 15919 17517 17610 18913 2491 29016 2919 32920 33319 3601922 36816 39120

focused 16220 23211 30315 3428


12122 27914 29917

folks 158512 2355 37719 40215 40810

follow 278 378 7411 1061 1562 16520 17114

1722 1865 19312 23011 2602 29518 29813 3628

followed 2804 29416 29612 3359

following 1016 1816 3121 433 5412 6910 7717 10014 1114 11314 1227 13421 20013 2339 2342 23918 29811 32817 3346 33513 34016 37815 40614

follows 4919 11219 2151

follow-on 37117 3720 18822 22115 26723 30218 3121 3559

follow-up 6115 144218 19015 2461

food 1111 6519 2676 27312


31515 4122 foreign 8818 9122

1004 10112 1601516 1618 25399 254311 25714 27714 4081418

foreign-brand 25422

foreign-source


2531215 foremost 5114


12420 1261 16216

formal 33715 33814


12515 former 16512




7210 21710 22515 22619

formulations 5314 1012 21817 30715 36111

forth 8713 1195 17219 20621 2231 24515 28713 35210


21219 forums 1907

20612 forward 1514

1815 4913 5914 681 12011 12915 15312 15710 20517

21313 248321 30118 3103 3152 3269 3481020 35619 3592 36016 37714 38211 3854 3991012 40115 402610 4046 4072 4111418

foster 176141721 18016


found 576 716 7510 9620 1395 18911 26613

foundation 21617 21920 58911 513 318 4019 4113 4231220 4419 4520 479 50312 644713 6417 7015 7218 739 7520 7612 1013 23315 2756 40111


32417 founder 5011 four 115141617

11518 1901 2003 2108 2494 2621 29212 30222 3234 38012 3837 3849


975 19520 2061718 2133 28122 282615

34811 3964 framing 392320

3947 frankly 6212



18011 28616 3816




892 9113 13511 17119 1904 2007 2486 26513 2681 28710 30812 3542 35520 38313 4037 40713 41120

fully 201 3320 7814 9118 929 935 1011 2333 24016 25811 2887 3212 33720 35312 37915 40515



23614 2383 2412 244412 26420 2658 30420 31218 37015


functioning 5220


Page 435

fundamental 21713 22215 2336 26313 2833 35222

funded 2210 32221


19522 1965912 2119 23519 23712 23817 24417 3029 31710 32320 32511 33118 36118 3643 37316 3753 3795 40318 4075

Furthermore 12412 3315 3321 3617 3637

future 1110 315 7713 8315 12012 1211 1225 1284 12917 1324 13710 2416 29210 36819 3731 4091

G gain 2122 31122

3124 gained 36312

3667 game 465 28317 gaming 284413




188111415 19521

Genentechs 18910 19214 19920

general 346 666 20522 21414 21617 2271217 22810 2292 28411 28712 28814 29010 30921 3376 3401

generalizable 2234

generally 16614 20615 21220 23518 2684 27117 27218 2751518 2812 33413 3361421 3531520 4114


1531 33521 3659 36615 40817




8712 generic 4716 710

1613 25111621 394 5816 7935 79810131921 8011222 8145 816 822 12145 1211221 12615 13115 1408 15218 1531 155911 1583 19321 21718

23216 2358 2471114 2493 25417 2607 30510 3233 3607 4027

generics 2517 9216 12317 2471217 24912 3151 37717 40015


314 3415 387 10711 14917 15810 2308 35816


4614 4910 girls 987 give 284 5915

22620 2999 given 134 159

3913 4916 5615 585 595 637 7017 826 10614 1117 11318 11491416 15119 1586 21718 21920 221613 23112 23914 24213 2534 2653 27317 2747 27713 28218 29116 33517 3379 34113 36911


14117 3191921 38717

glad 3973

Glaser 416 39818 39819 4101


58 620 294 4019 4112 4211 4418 479 1005 1007 1107 15821 1895 19210 20421 2166 2375 2471 25111 2531013 25429 25720 2789 3057 3091314 3265 33310 36016 39019 3921213 39615 40611

globally 1962 2807 3503 36018


38514 glycosylated

28119 GmbH 31920

61821 GMP 1817 go 814 1119 1315

1414 273 3113 391 861317 9677 972021 993 1317 13211 13613 1427 15018 18718 23110 2623 2697 3097 3144 32116 37517 38218 3887 4096

goal 9612 2265 2369 2375 24218 3349 34119

goalpost 29518 2961 29912

goals 39921 goes 1312 2422

893 1131 1467 18217 2517

going 218 2919 404 493 6021 617 941821 9817 9921 10612 11120 1136 13017 13422 1396 14117 1522 1549 15812 15918 16414 16611 1701314 1862 1876 24721 2623 26620 2961013 3001821 30118 3033 3103 31810 3226 3591 3791 4046

gold 4042 good 83 910 1522

1613 236 2518 282 4018 645 7517 7820 9516 105172021 11822 11912 13518 14813 15819 17112 17416 1849 18722 18812 20441113 2133 2164 21917 2326 24621 2516 2616 2719 27820 2827 28711 29917 30215 31920 3211 34310 3472 37522 37610 38511 38810 39017 3941320 39819 39822 4011 4121


Page 436

Goor 48 711 367131516


8822 925 11915 1651819


GPhA 39818 40069 4081521

grandmother 38020

granted 3420 19418 3514 3675 40712


13011 1488 1845 2306 2475 25611 26018 2612 2828 28620 38622 3874 39117

greater 4416 577 113822 15011 15213 15913 30513



39015 ground 1119 group 31020 68

621 2257 4021 658 11622 1566 18811 22424 2876 3232 4108

groups 41710 4217 4077


24118 grown 1711 2619

5018 27020 growth 15117


14421 1722 24322 2454 33214 3461 36517


3120 353 3917 4220 5112 5414 5915 6410 6711 6720 6825 693 694 7014 719 7112 725 7310 93720 108713 109210 11710 12212 123521 128410 12917 1505122122 15120 15718 1604 1636 17521 18819 18916 19121 1922 1951215 1951922 19612 205131420 206114 20718 20891319 2105 2116815 2128 21222 213222 2161619 2175 218314 21912 2211017 22314 2252 22710 2282 233416 2344 23920

240321 2416 2488 25611 26121 2622 26316 26412 26551316 266141522 27114 274712 27420 27513 27610 2779 27813 27912 2812 2845 29019 2911 29920 3038 308411 3101 3251216 3262 326101617 32791319 3288 32818 329411 32921 3307815 33022 331159 33118 3322 3349 34718 348141522 3491717 3506 35012 35114 35317 355815 360121418 3638 364468 3731 3791318 37922 38220 3838 3853 39321 3946 395171819 39720 41017

guidances 14 88 101416 117 36614 6716 7010 732 8314 831516 906 12011 12256 12314 1249 15713 16012 17810 18816 189111 2063 2071122 20815 21220 2131622 2393 2646 2679

27510 2825 287813 290211 29011 3036 30534 3091919 3103 32559 331202121 33315 34837 36720 3681013 3681919 3692 38116 39116 39219 39411 39911 40210 4091

guide 432 1245 1311621 20215 36817

guideline 3083 3642

guidelines 327 9422 13815 1508 1759 29014 33614 33816 3398 37119 38817

guides 8317 13113

guiding 1931114 1944 2035 2233

guys 37516 G-CSF 28919

Hhabit 31413half 568 14016


2692022 3093 3454 3881739612


7212 884 12213 1651



3145 3674 happening 3916

16514 3098 happens 259 happy 10416

13413 1486 16619 16715 18718 28318 286814 29712 4103

Harbor 6415 hard 14111 1822


5519 19210 harmonize 1962


16719 25614 31422


36713 HCB 4711 head 20417 2166

30216 38515 4081717


15822 headquarters


33413 health 27 98

2216 4610 5210 6516 7114 7212 775 8013 833 8320 8911211922 1494 15610 25221


Page 437

2678 2848 3474 3502 376611 3771 39922 406213

healthcare 675 7522 7818 8013 1201719 12317 126717 12714 1294 13022 1372021 1383 1401015 14214 1501 1521517 15221 15822 1594 17421 1781720 17918 17920 1806 1911012 19320 24016 29216 32017 34922

HealthHIV 411 37519 3763322 37712 37813 3791322

healthy 216 58 4019 4113 4212 4418 4520 479 3879 38915

hear 1322 3218 3517 386 521 16620

heard 3821 455 85514 865 10620 12713 13314 14222 1432 14718 1855 18721 1915 3584 37816 37910 4009

hearing 1611 86 8713 1012 116 133 14320 1514 2418 6416 87217 958 9613 1585 16218 20414 21610 26111


12922 18316 Heinz 320 620

3021316 Hello 96 help 2221 232

289 43112 8320 8518 9922 102418 10416 1245 12718 12810 1885 1927 19614 23120 24716 24822 2492 37420 3758 38212

helped 25020 25111 3027

helpful 155 6117 971 1023 1322 1358 16718 17221 18418 20211 2035 2117 29012 2911 32512 32915 39117 3965 41113

helping 12020 1223


11246 1496 18021 181611 1875 1973 2181 23421 23613 24117 24819 27413 27621 28844 3041718 3061 30818

3174 3296 34518 3602020 36519 36629 40012 40416 4093

higher 22021 23720 30856 3407 3441920 3455 3461314 38721


2062 21620 3047 30512 3487



35014 highly 171516

7819 1099 1387 1508 160821 1773 21118 2126 22017 24916 2501419 2511 2547 2551 255915 25617 25618 25713 2582121418 2591 26422 2741419 27910 29221 29324 29522 29918 30048 31221 3241 3378 3687 3697 37721 3867 3884 38910 40110 4095


1819 23613 24717



2435 history 447 6815

766 801 34616 38616 38812

hit 1323 1396 23511


3199 HIV 376420

37710 HIVAIDS 3767


354812 holding 8713



1198 2044 2118 23119



2042021 2058 20513 2069 207161722 20813 209322 210815 211411

21116 212213 hospital 1363

1428 36534 38013

hospitals 1068 11921 1413310


3763 HSA 21916 human 193 5311

552 1339 1696 1752 2388 2465 246915 26619 3116 3616 3878 38720 3889 3892 3901


IICH 2371517

26316 26463642 37119

idea 11220 1185 1194 16321 1851617 1916 2869 2999 3991


4069ideas 4915 11015

201319 33316 identical 2617

4313 5817 9716 1691617181789 1891919322 252132674 363223841

identifiable 10212


Page 438

identification 12610 1771316 18015 18921 19114 23515 3493

identified 10219 1609 30110 3732 40517


30911 32029 identify 102518

10712 1296 14719 1614 18521 1909 19921 3097 3145 37019 3714 4004 40921


IDF 501313 5110 549 563

IDFs 51311 5413


20419 illness 413 765

9210 3811319 38122 38415



196 2621 502 5012 527 33411 33818 33914

immunoassay 34010


immunogenic 3033 3632 37113 3831

immunogenicity 2712 681920 994712 21013 212710 21419 2151517 22021 22413 2271921 2284921 3074 30761021 3081 31010141921 328161920 32915 33321 33417141621 33551620 3365 336131619 3373712 3383 338811 339710 33921 34015 341518 34259 34219 3432 344512 34513 36315 372521 38311 3876910 389115 40315


immunoglobulin 52141821 536 53718 5415 55161116 5610 5710 592 597 62813 631314

immunoglobulins 538

immunosuppress 2283

immunosuppress


3366 impact 157 5315

6620 8219 838 846 951 2887 3364

impacted 39312 39318 3943




1407 24017 2653

impermissibly 16311

implement 10912 15314 15912 1765 17722 2375 23922 24112 3688 3752 37811 41118

implementation 1017 111 12010 1235 1267 2066 21315 2489 2492 25615 26119 34714 3554 35620 39912 40021


implemented 1914 1295 17221 24013 24217 2438

implementing 507 805 17914 1916 242115 25617 3484 4108

implements 36817



17817 218812 26521 2728 3957 4086


32110 implies 3087

33419 33620 imply 15717

34911 40615 implying 1788


9315 1776 2336 2653 3094 33321 34716 3925 40114

important 181 20916 2614 272 285 32814 3222 374 3811 4222 4619 4820 561 7018 786 80320 856 8717 904 938 9421 991114 1051220 12019 12514 1274 12913 1329 1332 1383 13917 14917 1637 17518 1762 1772 17816 1791116 1806 19211 2002 20516 21312 22015 22311 224913 22812 2361 240112 250122 25328 25613 3257 3264 3346 336815 34121

348415 3541 358621 3592 37115 3801 3831017 38416 39512 39821 39913 4012 4033 4049 40720 4087 41117

importantly 3721 3722 1225 12613 2409


1064 11412 11514 14012 1646 23646 24219 3798


2266 3774 improved 4610

773 785 22011 3452

improvements 1348 29922 3007 35611 382812 39922

improving 5014 7522 3829

impurities 21811 30710 36322 3899



16310 inappropriate


40120


Page 439



32820 3297 3432 34419 345615 3516


incidents 3113 6614 3394 34017

include 71713 8414 8513 10814 1213 19022 19313 20015 26217 26617 29714 33018 33522 34115 35018 35121 35315 37014 39212 39414

included 12418 17921 3348 35014

includes 1911 3314

including 1113 1219 222 532 589 7118 7917 9113 11722 11920 12022 1357 18915 21321 2191 2355 2407 2423 2917 31911 33119 34816 3758 37710 3935 39421 4009 40719 4084






5413 incorporation


1788 increase 8121

8320 8818 13712 16113 1777 3893 4083

increased 444 558 6820 1809 2191 2784 33417 33617 3421520 34316

increases 383 15913 34412

increasing 15211 2884 40715




IND 1406 28821 3273 3291 33113


index 110151722 11123 11222 11334 11767 117131314 1181315

Indianapolis 39020

indicate 686 7414 12322 1242 13213 1871 21912

indicated 612 12521 13218 1938 36616

indicating 354 9320

indication 691520 1391221 2226 2222022 2249 2273 27517 27620 2773 28013 306710 32811 3321722 33910 344910 34410 3721317

indications 535 13922 1401 14616 1941617 2113 2172 2767 2761319 2772 29418 2971 3012 3051516 30522 31214 3218 32810 3291618 3398 33911 3409 341220 3508 3514 3614 3624 4053


10020 24413 individual 191517

5320 6319 1221720 1231 20612 33121


4017 518 5222 6110 9019 18420 38915


28913 16517 20710 2139

23722 2434 3173 32222 32311 3269 34318 34622 3475 3506 35317 38619

industry-grade 3174




infection 444 5221


inferiority 33420 33612 337716 338115 34310

influence 18415 224719 22721 3316



72 115 5811 6520 711417 748 7719 7813 804 9916 10010 10013 10210 1239 1244 1252 1255 12619 12746 12916 13021 1318 132121719 13321 1341215 1352 1511 15621 1641821 1697 17911 19216 19317 1953 19989

20115 20234 2116 2317 2545 25416 26014 2904 2947 2974 2987 30010 30916 31122 3161717 3172 3174510 3222 3231820 3243 34418 35018 351813151721 35225 35316 354711 3564 35718 35820 359191418 36417 3658 3776 39117 39522 40413 4052 40719 40915


informed 402 458 571 768 7815 3272 37621



21914 25118 30617 4068


inherent 187 331 4317 13618 38221


29922 initial 1017 9613

12010 3484 initially 1031214

3979 initiated 1565



Page 440



2591620 26088 26012 294147 29491214 2987 30816 32213 40610 40768 4082


652 29215 34715 36722 3686 37314 39113 3999 40813

innovative 7718 8516 9213 964 159617 1752 18018 23210 2671922 2686 29217 3567

innovator 431318 443 9211 1401 16220 163216 16319 16521 18919 190220 19112 19220 1949 22020 22522 2362 2592 28015 32121 34919 35020 35415 3587 3786 3921113

innovators 13910 17116 2261 3758 3863

innovators 1633 16312 3525 35919

INNs 2525613 4061419 40717


input 1013 119 682 10816 11310 1201214 1921 206811 21414 3689 3731




901722 1509 15115 15755 3083 33221

instances 1728 213610 3306 3998

institute 41 73 15217 31627 37814






27115 2753 2917 31419

3275 intent 2381318




2483 intercellular


1921 2711 3713 436 4421 4517 516 6216 672 6710141822 6847 10220 1081722 11310 1146 11513 11712 12210 1243 12611 128811 13122 1385 1393 14010 1422 14313 1501719 1511214 15511 15513 157812 15718 18747 19811 199211 2111416 2171 22014 22112 23012 2341013 23420 2381 2466 2491114 2501621 2518 2533 25719 2583 2593 28012 28718 2901819 29316 29318 29546 2966 3086 3322 3481319 35512 36120 36216

36622 3675 38321 4054 40616 4071011



interchanged 14410

interest 14510 1513 1618 13014 2256 2351 2478 35719

interested 118 143 151 5110 8510 1309 13317 1595 2331

interesting 129 246 21812 3451 41121

interests 3544

interfere 921 349 488 40521


42414 618 75 76 293 5518 25114 324211 32415 333810 38510 4066 40891212

interpret 2106 2641

interpretation 10818 20815 2135 24315 2713



11022 17819 37715

introduced 3512 2178 2469 3052021

introducing 9221 13010 28919

introduction 17917 1846 2422 3409 37010 37617 38518



Page 441





541 10478 1683 1737 18518 19721 1982 2998 33312 3447

involves 1103 2772



3482 issue 1113 285

347 3610 3918 455 4619 494 7111 8119 995 1028 1039 10512 11711 1383 14419 14515 1466 1473 15016 1602 16513 1686 17434 1912122 1956 19810 20014 2014 21946 2231321 24910 2501 2511 2527 2533 28813 29421 29711 3269 34916 35515 3576 3912021 39224 39221 393114 395710 3996

40315 404921 4057 40725

issued 1016 20514 21221 36813

issues 27 98 1014 2416 36513 435 4510 4717 5021 5613 786 8020 8121 8215 1059 10915 12116 1479 16216 172913 1892 1915 2012 2212 25221 26714 27221 28115 28722 2907 29315 3007 3082 3096 3144 31915 3223 32420 3252 34721 3488 3495 35114 37614 39119 40312

issuing 30918 3648 39116


JJames 31416 411

61215 2324 2614 37518 3761


2162614 January 798 Jay 313 610 2162

2165 JD 510 Jean 32410 Jeanne 74 32418


41021 Joseph 39 65

17414 Journal 8721 887



2384 296345 3069 33722 37211

justified 20921 21921 3613912 3625 39422 40819


3001416 39215 398811

JD 119 24818 41216

KK 11311Kalyan 414 3858 Karl 320 620

3021316Kayla 41012keenly 5110 775

1595keep 1118 1510

1511 861610520 106151597 1732234417 37616

3815 keeping 5514 869

10517 keeps 29610

41015 key 5021 10811

10813 10922 1146 1227 16714 1863 2068 2415 2481518 2495 26315 290419 29121 2923 30117 3036 3258 33820 3488 4011

kidney 219 511 64471317 655 65611 66315 6618 7015 7218 739 1013

kind 9916 1195 13110 13316 13435 16517 20020 2023 24518 31212 3441 38814 40019

kinds 16812 24517 3234 39213


2517 2916 3018 312 3219 339 331118 3415 369 3711 388 3911 4035 4121 4510 492 6013 8515 9017 9118 9771014 98516 994 10213 1039 10514 10613 107710 1105 1261 13115

1323 13419 13817 14021 14116 14620 1558 15615 1651522 16917 17113 1761 1772 18312 19813 2153 22617 22722 228614 22920 230127 2318 2431621 2457 2508 26821 28015 2823 28411 2961517 312913 3157 3182 32114 3226 34510 3461 35415 37716 37822 3796 38022 3811 38220 3845 38613 39320 40216 4041 4102

knowing 447 21515 2577 34322 35716 35815 38613

knowledge 2623 998 1647 23214 3013 31211 3414 3757 39521 3961 4037 40718

known 1031 17520 19413 20524 2125 30613 3194 336410 3417 3471 36210 3745 38011 38814


818 264 36312 3710 471 6121


Page 442

10522 11721 11819 13222 14518 156116 1731518 19621 19713 1983 1994 21320 22512 2271 24314 24418 257321 2586 26813 2693913 2701018 2712 281814 2822 28522 29717 3126 34214 34511 3583 38921 390610 3978 3987


Kristin 36 48 62 711 1481014 3671316

L lab 9015 947 label 12322 12522

18778 19216 19321 194122 2961920 29710 3012


4821 495 7111 7112 1029 12319 124211 12518 13218 18661622 1871 1871017 18915 1921315 1933 193111314 1945812 1953 1957 19669 200131520 201101222 20221 27918 28010 32313 3492 35051318

labels 457 19316 19322 194215 19420 1955 2021 28011 37820 3843



lack 1242 1586 34917 38413


2138 33010 37318


9212 978 1693 27113 28119 3081 3199 3383 38222 41018

largely 27115 2835

larger 1719 11117 13819 28117 2841 33510 4108

largest 281922 296 9012 11917 2471011 27715 38120 3912

lastly 1403 23321 2969


16322 1641422 16520 1682 2587 26120

26222 2701522 2713 3545 35620 35713 3932410

laws 1286 35719 lawyer 1691 lay 831315 845

38019 3811 leached 6816 lead 489 1774

2204 2244 25011 25922 26012 35419 35720 3811

leader 1594 20421 26112 37619 39021


17421 1752 1763 2053 24721 25619 2865 30111 35422


25614 2892222 2903 29218 31422



221317 26416 27014 3531 393818



35615 39913





16914 31022 3121 4048

level 42191321 452022 465 4920 8514 9713 13821 14320 1459 2421317 24322 24414 24819 2725 27413 2762122 27939 283114 40710

levels 2022 21014 27921 3066 34412 3892

leverage 1544 3796


1981921 20021 35310

licensed 6712 691214 8917 915 12819 1606 1609 161918 16214 16316 23621 2372 2547 2771021 3264 33218 3521421 35345 3538920 3612 3749 39122 3933 39415

licensing 1622

licensure 5321 2468 3293 3513 3695 3745

life 196 4610 5015 6517 779 838 14918 2994 30410 37711 3861


3568 lifetime 3020


729 765 8213 light 1720 1036


2221 2309 likes 2238 likewise 164822

40618 Lilly 415 39016

3902021 39129 39412

Lillys 3915 limit 17018 1969


13389 1858 3717

limited 1112 8416 997 10114 1269 1381214 1612 16219 17516 24117 2883 33714

limiting 23110 3495


11014 24511 2647 27215


Page 443

2811011 28217 28222 28319 284271122 285111 28628 3085 35814

lines 373 9716 1665 18011

lining 1438 link 1925 1996

34515 list 149 1714

9619 10215 12315 1299 38922

listed 219 2212 31816 3488 35316 35515


14514 14722 2631012 28513

little 2120 2312 3711 4822 7417 1031 11418 1305 1515 16713 1842 185211 19911 23018 2589 25911 28813 2993 39714

live 86 4716 liver 2244 lives 313 5521

3774 living 216 58 313

4019 4113 4212 439 4419 479 5019 5211 8118 9711 2643 35616 36912 377220 38121

LLC 4414 76 3338

lobby 10411

local 1104 1112 11115 11221



1322 17217 1856

logistics 12213 12612 12715

long 204 358 10115 1118 25319 30819 32213 3595 40818

longer 1412 313 5612

long-standing 12120

long-term 5217 11921 1596

look 1513 4913 522 5914 681 983 12011 12914 13717 1439 14721 15312 1701214 1721 18122 20211720 2031 20517 21312 2483 2862914 29512 29817 3182022 3269 34437 3461315 34820 35619 3862 4085

looked 14515 14714 22410 2261 22816

looking 2215 948 9420 16811 2275 34217

looks 28610 3454 37610 39719

lose 425 24012 loser 4121


5811 10216 1402122 18321 2303 24611 27813 28611 28814 29015 2939 35822 36312 37820 38022 38210

lots 1348 20917 21412 33111 34618

lovely 4026 low 21518 32819

3296 34416 345317

lower 823 11116 1137 152313 1811214 27622 28920 3088 33921 35618 3801 38914


8921 lunch 108 2039

20313 2045 lung 3112


10515 2851431613

maintain 70127116 1958 1988 28217 309153544 40610

maintained 7016 1596 2063 20721 28519 34610 37919 40310 4063


maintains 1999 20714 39112

maintenance 29921

major 537 557 9015 9719 987 10713 114710 16314 26521 28014 3302 3359 382419 38422

majority 833 14019 27113 2746 33810

making 5122 571 598 17913 18017 18219 18319 18411 19017 1996 20515 22612 24517 2504 3589 40519

maligned 1369 14819

Maloney 24 945 381314 5922 605 611420 1421920 1441 1541415 1551 18213 1831 22910 2597 2601

manage 12020 12311

managed 8822 11922

management 211 36 62 916 5217 7610 1218 12110 1481116

manager 4112 1366 3762

managers 7616 14818

managing 12318 1495

mandate 332 379 3712 2381419 2396 25821

mandated 2441 2488 25318 25412 2555

mandates 25811 3532

mandating 3716 23319 25522

mandatory 1820 266


2073 20811 2338 2425

manufacture 921 931 10015 12818 2631822 3897


manufacturer 1916 5322 557 611 6918 7021 7322 10216 1761421 1787 18261618 1833 1837101218521 2578 30021 35310 3782 3961319

manufacturers 49 713 5113 5911 7220 12822 1416 1517 1584 17111 17610 17712 1813 20216 36717 39520

manufacturers


Page 444


188 1910 5313 5510 6514 661 7211 746 826 1008 10310 1189 1519 18020 1811522 198141518 24516 25018 2541820 2592 2831122 28521 29115 293420 29419 2955 29779 29922 3001517 30156 30714 3144 3547 3673 36917 40010 40217

Marchand 26 96 97 6222 10421 1301 18317 2017820 3018 3118

Marcia 217 59 50210 41012

Marcie 34 519 1191013

margin 33420 3361221 3377 3371516 3381 34310 3441 3988


1679 2873 30317


9117 9215 936 1005 12710 12820 1301620 13210 1371415 14516 1476 14916 15118 18010 2051611

20919 21510 24120 24719 25816 29820 31419 32117 36618 3677 37618 3803 3911 39918 400517 4056 4078 40812

marketed 17514 2666 294815 32319

marketing 72321 789 7924 922 13220 1398 17712 32012 3388 36116 40713

marketplace 329 14311 1779 1847 1925 20218 2424 2481 25520 40020 40522

markets 1508 30222 4095


4818 1672 3572 36513


40610 material 1317

13211 2644 27922 3785 3881 39812


8021 841013 13220


22111 23418 2395 26712 27015 3075



618 2873511 2984 2999 3001 3008 30116

MD 612 mean 2411 2519

3613 3945 4920 62712 6312 8510 11021 11219 113120 11610 1187 1447 16911 2072 21519 23120 2641 26722 26916 2866 2985 36218 38520


22221 22317 2451 30422 33410 3381822 345912 3698 37013 3716 3721 4051


11518 16917 2348 23616 26116 2643 31216 3507 3675 36914 37115 38520 3884 40519

meant 972 1545 33218 34611

measure 21515 37313

measured 2157

29612 measurement

12411 measures 5412

21513 2524 measuring 11013


2112 2241216 2241719 30517 30612 3127 329101217 34121

mechanisms 12413 22414 27919 29420


media 121416 18322

medical 1215 811 169 214 2213 441114 511920 7921 802 8115 8215 881014 964 1463 20418 2328 3091 35617 40718 4083


3221 3912346 8317 10514 1201821 1437 19013 19610

medications 3216 339 428 9418 12020 13722 149618 152411 15316 2245 3828 4007

medicine 33 518 2513 4122 426 466 711 1082 1221 17713 17820 1812 38418 3995


516 710 332 5216 5311 555 5515 5822 9514 9522 976 1753 18018 18922 1968 20516 3607 378713 37921 38222 38319 39146 39919 40121 4066

MedWatch 7215 12516 1468

meet 591 21918 2559 25818 2961 308517 3313 34122

meeting 101 1120 1221 4918 505 641317 7712 15318 18119 2474 25518 2881 289579 28911 33116 33319 36719 3833 41011 41121

meetings 1669 28821 3327 3526


6721 81720 91 9461014 164 2310 2415 264 36312 3814 471 4819 5922 605 61142021 6222 7316 7411 854 10421 10522 11721 11819 1301 13222 13418 14220 144117


Page 445

15322 15415 15517 156116 15813 1673 1731518 18213 183117 1851 1865 18811 19621 19713 1983 199415 20010 201820 21320 22512 2271 22910 23010 24314 24418 257321 2586 2597 2601 26813 2693913 2701018 2712 281814 2822 28522 29717 299216 3002 3018 3108 3113 3118 3126 34214 34511 3573 3583 36514 37515 38921 390610 3978 3987 40914

members 114 21 121 137 41419 649 9516 11918 11919 13013 1494 2356 3476 34716 4001012 40018 40112

memberships 2211

memorandum 1686

men 3020 mental 413 38112

3811921 38415 38422

mention 2111 2064 2225

mentioned 231 2657 3614 472 4722 4820 621

7317 8516 992 1099 1326 1333 14519 146210 1542 156218 1575 1674 18914 1985 19916 200513 2148 24419 24812 2985 3128 32618 34215 3979 40117 40215 41017




3141415 met 2566 method 20912


4003 40113 methods 20967

21321 2141 23212 330611 33013 33110 34010 3883 3894 402117


Michael 42 74 32410

Michelle 310 67 1881013

milestone 3036 3302


174151618 18221 1836 1844 18513

18621 1887 million 2989

7619 1367 1491 26113 28817

millions 1498 1538

mimic 3368 mind 9319 34418


19610 2183 22121 2221 37026


595 minor 532 982

21815 219617 21919 37022

minority 33518 3764





8612 mission 2122

2216 762 mistakes 885

9015 9116 947 10616



misunderstood 1896

mis-dosing 25221 2591022




27313 33019 modified 1161418


37014 386817 molecule 185

4322 5422 9222 97918 13816 15220 1903 19110 2091113 24912 28218 30412 31019 3129 31818 3861422 3882 38910 40421 40721

molecules 179 97822 988 9911 13820 1788 283689 28321 2841 30713 3122 3861520

moment 103 8611 2029 4031

Momenta 314 612 2324910 23314 24611


1502 monitor 1007

10317 3468 monitored 1910

10313 33812 monitoring 1622

198 2222 4416 708 725 12821 36116 37417



33922 month 3178 months 289789

28910 38013 morning 84 911

107 1522 282 4018 645 7517 87217 9516 11912 13518 14813 15819 17416 18812 24422 26019 36415 41016

mother 2914 5018 38021


15710 2784 38210 3854 39911 40210 4111417


34810 3593 37714

moving 967 19212 1943 2387 24821 3592 40114


Page 446



2095 multiple 608 832

1416 1475 17319 17712 34920 37018


15410 24620 247210

myriad 2529 MBA 311 MD 115 2213

31911131418 52415 65910 618 1518

MPA 218 MPH 115 411

N N 21710 3301618 nailed 3873 name 151821

2515 2816 345 4111 5010 662 7017 824 874 9518 10121 10412 10612 1071022 11912 12217 1337 13521 1408 14118 1431222 144412 14716 1482 15219 15820 17418 17719 1784 1853 1879 18920 1902121 19181319 20416 2303 24622 25916

2607 2802345 2807 29451214 2963 29718 298156 30819 3132222 3157 31522 32116 33315 3473 349679 3609 36214 3761 39018 4051818 4067

named 7011 7914 3225

names 1912 3314 457 5811 6220 733 1021 10511 106522 1334 1412222 14213 1457 17718 1786 1838 1902 190611 19212 19917 20029 2047 25220 25417 259920 27918 2982 30915 31716 3191921 32029 32011111418 32022 3211210 32111 3225710 323351217 34913 3741317 38438

NAMI 3811819 383819 38429

naming 3313 364 36711 437 4517 7012 718 10118 1061 12319 12413 12516 13514 1405 14222 1435 18529 186615 18914 19018 19122 1923 19612 19917 22120

22913 251810 25114 2533 2599 2608 27210 27916 2931621 30814 31918 349217 34918 3503 3734 37411 37817 3845 40316 4063 4091617



268 national 21820

412 51112 2121 226 2819 4112 5013 563 6447121517 7015 7218 739 7520 8912 3764 3811218



20711 2988 3091 35022

NDA 26720 2698 27015 28212

NDAs 28211 NDC 7135 13314

13316 14018 1411 14520 2524 2988 30910 313614 31315 40512

NDCs 1341 1414 Neal 38 64 15817

15820


1467 18120 2142 2301 27015 3465 36218

necessary 215 3620 4316 5722 7114 12616 13812 1931115 2137 2177 2184 24320 26514 28217 28912 3045 3081 3384 37313 40414 40519


429 499 622 6918 7812 806 9917 10313 1221620 1239 125122 12636 1269 12712 1293 13811 1629 17011 1736 18819 18913 1906 1918 19511 1981 1991 2102 2158 22410 22967 24820 252510 2632 27322 2781 28868 31020 31212 31920 33419 33814 34311 36212 37017 3826 38420 38821 39320 4031020

needed 1413 355 356 5220 586 1256 1285 1638 16315 16816

17512 23518 28311 3202 32318 32715 3318 36119 3643 37213 37914 3946


3321 10316 1299 14617 1641 2072 20813 22320 2261 2581519 26916 3224 33621 34015 35617 35921 36120

negative 489 711 7918 2848 3353 33610 34021




10322 neutralizing

34019 34615 never 3912 5817

6014 22715 2468 2578 28017 2948 32216

nevertheless 16311

Neville 35 520 1351718211434 1446 1454 14517 14612 1486

new 11217 93 303 5621 578 5712 587 6021 691519 7816


Page 447

909 9213 938 10113 1321212 13220 13711 1419 1598917 1781420 22415 22419 2352 2427 24722 25410 2553 27310 2807 29216 29913 303911 30412 30616 30712 32078 3211516 34617 36616 3686 3743 37817 3822 40512 40714


19210 3171517 3187 31917 32120 3221 32322

non 5416 844 1618 1623 19316 22212 28118 28718 3289 33419 33611 337615 33722 33814 3439 3538


noncompliance 3577


nonproprietary 3314 5810 7017 10121 1021 10511 10611 1408 1459 1902121 19119 32011 3497913 3503 36213 37413 3843 40518 4067





21016 2239 27815 2797 33621 3988

non-licensed 16110



7521 8112 876 9619


10110 12819 13913 15919 1606 16191022 1678 2081 23621 23729 2771021 29022 3056 3264 3521421 3535 35320 3612 39122 392721 3936 39491421 3955 3966

3971113 non-351(k) 39322 Nordisk 316 615

261581011 26320 26611


37115 note 671015 7010

821 10111 15021 16212 22016 23613 2389 273821 2749 27516 27711 27816 2891 3531419 3557 36520

noted 6512 6814 727 7911 8919 8921 1108 1527 2351 2751319 2844 28515

notes 8817 10518 10521

notice 152 7713 9722 3447 3575

noticed 1144 3441113

notified 3411 3920


36518 Novak 74 32410

32418 Novartis 319 619

8911 28746 28815 29811

novel 2206 28816 2895 2945 3894


9614 Novo 316 615

261581011 26320 26521 26611


7622 7721114 7811 8016 8111 8312 843922


1322 204 2522 314914 3215 5211 602 7118 7119 7916 8220 10216 11118 1331 14022 15914 1809 2176 2304 2314 2318 248211 2499 2839 3199 31915 32714 3295 33110 34816 3521117 3584 36517 38213 383817 38322 3849 38720 4076 40838

numbers 1912 14021 21412 3434 37820



20915 24083034 3515


36017obtained 116

11121 1122023618


1916 2619 14922 1732 24419 2465 2734 2759 2761 2762 31618 31712 3225 34514 3876


398 14313 14620 18617 22019 2222

occurred 343 3922 406 15619 22214

occurrence 702 7414


40020 Ocean 912 offer 778 1528

26621 38115 40915

offered 20611 3757


2257799 818 821 938812 1043 14115 24822

officer 11316 52 8313 917 235 2771621 2817 3520 377 3812 40710 4620 4719 4817 4912 501 5919 6321 642 7312 749 75615 85119 8620 9310 953 9511 10418 10617 107161911718 1197


Page 448

12920 13416 1351422 14217 14415 14710 1488 15319 15413 15521 15711 15815 16621 16821 1691421 1706 1713 17214 17313 17412 18211 18316 18421 18720 1889 19618 2016 2036 2043 2041017 21317 21520 21615 2259 23117 23238 24311 24521 24617 25622 2596 26017 26810 26918 2714 2815 28418 28558 28619 28729 29714 29822 30211 3105 3133913 3147 31551218 3163 32469 33211 3335 34211 34619 3571 3604 36512 36710 37511 3818 3855 38918 39013 3975 3981317 40911 4105



40418 oh 86817 967

22616 23021 2879 3908

oil 6821 okay 401 4720

8615 95411 13320 15815 17313 1983 2037 20410 23117 2597 28615 28711 31521 31913 3229 32412 3337 36711 39012

old 2918 older 878 9010


1563 once 807 1038

2254 2512 25422 2581822 25919 2618 40121 4117


33617 3439 ongoing 567 9812

24114 2483 2997 31022 3687 4103

online 12722 31615 32316 3244

on-call 257 open 410 714 142

14421 932 23610 25715 375517 41111




8920 opinion 10912

2554 36619 3898


opportunity 138 1310 284 348 3515 3811 508 649 681 7518 8421 9517 1087 1203 13519 1499 1529 15318 1592 17417 1813 20415 21218 32414 3329 33313 3428 3477 34821 35621 3649 36718 3768 3805 38115 38517 3918


26721 26817 2691014 2705 39615



13116 order 1117 696

7814 1091218 11021 1151115 116512 12117 1232 12420 1277 13411 13917 1472 1607 19117 2102 24919 27121 31417 37919 38721 39616 4074

ordered 1222

orders 12178 12216 1231118 12417 1274 1328

ordinarily 703 33418 33618


78 167 28720 2937 368 415 49117 501214 5210 612 7521 7611 876 9628 969 14721 15419 33311 34622 3475 38120 406213

organizations 1117 442 8522 1201 34712



395 453 5815 9112 115421 12418 1857 198161821 20021 22112 2341320 23612 29367 30018 301456


7322 1997 20117 2026 2126 22514 25817 2951721 30091113 3025 35815 36419 36612 3672 39210 4035



424 489 34611 34617

outcomes 489 6421 12021 2218 383614 39922


27112 27413 outlined 515 857

12320 18816 239320 2769 29010 29222 3505

outpatient 12510 13315 1342

outreach 12658 12722 17920 18612

outside 10017 20310 28917 2916 29520 296214 3942 40512

overall 10921 137412 15013 18815 27529 2882 3349 3389 34017


25911 overly 1506 1535



Pp 3913 6510


Page 449

11357 17414 2162


8319 10215 14019 14745 17119 2179 24412 33115 3937 3941720

packages 10212 24514 26616

packaging 6515 661 68810 697 7211 102918 14622 22121 2291317 3844

PAF 76131517 834

PAFs 7620 page 772022 784

326316 3283 33015


2921 3013 panel 114 21 817

820 91461014 121 137 161 23810 2415 264 28315 361 36312 381314 4120 4622 471 4819 592122 605 61142021 6222 7316 7411 7721 8534 864 861215 9312 951216 10420 10421 10522 1086 11721 11819 12922 1301 13222 13418 1394 1421920 1441 14417 1451318 1532122 15415 1551 156116

16713 1731518 18213 183117 1851 1865 1962021 19713 1983 199415 20010 201820 20413 2131920 21610 2251112 2271 22910 23010 2356 2431314 24418 2477 2572321 2586 2597 2601 2681213 26939 26913 2701018 27125 28178 28114 2822 28522 28621 2971617 2992 29916 3002 3018 31078 31138 3126 3148 3248 33213 3421314 34511 3573 3583 36514 36712 37515 38110 385716 3892021 3906 39010 39778 3987 40914 4107

panelist 1416 8612



21215 3115 32621 3274 36221



Pardon 313811



33389 34012 Park 1591 Parker 38 64

158171920 16714 1691019 17028 17112 17222 1731722

part 16 87 1017 1212 2418 288 496 6416 8311 11318 15422 1563 17212 22615 22714 24720 2839 2982 32314 33517 33812 34320 362120 3927 393718 39417 3951 40920 41018





597 6310 7021 757 867 1333 2382 2396 2826 29614 3489 3752 39914 41022

particularly 8510 1308 13915 1849 18711 1893 20012 31612 35321 3841416 3956

parties 151 2021

213 421114 4521 4627 20712 39617

partner 861 20518




13616 patent 354221


27521 pathway 172613

1812 251 3118 3421 508 515 5416 551216 594 6216 6411 651 665 677 9811 12211 12710 1292 13211 13618 1412 1491112 14915 1528 15719 158811 17813 1825 18821 21613 2171422 2206 2201013 2257 22615 233212 240114 2421 2438 24913 25618 2627 3141218 31512 34720 34812 3683 3695 3709 37715 3795 41116

pathways 13019

patient 21320 55 512 1519 1658 1621 181314 2121 22121 24124 2513 2819 2936 322 321118 349 351318 374 38622 391114 40221 4312 447 4516 468 471116 48616 50614 51717 548 5621 574 58521 6010 6482121 7021 7022 716 7520 7522 7661113 761822 77316 8113141517 8219 846 864 8611 923 9610 974 981618 102613 1032 10415 1051417 10518 10614 11318 114914 11416 12118 1263 142610 14418 15316 1595 17513 1768 17714 1805 1811 1901117 1964 19615 2216 2292222 2317 23113 24116 26121 288217 2891516 29110 334422 33916 33919 340313 3422 3444 3469 3494 36822 37241719 37418 3759 3761416 3777 37713 37920


Page 450

3803 3816 38315 3992122

patients 1615 189 204 2115 2214 252022 2810 292122 3119 32101415 339 331116 341417 3510 381618 403 411014 421015 4810 50921 51119 52215 5315 54920 5520 56512 577914 571920 587 591216 6027 60141517 611 61611 6319 6521 736 7639 761920 7710 78512 80212 828 834417 901620 937 962 1069 12018 12020 1214 1223 12522 12617 12914 13812 1491922 152414 1537 156911 15914 1644 1695 17817 17912 18922 19115 1929 1934 1968 20517 2186 21910 22019 2217 2283567 2311 24016 2411922 24716 26614 28017 28918 3392222 3496 3501 3551 35681216 35722 36922 37116 37620 377410 37810

37923 3815 3836 384620 39111 40716 4094

patients 263 3321 13121 38417




Patrick 315 613 2462022


2748 pave 15111 payer 4416 1364

1369 1372 1932 payers 1810 3418

4722 48112 714 13719 14819 1492 17818 17913 18419 25112


PBMs 1555 PCMA 1481417

14912 PD 238815 32815

3362 38914 pediatric 21120

2122 25571320 256158 27521 3061921 3073 3111217 31234 36213


411 454 6317 6611 9420 10616 1077 13014 18411

22617 2307 25917 26113 3767 3772 3811 38121 38414


56913 571013 5715 60142222 661616 812021 82311 8357 9010 11115 112812121313 1137 13612 13767813 28918 34325 3451718 34614

perception 794 1793

perceptions 797 79121619 808 32019

perfect 18515 2049 2861


34014 3621219 performance 205

26618 3415 3886

performed 563 1183

period 1412512 162 204 342 3921 6613 1085 14213 26721 2688 3449 37310 37428 37518 37916


22012 person 2319 258

4410 1043

31610 3801019 41022

personal 2912 478

personally 4118 9415 16515 1875


13317 1349 13691414 1372 14011 15849 2093 2108 2394 24221 2534 28517 2912 29211 29417 2953 2969 2989 31417 3345 3532 36011



23 36 4917 62 712 2117 2617 2813 4015 4216 1481116 2167 21914 36716


pharmacies 11920 12618 13315 13611 1402021 14957

pharmacist 5819 1044 1191314 13120 14210 1931

pharmacists 34 519 7911 1041 1191118 12016 121320 122215 12311 12456 12719 12912 13022 13116

1361 1423 18011 4081


pharmacodynam 3902



pharmacologic 40615




pharmacy 3322 392 783 813 10215 1221416 12416 12620 1272 13414 13635613 1401717 1429 14818 19716


33813 34115 34415 3882020



36721 368611 36821 3701117 371141620


Page 451

37212 373111 37316 37412 3754

PhRMAs 36815 3723

PHSA 24918 26714 35512



3320 3429 442 4459 4515 469 4857 5820 8320 9519 9915 10321 10519 1073 1799 1933 197141720 1981 2603 37418

physicians 2022 21222 226 339 331518 3410 3817 4214 458 476 5120 5622 7811 7911 8814 962 9919 12310 1411620 1569 32016 36416 3653 3766 38417 4064





3865 PhD 117 210 32

3910111718 320 42481415 517 65791618 620 74461112

pi 1122020 1133 pick 391



1679 1704 21515 2531214 25321 25717 2781 3303 33813 34115 39419

PK 2151 238814 24316 2446 246516 32518 3275 34020 38913

PKPD 23712 25716 3112 32518 3616 3875 39057

place 338 3920 6414 922 936 10316 1271 1327 15219 17915 22813 2334 2487 35921 3601 36620 38410 40813


24121 32719 3821


37318 38713 plan 8321 12110

12111 15613 1754

planned 3323


15610 plasma 5312 541


14110 17811 1807 1828 19319 24818


4221 4521 461 465 4920 8514

plays 2610 9914 37115

please 920 1211 1461315 151 6213 908 10111 31514 3271315 32721 32817 32911 33017 4117

pleased 8715 14819 14914 20514 20613 20717 21220 38218

pleasure 2875 36010


4613 635 9111 9717 1003 10515 1247 125318 1415 1472 15810 16415 16710 1742 1821519

1918 1937 1987 19822 20114 2133 227310 23011 2415 251721 252618 253722 25421 2556 26312 26620 26820 27219 2819 2831620 28412 2891 29818 31411 33714 36414 3939 39512 3966

pointed 796 1013 1058 15212 2462 2823 3385 3931


1332 1397 17518 18319 30512 3257 3346 33512 36117 36411 3837

policies 1111 1213 5418 7713 7716 176212 2421517

policy 121519 25 81121 95 5514 761 805 9611 14815 17619 1781 17915 18016 24112 25320 27911 35521 39110 39424 41010

polymer 2642 27016




5118 835 9011 9417 25620 27514 3061921 3073 31112 334422 3363 3391216 34011 34014 34112 3422 3444 37220

populations 4314 574 27517 31118 31234 3276 3403 3721618



16014 1689 18612 1874 19214 2117 2574 3059 31013 3389


523 possibility 667

2221016 2349 23610 36148

possible 1119 1411 253 4816 759 781022 888 94412 10615 107815 10821 114814 11715 12213 14717 1839 1851520 2004 2221 2267


Page 452

22711 22818 23310 2369 2602 3407 34110 3623 3707 37318 38314 4051519

possibly 3720 1783

post 72220 2159 30519 3387 36115


10118 3294 35421

post-market 2038 1257 33510 37416

post-marketing 586 6368 708 724 741621 32822 36417



3741 4039 potential 4312

5316 6819 6911 7320 825 1172 12413 1285 13410 14420 1461718 1604 1663 18315 21721 22815 23311 2411922 2665 2871617 28718 3263 3395 34021 34316 3581 36920 370220 3957 40917

potentially 3820 778 12810 1291

1346 2152 23222 2385 2431 2488 29020 3131 3401 3716 4079


211012 231819 11412 11919 1213 1222 12721 27817 36510



233 241 PRCA 2312 pre 207 28820


32818 3292 35417



21512 22213 33120 3618 37016 371914 37117


32019 predecessors

40322 predict 997 1379


15310 1586 18114 2649 3959

predicted 318 2189



30113 36019 preparing 8313

8720 prerequisite


216 244 10217 12612 12910

prescribed 3311 3416 3822 3913 5115 8011 19010 2607

prescriber 8318 12114 19016

prescribers 12310 1275 40720


232 2412 3319 675 7019 7115 1029 1071 1237 1253 127616 1436 179913 1952 30821 37421

prescription 222 399 8319 1219 12117 1221617 12221 1232311

12318 12419 1273 13134 132821 14237 15218 1857 18921 19114 1967 32013

prescriptions 1217 122914 13215 14420 1498 24713


7519 8421 10222 12415 13519 1593 16618 17013 1757 2501 27221 33314 3421 3477 35622 36010 3769 3788 38513 4031

presentation 1122 1320 2311 2518 265 496 1175 1514 1899 1977 2494 27121 3256 32613 3426 3603

presentations 53 1220 1516 17922 2478

presented 23612 2398 274820 305411 3522






president 4114 5011 8759 14815 17419 18813 2327 2471 2617 3161 3166 3474

presiding 11313 116 52 8313 917 235 27716 2721 3520 377 3812 40710 4620 4719 4817 4912 501 5919 6321 642 7312 749 75615 851 8519 8620 9310 95311 10418 10617 1071619 11718 1197 12920 13416 13514 14217 14415 14710 1488 15319 15413 15521 15711 15815 16621 16821 1691421 1706 1713 17214 17313 17412 18211 18316 18421 18720 1889 19618 2016 2036 2043 20410 21317 21520 2161 2259 23117 2323 24311 24521 24617 25622 2596 26017 26810 26918 2714 2815 28418 28558 28619 28729 29714 29822 30211


Page 453

3105 3133913 3147 31551218 3163 32469 33211 3335 34211 34619 3571 3604 36512 36710 37511 3818 3855 38918 39013 3975 3981317 40911 4105



16315 1646 16514 37420


993 10221 1386 14718 19622 22413

previously 232 6814 7277 1767 18914 26715 28615 33022 33711 34721 39621

pre-IND 28956 33116


price 1018 7718 82239 892 34714 36722 3999


3172 primary 501619

519 52591215 5222 534 5420 5520 565 5912 973 2093 2108 2384 26322 2668 28919 34117 3723

principle 6922 223512 22421 2824 30820 39018

principles 19311 193121518 1944 223211 2358 237817 26729 2706 27413 28022 2821013 29113 304916 3052 3639 36816

print 13110 prior 1416 7917

1044 16214 16419 1709 19414 22212 2823 33721 35715 36815 38311 38417 40117



3732 priority 3514 975

1769 3822 private 1612 4016


11117 112235 112921 11816

probably 147 499 9110 10820 11914 15610 18521 1861

22416 23121 27511 30822 32117 3433 3909


3220 6621 712 755 107511 1373 14317 14414 1461721 14720 1484 18013 18315 18411 1856 23112 26822 2981419 30111 40213


problems 7421 13312 17717 22622 23013 2667 2905 29618

procedures 1213 184 125912 3562 37019

proceed 804 1291 2448 2549



process 161719 1622 1881618 1910 2018 2222 272 326 4211 4218 432 5510 599 7211 746 8322 1008 10310 10489 1189 12121 12615 12818 17511 19910 20513 20610 2076 20817 21219 21612 2256 27412

29115 30118 3324 35118 354718 355421 3673 3756 37617 3783 38066 38315 39521 40822

processes 6515 827 9716 1206 12116 12516 12611 1277 1421 18020 30715 3569 3961

processing 541 553 122915 1232 12417 1314


produce 583 1754 18111

produced 17912 26116 2642 37718 3789 3863

product 1022 114 182022 191522 243 25411 351 372171921 381 531117 557 5622 578 5712141620 58351218 6021 6214 662 67413 6813 69121415 7016 7020 7121321 781 8211 9222 10022 101910 1062021 11122 1121 1131213 113151521 114120 11535 1156789910 11521 1161 11821 12220

12321 1241611 12421 1262421 1311721 1323 13212131619 141812 142610 14212 1431822 1443 1471519 1513410 15418 15622 15921 1606691518 16018 1617911 161121718 162145610 16546 16678 1676 16831819 169121315 170161922 17121821 1722 17210 173812 17711416 1782 1786 1796 18015 18314 186141720 187213 18919 1901020 1926 192151721 19318 194610 19419 195117 19722 1981417 19820 19978 200161720 20116 202513 20333 2053 20817 20915 21020 21518 2181020 22026 2219 2266816 228131617 2311114 23213 23621 2372910 2406711 2419 2468 25316 254151719 257791520 25816 2591515 2591721 26046 2609 26118


Page 454

26217 2641621 2642122 2654 2651218 2669 2672022 2681 2681416 27211 27421 27614 2771621 2799 27917 280118 284614 28719 2911916 2937 29312 2949 29518 29622 297237 29817 29820 299519 300101121 3031621 3042 3051722 3063 306141618 3079181922 30816 309211 31018 31220 31613 31719 3201 32171215 3221 3231316 32420 3255 3264 3281221 32991418 331112021 332119 33423 33412131618 3357 3361619 33620 33712 3381920 34114 3448 3456 34616 3493815 3501010 35179 35122 352615 353459 35422 35722 36020 361313 36211 3634 36419 3655 36610 3676 36961021 370521 3715 37222 37338 3731122 3749 3741415 3786

3781920 38116 38427818 3864 3899 3933 3934 3941516 395322 396913 4037 4069 40818



productively 38814

products 14 22 320 620 8919 1015 20810 2218 2321 276 33517 371 544 56111619 573 5718 5817918 6018 61459 62913 631516 6319 673 703 734 777 787 791 8069 8212 8221 842 1005 10119 12069 12312 1243 127915 12820 12911 13020 1315 1321021 1347 1371113 13714 13916 1402 14313 144812 14519 1467 1475 1518 15315 1553 15618 1591720 16317 1732021 1771019 1792 18010 181610 18112 18917 19013 1911315 1925 1935 1958 19661422 1986 1993191922 2002468

20917 2178 220711 2215 22218 22621 22914 23179 23222 2337 2351016 23617 2399 2409 2432 24820 24917 25117 25211 25351220 2544 257514 2603 2611415 26269 263917 26515 266321 26734 267517 2687 26925 2707 27216 2742 27722 2781722 279520 28015 2825 28312 285161820 29217 2944 29720 29820 30222 3034 304117 30817 31361522 31618 3171422 318591617 3191241921 32036781520 32191822 3228 32221 323419 32422 325313 3251721 33519 34045 34911 35020 35322 35420 3552913 35610 358910 35927 36215 364120 365222 36645121317 3675 3684 3691 36918 373519 3741216 3759 3799 38312 3841121 39218 39317 3949

4035 4061620 40814 40919



professional 648 7115 11917 17920



3633 profiles 2531

3829 38912 profit 4413 463


4112 1564 1765 1802 2354 2376 2404 24520 2467 25314 2549 26510 3022 33518 36220 3718 38922

programs 471114 891 12112 12721 1289 15622 17921 21312 2482 25311 2542 2789 28913 29810 3021 3251 33811 34114 3446

progress 325 27120




22116 4006 promotion 18916

1951113 19613 prompt 17715 promptly 3411



5512 596 30420 31218 37015 3831


1111 11514 19118 31715 39319

proposed 582 6411 6812 7113 10812 1092 11011617 1176 11715 11812 1605712 1616 16181920 1623 16912 1702021 19018 23711 240611 26211 263711 26415 27214 28613 31715 334112 33416 3361619


Page 455

33819 34821 3504 3521118 369121 370420 3714 3953


32219 3231115 proprietary 1912

26117 294512 29414 29718


35213 36420 protect 221 232

587 16210 16521 16614 26614 35821 37116 37313

protected 4210 17411 35117 3591420 3747

protecting 173 2216 6420 4098

protection 168 562 15921 16213 38419


13910 protein 114 1712

695 26261012 26321 26417 2653 27017 272313 27315 2819 28212 28610 33412

proteins 414 1718 552 12818 26115 26217 2631 2671013 26714 268516 27318 28117 28211 3184 3369 3559 3859 3864



9217 1876 30320 38721 3883

proven 9118 14413 30314


6713 681 7117 9922 10816 1139 1203 1251 12719 13321 13414 1927 19520 1965 19920 2028 2111 2133 22422 23817 2411 25122 2648 28618 2877 3102 32317 3251821 32713 328818 3329 354611 35517 3658 37651522 3774 38819 39718

provided 7122 9321 1264 17515 21018 2182 2736 28313 28616 28719 30813 33117 36319 3643 37211 3893

provider 676 12017 1753

providers 2214 2318 12317 125222 126717 1294 1311 17818 1806 1928 34922 3551 4081

provides 4518

7112 803 815 1622 20616 23720 28422 2851 2871415 28716 3279 3736

providing 283 328 359 4520 1086 1178 12012 24021 36417 38517

provision 718 3555 37312 3746

provisions 10118 2683 3561


714 1169 1212 121418 132 1424 1514 162 2216 7311 775 8178 875 9613 12013 14014 17921 1819 20414 20611 25221 25416 2678 2848 31716 323716 3419 3511316 35121 36719 3689 37222 375517 38115 3961920 40822 41119



8112 844 8511 32222

published 7310 1471222 2061 20614 26020 2927 3242


14167 20310 29216

purchased 8811 3654


1415 pure 6522 6815

21821 purely 2073 3925


33017 3741 4039

purpose 1012 13617 2229 2404 30617 30913 3989

purposes 7019 7122 26222 32013 32313 3564 39713

pursue 4629 20510

pursuing 2121 2482


9614 13511 1481 15120 15714 1582 16116 1698 2012 20621 2487 28713 38410 3905

putting 4710 9020 17915 24515


81 pm 102 1414

2042 3151617 4122

p0 111182020 11271214 1138

Q qualified 4410


4610 5015 7013 712 1188 13914 18022 18112 2081120 2092 2334 24914 26316 2724 274511 2885 29112 2932 29611 29922 3001219 3014 3041017 30849 30812 3096 3174 3252 32921 3308 35318 36021 36610 3676 3701 4001113 4039 40410 40815 4093


1314 278 362 3815 499 6016 6122 6922 7410 7412 867 9313 9319 10319 1061 1191 13011 13422 14221 144218 14421 154111 15712 16715 1692 1701015 1701717 17113


Page 456

17316 1821417 18222 1832 19512 1984722 2001118 20821 2272 229811 23118 23619 2371314 2387 23810 24315 24419 24614 2598 27011 28220 2991015 29917 3019 3067 3109 3134 314810 31920 3201 3212 35915 36414 3937


1371117 239 2717 3813 408 461521 471720 4915 5920 7315 7920 816 852 8614 9311 954 10419 10618 11720 12921 14218 14711 15320 15522 1661922 16822 171422 18212 18422 19619 2037 21318 21521 22510 22812 23415 24312 24522 25621 2571 26811 2715 2816 28419 2971315 2991 3045 3106 3247 33212 34212 34620 3572 3605 36513 36711 3751214 3819 3856 38919 39014

39746 39814 40913

quick 13419 17315 3837

quickly 5812 15122 23415 24120 3495

quite 126 3710 9778 15713 1733 20210 33216 4022 4088

quo 32212 quote 1641215

18117 23511 quoting 2426 QampA 6810 691

19515 211510 25722 27519 3262 33021 3313 35112 3521019 35317 39411

QampAs 35517 Q5E 2371517

R R 215 414 56

1164771015 11615 3858

RAC 711 race 8418 Rachel 11315 52

810 Radcliffe 45 77

34621 34723 35712 3593

Rader 41 72 315202122 3166

radio 818 rail 11519 raise 1038 1629

22613 26713 40311

raised 7920 1331 16215

raises 9318 31915 35222

Ramachandra 311 69 204891216 21421 21522



2748 27612 2773 27820 3757 38314 3995


41018 rare 743 2159

3357 rate 5316 6614

7217 1092021 3455



2516 252115 30518



40414 react 6111 reaction 5712 711

1911618 37822 reactions 5410

6320 19016 read 156 16414


1451 32117 reality 18513

2155 realize 305 14211

2102 23311 2887

realized 1526 24017

really 6313 856 13016 1326 1504 16819 17219 18515 215911 2196 22320 2293 23415 2458 2553 2562 27314 28912 29017 291521 2923 2932917 29710 30117 318220 3441 3457 35822 37516 3768 3873 3994 4001720 4011 40111 40311 40429 4063


40212 reason 1712 456

5614 7213 751 1732 1742 2268 26315 28315 3598 39315

reasonable 342 3921 1746 20616 21716 3073 34313

reasonably 2185 2191315 23121 27619

reasons 1335 1436 22610 26417 2659 27316 2839 4084

recall 123 1318 751 867 1473 16421 23020


5321 6612 769 10010 1152022 1312

received 2811 7618 8814 17714 19010 3493

receives 6915 7022

receiving 3310 10214 1316 1644 2287 28918 33919 35717

receptor 30519 3066 31118 312915


24814 32517 34818 35217

recognize 141315 1619 175 2219 2420 331 383 443 676 989 1641 1743 18012 21719 33321 37911 38318 39221

recognized 5210 1646 26716 3712 40016 40816

recognizes 5318 1266 2656 3482

recognizing 1234 18518 3494 3708 37219 4028



Page 457

recommend 10410 122612 12520 1283 14121 21016 26412 27413 29221 32615 3705 37215



recommended 6721 7214 32620 3326

recommending 1213

recommends 4419 21213 3287 3293 33010 37116 37814 38320

reconsider 689 36122 3627 36315


1351012 15412 17919 2316 31516 38218 39620

records 716 1463 18014

recycle 28617 red 6522 6815


22711 24216 24420 3291 34222

reduced 1314 7710 23519 2923 3392 4016

reducing 2384 2421218

reduction 20716 2432 29119 4018



499 1548 2239 3153

reference 1022 114 584 6214 6628 674 9218 1004161819 101910 1035 10621 1112222 1123510 11313 113152122 11422 115689 1169 1209 12219 12315 12413811 1262 1299 1317 13216 13314 13512 1514 1591021 16010 16018202122 1611791117 1625610 1637 16318 1667 1675 16819 16913 17019 1712 17210 1782 1796 1854 18713 19220 1949 19517 1981619 20016 20116 202512 2032 2081 2091517 21020 22218 237910 257591420 25817 26321 2641622 26518 2668 27613 2799 28719

29022 2919 29312 29622 297236 30316 3041 3051722 3061318 3078 30816 31616 31716 321821 3281221 3298 3291418 33111 33218 334212 33417 3357 33620 3371215 33819 34114 3456 34616 3499 35010 351722 3534 354812 3612 3621115 3634 3641 36612 3691021 3705 37021 3715 3722 373311 37415 3842 38722 3934 39416 396913 40814

referenced 254 351 5817 6914 6915 7121 8211 1422 19419 23011 2406 3034



22916 3119 refers 3009 33015 reflect 205 5419

11214 1287 2345 3992

reflected 15012 3052 35219


reflects 5322


35412 refuses 321 regard 3816 6814

6921 727 1306 13122 1433 15420 18711 1894 19510 2024 2173 21911 22014 2239 22820 2417 27717

regarding 111 4013 666 7714 7720 8810 897 995 10117 10222 10319 10816 11310 1729 1844 21014 21622 21712 22216 2388 2416 26814 2765 2778 27811 28011 3022 30814 32015 3224 32610 3289 33010 33314 33514 33611 3395 3486 35019 36115 37419 39618 39720


21021 3083 regimen 3351



24918 2702 28210 4095




3418 3818 4216 21818 2659 3236 37911

regulatory 119 821 459 51211 5516 9811 11216 1192 1539 18814 20418 20513 2166 2181 2234 2252021 2362 24221 25112 25318 25511 27110 27221 28121 282615 2833 28516 2892 32420 3324 34811 35211 39019 39621 40312


37816 relate 517 30413 related 88 13313

13422 14621 1479 16213 1903 19919 2006 3143 3201 32420 3347 33512 34712 3511422 37410 39512


Page 458

relates 13115 3041314


3410 435 4516 4858 29516 3218 37919


relative 11622 19516 20115 2531 33322 33417 3387 34022 3412



35116 3539 relevance 32720

33718 37112 relevant 7918

1938 23416 2351 25119 30022 3074 3254 32722 33714 35920 3642 37119 40622

reliable 18022 1819 18311



5622 31321 3524 36314

relying 31314 32212

remain 21112 22812 23610 23918 37910 41111

remaining 3521 22211 36411

3748 remains 125 2922

26914 38318 3997

remarks 52 284 4118 1175 15918 16219 18912 2254 3247 3605

RemarksAdjour 715



2181316 2195 21917






7959 822 19120 2301

reported 569 579 5711 8120 919 29812 30711

reporting 603 125712 18519 1911717

reports 558 7214 8118 889 14521 19118 22921 2308 29722

represent 3214 413 509 511 725 777 833 8716 11918 14817 1506 3169 3916 4008 4109



representing 297 1368 2876 38121




1111217 11229 11221

reproducible 11816


3322 4422 4612 1664 19121 2344 23816 2391 2741 2899 32922 35516 3574 40915



requests 34916 355314

require 193 3621 3919 4221 5216 5416 5722 7219 1289 18021 1816 19411

1971417 2065 2129 21722 2211 22415 2697 29920 3096 31113 320621 32717 35410 3575

required 5617 5910 742 9217 1091618 11216 13918 14119 19120 19415 19917 2111 2129 23722 23917 24316 26518 29114 31015 3225 32620 32710 3299 33013 33415 335616 3373 3387 38611 38721 38820 39417 40422

requirement 575 7222 2123 2389 2381419 2397 244617 27814 3376 3611922 37122

requirements 6721 12110 15019 1897 1945811 1961 1963 2084 2104 21013 2111517 21121 23319 2341 238622 2433 27414 2758 2786 29121 30410 32711 329122 34918 3503 354314 35510 357710 3669 3693 38410 4014 4041212

requires 5319 14017 2181 25718 268144 27410 3545 3932 40020

requiring 14320 1782 2552 3208 40712

research 111618 120 23511 49 712 812 5018 7910 881 9016 13914 1476 17419 20417 36716 3772 38078 3851



22322 22720 23917 24212 24420 24614


23614 23721 35418


31916 35715 resource 28813


12616 28811 28912 35420 3582

respect 2313 4211 4217 495 671 688 699 72217 7412 15114 16222 23017 23316 23412 23619 23714 2418 3574 35922 36818 37411 38320


Page 459


30815 respects 424

39114 respond 4616

17222 response 196

2622 379 6410 689 73110 1481 27819 2827 3286 33411 33818 3838

responses 561621 6012 33914 3408 3453 37113

responsibility 353 5114 1074 2437 3877




584 651622 7212 773 845 11481315 20816 2568 25910 2637 3351 3382 34921 35417 3742 3781 38412 3852 40016 40715


results 189 571 7917 9919 11317 3397

34119 resumed 959


514 8618 875 8716



9621 976 15922 16211 16422 173821 17510 23218 23317 2342 2359 23822 2707 28913 35118 35217 354920 3628 38711


172916 17320 2079

reviewers 16315 1641017 1669 17011 173610

reviewing 16317 1669 17319 2358 2451314 24520 3882222


1285 revolutionized




2285 rich 1695 Richard 31 515

9518 right 105 3311

3414 3615 403 405 4410 474 8610 8715 987 981818 1702 19713 20713 22456 2281314 24220 24317 24619 25612 2699 27018 27212 2751 27916 281213 2821 28513 3001 31012 35816 37515 38422 39011 39719

rigor 21315 22119 28218 2832 33012

rigorous 1622 2221 1815 20619 20715 23310 244410 27828 36919

rigorously 9113 33322 34111

rise 23112 risk 195 385 444

446 577 9021 923 933 11319 11322 142515 1436 14513 19012 19421 2187 2198 22021 2246 22516 2264 22720 3101718

3271 37621 3772 38315

risks 549 5721 786 21720 2184 22018 2217 22211 225217 2264 24119 30717 3495 35019

risk-based 18817 19520 23320 24018 2429 30720 3354 3386


232467 24321 2457 24610

road 2459 35818 Robert 21013 54

1518 robust 1911 1053

11816 14119 181720 19611 23615 26615 32517 40511

Roche 310 67 1881114


188101213 197819 19812 19914 200111 20022 20118 2027

role 231420 2417 2610 3211 3916 6818 8515 9914 12019 12913 17812 1807 18611 19319 22716 24722 2481518 3128 3541 3645 37115


Ronald 41 72 31519

room 112 922 147 259




2458 rubric 15518 rule 1732 1742

20112 29410 rules 111921 467


29711 running 36220

41015 rush 24119 RampD 313 611

2163 R)7 11631015 RAC 48

Ssacred 486 safe 31 516 1615

1618 295 311 323817 334 3621 37118223722 416 449 9013 9118 9513 9522 120515015 15231796 18921


Page 460

19114 1967 22017 2422 25618 28812 31421 35618 37510 37617 3812 39112 400710 40122 40411


safeguard 94912 9417 16314 37810

safeguards 338 944 1638 1664 1665 17456 37815

safely 216 5116 safety 1621 1722

1813 194 2217 2221 322 331 3513 376 4320 451012 507 518 5317 548 541119 56713 5618 573 591 6421 708 7234 7913 808 9217 931616 9610 974 10517 12122 12622 14419 17513 176810 17812 1805 1811 1828 18820 196415 208811 21018 21215 2151 22921 24010 2414 2531 26118 26521 2666 2907 29113 29816 3031321 3051 3111 3131 33017 3353 33610 3393 34022 3413

3495 36116 3657 36617 3679 36822 3701 372921 374117 378812 37920 38038 38316 38913 3907 4015 4039 40410 4051620 40719


57 401112 4111 4727 484 49822


35816 Sandoz 318 618




16612 saved 15220 savings 7910 828

15326 25619 2926681214 40015

saw 1514 2519 saying 6212 943

10114 1735 1833 1985 2296

2691022 3026 31211

says 1988 27015 2711


3296 schedule 1512


1117 schizophrenia

3824 school 33 518

5120 1082 38015

science 23 5513 5717 594 999 138781014 1391 14514 1641 18118 23213 23322 2398 2418 25413 2563 27221 28120 282813 28516 2951 32112 359317 36019 3694 37118 3941320 4011 4043

science-based 321 26121 2888 29219 2959 3797 4054

science-drive 41115

science-driven 18817 19520 21612 2257 39114

scientific 1020 693 998 1088 10914 1576 17815 20417 20511 2082620

2107 2111 21315 21417 2211119 22324 23221 23317 23418 2357 2362 237817 2395 24113 24510 251618 2541 2631013 26318 26417 2652 2671911 2671417 2706 2811216 28249 28218 2831 28512 28714 2892 29021 29113 3049 30518 30922 32419 325215 32617 327818 33012 3348 3506 3518 35211 353115 35510 3639 36816 37210 3753 3925 3931 39314 394811 3951317 4002 4013 40212 4061721

scientifically 1205 20619 20921 22411 24210 2638 26911 27016 28021 36317 36919 40118 4036 40819



scientists 9015 9115 963 16519 17011




13517 13615 scrutinize 139

154 se 23111 29111


28512 second 1022 1610

198 3068 7712 9017 10918 11316 1162 1412 16268 17615 17810 19218 20914 21012 251721 25322 2626 2636 26516 26718 2745 2791 3491 39220 3992


seconds 2878 40912


16210 163313 16541221 1666 17116 17449 3585

section 19410 20215 211511 23913 275712 350141516 3556 39516

security 2218 see 146 1517 239

2314 24118 2517 325 345


Page 461

3819 6318 7511 7512 982 10519 1275 1374 13815 13918 17220 1842 18922 19511 20634 20720 21116 246415 24821 2492022 2501422 2515 25214 25322 25912 3113 31721 31815 319813 33047 34519 34616 4048

seeing 4913 13018

seek 10012 17819 2077 3689 3773

seeking 12013 1291 3399 3721416 40168


729 36913 37022

seen 6019 6716 9115 1305 1763 20918 24915 3282 33119


11817 21621 3363

selection 8412 124621 12622 33915 34013 3422


11915 14815 16412 17419 2327 24622 39018

seniors 871314 907 9415 951

sense 606 2019 20622 28417 34413

sensitive 171620 1773 22371618 224218 2273 2284 23615 27514 32722 32814 3332 334422 33710 3391316 34010 34013 34111 3424 3444 37018 3721819


22310 2251 2275 32720 3416 3421520 34317


146116 14715 2523

separate 1429 18617 3276 35012


11624 2651820 sequential 2073


35612 38121 3841522

seriously 354 41112

seropositives 3297

serve 813 4315 7622 874 11915 1922 19320 21311


2678 31614 services 76110

1202 33311 serving 766 2383

3173 33714 session 1078

24422 31519 set 592 731 8513

11810 12110 1745 18120 19315 20916 2383 241311 2445 2864 33622 3376 33815 34418

Seth 411517 4910


21510 2237 24213 33715 3965

settings 2713 11920 1201 12510 25922 260613

seven 302 3115 2877 2898 3263 32616

severe 6516 7212 35721 3825 3996


496 508 20521 2436 25213 2915 3428 36719 4098 4102

shared 34120 36515


1781 Shehan 615 2615

26167 26916 26911 270414 27021

Shein-Chung 32 517 10720 1081


52 8310 917 235 2771621 3520 377 3812 40710 4119 4620 4719 4817 4912 501 5919 6321 642 7312 749 75615 851 8519 8620 871 9310 9531115 10418 10617 1071619 11718 1197 12920 13416 13514 14217 14415 14710 1488 15319 15413 15521 15711 15815 16621 16821 1691421 1706 1713 17214 17313 17412 18211 18316 18421 18720 1889 19618 2016 2036 204310 21317 21520 2161 2259 23117 2323 24311 24521 24617 25622 2596 26017

26810 26918 2714 2815 28418 28558 28619 28729 29714 29822 30211 3105 3133913 3147 31551218 3163 32469 33211 3335 34211 34619 3571 3604 36512 36710 3751122 3818 3855 38918 39013 3975 3981317 40911 4105




1148 14616 25213 26222 26421 29510 29757 3332 3885 4019

showed 2664 38016

showing 2651 29310 29514 31814

shown 10110 11522 2125 2551 27311 34817 3668

shows 15217 31718 3195

side 5614 57911 8922 919 13115 1311920 1364


Page 462

13911 15220 1719 2452 2847 28421 29512 382914 38712

sides 454 911 13910 27819

Siegel 313 610 21624 22519 22714 22918 23020 2322


8116 821920 18021 23914 2432 24919 34716 35611 3711 38815 3945

significantly 1718 5513 595 17219 1737 1777 21019 2664 30310


2616 8520 9219 9722 982 10314 10989 1106 11220 11315 11710 12316 1249 1388 1608 1602021 1656 1809 18918 19315 21024 211319 2126 22017 2267 23515 2491621 2501519 2547

2551915 2561 2567 25713 2582121418 2591 2639 26422 27222 27315 2911218 29221 29324 2961 29918 30049 31221 33118 33921 3697 3785 3833 3841 3852122 3867 38718 3885 40110 40714

similarity 269 2182 2278 24819 2512 25410 2757 2924 30315 304619 30517 306110 3071 36020 3611 36519 3663 39513 4019 40416

similarly 1255 2543 29210 4033

simple 13112 18116 1919 27217 28118 3878

simply 926 16420 2369 2925

single 923 1375 16117 1675 1862 34115 3699 39120


1172 1456 15514 16510 18514 19720 2007 20221

22712 2554 2641318 27615 29514 33717 38716

situations 6717 1651 21413 24519 2528 25914 27422 39315 39416

six 3024 479 2897 36517

size 10967 14019 2158 26319 32819 3292 3412 34222 36911 37117 3727 38222

sizes 1475 22516 3295


16116 1641112 166612 1714 19415 28915 2913 2925 2951111 29917 3019 3119 31718 3304 33215 3488 3551618 36517 36517

slides 812 22912 4073

slight 701 731720 741322


slot 13513 slots 1117 small 1611 1710

184 2317 2620 431022 5422 559 9791718 988 15220 1773 24912 2836 2961 36913 37020 3728

3787 3835 3868 smaller 2701922



3362 solid 2058 21512 solution 6022



37018 38911 sorry 8617 11620

1405 18221 24411 31645 3908 4073

sort 2417 3446 494 1065 1309 15619 1866 19715 2148 2197 2264 23115 40288 40521 40713


25319 2563 3048 36019 3694 37118

sounds 1351 21422

source 1004 16615 1695 1763 19218 2643 3981

sourced 5312 3056 3928 39811 40818

sources 14522 19616

so-called 11014 11015 1181216 27617

space 2059 3017 speak 141 3516

4020 4619 6313 9415 9517 1432 18511 20415 2993 32414 3919 39821

speaker 1341215 131618 151016 2116 2722 4011 502 643 7516 9512 1013 10322 10720 11910 13516 1386 14810 15817 17414 18810 19622 2047 2162 22413 2324 24619 26020 2614 2717 2823 2873 30213 31519 3337 34621 3606 37518 38111 3858 39015 39818 3991 40214 41016

speakers 111516 1220 1411 4721 6512 709 7110 993 10221 14718 22119 3149 32410 36614 36712 40117 4111

speaking 4113 481 493 18910 30122


Page 463

speaks 21779 2214 2282



1495 15211 specific 1916

2013 268 3321 4915 7020 7511 85721 10521 110556 1196 1308 1353 14018 1479 15120 15919 16213 1631619 1872222 19217 19318 1944 201119 2064 20818 22811 22914 23013 23411 2455 2741422 2785 28315 3071417 31020 3518 36813

specifically 5217 796 8916 1638 1957 20210 20722 2174 21819 23021 26322 32713 32811 3846 40614


specificity 758 859 2143 3417



20910 spectrum 279 527

7621


23122 29015 spent 1362 38012 Sperling 412

381121417 Spiegel 215 56

2722 28216 364918 3715 3821 409


3587 spoken 454 22120

36516 40113 sponsor 11217

11933 15922 1688 26719 2701 2894 3024 32622 3319 339911 35716 3877

sponsors 15311 2035 20710 21022 2136 34921 3582 36017 36121 39213 3945 3969

sports 4120 422 461 4916


18017 1827 38912



4712 842 9814 12718 12916 15314 17811 179112 18321 18410 1921 2068 2476 3758 39115 3958 40320

stand 17119 3529 3602 38010


707 7415 979 1212 1258 1704 1724 1875 2111819 21622 2174 21919 2213101418 24916 25015 2511 25591518 25713 2584712 25815151920 25914 27822 2889 29219 2933518 3005 3009 30857 36518 3662319 36620 3671 3949 40110 4042


268 592 679 9316 10116 12812 181468 1811520 24921 25041519 2514 2567 29222 36521 3754 38321 3926 4002 40310 404417

standing 146 4614 25320 30820


13017 1328 20411 2721

started 1082 1985 3443 3793

starting 811 2133 28411 3966

state 761 128269 14020 17914 18419 1882 19222 1934 194620 2365 2418 24816 2502 2582 2651316 2671 26815 3031 31220 33614 33719 33816 3398 34711 35818 3713 40710

stated 728 7319 1063 1767 1972 197317 2659 27912 2943 3832

statement 671115 69310 1351011 1543 1868 19412 2427 2694 29920 3662 40614


states 203 3119 6510 6611 6810 88810 1001617 10410 128410 17514 17818 2258 23810 2639 2685 3085 3316


24317 3508 38710



status 1959 19710 19711 23611 2648 28012 32212 36216

statute 627 14913 15811 1611522 1626 1631 25821 2621516 2646 2683 2696 27038 36521 3736


170317 17114 18416 22113 2935 357710 3693 37121


3621 stem 1911 3576 step 199 273 328

10935 111511 11114 1135 16320 24810 25611 3484 36016 3801 39910

steps 3620 5418 5814 624 1006 10916161920 1114 1224 1738 1764

stepwise 10814 109313 12014 2062122 21211 2227 233822 2393 2448 24813 27121 28715 3261819 32622 36218 4025



Page 464


901 stopping 3916

5614 storage 6515

7211 10310 stories 3822 897 story 885717


1114 18019 33918 39612


strategy 4611 27111 3872

Strauss 42 74 3241112 33220

Street 8721 887 896




679 strive 429 4920

16520 strong 1617 934

21617 2294 3121 37210


1614 981420

1037 14912 18622 3839 40415


23614 2382 2412 24441011 26420 273320 2776 2841 37022


structure 696 8511 1056 2096 2654 2668 27314 3217 36914 37322 3784 3861722

structures 439 27220 37721



1161121 1566 20911 2212 22221 22425 23115 27516

studies 561720 7118 7918 992 9910 10917 118337 12819 13822 14320 14515 14619 15614 16015 16812 17019 2101017 21216 215123 22517 2351719 23916 23920 2569 25710 2937812 30415 3055 3072 31021 3111317 3123 3131 32731012 3281013 3292 3362 3384

34217 3511 35312 36168 36213 3635 36418 3655 3711013 3839 38611 3952 39720 3984 4041618 40817 40820

study 317 355 71181920 742 10821 11019 11514 11715 15916 1645 1684571216 16916 21014 22418 238815 23913 24020 2431619 2447 25522 25718 2729 27618 3081 3111256 3177920 31814 3272122 32813 335810 33912 342192122 34519 35015 3642122 3652 37217 3879 39722 40412



5310 568 subject 121317

6419 1191 2134 2682 3277 32816 35420 3737919 39821

subjects 32714 387920 40119

submission 17218 17516 18912 26015 2738

3562 38822 40920

submit 611619 7514 1198 15312 1882 4018 4117

submitted 139 941 13621 1468 1621420 16721 1687 20818 21614 2496 2687 3485 35519 36811




3911 405 674 1971512 2609


substitution 343 341112 365 3922 436 4421 4516 5418 5815 62471121 783 7922 9110 925 1048 1286 13117 15117 15561216 1564 1568 1798 18417 1869 19222 19610 31420

substitutions 3611 3919 13121 1445 15589 19012 19716


33511

success 17812 17917 26510

successful 7818 8015 12017 17920 2788


suffice 2715 33511


1512 29719 2986 3636 3642 36610 38710 38916 4019

suffix 1783 1854 18568 18722 1881 1912 2608

suffixes 1241415 12417 1336

suggest 6620 1046 11013 14422 1452 1814 18320 19921 210912 2263 27615 2901516 2945 29410 2976 30115 31115 31318 3312 3322 36122 362722 3644

suggested 843 29322 2943 38922 40019

suggesting 10111 1515 1698 22614 26920 311410 325911

suggestion 2446 26822 2863 3311

suggestions 36810 85721 9822 18719 2081822 26622 28616 32817 33117


Page 465

suggests 2101115 22318 3313 36118 362317 3634715



8315 845 summarize 6410

3647 summary 2213

5822 1824 19518 20822 30917 35514




6919 supplementary

682 supply 1007

13311 17617 1801722 1819 1827 26014

support 4322 467 6791415 9815 9820 10113 10413 1066 12014 1231321 1248 1281415 14222 143514 17020 1852 196414 20718 2228 2333 23622 23712 23815 2405 248712 25315 25811 26312 26616 2752 278812 31115 32513 3293 353614 3771 38219 3853

39515 39620 supported 14912

1689 19416 1997 27720 29322 34120 35614 36721


1001013 1482 35215

supportive 16716 2411 28712 3687

supports 772 8920 1204 18815 23314 26310 2779 3059 3504 37017 3806 39110 4081521

supposed 882 1132 1312


4813 498 598 13021 1327 1344 1432 15519 1587 17317 2281 2292 23014 2441 30811 33622 3579 38810 40411 40514



586 636818 7221 7416 921 10119 1053 1258 12820 14611 1572 29719 30914 3792

survey 5646 576 601 6115

surveys 601015 6015 6119


1142021 11512 115367 1236 1683

switched 2515 578 15618 22019 38418


5720 608 1031 10819 1091 11320 114218 11419 1151216 11612 117213 11714 1685 1934 19421 2217 2222 2311016 25017 29815 3641921 3651 36611

Sykes 411 37519 37520 3762

synthesized 26219 2633 27222 2732


3314 4517 527 7819 8015 9119 921 935 10120 1054 11013 11812 12621 12714 1401015 14414 14511 1501 1521521 1537 17821

17918 1862 19018 191610 19112 1924 19321 22515 24016 25114 2536 26921 2841314 28519 2861 32121 37817 384516 4051112 4063 40611

systems 698 12416 14614 28313 31321 36111 36912 37720 4084

S-E-S-S-I-O-N 2041

T T 11422 115112

11518 116347 116710141415 11615


3919 4110 547 5813 624 752 955 11813 15419 16320 2027 2471721 2575 26612 28420 29712 315113 3364 3385 34016 35921 3601 3804 3846 38712 3974 3992 41112

taken 3517 4511 8911 1007 1381 1739 1764 20314 30918 3491021

takes 1655 20713 24018 3924

talk 5020 1055 11417 1304 15716 15823 17220 1832 1841 2005 2141 2147 2174 2272 2723569 28812 29621 31113 3187 3769 4104

talked 271011 364 601 1307 13013 2599 2906 39718 4022

talking 2615 316 1709 1867 22916 2691 3186



29013 3175 35912

technologies 30413 38911 4091821

technology 7817 1349 2321520 3713



991619 10520 14612 1718



Page 466

2238 temptation 2856 ten 6022 10810

1362 137113 18122 30221 32418 33215 3435 4021920 40912

tend 10311 tens 21910 term 8514 2104

3086 terminal 21710

3301618 terminology

12611 terms 2416 285

2810 553 1194 1339 184814 18613 2491 2892 2921 29310 2951 29819 29910 3004 3027 30419 31114 3168 31819 343422 34611 35721 3861617 38618 38913

test 11422 11579 115102021 1161 1681018 16820 17010 2156 22822 2647 2783 2997 37811 38310

tested 5411 591 7814 9113 2223 22315 30619



333 3791216 382 434 441 4515 7117 9913

9922 2128 2184 219910 22210 2221213 2235 22715 22819 22956 2568 266181819 27914 3304 37016 3711417 37121 3725 40171119


19219 40120 40216

Teva 32020 620 621 302141717 3035 30591112 306815 30719 30814 3093817 30922


2345610 2717 2719 28315 3116 35151920 3814 408920 4222 461820 4720 492122 504 59131819 5922 6120 631 6321 6416 737 7312 7561318 8420 851 8638 8691922 871 93910 95247 9516 1041718 107161822 1086 1171618 1197 1202 1291920 1301 13222 1341518 1351319 14216 1421720 14417 1489 1531719 15322 1581616

1592 1661721 17314 1741217 1821011 18317 18867 1961718 20010 203711 2041214 21218 2131617 21521 21522 2169 22549 23122 243911 24617 24737 2562122 261210 268910 2715 2815 28621 2871 2971314 30211 31058 31514 3245681213 332811 333513 342711 34620 34727 35621 3571 3605 3651112 3666 3671115 37511 37513 3817810 38114 3854516 3891718 3975 398141520 409911 41045 410101420 411122

thanks 10421 13514 15415 18213 18721 2018 22910 2598 3104 3118 3647


538 5615 7922 15116 1556815 1563 33521 33813 34116 35610 3859


therapies 1615 1879 2022 211

217 311 5415 551 597 779 15968 35618 382616

therapy 521418 537 56813 5710 593 10515 12021 3853


386 1186 1333 1876 25115 2808 30514 3594 38612

things 373 10615 1189 1308 15518 1761 18117 18322 2146 22620 227420 24611 25217 258122 28216 28921 2914 2988 29912 38713 38811 40222 41015

think 155 2422 261214 2712 2714 34356 3618 371519 38410 3915 402 5118 5212 6117 626 7322 745 8558 904 9622 991013 10122 1059911 1063 107578 107131515 1081519 10911 1091221 11011 11012 1111519 112715 11318 11319 114911 11421 115513 11519 116613 1186101114 1191 1238 1329

1359 1421422 1431214 14616 1491621 1505 15113 152157 1546 1551315 15516 15616 15717 15812 16381419 16616 1671116 16717 1684 17121 17246 1738 17427 18410 185313 18516 186321 18757 1918 197815 19812 1995 20017 20114 2027 2034 21322 21461016 21510 2214 2227 22319 22810 2294 23022 2319 23522 243618 24518 24612 2474 2622 26919 2704 27317 27921 28010 2821621 2832 2841015 28699 2903 2913 29422 29620 3011216 30319 31016 3121319 31320 31416 343813 34318 3464 35712 3585 35915 36015 3666 39822 4021314 40416 4071 41016 41110

thinking 2712 3713 4821 515 5117 1707


Page 467

19715 2011521 20122 202910 2195 3159 34719


2020 213 9022 10919 1163 14113 16112 17617 18016 19222 20922 21014 2537 2628 26610 3961017

third-party 2313 4411 487 925


thoroughly 591 2336


8520 10314 13012 1331 1859 19716 20110 2022 2801719 3258 39045 39710 4112

thoughtful 5916 20012 2038 30918

thoughtfully 20512

thoughtfulness 632

thoughts 2610 474 13311 20113 3156 33314 3428 41116

thousand 5312 6012 8714 1694

thousands 6110 9020 21910


three 1013 128 1812 3021 4122 8314 8718 895 903 981 11114 1135 1166 1376 14014 15714 1603 1681 19518 20819 2093 21621 2656 29314 31219 32510 32615 34517 34836 3681218 38322 39116

three-armed 25716




13513 141718 151112 205 291818 342 35417 3921 421 5713 6613 7314 8617 9212 1031914 1085 11719 1314 13420 14168 14214 16612 17215 17516 18118 18210 19413 20017 20916 2119 2157 21621 2254 2311822 2439 2509 25918 26010 2618 28320

2866 29015 29818 2991321 32213 32511 3328 34017 344289 3451 3553 3595 37613 3781 3791014 38610 38618 38816 38912 39120 3972 39820 4111


2424 times 34321 4016 timing 1309 1843

3355 tipping 16710 titer 34531718

34613 titers 5522 today 10212

1220 1311 163 291122 3116 323 351618 4014 431 4615 481 493 5021 6611 678 7010 7711 8711 944 9518 1203 12713 1326 13520 1369 1373 1387 1404 14013 144710 14411 145611 14516 14620 1474 14820 159318 16218 16618 1709 17418 1751720 1761 1779 18020 1821 1855 18912 1908 1917 2004 2008 20220 20415 247413

24813 2665 27115 287620 29315 30511 3168 32414 33317 3478 3487 35622 36410 36516 36815 3769 37816 37911 38214 3832 39126921 3973 39821 4009 4021516 40218 4089 40910

todays 4918 505 3254 33319 41011 41121

told 3912 512022 8813




23212 24816 2502 29810

top 1471 2264 31816

topic 856 13313 1628 1637 1921113 1943 26610 2721 39322

topics 2119 35515 35517 3732

total 3186 32211 totality 6921 726

10815 1101214 1101822 11218 11324 11778 11813 1281314

20620 23320 23512 2392 24018 24814 2755 30611 3391 3611 3626 38819 4024 4099

totally 2615 22715 3221415



911 2310 2415 4819 7411 1673 19915 23010 3573 36514 40914


21010 2244 3875


10117 1064 14714 1484 22122 22914 31310 40511


3094 37821 traceable 2309

38411 tracing 1024 1062

10821 17622 1777 22917 23013 23111

track 1918 459 5417 7214 869 934 10117 1024 1064 13315 1402122 14134 14111 1484 17919 1919


Page 468

2312 31310 40511

tracked 735 14520 29415 30911

tracking 191114 713 1062 1256 12514 1344 14119 1438 17621 1776 2301617 31722 34914 4057 40919


13522 1554 15922 16210 163312 165411 16521 166615 17116 17439 280237 3524 3585

traditional 1719 184 4322 2803



2671021 26828 26820 35529 39317

transitional 2629 26621 2673519 26722 2686 2692

translate 4413 8413 12119 30113 3458

transparency 17211 1747 18711 2491


3755 40821 41115


8914 916 9210 treated 2521 5612

10518 2737 28415 35910

treating 10519 1068 36112

treatment 2920 3017 447 4815 5015 564 5726 661219 8917 902 914 1967 19615 2628 2638 3351 33912 35613 37419 37622 3775 38018 38210111315 3841315

treatments 169 222 5222 609 82172122 8310 9213 1599 3568 3794 3823717 3995


571 10112 1694 19417 20211 2385 2433 2791 2923 33721 34116 3727

trials 1819 194 202 266 275 3622 4319 4513 517 5417 581 62210 9114 1037 13811 139218 18712 20117 2025

21571415 23618 23919 24022 2531315 2531618 2555 32621 3271516 33522 33814 37811 3871415 38881120 3895 39122 3929911 3921422 39316 39317 39410 39615 3971421 4041921



16522 2857 34011 3594 36310 4071

truly 9819 1897 24018 244913 4031



1698 2691920 26921 28721 2915 41118

trying 3819 487 10614 15416 15811 16110 2046 22613 2312 2459 3032022 3443

tumor 882 2664 turn 920 238

7914 1774 turned 882 9414 turning 1115


2914 301519 5718 702 7314 927 971515 10313 1081113 1103 11111 115161718 1166 117520 14212 14321 1457 15919 171415 23217 23516 24413 266121 26816 26819 2695 27324 2761618 2771022 27818 28115 2834 30222 35113 36416 3732 3798 38317 3923 39614


1075 1318 1321 132517 14622 1471515 1511 21920 31617 32169 32522 3317 3516 35312

types 355 1716 2004 23916 32521 32716 3469 3664 39217

typically 1376 1417 1555 33710 33920

typo 1406 T)7 11671015

Uulceration 38017

Ulm 47 79 3606 36099 3666

ultimately 1811 9816 10415 10516 1735 38315 4029





16114 2265 23917

uncertainty 20716 2271116 24212 2421618 24420 24614 2776 28611 2981 38318 3945


23810 underestimate


3367 40721 undermine 8722


3419 3819 4315 4919 6719 1036 127511 15417 1731 1756 18222 20212 23417 33216 35811 37613 378619 37915

understandable 1094


Page 469

understanding 214 781621 14615 1559 15722 2419 3029 3053 31011 3717 4072022


32919 33720 3418 37722





72815 932 19012 19610 36915 3703


unique 1620 177 1911 2219 2616 3313 3915 439 456 5119 5318 5810 596 618 62920 7017 733 755 10212 10217 1057 106522 12217 1231 14716 1783 1891320 190261120 19113822 19212 1962 1991617 20029 2644 27417 27918 2802 2941114 29718

3091020 3168 32021 3213 3225 3232 3496 37417 38434 40311 4051718

United 203 3119 6510 6611 8910 1001617 17514 2258


University 32 518 10721 1081


35616 unnecessarily


25317 25412 2555 2569 2856 3072 30822 31112 3581 4011819 40819

unpredictable 21812


2906 unusual 523

25313 upcoming 317620


6858 753 15020 15118 1538 1801 21912 22115 22912 28911 38215 3853


urges 8017 17722 26320 38410


4069 USANs 30912

32213 use 2112 2489

537 6510 6821 6913 715 7810 7815 7961015 8514 89131721 912420 9921 1001 10121 10217 10821 1093 11320 12018 12536 1264 1276 1281418 1298 1381011 13913 13916 1424 14318 15218 1531 158713 15919 1605 16121 163211 16511 167822 1754 18714 19020 1939 19921 2081 22315 23620 23811 2579 262221 26818 2804 2829 2917 2929 29322 2989 30210 30819 3164 3226 3237 3263 3289 3305 34022 3423 3462 349813 35220 35319 3581 36510 36912 37611 3842 3894 39215 39611 39811 40012 40816

useful 126 859 11017 116815 117815 15617 15621 1573 15813 2146 28110 3311418 34814 35215



22821 25718 31321 3471



23622 23721 24015


23719 29821 3708

US 326 538 547 8922 1001218 1019 15220 160817192022 161171118 1624 16316 1705 1711 1778 17814 18813 20422 2051117 2193 2379 2471214 2481 2536 2541122 2575914 27714 2833 28719 28917 29211 3038 30821 3156 31713 32013 32219 32712141517 3321822 34712

353389 37618 37715 3802 39323 39416 39545 3968 39811


27217 2901733714 35815361915 38812


36022 3617Van 48 711


2149 2951730011 38715




31811variety 1714 2112

2117 2210 4710 12413 1335 1451922 1462

various 475 8413 2252 2749 3403 3421 40113

vary 1109 13822 20918 227529520 2962



Page 470

version 8812 20721 2796 3288 3318 3785

versions 17713 23216 3208 32615 34910 396811

versus 1106 1645 18713 24217 2515 25212 25720 27214 2781515 29513 3285 3301 3387


17419 18813 2327 24622 2617 3474


1415 18511 24317 2456 2574 2811 33821 3681 3723 3878 38817

viewed 6220 32119


36719 37922 vigorous 25011 Vink 315 613

1549 2462021 24622 25711 258510 25913 2605 3141015 31510



9416


896want 1918 2110

2447 2913 3213 351113369 4019 4314 4417 5913 8522 9013 937 9411 9717 102211061 118713020 13261342 1384 1391 14119 1621816617 1722018312 185171989 2063 2169 2174 2198 2464 24615 247362486 250625421 255625610 268152694 280628320 28432851 2949 2974 3047 346583939 409641114

wanted 634 10422 1332 1404 2012 201913 2588 3031 32413



3501519warnings 12622


4917 wasnt 2521

1691921 1701 1976 23014 31012

wave 31911 way 30113 3313

358 371619 474 652 8317 1023 10416 10956 13711 1389 14511 15111 15315 1555 1566 1581 1651 17014 1745 21422 22713 2307 2421 24912 2535 26220 27112 28021 28210 29416 3041 34312 35714 36310 3792 38310 38518 38811 40022 40120 41119

ways 177 858 9613 14014 14519 1515 1861316 22621 38213 40717

wearing 163 33214


9614 1801 1841 website 131 2248

7720 814 9620 9622 13112 31622



8621 951214 2044 21414 2322 2813 3842 39911 40813

welcomes 2077 3035 3688



23115 went 958 31515

3421 34517 werent 1677




2457 40117 40515

Wisner 41013


1304 1995 35813

wondered 269 21419 2588 3902

wonderful 1084 3594 40011

wondering 473 1469 3003 31212 3661


26221 3165 3462

wording 22317 23811 2645

words 2322 3614 1121 11519 16121 1659 16716 2782 29117 32161232113 3392 3412 38519

work 243 3721 389 428 4813 7813 8518 9815 9820 991 10414 12515 12717 13413 1355 1461014 1516 15313 1546 16517 1822 1962 2256 2921 29310 2951 31222 3267 3501 35619 39920

workable 705 1399 1472

worked 14110 15114 16316 16421 24918 3777 39919


Page 471

working 226 3220 478 1044 1068 1076 12915 14911 15610 21313 29020 30217 34318 36121

works 3219 388 4022 1043 14511 1556 2524 31022 37622

world 297 5120 5210 13722 1766 2192 2442 26112 2916 32117 3913 4001214 4062 40613

worldwide 2910 307101215 3110 555 6521 26114 3236 3568 4065

worlds 17420 24710



32117 40513 worthy 39119 wouldnt 2520

1342 14620 2442 25813 3465


10612 1217 12419 13322 13413 16613 18818 20818 2131 21422 2496 2611 27218 34414 3485 36812

wrong 1815

21518 38717 wrote 1686 22314

XX 13216

Y Yapundich 213

54 151820 2316 2420 265 2612 271419

year 301117 319 6613 9415 1378 13713 15212 1534 26114 31620 3243

years 2919 304 3115 4116 4710 13623 13719 14321 16517 16720 1681 17521 18122 23217 2471618 24915 25017 25615 29212 30221 3031 31910 32418 3581417 3595 36313 3668 373621 3778 402192020



24533

1 1 433 1131 1229

1902 21514 1100 3479 12 298 19 6616

14 36517 100 109 104 2042 10 2812 8210 10000 909 1000 955 1014 9510 1015 957100 1118 28117 107 51810903 112 11 19 24713 3307 11th 316191158 20313110000 7617119 519 12 2919 3581317

3595 37362012-year 1398

37421200 109125 111813 2919 4116 888

881013-year-old 38011135 52114 1363142 3085148 6315 16 55 87 1212

2418 5714 955 2471618 24915 25017 25615

15-minute 1067 31513

15-year 765150 528 1532 1503 112158 64 17 4116 837 1377

3283 174 66188 6819 81211922 390221952 40661970s 32310

1980 5013 17422 1989 6511 1996 25517 1999 2913

22 434 12319 1726

1903 3441538820

24 6616 248 31516 20 3016 9010

1378 25615 3548 40220

20-year 16516 2001 15222 2002 21822 2003 6617 21822 2006 25191115

40612 2008 563 2009 1019 7719

8122 829 34715 3681

2010 514 557 9614 15222 1531 28617 35218 3801215

2011 225 2811 7617 8117 834 11016 2427 38015 3915

2012 19 799 8721 2019 3557 2020 319 2677 204 69 21 8720 3283 21st 887 210 14822 216 61123rd 8712232 61224 2611324th 896246 61425 1371 29211 25th 1422 4059

409720 41112 250000 5213 260 7615 261 615 271 617 28 56 5710 287 619

33 435 1265 1904

33813 3411534416 38820

3C 1448304 3151730 1116 132 8210

13612 1672017520 34713

302 62131 112 8120 316 73324 7533 2928333 76347 7835 2891735000 521335-years 2917351(a) 35520

373919351(k) 22113

2331 2342023922 243735119 35278153545101335522 35625

360 710 3181 367 71337 569 27312 376 714

44 436 6618 1282

19054C 14474(b) 39516444 412240 58 26213

2631114 27215


Page 472

28117 2851 3193

400 2122 400000 6610 877 41 26315 27215

27220 27318 410 715 425 31722 45 2851

5 5 436 12813 500 102 1414 50 59 6013 2851

2881718 3193 34518

50000 3010 648 50-year-old 25113 501(c)(3) 287

4021 5011 505 3556 505(b)(2) 17210 505(j) 1723 55 2851 55000 413 5214 59 2878

6 6 2287 60 6013 2896 600000 3012 62000 11919 64 511 65 9414 69 835

7 7 11422 115111

1163 70 415 700000 6617 72 11213 75 513 823 76 8813

8 8 52 830 112 101

832 82 80 6816 1118

112812 82 6521 86 514

9957 959 90 1121113931 15221 95 516 11115

1136


473




Before FDA

Date 05-11-12





-----------------------Court Reporter



Documents

DEVELOPMENT OF BIOSIMILAR PRODUCTS + + + + + PART 15 … · 2014. 10. 16. · PANEL MEMBER MALONEY: Diane Maloney, Associate Director for Policy, CBER. PANEL MEMBER MARCHAND: Hello