1 The Law Firm That Knows its Science ENGEL & NOVITT, LLP The Law Firm That Knows its Science Keynote Address Regulatory Influences in Biogenerics-the

1ENGEL & NOVITT, LLP The Law Firm That Knows its ScienceThe Law Firm That Knows its Science

Keynote Address

Regulatory Influences in Biogenerics-the Next

Horizon

Gillian R. Woollett, M.A., D.Phil.Chief Scientist

Engel & Novitt, LLPThe Law Firm That Knows Its Science

October 19, 2009, San Francisco, CA

Second Annual Biotech Supply Chain Academy

The material and viewpoints set forth in this slide deckand conveyed during this presentation are presented by the author

in her capacity as Chief Scientist of Engel & Novitt, LLP.They do not represent and do not purport to represent the views of the law firmor any current or former-client of the firm, and should not be construed as such.


OUTLINEOUTLINE The premise of competition when patents expireThe premise of competition when patents expire Biotech products and the biotech pipeline – a Biotech products and the biotech pipeline – a

whole lot more are on the way…whole lot more are on the way… Minimal terminology for the biologics debateMinimal terminology for the biologics debate The current US regulatory framework The current US regulatory framework Biologics - the need for them is global, but can Biologics - the need for them is global, but can

they be made for a global market?they be made for a global market? Biologics business models and lessons from the EU Biologics business models and lessons from the EU

biosimilars experiencebiosimilars experience Current legislative efforts to create a new Current legislative efforts to create a new

regulatory pathwayregulatory pathway Opportunities and ConclusionsOpportunities and Conclusions


Obsolescence

The Traditional Incentives for InnovationThe Traditional Incentives for Innovation

Innovative drugs offer: Improved treatment Less side effects New therapeutic optionsand thereby replaceolder/less effectivemedications

Net Progress Radical New

Therapies and Iterative

Improvements

Generics offerhigh quality drugs for

established treatments

affordable costsand thereby free up healthcare funds for new innovative drugs

Incentives created by competition create new medicines & increase access

Patents ExpirePatents Expire


The Context for ALL BiolThe Context for ALL Biologicsogics

The 200 year history of biologics is the basis for their future:The 200 year history of biologics is the basis for their future:

Started with the very complicated – smallpox vaccine – and the Started with the very complicated – smallpox vaccine – and the decisions were empirical, and the studies “unethical”decisions were empirical, and the studies “unethical”

The biotech industry is much younger (first recombinant insulin The biotech industry is much younger (first recombinant insulin 1982), and the original biotech products were “biosimilars” - 1982), and the original biotech products were “biosimilars” - essentially biotech was a means of manufacturing previously essentially biotech was a means of manufacturing previously approved naturally-sourced products. Now we can do way more as approved naturally-sourced products. Now we can do way more as in Never-before-seen-in-nature products…in Never-before-seen-in-nature products…

FOBs are not just biosimilars, but also bioidenticals, second-FOBs are not just biosimilars, but also bioidenticals, second-generation products, biobetters, and bio-I-just-don’t-knowsgeneration products, biobetters, and bio-I-just-don’t-knows

Biobetters can be clinically-better, but Biobetters can be clinically-better, but alsoalso perhaps safer, more perhaps safer, more stable, more reliably manufactured and cheaper, or all of the stable, more reliably manufactured and cheaper, or all of the aboveabove


The Economic Issues for Biologics The Economic Issues for Biologics Matter NOWMatter NOW

Healthcare costs are high and increasing - all economies are under Healthcare costs are high and increasing - all economies are under pressure, but access is life/deathpressure, but access is life/death

Individual biopharmaceuticals are more expensive than drugs on a Individual biopharmaceuticals are more expensive than drugs on a per-patient basis, so prices have become conspicuous - attracting per-patient basis, so prices have become conspicuous - attracting political and media attention.political and media attention.

Medicines are a critical part of healthcare worldwide, but there is Medicines are a critical part of healthcare worldwide, but there is considerable price and product disparity, yet the companies and considerable price and product disparity, yet the companies and the patients are the samethe patients are the same

Biologics are, or are coming, off-patentBiologics are, or are coming, off-patent

Arguments for free-market pricing of drugs evoke an expectation Arguments for free-market pricing of drugs evoke an expectation of competition in the marketplace at the conclusion of patent of competition in the marketplace at the conclusion of patent termsterms

The opportunities from multiple sponsors are increasingly apparent The opportunities from multiple sponsors are increasingly apparent to all stakeholders; conversely their lack is a liability to biopharma to all stakeholders; conversely their lack is a liability to biopharma and patientsand patients


BIOTECHNOLOGYBIOTECHNOLOGY


Biotech Medicines in DevelopmentBiotech Medicines in DevelopmentN

um

ber

of

Pro

du

cts

in

Clin

ical Tri

als

Source: PhRMA Biotech Medicines in Development Surveys

Represents Represents pipeline for pipeline for

future Brand future Brand products and products and

then, then, subsequentlysubsequently

, for , for biosimilarsbiosimilars

8ENGEL & NOVITT, LLP The Law Firm That Knows its ScienceThe Law Firm That Knows its Science http://www.phrma.org/images/110308%20biotech%202008.pdf

The majority of Medicines in clinical

trials for the US may now be biotech

9ENGEL & NOVITT, LLP The Law Firm That Knows its ScienceThe Law Firm That Knows its Science http://www.phrma.org/images/110308%20biotech%202008.pdf

PhRMA Biotech Medicines in Development PhRMA Biotech Medicines in Development 2008 2008

Total Biotech

Medicines in clinical trials

for the US 633


Current US Regulatory PathwaysCurrent US Regulatory Pathways

STATUTESTATUTE

Derived from a Presentation By Keith Webber, Deputy Director, OPS, FDA. 25Sep07 GWU “Biosimilar 2007”

NEW DRUGNEW DRUGAPPLICATION (NDA)APPLICATION (NDA)AND 505(B)(2) NDAAND 505(B)(2) NDA

U.S. FOOD DRUG U.S. FOOD DRUG & COSMETIC ACT& COSMETIC ACT

ABBREVIATED NDAABBREVIATED NDA(ANDA) = (ANDA) = GENERIC DRUGGENERIC DRUG

U.S PUBLICU.S PUBLICHEALTH SERVICEHEALTH SERVICE

ACTACT

BIOLOGICBIOLOGIC LICENSELICENSEAPPLICATION (BLA)APPLICATION (BLA)

EXPEDITEDEXPEDITEDBLABLA

APPLICATIONAPPLICATION


Terminology has been distracting…Terminology has been distracting…

Biologic Biologic – is a prophylactic, in vivo diagnostic, or therapeutic – is a prophylactic, in vivo diagnostic, or therapeutic substance that is made in a living system, and that, generally, has substance that is made in a living system, and that, generally, has a large and complex molecular structurea large and complex molecular structure

Follow-on Biologic (FOB)Follow-on Biologic (FOB) – a subsequent version of a biologic, – a subsequent version of a biologic, independently developed and approved, but that shares the same independently developed and approved, but that shares the same mechanism of action as a previously approved product (includes mechanism of action as a previously approved product (includes so-called EU so-called EU BiosimilarsBiosimilars, plus some second generation biologics), plus some second generation biologics)

Second-generation biologicSecond-generation biologic - subsequent versions of biologics that - subsequent versions of biologics that are independently developed and approved, share the same are independently developed and approved, share the same mechanism of action as a previously approved product but are mechanism of action as a previously approved product but are explicitly different in some manner, e.g. inhaled. Sometimes called explicitly different in some manner, e.g. inhaled. Sometimes called “evergreened”.“evergreened”.

Biogeneric, or Generic Biologic Drugs Biogeneric, or Generic Biologic Drugs – should only be applied to – should only be applied to ANDAs for biologic drugs approved by FD&C Act. ANDAs are ANDAs for biologic drugs approved by FD&C Act. ANDAs are interchangeable with their reference productinterchangeable with their reference product


And please remember, while there may And please remember, while there may be a debate on naming…be a debate on naming…

……THE NAME DOES THE NAME DOES NOT CHANGE THE NOT CHANGE THE CONTENTS OF THE CONTENTS OF THE

TUBETUBE


So how do you tell what is in the tube…So how do you tell what is in the tube…

……with with

DATADATAAnd hence the issue for any biologic sponsor is what data, to And hence the issue for any biologic sponsor is what data, to demonstrate what, and to whom, at what price to get what demonstrate what, and to whom, at what price to get what market…market…

Answer:Answer: data to show safety, purity and potency or a data to show safety, purity and potency or a relationship to a reference product (with known safety, purity relationship to a reference product (with known safety, purity and potency) at the structural, functional, and clinical levels and potency) at the structural, functional, and clinical levels to the regulatorsto the regulators


Where are we with biosimilars Where are we with biosimilars todaytoday??

Generally accepted that the science is sufficient for some/most Generally accepted that the science is sufficient for some/most biosimilars todaybiosimilars today

Europe, Australia, Canada, Japan have biosimilars and Europe, Australia, Canada, Japan have biosimilars and competition is beginningcompetition is beginning

No Enacted US legislation but bills in play (albeit drowned in No Enacted US legislation but bills in play (albeit drowned in the larger health care reform debate)the larger health care reform debate)

Recognition of need for biologics competition in US as patents Recognition of need for biologics competition in US as patents expire, but aggressive defense by some Brandsexpire, but aggressive defense by some Brands

Huge confusion on the role of reimbursement, and need for Huge confusion on the role of reimbursement, and need for interchangeability to gain savings and accessinterchangeability to gain savings and access

Health care reform an Administration priority, and biosimilars Health care reform an Administration priority, and biosimilars seen to have potential to increase access seen to have potential to increase access andand save money save money

Global issues Global issues


The Biosimilars Story of Europe – a The Biosimilars Story of Europe – a TimelineTimeline

17Dec03 European Parliament “Future Medicines Legislation” (also 17Dec03 European Parliament “Future Medicines Legislation” (also called “Pharma Review Package”)called “Pharma Review Package”)

31Mar04 Directive 2004/27/EC (also known as Directive 31Mar04 Directive 2004/27/EC (also known as Directive 2001/83/EC as amended) and Regulation 726/2004. Came into 2001/83/EC as amended) and Regulation 726/2004. Came into effect 20Nov05effect 20Nov05

EMEA published general guidelines on biosimilars, as well as EMEA published general guidelines on biosimilars, as well as “class”-specific ones, but accepts and reviews applications “class”-specific ones, but accepts and reviews applications concurrentlyconcurrently

Approvals: April 06 First Approvals: April 06 First biosimilar approval biosimilar approval was Omnitrope was Omnitrope (somatropin); August 07 First (somatropin); August 07 First glycosylated protein glycosylated protein approved as a approved as a biosimilar, Binocrit (Epoetin alfa); March 09 EMEA Guideline on biosimilar, Binocrit (Epoetin alfa); March 09 EMEA Guideline on LMWH – first for a LMWH – first for a naturally-sourced biosimilarnaturally-sourced biosimilar

EMEA meeting on Biosimilar Monoclonal Antibodies Jul09EMEA meeting on Biosimilar Monoclonal Antibodies Jul09

Average <50Kd

Average ~150Kd

Selected Therapeutic Biologics by Product Selected Therapeutic Biologics by Product ClassClass


European Biosimilars are based on well-European Biosimilars are based on well-established regulatory standardsestablished regulatory standards

1996 US Guidance on Comparability for Manufacturing Changes for 1996 US Guidance on Comparability for Manufacturing Changes for drugs and biologics developed by FDA and Pharmadrugs and biologics developed by FDA and Pharma

Early 2000’s ICH Q5E Comparability standards adopted by EU US Early 2000’s ICH Q5E Comparability standards adopted by EU US and Japan – and Japan – HIGHLY SIMILARHIGHLY SIMILAR

EU Biosimilars based on similarity and guidelines developed, but EU Biosimilars based on similarity and guidelines developed, but MEANWHILE biosimilars were developed and approved. MEANWHILE biosimilars were developed and approved.

No central EU regulatory designation of interchangeability, up to No central EU regulatory designation of interchangeability, up to the health authorities in each countrythe health authorities in each country

Review and approval not coupled to patentsReview and approval not coupled to patents

Innovator exclusivity 8+2+1 for all medicines (drugs and biologics Innovator exclusivity 8+2+1 for all medicines (drugs and biologics are the same)are the same)


ICH HARMONISED TRIPARTITE GUIDELINE ICH HARMONISED TRIPARTITE GUIDELINE COMPARABILITY OF BIOTECHNOLOGICAL/BIOLOGICAL COMPARABILITY OF BIOTECHNOLOGICAL/BIOLOGICAL

PRODUCTS SUBJECT TO CHANGES IN THEIR PRODUCTS SUBJECT TO CHANGES IN THEIR MANUFACTURING PROCESS MANUFACTURING PROCESS

Q5E Q5E COMPARABLE: COMPARABLE: A conclusion that products have A conclusion that products have highly similar highly similar quality quality attributes before and after manufacturing process attributes before and after manufacturing process changes and that no adverse impact on the safety or changes and that no adverse impact on the safety or efficacy, including immunogenicity, of the drug product efficacy, including immunogenicity, of the drug product occurred. This conclusion can be based on an analysis of occurred. This conclusion can be based on an analysis of product quality attributes. In some cases, nonclinical or product quality attributes. In some cases, nonclinical or clinical data might contribute to the conclusion. clinical data might contribute to the conclusion.

Federal Register, Vol. 70, No. 125, June 30, 2005, pages 37861-37862Federal Register, Vol. 70, No. 125, June 30, 2005, pages 37861-37862

The Established Definition of Comparability The Established Definition of Comparability (EU, US, Japan)(EU, US, Japan)


The comparability/similarity with the reference The comparability/similarity with the reference product must be demonstrated at all levels of product must be demonstrated at all levels of product development:product development:Analytical comparability - physicochemicalAnalytical comparability - physicochemical

Functional Comparability in assays, and shown Functional Comparability in assays, and shown by animal studiesby animal studies

Clinical Comparability shown in Phase I and III Clinical Comparability shown in Phase I and III studiesstudies

A biosimilar product is designed to meet the A biosimilar product is designed to meet the criteria of the reference product with regards to criteria of the reference product with regards to quality, safety and efficacy.quality, safety and efficacy.This rigorous comparability exercise qualifies This rigorous comparability exercise qualifies Biosimilars for therapeutic interchangeBiosimilars for therapeutic interchange

The Comparability Exercise is fundamental to the The Comparability Exercise is fundamental to the Development of an EU Biosimilar ProductDevelopment of an EU Biosimilar Product

Define

targ

et

Pro

duct

deve

lopm

ent

Confirm

com

para

bility

with refe

rence

pro

duct

Preclinical

PK/PD

Clinicalsafety & efficacy

Biologicalcharacterization

Physicochemicalcharacterization

Complete product and process development

Define and characterize

reference productDefine

targ

et

Pro

duct

deve

lopm

ent

Confirm

com

para

bility

with refe

rence

pro

duct

Preclinical

PK/PD

Clinicalsafety & efficacy

Biologicalcharacterization

Physicochemicalcharacterization

Complete product and process development

Define and characterize

reference product

ESTABLISHING SIMILARITYESTABLISHING SIMILARITY

CONFIRMING SIMILARITYCONFIRMING SIMILARITY

Derived from a Presentation By Ingrid Schwarzenberger, Sandoz23Sep08 GWU “Biosimilar 2008”

Comparability is not e

asy, but th

e

concept is well e

stablished

20ENGEL & NOVITT, LLP The Law Firm That Knows its ScienceThe Law Firm That Knows its SciencePresented by Thomas Moore at Sanford Bernstein Biosimilars Conference, 3Dec09


The Safety and Efficacy of EU BiosimilarsThe Safety and Efficacy of EU Biosimilars

Nicolas Rossignol, then Administrator of the EC’s Nicolas Rossignol, then Administrator of the EC’s pharmaceuticals on questions of safety for EU biosimilars: pharmaceuticals on questions of safety for EU biosimilars:

"I don't judge case by case, but I have a message: we "I don't judge case by case, but I have a message: we have promoted and developed with the European have promoted and developed with the European Medicines Agency a special biosimilars framework. So Medicines Agency a special biosimilars framework. So we are confident that if a product meets all the we are confident that if a product meets all the requirements and gets a marketing authorisation from requirements and gets a marketing authorisation from the commission, it means that the product is as safe the commission, it means that the product is as safe and effective as any other product authorized by the and effective as any other product authorized by the commission" commission"

SCRIP World Pharmaceutical News 24 April 2008, reporting on EGA SCRIP World Pharmaceutical News 24 April 2008, reporting on EGA Meeting, LondonMeeting, London

22ENGEL & NOVITT, LLP The Law Firm That Knows its ScienceThe Law Firm That Knows its Science22

EU BiosimilarEU Biosimilar INNINN Reference ProductReference Product Auth./Pos. Op. DateAuth./Pos. Op. Date

OmnitropeOmnitrope(Sandoz)(Sandoz) SomatropinSomatropin GenotropinGenotropin

(Pfizer)(Pfizer)12 April 200612 April 2006

ValtropinValtropin(Biopartners)(Biopartners) SomatropinSomatropin HumatropeHumatrope

(Eli Lilly)(Eli Lilly)24 April 200624 April 2006

BinocritBinocrit(Sandoz)(Sandoz) epoetin alfaepoetin alfa Eprex/ErypoEprex/Erypo

(Janssen-Cilag)(Janssen-Cilag)28 August 200728 August 2007

Epoetin alfa HexalEpoetin alfa Hexal(Hexal)(Hexal) epoetin alfaepoetin alfa Eprex/ErypoEprex/Erypo


AbseamedAbseamed(Medice)(Medice) epoetin alfaepoetin alfa Eprex/ErypoEprex/Erypo


RetacritRetacrit(Hospira)(Hospira) epoetin zetaepoetin zeta Eprex/ErypoEprex/Erypo

(Janssen-Cilag)(Janssen-Cilag)18 December 200718 December 2007

SilapoSilapo(Stada)(Stada) epoetin zetaepoetin zeta Eprex/ErypoEprex/Erypo

(Janssen-Cilag)(Janssen-Cilag)18 December 200718 December 2007

BiograstimBiograstim(CT Arzneimittel GmbH)(CT Arzneimittel GmbH) filgrastimfilgrastim NeupogenNeupogen

(Amgen)(Amgen)16 September 2008/16 September 2008/24 July & 21 Feb 200824 July & 21 Feb 2008

Filgrastim RatiopharmFilgrastim Ratiopharm (ratiopharm GmbH)(ratiopharm GmbH) filgrastimfilgrastim NeupogenNeupogen

(Amgen)(Amgen)16 September 2008 /16 September 2008 /24 July & 21 Feb 200824 July & 21 Feb 2008

RatiograstimRatiograstim(ratiopharm GmbH)(ratiopharm GmbH) filgrastim filgrastim NeupogenNeupogen

(Amgen)(Amgen)16 September 2008 /16 September 2008 /24 July & 21 Feb 200824 July & 21 Feb 2008

TevagrastimTevagrastim(Teva Generics GmbH)(Teva Generics GmbH) filgrastimfilgrastim NeupogenNeupogen

(Amgen)(Amgen)16 September 2008/16 September 2008/24 July & 21 Feb 200824 July & 21 Feb 2008

ZarzioZarzio(Sandoz)(Sandoz)

FilgrastimFilgrastim NeupogenNeupogen(Amgen)(Amgen) 13 February 2009/20 November 200813 February 2009/20 November 2008

Filgrastim HexalFilgrastim Hexal(Hexal)(Hexal)

filgrastimfilgrastim NeupogenNeupogen(Amgen)(Amgen) 13 February 2009/20 November 200813 February 2009/20 November 2008

The EU Biosimilars approved to dateThe EU Biosimilars approved to date

With With approval approval sponsors sponsors

gain gain access in access in

all 27 all 27 countries countries of the EU, of the EU,

but but reimbursereimburse

-ment -ment systems systems still vary still vary

by by countrycountry


FDA Precedents for Everything?Brand Name Generic Name Regulatory

PathwayDate of FDA

approvalSponsor Reference product

(sponsor, date of original approval)

Naturally-sourced products

Repronex menotropins ANDA 10-Jan-97 Lederle/ Ferring

Pergonal (Serono, 1969)

Naturally-sourced products

Repronex menotropins 505(b)(2) 27-Aug-99 Ferring Pergonal (Serono, 1969)

Vitrase hyaluronidase 505(b)(2) 5-May-04 Ista Pharms Wydase (Baxter, 22-Mar-1950 )

Amphadase hyaluronidase 505(b)(2) 26-Oct-04 Amphastar Wydase (Baxter, 22-Mar-50 )

Hydase hyaluronidase 505(b)(2) 25-Oct-05 Primapharm Wydase (Baxter, 22-Mar-50 )

Recombinant products

Glucagen glucagon hydrochloride recombinant

505(b)(2) 22-Jun-98 Novo Nordisk Glucagon (Lilly, 14-Nov-60)

Fortical calcitonin salmon recombinant

505(b)(2) 12-Aug-05 Upsher Smith Miacalcin (Novartis, 17-Aug-95)

Hylenex hyaluronidase recombinant

human

505(b)(2) 2-Dec-05 Halozyme Wydase (Baxter, 22-Mar-50 )

Omnitrope somatropin 505(b)(2) 30-May-06 Sandoz/ Novartis

Genotropin (Pharmacia and Upjohn, 24-Aug-95)


But, for all biologics suppliers…But, for all biologics suppliers…

Regulatory requirements have increased as the collective ability to Regulatory requirements have increased as the collective ability to do “more science” has increased - sameness has become pursuing do “more science” has increased - sameness has become pursuing everything with every technique every time to show the absence everything with every technique every time to show the absence of a difference…of a difference…

Reference standards are not routinely available. No API commercial Reference standards are not routinely available. No API commercial model for biologicsmodel for biologics

Comparability has become increasingly difficult, even for Comparability has become increasingly difficult, even for innovators with their own products, e.g. when getting new facilities innovators with their own products, e.g. when getting new facilities on line, resulting in shortages. This drives pressures for more on line, resulting in shortages. This drives pressures for more suppliers. Quality matters.suppliers. Quality matters.

Alternative sources/products are needed, and also incented by the Alternative sources/products are needed, and also incented by the expanding markets (range of products, and more patients needing expanding markets (range of products, and more patients needing access), and manufacturing can be more efficient…access), and manufacturing can be more efficient…

Products in one market drive demands in others – global needsProducts in one market drive demands in others – global needs


Innovator comparability complicates the Innovator comparability complicates the storystory

AVONEX (Interferon Beta 1A) approved in 1996 based on AVONEX (Interferon Beta 1A) approved in 1996 based on comparability and without clinical studies on final materialcomparability and without clinical studies on final material

MYOZYME (alglucosidase alfa) for the treatment of late onset MYOZYME (alglucosidase alfa) for the treatment of late onset Pompe disease. FDA decides material made at different scales are Pompe disease. FDA decides material made at different scales are different products (Oct08)different products (Oct08)

CEREZYME (Imiglucerase) manufacturing shortages due to viral CEREZYME (Imiglucerase) manufacturing shortages due to viral contamination such that different products subject to expanded contamination such that different products subject to expanded access studies (Protalix – Glucocerebrosidase) or switching access studies (Protalix – Glucocerebrosidase) or switching (Zavesca - miglustat) (Zavesca - miglustat)

FDA authority to use comparability is clear, but their caution FDA authority to use comparability is clear, but their caution continues to be evident. Hence, it has become a very high continues to be evident. Hence, it has become a very high regulatory standard, and innovators inability to achieve it for their regulatory standard, and innovators inability to achieve it for their own products suggest that biosimilars sponsors will have own products suggest that biosimilars sponsors will have challenges too.challenges too.


Biosimilars can enable Regulatory Biosimilars can enable Regulatory Progress for all BiologicsProgress for all Biologics

The PHS Act (1903) requires a demonstration of safety, purity and The PHS Act (1903) requires a demonstration of safety, purity and potency. New legislation can enable, not impede, the potency. New legislation can enable, not impede, the accommodation of scientific progress into the regulatory accommodation of scientific progress into the regulatory framework – a win:win for all sponsors. framework – a win:win for all sponsors.

The goal of regulations for ANY biologic should be only to require The goal of regulations for ANY biologic should be only to require actionable data, i.e. ONLY, but ALL, necessary data on which to actionable data, i.e. ONLY, but ALL, necessary data on which to make appropriate decisions. Regulations need to evolve with the make appropriate decisions. Regulations need to evolve with the science if innovator products are to be licensed, and the promise science if innovator products are to be licensed, and the promise of biotech fulfilled. of biotech fulfilled.

Biosimilars are self-evidently possible, and FDA needs to the Biosimilars are self-evidently possible, and FDA needs to the authority to evaluate them and when appropriate designate them authority to evaluate them and when appropriate designate them as interchangeable. Only FDA will see the data and the licensure as interchangeable. Only FDA will see the data and the licensure has to be data-driven.has to be data-driven.

The FDA already has a >12 year old “sameness standard” for The FDA already has a >12 year old “sameness standard” for biologics and drugs called comparabilitybiologics and drugs called comparability


Progress in science and regulations is a Progress in science and regulations is a continuum… …and should be globalcontinuum… …and should be global

•Improved technology

•Orthogonal methods & data integration

Bio-manufacturing-technology

•Process Analytical Technology

•MOA•Quality by Design

Clinical•Critical Path•Adaptive clinical trials design

•Post-marketing studies

•More predictable outcomes

•Validation of biomarkers as surrogate endpoints

Pre-clinical •Better disease models

•Comparative immungenicity

•Better predictive safety models

•First generation biologics

•Follow-on biologics

•Including second generation

Progress in ALL or ANY give greater certainty to the development of:

Analytics

Note: Biologic can be manufactured using biotechnology, synthetic chemistry or using natural sources; some have been made with all three


So why are we having these discussions So why are we having these discussions about biosimilars, and why now? about biosimilars, and why now? BIOTECH IS A STORY OF SUCCESS BIOTECH IS A STORY OF SUCCESS Innovator biologics work and Innovator biologics work and

patents are expiring. Consumers want more of them, both as patents are expiring. Consumers want more of them, both as innovator products, and as cheaper versions of old products. innovator products, and as cheaper versions of old products. Access matters and is an unmet medical need.Access matters and is an unmet medical need.

ECONOMIC PRESSURES ARE ADDING TO THE NEED FOR A ECONOMIC PRESSURES ARE ADDING TO THE NEED FOR A SOLUTION ASAP SOLUTION ASAP Patents ending are visible, as are EU successes Patents ending are visible, as are EU successes with biosimilars, but cost is the biggest issue by far (both individual with biosimilars, but cost is the biggest issue by far (both individual and collective).and collective).

WE NEED COMPETITION FOR BIOLOGICS, AS WELL AS WE NEED COMPETITION FOR BIOLOGICS, AS WELL AS DRUGS DRUGS A lot can be learnt from the successes and failures of A lot can be learnt from the successes and failures of generic drugs, but we need a process to be appropriate for generic drugs, but we need a process to be appropriate for biologics. That requires legislation and the details will determine biologics. That requires legislation and the details will determine the savings. the savings.

THE ISSUES ARE GLOBALTHE ISSUES ARE GLOBAL


REGIONAL/NATIONALGLOBAL

Patient access Patient access toto Rx depends on market Rx depends on market access access forfor Rx Rx

ACCESSPatients are everywhere (albeit Dx and healthcare

infrastructure vary)IP varies, and getting a

little better harmonized, but barely (certain global

free-trade norms are emerging but limited)

Healthcare systems vary (affects reimbursements and ROI, 1y & 2y markets)

Companies develop and manufacture for the

leading markets, ideally global standards

(inconsistent requirements lead to requirements for

different products)

Regulations are regional with some

harmonization for drugs, and innovator

biologics (cost of getting to market less if can use a

single data set)

Market access is determined by

regulatory approval, market viability by

reimbursementCOMPETITION REQUIRES

MARKET ACCESS & FREEDOM TO PRICE


Canada Guidance

Final 0.03

BRIC plus others (2nd World)

BRIC plus others (2nd World)

ROW (Largely 3rd World)Largely lack health care infrastructure for complex biologics

WHO less relevant, but will recognize those standards

AustraliaUsing EU approach

0.02WHOBiosimilar Guidelines near final

BIOLOGICS/SIMILARS – the need for them is global, but can they be made for a global market?

Largely Supporting

WHO GuidelineInitiative

ICH plus others(1st World)

World Population Total 6.7

31ENGEL & NOVITT, LLP The Law Firm That Knows its ScienceThe Law Firm That Knows its Science http://www.ftc.gov/bc/workshops/hcbio/docs/fob/rgal.pdf

Top Approved and Marketed BiologicsTop Approved and Marketed Biologics


Current US Regulatory PathwaysCurrent US Regulatory Pathways

STATUTESTATUTE

Derived from a Presentation By Keith Webber, Deputy Director, OPS, FDA. 25Sep07 GWU “Biosimilar 2007”

NEW DRUGNEW DRUGAPPLICATION (NDA)APPLICATION (NDA)AND 505(B)(2) NDAAND 505(B)(2) NDA

U.S. FOOD DRUG U.S. FOOD DRUG & COSMETIC ACT& COSMETIC ACT

ABBREVIATED NDAABBREVIATED NDA(ANDA) = (ANDA) = GENERIC DRUGGENERIC DRUG

U.S PUBLICU.S PUBLICHEALTH SERVICEHEALTH SERVICE

ACTACT

BIOLOGICBIOLOGIC LICENSELICENSEAPPLICATION (BLA)APPLICATION (BLA)

EXPEDITEDEXPEDITEDBLABLA

APPLICATIONAPPLICATION


Product C

Licensure of Biologics in the US today: Licensure of Biologics in the US today: The only pathway is the “Full The only pathway is the “Full

BLA”BLA”

As long as A and B stay the same, can be sold without more clinical trials

can be made and licensed today.


Interchangeability versus Interchangeability versus SubstitutabilitySubstitutability

Responsibility of regulators (EMEA Responsibility of regulators (EMEA or FDA) or FDA)

Interchangeability = Therapeutic Interchangeability = Therapeutic EquivalenceEquivalence (based on (based on Pharmaceutical equivalence plus Pharmaceutical equivalence plus Bioequivalence)Bioequivalence)

SMALL MOLECULE DRUGSSMALL MOLECULE DRUGS

Responsibility of regulators Responsibility of regulators (EMEA or FDA)(EMEA or FDA)

Interchangeability =Interchangeability = Comparability Comparability (based on (based on highly similar at structural, highly similar at structural, functional, and clinical levels)functional, and clinical levels)

BIOLOGICSBIOLOGICS

DO PAYORS NEED THE SUBSTITUTABILITY MODEL OF GENERIC DRUGS TO GET REAL SAVINGS?

Responsibility of health authorities Responsibility of health authorities (Countries or States)(Countries or States)

SubstitutabilitySubstitutability

Responsibility of health Responsibility of health authorities (Countries or States)authorities (Countries or States)

SubstitutabilitySubstitutability


The US is falling behind…The US is falling behind…

European biosimilars are succeeding European biosimilars are succeeding – 13 marketing – 13 marketing authorizations, increasing visibility and no evidence of authorizations, increasing visibility and no evidence of quality, safety or efficacy problemsquality, safety or efficacy problems

The US is the largest biotech market The US is the largest biotech market – patents are expiring; – patents are expiring; the science is universal; 8 FD&C Act follow-ons to biologic the science is universal; 8 FD&C Act follow-ons to biologic drugs have been approved as 505(b)(2)s, one ANDA and two drugs have been approved as 505(b)(2)s, one ANDA and two in the wingsin the wings

Economic pressures have increased as biotech products have Economic pressures have increased as biotech products have succeeded succeeded – free-market pricing for Rx in the US cannot – free-market pricing for Rx in the US cannot expect to continue without competition becoming evident in expect to continue without competition becoming evident in the biologics market the biologics market

Health care reform in the works Health care reform in the works – maybe. Biosimilars bills are – maybe. Biosimilars bills are included in both US Senate and US Houseincluded in both US Senate and US House

Highlights important of availability of US pathway from date of enactment

Now

Biologics Patent Expiration Estimates Biologics Patent Expiration Estimates

Summary of Estimated Biosimilars SavingsSummary of Estimated Biosimilars Savings

Source

Population

Entire US Population Entire US population, but reported Federal Government savings

Medicare Part B beneficiaries

Entire U.S. Population

Timeline Rolling 10-year period 2008-2017, with no savings 2007-2012

“next ten years” beginning with pathway available in 2007

“over the next 10 to 20 years”

Therapies Evaluated

Erythropoietin, Interferons for Multiple Sclerosis, Growth Hormone for growth deficiency, Insulin for diabetes

Non-specific therapies.(Erythropoietin excluded almost entirely due to timeline and gradual market movement)

All PHS Act regulated biologics within the top 200 HCPCs that are currently reimbursed by Medicare Part B

Generic versions of the top 12 categories of biologic treatments with patent protections that have expired or are due to expire in the near future

Assumptions

Product specific analysis to calculate movable market share. Substitution rates of 83.4% (directly substitutable) and 49% (therapeutically substitutable). 25% discount on biogeneric products.

Assumes 10% of biologic spend goes off patent per year. Market penetration reaches 60% over 3-year period. Large revenue products reach discounts of 30%, medium revenue products achieve 10% discount.

Assumes only a single competitor to each already-approved biologic when it goes off patent (and that all patents are valid); that the savings will begin at 15% rising to 30% over 10 years

Assumes that a biogeneric pathway is approved in 2008 and those products already off patent could be approved by 2010. Assumes rapid introduction of biogenerics following patent expirations of original products. Price discount of 25-35% over a 10 and 20 yr period.

Conclusion $71 Billion savings opportunity in ten years following approval of generic biotech products.

Federal Government can save $3.6 Billion over ten years

Medicare Part B can save $14 Billion over next 10 years.

$67 billion to $108 billion over first 10 yrs and $236 billion to $378 billion over 20 yrs

Government Projections for Biosimilars SavingsGovernment Projections for Biosimilars Savings

SourceCBO-1CBO-1 CBO-2CBO-2 OMBOMB CBO-3CBO-3

Population

Entire US Population, but reported Federal Government savings

Entire US population, but reported Federal Government savings with and without Medicare Coding Reform

Entire US Population, but reported Federal Government savings

Entire US Population, but reported Federal Government savings (CBO Score of Pres. Budget)

Timeline 10-year period (2009-2018) 10-year period (2010-2019) 10-year period (2010-19) 10-year period (2010-19)

Therapies Evaluated

Non-specific therapies. Subset of biologics, that make up roughly three-quarters of the current market, that might face competition by Follow-On Biologics over the next 10 years

Non-specific therapies. Subset of biologics, that make up roughly three-quarters of the current market, that might face competition by Follow-On Biologics over the next 10 years

None identified. None identified.

Assumption Assumes S.1695 will be enacted near start FY 2009 & for interchangeability with 1 yr of market exclusivity to the 1st interchangeable FOB, 12 yrs of exclusivity to the innovator, and accounts for the possibility of “evergreening”. Assumes 35% market share for FOB and price discount of 40 % by 4th year of competition.

Same assumptions as CBO-1 but with the additional assumption that Medicare Part B would be modified to place the follow-on biologic in the same billing code as the reference product.

Assumes a period of innovator exclusivity “generally consistent with” Hatch-Waxman and that brands would be prohibited from “evergreening”.

Assumes a period of innovator exclusivity “generally consistent with” Hatch-Waxman and that brands would be prohibited from “evergreening”.

Conclusion Federal Government would save $6.6 Billion over 10 years. Figure includes revenue changes.

With no coding reform the total savings to Federal Government on Medicare and Medicaid would be $9.2 Billion; with the modification savings would total $12 Billion over 10 years. Figures include revenue changes.

Federal Government can save $9.24 Billion over 10 years. It is unclear whether this figure includes revenue changes.

Federal Government can save $13 Billion over 10 years. Figure includes changes in revenue.


An FDA designation of interchangeability can give options for An FDA designation of interchangeability can give options for automatic substitution with the reference product – the “Generic automatic substitution with the reference product – the “Generic Drug Model”Drug Model”

The absence of an interchangeability designation may give greater The absence of an interchangeability designation may give greater or fewer choices for payors, and this will depend on the or fewer choices for payors, and this will depend on the reimbursement infrastructure. Options may include:reimbursement infrastructure. Options may include:– Co-pays incentives for patients (tiering)Co-pays incentives for patients (tiering)– Prior authorization for physiciansPrior authorization for physicians– Step Therapy and/or switching (happens between payors, but Step Therapy and/or switching (happens between payors, but

less likely within)less likely within)

De Facto De Facto therapeutic substitution may give the greatest potential therapeutic substitution may give the greatest potential for savings to payors and patientsfor savings to payors and patients

The role of Government payors will be very influentialThe role of Government payors will be very influential

The Payor Role in the utilization of The Payor Role in the utilization of biosimilars is not yet clearbiosimilars is not yet clear


MedPAC recommendations to Congress MedPAC recommendations to Congress (June2009)(June2009)

Absent a free-market solution, alternative approaches will be Absent a free-market solution, alternative approaches will be considered, and they may be difficult for biopharma.considered, and they may be difficult for biopharma.

MedPAC examined three strategies to pay for biologics under Parts MedPAC examined three strategies to pay for biologics under Parts B and D that “by considering information about a drug’s clinical B and D that “by considering information about a drug’s clinical effectiveness, have the potential to improved the value of effectiveness, have the potential to improved the value of Medicare spending on drugs”:Medicare spending on drugs”:

Reference PricingReference Pricing: Set a drug’s payment rate no higher than : Set a drug’s payment rate no higher than the cost of currently available treatments unless evidence the cost of currently available treatments unless evidence shows the drug improves beneficiaries outcomesshows the drug improves beneficiaries outcomes

Payment for resultsPayment for results: Link a drug’s payment to beneficiaries : Link a drug’s payment to beneficiaries outcome through risk-sharing agreements with manufacturersoutcome through risk-sharing agreements with manufacturers

BundlingBundling: Create payment bundles for groups of clinically : Create payment bundles for groups of clinically associated products and servicesassociated products and services

Thus it would appear to be in biopharma’s interest to find a fair Thus it would appear to be in biopharma’s interest to find a fair and sustainable solution. and sustainable solution.


So what could legislation for the US So what could legislation for the US include in order to increase include in order to increase competition…competition… Delegate authority to FDA to approve biologics that reference a Delegate authority to FDA to approve biologics that reference a

previously approved PHS Act biologic (data will always be product previously approved PHS Act biologic (data will always be product specific, and sponsor must show safety, purity and potency). To specific, and sponsor must show safety, purity and potency). To maximize competition pathway must be:maximize competition pathway must be:– Immediately available Immediately available – Apply consistent regulatory standardsApply consistent regulatory standards– Allow for an interchangeability designationsAllow for an interchangeability designations– Flexible enough to absorb scientific developmentsFlexible enough to absorb scientific developments

The PHS Act is a paragraph, and works for innovator products, the The PHS Act is a paragraph, and works for innovator products, the ones we know the least about at time of initial approval - ones we know the least about at time of initial approval - something equally simple will do for biosimilarssomething equally simple will do for biosimilars

Respect IP rights of innovators and biosimilar sponsors, plus a fair Respect IP rights of innovators and biosimilar sponsors, plus a fair exclusivity incentive for innovator products.exclusivity incentive for innovator products.

Support global consistency in regulatory requirements, such that a Support global consistency in regulatory requirements, such that a global market access to biosimilars is possible tooglobal market access to biosimilars is possible too


US Legislation - OverviewUS Legislation - Overview

• Two Biosimilar Bills are in currently in play in 111th Congress:Two Biosimilar Bills are in currently in play in 111th Congress:• House Energy & Commerce Committee adopted “Licensure House Energy & Commerce Committee adopted “Licensure

Pathway for Biosimilar Biological Products”Pathway for Biosimilar Biological Products”• Senate H.E.L.P. Committee adopted “Biologics Price Senate H.E.L.P. Committee adopted “Biologics Price

Competition and Innovation Act of 2009”Competition and Innovation Act of 2009”• Both now part of Health Care Reform and to a great extent Both now part of Health Care Reform and to a great extent

dependent on how that develops over the next few monthsdependent on how that develops over the next few months• Neither have gone to the floor of their respective houses, and Neither have gone to the floor of their respective houses, and

amendments are expected.amendments are expected.• The disparate elements in the two bill will need to be reconciled at The disparate elements in the two bill will need to be reconciled at

Conference:Conference:• Regulatory Pathways– sameRegulatory Pathways– same• Exclusivity – similarExclusivity – similar• Patent provisions – differentPatent provisions – different

• Even if overall health care reform fails, biosimilars legislation may Even if overall health care reform fails, biosimilars legislation may become a “lifeboat”become a “lifeboat”


Senate Biosimilars BillSenate Biosimilars Bill

• Two-Step regulatory pathway based on “highly similar” Two-Step regulatory pathway based on “highly similar” standard (identical to House)standard (identical to House)

• Biosimilars - analytics, preclinical, clinical (any of which Biosimilars - analytics, preclinical, clinical (any of which can be waived by FDA), extrapolation between indications;can be waived by FDA), extrapolation between indications;

• plus switching studies for interchangeability designationplus switching studies for interchangeability designation• No blocking guidances or regulations as part of pathwayNo blocking guidances or regulations as part of pathway• REMS requiredREMS required• Same generic name (INN) possible Same generic name (INN) possible • 12 year innovator exclusivity (and 180 notification prior to 12 year innovator exclusivity (and 180 notification prior to

marketing biosimilar); 1 year for first interchangeable marketing biosimilar); 1 year for first interchangeable biosimilarbiosimilar

• Complex compulsory patent exchange provisions which put Complex compulsory patent exchange provisions which put patents at risk early, amends Title 35patents at risk early, amends Title 35

• No requirement for regulations to be promulgatedNo requirement for regulations to be promulgated


House Biosimilars BillHouse Biosimilars Bill

• Two-Step regulatory pathway based on “highly similar” Two-Step regulatory pathway based on “highly similar” standard (identical to Senate)standard (identical to Senate)

• Biosimilars - analytics, preclinical, clinical (any of which can Biosimilars - analytics, preclinical, clinical (any of which can be waived by FDA), extrapolation between indications;be waived by FDA), extrapolation between indications;

• plus switching studies for interchangeability designationplus switching studies for interchangeability designation• No blocking guidances or regulations as part of pathwayNo blocking guidances or regulations as part of pathway• REMS requiredREMS required• Requires unique name, but same generic name (INN) possibleRequires unique name, but same generic name (INN) possible• 12 year innovator exclusivity, plus possibility of 6 month 12 year innovator exclusivity, plus possibility of 6 month

pediatric extension; 1 year for first interchangeable biosimilarpediatric extension; 1 year for first interchangeable biosimilar• Complex compulsory patent exchange provisions which put Complex compulsory patent exchange provisions which put

patents at risk early, new regulations required, does not amend patents at risk early, new regulations required, does not amend Title 35Title 35


FDA Implementation - ExpectationsFDA Implementation - Expectations

• Will depend on the details in the final legislationWill depend on the details in the final legislation• Hope/expect:Hope/expect:

• Pathway implemented immediately (products already in Pathway implemented immediately (products already in queue - Woodcock testimony Mar07) queue - Woodcock testimony Mar07)

• FDA adequately resourced through user feesFDA adequately resourced through user fees• No requirement for new FDA regulations for pathway to be No requirement for new FDA regulations for pathway to be

availableavailable• Guidances will be developed, as in Europe, concurrently with Guidances will be developed, as in Europe, concurrently with

the biosimilars being reviewed and approvedthe biosimilars being reviewed and approved• Patent litigation could continue as today for biotech, i.e. Patent litigation could continue as today for biotech, i.e.

independently of FDA review and approval, but current independently of FDA review and approval, but current proposals have it linked such that FDA completes it review, but proposals have it linked such that FDA completes it review, but waits for the outcome of litigation before issuing the biosimilar waits for the outcome of litigation before issuing the biosimilar license. As such patents are at risk early. However, no Orange license. As such patents are at risk early. However, no Orange Book for biologics.Book for biologics.

• Full BLAs, including for second generation products, continue Full BLAs, including for second generation products, continue with patent litigation as today – unencumbered with patent litigation as today – unencumbered


Fundamental questions for any biologic Fundamental questions for any biologic sponsor - what data, what label, what market?sponsor - what data, what label, what market?

Are the regulatory standards for all biologics to be Are the regulatory standards for all biologics to be consistent, namely safety, purity and potency, and are consistent, namely safety, purity and potency, and are separate products evaluatable using comparability (ICH, separate products evaluatable using comparability (ICH, basis for EU & WHO)?basis for EU & WHO)?

Are regulatory authorities to be allowed to designate a FOB Are regulatory authorities to be allowed to designate a FOB and its reference as interchangeable or will payors decide and its reference as interchangeable or will payors decide individually, absent data and according to their own rules?individually, absent data and according to their own rules?

Is the US to get a new pathway – what is it and when is it Is the US to get a new pathway – what is it and when is it usable? Is FDA approval to be linked to the patent system?usable? Is FDA approval to be linked to the patent system?

Is competition in the market going to occur, and be seen to Is competition in the market going to occur, and be seen to occur? Or is “sameness” going to be a barrier…occur? Or is “sameness” going to be a barrier…

Are the rules enabling access to FOBs going to be consistent Are the rules enabling access to FOBs going to be consistent globally?globally?


Second-generation products, biobetters, Second-generation products, biobetters, and bio-I-just-don’t-knowsand bio-I-just-don’t-knows If it costs more to be biosimilar than to do a “full BLA”, why not be If it costs more to be biosimilar than to do a “full BLA”, why not be

better but use the advantages of:better but use the advantages of:– An RLD that has already defined the market valueAn RLD that has already defined the market value– Lower failure rate as have a model productLower failure rate as have a model product– Studies can be focused, and manufacturing efficientStudies can be focused, and manufacturing efficient– Tweaks can be market-based too, e.g. devices, stabilityTweaks can be market-based too, e.g. devices, stability– Not constrained by reverse engineering limitationsNot constrained by reverse engineering limitations– Get your own 12 year exclusivity Get your own 12 year exclusivity

Avoids innovator exclusivity should it be granted in US legislation Avoids innovator exclusivity should it be granted in US legislation (albeit patents still apply – same as today)(albeit patents still apply – same as today)

We all learn from prior knowledge, so biobetter can be just not-We all learn from prior knowledge, so biobetter can be just not-shown-to-be-the-sameshown-to-be-the-same

Biobetters can be developed for a global marketBiobetters can be developed for a global market


Opportunities and ConclusionsOpportunities and Conclusions We can learn from generic drugs, but we do not repeat the We can learn from generic drugs, but we do not repeat the

mistakes – no need to reinvent the patent morassmistakes – no need to reinvent the patent morass All stakeholders understanding their own interests, and engaging All stakeholders understanding their own interests, and engaging

to generate an expedited pathway to enable/increase competition to generate an expedited pathway to enable/increase competition and access will be a collective win:win. Poles are not helpful.and access will be a collective win:win. Poles are not helpful.

Quality will always matter, especially in the Post-Eprex and Post-Quality will always matter, especially in the Post-Eprex and Post-Vioxx world, and that affects the whole supply chainVioxx world, and that affects the whole supply chain

Realistic expectations of biologics, as well as drugs, such that the Realistic expectations of biologics, as well as drugs, such that the new products can reach patients and drive the upward cycle of new products can reach patients and drive the upward cycle of innovation, access and health matters. That means new biologic innovation, access and health matters. That means new biologic approvals tooapprovals too

Global consistency in regulatory requirements key – lessons from Global consistency in regulatory requirements key – lessons from Europe and beyond are useful Europe and beyond are useful

Reimbursement models must recognize biosimilars in a manner Reimbursement models must recognize biosimilars in a manner that fosters legitimate competition, not therapeutic substitutionthat fosters legitimate competition, not therapeutic substitution

Result can be creation of a regulatory pathway for FOBs in the US, Result can be creation of a regulatory pathway for FOBs in the US, that enables competition in the biologics market when patents that enables competition in the biologics market when patents expireexpire


Thank You!Thank You!

Gillian R. Woollett, M.A., D.Phil.Gillian R. Woollett, M.A., D.Phil.Chief scientistChief scientist

Engel & Novitt, LLPEngel & Novitt, LLPThe Law Firm That Knows Its ScienceThe Law Firm That Knows Its Science

www.engelnovitt.comwww.engelnovitt.com202.207.3307202.207.3307

[email protected]@engelnovitt.comThe material and viewpoints set forth in this slide deck

and conveyed during this presentation are presented by the authorin her capacity as Chief Scientist of Engel & Novitt, LLP.

They do not represent and do not purport to represent the views of the law firmor any current or former-client of the firm, and should not be construed as such.

Documents

1 The Law Firm That Knows its Science ENGEL & NOVITT, LLP The Law Firm That Knows its Science Keynote Address Regulatory Influences in Biogenerics-the