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■ The Keys to Precision Medicine

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4 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com

CONTENTS

April/May 2016

O U R M I S S I O N

Applied Clinical Trials is the authoritative, peer-reviewed resource and thought leader for the global community that designs,

initiates, manages, conducts, and monitors clinical trials. Industry professionals learn effective and efficient solutions

to strategic and tactical challenges within the tightly regulated, highly competitive pharma ceutical environment.

A P P L I E D C L I N I C A L T R I A L SVOLUME 25, NUMBER 4/5

COMMENTARY

VIEW FROM BRUSSELS

10 New Policy Could Temper

Europe’s Data-Disclosure Debate

Peter O’Donnell

CLINICAL TRIAL INSIGHTS

16 The Impact of Protocol

Amendments On Cycle Time

Kenneth A. Getz

A CLOSING THOUGHT

50 The Promise of

Precision Medicine

Steve Rosenberg

CLINICAL TRIALS COMMUNITY

6 APPLIED CLINICAL TRIALS ONLINE

8 NEWS

48 BUSINESS AND PEOPLE

MARKETPLACE

49 CLASSIFIED

CRO/SPONSOR

36 Imagining the Impossible:

Immunity to Cancer

Chris Smyth, PhD

The smaller biopharmaceutical

company perspective on mastering

oncology immunotherapy clinical trials.

TRIAL DESIGN

26 Value-Based Planning &

Drug Development Productivity

Frederic L. Sax, MD, Marla Curran,

DrPH, Sarah Athey, Christoph

Schnorr, MD, Martin Gouldstone

How to integrate evidence-based

planning and real-world evidence to

boost clinical trial productivity.

42 Overcoming Early Phase

Oncology Challenges

Karen Ivester

How to meet the rigorous safety and

efficacy demands critical to evaluating

newer targeted cancer therapies.

COVER STORY

18 How Biosimulation Can Predict Drug SuccessJ.F. Marier, Trevor N. Johnson, Suzanne Minton

Pediatric trials now feature increased modeling and

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6 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com April/May 2016

WEB CONTENTS

appliedclinicaltrialsonline.comwww.linkedin.com/groups/Applied-Clinical-Trials-2949042/about

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NEWS

V I E W F R O M W A S H I N G T O N

Among the multiple items on the “to-

do” list of new FDA Commissioner

Robert Califf is to make clinical re-

search more efficient and reliable to ac-

celerate the development of safe and

effective treatments for patients. Cal-

iff has long advocated for a “learning

healthcare system” that taps electronic

health records to facilitate clinical trial

design and enrollment, and to provide

ongoing information on the effects and

side effects of therapies in real-world

use. Now Califf has a ready platform to

promote such strategies to further preci-

sion medicine and expedited approval of

innovative medical products.

In a March appearance before a Sen-

ate Appropriations subcommittee to dis-

cuss FDA’s requested budget for fiscal

year 2017, Califf noted the agency’s suc-

cess in approving more innovative drugs

for market, many facilitated by expedited

review programs and patient engage-

ment in product development. His testi-

mony cited efforts to refine clinical trial

design and statistical methods of analy-

sis, and to utilize advances in genom-

ics and information technology to gain

“more rapid, less expensive and more re-

liable answers about medical products”

(see http://1.usa.gov/1pj7Kys).

Most of the hearing, though, focused

on the many other FDA activities im-

portant to the legislators, from effective

monitoring of the nation’s food supply

to halting the lethal abuse of opioids

(see page 13). Other top priorities for

FDA involve tobacco regulation, combat-

ing antibiotic resistance, reducing high-

risk drug compounding, and developing

medical countermeasures to Ebola and

Zika. Califf promised to soon issue guid-

ances and regulations to further biosimi-

lar development and to better manage

FDA’s IT infrastructure. He also will have

to seek Congressional backing for multi-

ple new user fee proposals now being fi-

nalized by FDA and industry task forces.

During his confirmation process, Cal-

iff pledged that he would not lower FDA’s

standards in evaluating the safety and

efficacy of drugs and medical devices in

response to challenges from legislators

who feared that his ties to pharma would

bias him towards industry. And while he

avoids discussing drug prices, he rec-

ognizes that FDA can promote drug ac-

cess by bringing more generic drugs to

market, and that good information about

medical product risks and benefits can

support those who make coverage deci-

sions.

Califf’s expertise in biomedical re-

search should help him tackle these

and other difficult regulatory and policy

issues, as seen in his activity as FDA

deputy commissioner for the past year.

At a December 2015 FDA workshop on

enhancing the collection and assess-

ment of clinical data on diverse patient

subgroups, he described the challenges

in managing trials to generate such data.

He recently opened a meeting of FDA’s

Science Board that was called to advise

the agency on the development and reg-

ulation of medical treatments for pain,

where new product research is impor-

tant for lowering opioid abuse.

A blog posted on FDA’s website in

February cites progress in clarifying

terms and definitions related to the de-

velopment of biomarkers and other tools

needed to advance biomedical research

and inform clinical trials. And last Oc-

tober, the commissioner endorsed an

FDA report on coordinating the review of

combination products, a hot topic in the

biomedical research community. Cancer

advocates have been pressing for a new

entity to coordinate the development

and oversight of cancer therapies and

diagnostics, and Califf has said he will

establish such a center under the White

House Cancer Moonshot initiative.

At a March Institute of Medicine (IOM)

workshop on “Neuroscience Trials of the

Future,” Califf described some of the dif-

ficulties and opportunities facing FDA

and sponsors in achieving more effective

clinical studies on treatments for nervous

system disorders. In the “ideal world”

of a learning healthcare system, Califf

commented, sponsors and investigators

would conduct concept studies that lead

to informed clinical trials, and those re-

sults then would be used to write practice

guidelines and to guide more “real-world”

studies that, in turn, would provide more

evidence and refine practice.

Complexity and costs

Unfortunately, Califf sees the research

community opting for larger, more com-

plex clinical trials, with the result that

costs are “going off the scale.” Inves-

tigators enroll fewer patients per site

because “we’re making things more

and more complex,” something that he

hopes FDA can address. He suggested

that trials stop running multiple blood

tests and collecting rare, non-serious

adverse events from all patients, which

“costs a ton of money.”

It’s not necessarily FDA that seeks

more data from larger studies, Califf

observed, but sponsors that shy away

from simplified studies—often to avoid

greater uncertainty. The challenge for

FDA, he said, is to develop study models

that all parties “feel good about.” FDA

can’t promise it will approve a new prod-

uct if the researchers do things in a cer-

tain way, as there are “always surprises

with medical products,” he commented.

But the agency can assure, Califf said,

that it won’t come back later and say it

didn’t like that approach.

— Jill Wechsler

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To see more View From Brussels articles, visit

appliedclinicaltrialsonline.com

NEWS

It’s a long-running battle, and the fat

lady still hasn’t sung, so it ain’t over

yet. But Europe moved one step

closer in March to quenching the

conflagration over transparency and

clinical trial data. A weighty document

running to nearly a hundred pages

appeared from the European Medicines

Agency (EMA), aiming to squeeze much

of the oxygen out of the debate that has

been raging for years about how much

information companies should disclose

about their products and their trials of

them. (view the report at http://bit.ly/1RsfIeS).

The guidance for the publication of

clinical data explains to everyone who

wants to know just how the agency is

going to operate its new system of

mandatory publication of data, and just

what requirements are to be imposed on

industry on submission of clinical data

for publication.

The new policy entered has been in

force since Jan. 1, 2015, in that it covers

the clinical reports contained in all

marketing-authorization applications

submitted from then onwards, but the

first actual reports to appear are—

because of the time-lag in processing

applications—currently likely to appear

only from this coming September.

One of the hot spots in the document

is the guidance on how to anonymize

clinical reports for publication, so as

to prevent any re-identification of trial

participants. Bowing to the inevitable,

given the wide range of methods

available, EMA recognizes that no one

method can be imposed, and permits

some freedom of approach. But it

gives recommendations to companies

on how to best balance data utility for

researchers with a minimal risk of re-

identification, and companies will need

to provide a report explaining their

approach. That report will in turn be

reviewed and published by EMA.

But the real heat will be emitted by the

document’s approach to commercially

confidential information (CCI). Fierce

arguments over the very concept of CCI

have put drug companies (and regulators)

at odds with healthcare campaigners in

Europe, many of whom flatly refuse to

recognize the merits of any methodology

for identification and redaction of what

companies perceive as sensitive material.

In a scorched earth approach, the most

vocal campaigners reject any such rights,

and argue that the only ownership of such

data lies with the trial participants whose

involvement has generated the data.

EMA has trodden a middle path

of reason on the issue. It knows how

inflammable this discussion is, and how

determined industry critics are to pursue

the fullest access to information. So its

guidance makes clear that we are now

very much into open season for data

hunters.

“The vast majority of the information

contained in clinical reports is not

considered CCI,” it says. But “the vast

majority” is not the totality, and EMA

goes on to spell out its exceptions. It

defines CCI as “any information

contained in the clinical reports

submitted to EMA by the applicant

which is not in the public domain or

publicly available and where disclosure

may undermine the legitimate economic

interest of the applicant.” There are, it

says, “limited circumstances in which

clinical reports might contain CCI,” and

the data classified as CCI may indeed be

redacted (or, to put it plainly, lest this

column should be accused of unjustified

redaction, simply blacked out).

With masterful understatement,

the guidance document remarks: “It is

anticipated that the preparation and

publication of the documents will raise

some practical questions, such as on how

to apply the aforementioned redaction

principles, and on the presentation and

justification of the proposed redactions.”

Where redact ion takes place,

companies will need to provide

justification to EMA. The guidance

clarifies which type of data EMA would

typically refuse as being CCI and how the

redaction of such data will be handled.

Its broad framework starts from the

principle that it will not accept redaction

of any information in the public domain

or that has no innovative features.

It will also frown upon attempts to

redact quality, non-clinical and clinical

data which it believes to be necessary

for the understanding of the rest of the

clinical report, thus making its disclosure

a matter of public interest. And the

agency helpfully supplies some real-life

examples of attempts that have already

been rejected to justify redaction of

material in reports.

So don’t waste any time with the

following arguments: “Unpublished

data—These study results have not been

published in any peered-reviewed [sic]

Will EMA Rules Take Heat Out of Transparency Debate?

New policy hopes to calm the fervor around clinical trial data disclosure and confidentiality issues

Peter O’Donnell

is a freelance journalist who

specializes in European

health affairs and is based

in Brussels, Belgium.

V I E W F R O M B R U S S E L S

appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 11April/May 2016

NEWS

publication.” “Company confidential

information—Disclosure of these

elements will harm [the company]’s

commercial interests because it may

enable third-party access to business-

critical information.” “This information

can be interpreted out of context. Such

interpretation could lead to a misleading

image of the safety profile of the product.”

Clinical reports will be published at

the conclusion of regulatory decision-

making in the centralized marketing

authorization procedures—irrespective

of whether the decision on a marketing

authorization application is positive or

not. The reports—with anonymization

and agreed redaction—will be published

by EMA on its corporate website, within

60 days of the final decision for marketing

authorization applications, line extension

applications, and extension of indication

applications. Where an application

is withdrawn, the publication of the

redacted/anonymized clinical reports

will take place within 150 days after the

receipt of the withdrawal letter.

The hope within EMA is that its

approach will damp down the debate and

allow attention to return to the content

of reports, rather than the processes for

accessing the data they contain. The

agency has been engaged in extensive

consultation with all parties concerned

throughout 2015, and is cautiously

optimistic that its patient negotiation

has permitted a well-balanced set of

requirements to emerge that can satisfy

all sides.

Now that D-Day is approaching for

publishing the first reports under this

new dispensation, the agency is planning

to hold talks with the companies at the

front of the firing line—those for which

the decision-making process has been

finalized since the policy entered into

force, and whose reports will constitute

the first wave of publication. It is also

planning a webinar in the late spring for

companies to raise outstanding practical

questions.

Further down the track, still more fiery

exchanges can still be expected, because

the scheme now starting to deliver real

reports is only the first phase of the

agency’s CT transparency bid. While this

first phase deals only with publication

of clinical reports, a second phase will

deal with the still-more sensitive issue of

publishing individual patient data. But this

is still on the back burner; the agency says

that although it is committed to moving in

that direction, no dates have been set, and

it “will be implemented at a later stage.”

Ultimately, the success—or failure—of

this attempt to calm spirits on access to

trial data may depend more on emotion

than on logic. There are implacable views

among the most earnest advocates of

access to data, who recognize no claims

for exemption and who, in the style

of Wikileaks, demand full release of

everything all the time. A lengthy and

carefully-reasoned list of guidelines on

the right and wrong way of doing things

may not prove a sufficient response to

that type of argument.

Ultimately, the success—or failure—of this

attempt to calm spirits on access to trial data

may depend more on emotion than on logic.


NEWS

G L O B A L R E P O R T

The European Medicines Agency

(EMA) has published draft guidance

on the evaluation of anti-cancer medi-

cines in humans.

The 39-page document, which was is-

sued on March 15 and is open for feed-

back until September 15, covers all

stages of clinical development and ad-

dresses the development of treatments

for malignancies, including drug resis-

tance modifiers or normal tissue protec-

tive compounds.

The agency is concerned that although

many anti-cancer compounds are be-

ing developed, companies have only ob-

tained a marketing authorization for a

relatively small percentage of them due

to poor activity or evidence of a detri-

mental safety profile. Until non-clinical

models with good predictive properties

have been defined, this situation is un-

likely to change, and the absence of such

models represents the greatest hurdle for

efficient drug development in the near

future, EMA noted.

A central aim of the document is to

promote the development of molecule-

specific preclinical models to assess and

predict anticipated activity as well as

safety, which tends to be a standard ap-

proach used by developers of targeted

molecules. The validation and predictive

reliability of these models is a complex,

time-consuming, and specialist process

that requires tumor immunologists.

EMA has sought to classify com-

pounds according to reasonable de-

signs of exploratory studies. This ap-

plies to cytotoxic compounds where the

toxicity and overall response rate (ORR)

are thought to be suitable markers of

activity in dose-finding studies, com-

pared with non-cytotoxic compounds

where ORR and/or toxicity may not

serve this purpose.

Importantly, intra-patient dose esca-

lation in Phase 1 can allow more effec-

tive drug levels to be reached, provided

no toxicity is seen in two dosing cycles,

state the authors of the document. This

might help smaller biotech companies,

for example.

“The requirements of the characteriza-

tion of the safety profile have changed

with the emergence of molecularly tar-

geted agents, immunomodulating drugs,

and other non-cytotoxic agents. These

types of agents may have other types of

toxicity and are often dosed differently to

conventional chemotherapy,” they wrote.

“The dose-finding process and concepts

such as dose-limiting toxicity may, there-

fore, need to be addressed differently

than for standard cytotoxic agents.”

Moreover, cumulative incidences

by toxicity grade are not sufficient to

characterize the toxicity profile. The im-

pact of an adverse drug reaction on the

benefit-risk balance may, for instance,

differ importantly depending on how

the incidence, prevalence, and severity

change with time on treatment, and on

the possibility to alleviate the reaction

by dose reduction.

Survival clues

EMA is urging companies to submit over-

all survival data compatible with a trend

towards favorable outcome to capture

potential negative effects on the activ-

ity of next-line therapies and treatment-

related deaths. This approach is likely to

have consequences on interim analyses,

other than for futility, and cross-over,

which should be undertaken only when

available survival data provide the infor-

mation needed for a proper evaluation of

benefits and risks, explained the authors.

As well as defining the appropriate

doses and schedules of a cancer drug,

the EMA emphasize’s the importance of

identifying a target population with op-

timized benefits and risks in the section

about exploratory studies. Advice is also

supplied about studies for combinations

of drugs with minimal activity, as well as

combinations of conventional cytotoxics.

No precise definition is given for ei-

ther “trend towards favorable effects on

survival” or “reasonably excluding nega-

tive effects on overall survival,” but the

authors explain that if a major increase

in toxicity is foreseeable, it is recom-

mended that confirmatory studies are

undertaken with the aim of showing

overall survival benefit. They acknowl-

edge that improved safety without loss

in efficacy may constitute tangible aims

and the design of non-inferiority efficacy

studies.

The safety focus of the document has

added relevance in the light of the re-

cent events of Zydelig, the PI3K inhibitor

made by Gilead Sciences. The drug is be-

ing investigated by EMA after reports of

serious side effects—including multiple

deaths—among patients in several stud-

ies testing Zydelig in newly diagnosed

leukemia and lymphoma. Gilead halted

those trials in March.

Earlier in March, EMA published

long-awaited guidance on how to com-

ply with its policy on publication of

clinical data. The agency is moving to-

ward the operational implementation of

its proactive publication policy, which

has launched a new era of transparency,

said Noël Wathion, the agency’s deputy

executive director.

The guidance will ensure that com-

panies are aware of what is expected of

them and are ready for the publication of

these critical data, he added. EMA wants

to work with companies that are con-

cerned by the first wave of publication

(i.e., those for which the decision-making

process has been finalized since the pol-

icy entered into force). EMA is organizing

a webinar in the second quarter of 2016

to allow companies to ask any outstand-

ing practical questions. This webinar will

be a live broadcast and will be available

for future reference on the EMA website.

— Philip Ward

EMA Releases New Advice on Human Trials for Cancer Drugs


NEWS

R E G U L A T O R Y R E F O R M

Another European Approach to Early Drug Access

Rising concerns among Europe’s health-

care payers about the additional costs

of innovative medicines are doing

nothing to stem the tide of initiatives to

speed new products to the market.

The latest new scheme is the European

Medicines Agency’s “PRIME” (short for

“PRIority Medicines”), launched in March

“to strengthen support to accelerate med-

icines that target an unmet medical need.”

It will offer early advice to medicine devel-

opers so that they have the best chance

of producing robust data on benefits and

risks, and allow more rapid assessment.

Improved clinical trial designs should

ease data generation and the evaluation

of applications for marketing authoriza-

tion, and early dialogue will also serve to

boost patient participation in trials and

make best use of limited resources, said

the European Medicines Agency (EMA) in

its announcement.

The scheme focuses on medicines that

may offer a major therapeutic advantage

over existing treatments, or benefit pa-

tients with no treatment options—drugs

formally considered priority medicines

within the European Union (EU). It builds

on existing EU regulatory tools, and will

take advantage of the shorter timeframe

envisioned for decisions on drugs for un-

met needs that have been evaluated un-

der an accelerated assessment procedure.

To qualify for the scheme, potential

must be demonstrated by early clini-

cal data, and once selected, a medicine

will receive attention from an expert ap-

pointed by the EMA who will help build

knowledge ahead of a marketing authori-

zation application, organize meetings with

relevant EMA committees and working

parties, as well as with health technol-

ogy assessment bodies, and will mentor

throughout the development process.

This arrangement is made in agree-

ment with the European Commission,

which is legally responsible for market-

ing authorization decisions in Europe’s

tangled drug control system. Vytenis An-

driukaitis, EU Commissioner for Health,

gave his blessing to PRIME as “a major

step forward for patients and their fami-

lies that have long been hoping for earlier

access to safe treatments for their unmet

medical needs.”

In fact, Andriukaitis is viewing it as

something of a panacea for many current

ills. He is looking forward to the enhanced

scientific support of PRIME to help “ac-

celerate the development and authoriza-

tion of new classes of antibiotics or their

alternatives in an era of increasing anti-

microbial resistance.” He also sees it as “a

potential godsend for those suffering from

diseases for which there are currently no

treatment options”—and particularly rare

cancers, Alzheimer’s disease, and other

dementias.

— Peter O’Donnell

FDA to Address Opioid Trial Challenges

FDA is under tremendous pressure from

Congress, state officials, and the pub-

lic health community to do more to

address the national epidemic of opioid

abuse that is causing thousands of deaths

and medical emergencies. But while pa-

tients and providers demand effective

treatments for chronic and acute pain,

the public wants safeguards to prevent

overdosing and misuse of these products.

Drug labels, boxed warnings, prescriber

education, and postapproval monitor-

ing have not deterred abusers. Now FDA

leaders are implementing a new Action

Plan to address the problem more force-

fully, and hopefully to quell critics on Cap-

itol Hill and in the medical community.

One important element of the plan is

to encourage development of new, more

effective pain medications with abuse

deterrent (AD) properties, an issue ad-

dressed at a March meeting of the FDA

Science Board. FDA is reassessing how

it weighs risks and benefits in approving

opioid drugs and expanded use of its ad-

visory committees is part of this process.

A main FDA strategy in recent years

has been to encourage development of

abuse-deterrent formulations (ADFs) of

opioids. Five products with AD claims

in labeling have been approved by the

agency, supported by guidance final-

ized in 2015 on what studies and data is

needed to support AD product develop-

ment and approval. The Office of New

Drugs (OND) in the Center for Drug Evalu-

ation and Research (CDER) is evaluating

some 30 active investigational new drugs

(INDs) for these products and other new

technologies.

Despite these efforts, many develop-

ment programs for new pain medicines

fail, said Sharon Hertz, director of the

Division of Anesthesia, Analgesia and Ad-

diction Products in OND. There are many

sources of variability in clinical analgesic

trials, which makes it very difficult to mea-

sure treatment effect, Hertz explained.

FDA seeks to address such R&D issues

through collaboration with academics,

health professionals, advocacy groups,

and industry. The aim is to gain consen-

sus on standards for measuring pain in-

tensity and on different outcomes in clini-

cal studies and to optimize clinical trial

methods to increase study efficiency.

— Jill Wechsler


NEWS

D A T A A N A LY S I S

C L I N I C A L T R I A L T E C H N O L O G Y

Are pharmaceutical company Phase III

clinical trials becoming more com-

plex? The most broadly based data-

base available, ClinicalTrials.gov, does

not support the assertion that clinical

trials have become more complex in

study/protocol design or execution. Illus-

trative is the number of countries used

in pharmaceutical company sponsored

Phase III clinical studies.

The number of countries used in

commercially sponsored Phase III trials

has not changed in recent years. It is

essential to stratify the results or oth-

erwise the data appear to show that the

number of countries per study has actu-

ally declined. The chart at right strati-

fies the studies by planned study dura-

tion: less than one year, 1 to 2 years

and 3 or more years. This is important

because the longer the planned study,

the more likely the study may be open-

ing sites in additional countries. When

stratified this way, the data show practi-

cally no change over the years covered.

— Harold E. Glass, PhD

After eight years in development, FDA’s

Sentinel system is poised to play a

more visible role in assessing medi-

cal product efficacy, as well as safety.

There are plans to expand it to gather

information on the performance of medi-

cal products in real-world settings, which

may assist researchers and clinicians in

answering broader questions about treat-

ment use.

Sentinel has been a big investment for

FDA, commented Janet Woodcock, di-

rector of the Center for Drug Evaluation

and Research (CDER), at the recent 8th

Annual Sentinel Initiative Public Work-

shop. A future pay-off, she noted, will

enable other groups to utilize the system

to “assess product performance beyond

safety.” FDA intends to expand the use of

Sentinel by leveraging its data for addi-

tional research, public health, and qual-

ity improvement activities.

The Sentinel program was launched

in 2008 to expand FDA’s capacity to

actively identify and assess postmar-

ket risks for medical products. It now

has become an “integral part of routine

safety surveillance” for drugs, biologics,

and other medical products, Woodcock

noted.

This has involved establishing an in-

frastructure and governance policies

that are transparent and respect patient

privacy. Health plans and providers par-

ticipating in the Sentinel network now

provide access to patient electronic

health records and claims data on some

193 million individuals. An important

recent addition is the Hospital Corp. of

America, which can provide patient re-

cords from 168 hospitals and 113 surgery

centers across the US. Data from the

Medicare Virtual Research Center, more-

over, will significantly increase informa-

tion related to older patients.

In addition to building Sentinel use

by CDER, the system is expanding sur-

veillance and analysis of vaccines and

blood products by the Center for Biolog-

ics Evaluation and Research (CBER). A

Sentinel “Tree Scan” project involves

assessing vaccine safety and outcomes

in pregnancy. Another CBER project will

tap added hospital data to evaluate if

there is a relationship between blood

transfusion and lung injury and death.

— Jill Wechsler

Number of Countries in Phase III Studies Remains Steady

Sentinel Initiative Expands to Support Clinical Research

Source: Department of Health Policy and Public Policy, University of the Sciences, Philadelphia,

PA, using ClinicalTrials.gov data

The average number of countries per study by designed study duration by

year.

14

12

10

8

6

4

2

02008 2009 2010 2011 2012 2013

<1yr 1-3yrs 3+yrs

Phase III Clinical Trials: Number of Countries and Duration

TECHNOLOGY IS ONLY

AS SMART AS THE

THINKING BEHIND IT.

An innovative approach. One that infuses clinical

research expertise from across our organization

into the designs of our Informatics solutions.

And an eClinical platform, Perceptive MyTrials,®

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So you can do more with your data—at every step.

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at proof.PAREXEL.com/informatics

© 2015 PAREXEL International Corp. All rights reserved.



To see more Clinical Trial Insights articles, visit


Cl inical trials with at least one

substantial protocol amendment

require several hundred thousand

dollars in unplanned direct costs

to implement. But perhaps the most

expensive impact is the unplanned

incremental cycle time tacked on to the

study. A new analysis by the Tufts Center

for the Study of Drug Development (Tufts

CSDD), in collaboration with more than

a dozen sponsors and contract research

organizations (CROs), indicates that

protocols with at least one substantial

amendment take an average of three

unplanned months more to complete

than do those without an amendment.

These findings shed new light on the

importance of adopting new strategies to

reduce select amendments.

Collecting amendment data

Between March and July 2015, Tufts CSDD

and 15 pharmaceutical companies and

CROs collected data from 836 Phase I –

IIIb/IV protocols approved between 2010

and 2013. Protocols approved within the

more recent 12-month period were excluded

from the study, as these had the potential

to continue accumulating amendments

following the conclusion of clinical trial data

collection. From the protocols reviewed,

Tufts CSDD analyzed data from 984

amendments. Seven of the 15 participating

companies also gathered direct cost data

from 52 protocols for which substantial

amendments had been identified during the

January and May 2015 timeframe. This study

was supported in part by an unrestricted

grant from Medidata Solutions.

Only substantial protocol amendments

were evaluated in this study to ensure a

more consistent assessment of prevalence

and impact. Substantial amendments

were defined as any change to a protocol

on a global level requiring internal

approval followed by approval from the

institutional or ethical review board or

regulatory authority. Country-specific

amendments that affected protocol

designs for clinical trials within a given

region alone were excluded.

High prevalence... and avoidability

The majority of protocols (57%) had at

least one substantial amendment.

On average, across all phases, the

typical protocol had 2.1 substantial

amendments. Phase II and III studies had

the highest prevalence at 77% and 66%

of the total, respectively. The average

number of substantial amendments

per Phase II protocol was 2.2; Phase III

studies—typically the longest duration

and the costliest to conduct—had the

highest mean number (2.3) of substantial

amendments.

Sponsors report that the vast majority

of changes made to an approved protocol

originate internally. Only one-in-six (16%)

stems from a regulatory agency request.

The most common changes addressed by

a substantial amendment are associated

with modifications and revisions to study

volunteer demographics and eligibility

criteria (53%). Four-out-of-10 (38%)

changes are related to modifications

to safety assessment activity; 35% are

related to typographical errors; 27% are

associated with endpoint modifications.

In the Tufts CSDD study, sponsors

and CROs reviewed their respective

amendments and indicated the degree to

which they could have been avoided. One-

out-of-four substantial (23%) amendments

were considered “completely avoidable”

and 22% were considered “somewhat

avoidable.” Avoidable amendments

included protocol design flaws, errors and

inconsistencies in the protocol narrative,

and infeasible execution instructions and

eligibility criteria.

Approximately one-third (30%) of

substantial amendments were deemed

“somewhat unavoidable” and 25% were

classified as “completely unavoidable.”

The causes of unavoidable amendments

included manufacturing changes, the

availability of new safety data, changes in

standard of care, and regulatory agency

requests to change the protocol design.

The total median direct cost to

implement a substantial protocol

amendment for Phase II and III protocols

was $141,000 and $535,000, respectively.

The magnitude of impact

No surprise—substantial protocol

amendments significantly impact some

study scope elements and the entire

study conduct cycle. But the new Tufts

CSDD study puts some real metrics on

the table: Studies that had at least one

substantial amendment saw a significantly

higher reduction in the actual number of

patients screened and enrolled relative

to the original plan. This may have been

due to sample size re-estimations and

concrete steps taken to reduce patient

screening and enrollment burden. In

contrast, protocols that had no substantial

amendments saw only a modest reduction

in the actual number of patients screened

relative to plan; and a modest increase in

the actual number of patients enrolled

relative to the original plan.

Substantial amendments significantly

increased cycle times at individual time

points and throughout the study duration,

suggesting that the delays associated

Kenneth A. Getz

MBA, is the Director of

Sponsored Research at

the Tufts CSDD and

Chairman of CISCRP, both

in Boston, MA, e-mail:

[email protected]

Acknowledging Cycle Time Impact from Protocol Amendments



with amendment implementation

are not recovered or reversed later in

the study. Study initiation durations

(i.e., protocol approved to first patient

screened) were, on average, 18% longer

for protocols with at least one substantial

amendment compared to those without

an amendment. This difference was not

statistically significant, as expected, since

the majority of substantial amendments are

implemented once the study is underway.

For those protocols with at least one

substantial amendment, the time points

from protocol approval to last patient last

visit (LPLV) and from first patient first visit

(FPFV) to LPLV were significantly longer—

at 90 days and 85 days, respectively—

compared with those protocols without

an amendment.

A whopping 5.5-month increase in

time was observed in the “first patient

participation cycle” (i.e., from first FPFV to

first patient last visit [FPLV]), suggesting

that the implementation of substantial

amendments impacts study volunteers

differently depending on when they are

randomized and enrolled in the clinical trial.

Eyes on the prize

A large and growing number of sponsors

and CROs recognize the incredible

unplanned and unbudgeted toll that

protocol amendments take on study

budgets and timelines, and the major

opportunity to improve clinical trial

efficiency and performance. Companies

are routinely gathering metrics to monitor

their protocol amendment experience.

A number of sponsors and CROs

are leveraging new technologies and

implementing new mechanisms, functions,

and processes to optimize protocol design.

Amgen, for example, has implemented

a new Development Design Center to

assist clinical teams in designing better

studies before going to the protocol-

authoring stage. The Center taps experts

and data to facilitate decision-making

and promote a deeper understanding of

design-related trade-off decisions and

their impact on executional feasibility.

Pfizer and GlaxoSmithKline have

implemented extensive internal review

processes to improve protocol quality and

reduce amendments. GSK implemented a

new governance mechanism several years

ago. Pfizer recently revised its standard

operating procedures (SOPs) to require

that all protocols go through a detailed

protocol and amendment review prior

to implementation. The first step in this

process calls for a review by a senior-

level governance committee to achieve

consensus on the design elements of

the study, to ensure that the protocol is

consistent with the overall development

plan, and to challenge the executional

feasibility of the protocol.

Eli Lilly has implemented three core

initiatives throughout the organization

to simplify and focus protocol design; to

incorporate patient-centered approaches;

and to streamline the drug development

process. One approach to support these

initiatives is to solicit input—before

protocol approval—from patients and

investigative site staff during a simulation

of study execution and the participation

experience. Lilly’s study teams observe

these simulations to identify and address

feasibility issues that could potentially

trigger the need to amend the protocol.

EMD Serono routinely conducts patient

advisory boards to solicit patient feedback

on protocol design and the feasibility

of the schedule of assessments. These

boards are conducted globally, each

among six to 10 patients in collaboration

with patient advocacy groups.

Lastly, TransCelerate BioPharma has

made protocol feasibility one of its top

areas of focus in 2016. TransCelerate

recently released a Common Protocol

Template, offering a common structure

and language to drive protocol design

quality and identify areas of misalignment

between protocol endpoints and their

respective procedures. TranCelerate’s

initiative is among several other common

authoring templates now available,

including one developed by a community

of global medical writers—the SPIRIT

initiative—and launched a number of

years ago.

Sponsors and CROs are rallying

to reduce the number of avoidable

amendments and ultimately improve

protocol quality, executional feasibility, and

efficiency. The anticipated improvements

in study performance and cost could not

come at a better time, given rapid growth

in the scientific and executional complexity

of protocol designs and growing interest in

patient-centric drug development.

Source: Tufts CSDD, 2016; <csdd.tufts.edu>

Protocols without a Substantial Amendment

Days

700

238

403352

437490

580600

500

400

300

200

100

0

First Patient First Visit(FPFV) to First Patient Last

Visit (FPLV)

FPFV to Last PatientLast Visit (LPLV)

Protocol Approved to LPLV

Protocols with at least one Substantial Amendment

Impact of Implementing an Amendment on Study Cycle Times


TRIAL DESIGN


PEER

REVIEW

How Biosimulation Can Predict Drug Success J.F. Marier, Trevor N. Johnson, Suzanne Minton

Historically, most medications given to

children had not been evaluated in pe-

diatric clinical trials due to logistical

and ethical challenges. Indeed, while

children represent about 40% of the

world’s population, only 10% of the drugs on

the market have been approved for pediat-

rics.1 Without a proper and approved clinical

process, physicians are left with potentially

unsafe dosing and therapeutic approaches for

children. The result is a continuation of the off-

label prescribing.

To address this urgent medical need, both

the U.S. Food and Drug Administration (FDA)

and European Medicines Agency (EMA) now re-

quire pediatric trial plans—the Pediatric Study

Plan (PSP) and the Pediatric Investigation Plan

(PIP), respectively—as part of the approval

process for new drugs. The combination of the

Best Pharmaceuticals for Children Act (BPCA)

and the Pediatric Research Equity Act (PREA)

and these new regulatory requirements are

starting to move the pendulum towards safer,

more effective medicines for children. During

the five-year period between 2007 and 2013,

469 pediatric studies were completed under

BPCA and PREA; by August 2014, 526 labeling

changes were made.2 Similarly, in the European

Union, around 300 products have had label

changes approved for safety, efficacy, or dosing

for pediatrics since 2007.2

While these requirements have spurred

growth in pediatric clinical research, there are

still major barriers to successful pediatric drug

development. Almost half of the trials con-

ducted in recent years have failed to demon-

strate either safety or efficacy. A total of 44

products had failed pediatric drug develop-

ment trials submitted to the FDA between 2007

and 2014.3 An analysis by Gilbert J. Burckart,

PharmD, and his FDA colleagues revealed sev-

eral common factors that contributed to the

widespread failures: suboptimal dosing, differ-

ences between adult and pediatric disease pro-

cesses, and problematic study designs.

In the cases where suboptimal dosing con-

tributed to the failure to show efficacy, there

were two frequent issues: not testing a range

of doses, and limiting pediatric drug exposure

to that which was shown to be efficacious in

adults. Testing a range of doses is critical to

understanding dose-response relationships for

a drug. Also, if the disease process differs be-

tween children and adults, then matching the

drug exposure to that observed in adults may

not be effective, and ultimately result in clini-

cal trial failure.

An understanding of pediatric disease—its

natural progression—is crucial for selecting

outcomes for clinical studies, including the

primary efficacy endpoint, safety, and biomark-

ers. Finally, problematic study designs are a

significant contributing factor in clinical trial

failures. Some of these issues included lack of

a control group, stratification, and inadequate

assay sensitivity.

Pediatric trials now feature increased modeling and analytics for safer drug dosing and response.

Your clinical research program is different – because it’s yours. To make the most of it, you need a CRO who brings more to the table than a predetermined process. You need a partner who starts by understanding your situation and learning about your exact specifications – experienced professionals who customize engagements so the services you get are perfectly matched to your vision and goals. That’s our approach. Let’s talk about yours.

US: +1 910 338 4760UK: +44 0 1753 512 000

www.Chiltern.com

©2016 C

hiltern International Ltd

. All rig

hts reserved. C

hiltern is an Eq

ual Op

po

rtunity Em

plo

yer.


TRIAL DESIGN

A biosimulation framework to support strategic

decision-making

First, it’s important to clarify some definitions regarding pe-

diatric age groupings. According to the FDA guidance, neo-

nates are from birth to one month, infants are from one

month to less than two years of age, children are from two

to 11 years old, and adolescents are from 12 to 18 years

old. As pharmacokinetics (PK) and pharmacodynamics

(PD) may change between each age range, drug develop-

ers may need to develop dosing regimens specific to each

subgroup.5

The very nature of human growth and maturation makes

the prediction of pharmacokinetics in children especially

challenging. Drug disposition in children differs from

that of adults in numerous ways. For example, the kinet-

ics of drug absorption may be different in children versus

adults due to changes in the expression of intestinal drug

transporters and drug metabolizing enzymes during devel-

opment.4 Likewise, drug distribution changes with age as

neonates (birth up to one month) have much higher total

body water compared to adults. Finally, organ maturation

has a significant effect on drug metabolism and excretion.

Children have relatively larger livers, lower glomerular

filtration rates, and less renal tubular absorption and

excretion compared to adults.6 This distinct physiology

means that traditional approaches such as allometry risk

greatly over or under predicting drug clearance in pediatric

patients, especially those that are less than one year old.7

Because of the special needs of children as well as ethi-

cal concerns, there are significant differences in clinical

trial protocols for children versus adults. The FDA guid-

ance document discusses these issues at length.5 Some

of the major issues in pediatric clinical trials include the

following:

t� The type of PK study that is possible is often different

in adults and children. While rich sampling is often con-

ducted in adults, a sparse sampling procedure is gener-

ally preferred for young children to minimize the number

and volume of blood draws.

t� When studying neonates, sponsors may need to con-

sider gestational as well as postnatal age when deter-

mining covariates for a population PK study.

t� The formulation of a drug may change between age

groups. Young children generally cannot swallow pills

and may require liquid formulations.

How can pediatric drug developers satisfy regulatory

requirements and maximize drug safety and effectiveness

while minimizing children’s exposure to experimental

medications? Biosimulation—also known as model-based

drug development—includes both empirical “top down”

PK/PD modeling and simulation as well as “bottom up”

physiologically-based pharmacokinetic (PBPK) models.

It leverages prior information from preclinical studies,

adult trials, peer-reviewed literature, and pediatric studies

of related indications or drug actions. The integration of

patient physiology, drug actions, and trial characteristics

in models enables sponsors to optimize dosing and trial

design. Indeed, in a study of 11 well characterized drugs,

PBPK models of virtual subjects (birth to 18 years of age)

showed greater accuracy in predicting drug clearance than

simple allometry, especially in children less than two years

of age.8 The increased certainty in biosimulated outcomes

can help sponsors to ensure informative pediatric trials

are performed and will gain approvals based on a smaller

number of pediatric patients.9

Opportunities during drug development for applying

modeling and simulation techniques

As the benefits of biosimulation become increasingly

clear, regulatory agencies are also advocating its use to

improve the success rate of pediatric trials from current

levels.10 Indeed, a 2014 draft guidance from the FDA states

that “modeling and simulation using all of the information

available should, therefore, be an integral part of all pedi-

atric development programs.”5

At each stage of clinical development, there are specific

trigger points and opportunities to apply modeling and

simulation techniques to increase the likelihood of suc-

cess. Submission of the PIP is required by the EMA by the

end of Phase I clinical studies. Biosimulation methods

should be used to support the dosing rationale stated in

the PIP. Population PK and PBPK models based on Phase

I data from adults are frequently used to develop a drug

model that aids with pediatric dose selection. Population

PK or PBPK models can predict drug exposure across a

wide range of ages and weights as well as maturation and

organ function. The predicted drug exposure in pediatric

patients can then be compared against observed values

in adult subjects in Phase I to confirm the models and

optimize the safety of treatments. This approach can also

be used to develop a sparse sampling strategy that opti-

mizes the assessment of PK parameters while minimizing

the number of blood draws and other invasive procedures.

Pediatric PBPK and population PK models can be used

synergistically during drug development. The former have

recently been used to aid in the determination of optimal

dose and sampling times for population PK.11 Conversely,

An understanding of pediatric disease—

its natural progression—is crucial

for selecting outcomes for clinical

studies, including the primary efficacy

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TRIAL DESIGN

the results from population PK models can be used to fur-

ther optimize pediatric PBPK models.

Another important use for PBPK models in pediatric

drug development is evaluating the risk of drug-drug in-

teractions (DDIs). DDIs are a primary threat to the safety

and efficacy of clinical practice. Clinically-relevant drug in-

teractions are primarily due to drug-induced alterations in

the activity and quantity of metabolic enzymes and trans-

porters. Indeed, DDIs that cause unmanageable, severe

adverse effects have led to restrictions in clinical use, and

even drug withdrawals from the market.

The magnitude of any DDI depends on the fractional im-

portance of the inhibited metabolic pathway. The pattern

of CYP metabolic enzymes that contribute to the elimina-

tion of a drug may not necessarily be the same in children

compared to adults. Thus, it is difficult to use information

about DDIs in adults to inform the likelihood of pediatric

DDIs. And, again, there are practical and ethical problems

with evaluating DDIs in pediatric clinical studies. A 2012

guidance from the EMA states that PBPK simulations

may be used to predict the effects of drug interactions in

multiple special populations, including young pediatric

patients.12

Use of the Simcyp Pediatric Simulator to simulate DDIs

revealed that in certain scenarios, neonates could be more

sensitive to a DDI than adults while the opposite might be

true in other scenarios involving different CYP enzymes.13

Pediatric PBPK models may help provide information

about the risk and magnitude of potential DDIs where

there are no existing clinical data.

Pharmacometrics tools are also invaluable in support-

ing pediatric study plans. The PSP should be submitted

to the FDA at the end of the Phase II meeting, following

the availability of exposure-response data in adults. To

provide guidance on the conduct of pediatric trials, the

FDA has articulated a pediatric study decision tree.14 The

degree of similarity of disease progression and drug re-

sponse between adults and children determines which of

three major pediatric studies should be undertaken: PK

only, PK/PD, PK, or efficacy. Safety studies are required in

all of these scenarios.

The regulatory path taken determines the strategy for

optimizing dosing. In the case that PK studies alone are

used, the sponsor should build a population PK model

customized for size and maturation and perform dose

simulations that will result in drug concentrations within

the range of those observed in adults. Using the PK/PD ap-

proach means creating a population PK/PD model that is

customized for size and maturation and performing dose

simulations that will achieve a target concentration based

on the PK/PD relationship. Finally, utilizing a PK and ef-

ficacy approach involves building a population PK model

and an exposure-response model, and performing simula-

tions to find a dose that will produce a drug concentration

that results in an adequate response.

Phase III studies in adults are performed to determine

whether there is statistically-significant evidence of clini-

cal efficacy and safety for an investigational drug. At this

point, the PIP and PSP should be updated to reflect any

new insights. This is also the time to develop final pedi-

atric protocols. Clinical trial simulations using Phase II

results can be useful for evaluating probability of success

in Phase III.

Two case studies showing successful use of

biosimulation for pediatric drug development

Learning from one indication to the next: Eculizumab for atypical hemolytic

uremic syndrome

In some cases, information gained developing a drug for

one indication can be leveraged to inform its approval

for a different indication. PNH (paroxysmal nocturnal he-

moglobinuria) is a rare, progressive, and life-threatening

disease. It is characterized by rampant destruction of red

blood cells (hemolysis) and excessive blood clotting.15

Likewise, aHUS (atypical hemolytic uremic syndrome) is

an ultra-rare genetic disease that causes abnormal blood

clots to form in small blood vessels throughout the body.

The sequelae of aHUS include kidney failure, damage to

other organs, and premature death. There were no FDA-

approved treatments for this rare disease.

Both aHUS and PNH are caused by chronic, uncon-

trolled activation of the complement system. During ac-

tivation of the complement system, the terminal protein

C5 is cleaved to C5a and C5b. C5a and C5b have been

implicated in causing the terminal complement-mediated

events that are characteristic of both aHUS and PNH. Ecu-

lizumab is a humanized monoclonal antibody (mAb) that

binds C5, thereby inhibiting its cleavage. In 2007, this mAb

received approval for treatment of PNH based on evidence

of effectiveness from clinical studies.16

To help the sponsor obtain accelerated approval of

eculizumab for the treatment of aHUS in both adults and

pediatric patients, Certara scientists leveraged previous

knowledge gained during its development for PNH. Their

starting point was a population PK model that had been

previously constructed in adult patients with PNH.17 This

model was customized and used to develop optimal dos-

ing strategies for adult and pediatric aHUS patients.

The increased certainty in biosimulated

outcomes can help sponsors ensure that

informative pediatric trials are performed

and will gain approvals based on a

smaller number of pediatric patients.


TRIAL DESIGN

Comparing the case of adults with PNH to pediatric

aHUS, it became apparent that children have a different re-

sponse to intervention and that a different endpoint should

be used. The PK/PD relationship in PNH was leveraged to

measure the drug’s exposure and inform pediatric dosing for

aHUS. Knowledge about eculizumab’s mechanism of action

for PNH also suggested that optimal binding to the pharma-

cological target (C5) should translate into a clinical benefit.

Identification of the therapeutic dosing window for a

mAb in pediatric patients with a rare disease involved

several steps. First, to ensure patient safety, the upper

exposure limit needed to be determined. As a safeguard

against toxicity, the upper exposure limit was capped

at what had been previously observed in adults. To en-

sure efficacy, the minimum drug exposure also had to

be determined. Using the predicted concentration of the

soluble target and the binding characteristics of the mAb

to its target, a minimum concentration threshold was set

to obtain close to full inhibition of the target. Then, trial

simulations using a population PK model were performed

to determine which doses would optimize the probability

of obtaining the mAb within the window of target engage-

ment. This enabled the dosing recommendations to be de-

termined for pediatric patients of varying weights.17

The clinical program for aHUS involved two Phase II

studies and a retrospective observational study. A total

of 57 patients with aHUS participated in these studies

(35 adult, 22 pediatric patients). Two different biomarkers

were used to assess the efficacy of treatment. The proxi-

mal biomarker, free C5, showed complete suppression

upon treatment with the mAb. Likewise, the mAb caused

full inhibition of hemolytic activity (the distal biomarker).17

The primary endpoint indicated that the response to the

intervention exceeded 95%. Patients treated with the mAb

experienced several benefits including higher improve-

ment in platelet counts and other blood parameters and

better kidney function, even eliminating the requirement

for dialysis in some patients. Soliris® (eculizumab) re-

ceived FDA approval to treat aHUS patients in 2011.18

Using PBPK modeling to assess differing drug formulations

for pediatric patients

Quetiapine is an atypical antipsychotic drug for the treat-

ment of schizophrenia, bipolar disorder, major depressive

disorder, and generalized anxiety disorder. An immediate

release (IR) formulation of quetiapine was first approved

by the FDA in 1997 and has been extensively studied in

adults, children, and adolescents. Regulatory approval for

the extended release (XR) formulation was granted for use

in adults, with the requirement that pediatric studies must

be carried out for children over the age of 12.

Various factors influence the bioavailability of different

formulations including the release of the active ingredi-

ent, its dissolution and permeability across the GI tract, as

The high rate of trial failures,

increasing regulatory demands, and

ethical imperatives all require a

reexamination of the current approach

to pediatric drug development.

Almost half of pediatric clinical trials conducted in recent years have failed to demonstrate either safety or efficacy.

Getty Images/ Phil Boorman


TRIAL DESIGN

well as intestinal metabolism. Furthermore, alterations in

PK in children can be due to differences in absorption and

transit rate, organ size, blood flow, tissue composition,

and metabolic capacity at various developmental stages.

The challenge was to integrate the available in vitro ADME,

physiochemical, and clinical data into PBPK models to

predict the effects of age and formulation on the PK of

quetiapine in young subjects.

Scientists at Certara and AstraZeneca developed PBPK

models that predicted, with reasonable accuracy, the ef-

fects of CYP3A4 inhibition and induction on the PK of

quetiapine, the PK profile of quetiapine IR in both chil-

dren and adults, and the PK profile of quetiapine XR in

adults. These validated models were then used to simulate

relative exposure following XR formulation in adolescents

(age 13-17) and children (age 10-12). In both groups, the

predicted exposure to quetiapine XR followed a similar

pattern to the IR formulation, with 300mg XR once-daily

being comparable with 150mg IR twice-a-day.19

Conclusion

The high rate of trial failures, increasing regulatory de-

mands, and ethical imperatives all require a reexamination

of the current approach to pediatric drug development.

Biosimulation is a proven approach that will help optimize

trial design and inform the drug label. This approach can

support global regulatory strategies that increase the likeli-

hood of success for pediatric drug development programs.

References

1. Milne CP and Bruss JB. The economics of pediatric formulation devel-

opment for off-patent drugs. Clinical Therapeutics. 2008; 30(11):2133-45.

2. Ito, S. Children: Are we doing enough? Clinical Pharmacology and

Therapeutics. 2015. doi: 10.1002/cpt.167. [E-pub ahead of print]

3. Momper JD, Mulugeta Y, Burckart GJ. Failed pediatric drug devel-

opment trials. Clinical Pharmacology and Therapeutics. 2015. doi:

10.1002/cpt.142. [Epub ahead of print]

4. Yaffe SJ and Aranda JV. (2010). Neonatal and pediatric pharmacol-

ogy: Therapeutic Principles in Practice, 4th edition. Philadelphia, PA:

Lippincott Williams & Wilkins.

5. U.S. Food and Drug Administration, “Guidance for Industry: Gen-

eral Clinical Pharmacology Considerations for Pediatric Studies

for Drugs and Biological Products,” December 2014, http://www.

fda.gov/downloads/drugs/guidancecomplianceregulatoryinfor-

mation/guidances/ucm425885.pdf

6. Barrett JS, Della Casa Alberighi O, Läer S, Meibohm B. Physiologi-

cally-based pharmacokinetic (PBPK) modeling in children. Clinical

Pharmacology and Therapeutics. 2012; 92(1):40-9.

7. Edginton AN, Schmitt W, Voith B, Willmann S. A mechanistic

approach for the scaling of clearance in children. Clinical Pharma-

cokinetics. 2006; 45(7):683-704.

8. Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the

clearance of 11 drugs and associated variability in neonates,

infants and children. Clinical Pharmacokinetics. 2006; 45(9):931-56.

9. Maharaj AR and Edginton AN. Physiologically based pharmaco-

kinetic modeling and simulation in pediatric drug development.

CPT: Pharmacometrics and System Pharmacology. 2014. DOI: 10.1038/

psp.2014.45.

10. Gobburu, J. (2010, March). How to Double Success Rate of Pedi-

atric Trials? Presented at the meeting of the American Society of

Clinical Pharmacology and Therapeutics , Atlanta, GA.

11. Thai HT, Mazuir F, Cartot-Cotton S, Veyrat-Follet C. Optimizing

pharmacokinetic bridging studies in paediatric oncology using

physiologically-based pharmacokinetic modelling: application to

docetaxel. British Journal of Clinical Pharmacology. 2015. Accepted

manuscript DOI 10.1111/bcp.12702.

12. European Medicines Agency, “Guidelines on the Investigation

of Drug Interactions,” June 2012, http://www.ema.europa.eu/

docs/en_GB/document_library/Scientific_guideline/2012/07/

WC500129606.pdf

13. Salem F, Johnson TN, Barter ZE, Leeder JS, Rostami-Hodjegan,

A. Age-related Changes in Fractional Elimination Pathways for

Drugs: Assessing the Impact of Variable Ontogeny on Metabolic

Drug–Drug Interactions. Journal of Clinical Pharmacology. 2013.

14. U.S. Food and Drug Administration, “Guidance for Industry: Expo-

sure-response Relationships – Study Design, Data Analysis, and

Regulatory Applications,” April 2003, http://www.fda.gov/down-

loads/Drugs/GuidanceComplianceRegulatoryInformation/Guid-

ances/ucm072109.pdf

15. Lathia C, Kassir N, Mouksassi MS, Jayaraman B, Marier JF, Bedro-

sian CL. Modeling and Simulations of Eculizumab in Paroxysmal

Nocturnal Hemoglobinuria (PNH) and Atypical Hemolytic Uremic

Syndrome (aHUS) Patients: Learning From One Indication to the

Next. Clinical Pharmacology and Therapeutics. 2014, PII-107; 93(1): S97.

16. U.S. Food and Drug Administration. (2007) FDA Approves First-

of-its-Kind Drug to Treat Rare Blood Disorder [Press release].

Retrieved from http://www.fda.gov/NewsEvents/Newsroom/Pres-

sAnnouncements/2007/ucm108869.htm

17. Lathia C, Kassir N, Mouksassi MS, Jayaraman B, Marier JF, Bed-

rosian CL. Population PK/PD Modeling of Eculizumab and Free

Complement Component Protein C5 in Pediatric and Adult

Patients with Atypical Hemolytic Uremic Syndrome (aHUS). Clini-

cal Pharmacology and Therapeutics. 2014, PII-108; 93(1): S97.

18. U.S. Food and Drug Administration. (2011) FDA approves Soliris

for rare pediatric blood disorder [Press release]. Retrieved from

http://www.fda.gov/NewsEvents/Newsroom/PressAnnounce-

ments/ucm272990.htm

19. Johnson TN, Zhou D, Bui KH. Development of physiologically-

based pharmacokinetic model to evaluate the relative systemic

exposure to quetiapine after administration of IR and XR formu-

lations to adults, children and adolescents. Biopharmaceutics and

Drug Disposition. 2014; 35(6):341-52.

J.F. Marier, PhD, FCP, is a Vice President and Lead Scientist; Trevor

N. Johnson, PhD, is a Principal Scientist; Suzanne Minton, PhD, is

the Manager of Scientific Communications; all with Certara

DIA 2016 is packed with 175+ educational offerings

over 22 tracks on today’s hottest topics. It is our

largest interdisciplinary event, bringing together a

global network of 7,000+ life sciences professionals

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from around the globe, to foster innovation in the

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of health care products.

Featured Sessions:đƫ� 2�*�%*#ƫ0$!ƫ�,,.+,.%�0!ƫ�/!ƫ+"ƫ +�%(!ƫ�(%*%��(ƫ

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A GATHERING OF GLOBAL PROPORTIONS

J U N E 2 6 – 3 0 | P H I L A D E L P H I A , P A

21st Century Cures

Pati

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Current Issues in

Policy and Law

Pricing, Reimbursement & Access

Mobile/Wearables Technology

Value-Based Evidence

Risk-Based Monitoring

IDM

P Benefit-RiskPatientRegistries

BigDataPersonalized Medicine D

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Tech

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Design Thinking

Social Media Strategies

Clinical Trial Transparency

Clo

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Biologics/Biosimilars

Regulatory

HarmonizationApproval Pathways

Observational Studies


TRIAL DESIGN


PEER

REVIEW

Value-Based Planning & Drug Development ProductivityFrederic L. Sax, MD, Marla Curran, DrPH, Sarah Athey, Christoph

Schnorr, MD, Martin Gouldstone

Until relatively recently, the number often

quoted as the cost of bringing a new drug

to market was $1 billion.1,2 In November

2014, the Tufts Center for the Study of

Drug Development reported that devel-

oping a new prescription medicine that gains

marketing approval, a process often lasting lon-

ger than a decade, is estimated to cost $2.558

billion.3 Recent analysis shows that not only

have costs risen, but there is high variability

among companies in their “costs-per-successful-

product” reaching the market.4 Improvements in

product selection, product development, and in-

vestment decision-making would all improve the

likelihood of a product’s successful market entry.

The key issue facing the industry can be de-

scribed as development productivity. On a port-

folio level, this can be defined as a ratio of the

current projects in the pipeline (work in progress

or WIP), the probability of technical success

(p(ts)), and the value of the pipeline (V) divided

by the cycle time (CT) and the cost to deliver the

pipeline (C)5

P = WIP * p(ts) * V

CT * C

This equation conveys the balance of risk,

time, and cost (with a factor included for num-

bers of compounds in a portfolio, though the

equation is equally relevant for a single com-

pound [i.e., WIP=1]), weighted against the prob-

ability of its technical success and its potential

future value; each compound has its own set

of dynamics related to the size of the popula-

tion, market share/competitive landscape, unmet

need, differentiation, and market access/pricing

considerations.

Biopharmaceutical companies have attempted

to address the productivity issue by increasing

the number of compounds entering a portfolio

(“shots on goal”) and doing whatever they can

do to decrease costs and cycle time. However,

the productivity equation is dominated by the

very low industry-wide “probability of success,”

which, in the most recent data, is still only about

15% of new medical products entering human

trials.6

Companies have tried to change these odds

by targeting patient populations who are most

likely to respond to therapy (e.g., through use

of biomarkers); the goal is to try to increase

the likelihood of positive efficacy results and

corresponding positive pricing and reimburse-

ment decisions. Even if a compound meets the

regulatory standards that allow for its success-

ful registration, there is no guarantee that the

product will be accepted by boards/formularies

responsible for pricing and reimbursement, mak-

ing successful commercialization and patient ac-

cess challenging. “Effectiveness” has essentially

been added as the fourth hurdle to safety, ef-

ficacy, and manufacturing quality. Market access

strategies continue to be shaped by influential

stakeholders.

There are a number of recent examples that

speak to this point: England’s National Institute

for Health and Care Excellence (NICE) did not

How to integrate evidence-based planning and real-world evidence to boost clinical trial productivity.

TRIAL DESIGN

recommend GlaxoSmithKline’s belimumab for the treat-

ment of active lupus erythematosus.7 NICE concluded

that there was insufficient evidence of improved efficacy

versus standard of care and did not recommend use, even

though it was the first new approved drug in this indication

for decades. In Germany, the law governing pharmaceu-

ticals (AMNOG) was amended in 2011, introducing a for-

mal Health Technology Assessment (HTA). Following this

change, Boehringer Ingelheim decided not to launch the

new oral anti-diabetic compound linagliptin (Trajenta®).

Under the new law, the comparator was not the agreed

comparator and the submission was assessed as not ad-

equately justified.8 9

These examples illustrate that only focusing on develop-

ment costs and cycle times is not sufficient and needs to

be balanced continuously with the potential for a prod-

uct’s reimbursement and commercial viability to ensure

an adequate return on investment for new therapies. This

requires forward-looking (and likely, disruptive) thinking at

the earliest stages of development. Bringing unmet medi-

The goal is to try to increase the

likelihood of positive efficacy results

and corresponding positive pricing

and reimbursement decisions.

Source: Sax et al.

Figure 1. Value capture from real-world evidence

across the product life cycle for a top 10 biopharma-

ceutical company.

Development

Initial pricing & market access*$100m

Clinical development*$100-200m

Safety & valuedemonstration$200-600m

Launch planning& tracking$150m

Productivity and cost savings$100m

*Selected operational opportunities only; excludes increased R&D pipeline throughput and better pricing

1Hughes B, Kessler M. RWE market impact on medicines: A lens for pharma. IMS Health Access Point 2013; 3(6): 12-17

Commercialspend effectiveness$200-300m

Launch In-market

Value Impact: Real-World Evidence

EVENT OVERVIEW:

During this webcast we will highlight how Oracle Health Sciences’ holistic,

advanced risk-based monitoring cloud solution enables life sciences compa-

nies to automate their risk-based monitoring strategies, optimizing action-

able results from the comprehensive analysis of clinical and operational data.

We will demonstrate how this new and comprehensive approach aligns

with regulatory guidelines and seamlessly incorporates TransCelerate tools

and best practices, including the Risk

Assessment Categorization Tool (RACT)

and TransCelerate Key Risk Indicators.

Who Should Attend:

�� Clinical operations, clinical data management, risk management, data quality, clinical research associates

Key Learning Objectives:

�0� Provide insight as to how sponsors are using risk-based monitoring technology as part of their new and improved approach to monitoring

�0� Demonstrate the ease with which sponsors and CROs can adopt a comprehensive central monitoring platform to enhance patient safety and trial quality.

�0� Show how cloud solutions incorporating TransCelerate tools and practices deliver significant efficiency benefits while reducing the cost and manual effort of conducting RBM

�0� Discover how to make critical decisions throughout the course of a trial through actionable insights, execute risk based monitoring strategies and increasing resource productivity with the ability to get access to information anywhere, anytime from any device

ON-DEMAND WEBCAST Originally aired March 15, 2016

Register free at www.appliedclinicaltrialsonline.com/act/fastermonitoring

Introducing

A Faster, Easier, and More Effective Approach to Risk-Based Monitoring

Sponsored by Presented by

Presenter:

Jennifer Bush

Director of Product Strategy

Oracle Health Sciences

Moderator:

Lisa Henderson

Editorial DirectorApplied Clinical Trials

For questions contact Daniel Graves at [email protected]


TRIAL DESIGN

cal need, differentiation, and value-based thinking into the

product development cycle in a way that is easily manifest

and transparently addressable for both product develop-

ment teams and decision-making stakeholders is essential

in this approach. Integrating evidence-based planning and

real-world evidence (RWE) has the potential to reap even

bigger rewards for development productivity, as shown in

Figure 1 (see page 27).10 To achieve this, we propose the

Three-Pillar approach outlined in this paper.

Enhance probability of technical success

If biopharmaceutical companies are to realize the next

level of transformation and achieve greater development

productivity, they need to address the development cycle

itself by integrating health outcomes, and using better,

evidence-based decision-making approaches. As shown in

Figure 2, the net present value of a product is highly de-

pendent on development risk, costs, and cycle time.

Not surprisingly, including commercial viability and mar-

ket access in the value equation when addressing develop-

ment risk and cost early provides a far more complete pic-

ture for sound development decision-making. To achieve

the desired outcome of better development productivity

and commercial success, we propose a Three-Pillar ap-

proach based on identification of evidence needed for

successful market entry and selection of the right plan to

generate this evidence. These three pillars are illustrated in

Figure 3 on facing page.

In Pillar 1, a question-based process identifies what suc-

cess looks like for the patient, physician, provider, payer,

and regulators. A robust target product profile (TPP) is

built from the answers to these questions; this will guide

creation of an integrated evidence plan that incorporates

the clinical and value evidence requirements to support the

TPP. Refinement of product needs continues throughout

the product life-cycle, including the design of late-stage

development and post-marketing programs. This will result

in intermittent, but iterative reassessments of the TPP and,

correspondingly, the required evidence generation that

such a reassessment will necessitate.

Second, an integrated evidence plan (IEP) is designed.

The goal is to create a direct line of sight from the TPP

to the development strategy and straight through to the

trials/studies in the program. The IEP divides required

information into two categories: (i) data already available,

and (ii) evidence that needs to be generated to advance

stakeholder decision-making. The IEP then defines how

the evidence will be generated within each clinical trial

and real-world observational study, and how this will be

leveraged to satisfy patient, physician, provider, payer,

and regulatory requirements as defined by the TPP. When

value-proving outcomes are investigated early in devel-

opment, they validate the benefit statements and secure

a positive recommendation from HTA and regulatory au-

thorities. The IEP also allows a team to set futility criteria,

so that if value evidence is not realized in a timely manner,

informed and effective decisions to terminate the program

can be made.

In Pillar 3, scenario development and trade-off analysis

are used to challenge assumptions both scientifically and

operationally and create an evidence-based “level playing

field.” This can be done most effectively through facilitated

workshops where collective expertise (subject matter ex-

perts) and various options for generating needed evidence

are reviewed, modified, and critically evaluated. Advanced

analytics optimizes the evaluation of complex time/cost/

risk/value scenarios in a transparent way to drive the deci-

sion-making process for key stakeholders.

Productivity will benefit most when the approach to the

pillars is taken in the context of an integrated partnership

of the key stakeholders, with early modeling, visualiza-

tion, and agreement on the “end game.” True end-to-end

integration leverages business processes aligned with the

three pillars and also leverages good information technol-

ogy. Using innovative design approaches, timely access

to real-world data (RWD) and patient insights can further

drive positive results. This is especially true if the entire

endeavor is focused on increasing access to more afford-

able innovative medical solutions that are not only com-

mercially viable, but also deliver better health outcomes

for patients.

Source: Sax et al.

Figure 2. The relationship between development

risk, cost, cycle time, and net present value. Net

present value (green) is highly dependent on develop-

ment risk (blue), development costs (red), and devel-

opment cycle time.

Net Present Value

Time points: CDN: candidate selection; POC: proof of concept;DFL: development for launch; NDA/BLA: new drug or biologics approval

TRIAL DESIGN

Identify evidence needs

Rethinking the development model within today’s health-

care model requires companies to successfully apply the

principle of “designing with the end in mind.” This means

the starting point and the first pillar in our approach is a

robust TPP, based on value to the patient, physician, and

provider while meeting payers’ and regulators’ expecta-

tions (Pillar 1). Examples of key issues that might be ad-

dressed on a question-driven basis during this phase might

include: defining the unmet medical need, key points of

competitive considerations (versus the existing or emerg-

ing standard of care), key scientific claims required for reg-

istration, and early market access issues.

These can be further refined to include the benefit of

the treatment to the patient, how this benefit might be as-

sessed, how the medicine will be differentiated in the mar-

ket, what will drive physicians to prescribe the therapy, what

would a payer require to increase or decrease access, and

any likely evolution of regulatory requirements during the

time-course of development. This forward-looking thinking

is essential, since given the usual time-course of product

development, it can be nearly a decade from the time of

original decisions until a product reaches the market.

Source: Sax et al.

Figure 3. The Three-Pillar approach linking clini-

cal science and clinical operations underpinned by

access to data, information, and knowledge.

‘Three Pillar’ Value Approach

Pillar 1

Use a ques-tion-based

approach to identify value to the patient,

physician, payer, and regulator

Pillar 2

Create line of sight from

target product profile through to the studies

with an integrated

evidence plan

Pillar 3

Challenge assumptions

using advanced decision analytics

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Advancing Drug Development with Digital Health

4 Key Ways to Integrate Patient-Generated Data into Trials

PRESENTERS

DREW SCHILLER

Chief Technology Officer

and Co-Founder

Validic

JOE DUSTIN

Principal, Mobile Health

Medidata

MODERATOR

LISA HENDERSON

Editorial Director

Applied Clincial Trials


TRIAL DESIGN

Focusing on these issues upfront is essential to success

of the Three-Pillar approach; the issues defined in the TPP

will determine what evidence is required to support the

program and ultimately, what results in terms of cost, time,

risk, and value of the product. This closely knit interplay is

shown in Figure 4. Furthermore, a value-based TPP defines

the threshold that must be achieved for the product to be

commercially viable. This then can be used to structure

more formal “go/no-go” decisions that can help frame

decision-making strategy and help to control biases that

tend to favor continuing product development even in the

face of low probabilities of success both scientifically and

commercially.

Create an integrated evidence plan

Once key product attributes are defined, the next step

(Pillar 2) is to identify key scientific and operational re-

quirements (“specs”) in light of the evidentiary needs for

the program. The process of defining requirements seg-

ments information into two groups: (i) data/information

readily accessible, for example, real-world data, research,

literature, and subject matter experts, and (ii) evidence

that needs to be generated. The interplay between the data

needs for the TPP and evidence needs incorporated into

the IEP is shown in Figure 5 (see page 32).

Once all the available information and evidence needs

have been explored, the next step in the pillar is to use

this information to create a line of sight from the TPP

through to potential studies (the fundamental unit of

evidence-generation within a program) by developing an

IEP. The development team will look at the evidence needs

and begin to link them to study design options that can

be used to generate this evidence. Generation of study

options encourages teams to explore new and innovative

approaches that can later be challenged and evaluated

(Pillar 3).

Critical to this evaluation is transparency of data and in-

formation. Use of unbiased historical data is critical to trial

design because it informs the decision criteria for success,

failure, and areas of uncertainty. This has led to increased

industry and regulatory efforts—such as the creation of

TransCelerate BioPharma11 and the European Medicines

Agency (EMA) policy on access to clinical trial data12—to

open up “pre-competitive” data for appropriate and ap-

proved research.

Biopharmaceutical companies have also taken indepen-

dent steps to provide external researchers with the ability

to request access to anonymized patient level data. This fa-

cilitates further independent research to improve scientific

knowledge and patient care, which, in turn, can contribute

to the information generation process during product de-

velopment.

Challenge assumptions

Creating a level playing field with a focus on all relevant

data, information, and collective expertise is an effective

way to evaluate development options (right information/

people/time/decisions). In this third pillar, the team builds

and evaluates scenarios based on integrated data, analyt-

ics, and subject matter expert knowledge. The trade-offs

among options can then be transparently considered, to

select the clinical program that optimally addresses the

needs defined in the TPP and balances those requirements

against cost/time/risk and value considerations.

To accomplish this goal, internal siloed subject matter

expertise is no longer sufficient—a truly beneficial out-

come of Pillar 3 hinges on the ability of the team to model

potential scientific, operational, and business outcomes

simultaneously, and to identify the decision elements most

likely to drive value. This makes integrated evidence plan-

ning an increasingly cross-functional responsibility that

will benefit from an integrated decision-making framework,

based on visualization of information and modeling of

Use of unbiased historical data is

critical to trial design because it informs

the decision criteria for success,

failure, and areas of uncertainty.

Source: Sax et al.

Figure 4. The critical interplay of clinical science

and clinical operations in driving successful drug

development outcomes.

Planning and design

Execution

Clin

ical o

pera

tio

ns

Clin

ical scie

nce /

co

mm

erc

ial via

bilti

y

Operationaldesign

Scientificdesign

Healthoutcomesand value

Operationaldesign

Clinical Synergy: Science & Operations

TRIAL DESIGN

options. Such a decision framework also provides the op-

portunity to identify clear futility criteria at the study level,

and define program “go/no go” criteria.

Maximum productivity and value benefits in the devel-

opment cycle will occur when clinical development and

health outcomes groups function interdependently while

leveraging outside sources of expertise and data access.

These outside sources can be used to refine the IEP and

modify options during Pillar 3, further enhancing the preci-

sion of the decision-making process.

Benefits of the Three-Pillar approach

As of 2014, GSK had adopted facilitated workshops simi-

lar to the one described here and requires integrated

evidence plans for all assets in development. GSK has

also mandated study-level facilitated clinical reviews for

all protocols in the design phase at the company. More

specifically, an objective facilitator, external to the team,

leads a full-team discussion regarding core components

of protocol quality (i.e., alignment with product strategy,

clarity of objectives/endpoints, appropriate entry criteria,

and intent behind the assessment schedule); and offers

study design alternatives. Since introducing these work-

shops at the study level in 2010, GSK has demonstrated

that studies that completed the review have experienced

measurable benefits, such as fewer amendments and fewer

non-recruiting sites, with a higher likelihood of recruiting

to plan.

Facilitated workshops have also been conducted at the

above study, full program level, enabling development

teams to identify and prioritize the critical questions,

evaluate the evidence needs at each stage of development,

and at times use more advanced decision analytics such

as Decision Lens™ or D-Sight™, to identify the right plan

and evaluate benefit-risk. For instance, a development

team can be asked to identify development Plan A based

on traditional study designs to generate required evidence

and answer the critical questions, then consider options

based on variations: Plan B (adaptive designs), Plan C

(seamless designs), Plan D (observational studies and

pragmatic trials included), etc.

The team then considers the key factors that differen-

tiate one plan from the next. These can be operational

factors, such as the ability to recruit or availability of

drug supply; or scientific, such as the ability to identify

responders, select dose, or collect key endpoints. Once the

Increasingly complex biomarker and other specialized testing requirements

present a significant challenge to sample testing, logistics and storage.

Drug development for early stage and adaptive protocol designs requires a

comprehensive, real-time grasp of exactly what samples you have, where they

are, and how they are collected, shipped, processed and stored especially from

the moment of collection.

■ Increasing blood collection volumes, unique specimen types and specialized collection materials have created new challenges for sites and sponsors for their early phase studies.

■ Decisions regarding patient care/safety and treatment are based on real-time data from samples collected during the course of the study.

■ Protocols are amended quickly needing flexible resources to implement changes quickly.

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■ Learn how study complexity poses challenges in sample logistics and management in today’s early stage and adaptive protocol designs.

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■ Understand the benefits of a comprehensive sample tracking and management plan that forecasts and determines when, where and how samples will be collected, shipped and stored before the trial begins.

Who Should Attend

■ Pharmaceutical and biotech companies. Anyone whose job responsibility is global clinical trial sample management.

For questions, contact Daniel Graves at

[email protected]

BEST PRACTICES IN

Acquiring, Tracking and Maintaining

Biological Study Samples Across Global Trials

ON-DEMAND WEBCAST | Originally aired March 17, 2016

Register for free at www.appliedclinicaltrialsonline.com/act/labconnect

Presenter:

Stephanie Weber

Director, Early Development ServicesLabConnect

Moderator: Lisa Henderson,

Editorial Director, ACT


TRIAL DESIGN

team has decision drivers and plan options, prioritization

can be conducted through advanced analytics, and selec-

tions made.

Transparency, of development challenges and stake-

holder opinions, is created when the session is conducted

in this way. When making decisions under uncertainty, it is

very helpful to have a framework that comprises the vari-

ous quantitative pieces of available and important data,

coupled with the more subjective, intuitive, and quali-

tative factors, with a clear understanding of how much

weight or importance the various criteria have.13

Often, within companies, there is a challenge around

the early assignment of senior expert resources to do such

evaluations (i.e., costs will be incurred before the benefits

are fully understood).

However, better use of technologies that can be used to

evaluate scenarios helps to identify the quick wins early on

and can minimize the drain on senior expert time and fa-

cilitate decision-making. Early use of a computer-assisted

design tool as the data-integration platform for facilitated

workshops has also led to substantial reductions in early

protocol amendments for Eli Lilly14 teams, as well as re-

ductions in design cycle times.

Focused engagement by knowledgeable drug developers

can lead to “quick wins” in decision-making that feed into

early development planning. The evidence requirements

that result then naturally lead to a decision matrix (i.e.,

early “no-go” decisions based on informed futility criteria

can be made with the confidence that a potential target

has not been “killed” too early).

Implications for drug development

The critical success factors that will influence the probability

of success are: (i) creating a focus on evidence generation to

level the playing field across all players involved in develop-

ment strategy planning and execution; (ii) making sure the

right expertise is involved in the decision-making process;

(iii) using all relevant data and advanced analytics to in-

form decisions and aligning this information with the TPP;

Source: Sax et al.

Figure 5. The interplay between the data driving the target product profile and the evidence required from the inte-

grated evidence plan.

Data Available Evidence to be Generated

ScientificScientific

Burden of illness

Natural history of disease

Event rates (previous trials)

Safety profile (pre-clinical,

other therapies)

Regulatory requirements

Formulary requirements

Patent life

Potential risks biases

Feasibility assessment

Patient availability

Enrollment actual for re-

forecasting

Frequency of risk triggers

Ability to achieve

milestones

Early “value” data

Key differentiation data

Final Value Dossier

Market access evidence

Payer response to value

proposition

Pricing sensitivity analyses

Site feasibility

Patient eligibility

Enrollment projections

Operational risk

assessments

Drug supply/availability

Trial costs

Market opportunity

Competitive landscape

Points of unmet

need/differentiation

Estimated time to launch

Likely market

access/pricing/penetration

ROI/NPV

Pricing benchmarks

Portfolio “fit”

Correct formulation

Dosing regimen

Responder population

Efficacy endpoints

Safety signals

Risk-Benefit proposition

Commercial Operational

TPP IEP

Commercial Operational

Data-Driven Evidence

Focused engagement by knowledgeable

drug developers can lead to “quick

wins” in decision-making that feed

into early development planning.


TRIAL DESIGN

and (iv) delivering excellence in planning and execution to

reduce cycle time and decrease operational costs. The rela-

tive impact of these is shown in Table 1. One of the greatest

challenges is establishing ownership of strategic decision-

making and engaging all of the relevant experts. Including

the right experts in a knowledge-sharing session (Pillar 1) at

the start of the planning process, with access to all relevant

data and information (Pillar 2), will enable creation of an ini-

tial set of risk-based scenarios for evaluation (Pillar 3).

With data and evidence requirements in hand, the pri-

mary objective of the scenario-generation/trade-off analy-

sis step is to evaluate plans based on cost, time, and risk

to optimize value or probability of success. There should

be a clear justification for each piece of evidence to be

collected with a clear line-of-sight to the requirements for

the trial, derived from the TPP. Time spent generating and

testing options will ultimately lead to reduced protocol

amendments, greater ability to predict enrollment, less

redundant data collection, and fewer issues in data qual-

ity. This also allows a more accurate forecast of a trial’s

budget, which can be mapped to actual costs in execution.

The baseline assumptions also provide an objective basis

for monitoring trial progress and outcomes, keeping sub-

sequent decision-making evidence-based, and minimizing

potential bias.

Encouragingly, the industry recognizes that decision-

making requires a business model that is expert-led, but

data/evidence-driven. However, implementation of such a

model requires an understanding of and sharing of risk by

all key stakeholders. The healthcare environment is com-

plex and there is an urgent need to simplify and have ef-

ficient, directed development plan execution. This can only

be done with early design and planning linked to evidence

requirements based on value generation.

Ultimately, bringing science, operations, and commercial

understanding together to design a medicine’s develop-

ment program can result in earlier and more successful

product launches with value to the patient at the core. Suc-

cess requires truly integrated end-to-end partnerships that

go beyond current organizational paradigms, to bring evi-

dence and execution together and into alignment. Joining

efforts in this way will increase the probability of success

and, therefore, patient access to more affordable, innova-

tive, and commercially viable medical solutions.

References

1. $1bn cost to bring a new medicine to the market. The Times, Nov 5

2005. http://www.thetimes.co.uk/tto/news/world/article1981765.

ece

Maximum productivity and value

benefits in the development

cycle will occur when clinical

development and health outcomes

groups function interdependently

while leveraging outside sources

of expertise and data access.

Productivity Measures

Productivity = [WIP* p(ts)* V] / [CT* C]

EffectIncrease of probability

of technical successIncrease of value

Decrease in

cycle timeReduction of cost

Planning &

Design

Target product profile drives

integrated evidence plan++ +++ ++ ++

IEP options consider internal

and external data (both positive

and negative)

++ +++ +++ +++

Stringent management of

portfolio++ ++

Trial

Execution

Strict limitations of collection of

data point to objective(s) of trial+ + ++ +++

Data-driven clinical trial

execution++ +++

Lean, but compliant closure of

exit trials++

Source: Sax et al. Positive effect: + Low ++ Medium +++ High

Table 1. The level of impact on productivity in the planning and design and trial execution functions.


TRIAL DESIGN

2. Scannell JW, Blanckley A, Boldon H and Warrington B, Diagnos-

ing the Decline in Pharmaceutical R&D Efficiency, Nature Reviews

Drug Discovery, Volume 11, March 2012, 191 – 200

3. Tufts Center for the Study of Drug Development press release:

Cost to Develop and Win Marketing Approval for a New Drug

Is $2.6 Billion, November 18, 2014. http://csdd.tufts.edu/news/

complete_story/pr_tufts_csdd_2014_cost_study

4. Sources: InnoThink Center For Research In Biomedical Inno-

vation; Thomson Reuters Fundamentals via FactSet Research

Systems

5. Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH,

Lindborg SR et al, How to improve R&D productivity: the phar-

maceutical industry’s grand challenge, Nature Reviews Drug Dis-

covery, Volume 9 , 2010 , 203-214.

6. Hay M, Thomas DW, Craighead JL, Economides C and Rosenthal

J, Clinical development success rates for investigational drugs,

Nature Biotechnology, Volume 1, 2014, 40-51

7. NICE says no to belimumab for lupus. Arthritis Research UK, April

27 2012. Available at: http://www.arthritisresearchuk.org/news/gen-

eral-news/2012/april/nice-says-no-to-belimumab-for-lupus.aspx

8. Trajenta will not be launched in Germany following AMNOG

decision. Pharma Relations, May 2014. Available at: http://

www.pharma-relations.de/news/trajenta-r-steht-patienten-in-

deutschland-vorerst-nicht-zur-verfuegung

9. HTA in Germany: IQWiG assessment of Linagliptin (Trajenta)

and Abirateron (Zytiga). European Confederation of Pharma-

ceutical Entrepreneurs. January 2 2012. Available at: http://www.

eucope.org/en/2012/01/02/hta-in-germany-iqwig-assessment-

of-linagliptin-trajenta-and-abirateron-zytiga

10. Hughes B, Kessler, RWE market impact on medicines: A lens for

pharma, IMS Health Access Point, Volume 3(6), 2013, 12-17

11. Mansell, P, TransCelerate’s Comparator Network now active,

Pharma Times, August 17 2013. Available at: http://www.pharma-

times.com/Article/13-08-07/TransCelerate_s_Comparator_Net-

work_now_active.aspx?rl=1&rlurl=/13-11-12/TransCelerate_

unveils_second-year_initiatives.aspx#ixzz2sGtSIOng

12. Publication and access to clinical-trial data EMA/240810/2013,

Draft consultation paper, European Medicines Agency, June

2013. Available at: http://www.ema.europa.eu/ema/index.

jsp?curl=pages/includes/document/document_detail.jsp?webC

ontentId=WC500144730&mid=WC0b01ac058009a3dc

13. A new paradigm for decision-making in the pharma, biotech and

life-sciences industries, report by Decision Lens, 2011. Avail-

able at: http://www.decisionlens.com/docs/WP_Decision_Mak-

ing_in_Pharma_Biotech_LifeSciences_2.pdf

14. Sax R and Ramsey J, Using Computer-Assisted Design to Improve

the Outcomes of Clinical Trials: A One-Year Follow-Up, Meeting

presentation at Disruptive Innovations, Boston, Sept. 20, 2013

Frederic L. Sax, MD, is Global Head, Center for Integrated Drug

Development, Quintiles, email: [email protected]; Marla Curran,

DrPH, is Real World Evidence Director, Value Evidence and Outcomes

US, RD Projects, Clinical Platforms & Sciences, GlaxoSmithKline,

email: [email protected]; Sarah Athey is Director, Consulting

Europe, Quintiles, email: [email protected]; Christoph

Schnorr, MD, is Vice President, Drug Development, Consulting Europe,

email: [email protected]; Martin Gouldstone is Director –

Lifesciences Advisory, BDO LLP, email: [email protected]

Getty Images/ Jupiterimages

Presenters:

Dr. Jonas Renstroem Associate Director, Strategic Solutions, Quintiles

Edward Tumaian Senior Director, Global Project Leadership, Quintiles

Moderator:

Lisa Henderson Editorial Director, Applied Clinical Trials

Presented by:

Sponsored by:

Cop

yrig

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201

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uint

iles

Quintiles: +1 973 850 7571 Toll free: +1 866 267 4479 www.quintiles.com/services/riskbased-monitoring [email protected]

For technical questions about this webinar, please contact Daniel Graves at [email protected]

Mitigating risk using Risk-based Monitoring

Learn more about

Risk-based Monitoring (RBM) is quickly becoming the standard model for clinical development trial execution. Quintiles, as the RBM market leader, is delivering benefits from their RBM approach to improve data and study quality, enable faster, more informed decisions, and enhance patient safety while mitigating risk.Register for this webinar to understand how to:

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@� �valuate scientific and operational risks using Key Risk Indicators (KRIs) and data checks.

@ Mitigate risk while utilizing a risk-based monitoring (RBM) approach

@ Understand key steps in developing an optimized RBM data management plan

@ Build a Risk Assessment Mitigation Plan for your RBM studies

On-demand webinar:Originally aired March 22, 2016

View now for free! www.appliedclinicaltrialsonline.com/

act/mitigatingrisk


CRO/SPONSOR


PEER

REVIEW

Imagining the Impossible: Immunity to CancerChris Smyth, PhD

During the past few years, several novel cancer

treatments have emerged that are designed

to leverage a patient’s own immune system

to disrupt, halt, or reverse cancers. This cat-

egory, known as immunotherapy or immuno-

oncology, features mechanisms of action as varied

as the candidates themselves. Early data with this

class of drugs, particularly with checkpoint inhibi-

tors such as ipilimumab, nivolumab, and pembroli-

zumab, as well as “personalized” immunotherapies

such as chimeric antigen receptor T cells (CAR-T)

and dendritic cell vaccines, has been so compelling

that standards of care in a range of tumors are rap-

idly shifting, and drug developers are clamoring for

ways to leverage these technologies.

In light of such innovative treatments, many

traditional clinical trial parameters common to

chemotherapy or even the more recent targeted

antibodies or kinase inhibitors must be revisited

for their application to examine the safety and ef-

fectiveness of immunotherapies. This challenge,

and others presented by immunotherapy trials,

require expertise and experience to master, and

can be especially challenging within biopharma-

ceutical companies with smaller staff. This article

explores five challenges smaller biopharmaceuti-

cal companies should prepare for when embark-

ing on immunotherapy studies.

Three approaches dominate

Monoclonal antibodies

Monoclonal antibodies (mAbs) are one of the

three most significant immunotherapy ap-

proaches, along with vaccines and non-specific

immunotherapies, that pharmaceutical and bio-

tech companies are pursuing to thwart cancer’s

hallmark ability to evade the immune system.

Targeted mAbs for cancer by themselves are not

new—the first FDA approval being rituximab for

the treatment of lymphoma, followed closely by

trastuzumab for breast cancer nearly 20 years ago.

What has emerged recently, however, is an ability

to leverage mAbs to reengage the immune system

to identify and attack one’s own cancer cells. This

category, generally characterized as checkpoint

inhibitors, has garnered much interest because

such products are designed to, in combination

with traditional agents or other immunotherapies,

prompt immune attacks that target only cancer

cells and spare healthy tissues. They can help the

immune system act as it was designed to do, with

quite durable effects that can last years.

Immunotherapies, particularly more recent im-

muno-oncology products, are not yet as common

as first-line therapies, but pharmaceutical and

biotech companies are aggressively pursuing such

indications as they examine candidates in a va-

riety of combinations and against various tumor

types. The estimated cancer immunotherapy mar-

ket value, totalling about $41 billion in 2014, is

almost half of the overall oncology drug market.1

Vaccines

Immunotherapy cancer vaccines are designed to

fight, not prevent, existing cancer. Together with

preventive cancer vaccines, such as Gardasil and

The smaller biopharmaceutical perspective on mastering oncology immunotherapy clinical trials.


CRO/SPONSOR

Cervarix, which are designed to thwart human papilloma

virus infections that can lead to cervical cancer, cancer

vaccines sales comprised a market valued at about $4.0 bil-

lion in 2014, with modest growth rates anticipated to reach

about $4.3 billion in 2019.2,3 One tally estimates more than

280 candidates in cancer vaccine pipelines globally.4

However, to date, the only immunotherapy cancer vac-

cine approved by the U.S. Food and Drug Administration

(FDA) is Provenge (sipuleucel-T), made by Dendreon Cor-

poration, now Valeant Pharmaceuticals. The vaccine was

cleared for marketing in April 2010. A second vaccine was

cleared in October 2015—Amgen’s T-VEC (talimogene la-

herparepvec)—which is a dual-acting cancer vaccine/viral

therapy for melanoma patients.5

Non-specific immunotherapies

Non-specific immunotherapies target cancer cells indirectly

by prompting immune system attacks. Among this group

of treatments are laboratory-made cytokines, interleukins,

interferons, and GM-CSF, as well as mAbs designed to alter

the function of T-cell checkpoints.6

PD-1/PD-L1. Cancer cells are adept at manipulating and

controlling T cells to ignore tumor cells. Recent drugs are

designed to target a T-cell checkpoint protein’s function to

help counter that control. Such drugs interfere with either

the programmed death 1 (PD-1) receptor or its binding pro-

tein, PD-L1. PD-1, when activated by PD-L1, puts the brakes

on T cells, which while useful for regulating autoimmunity,

also allows cancer to proliferate. Cancer cells can express

PD-L1, thus permitting them undue influence over T cells.

Such cancers are often aggressive and, in the past, patients

had a poor prognosis.

Checkpoint inhibitors are helping to change this progno-

sis via two different mechanisms of action. They can protect

PD-1 from cancer cell manipulation or they can bind up the

cancer cells’ PD-L1 to limit its interaction with T cells. The

mAb pembrolizumab was, in September 2014, the first PD-

1-blocking drug to receive FDA approval, with the second,

Opdivo (nivolumab), made by Bristol-Myers Squibb, receiv-

ing approval in December 2014, both indicated for certain

melanomas. In March 2015, the FDA expanded Opdivo’s in-

dication to certain lung cancers, and in July it was approved

in Europe for non-small cell lung cancer. Morningstar

projects these two drugs will be worth $33 billion by 2022

because both are being tested for other cancer types.7

CAR immunotherapy uses a patient’s own T cells to fight

cancer. Through genetic engineering, the T cells are modified

and induced in the laboratory to produce CARs correspond-

ing to an antigen of a patient’s specific cancer cells, such as

the CD19 protein on the surface of cancerous B cells. After

billions of copies are made and reintroduced to the patient,

the T cells recognize the cancer cells bearing the antigen and

induce a lethal immune response. Oncologists have hailed

CARs as very promising for both solid tumor and hemato-

logic malignancies; in fact, CARs eventually may “become a

standard therapy for some B-cell malignancies.”8

BiTE antibodies are two separate laboratory-made anti-

bodies that are bound together. One antibody binds to a pa-

tient’s T cells, while the other links to certain markers largely

expressed on the cancer cell, such as CD19. When bridged

together, the T cells can launch attacks that induce cancer

cell death. Amgen’s investigational BiTE antibody blinatu-

momab received FDA breakthrough therapy designation in

July 2014 and was approved in December 2014 for a specific

type of acute lymphoblastic leukemia. The company also an-

nounced an agreement in January 2015 with The University

of Texas MD Anderson Cancer Center to explore the use of

BiTE technology for myelodysplastic syndrome (MDS).9

Special challenges for smaller biotechs pursuing

immunotherapy clinical programs

Small and mid-sized biopharmaceutical companies play sig-

nificant, pioneering roles in innovating and adapting exist-

ing drug designs to create new immunotherapies. Because

such sponsors typically have limited staff, they often require

Small and mid-sized biopharmaceutical

companies play significant,

pioneering roles in innovating and

adapting existing drug designs to

create new immunotherapies.

Source: Smyth

Figure 1. These are the three main targets bio-

pharmaceutical companies are focusing on in the

immuno-oncology therapy space.

Cancer Fighters


CRO/SPONSOR

outsourcing support to plan, launch, and manage clinical

investigations. When seeking support, sponsors should as-

sess their CROs and vendors for expertise and experience

specific to immuno-oncology, because these types of trials,

more than traditional chemotherapy studies, bring with

them several obstacles, such as those characterized by the

Society for Immunotherapy of Cancer (SITC).10

Obtaining protocol approvals

Smaller-sized sponsors may find themselves for the first time

negotiating the trial protocol, conduct, and endpoints, as

well as the regulatory pathway, either alone or with a larger

partner. A CRO can provide experience-based counsel and

tactical support to write or review a trial protocol that en-

sures successful recruitment and data collection, as well as

the required evaluations. Because immunotherapy endpoints

are not traditional, and oncology practitioners are still gain-

ing experience with this class of drugs, a well-written proto-

col can guide the investigators and trial staff as they adapt to

this new class of treatments. The protocol design is particu-

larly important because of the emerging popularity of testing

combinations of drugs within the same protocol.

As part of protocol drafting, or even a near-final review

before finalization, sponsors should understand the “stick-

ing points” in the regulatory processes as well as the insti-

tutional review boards and independent ethics committees

(IRB/IEC) processes, enabling sponsors to address them

proactively in their trial design and submission material. As

with oncology practitioners, while site-level regulatory bodies

have reviewed and approved immunotherapies, many IRB/

IECs may be unfamiliar with immunotherapy clinical trial de-

signs, methods of action, evaluations, or side-effect profiles.

Country-level approval processes for sponsors of interna-

tional trials must address the varying requirements regard-

ing the production and use of biologics by different national

or regional regulatory bodies. For example, good manufac-

turing practice (GMP) regulations are required for trials in

the European Union, but FDA recognizes that commercial

production and warehousing, which are subject to GMP

regulations, may not be appropriate for the manufacture of

Phase I investigational drugs. Therefore, the FDA requests

sponsors submit product chemistry, manufacturing, and

control information as part of an investigational new drug

application (IND) for a determination of sufficient safety.

Enrolling and retaining the right patients

Another challenge for sponsors is identifying, recruiting,

and retaining specific patient populations as defined by

their immune status and genetic makeup of their cancers,

both of which are entwined with the development of enroll-

ment and endpoint criteria and may require companion

diagnostic tests. Addressing this challenge involves many

evolving strategies, including the use of biomarkers and ge-

netic sequencing data. Smaller companies may need assis-

tance from a CRO’s scientific and data team to plan robustly

for how they and trial sites might address such issues for

the duration of a trial.

The International Cancer Genome Consortium (ICGC),

coordinated by the Ontario Institute for Cancer Research in

Toronto, Canada, publishes information to help guide treat-

ment development and patient selection. The ICGC aims to

catalogue every genetic mutation in 50 different cancer types

by analyzing a minimum of 500 individual samples of each

type. ICGC participants hail from Australia, Canada, France,

India, China, Japan, Singapore, the U.K., and the U.S.

Another resource is a SITC catalogue of “references and

online resources relevant to the discovery, evaluation, and

clinical application of immune biomarkers” so that they

might be applied to the “development, clinical evaluation

and monitoring of cancer immunotherapies.”11

Moreover, the Cancer Immunotherapy Trials Network

(CITN) is addressing diagnostics and bioinformatics as

part of its mission to make immunotherapies broadly avail-

able to patients with cancer. CITN, funded by the National

Cancer Institute (NCI) and Fred Hutchinson, designs and

conducts early phase trials to provide “high-quality immu-

nogenicity and biomarker data that elucidate mechanisms

of response or failure and thereby facilitate the design

of subsequent trials ... [and uses] only GMP agents with

validated reproducible and reliable manufacturing at scale

by a company, the NExT (NCI Experimental Therapeutics)

program, the former RAID (Rapid Access to Interventional

Development) program, or an equivalent experienced orga-

nization.”12 CITN member sites include NCI and 29 academic

medical centers, and works in collaboration with foundation

and industry partners.

Planning for logistics, product production, and assessment

Preclinical immunotherapies can be made in the laboratory

on a small scale. In contrast, immunotherapy clinical trials

require larger scale product production but with the same

purity and specificity. Unlike small molecules, however,

targeted vaccines are not typically made in homogenous

batches. Rather, they require harvesting immune cells and

tumor samples from individual patients and different trial

sites at different times, transport of these samples to quali-

fied facilities for manipulation and proliferation, and then

shipping back to the investigator for patient infusions.

Immunotherapy clinical trials require

larger scale product production

but with the same purity and

specificity as preclinical studies.


CRO/SPONSOR

Temperature control, customs clearance facilitation and

regulation compliance are just part of what sponsors need

to consider and require for their secure chains of custody

during immunotherapy trials.

Sponsors may need counsel on manufacturing sources

for their candidate immunotherapies if they do not own

facilities or have access to one via a large pharmaceutical

partner. A CRO can advise sponsors on the availability and

capability of academic or contract-based manufacturing fa-

cilities that can reliably provide the quality and quantity of

product needed to support the trial’s sites. CROs also can

advise on a trial’s assessments, such as the best methods

and facility for centralization of immunological monitoring

or how to use training and protocols to reduce data vari-

ability if different laboratories must be used to accommo-

date trial sites.

Dosing and measuring response

Determining the ideal dosing protocol for the best patient

response can be novel territory for immunotherapy de-

velopers. Large pharma companies can obtain experience

through multiple advisors, trials, and resources that permit

revisiting the drawing board to make such determinations.

In contrast, smaller sponsors usually have the budget for

one trial.

Early phase trials in oncology traditionally aim to es-

tablish the maximum tolerated dose (MTD) for later phase

trials. The challenge for sponsors here is that immuno-

therapies can exhibit therapeutic responses at dose levels

below where toxicity is seen, and thus one may not nec-

essarily want to identify the highest possible dose that a

patient can tolerate. In addition, immunotherapies are now

typically being investigated as part of a combination treat-

ment with other marketed or investigational agents. Even

if the safety profile of each agent as a monotherapy is well

characterized, the effects in combination are unknown and

can be substantially different than anticipated. SITC noted

that such combinations are problematic for using classical

methods to determine MTD and recommended that an opti-

mal biologically active dose (BAD) might best consider both

a toxicity grade and an immune response score.14

Measuring patient response is a known challenge for im-

munotherapies that has prompted the revision of clinical

trial designs. No “universal” criteria to measure immuno-

therapy response have been adopted for research or clinical

care, and the FDA still holds survival as a gold standard

for cancer treatment. That said, both pembrolizumab and

nivolumab were initially approved based on small, single-

arm trials that utilized surrogate endpoints such as overall

response rate and duration of response.

Looking back, traditional chemotherapy patient response

assessment drove the development of Response Evalua-

tion Criteria in Solid Tumors (RECIST) and modified World

Health Organization (WHO) criteria, which rely on a reduc-

tion in tumor burden. RECIST uses straightforward, one-di-

mensional measures, such as the sum of the longest diam-

eter of the tumors.13 Immunotherapies are not well served

by these criteria, in that patients’ responses may not imme-

diately result in tumor burden reduction. Rather, they may

experience pseudo disease progression before regression

or stabilization. For example, an immune response such as

T-cell infiltration can increase a lesion size that without a

biopsy may appear as tumor cell proliferation.

Of note, as part of the ipilimumab Phase II melanoma

clinical trial program, investigators proposed four immune-

related response criteria (irRC), noting all were associated

with favorable survival: “(a) shrinkage in baseline lesions,

without new lesions; (b) durable stable disease (in some

patients followed by a slow, steady decline in total tumor

burden); (c) response after an increase in total tumor bur-

den; and (d) response in the presence of new lesions.”14

irRC, which quantifies response in two dimensions and then

calculates their products and their sums, helps reinforce

that disease progression is not equivalent to drug failure,

and that longer times, even months, may be needed for

therapeutic effect and evaluation.

To address limitations of RECIST and irRC, new criteria,

irRECIST, were introduced in 2014.15 Created as an adapta-

tion of irRC, irRECIST is designed “to allow for treatment

evaluations and assessments that better meets both inves-

tigators’ and patients’ needs and with that better reflects

sponsors’ demands for more reliable and reproducible study

data analyses.” irRECIST also contains guidance for ambigu-

ous cases. Like RECIST, irRECIST is unidimensional and en-

ables high reproducibility of results, and its design produces

results that highly correlate to irRC. However, the clinical

relevance of irRECIST needs confirmation. The authors

intended that irRECIST would reduce ambiguity in assess-

ments and promote harmonization between trial sites and

central or independent data reviewers, so that all would use

the same criteria specifically designed for immunotherapies.

Source: Smyth

Figure 2. Measuring patient response is a known

challenge for immunotherapies, a reality that has

prompted the revision of clinical trial designs.

Response Criteria Adjusted


CRO/SPONSOR

Many immunotherapy clinical trials continue to use ob-

jective response and progression-free survival as endpoints,

but overall survival is still strongly suggested.

Reactions — adverse and otherwise

Immunotherapy sponsors and investigators must be adept

at recognizing, characterizing and monitoring both immune-

related adverse events (irAEs) and emergent resistance.

Sponsors will readily anticipate known irAEs such as flu-like

symptoms of chills, fatigue, fever, back pain, nausea, joint

ache, and headaches. However, serious adverse reactions

(SAEs) are possible in immunotherapy trials that for the

unaware can have dire consequences. For example, SAEs

among patients receiving sipuleucel-T included acute infu-

sion reactions. One health concern with ipilimumab is its

ability to enable damaging autoimmune responses, which

can be fatal. Consequently, the FDA required a risk evalua-

tion and mitigation strategy (REMS) and a patient medica-

tion guide as part of the ipilimumab approval.

Cancer immunotherapies, because of their significant

patient-specificities and durable responses even after treat-

ment ends, have the potential to enable a patient’s immune

response to recognize and adapt as a cancer mutates. To

date, they have been quite successful for small populations

of patients, while demonstrating the possibility to define

optimal use for a majority of patients with cancer. Future

studies will help define the optimal use of immunothera-

pies in different tumor types as single agents or as part of

combination therapies with other immunotherapies or can-

cer drugs.

If proven, first-line, earlier stage immunotherapy treat-

ment may improve the efficacy and longevity of patient

responses. Robust clinical trials that address the challenges

of assessing the efficacy and safety of immunotherapies in

the most appropriate patients will yield the data to build

this new treatment paradigm.

References

1. Kelly Scientific Publications, “Global & USA Cancer Immunother-

apy Market Analysis to 2020.” April 2015. http://www.lifesciencein-

dustryresearch.com/global-usa-cancer-immunotherapy-market-

analysis-to-2020.html

2. BCC Research, “Cancer Vaccines: Technologies and Global Mar-

kets.” January 2015. Report Code: PHM173A. http://www.bccre-

search.com/market-research/pharmaceuticals/cancer-vaccines-

technologies-global-markets-report-phm173a.html.

3. BCC Press Release, “Global Cancer Vaccine Market to Reach $4.3

Billion in 2019.” Dec. 19, 2014.

4. Research and Markets, “Cancer Targeted Therapy Market & Clini-

cal Insight 2015.” April 9, 2015. Press Release. http://globenews-

wire.com/news-release/2015/04/09/722930/0/en/Global-Cancer-

Targeted-Therapy-Market-Clinical-Insight-2015.html.

5. FDA, “FDA Approves First-of-its-Kind Product for the Treatment

of Melanoma.” Oct. 27, 2015. Press Release. http://www.fda.gov/

NewsEvents/Newsroom/PressAnnouncements/ucm469571.htm.

6. American Cancer Society, “Non-specific cancer immunotherapies

and adjuvants.” Sept. 5, 2014. http://www.cancer.org/treatment/

treatmentsandsideeffects/treatmenttypes/immunotherapy/can-

cer-immunotherapy-nonspecific-immunotherapies

7. Staton, T. “The PD-1 wave? Report says it’s a $33B tsunami, with

BMS surfing for first place.” FiercePharmaMarketing. March 4,

2015. http://www.fiercepharmamarketing.com/story/pd-1-wave-

report-says-its-33b-tsunami-bms-surfing-first-place/2015-03-04

8. NCI, “CAR T-Cell Therapy: Engineering Patients’ Immune Cells

to Treat Their Cancers.” October 16, 2014. http://www.cancer.gov/

cancertopics/treatment/research/car-t-cells

9. MD Anderson, “MD Anderson and Amgen announce agreement

to develop BiTE® therapies for myelodysplastic syndrome.” Press

Release January 12, 2015. http://www.mdanderson.org/newsroom/

news-releases/2015/md-anderson-amgen-agree-to-develop-bite-

therapies-for-myelodysplastic-syndrome.html

10. Fox, B.A., et al. “Defining the critical hurdles in cancer immuno-

therapy.” Journal of Translational Medicine. 2011, 9:214. http://www.

translational-medicine.com/content/9/1/214 (Dec. 14, 2011)

11. Bedognetti, D., et al. “SITC/iSBTc Cancer Immunotherapy Bio-

markers Resource Document: Online resources and useful tools

- a compass in the land of biomarker discovery.” Journal of Trans-

lational Medicine 2011, 9:155. http://www.translational-medicine.

com/content/9/1/155 (Sept. 19, 2011)

12. Cancer Immunotherapy Trials Network. 2015 http://citninfo.org/

index.html

13. Park, J.O., et al., “Measuring Response in Solid Tumors: Com-

parison of RECIST and WHO Response Criteria,” Jpn. J. Clin.

Oncol. (2003) 33 (10): 533-537.http://jjco.oxfordjournals.org/con-

tent/33/10/533.full

14. Wolchok JD, Hoos A, O’Day S, et al: Guidelines for the evalua-

tion of immune therapy activity in solid tumors: immune-related

response criteria. Clin Cancer Res. 2009, 15:7412-20

15. Bohnsack, O., Hoos, A., Ludajic, K., “Adaptation of the immune

related response criteria: irRECIST,” Poster 1070P, ESMO 2014,

Sept. 14, 2014. Annals of Oncology. 2014, 25 (suppl_4): iv361-iv372.

10.1093/annonc/mdu342. http://oncologypro.esmo.org/Meeting-

Resources/ESMO-2014/Immunotherapy-of-Cancer/Adaptation-

of-the-immune-related-response-criteria-irRECIST.

Chris Smyth, PhD, is Managing Director, Novella Clinical

Immunotherapy sponsors and

investigators must be adept at

recognizing, characterizing, and

monitoring both immune-related adverse

events and emergent resistance.

Live webinar:Thursday, April 7, 201611 am – 12 pm EDT

Presenters:

Eric Groves, MD, PhD Vice President, Advisory Services, Quintiles

Matthew Bentley, PhD Clinical Project Manager, Oncology, Quintiles

Kathleen Gray, PhD Scientific Advisor, Q2 Solutions

Moderator:


Presented by:

Sponsored by:

Cop

yright

© 2

016

Quintiles

Quintiles: +1 973 850 7571 Toll free: +1 866 267 4479 www.quintiles.com/oncology [email protected]

For technical questions about this webinar, please contact Daniel Graves at [email protected]

Register now for free! www.appliedclinicaltrialsonline.com

/act/trials

Immuno-Oncology Insights:Top 5 Challenges in Today’s Immuno-Oncology Trials

Learn more about

Immunotherapy is one of the most promising avenues of research in the battle against cancer. As initial checkpoint inhibitors come to market, the immuno-oncology development landscape is exploding. Now, the pressure is on to apply insights from existing studies to ensure future trials are quick and efficient, yield high-quality data, and assure patient safety. In this webinar, we’ll share lessons learned for your immuno-oncology program through examining the challenges that come with the new complexities of immuno-oncology studies:

A Rapidly changing SOC

A Highly complex early phase studies

A Faster than expected enrollment

A New safety signals and combination therapies

A Specialized laboratory criteria

By attending this webinar you will:

A Understand the impact of new therapies and care standards on trial planning and design.

A Learn about the new operational challenges of immuno-oncology studies and critical success factors

A Identify new demands of laboratories for expedited TAT and fail-proof sample tracking.


TRIAL DESIGN


PEER

REVIEW

Overcoming Early Phase Oncology ChallengesKaren Ivester

Developing novel, safer treatments that

may be curative for many individuals liv-

ing with cancer depends not only on con-

tinued use of existing products but on

the clinical and regulatory success of the

newest treatments—including promising devel-

opments focused on targeted/immunotherapy

combinations and immune checkpoint blockade

therapies which are demonstrating that immu-

nity is the key to long-term responses. Rigorous

evaluations in clinical trials to assess efficacy

and safety in patients are critical to the develop-

ment of these highly sensitive targeted/immu-

notherapy combinations. New molecular entity

(NME) selection, protocol development, patient

population, and principal investigator (PI) and

site selection are key areas in which to focus to

establish a foundation for the successful execu-

tion of an early phase oncology trial.

New molecular entity selection

A substantial number of NMEs move through

Phase I into Phase II; however, progression from

Phase I through approval each year is very low.

In 2014, approximately 64% of drugs moved from

Phase I to Phase II and 10.4% moved from Phase

I through approval.

From 2005 through 2013, FDA’s Center for

Drug Evaluation and Research (CDER) has aver-

aged approximately 25 novel new drug approvals

per year. These include drugs for all diseases

and all indications. In 2014, 41 novel new drugs

were approved—six in total for oncology. These

drugs were approved under the FDA accelerated

approval program, which allows early approval

of a drug for serious or life-threatening illnesses

that offer benefit over current treatment. Once

accelerated approval is granted, these drugs

must undergo additional testing. These recent

approvals in oncology were based on a “sur-

rogate endpoint” (e.g., a laboratory measure) or

other clinical measure considered to predict the

clinical benefit of a drug.1

Given the cost of drug development (which

now exceeds $2.5 billion2), the selection of those

molecules that have the highest potential for

success is crucial. There is more at stake than

the financial cost—we must consider the patient

population, the PIs and the sites. They are all

finite and the demands placed upon them are

seriously impacting the future of clinical tri-

als—especially early phase clinical trials.

Protocol development and optimization

of design

Nearly 60% of protocols are amended during

the trial, according to the Tufts Center for the

Study of Drug Development.2 In order to reduce

or avoid costly protocol amendments, oncology

sponsors must view early phase protocol devel-

opment holistically and assist our sponsors in

optimizing their protocol development. Impor-

tant questions to consider include:

t� Has the early work been done (toxicology,

animal studies, targeted starting dose estab-

lished, appropriate formulation and manufac-

How to meet the rigorous safety and efficacy demands critical to evaluating newer targeted cancer therapies.


TRIAL DESIGN

turing stability and scalability evaluated)? Performing a

gap analysis can assist the client in identifying potential

issues early on; therefore, an early evaluation by regula-

tory can be of added value.

t� Has the sponsor identified biomarkers for the mecha-

nism of action (MOA)? Has the patient population been

selected based on these biomarkers and the MOA? Are

assays validated?

t� What is the turnaround time for any procedures or as-

sessments and how will this impact patient enrollment?

We must keep in mind these patients have been diag-

nosed or their disease has progressed and may also be

aggressive. Asking them to wait four to six weeks may

not be acceptable for them or for their treating surgical

or medical oncologist.

t� Are all of the protocol-defined procedures and assess-

ments appropriate for collecting data that will support a

new drug application or investigational medicinal prod-

uct dossier?

t� Is all of the information critical in a Phase I or Phase

IIa (proof of concept, efficacy, or mechanism of action

study) where the intent is to inform early go/no-go de-

cisions? If it isn’t critical to inform the decision (e.g.,

not a critical variable) and not critical for safety, then

there is a need to provide a rationale for collecting the

variable, entering it into the data collection system and

monitoring it. Significant costs lie in the collection of

unnecessary information in early phase clinical research

and this is an area where protocol and electronic case

report forms (eCRFs) can be optimized and improved

considerably. As sponsors, researchers, and contract

research organizations (CROs) gain expertise in early

phase research, this will greatly improve and reduce

sponsor and CRO costs as well as reduce site burden in

data collection.

First-in-man studies for many candidate chemothera-

pies are constructed to identify the maximum tolerated

dose and dosing schedule. Yet, technologies have yielded

investigational agents that are designed to act with greater

precision to inhibit cancer cell growth or promote cancer

cell death.

For sponsors of these newer targeted molecular agents,

trial protocols may require an optimal biological dose

endpoint rather than a more traditional maximum toler-

ated dose (MTD) endpoint. Consequently, the protocol will

need to clearly define how to determine the recommended

Phase II dose, and describe new assays or procedures to

measure biologic endpoints, as well as to capture tradi-

tional patient safety assessments.

The investigational brochure (IB) contains the informa-

tion that will assist and guide the regulatory and safety

advisory committees in assessing the risk/benefit of the

NME. Early compound knowledge can also assist in the

most critical variables to collect regarding safety, thereby

reducing the collection of unnecessary data.

Thoughtful design of an early stage trial protocol can

help characterize biomarkers that will facilitate appropri-

ate patient enrollment in follow-on advanced trials. Re-

member that most of the oncology drugs approved in 2014

were approved based on a surrogate endpoint or a predic-

tor of clinical benefit.

Importance of adaptive design in early phase

clinical trials

Utilizing pharmacokinetic/pharmacodynamic (PK/PD) to

guide dose escalation decisions and adaptive designs that

enable adjustments to the study design and/or specific pa-

tient population as the trial progresses may increase the

speed of the dose escalation and reduce patient exposure

to doses that are not effective, as traditional designs often

start with a dose well below animal toxicity. This lowest

dose has no effect and the traditional method doesn’t al-

low reaching higher doses quickly.

Interest in adaptive design study methods arises from

the belief that these methods hold promise for improv-

ing drug development compared to conventional study

design methods (such as 3 + 3 designs). Adaptive design

approaches may lead to a study that provides the same

information, but more efficiently, increases the likelihood

of success, or provides more information regarding the

drug’s effect, which may also lead to more efficient follow-

on studies.

The more progressive adaptive design algorithms permit

a change in dose level after each patient is treated based

on the accumulated responses of previously enrolled sub-

jects. These algorithms lead to more dose-level changes,

both increases and decreases of the dose, as the algo-

rithm selects an exposure for each subject to the dose that

will contribute the greatest amount of information towards

the ultimate conclusion. By permitting escalation after

each individual subject if that subject did not have a dose-

limiting toxicity (DLT), it is possible to reach the middle or

higher end of the dose-response curve with fewer subjects

at each of the prior levels.

Adaptive designs allow for completing the study more

rapidly than the traditional sequential fixed-size cohort

For sponsors of newer targeted

molecular agents, trial protocols may

require an optimal biological dose

endpoint rather than a more traditional

maximum-tolerated dose endpoint.


TRIAL DESIGN

design. CROs can assist sponsors in exploring the features

of different study designs with regard to the balance of ef-

ficiency (study size) and subject safety. Study simulations

with multiple combinations of escalation criteria, dose-

step size, and hypothetical assumptions around relation-

ships of exposure to severity and frequency of adverse

events (AEs) may be useful in evaluating different designs.

These simulations can assist in assessing the risks and

selecting a design that offers improved efficiency without

increasing risk excessively.4

Adaptively designed studies that enroll patients who

are most likely to benefit could finish faster and consume

fewer resources, which could yield economies in time to

development, as well as cost and reduced burden on PIs

and sites.

Finally, in assessing the protocol development, is the

imaging, procedures, and assessments in line with the

standard of care (SOC) for the patient population, the dis-

ease indication, and the country/site in which the clinical

trial is being conducted? This can vary significantly and,

prior to site selection, feasibility, and the use of prescrib-

ing data can help determine the most appropriate coun-

try/site mix. Keeping imaging and disease assessments

SOC will decrease costs and minimize regulatory delays

from radiation committees at both the country and site

levels.

Patient selection in early phase clinical trials

Novel approaches to patient/subject selection can be

used to ensure we are selecting the patients most likely to

benefit from the NME. “Genotyping” tumors from patients

is paving the way for targeted therapies for people living

with cancer. The translational research and the technical

capacity to screen large numbers of tumors have taken

years and significant collaboration between oncologists

and pathologists. Molecular profiles and tumor typing

has identified the genetic abnormalities that activate and

drive tumor growth. Understanding cancer development

at the molecular genetic level, identifying mutations, and

creating NMEs that target them are significantly improving

outcomes for patients with lymphoma, breast, brain, GI,

and lung cancers, as well as other indications. The process

of extracting and purifying DNA and genotyping it using

sophisticated software and assays can screen for hundreds

of mutations that have been identified and linked with tu-

mor growth.5

The identification of genetic mutations in tumors has

been critical in the development of multiple treatments

in oncology and now serves as the basis for personalized,

targeted therapies as we have seen in adaptive clinical

trials such as the I-SPY 2 TRIAL. This clinical trial was

designed to treat patients with breast cancer, and the pa-

tients are assigned to treatment options (of which there

are many in a single trial) based on the molecular charac-

teristics (or biomarker signatures) of their disease.6

The genotype and mutations within specific tumors and

indications are driving the patient population for targeted

therapies. These innovative, genomically targeted thera-

pies often provide good initial responses. For example,

drugs that target a specific BRAF gene mutation in mela-

noma can shrink the tumors in about half of the patients.

This approach has resulted in frequent, short-lived re-

sponses for multiple targeted therapies.

Resistance develops when tumors have multiple ge-

nomic defects that drive the disease. After the targeted

therapy knocks out one driver, another driver can take over

and activate tumor growth again. To combat resistance

and relapse, cancer immunotherapy has found a role in

combination with genomically targeted therapies. This

immune checkpoint blockade therapy has resulted in an

approach that treats the immune system which is capable

of recognizing distinctive features of cancer cells and

launching T-cells that target and shut down tumor-specific

antigens at the peptide level. The first immune checkpoint

blockade, ipilimumab (Yervoy®), has been approved for

melanoma. A second immune checkpoint inhibitor showed

that pembrolizumab (Keytruda®) is also effective in the

treatment of melanoma, and the drug was approved in

2014.

Collaboration between researchers who focus on tar-

geted therapies and researchers who focus on immune

checkpoint therapies will likely result in the development

of targeted/immunotherapy combinations which will have

“curative potential.”7

Patient selection, down to the genetic mutation level,

is impacting early phase clinical trials in ways not previ-

ously anticipated. The institutions that have the capabil-

ity to utilize genotyping, in mass, will be at an advantage

to quickly identify patients with tumors that match the

novel therapies in these clinical trials. As adaptive de-

signs expand and we learn more about specific therapies

and combination therapies for multiple indications, there

will be more I-SPY 2-type clinical trials in which patients

have their tumor genotyped initially and are then given

combination(s) of treatment developed specifically for

their disease.

Currently, this means sites will need to identify patients

for clinical trials that have these specific mutations. In

reality, this translates to a lower enrollment rate in some

instances, especially if there are rare or multiple genetic

mutations in the targeted tumor types or indications. It

becomes very important to research and learn more about

the occurrence of each of the genetic mutations in various

oncology indications in order to plan for the number of

sites required to enroll the study.

Working with feasibility teams to research the indica-


TRIAL DESIGN

tion, frequency of mutation, and specific line of therapy

for each therapy or combination therapy will be critical to

the success of early phase oncology clinical trials as the

targets become more specialized. While challenging, the

potential for effective, long-lasting treatment outcomes in

multiple indications is a reality.

Site selection and management

With the NME identified, a well-designed protocol in

place, and the patient population selected, attention

turns to the selection and activation of appropriate clini-

cal sites. Historical site data, specifically site enrollment

patterns with similar oncology indications, are critical to

choosing experienced and qualified sites. Knowledge of a

site helps determine which facilities have reliable PIs and

clinical research staff that both understand and can “bring

to life” the complexities of Phase I clinical trial protocols,

including:

t� Patient cohort management

t� Recruitment of niche patients, often with specific ge-

netic mutations/alterations

t� Management of DLTs and participation in dose-escala-

tion decisions

t� Collecting, processing, and analy-

sis of PK/PD samples

t� Extensive biological specimens

are collected, genotyped, and an-

alyzed

t� Commitment to timely data entry

and query resolution

Site efficiencies can also be cre-

ated when a sponsor or contracted

CRO is familiar with each site’s in-

stitutional contracting procedures,

scientific and ethics review board

practices, and document require-

ments. Detailed knowledge of local

trial site compliance with federal,

local, and its own institutional regu-

lations to protect and care for hu-

man subjects is critical.

Finally, the use of document

exchange portals can accelerate

overall clinical trial timelines and

increase efficiencies without sacri-

ficing quality or endangering regula-

tory compliance.

Principal investigator burden

and impact on clinical trials

While the number of NMEs and clin-

ical trials are increasing, the num-

ber of PIs are declining and many

are withdrawing from clinical research and development

altogether. The number of clinical trial investigators has

fallen significantly since 2008 and there is a high turnover

rate among those filing 1572s.

Thirty-five percent of investigators in the U.S. are not

returning to conduct another clinical trial since initially

submitting a 1572 in 2006. The numbers of investigators

not returning to conduct clinical studies are even higher in

other countries, as reflected below:

t� Canada: 55%

t� South America: 53%

t� Asia Pacific: 53%

t� Africa: 47%

The reasons given are system and organization, time

involvement, resources, lack of clinical or scientific ratio-

Patient selection, down to the

genetic mutation level, is impacting

early phase clinical trials in ways

not previously anticipated.

When you’re passionate about what you do, it doesn’t feel like work.

At WCG, we’re more than an IRB; we’re a clinical services

organization. We’re passionate about protecting others, and

committed to optimizing the performance of clinical trials.

www.wcgclinical.com/careers.Join the team. Join the revolution.


TRIAL DESIGN

nale for the research, lack of interest in the research topic,

complexity of trials, excessive trial costs not covered by

the sponsor, and disruption to clinical practice.

Some of these barriers, such as ethics submissions, are

essential; however, many of the system, organization, and

other obstacles are under the direct control of the spon-

sor company and the contract research organization (CRO)

partner.3

The most burdensome tasks identified by PIs and sites

were:

t� Completing contractual and regulatory documents

t� Getting paid for clinical trial work on time

t� Recruiting patients

t� Budgeting clinical trials

t� Completing feasibility surveys

t� Reporting serious adverse events (SAEs)

t� Taking GCP training

t� Completing site information forms

t� Working with ethics committees

t� Interacting with remote and on-site monitors

t� Retaining patients

t� Tracking clinical trial supplies

This leads to a lower proportion of experienced sites

and a high turnover rates among new PIs. The resulting

impact for sponsors is higher operational costs, including

substantially higher site start-up costs in areas of site se-

lection, qualification, and training.

What can sponsors and CROs do to assist PIs and sites?

It is important to:

t� Guarantee site payments within 30 days

t� Streamline start-up activities (GCP training, contracting,

essential document collection)

t� Utilize innovations such as TransCelerate BioPharma

Inc.

t� Standardize CDAs and CTA clauses

t� Share contractual preferences

If we are to reverse the trends of declining early phase

physicians and sites and reduce turnover, sponsors and

their CRO partners must be willing and able to change

their processes and to decrease the burden for clinical

trial investigators and sites.

By assisting sponsors in becoming selective regarding

their NMEs, thoughtful about protocol designs and their

selection of the right target patient population, we can

significantly impact the exciting landscape of early phase

clinical research. We have a lot of work to do in identifying

the ideal sites and PIs and, when we find them, we must

seek to understand their needs, minimize their burdens,

and let them know we value them so they continue to

engage in the collaborations that will result in bringing

cancer treatments to people living with the disease. Spon-

sors, CROs, sites, PIs, and, most importantly, patients will

benefit.

This is an exciting time in early phase oncology—novel,

targeted/immunotherapy treatments are being identified

that target significant mutations and engage the immune

response using multiple formulations and delivery sys-

tems.

Oncology drugs and medical device, diagnostics, ra-

diation, proton therapy, and nanotechnology are fusing

to have a significant impact on cancer treatment that will

continue to fuel innovation. Within the next decade or

two, many cancers could become a fully treatable illness

for many individuals. We may even find, in many indica-

tions, cancer is curable as we focus and extend our col-

laborations and share knowledge as we move forward.

References

1. CDER’s Novel New Drugs 2014 Summary, January 2015.

2. Source: Tufts Center for the Study of Drug Development

3. E. Cascade, M. Nixon, and C. Sears, “Sustaining the Investiga-

tor Pool: Understanding Operational Burden and Implementing

Valuable Supportive Solutions,” Applied Clinical Trials (Nov. 3,

2014).

4. Adaptive Design Clinical Trials for Drugs and Biologics, Draft

Guidance, U.S. Department of Health and Human Services,

Food and Drug Administration, Center for Drug Evaluation and

Research (CDER) Center for Biologics Evaluation and Research

(CBER), February 2010.

5. L. Ellisen, K. Flaherty, and A. Shaw, “Tumor Genotyping Brings

Personalized, Targeted Therapies to Patients, “Advances at the

Mass General Cancer Center, Summer 2010

6. Sponsor: QuantumLeap Healthcare Collaborative, Clinical Tri-

als.gov

7. P. Sharma and J Allison, “Review highlights potential of can-

cer immunotherapy plus targeted therapy, “MD Anderson News

Release (April 9, 2015).

Karen Ivester, RN, MA, is Vice President, Clinical Operations,

Ivester Research

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Julie Ross Martin Cook Colleen Colson Matt Hodskins

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A CLOSING THOUGHT

To see more A Closing Thought articles, visit


Technology continues to shape the

way people live, with on-demand ac-

cess to immense information and multi-

channel communication. The scientific

boom of gene sequencing is amplified

by our ability to correlate genotype

with phenotype and behavior, enabling

rapid advances in disease diagnosis and

treatment.

A single, human, whole genome se-

quence often can generate 500 mega-

bytes of raw data. It’s easy to see how

this can quickly turn into petabytes of

data with even a relatively small cohort

of patients. Even then, more data will

be added to the mix, as pathogenomics,

proteomics, and metabolomics evolve.

Researchers require high-performance

tools to manage increasingly large, com-

plex data sets to extract scientific intel-

ligence from raw data.

The White House Precision Medicine

Initiative’s Cancer MoonShot program

migrates from the realm of fantasy, to

distinct possibility, and perhaps, to real-

ity through a merger of information tech-

nology and genetic science. To improve

the lives of people with cancer and other

life-threatening diseases, a set of key

technology elements will be necessary

to ensure success:

t� Collaboration between researchers and

clinicians, aggregating data at the pa-

tient level in support of disease-oriented

research cohorts.

t� A high-performance, technology infra-

structure to enable rapid, accurate analy-

sis of large volumes of data.

t� Structured data models to ensure con-

sistency and reproducibility in results.

.

t� Scalability to ensure that knowledge

generated through research can be ap-

plied broadly across the clinical setting,

while longitudinally, clinical data contin-

ues to feed the research environment.

Ultimately, cancer therapy is only the

beginning of the coming wave of the

kinds of scientific advancements linked

to genomics and accelerated by infor-

matics. Every aspect of the human care

spectrum offers areas of potential ad-

vancement, from birth and hereditary

disorders, through wellness and pre-sick-

ness, all the way to disease management.

Today, only about 38% of consumers

have heard of precision medicine, have

only shallow knowledge about it and do

not associate it with genetic medicine.*

In the end, the marker of success for pre-

cision medicine is that the term simply

vanishes, and its principles become fun-

damental to modern medicine.

*PMC Survey: U.S. Public Opinion About

Personalized Medicine, 2014

http://www.personalizedmedicinecoalition.org/

Userfiles/PMC-Corporate/file/us_public_opin-

ion_personalized_medicine.slides.pdf

Our health is a reflection of who we are and how we live. In an

information age that allows freedom of choice and ubiquity of

options, the rise of personalized care is inevitable. The promise

of precision medicine not only offers a newfound science to treat

life-threatening illnesses, but also realizes an ideal medical care ap-

proach, treating each person as a valued individual via pinpointed

diagnostic assessments and optimized therapeutic interventions.

The Promise of Precision Medicine

The marker of success

for precision medicine

is that the term simply

vanishes, and its

principles become

fundamental to

modern medicine.

Steve RosenbergSenior Vice President and General

Manager, Oracle Health Sciences

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