EXECUTIVE SUMMARY

Decrease Cost and Increase Efficiency in Early Phase Clinical Trials While Addressing Challenges, Biomarker Techniques and Compound Development Strategies

CLINICAL TRIALS PHASE I & PHASE IIA

INTRODUCTION 3

2014 SESSION SUMMARIES 4

RESOURCES FOR INFORMATION AND DISCUSSION 9

CONTENTS

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INTRODUCTION: HERE’S WHAT YOU MISSED AT EXL PHARMA’S CLINICAL TRIALS PHASE I AND PHASE IIA EVENT

If you weren’t able to join us in 2014, here is what you missed at ExL Pharma’s Clinical Trials Phase

I and Phase IIA event.

With a focus on decreasing costs and increasing efficiency in early phase clinical trials while

addressing challenges, biomarker techniques and compound development strategies, this unique

event was held October 15-16, 2014 in Philadelphia, PA.

Attendees learned how to identify compound development strategies to optimize success in clinical

trials and discovered best practices for early decision-making through the analysis of biomarker

utility in drug development. Using analytical technology, they explored solutions behind increasing

the feasibility of drugs in clinical trials, implementing adaptive design in proof-of-concept studies to

increase efficiency and decrease time, and much more.

Speakers at the event included:

Likewise, conference attendees shared the following testimonials:

“Excellent content & entertaining speaker!” Director of Early State Development, Merck

“Excellent presentation!” Director, Clinical Operations, Gilead Sciences

“Very valuable content!” Clinical Operations Lead, Biogen Idec

“Excellent discussion/presentation of biomarker utility.” Associate Director, Early State

Development, Merck

“Great presentations, clearly provided complex information!” Director, Clinical Operations,

Janssen R&D

“Great presentations. Learned a lot!” Senior Scientist, Teva

The following session summaries and highlights will give you an idea of what you may have missed at

our 2014 Clinical Trials Phase I and Phase IIA event.

INTRODUCTION

Samuel Blackman, Senior Medical Director, JUNO THERAPEUTICS

Ken Chang, Clinical Assay Development & Outsourcing Lead, MERCK

Timi Edeki, Senior Director, Global Clinical Research, ASTRAZENECA PLC

Maureen Ho, Senior Scientist, Early Stage Development, MERCK

Larry Lesko, Director, UNIVERSITY OF FLORIDA

Sid Roychoudhury, Compound Development Team Leader, JANSSEN

Norah Shire, Translational Medicine, MEDIMMUNE, LLC

Alessandra Tosolini, Associate Director, MERCK

Erika Zavod, Director, Operational Lead for Immunology, Head of Procedures GCO, TEVA

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Alessandra Tossonli of Merck offered information on oncology clinical trials in

a presentation titled “Clinical Feasibility and Implementation of Biomarker

Enrichment Strategy in Phase I/II Clinical Studies.” Biomarker selective trials

have operational challenges that may affect patient accrual. Biomarkers are

valuable drug development tools that provide more accurate/complete information

regarding drug performance and disease progression. In the clinic, they can be

used to facilitate precision and decrease invasiveness in a cancer diagnosis, for

patient selection treatment based on estimation of natural history of the disease,

to estimate the probability of response to a particular agent, and for detecting

toxicity. However, the majority of biomarker patients failed to join a recent study

for the following key reasons: they were receiving another cancer treatment, were

ineligible after screening, had a decline in performance status, lacked a metastatic/

measurable disease, were lost to follow-up or had status pending. The Merck study

concluded that biomarkers are likely required to reach high clinical efficacy bars;

that communication among all functional areas is imperative when developing

enrichment strategies; that sites are willing to conduct a prospective biomarker

strategy, but prefer screen failure rates around 50 percent; that sites are pre-

selecting a larger pool of potential future eligible patients based on turnaround

times; and that the matching of pre-clinical understanding and clinical final protocol

is critical for enrichment strategies.

Erika Zavod of Teva Pharmaceuticals delivered a session

on the “Seamless Development of Early Stage Clinical

Development” that focused on accelerating later phase

development via early phases. Since only one-third of

programs fail in Phase I, Zavod said it is important to

proactively plan Phase II via outsourcing strategy, defining

the population and accurately projecting costs. The risks of

planning Phase II too early, however, include using resources,

increasing spending early, facing communication challenges,

engaging vendors and experiencing false starts. Rewards are

better knowledge of the population early on, more accurate

cost projections, longer discussions regarding regulatory

issues, more robust data, more time to thoroughly vet vendors, an increased

chance of collecting data from actual potential sites, and more. Moving from Phase

II to Phase III, then, involves developing a protocol while Phase II is active, having

alternate strategies based on finite outcomes, conducting feasibility and protocol

assessments with active sites, and fast-tracking certain regulatory submissions.

Zavod also shared a model for partnerships based on increasing levels of complexity

and value.

SESSION SUMMARIES

Valu

e

Complexity

Functional Management

Compound Management

Preferred Partnership

Co-development

Business Process Outsourcing

Therapeutic Area Management

PARTNERSHIP MODELSINCREASING LEVEL OF COMPLEXITY AND VALUE

Tactical Outsourcing

© 2012 INC Rsearch, LLC

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Tatiana Beletskaya of Arensia broached the subject of an “Innovative Approach

to Increase Efficiency in Early Clinical Trials: Fast Patient Recruitment in

Phase IB/IIA Trials.” The current challenges facing the pharmaceutical industry

are unprecedented, including the industry’s lower revenue growth, poor stock

performance, the lowest number of new chemical entity approvals, and the poor

late-stage R&D pipelines. The solution? Improving R&D productivity. The increase in

the number and quality of innovative, cost-effective new medicines can impact the

industry’s profitability only if accomplished at reasonable R&D costs. The number of

Phase I studies in healthy volunteers has decreased and been replaced by Phase IB/

IIA studies, which have become increasingly complex in terms of design, end points

and required number of subjects. The need for patients in Phase I and II exploratory

trials is posing a great challenge to sponsors due to slow recruitment. Arensia

has built a network of state-of-the-art Phase I units across reputable university

hospitals in Eastern Europe, selecting this area based on its large patient pools,

well-documented medical records, experienced physicians, modern diagnostics

technology and lack of issues regarding IP protection. Shorter recruitment time

means sponsors save in direct and indirect costs.

Larry Lesko, professor and director for the Center for

Pharmacometrics and Systems Pharmacology at the

University of Florida, Lake Nona, presented “The Definition

of Breakthrough and Requirements for Achieving Success.”

Lesko discussed how breakthrough drugs (BTD) can affect

Phase I/IIA trials. Impacts include the increased frequency/

intensity of interactions with senior FDA personnel, access

to a cross-disciplinary review team to act as a liaison

across offices with supporting MAPP-GRP, the benefit of

FT designations, and an early read of regulatory flexibility

with regard to evidentiary standards. By therapeutic

area, most breakthrough drug requests are for cancer

or infectious diseases. Breakthrough drug status may be

denied for a number of reasons — clinical evidence may suggest only incremental

(not substantial) improvement over existing therapies, or the clinical value of

primary trial endpoints could be relative to outcomes and un-validated biomarkers,

for instance. Current reaction to BTD is mixed, and companies with few assets are

over-relying on it while competing enrollment in early clinical trials has increased.

Future advancements include greater clarity on the rapid development and approval

of companion diagnostics for targeted therapies as well as greater clarity on what

constitutes substantial improvement over standard therapy.

41%  

24%  

19%  

8%   8%   Cancer  

Infectious  Disease  

Rare  Diseases  

Other  

Cardiovascular  

http://www.focr.org/breakthrough-­‐designations  

SESSION SUMMARIES

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Samuel Blackman of Juno Therapeutics spoke to conference delegates about

“Accelerating Drug Combinations in Oncology.” Blackman offered a variety of case

studies on the topic. Issues to consider with drug combinations include scientific

rationale, single agent activity, compatible safety profiles, the possibility of drug-

drug interactions, dose, schedule and sequence, and patient population. Early

combination development should be considered for new oncology development

programs since history has taught us that monotherapy approaches to cancer rarely

lead to long-term survival, time is limited, and the number of combination partners

is huge — combination strategies should be considered as early as possible in

development.

Siddharta Roychoudhury of Janssen R&D shared information on “Compounding

Development Strategies to Optimize Success in Clinical Development.”

Conventional POC studies have the lowest probability of success, so taking the risk

out of Phase II POC trials involves targeting the right patients. This process entails a

more precise definition of diseases, which may involve sub-categorization. Increasing

rigor in Phase I/IB trials is also important for success. In this case, MoA-based patient

selection/enrichment prior to major investment in Phase II trials could be helpful.

Furthermore, leveraging disease models with the highest relevance to MoA, having

access to appropriate samples and knowing clinically relevant biomarkers can all

serve to further strengthen Phase II trial design.

Maureen Ho of Merck presented a case study on “Adaptive

Design in Proof of Concept Studies to Increase Efficiency,

Decrease Time and Decrease Overall Cost.” The study

focused on the company’s Hepatitis C compound

development program. Hepatitis C has infected up to

170 million people globally, and 20 percent develop liver

cirrhosis. The development of additional oral direct-acting

antivirals is needed to improve safety and tolerability, reduce

overall treatment durations and address resistance. The

use of adaptive design in the company’s program strategy

saved Merck more than $1.5 million as well as 10-12 months

of development time. Interestingly, dosing of only nine

patients was required to achieve the study’s objectives,

minimizing patient exposure to the study drug, and placebo/blinding wasn’t needed.

Furthermore, adaptive design allowed a no-go decision to be made early on.

Results of Use of Adaptive Design in Overall Program Strategy

24

Overall Program timing

~ 12 1/2 months ~$1.1 million

PA LPLV

~22-24 months* ~$2.5 million

PA LPLV

Using Adaptive POC Ib Design

Using Traditional POC Ib Design

January January-next year

January October / December-next year

Saved ~10-12 months and ~$1.5 million

*NOTE: traditionally, all studies start sequentially and don’t overlap.

SESSION SUMMARIES

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Ken Chang of Merck Research Labs offered another case study on how to “Address

Issues and Lessons Learned in Oncology Clinical Trials with an Emphasis on

Biomarkers and Diagnostics.” General considerations of clinical biomarkers and

diagnostics development include the following: a balanced clinical biomarker assay

development strategy, a companion diagnostics strategy, and the answer to “Is

it an experienced judgment call or is it still an art?” Lessons learned from clinical

mutation assay development and validation were the importance of understanding

the clinical team’s intention regarding the list of mutations/plans for patient consent,

the initial intention of developing and validating assays internally and the later

decisions of transferring out, and the need to be more conservative in estimating

delivery time for developing assays. Through the course of the case study, Merck

realized that clinical team members may not be aware of the challenges facing the

assay development and validation, and that there is a long discussion process when

it comes to finalizing clinical strategy. Further, when it comes to high-profile projects,

everything is needed yesterday.

A presentation on the “Utility and Development of

Biomarkers in Drug Development” was delivered by Norah

Shire of MedImmune. The costs of developing a new drug

have dramatically increased, although the cycle times for

pharmaceutical R&D are long. Meanwhile, the probability

of success for new mechanisms is only 11 percent. This low

success rate is due to inefficiencies, costs, the historical

reluctance in the industry to make early no-go decisions,

and the fact that the introduction of more compounds has

not translated into increased productivity. Biomarkers can

provide critical and needed information and guide early and

late decisions. Internal factors for biomarker success include

culture buy-in to the value of early decisions and late-stage

differentiation, early alignment among the development

team, dedicated resources to assay development, clinical

qualification, and technology transfer to teams. She

showcased four different examples, which all concluded that

biomarkers deserve a dedicated place in drug development,

that planning is essential and that adequate resources must

be allocated throughout the development process, that not

all biomarker efforts will yield positive results (the regulatory

path for qualification is not always obvious), and that — if

planned properly — biomarkers have the potential to infuse

drug development with both creativity and new life.

5

Cycle Times for Pharmaceutical R&D are Long

1. Adams, CP, Brantner VV, Health Economics 2010 2. Outlook 2011, Tufts Center for the Study of Drug Development 3. DiMasi JA and Grabowski HG, Managerial and Decision Economics 2007 4. DiMasi JA, Hansen RW, Grabowski HG, Journal of Health Economics 2003

1

5,000-10,000 Compounds

10-20 Compounds

2-4 Compounds

Year

s

Phase III n=1000-5000

Phase II n=100-500

Phase I n=20-100

FDA Review

Drug Discovery

Clinical Trials

Post-Marketing

Preclinical

Iterative and Not Strictly Linear Process

2

6

1.5

5

It takes ~10-15 years and ~$1.3 billion to develop one new medicine 1-4

SESSION SUMMARIES

Probability of Success of New Mechanisms: 11%

Source: Kola and Landis (2004)- Nature Reviews/Drug Discovery

Many compounds fail due to lack of efficacy or demonstrated benefit

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Beatrice Setnik of Inc. Research focused her session on

“Assessing Abuse Potential: Evaluation of CNS-Active

Drugs.” Setnik noted that all CNS-active/penetration

compounds are evaluated for abuse and dependence

potential by regulatory agencies, and that abuse-related

events are evaluated to determine drug scheduling. Further,

regulatory agencies may request additional abuse potential

studies, and the new drug application or NDA includes an

abuse potential evaluation and proposal for scheduling.

Controlled substances under the Controlled Substance Act

are divided into five schedules based on whether they have

a currently accepted medical use in treatment in the United

States and their relative abuse potential and likelihood of

causing dependence. Abuse potential, then, is equated with addiction sustaining and

abuse liability; prescription drugs can be abused by both intended and unintended

routes of administration. Throughout the drug development process, there are three

major abuse decision points in which “abuse signals” resulting from study outcomes

answer the following questions: Is the drug CNS-active? Is a human abuse potential

study needed? Does the abuse-related data in the NDA show that the drug has

abuse potential? In a human abuse study, the measures most directly related to the

likelihood of abuse are examined, including drug liking, willingness to take the drug

again and drug identification. These studies provide an important assessment of

the likelihood of abuse, and this evaluation begins early in the drug development

process.

For internal use only

Drug Scheduling

Schedule Potential for Abuse

Accepted Medical Use

Uses/ prescribing practice

Example Drugs

I High No Research only Heroin, marijuana, LSD, amphetamine variants

II High Yes Rx; no refills Opium, oxycodone, cocaine PCP, morphine, amphetamine, barbiturate types

III Lower relative to II

Yes Rx; no more than 5 refills/ 6 months

Hydrocodone/codeine when compounded with an NSAID/APSAP/IBU (now Schedule II)

IV Lower relative to III

Yes Rx refilled up to 5 times/6 months

Darvocet, Xanax, Ambien, Lunesta, valium, other CNS depressant, Tramadol (previously unscheduled)

V Lower relative to IV

Yes OTC possible Lomotil, Phergan, Lyrica, liquid cough suspensions with small amounts of codeine

© 2011 INC Research, LLC 4

Recently rescheduled to more conservative rating (2013)

SESSION SUMMARIES

The 2nd Clinical Trials Phase I and Phase IIA Summit will explore paramount strategies

behind increasing efficiency in early phase clinical trials. As the early clinical development

space is continuously evolving, this must-attend event will feature case studies and

networking opportunities to address current challenges. In addition to hearing about

pharmacokinetic, pharmacogenomic and pharmacovigilant methodologies, this conference

will provide the audience with the opportunity to hear from top industry thought leaders

regarding driving success in their clinical trials.

Join us in Boston, MA, May 7-8, 2015 to learn from the best. This is a not-to-be-missed summit with

exciting case studies, panels and sessions, including:

n Highlight Major Challenges in Early Clinical Development and Optimize Strategies Behind Driving Efficiency

n Drive Efficiency in Early Cardiac Safety Evaluation Using Highly Automated Systems vs. a Standard Semi-Automated Method

n Prepare for the Introduction of Novel Safety Biomarkers into an Early Stage Clinical Trial

n Demonstrate Clinical Trial Efficacy with Optimization of Phase IIA Proof-of-Concept Studies

n Improve the Probability of Success in Clinical PoC and Enhance Implications for Decision-Making

www.exlevents.com/Phase1

RESOURCES FOR INFORMATION AND DISCUSSION

Optimize Effi ciency and Explore Innovative Strategies Behind Increasing Success in Early Phase Clinical Studies

MAY 7-8, 2015 • SHERATON BOSTON HOTEL • BOSTON, MA

NEW SUMMIT LEARNING OBJECTIVES FOR 2015:

• Hear case studies about effective approaches

to pharmacogenomics, pharmacokinetics and

pharmacovigilance from industry experts

• Learn strategies to proactively accelerate Phase I

clinical development partnerships that can drive trial

effi cacy

• Discover best practices to seamlessly implement and

qualify biomarkers for a clinical study

• Increase the effectiveness of a Phase IB proof-of-

concept study

• Understand successful experiences in Phase I

and Phase IIA development and enhancement

procedures

Jamie Oliver, PharmD Chief Science Offi cer, ACCELOVANCE

Larry Blankstein Senior Director of Clinical Research, GENZYME

Matt Anderson, PhD, Director, Clinical Pharmacology and Experimental Therapeutics,MERCK RESEARCH LABORATORIES

Jesse CedarbaumHead, Neurology Early Clinical Development, BIOGEN IDEC

Tami CrumleyGlobal Trial Management, Early Development, MERCK

Stephen FurlongSafety Science Lead, ASTRAZENECA

Mark Day, Ph.D,Senior Director, Corporate Development, ALEXION PHARMACEUTICALS

Alessandra TosoliniAssociate Director, Clinical Oncology, MERCK

SPOTLIGHT FACULTY MEMBERS

SPONSORED BY:

CLINICAL TRIALS PHASE I & PHASE IIA

SUMMIT

“VERY VALUABLE CONTENT! GREAT INFORMATION AND APPROACH!” – Clinical Operations Lead, BIOGEN IDEC

CHAIRMAN

2ND

TO REGISTER CALL 866-207-6528 OR VISIT WWW.EXLEVENTS.COM/PHASE1