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
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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.
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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