Building a National Framework for the Establishment of REGULATORY SCIENCE FOR DRUG DEVELOPMENT

Workshop Summary

Yeonwoo Lebovitz, Rebecca A. English, and Anne B. Claiborne, Rapporteurs

Forum on Drug Discovery, Development, and Translation

Board on Health Sciences Policy

INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.
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Yeonwoo Lebovitz, Rebecca A. English, and Anne B. Claiborne, Rapporteurs Forum on Drug Discovery, Development, and Translation Board on Health Sciences Policy

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Gov- erning Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engi- neering, and the Institute of Medicine. This project was supported by the Department of Health and Human Services (Contract Nos. N01-OD-4-2139 and 223001003T), the American Diabetes Asso - ciation, the American Society for Microbiology, Amgen Inc., the Association of American Medical Colleges, Bristol-Myers Squibb, the Burroughs Wellcome Fund, Celtic Therapeutics, LLLP, the Critical Path Institute, the Doris Duke Charitable Foundation, Eli Lilly & Co., GlaxoSmithKline, Johnson & Johnson, Novartis Phar- maceuticals Corporation, and Pfizer, Inc. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-15889-3 International Standard Book Number-10: 0-309-15889-3 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2011 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2011. Building a National Frame- work for the Establishment of Regulatory Science for Drug Development: Workshop Summary. Washington, DC: The National Academies Press.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” — Goethe Advising the Nation. Improving Health.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal govern - ment on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its mem - bers, sharing with the National Academy of Sciences the responsibility for advis - ing the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in pro - viding services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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FORuM ON DRug DISCOvERy, DEvELOPMENT, AND TRANSLATION1 gail H. Cassell (Co-Chair), Eli Lilly and Company, Indiana Jeffrey M. Drazen (Co-Chair), New England Journal of Medicine, Massachusetts Barbara Alving, National Center for Research Resources, Maryland Leslie Z. Benet, University of California-San Francisco, California Ann Bonham, Association of American Medical Colleges, Washington, DC Linda Brady, National Institute of Mental Health, Maryland Robert M. Califf, Duke University Medical Center, North Carolina Scott Campbell, Foundation for the National Institutes of Health, Maryland C. Thomas Caskey, University of Texas-Houston Health Science Center, Texas Peter B. Corr, Celtic Therapeutics, LLLP, New York James H. Doroshow, National Cancer Institute, Maryland Paul R. Eisenberg, Amgen Inc., California gary L. Filerman, Atlas Research, Washington, DC garret A. Fitzgerald, University of Pennsylvania School of Medicine, Pennsylvania Elaine K. gallin, The Doris Duke Charitable Foundation, New York Steven K. galson,2 Amgen Inc., California Harry B. greenberg, Stanford University School of Medicine, California Stephen groft, National Institutes of Health, Maryland Peter K. Honig, AstraZeneca, Delaware Annalisa Jenkins, Bristol-Myers Squibb, New Jersey Michael Katz, March of Dimes Foundation, New York Jack D. Keene, Duke University Medical Center, North Carolina Ronald L. Krall, GlaxoSmithKline (retired), Colorado Freda Lewis-Hall, Pfizer, Inc., New York William D. Matthew, National Institute of Neurological Disorders and Stroke, Maryland Mark B. McClellan, Brookings Institution, Washington, DC Carol Mimura, University of California-Berkeley, California John Orloff, Novartis Pharmaceuticals Corporation, New Jersey Amy P. Patterson, National Institutes of Health, Maryland 1 IOM forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. 2 Steven K. Galson was with Science Applications International Corporation until Sep - tember 30, 2010. v

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Janet Shoemaker, American Society for Microbiology, Washington, DC Ellen v. Sigal, Friends of Cancer Research, Virginia Nancy S. Sung, Burroughs Wellcome Fund, North Carolina Jorge A. Tavel, National Institute of Allergy and Infectious Diseases, Maryland Janet Tobias, Ikana Media, New York Joanne Waldstreicher, Johnson & Johnson, New Jersey Janet Woodcock, U.S. Food and Drug Administration, Maryland Raymond L. Woosley, The Critical Path Institute, Arizona IOM Staff Anne B. Claiborne, Director (from April 5, 2010) Robert B. giffin, Director (until February 26, 2010) Rebecca A. English, Research Associate yeonwoo Lebovitz, Program Associate genea S. vincent, Senior Program Assistant Rona Briere, Consulting Editor vi

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Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its pub- lished report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We wish to thank the following individuals for their review of this report: STEvEN K. gALSON,1 Amgen Inc., California PETER K. HONIg, AstraZeneca CARL C. PECK, University of California, San Francisco ELLEN v. SIgAL, Friends of Cancer Research Although the reviewers listed above have provided many construc- tive comments and suggestions, they did not endorse the final draft of the report before its release. The review of this report was overseen by LESLIE Z. BENET, University of California, San Francisco. Appointed by the National Research Council and the Institute of Medicine, he was 1 Steven K. Galson was with Science Applications International Corporation until Sep - tember 30, 2010. vii

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viii REVIEWERS responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authors and the institution.

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Contents ACRONyMS xiii PREFACE xv 1 INTRODuCTION 1 Workshop Purpose and Objectives, 2 Organization of This Report, 3 2 DEFININg REguLATORy SCIENCE 5 3 THE uRgENT NEED FOR REguLATORy SCIENCE 13 Challenges Faced by FDA, 13 The Need for Regulatory Science in Predicting or Addressing Rare Adverse Reactions, 15 The Need for Regulatory Science in Genomics, 17 The Need for Regulatory Science in Statistical Design and Analysis, 19 4 BARRIERS TO ENHANCED REguLATORy SCIENCE 23 Findings of the FDA Science Board, 23 Systemic Barriers, 29 ix

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5 POTENTIAL MODELS FOR BuILDINg A REguLATORy SCIENCE INFRASTRuCTuRE 31 Collaborative Models, 32 The Centers of Excellence Model, 35 6 CHALLENgES IN ENgAgINg THE PuBLIC POLICy COMMuNITy 39 Challenges in Engaging the Public Policy Community, 40 Public Opinion Poll Data on FDA, 40 The Power of Patient Advocacy, 43 7 ENvISIONINg SuCCESSFuL REguLATORy SCIENCE AT FDA 45 Key Areas of Scientific Emphasis, 45 8 CONSIDERINg NEXT STEPS 49 Immediate Next Steps for FDA, 50 Building a Framework: Themes from the Workshop, 51 REFERENCES 53 APPENDIXES A Agenda 57 B Participant Biographies 61 x

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Figures and Boxes FIguRES 3-1 Graphic presentation of the effect of acetaminophen on various mouse gene strains, 16 4-1 Breadth of FDA responsibilities by number of establishments as of 2007, 24 4-2 Flow of data in an Incubator for Innovation in Regulatory and Information Science (IIRIS)/Centers-of-Excellence (COE) model, 27 5-1 Visualization of how the current drug development model is growing disaggregated with involvement of various sectors to reduce risk in innovation, 32 5-2 Centers of Excellence in Regulatory Science Network, 35 6-1 Shifting opinions on America’s most important health issue, December 2003–February 2010, 41 6-2 Americans’ level of confidence in systems for monitoring the effectiveness and safety of new medicines and medical devices, 42 6-3 Americans’ views on FDA’s most important role, 42 xi

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xii FIGURES AND BOXES BOXES 2-1 Some definitions of regulatory science, 6 2-2 Excerpts from the Commissioner’s speech, 8 3-1 Potential contributions of regulatory science to cancer therapy, 14 3-2 Hamner Institute’s study of inbred mice panels, 16 4-1 The IIRIS model, 28 5-1 Collaborative models in oncology, 34 6-1 The impact of patient advocacy for cancer therapeutics at FDA, 44

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Acronyms AHRQ Agency for Healthcare Research and Quality AIDS acquired immune deficiency syndrome ARRA American Recovery and Reinvestment Act of 2009 BC Biomarkers Consortium CBER Center for Biologics Evaluation and Research CDC Centers for Disease Control and Prevention CDER Center for Drug Evaluation and Research CERTS Centers for Education and Research on Therapeutics COE Centers of Excellence COERS Centers of Excellence in Regulatory Science Network CPI Critical Path Initiative CTTI Clinical Trials Transformative Initiative DARPA Defense Advanced Research Products Agency FDA Food and Drug Administration FDAAA FDA Amendments Act of 2007 FDAMA FDA Modernization Act of 1997 FNIH Foundation for the National Institutes of Health GAO Government Accountability Office xiii

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xiv ACRONYMS HHS Department of Health and Human Services HIV human immunodeficiency virus ICT-21 Information Communication Technology for the 21st Century IIRIS Incubator for Innovation in Regulatory and Information Science IND Investigative New Drug Application IOM Institute of Medicine IOTF NCI–FDA Interagency Oncology Task Force IT information technology NCI National Cancer Institute NDA New Drug Application NIH National Institutes of Health NIST National Institute of Standards and Technology OMOP Observational Medical Outcomes Partnership OODP Office of Oncology Drug Products PDUFA Prescription Drug User Fee Act PhRMA Pharmaceutical Research and Manufacturers of America SAE serious adverse event

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Preface Regulatory agencies worldwide are tasked with a difficult mandate to provide large populations with efficient access to drugs that are both safe and effective. They must also balance this task while adapting to new technologies in medicine and information technology. These demands are further complicated by the increasing globalization of drug development and regulatory relationships. These challenges, along with problems with contaminated supplies, serious adverse events, and other compounding issues that accompany changes in administration, contribute to the over- burdening of a regulatory system whose resources have not increased along with its demands. We urgently need to ensure that our regulatory bodies have the autonomy, resources, and scientific support needed to function effectively to promote public health and safety. The U.S. Food and Drug Administration (FDA) is a science-based agency responsible for regulating 80 percent of Americans’ consumable goods and a quarter of the U.S. economy. It is imperative that every one of FDA’s regulatory decisions be based on the best scientific evidence. Unfortunately, this has not always been possible due to several factors, including—but not limited to—inadequate human capital, leadership support, and funding. Above all, a weakening science base at the agency has threatened its ability to support its core regulatory functions and decisions. FDA needs to resolve this gap between scientific and regula- tory decision making to ensure continuity of its duties in an environ - ment of heightened public scrutiny on drug safety and rapid scientific advancements. The public increasingly recognizes the importance of regulatory science. The notion of basing regulatory decisions on the best scientific knowledge xv

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xvi PREFACE available is not new, but never before have funds been deliberately appro- priated for the accomplishment of this task. FDA’s 2011 budget proposal includes $25 million specifically allocated to the building of a regulatory science infrastructure at the agency. In anticipation of this event and as an acknowledgment of the “reform-ready” political atmosphere, the Institute of Medicine’s Forum on Drug Discovery, Development, and Translation held a public workshop with the following goals in mind: • Establish a clear definition of regulatory science, and engage the public and the policy community in a discussion of its challenges and opportunities. • Increase awareness of inadequate funding for regulatory science and the impact on the development of new therapies on patients. • Articulate priorities and strategies for building or rebuilding the infrastructure for regulatory science. The one-day workshop featured leaders from government, such as Representative Rosa DeLauro (D-CT); Department of Health and Human Services Deputy Secretary, William Corr; and FDA Commissioner, Margaret Hamburg. Speakers from academia, industry, and patient advo- cacy groups provided a variety of perspectives and illuminated exam- ples of the urgent need of a regulatory science infrastructure. Leaders in emerging technologies, such as genomics, biostatistics, and information technology—whose fields of study are influenced daily by regulatory decisions—deliberated on potential consequences arising from the failure to establish a robust scientific base at the agency level. In addition, mod - erated panels considered mechanisms for building a regulatory science infrastructure at FDA, analyzed existing implementation models, and posed strategies for engaging the public and policy makers. This was a timely workshop that provided a valuable opportunity to bring together a diverse group for thoughtful discussion about improving drug development and strengthening regulatory science. I would like to thank all of the individuals—speakers, moderators, and panelists—who contributed to and participated in the workshop. In particular, I would like to thank a small team of participants in the workshop who spent many hours in advance of the workshop discussing the merits of Cen - ters of Excellence in Regulatory Science and the critical characteristics of these centers including: K. Ahlport, M. Anderson, L. Benet, R. Califf, G. FitzGerald, S. Kim, J. Kramer, R. Nerem, D. Nordenberg, M. Osterholm, K. Schneeman, J. Shoemaker, E. Sigal, N. Sung, and J. Tobias. I would also like to thank the members of the Forum and Forum staff for their dedica- tion and commitment to developing and executing this workshop. Gail H. Cassell, Co-Chair Forum on Drug Discovery, Development, and Translation