ACCELERATING THE DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY

Workshop Summary

Steve Olson, Sally Robinson, and Robert Giffin, 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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ACCELERATING THE DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY Workshop Summar y Steve Olson, Sally Robinson, and Robert Giffin, 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 Govern- ing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineer- ing, and the Institute of Medicine. This project was supported by the American Diabetes Association; the American Society for Microbiology; Amgen, Inc.; the Association of American Medical Col- leges; AstraZeneca Pharmaceuticals; Blue Cross Blue Shield Association; the Bur- roughs Wellcome Fund; Department of Health and Human Services (Contract Nos. N01-OD-4-2139 and 223-01-2460); the Doris Duke Charitable Foundation; Eli Lilly & Co.; Entelos Inc.; Genentech; GlaxoSmithKline; the March of Dimes Foun- dation; Merck & Co., Inc.; Pfizer Inc.; and UnitedHealth Group. 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: 978-0-309-13124-7 International Standard Book Number-10: 0-309-13124-3 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 2009 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). 2009. Accelerating the Develop- ment of Biomarkers for Drug Safety: 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 wel- fare. 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 government 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 members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is presi- dent 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 Insti- tute 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 providing 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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PLANNING COMMITTEE FOR ASSESSING AND ACCELERATING THE DEvELOPMENT OF bIOMARkERS FOR DRuG SAFETy: A WORkSHOP Robert Califf (Workshop Chair), Duke University Medical Center, North Carolina Garret A. FitzGerald, University of Pennsylvania School of Medicine Marlene Haffner, Amgen, Inc., Washington, DC Ronald L. krall, GlaxoSmithKline, Pennsylvania William b. Mattes, Critical Path Institute, Maryland Aidan Power, Pfizer Inc., Connecticut Janet Woodcock, U.S. Food and Drug Administration, Maryland Study Staff Robert b. Giffin, Director Sally Robinson, Program Officer Andrea Rebholz, Senior Program Assistant Genea S. vincent, Senior Program Assistant Rona briere, Consulting Editor v

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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 Hal barron, Genentech, California Leslie Z. benet, University of California, San Francisco Catherine bonuccelli, AstraZeneca Pharmaceuticals, Delaware Linda brady, National Institute of Mental Health, Maryland Robert M. Califf, Duke University Medical Center, North Carolina Scott Campbell, American Diabetes Association, Virginia C. Thomas Caskey, University of Texas-Houston Health Science Center Peter b. Corr, Celtic Therapeutics, New York James H. Doroshow, National Cancer Institute, Maryland Paul R. Eisenberg, Amgen, Inc., California Garret A. FitzGerald, University of Pennsylvania School of Medicine Elaine k. Gallin, The Doris Duke Charitable Foundation, New York Steven k. Galson, Office of the Surgeon General, U.S. Department of Health and Human Services, Maryland Mikhail Gishizky, Entelos, Inc., California Stephen Groft, National Institutes of Health, Maryland Edward W. Holmes, National University of Singapore Peter k. Honig, Merck & Co., Inc., Pennsylvania A. Jacqueline Hunter, GlaxoSmithKline, United Kingdom Michael katz, March of Dimes Foundation, New York Jack D. keene, Duke University Medical Center, North Carolina Ronald L. krall, GlaxoSmithKline, Pennsylvania Musa Mayer, AdvancedBC.org, New York Mark b. McClellan, Brookings Institution, Washington, DC Carol Mimura, University of California, Berkeley Amy P. Patterson, National Institutes of Health, Maryland Janet Shoemaker, American Society for Microbiology, Washington, DC Lana Skirboll, National Institutes of Health, Maryland Nancy S. Sung, Burroughs Wellcome Fund, North Carolina Irena Tartakovsky, Association of American Medical Colleges, Washington, DC 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. vi

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Jorge A. Tavel, National Institute of Allergy and Infectious Diseases, Maryland Joanne Waldstreicher, Johnson & Johnson, New Jersey Janet Woodcock, U.S. Food and Drug Administration, Maryland Raymond L. Woosley, Critical Path Institute, Arizona vii

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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 published 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 deliberative process. We wish to thank the following individuals for their review of this report: Mark Avigan, U.S. Food and Drug Administration, U.S. Department of Health and Human Services Jacqueline Hunter, GlaxoSmithKline Neil kaplowitz, USC Research Center for Liver Diseases, Keck School of Medicine, University of Southern California Dan M. Roden, Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the final draft of the report before its release. The review of this report was overseen by Dr. Johanna T. Dwyer, Tufts University School of Medicine & Friedman School of Nutrition Science & Policy, Frances Stern Nutrition Center, Tufts- ix

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x REVIEWERS New England Medical Center. Appointed by the Institute of Medicine, she was 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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Preface Biomarkers are central to the future of medicine. By providing a mea- sure of a biological state, they can indicate normal biological processes, pathogenic processes, or responses to an intervention or perturbation in the environment. They can be used to monitor the on-target and off-target effects of medical interventions, including treatments for disease; they can be used in diagnostic and prognostic tests; and they can define the indi- viduals and populations most likely to respond to therapy. At the broadest level, they can provide insight into biological pathways and networks. It is also important to recognize that biomarkers have limitations. In isolation, they reveal just one aspect of complex biological systems. There- fore, they may or may not be correlated with clinical outcomes, since other biological systems may override the particular marker being measured. The work needed to understand the relation of a biomarker to either a clinical outcome or a biological system can be enormous. Yet biomarkers are most powerful when they are linked with knowledge about biological systems, with empirical data about diagnostic and therapeutic trials, or with clinical outcomes derived from large populations. The power of modern biology comes from the ability to integrate disparate bases of knowledge, leading to better decisions. As the cost of developing drugs has risen and the number of new drugs approved for use has fallen, many people have looked to the development of biomarkers as a way to cut costs, enhance safety, and provide a more focused and rational pathway to drug development. Accordingly, greater regulatory emphasis has been placed on the development and use of bio- markers in drug development, which has increased the urgency of accel- xi

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xii PREFACE erating preclinical and clinical research on these markers and establishing evidentiary standards for their use. Biomarker advocates tend to emphasize the progress that has been made, while many drug development teams and experts in clinical effectiveness are skeptical. In fact, both perspectives have merit, and the workshop summarized in this report provided some reassurance that biomarkers, placed in proper perspective, will advance both biomedical science and the pragmatic science of developing drugs that improve human health. At the same time, the workshop also demonstrated the inability of current biomarkers to substitute fully for actual measure- ment of the risks and benefits of interventions since multiple biological networks and pathways are always in play. The workshop’s final sessions considered the increased complexity of validating and qualifying multimarker panels of biomarkers. Until recently, biomarkers had been developed one at a time. But the advent of large-scale genomic, proteomic, metabolomic, and advanced imaging technologies is changing the environment in which biomarkers are identified and assessed. In the final session, speakers explored the potential for applying cutting- edge scientific technologies to enhance the prediction and detection of drug-induced toxicity, discussed the integration of systems biology and computational biology into toxicity assessments early in drug develop- ment, and considered the regulatory and scientific challenges involved in the development and use of multimarker panels. The workshop was not designed to produce consensus on future steps that should be taken, but in the course of the discussion, numerous ideas arose that can provide insight into measures that might be useful. The workshop challenged participants to consider how each individual and group might contribute to advancing this work, and the workshop orga- nizers hope that this publication will do the same for a broader group of readers. Robert Califf Workshop Chair

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Contents 1 INTRODUCTION 1 Workshop Purpose, Scope, and Objectives, 2 Crosscutting Issues, 3 Organization of the Report, 5 References, 5 2 OVERVIEW OF KEY ISSUES 6 Predictions Based on Biomarkers, 9 Validation vs. Qualification, 10 Mechanisms vs. Patterns, 11 Regulatory Approval of Biomarkers, 12 Regulation of Single Biomarkers vs. Panels of Biomarkers, 13 Measures of Success, 13 An Example: Biomarkers for Toxicity of Psychiatric Drugs, 14 References, 16 3 CARDIAC SAFETY BIOMARKERS 17 The Regulatory Response, 19 Responses of Drug Developers, 20 Effects on Physician Decision Making, 21 Other Cardiac Safety Biomarkers, 22 The Cardiac Safety Research Consortium, 24 Lessons Learned, 26 Highlights of the Breakout Discussion, 26 References, 28 xiii

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xiv CONTENTS 4 ASSESSING AND PREDICTING KIDNEY SAFETY 29 The Current State, 30 A Vision of the Future, 37 Highlights of the Breakout Discussion, 39 References, 41 5 BIOMARKERS OF ACUTE IDIOSYNCRATIC HEPATOCELLULAR INJURY IN CLINICAL TRIALS 42 Acute Idiosyncratic Hepatocellular Injury (AIHI), 43 Current State of Biomarkers for AIHI, 45 Potential New Biomarkers for AIHI, 50 Highlights of the Breakout Discussion, 52 References, 55 6 FUTURE CONSIDERATIONS 58 Creating Incentives for Collaboration, 58 Moving Forward Without Understanding Mechanisms, 61 Dealing with Different Levels of Risk, 63 Reference, 64 APPENDIXES A Workshop Agenda 65 B Speaker Biographies 71

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Tables, Figures, and Boxes TAbLES 3-1 Strengths and Weakness of the QTc Interval as a Safety Biomarker, 18 4-1 Promising Translational Biomarkers of Acute Kidney Injuries, 32 4-2 Current Deficiencies, Needs, and Proposals to Address Kidney Safety Issues in Early Drug Development, 38 5-1 Regulatory Actions on Approved Drugs Due to Hepatotoxicity, 1995–2008, 44 FIGuRES 2-1 The number of new molecular entities (NMEs) submitted to the FDA has fallen since the mid-1990s, 8 5-1 Acute idiosyncratic hepatocellular injury, 44 bOXES 2-1 The Toll of Mental Illness, 15 4-1 Initiatives to Advance Understanding of Kidney Safety Biomarkers, 33 6-1 Systems Biology and Biomarker Development, 62 xv

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