EMERGING SAFETY SCIENCE

WORKSHOP SUMMARY

Sally Robinson, Robert Pool, and Robert Giffin

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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Sally Robinson, Robert Pool, and Robert Giffin 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 Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. Support for this project was provided by the Department of Health and Human Services (Contract Nos. N01-OD-4-2139 and 223-01-2460); American Diabetes Association; American Society for Microbiology; Amgen, Inc.; Association of American Medical Colleges; AstraZeneca Pharmaceuticals; Blue Cross Blue Shield Association; Burroughs Wellcome Fund; Doris Duke Charitable Foundation; Eli Lilly and Company; Entelos, Inc.; GlaxoSmithKline; March of Dimes Foundation; 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: 978-0-309-11012-9 International Standard Book Number-10: 0-309-11012-2 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 2008 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). 2008. Emerging safety science: Work- shop 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 char- ter of the National Academy of Sciences, as a parallel organization of outstand- ing 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 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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PLANNINg COMMITTEE FOR THE WORkSHOP ON EMERgINg SAFETy SCIENCE Naomi Aronson, Blue Cross Blue Shield Association, Illinois C. Thomas Caskey, University of Texas-Houston Health Science Center gail H. Cassell, Eli Lilly and Company, Indiana Mikhail gishizky, Entelos, Inc., California Edward W. Holmes, A*Star Biomedical Research Council, Singapore William keane, Merck & Co., Inc., Pennsylvania Ronald L. krall, GlaxoSmithKline, Pennsylvania Janet Woodcock, U.S. Food and Drug Administration, Maryland IOM Staff Robert B. giffin, Director Sally Robinson, Program Officer Andrea knutsen, Senior Program Assistant Rona Briere, Consulting Editor 

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FORuM ON DRug DISCOvERy, DEvELOPMENT, AND TRANSLATION gail H. Cassell (Co-Chair), Eli Lilly and Company, Indiana Edward W. Holmes (Co-Chair), A*Star Biomedical Research Council, Singapore Naomi Aronson, Blue Cross Blue Shield Association, Illinois 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 Francis D. Chesley, Jr., Agency for Healthcare Research and Quality, Maryland Peter B. Corr, Pfizer Inc. (retired), New York James H. Doroshow, National Cancer Institute, Maryland Jeffrey M. Drazen, New England Journal of Medicine, Massachusetts Joseph M. Feczko, Pfizer, Inc., New York garret A. Fitzgerald, University of Pennsylvania School of Medicine Elaine k. gallin, Doris Duke Charitable Foundation, New York Steven k. galson, U.S. Food and Drug Administration, Maryland Alan M. garber, Stanford University, California Mikhail gishizky, Entelos, Inc., California Stephen groft, National Institutes of Health, Maryland Peter k. Honig, Merck & Co., Inc., Pennsylvania Richard Justman, UnitedHealth Group, Minnesota Michael katz, March of Dimes Foundation, New York Ronald L. krall, GlaxoSmithKline, Pennsylvania Jeffrey M. Leiden, Clarus Ventures, Massachusetts John R. Marler, National Institute of Neurological Disorders and Stroke, Maryland Musa Mayer, AdvancedBC.org, New York Mark B. McClellan, AEI-Brookings Joint Center for Regulatory Studies, District of Columbia Joshua J. Ofman, Amgen, Inc., California Suzanne Pattee, Cystic Fibrosis Foundation, Maryland Joanne L. Rhoads, National Institute of Allergy and Infectious Diseases (retired), Maryland B. A. Schwetz, U.S. Department of Health and Human Services, Maryland i

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Janet Shoemaker, American Society for Microbiology, District of Columbia Lana Skirboll, National Institutes of Health, Maryland Nancy S. Sung, Burroughs Wellcome Fund, North Carolina Jorge A. Tavel, National Institute of Allergy and Infectious Diseases, Maryland Janet Woodcock, U.S. Food and Drug Administration, Maryland ii

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Reviewers T his 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 respon- siveness 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: C. Thomas Caskey, University of Texas Health Science Center at Houston Joseph M. Feczko, Pfizer, Inc. Stephen groft, Office of Rare Disease Research, National Institutes of Health Patrice M. Milos, Helicos BioSciences Corporation Joanne L. Rhoads, National Institute of Allergy and Infectious Diseases (retired) Although the reviewers listed above have provided many construc- tive comments and suggestions, they were not asked to endorse the final draft of the report before its release. The review of this report was ix

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x REVIEWERS overseen by Hellen gelband, Scholar-in-Residence, Institute of Medicine. 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. SPECIAL ACkNOWLEDgMENTS In addition to our reviewers, we would like to especially thank mem- bers of the U.S. Food and Drug Administration (FDA) staff who provided assistance in the development of the workshop concept and agenda. They include Daryl Allis, Rachel Behrman, Howard Chazin, Lois Chester, Charles Cooper, Gerald Dal Pan, Felix Frueh, Steven Galson, Federico Goodsaid, David Jacobson-Kram, John Jenkins, Jan Johannessen, Elizabeth Mansfield, Robert Meyer, Shirley Murphy, Judith A. Racoosin, George Rochester, Wendy Sanhai, Paul Seligman, Judy Staffa, Ana Szarfman, Ellis Unger, Keith Webber, and Janet Woodcock.

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Preface T he genomic age of medicine and advancements in molecular medi- cine, bioinformatics, and information technology have equipped scientists with powerful new technologies that can be used to develop safer drugs and to monitor drugs more proficiently once they are on the market. These technologies have the potential to identify safety issues much earlier in the development process, reducing the number of expensive clinical trials, leading to more promising research avenues, and decreasing the exposure of human subjects and patients to products with safety problems. Furthermore, incorporating knowledge of these technologies in the U.S. Food and Drug Administration’s (FDA’s) review process can lead to more effective drug safety assessments and accelerate the drug approval process. To explore the application of these innovative technologies to the assessment of drug safety in both the pre- and postmarket environments, the Institute of Medicine’s Forum on Drug Discovery, Development, and Translation convened a workshop on Emerging Safety Science. A diverse group of experts from academia, industry, and government examined two broad approaches to improving drug safety: basic scientific approaches (genomics, metabolomics, pharmacogenomics, cell-based signaling, and standard toxicology) to better identify safety issues during development; and innovative techniques for collecting and analyzing postmarket data to identify safety signals more rapidly than is possible with traditional methodologies. The workshop presentations and discussions shed new light on the potential of these technologies to enhance the assessment of xi

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xii PREFACE safety, and provided important insights into the future challenges and opportunities in the promising field of safety science. It is our hope that this workshop summary will serve as a resource enabling scientists to survey cutting-edge technologies being applied in the field of safety science and to consider ways of applying these tech- nologies in their own work. The Forum remains committed to fostering an environment in which diverse groups of stakeholders can come together in a neutral setting to share their experiences, with the hope of furthering the advancement of drug discovery, development, and translation. Edward W. Holmes, Co-Chair Janet Woodcock, Member Forum on Drug Discovery, Development, and Translation

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Contents 1 INTRODuCTION 1 2 INvESTIgATIvE TOXICOLOgy: THE STATE OF THE ART 5 Pulmonary Hemorrhage, 6 Bone Physeal Abnormalities, 7 Heart Valve Lesions, 10 Summary, 11 3 SCREENINg TECHNOLOgIES I: HuMAN CELL–BASED APPROACHES 13 The Ideal Screen, 13 The BioMAP System, 14 Contextual Drug Analysis, 22 Summary, 27 4 SCREENINg TECHNOLOgIES II: TOXICOgENOMICS 28 Modernizing Predictive Toxicology, 28 Toxicogenomics at Iconix, 30 Toxicogenomics at Bristol-Myers Squibb, 35 Toxicogenomics at Abbott Laboratories, 41 Summary, 48 5 SCREENINg TECHNOLOgIES III: METABOLOMICS 50 Metabolomics at Metabolon, 51 Metabolomics at Biocrates, 55 xiii

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xi CONTENTS 6 SCREENINg TECHNOLOgIES Iv: PHARMACOgENETICS 59 Abacavir and the Hypersensitivity Reaction, 59 The Abacavir Pharmacogenetics Program, 60 Implications for the Future, 64 7 QuALIFyINg BIOMARkERS 65 The Ideal Biomarker, 65 Qualification of Nephrotoxicity Biomarkers, 66 Summary, 73 8 PHARMACOvIgILANCE 74 Pharmacovigilance at GlaxoSmithKline, 74 Statistical Issues in Analyzing Spontaneous Report Databases, 77 Active Surveillance for Anticipated Adverse Events, 84 9 INTEgRATION 93 An Integration Tool at GlaxoSmithKline, 93 The Elsevier Database (PharmaPendium), 96 An FDA Perspective, 99 10 THE FuTuRE OF SAFETy SCIENCE 106 Prediction, 106 Surveillance, 108 Summary, 114 REFERENCES 115 APPENDIXES A Workshop Agenda 117 B Speaker Biographies 125

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Tables and Figures TABLES Examples of BioMAP Systems, 16 3-1 FIguRES ALK5 (activin receptor-like kinase 5) inhibitors: the relationship 2-1 between dose and intracellular superoxide production, 7 Example of a BioMAP profile developed using a reference p38 3-1 inhibitor, 18 Example of a computational analysis of BioMAP profiles of 3-2 various compounds, 20 Strategy for pharmacological profiling of compounds with high- 3-3 content PCAs, 24 Exploring global mechanistic differences within multiple statin 3-4 compounds, 26 Example of gene expression changes highlighting early 4-1 mechanisms and pathways that contribute to nephrotoxicity, 33 Use of a principal component analysis (PCA) to identify 4-2 compounds that reverse surrogate disease phenotypes, 36 Observation of global changes within the transcriptome, 39 4-3 A global transcriptional profile as a biomarker for NOAEL, 40 4-4 Gene expression profile of a hepatotoxicity reference set, 43 4-5 x

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xi TABLES AND FIGURES Overview of the Metabolon process, 52 5-1 Global metabolomic analysis of commercially available HIV 5-2 protease inhibitors, 54 Cumulative patient/years of exposure to abacavir products and 6-1 spontaneous reports of HSR-associated mortality among those taking abacavir, 61 PREDICT-1 study design, 63 6-2 Serum creatinine as a biomarker for cisplatin-induced tubular 7-1 necrosis/apoptosis, 68 Kim-1 as a biomarker for cisplatin-induced tubular necrosis/ 7-2 apoptosis, 69 ROC (receiver operating characteristic) analysis to compare 7-3 biomarkers for cisplatin-induced tubular necrosis/apoptosis, 70 ROC (receiver operating characteristic) analysis to compare 7-4 biomarkers for tubular necrosis mostly proximal (but sometimes not clearly localized) in 10 studies with different nephrotoxicants, 71 ROC (receiver operating characteristic) analysis to compare 7-5 biomarkers for glomerular alteration/damage in 10 studies with different nephrotoxicants, 72 Disproportionality analysis calculation, 75 8-1 Heat map profiling of spontaneously reported adverse events for 8-2 a single drug, 81 Association between torsades de pointes and the drugs cisapride 8-3 and erythromycin, alone and in combination, 82 Example of hierarchical thesauruses for adverse events, drugs, 9-1 and targets, 98 Drug development as an iterative process, 101 9-2 Illustration of a product development timeline that includes a 9-3 monitored released phase, 104 Use of large health care databases to identify events of 10-1 interest, 109