EVALUATION OF BIOMARKERS AND SURROGATE ENDPOINTS IN CHRONIC DISEASE

Committee on Qualification of Biomarkers and Surrogate Endpoints in Chronic Disease

Board on Health Care Services

Board on Health Sciences Policy

Food and Nutrition Board

Christine M. Micheel and John R. Ball, Editors

INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

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EVALUATION OF BIOMARKERS AND SURROGATE ENDPOINTS IN CHRONIC DISEASE Committee on Qualification of Biomarkers and Surrogate Endpoints in Chronic Disease Board on Health Care Services Board on Health Sciences Policy Food and Nutrition Board Christine M. Micheel and John R. Ball, Editors

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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. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract No. HHSF223200810020I between the National Academy of Sciences and the Food and Drug Administration. Any opinions, findings, con - clusions, 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. Library of Congress Cataloging-in-Publication Data Evaluation of biomarkers and surrogate endpoints in chronic disease / Committee on Qualification of Biomarkers and Surrogate Endpoints in Chronic Disease, Board on Health Care Services, Board on Health Sciences Policy, Food and Nutrition Board, Institute of Medicine ; Christine M. Micheel and John R. Ball, editors. p. ; cm. Includes bibliographical references. ISBN 978-0-309-15129-0 (pbk.) — ISBN 978-0-309-15130-6 (pdf) 1. Biochemical markers—Evaluation. 2. Chronic diseases. I. Micheel, Christine. II. Ball, John, 1944- III. Institute of Medicine (U.S.). Committee on Qualification of Biomarkers and Surrogate Endpoints in Chronic Disease. [DNLM: 1. Biological Markers. 2. Chronic Disease. 3. Evidence-Based Practice. QW 541 E917 2010] R853.B54E93 2010 610.28—dc22 2010020157 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 2010 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). 2010. Evaluation of biomarkers and surrogate endpoints in chronic disease. 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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COMMITTEE ON QuALIFICATION OF BIOMARkERS AND SuRROgATE ENDPOINTS IN CHRONIC DISEASE JOHN R. BALL (Chair), Executive Vice President, American Society for Clinical Pathology MICHELLE A. ALBERT, Assistant Professor of Medicine, Associate Physician, and Director of Behavioral and Neurocardiovascular Cardiology, Brigham and Women’s Hospital, Harvard Medical School FRED APPLE, Medical Director, Clinical Laboratories, Hennepin County Medical Center, and Professor, Laboratory Medicine and Pathology, University of Minnesota School of Medicine ROBERT M. CALIFF, Vice Chancellor for Clinical Research and Professor of Medicine, Cardiology, Duke University School of Medicine VICTOR g. DE gRuTTOLA, Professor and Chair, Biostatistics, Harvard School of Public Health DAVID L. DEMETS, Professor and Chair, Biostatistics & Medical Informatics, University of Wisconsin–Madison ROBERT gERSzTEN, Research Director and Faculty Member, Massachusetts General Hospital, and Associate Professor of Medicine, Harvard Medical School WILLIAM R. HARLAN, JR., Consultant ALLAN S. JAFFE, Professor of Medicine, Mayo Clinic RONALD M. kRAuSS, Director, Atherosclerosis Research and Senior Scientist, Children’s Hospital Oakland Research Institute HARLAN M. kRuMHOLz, Harold H. Hines, Jr., Professor of Medicine and Epidemiology and Public Health, Yale University School of Medicine MARIA LOPES-VIRELLA, Professor, Bioengineering, Medical University of South Carolina ROBERTA B. NESS, Dean, University of Texas Health Science Center, School of Public Health JENNIFER VAN Eyk, Associate Professor, Physiology and Biochemistry, Johns Hopkins University JOHN A. WAgNER, Vice President, Clinical Pharmacology, Merck and Company, Inc. Consultant ELIzABETH A. yETLEy, Consultant, National Institutes of Health, Office of Dietary Supplements v

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Study Staff CHRISTINE M. MICHEEL, Study Director SHARyL NASS, Senior Program Officer ERIN BALOgH, Research Associate BERNADETTE McFADDEN, Research Associate (from July 2009 to January 2010) LISA BOyETTE, Christine Mirzayan Science and Technology Policy Graduate Fellow (September to November 2009) ANNA WOLOSzyNSkA-READ, Christine Mirzayan Science and Technology Policy Graduate Fellow (January to April 2009) CAIRA M. WOODS, Christine Mirzayan Science and Technology Policy Graduate Fellow (January to April 2010) DESH MOHAN, Intern (June to August 2009) ASHLEy McWILLIAMS, Senior Program Assistant PATRICk BuRkE, Financial Associate ROgER HERDMAN, Director, Board on Health Care Services LINDA D. MEyERS, Director, Food and Nutrition Board ANDREW POPE, Director, Board on Health Sciences Policy 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 deliberative process. We wish to thank the following individuals for their review of this report: RuSS B. ALTMAN, Stanford University DIANNE BIRT, Iowa State University JAMES DE LEMOS, University of Texas Southwestern Medical Center at Dallas THOMAS R. FLEMINg, University of Washington PHILIP gREENLAND, Northwestern University CHARLES HENNEkENS, Florida Atlantic University JANE HENNEy, University of Cincinatti WOLFgANg kOENIg, University of Ulm Medical Center VICTOR MONTORI, Mayo Clinic DAVID RANSOHOFF, University of North Carolina at Chapel Hill CHRISTINE SEIDMAN, Harvard Medical School and Howard Hughes Medical Institute vii

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viii REVIEWERS ALAN TALL, Columbia University STEPHEN WILLIAMS, Somalogic, Inc. ALAN Wu, University of California, San Francisco Although the reviewers listed above have provided many construc- tive comments and suggestions, they were not asked to endorse the con- clusions or recommendations nor did they see the final draft of the report before its release. The review of this report was overseen by CHARLES C. J. CARPENTER, the Miriam Hospital, and kRISTINE M. gEBBIE, Hunter College, City University of New York. Appointed by the National Research Council and the Institute of Medicine, they were responsible for making certain that an independent examination of this report was car- ried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final con - tent of this report rests entirely with the authoring committee and the institution.

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Preface Over breakfast during the second meeting of this committee, the members informally discussed a message on the package of one of the cereal offerings, a box of Cheerios. Against the backdrop of an image of a heart, the message was, “You Can Lower Your Cholesterol 4% in 6 weeks.” A month later (purely coincidentally), the Food and Drug Administration (FDA) sent a letter to the chair of General Mills, the producer of Cheerios. That letter stated, “based on claims made on your product’s label, we have determined that your Cheerios® Toasted Whole Grain Oat Cereal is promoted for conditions that cause it to be a drug because the product is intended for use in the prevention, mitigation, and treatment of dis - ease.” Five months later, the new FDA Commissioner Margaret Hamburg indicated, in an Industry Letter, that the agency was examining “Front of Package” (FOP) labels for false or misleading claims, citing consumer studies that found that, with FOP labeling, people are less likely to check the Nutrition Facts Panel, generally found on the side or back of food packages. Notably, H.R. 1105, the Omnibus Appropriations Act of 2009, included funds for an Institute of Medicine (IOM) study to examine and make recommendations regarding Front of Package nutrition symbols. In the context of the committee’s task, this instance illustrates two issues with which the committee wrestled. The first is how science may inform policy decisions when diverse, and sometimes disparate, interests are involved. In this case, consumers wish to choose healthier diets, the food industry has an interest to market its products as healthy, and the FDA needs to minimize risks to the food supply and to inform consumers appropriately. The second is how to make policy decisions before the full process of reaching scientific consensus has been completed. ix

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x PREFACE This report was initiated by the Center for Food Safety and Applied Nutrition of the FDA, which has received dozens of applications for approval of health claims for foods, most of which reflected claims of effects on a biomarker—a patient characteristic that can be measured and is believed to have a significant biological effect. The principal task requested of the Institute of Medicine was to recommend a framework for the evaluation of biomarkers; additionally, the IOM was to make ancillary recommendations for their application. As shown in Chapter 1, however, the task goes beyond claims on foods alone. A framework has been pro - posed that can be applied across many of the product areas regulated by the FDA. The Institute of Medicine convened a committee of experts from a variety of related fields, supported by a highly capable technical staff. The committee met face to face four times and had several teleconferences. The committee was further supported by presentations from outside experts in a workshop format, and it benefited from comments from interested parties. As always, the committee’s report underwent a rigorous external review, which helped significantly to focus and clarify the findings and recommendations. The committee met its principal task by recommending a three-part framework for biomarker evaluation: (1) Analytical validation—in essence, is the biomarker able to be accurately measured? (2) Qualification—is the biomarker associated with the clinical endpoint of concern? and (3) Utili - zation—what is the specific context of the proposed use? The committee met the additional task by making recommendations for implementing the evaluation framework, for supporting evidence-based decision mak - ing, and for promoting the public health. The committee notes that endpoints can be conceptualized in a spec- trum. At the end defined by endpoints with less relationship to patient or consumer experience are those that depend on biomarkers alone; in the middle are clinical events that depend on biomarkers as part of the definition; more closely related endpoints are those events that affect patients’ lives; and at the near end of the spectrum are the clearest clini- cal endpoints, such as death. Furthermore, the committee emphasizes that biomarkers cannot be qualified for a use without understanding the specific use and its context. The committee heard significant evidence of the public’s (and profes- sionals’) innumeracy, or numerical illiteracy, and the barrier that innu - meracy poses to understanding the balance of risk and benefit. Thus, the committee recognizes that significant efforts may be needed, both by government and by professional societies, to inform and educate the public and professionals on how to interpret scientific information so that good science can inform individual decision making.

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xi PREFACE Critical to the committee’s recommendations, and flowing from our consideration of the evidence and vigorous debate, is that there is neither rationale nor scientific basis for predicating regulatory decisions on dif - ferent levels of scientific evidence for different substances: “science is science.” That is, the same level of scientific evidence of benefit and risk should be required of foods as of drugs (and, indeed, of the other sub - stances the FDA regulates—biologics, devices, and cosmetics). The coun - terargument that some substances (e.g., drugs) pose greater risks than others (e.g., foods) is not dispositive. Counter to that argument is that foods are encountered by a greater population than the target group who encounter drugs, and though drugs are subject to professional mediation (e.g., prescription and counseling), foods are not. As for risk, no one who is allergic to peanuts, eggs, or shellfish would argue that foods are less risky than drugs. At the risk of using a personal anecdote, I have suffered three episodes of cardiac arrhythmia atrial fibrillation, all associated with drinking two glasses of red wine. Since making the correlation, I’ve ceased drinking red wine, and have ceased having episodes of atrial fibrillation. When I explained to my elderly mother why I no longer drank red wine, she said, “But I thought red wine was good for you.” The answer, of course, is “It depends.” “It depends” means that the context of health claims matters. Biomarkers can enable faster, more efficient clinical trials. They can help public health professionals identify and track disease outbreaks. In addi- tion, they can help healthcare practitioners and patients make decisions about care. But the context of their use matters, and the scientific base for their use should be rigorous. As chair of the committee, I thank personally all the committee mem - bers for their individual and group contributions, their diligence, and their comity. I am very grateful for the time and effort that such busy people were willing, often with short turnaround times, to devote to the work of the committee. As is the case with the best of these deliberations, their engaged back-and-forth nature led to a richer, more accurate, and—we all hope—helpful report for regulators, professionals, and the public. None of this could have been accomplished without the professional IOM staff, led by Christine Micheel, who, in addition to her technical expertise, was uncommonly responsive to the committee’s direction and to individual comments of the members. I know the committee would join in giving my heartfelt thanks to her. John Ball, Chair Committee on Qualification of Biomarkers and Surrogate Endpoints in Chronic Disease

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Acknowledgments The committee and IOM staff would like to thank many individuals for their contributions to this study. Elizabeth Yetley, consultant to the committee, provided needed guidance. We thank Thomas H. Lee, Susan Mayne, Gil Omenn, David Ransohoff, and John Wagner for their proj- ect initiation assistance. We thank Joseph Bonventre, Kathleen Ellwood, Federico Goodsaid, and Paula Trumbo for presentations at the first com - mittee meeting. We thank Nancy Cook, Charles Hennekens, and Marshall Joffe for their assistance with editing report sections. We thank all of the workshop speakers for their participation (please see Appendix E for the list of speakers). IOM staff Sharyl Nass, Christine L. Taylor, Roger Herdman, Linda Meyers, and Andrew Pope provided needed assistance. Finally, we thank the FDA for study funding. The committee would like to thank IOM staff for their assistance with report drafting. We would like to thank the fellows and interns involved with this study for their assistance. Lisa Boyette contributed to writing and edit - ing tasks. Anna Woloszynska-Read contributed to workshop planning and background research, Caira Woods contributed to report review and creation of report dissemination material, and Desh Mohan provided research and meeting assistance. Finally, the study director would like to thank project staff for their contributions. Research associates Erin Balogh and Bernadette McFadden were involved in writing many sections of the report. Ashley McWilliams arranged meetings and many other administrative tasks and contributed to research and writing tasks. xiii

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Contents SUMMARY 1 1 INTRODUCTION 17 Origin of the Task, 19 Definitions, 22 Related IOM Work, 29 Framework of the Report, 29 References, 29 2 REVIEW: EVALUATING AND REGULATING BIOMARKER USE 33 Introduction, 33 Survey of Biomarker Uses, 34 Evaluation Frameworks, 52 Evolution of Regulatory Perspectives on Surrogate Endpoints, 66 Biomarkers and Communication Strategies at the FDA, 80 Further Issues with Use of Biomarkers, 82 References, 86 3 THE BIOMARKER EVALUATION PROCESS 97 The Rationale for an Interrelated, Three-Step Process, 100 Application of the Evaluation Framework, 116 Scientific Process Harmonization, 121 Conclusion, 125 References, 125 xv

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xvi CONTENTS 4 CASE STUDIES 131 Introduction, 131 Tumor Size as Biomarker for Cancer Clinical Endpoints, 135 C-Reactive Protein, 142 Troponin, 153 LDL and HDL as Biomarkers for Cardiovascular Risk, 159 Beta-Carotene, Beta-Carotene, 168 References, 175 5 STRENGTHENING EVIDENCE-BASED REGULATION 197 Chapter Recommendations, 197 FDA Regulatory Authority, 198 Federal Agencies and Data Collection, 218 Tracking the Effects of Biomarker Use at the FDA, 223 References, 228 ACRONYMS 235 GLOSSARY 239 APPENDIxES A Table of Papers About Biomarker Qualification 253 B Recommendations from Related IOM Reports 279 C Committee Member and Consultant Biographies 287 D Staff Biographies 299 E Workshop Agenda 305 F Speaker Biographies 307

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Boxes, Figures, and Tables Summary Boxes S-1 Summary of Recommendations for Effective Biomarker Evaluation, 2 S-2 Important Definitions, 3 S-3 Ancillary Recommendations, 14 Figures S-1 The steps of the evaluation framework are interdependent, 7 S-2 Multiple ingredients, multiple biological pathways, and multiple outcomes illustrate some of the complexities of the use of biomarkers and surrogate endpoints in chronic disease, 14 Chapter 1 Box 1-1 Important Definitions, 23 Tables 1-1 Use of Biomarkers in Chronic Disease Patient Care, 24 1-2 Use of Biomarkers in Drug Development, 24 1-3 Regulatory Definitions of Surrogate Endpoint, 25 1-4 Literature Definitions of Surrogate Endpoint, 26 xvii

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xviii BOXES, FIGURES, AND TABLES Chapter 2 Boxes 2-1 Characteristics of Comparative Effectiveness Research (CER), 37 2-2 Hill’s Criteria, 55 2-3 Five Unique Features of Decision Analysis for Surrogate Endpoint Evaluation, 60 2-4 FDA’s Risk Communication Advisory Committee, 69 Figures 2-1 Reasons for failure of surrogate endpoints, 48 2-2 The setting that provides the greatest potential for the surrogate endpoint to be valid, 49 2-3 Receiver operating characteristic (ROC) graph of a varying decision threshold compared with a “useless test,” 61 2-4 Outline of the Food and Drug Administration’s (FDA’s) biomarker qualification pilot process, 70 2-5 Food and Drug Administration ranking system to approve health claims, 78 Tables 2-1 Categories of Biomarker Use, 35 2-2 Altar et al. (2008) Proposed Evidence Map for Biomarker Qualification, 64 2-3 List of Regulations and Guidances Pertaining to Surrogate Endpoints, 66 2-4 Health Claims Based on Surrogate Endpoints, 75 2-5 Qualified Health Claims Approved by the Food and Drug Administration, 76 Chapter 3 Boxes 3-1 Recommendations 1–4, 98 3-2 Tumor Size and Analytical Validation (Recommendation 1a), 107 3-3 CRP, Inflammatory Markers, and Qualification (Recommendation 1b), 110 3-4 Troponin and Utilization (Recommendation 1c), 115 3-5 LDL and HDL Cholesterol and Surrogacy (Recommendation 1c), 117 Blood Levels of b-Carotene, 122 3-6

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xix BOXES, FIGURES, AND TABLES Figure 3-1 The steps of the evaluation framework are interdependent, 99 Tables 3-1 Sources of Variability in Biomarker Measurements, 104 3-2 Information Needed for Package Inserts and Peer-Reviewed Publications Describing Biomarker Assays, 106 3-3 Utilization: Critical and Important Factors for Consideration (Recommendation 1c), 112 Chapter 4 Box 4-1 Conditions Associated with High Cardiac Troponins, 157 Figure 4-1 Inflammatory risk factors, 144 Tables 4-1 Brief Summary of the Results of the Case Studies, 132 4-2 Assays of Inflammatory Markers for Potential Clinical Use, 146 Chapter 5 Boxes 5-1 Expanding FDA Responsibilities, 201 5-2 Core FDA Regulatory Functions, 203 5-3 Dietary Supplements, 212 5-4 Role of NIH in Biomarker Data Collection, 224 Figures 5-1 Food and Drug Administration—Regulatory Industry (FY2006): The people, science, and information needed to support innovation, grow industries, and protect the public both in our country and around the world, 202 5-2 Comparison of Food and Drug Administration (FDA) health- related food label statements, 216 Table 5-1 Types of Claims, 210

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xx BOXES, FIGURES, AND TABLES Appendix A Tables A-1 Historical Review of the Biomarker–Surrogate Endpoint Literature with Special Reference to the Nomenclature, Initial Reports, Systems of Classification, and Statistical Methods Developed for Their Evaluation, 252 A-2 Continuation of Table A-1 for 2007–2009, 267 Appendix B Boxes B-1 Summary of Recommendations to Develop Biomarker-Based Tools for Cancer, 278 B-2 Summary of Recommendations for The Future of Drug Safety: Promoting and Protecting the Health of the Public, 279