Discussion Forum Summary

Alison Mack, Erin Balogh, and Christine M. Micheel, Rapporteurs

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



Washington, D.C.

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PERSPECTIVES ON BIOMARKER AND SURROGATE ENDPOINT EVALUATION Discussion Forum Summary Alison Mack, Erin Balogh, and Christine M. Micheel, Rapporteurs 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

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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 study was supported by Contract No. HHSF223200810020I between the National Academy of Sciences and the Food and Drug Administration. Any opinions, find- ings, 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: 978-0-309-16324-8 International Standard Book Number-10: 0-309-16324-2 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:// For more information about the Institute of Medicine, visit the IOM home page at: 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. Perspectives on biomarker and surrogate endpoint evaluation: Discussion forum 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.

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COMMITTEE ON QuALIFICATION OF BIOMARkERS AND SuRROgATE ENDPOINTS IN CHRONIC DISEASE JOHN R. BALL (Chair), Senior Advisor, 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 DE gRuTTOLA, Professor and Chair, Biostatistics, Harvard School of Public Health DAVID DEMETS, Professor, 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 HARLAN, JR., Consultant ALLAN JAFFE, Professor of Medicine, Mayo Clinic RONALD 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 NESS, Dean, University of Texas Health Science Center, School of Public Health JENNIFER VAN Eyk, Professor, Departments of Medicine and Biological Chemistry, Johns Hopkins University JOHN A. WAgNER, Vice President, Clinical Pharmacology, Merck & Co., Inc. Consultant ELIzABETH 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, Associate Program Officer CAIRA WOODS, Christine Mirzayan Science and Technology Policy Graduate Fellow (January to April 2010), Research Associate (April to July 2010) ASHLEy McWILLIAMS, Senior Program Assistant PATRICk BuRkE, Financial Associate ROgER HERDMAN, Director, Board on Health Care Services LINDA 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 process. We wish to thank the following individuals for their review of this report: Douglas Balentine, Unilever Thomas Fleming, University of Washington Philip greenland, Northwestern University James Mayne, Pfizer, Inc. Rebecca Miksad, Harvard Medical School Jack zakowski, Beckman Coulter, Inc. Although the reviewers listed above have provided many construc- tive comments and suggestions, they did not see the final draft of the report before its release. The review of this report was overseen by Sharon B. Murphy, scholar-in-residence, Institute of Medicine. Appointed by the Institute of Medicine, she was responsible for making certain that an vii

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viii REVIEWERS 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 1 INTRODUCTION 1 2 COMMITTEE FINDINGS AND RECOMMENDATIONS 3 Charge to the Committee, 3 Definitions, 5 Recommendations, 7 3 FDA PERSPECTIVES 29 Presentation by Paula Trumbo, CFSAN, 31 Presentation by Kathleen Ellwood, CFSAN, 33 Presentation by Marc Walton, CDER, 34 Presentation by Federico Goodsaid, CDER, 37 Presentation by Robert Becker, CDRH, 39 4 NATIONAL INSTITUTES OF HEALTH PERSPECTIVES 43 Presentation by Michael Lauer, NHLBI, 44 Presentation by Paul Coates, NIH Office of Dietary Supplements, 48 5 INDUSTRY PERSPECTIVES 51 Presentation by Douglas Balentine, Unilever, 55 Presentation by Melissa Musiker, Grocery Manufacturers Association, 56 Presentation by Andrew Shao, Council for Responsible Nutrition, 58 ix

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x CONTENTS Presentation by Stephen Williams, Somalogic, Inc., 59 Presentation by James Mayne, Pfizer, Inc., 63 Presentation by Jack Zakowski, Beckman Coulter, Inc., 64 Presentation by Richard Kuntz, Medtronic, 65 6 PUBLIC HEALTH, CONSUMER, AND CONSULTING ORGANIZATION PERSPECTIVES 69 Presentation by Guy Johnson, Johnson Nutrition Solutions, LLC, 69 Presentation by Mary Hager, American Dietetic Association, 71 Presentation by Ilene Heller, Center for Science in the Public Interest, 72 7 PRESENTATION BY THOMAS FLEMING: BIOMARKERS AND SURROGATE ENDPOINTS IN CHRONIC DISEASE 75 A Correlate Does Not a Surrogate Make, 75 Validating Surrogate Endpoints, 80 A Biomarker Hierarchy, 83 Concluding Thoughts, 85 8 KEY THEMES, CHALLENGES, AND OPPORTUNITIES 87 Biomarker Evaluation Framework, 87 The Value of Biomarkers and Surrogate Endpoints, 90 Considerations for Food and Nutrition Applications, 91 Improving Communication and Understanding, 93 9 IMPORTANCE OF THE BIOMARKER DISCUSSION FORUM 97 REFERENCES 99 ACRONYMS 103 GLOSSARY 107 APPENDIxES A Discussion Forum Agenda 113 B Summary from the Committee’s Report 115 Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease