GENERATING EVIDENCE FOR GENOMIC DIAGNOSTIC TEST DEVELOPMENT

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Theresa Wizemann and Adam C. Berger, Rapporteurs Roundtable on Translating Genomic-Based Research for Health 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 contracts between the National Academy of Sciences and the American College of Medical Genetics (unnumbered contract); American Medical Association (unnumbered contract); American Nurses Association (unnum- bered contract); Blue Cross and Blue Shield Association (unnumbered contract); Centers for Disease Control and Prevention (Contract No. 200-2005-13434); Col- lege of American Pathologists (unnumbered contract); Department of the Air Force (Contract No. FA7014-10-P-0072); Department of Veterans Affairs (Contract No. V101(93) P-2238); Eli Lilly and Company (Contract No. LRL-0028-07); Genetic Alliance (unnumbered contract); Health Resources and Services Administration; Johnson & Johnson (unnumbered contract); Kaiser Permanente (unnumbered con- tract); National Cancer Institute (Contract No. N01-OD-4-2139, TO#189); National Heart, Lung, and Blood Institute (Contract No. N01-OD-4-2139, TO#189); National Human Genome Research Institute (Contract No. N01-OD-4-2139, TO#189); National Society of Genetic Counselors (unnumbered contract); and Pfizer Inc. (Contract No. 140-N-1818071). Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the organizations or agencies that provided support for the project. International Standard Book Number-13: 978-0-309-21104-8 International Standard Book Number-10: 0-309-21104-2 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 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. Generating Evidence for Genomic Diagnostic Test 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 Acad- emy 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 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 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 Sci- ences 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 Coun- cil is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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PLANNING COMMITTEE1 NAOMI ARONSON, Executive Director, Technology Evaluation Center, Blue Cross and Blue Shield Association, Chicago, IL ANDREW FREEDMAN, Branch Chief, Clinical and Translational Epidemiology Branch, Epidemiology and Genetics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, MD ROGER D. KLEIN, Director, Molecular Oncology Laboratory at BloodCenter of Wisconsin; Clinical Assistant Professor of Pathology, Medical College of Wisconsin, Milwaukee DEBRA LEONARD, Professor and Vice Chair for Laboratory Medicine, Director of the Clinical Laboratories, and Director of the Pathology Residency Training Program, Weill Cornell Medical Center of Cornell University, New York, NY ELIZABETH MANSFIELD, Director of the Personalized Medicine Staff, Office of In Vitro Diagnostic Device Evaluation and Safety in the Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD ROBERT McCORMACK, Director for Technology Assessment, Ortho- Clinical Diagnostics; Vice President of Scientific and Medical Affairs, Veridex, LLC, Raritan, NJ ROBERT NUSSBAUM, Chief of the Division of Medical Genetics, Department of Medicine, Institute of Human Genetics, San Francisco, CA KIM POPOVITS, President and Chief Executive Officer, Genomic Health, Redwood City, CA RONALD PRZYGODZKI, Associate Director for Genomic Medicine, Acting Director of Biomedical Laboratory Research and Development, Office of Research and Development, Department of Veterans Affairs, Washington, DC ALLEN ROSES, President and Chief Operating Officer, Cabernet, Shiraz and Zinfandel Pharmaceuticals; Jefferson–Pilot Professor of Neurobiology and Genetics, Professor of Medicine (Neurology), Director of the Deane Drug Discovery Institute; Senior Scholar at the Fuqua School of Business, Duke University, Durham, NC DANIEL WATTENDORF, Deputy Chief, Medical Innovations, Department of the Air Force; Program Manager, DARPA/Defense Sciences Office, Arlington, VA 1 Institute of Medicine planning committees are solely responsible for organizing the work- shop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. v

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IOM Staff ADAM C. BERGER, Project Director CLAIRE F. GIAMMARIA, Research Associate TONIA E. DICKERSON, Senior Program Assistant vi

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ROUNDTABLE ON TRANSLATING GENOMIC-BASED RESEARCH FOR HEALTH1 WYLIE BURKE (Chair), Professor and Chair, Department of Bioethics and Humanities, University of Washington, Seattle NAOMI ARONSON, Executive Director, Technology Evaluation Center, Blue Cross and Blue Shield Association, Chicago, IL BRUCE BLUMBERG, Co-Chief of Medical Genetics, Kaiser Permanente, and Institutional Director of Graduate Medical Education, Northern California Kaiser Permanente, The Permanente Medical Group, Oakland, CA DENISE E. BONDS, Medical Officer, Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD C. THOMAS CASKEY, Director and Chief Executive Officer of the Brown Foundation Institute of Molecular Medicine, the George & Cynthia Mitchell Distinguished Chair in Neurosciences, and Executive Vice President of Molecular Medicine and Genetics, University of Texas Health Science Center at Houston STEPHEN ECK, Vice President, Translational Medicine and Pharmacogenomics, Eli Lilly and Company, Indianapolis, IN W. GREGORY FEERO, Special Advisor to the Director for Genomic Medicine, National Human Genome Research Institute, Bethesda, MD ANDREW N. FREEDMAN, Branch Chief, Clinical and Translational Epidemiology Branch, Epidemiology and Genetics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, MD GEOFFREY GINSBURG, Director, Center for Genomic Medicine, Institute for Genomic Sciences and Policy, Duke University, Durham, NC SHARON KARDIA, Professor and Chair of Epidemiology; Director, Public Health Genetics Program; Director, Life Science and Society Program; Co-Director, Center for Genomics & Public Health, University of Michigan School of Public Health, Ann Arbor MOHAMED KHAN, representing the American Medical Association; Leader of Radiation Oncology, Vancouver Cancer Centre, BC Cancer Agency, Vancouver, BC, Canada 1 Institute of Medicine 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. vii

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MUIN KHOURY, Director, National Office of Public Health Genomics, Centers for Disease Control and Prevention, Atlanta, GA DEBRA LEONARD, representing the College of American Pathologists; Professor and Vice Chair for Laboratory Medicine, Director of the Clinical Laboratories, and Director of the Pathology Residency Training Program, Weill Cornell Medical Center of Cornell University, New York, NY MICHELE LLOYD-PURYEAR, Chief, Genetic Services Branch, Health Resources and Services Administration, Rockville, MD ELIZABETH MANSFIELD, Director of the Personalized Medicine Staff, Office of In Vitro Diagnostic Device Evaluation and Safety in the Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD GARRY NEIL, Corporate Vice President, Corporate Office of Science and Technology, Johnson & Johnson, New Brunswick, NJ ROBERT L. NUSSBAUM, Chief, Division of Medical Genetics, Department of Medicine and Institute of Human Genetics, University of California–San Francisco School of Medicine AIDAN POWER, Vice President and Global Head of Molecular Medicine, Pfizer Inc., Groton, CT RONALD PRZYGODZKI, Associate Director for Genomic Medicine, Biomedical Laboratory Research and Development, Department of Veterans Affairs, Washington, DC ALLEN D. ROSES, President and Chief Operating Officer, Cabernet, Shiraz and Zinfandel Pharmaceuticals; Jefferson–Pilot Professor of Neurobiology and Genetics, Professor of Medicine (Neurology); Director, Deane Drug Discovery Institute; Senior Scholar, Fuqua School of Business, R. David Thomas Executive Training Center, Duke University, Durham, NC KEVIN A. SCHULMAN, Professor of Medicine and Business Administration; Director, Center for Clinical and Genetic Economics; Associate Director, Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC SHARON TERRY, President and Chief Executive Officer, Genetic Alliance, Washington, DC MARTHA TURNER, Assistant Director, American Nurses Association Center for Ethics and Human Rights, Silver Spring, MD MICHAEL S. WATSON, Executive Director, American College of Medical Genetics, Bethesda, MD DANIEL WATTENDORF, Deputy Chief, Medical Innovations, Department of the Air Force; Program Manager, DARPA/Defense Sciences Office, Arlington, VA viii

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CATHERINE A. WICKLUND, Past President, National Society of Genetic Counselors; Director, Graduate Program in Genetic Counseling; Assistant Professor, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL IOM Staff ADAM C. BERGER, Project Director CLAIRE F. GIAMMARIA, Research Associate TONIA E. DICKERSON, Senior Program Assistant ANDREW POPE, Director, Board on Health Sciences Policy ix

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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 process. We wish to thank the following individuals for their review of this report: Margaret Piper, Director of Genomics Resources, Blue Cross and Blue Shield Association Technology Evaluation Center, Atlanta, GA Jeffrey Roche, Medical Officer, Office of Clinical Standards and Quality, Center for Medicare and Medicaid Services, Baltimore, MD Steven Shak, Chief Medical Officer, Genomic Health, Inc., Redwood City, CA Sean Tunis, Director, Center for Medical Technology Policy, Baltimore, MD Although the reviewers listed above have provided many constructive comments and suggestions, they did not endorse the final draft of the report before its release. The review of this report was overseen by Harold J. xi

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xii REVIEWERS Fallon, Dean Emeritus of the University of Alabama at Birmingham School of Medicine. Appointed by the Institute of Medicine, he was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review com- ments were carefully considered. Responsibility for the final content of this report rests entirely with the author and the institution.

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Acknowledgments The support of the sponsors of the Institute of Medicine Roundtable on Translating Genomic-Based Research for Health was crucial to the planning and conduct of the workshop “Generating Evidence for Genomic Diagnostic Test Development.” Federal sponsors are the Department of the Air Force; Centers for Disease Control and Prevention; Health Resources and Services Administration; National Cancer Institute; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; and the Department of Veterans Affairs. Non-federal sponsorship was pro- vided by the American College of Medical Genetics, the American Medical Association, the American Nurses Association, Blue Cross and Blue Shield Association, the College of American Pathologists, Eli Lilly and Company, Genetic Alliance, Johnson & Johnson, Kaiser Permanente, the National Society of Genetic Counselors, and Pfizer Inc. The Roundtable wishes to express its gratitude to the expert speak- ers whose presentations helped outline the challenges and opportunities in generating evidence for genomic diagnostic tests. The Roundtable also wishes to thank the members of the planning committee for their work in developing an excellent workshop agenda. xiii

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Contents ABBREVIATIONS AND ACRONYMS xix 1 INTRODUCTION 1 2 STAKEHOLDER PERSPECTIVES ON EVIDENCE 5 FDA Perspective, 7 Payer Perspective, 10 Evidence-Based Review Group Perspective, 14 Health-Care Provider Perspective, 19 Panel Discussion, 22 3 APPROACHES TO EVIDENCE GENERATION 25 Pharmacogenomics Clinical Trials, 25 Use of Archived Samples to Evaluate Genomic Tests, 31 Coverage with Evidence Development, 33 Constructing Chains of Evidence, 39 Discussion, 41 4 OVERCOMING BARRIERS FOR EVIDENCE GENERATION 43 Balancing Stakeholder Needs, 43 Public-Private Partnerships, 44 The Evidentiary Bar for Clinical Utility, 46 Data Sources, 46 xv

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xvi CONTENTS 5 CONSIDERATIONS MOVING FORWARD 53 Medical Practice Versus Evidence-Based Recommendations, 53 Heterogeneity of Evidence-Based Decisions, 54 Research, 56 Broad Considerations, 57 Transparency, 57 Public Expectations, 58 6 FINAL REMARKS 59 Chair’s Summary, 60 REFERENCES 63 APPENDIXES A WORKSHOP AGENDA 67 B SPEAKER BIOGRAPHICAL SKETCHES 71 C REGISTERED ATTENDEES 81

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Tables, Figures, and Boxes TABLES 1-1 Evidence-Based Review of Select Genomic Tests, 3 2-1 Oncotype Dx Reclassification of Patients, 13 3-1 Classic Randomized Controlled Trials (RCTs) Versus Practical Clinical Trials (PCTs), 28 3-2 Summary of Ontario Field Evaluations, 36 FIGURES 2-1 Sample analytic framework, 16 2-2 Breast cancer mortality rates from 1950-2003 and the effect of screening and adjuvant therapy, 20 3-1 Pharmacogenomic trial designs, including retrospective, prospective stratified, and prospective screened, 26 3-2 Hypothetical genotype-guided versus usual care scenario to measure smoking cessation rates using varenicline or patch, 30 3-3 Prospective stratified RCT scheme, 30 3-4 MAS- and OHTAC-associated structures and linkages, 34 xvii

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xviii TABLES, FIGURES, AND BOXES BOXES 1-1 Speakers’ Perspectives on Barriers to the Collection of Clinical Validity and Utility Data for Genomic Diagnostic Tests, 4 2-1 Stakeholder Perspectives on Evidence, 6 2-2 Challenges to Establishing Analytical and Clinical Validity of Diagnostics, 8

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Abbreviations and Acronyms ACCE analytic validity, clinical validity, clinical utility, and associated ethical, legal, and social implications model AHRQ Agency for Healthcare Research and Quality ASCO American Society of Clinical Oncology CAP College of American Pathologists CDC Centers for Disease Control and Prevention CDRH Center for Devices and Radiological Health (FDA) CLIA Clinical Laboratory Improvement Amendments EGAPP Evaluation of Genomic Applications in Practice and Prevention EGFR epidermal growth factor receptor eMERGE Electronic Medical Records and Genomics ER estrogen receptor FDA U.S. Food and Drug Administration GAPPNet Genomic Applications in Practice and Prevention Network GWAS genome-wide association study HMO health maintenance organization IHC immunohistochemistry xix

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xx ABBREVIATIONS AND ACRONYMS LOE level of evidence MAQC microarray quality control MAS Medical Advisory Secretariat MSI microsatellite instability NCI National Cancer Institute (NIH) NHGRI National Human Genome Research Institute NIDDK National Institute of Diabetes and Digestive and Kidney Diseases (NIH) NIH National Institutes of Health OHTAC Ontario Health Technology Advisory Committee PET positron emission tomography PSA prostate-specific antigen RCT randomized controlled trial SSRI selective serotonin reuptake inhibitor TEC Technology Evaluation Center (Blue Cross and Blue Shield Association)