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EVOLUTION OF TRANSLATIONAL OMICS Lessons Learned and the Path Forward Committee on the Review of Omics-Based Tests for Predicting Patient Outcomes in Clinical Trials Board on Health Care Services Board on Health Sciences Policy Christine M. Micheel, Sharyl J. Nass, and Gilbert S. Omenn, Editors
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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW 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 Nos. HHSN261200900003C (National Cancer Insti- tute); HHSF223201010692P and HHSF22301018T (Food and Drug Administration); and 200-2011-38807 and 200-2005-13434 (Centers for Disease Control and Prevention). This study was also supported by the U.S. Department of Veterans Affairs, the American Society for Clinical Pathology, and the College of American Pathologists. 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: 978-0-309-22418-5 International Standard Book Number 10: 0-309-22418-7 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http:// www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www. iom.edu. Copyright 2012 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). 2012. Evolution of Translational Omics: Lessons Learned and the Path Forward. 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 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 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 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 THE REVIEW OF OMICS-BASED TESTS FOR PREDICTING PATIENT OUTCOMES IN CLINICAL TRIALS GILBERT S. OMENN (Chair), Professor of Internal Medicine, Human Genetics and Public Health; Director, University of Michigan Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor CATHERINE D. DEANGELIS, Professor of Pediatrics, Johns Hopkins School of Medicine, Professor of Health Policy and Management, Johns Hopkins School of Public Health, and Editor-in-Chief Emerita, Journal of the American Medical Association, Baltimore, MD DAVID L. DEMETS, Professor of Statistics and Biostatistics, University of Wisconsin, Madison THOMAS R. FLEMING, Professor of Biostatistics, Statistics, University of Washington, Seattle GAIL GELLER, Professor of Medicine, Berman Institute of Bioethics, Johns Hopkins University, Baltimore, MD JOE GRAY, Gordon Moore Endowed Chair, Department of Biomedical Engineering, Center for Spatial Systems Biomedicine, Oregon Health & Science University Knight Cancer Institute, Portland DANIEL F. HAYES, Clinical Director of the Breast Oncology Program, and Stuart B. Padnos Professor of Breast Cancer Research, University of Michigan Comprehensive Cancer Center, Ann Arbor I. CRAIG HENDERSON, Adjunct Professor of Medicine, University of California, San Francisco and Helen Diller Family Comprehensive Cancer Center LARRY KESSLER, Professor and Chair, Department of Health Services, University of Washington School of Public Health, Seattle STANLEY LAPIDUS, Founder, President, and CEO, SynapDx Corporation, Southborough, MA DEBRA G. B. LEONARD, Professor and Vice Chair for Laboratory Medicine, and Director of the Clinical Laboratories, Weill Medical College of Cornell University, New York, NY HAROLD L. MOSES, Director Emeritus, Hortense B. Ingram Professor of Molecular Oncology, and Professor of Cancer Biology, Medicine, and Pathology, Vanderbilt-Ingram Cancer Center, Nashville, TN WILLIAM PAO, Associate Professor of Medicine, Cancer Biology, and Pathology, Microbiology, Immunology, Ingram Associate Professor of Cancer Research, Director of the Division of Hematology/Oncology, and Director of Personalized Cancer Medicine, Vanderbilt University School of Medicine, Nashville, TN v
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REBECCA D. PENTZ, Professor of Hematology and Oncology in Research Ethics, Emory School of Medicine, Atlanta, GA NATHAN D. PRICE, Associate Professor, Institute for Systems Biology, Seattle, WA JOHN QUACKENBUSH, Professor of Computational Biology and Bioinformatics, Dana-Farber Cancer Institute, Boston, MA ELDA RAILEY, Cofounder, Research Advocacy Network, Plano, TX DAVID RANSOHOFF, Professor of Medicine, Clinical Professor of Epidemiology, University of North Carolina, School of Medicine and Gillings School of Global Public Health, Chapel Hill E. ALBERT REECE, Vice President for Medical Affairs, University of Maryland, and John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine, Baltimore DANIELA M. WITTEN, Assistant Professor of Biostatistics, University of Washington, Seattle Staff CHRISTINE M. MICHEEL, Study Director (through November 2011) SHARYL J. NASS, Director, National Cancer Policy Forum; Study Director (from December 2011) LAURA LEVIT, Program Officer (from June 2011) ERIN BALOGH, Associate Program Officer SARAH DOMNITZ, Christine Mirzayan Science and Technology Policy Graduate Fellow (from August to December 2011) JULIA E. DOOHER, Christine Mirzayan Science and Technology Policy Graduate Fellow (from January to May 2011) NIHARIKA SATHE, Research Assistant (from June 2011) MICHAEL PARK, Senior Program Assistant PATRICK BURKE, Financial Associate ROGER HERDMAN, Director, Board on Health Care Services ANDREW POPE, Director, Board on Health Sciences Policy Consultant JOHN BAILAR, Scholar in Residence 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 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: Wylie Burke, Professor and Chair, Department of Bioethics and Humanities, University of Washington Adam M. Clarke, Founder, MedTran Health Strategies, LLC Susan S. Ellenberg, Professor of Biostatistics, Associate Dean for Clinical Research, Perelman School of Medicine, University of Pennsylvania Charis Eng, ACS Clinical Research Professor, Chair, and Director, Genomic Medicine Institute, Cleveland Clinic Foundation, Case Western Reserve University School of Medicine Marcus Feldman, Professor of Biology, Stanford University David B. Flannery, Chief of Medical Genetics, Professor of Pediatrics, Vice Chair for Administration of the Department of Pediatrics, Georgia Health Sciences University Stephen Friend, President and CEO, Sage Bionetworks vii
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viii REVIEWERS Larry Gold, Chairman and Chief Executive Officer, SomaLogic, Inc. Steven Goodman, Associate Dean for Clinical and Translational Research, Professor of Medicine & Health Research and Policy, Stanford University School of Medicine Robert Gray, Professor of Biostatistics, Dana Farber Cancer Institute Stephen Grubbs, Principal Investigator, Delaware Christiana Care Community Clinical Oncology Program David Korn, Vice Provost for Research, Professor of Pathology, Harvard University Marc Ladanyi, William J. Ruane Chair in Molecular Oncology, Memorial Sloan-Kettering Cancer Center Bernard Lo, Professor of Medicine and Director, Program in Medical Ethics, University of California, San Francisco David Madigan, Professor of Statistics, Columbia University Bettie Sue Siler Masters, The Robert A. Welch Distinguished Professor in Chemistry, University of Texas Health Science Center at San Antonio Charles E. Phelps, Provost Emeritus, Professor of Political Science and of Economics, University of Rochester Dan Roden, Professor of Medicine, William Stokes Chair in Experimental Therapeutics, Professor of Pharmacology, Vanderbilt University Medical Center Larry Shapiro, Executive Vice Chancellor for Medical Affairs and Dean, Washington University School of Medicine Peter Shields, Professor and Chief, Deputy Director, Comprehensive Cancer Center and Professor, College of Medicine, The Ohio State University Medical Center Steve Teutsch, Chief Science Officer, Los Angeles County Public Health David Wong, Professor of Bioengineering, Director of the Dental Research Institute, University of California, Los Angeles Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Kristine Gebbie, Adjunct Professor, Flinders University School of Nursing and Midwifery and Lawrence D. Brown, Professor, Department of Statistics, The Wharton School, University of Pennsylvania. Appointed by the Institute of Medicine and the National Research Council, they were 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 authoring committee and the institution.
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Acknowledgments The committee is grateful to many individuals who provided valu- able input and information for the study, either through formal presenta- tions or through informal communications with study staff and committee members: Patrick Anquetil, SynapDx Keith Baggerly, MD Anderson Cancer Center John Bailar, Institute of Medicine William Barry, Duke University Robert Becker, Food and Drug Administration Robert Califf, Duke University Ned Calonge, The Colorado Trust Michael Cuffe, Duke University Jeffrey Drazen, New England Journal of Medicine John Falletta, Duke University Geoffrey Ginsburg, Duke University Alberto Gutierrez, Food and Drug Administration Scott Henderson, Vermillion Michael Kelley, Duke University Katrina Kelner, Translational Medicine and Science Véronique Kiermer, Nature Publishing Sally Kornbluth, Duke University Sumithra Mandrekar, Mayo Clinic Anne-Marie Mazza, The National Academies Ross McKinney, Duke University ix
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x ACKNOWLEDGMENTS Lisa McShane, National Cancer Institute Stephen A. Merrill, The National Academies Mitch Nelles, XDx Joseph Nevins, Duke University Nicole Osmer, Nicole Osmer Healthcare Communications Harold Paz, Pennsylvania State University Charles Perou, The University of North Carolina at Chapel Hill Peter Pronovost, Johns Hopkins University William Sellers, Novartis Institutes for BioMedical Research Steven Shak, Genomic Health Richard Simon, National Cancer Institute Ed Stevens, Pathwork Diagnostics Susan Su, United States Patent and Trademark Office Paul Uhlir, The National Academies Laura van ‘t Veer, Helen Diller Family Comprehensive Cancer Center Pablo Whaley, United States Patent and Trademark Office Scott Zeger, Johns Hopkins University We thank the National Cancer Institute, the Food and Drug Adminis- tration, the Centers for Disease Control and Prevention, the U.S. Depart- ment of Veterans Affairs, the American Society for Clinical Pathology, and the College of American Pathologists for supporting this study.
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Contents BOXES, FIGURES, AND TABLES xiii SUMMARY 1 1 INTRODUCTION 17 Origin of the Task, 18 Committee Appointment and Charge, 20 Engagement of Stakeholders and Implementation of the Recommendations, 29 Organization of the Report, 30 References, 30 2 OMICS-BASED CLINICAL DISCOVERY: SCIENCE, TECHNOLOGY AND APPLICATIONS 33 Types of Omics Data, 34 Emerging Omics Technologies and Data Analysis Techniques, 37 Statistics and Bioinformatics Development of Omics-Based Tests, 41 Completion of the Discovery Phase of Omics-Based Test Development, 57 Summary and Recommendation, 58 References, 59 xi
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xii CONTENTS 3 BEST PRACTICES FOR OMICS-BASED TEST VALIDATION PRIOR TO USE FOR PATIENT MANAGEMENT DECISIONS IN A CLINICAL TRIAL SETTING 65 Background, 68 Test Validation Phase, 70 Preparation for Investigational Use of the Validated Test, 75 Funding for Validation of a Candidate Omics-Based Test in a CLIA-Certified Clinical Laboratory, 76 Summary and Recommendation, 77 References, 78 4 EVALUATION OF OMICS-BASED TESTS FOR CLINICAL UTILITY AND USE 79 Background, 79 Evaluation for Clinical Utility and Use Stage, 82 Summary and Recommendation, 101 References, 102 5 RESPONSIBLE PARTIES 105 Intrainstitutional Parties, 107 Funders, 129 FDA, 136 Journals, 140 Summary and Recommendations, 149 References, 153 6 LESSONS FROM THE CASE STUDIES 163 Methods, 164 Lessons Learned from the Case Studies, 168 Concluding Remarks, 179 References, 179 APPENDIXES A Case Studies 183 B Gene Expression–Based Tests Developed at Duke University 239 and Used in Clinical Trials C Introduction to Biomarkers 281 D Reporting Guidelines 289 E Committee Member and Staff Biographies 301 F Information Gathering Sessions and Speakers 319 ACRONYMS AND ABBREVIATIONS 323 GLOSSARY 327
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Boxes, Figures, and Tables BOXES S-1 Development and Evaluation Process Recommendations, 8 S-2 Recommendations on Appropriate Actions to Ensure Adoption and Adherence, 10 1-1 Committee Statement of Task, 20 1-2 Important Definitions, 22 2-1 Considerations in Data and Information Sharing, 52 5-1 Themes from the Case Studies for Investigators, 109 5-2 Themes from the Case Studies for Institutions, 116 5-3 Examples of Institutional Oversight Bodies, 119 5-4 Clinical Trial Management Systems (CTMSs), 121 5-5 Themes from the Case Studies for Funders, 131 5-6 Themes from the Case Studies for FDA, 137 5-7 Themes from the Case Studies for Journals, 141 5-8 Lessons from the Banking Industry on Data and Code Sharing, 145 D-1 Example of a Reporting Guideline Checklist: The REMARK Checklist, 294 D-2 The EQUATOR Network, 296 xiii
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xiv BOXES, FIGURES, AND TABLES FIGURES S-1 Omics-based test development process, 6 1-1 The steps of the biomarker evaluation are interdependent, 27 2-1 Omics-based test development process, highlighting the discovery phase, 35 3-1 Omics-based test development process, highlighting the test validation phase, 66 4-1 Omics-based test development process, highlighting the evaluation for clinical utility and use stage, 80 4-2 Two clinical trial designs in which the test is not used to direct therapy, 96 4-3 Enrichment design, 99 4-4 Example of a test-guided strategy versus standard of care, 100 4-5 Example of a test-guided strategy versus non-guided strategy with randomized treatment design, 101 A-1 Venn diagrams illustrating overlap in patient blood samples used for AlloMap development, 219 TABLES 1-1 Categories of Biomarker Use, 25 1-2 Use of Biomarkers in Clinical Practice, 26 4-1 Examples of Clinical Study Designs for Test Assessment, 88 6-1 Overview of Commercially Available Omics-Based Tests, 165 6-2 Data Availability, 170 6-3 Statistical and Bioinformatics Validation Considerations, 173 6-4 Choice of Trial Designs for Clinical/Biological Validation, 177 A-1 Archival Tissue Used in the Development of Oncotype DX Computational Model and Gene List, 188 A-2 Clinical/Biological Validation Studies for Oncotype DX, 190 A-3 Clinical/Biological Validation Studies for MammaPrint, 198 A-4 FDA 510(k) Clearances for MammaPrint, 202 A-5 Clinical/Biological Validation Studies for the Tissue of Origin Test, 207
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xv BOXES, FIGURES, AND TABLES A-6 Performance Characteristics for OVA1 Applied to Pre- and Postmenopausal Subjects Evaluated by Non-Gynecologic Oncologist Physicians, 212 A-7 Clinical/Biological Validation Studies for AlloMap, 220 B-1 Clinical Trials Related to Duke University Gene Expression–Based Tests and the Clinical Trials Listed in the Institute of Medicine Committee’s Statement of Task, 241 B-2 Time Line of Events Surrounding the Duke Gene Expression–Based Tests, 269 D-1 Reporting Standards Used in Omics Research, 292
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