GENOME-BASED DIAGNOSTICS

Clarifying Pathways to Clinical Use

WORKSHOP SUMMARY

Steve Olson and Adam C. Berger, Rapporteurs

Roundtable on Translating Genomic-Based Research for Health

Board on Health Sciences Policy

INSTITUTE OF MEDICINE

OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
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Steve Olson 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, 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. This project was supported by contracts between the National Academy of Sciences and the American College of Medical Genetics and Genomics (unnumbered contract); American Heart Association (unnumbered contract); American Medical Association (unnumbered contract); American Nurses Association (unnumbered contract); American Society of Human Genet- ics (unnumbered contract); Blue Cross and Blue Shield Association (unnumbered contract); Centers for Disease Control and Prevention (Contract No. 200-2011-38807); College 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 (Contract No. HHSH250201100119P); John- son & Johnson (unnumbered contract); The Kaiser Permanente Program Offices Community Benefit II at the East Bay Community Foundation (Contract No. 20121257); Life Technologies (unnumbered contract); National Cancer Institute (Contract No. N01-OD-4-2139, TO#189); National Coalition for Health Professional Education in Genetics (unnumbered contract); National Heart, Lung, and Blood Institute (Contract No. N01-OD-4-2139, TO#275); National Human Genome Research Institute (Contract No. N01-OD-4-2139, TO#264); National Institute of Mental Health (Contract No. N01-OD-4-2139, TO#275); National Institute on Aging (Contract No. N01-OD-4-2139, TO#275); National Society of Genetic Counselors (unnumbered contract); Office of Rare Diseases Research (Contract No. N01-OD-4-2139, TO#275); 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 neces- sarily reflect the views of the organizations or agencies that provided support for the project. International Standard Book Number-13: 978-0-309-25394-9 International Standard Book Number-10: 0-309-25394-2 Additional copies of this report are available for sale 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. Genome-Based Diagnostics: Clarifying Pathways to Clinical Use: 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 DEBRA LEONARD (Co-Chair), Professor and Vice Chair for Laboratory Medicine; Director of the Clinical Laboratories; Director of the Pathology Residency Training Program, Weill Cornell Medical Center of Cornell University, New York, NY ROBERT McCORMACK (Co-Chair), Head of Cellular Research and Development and Technology Strategy, Veridex, LLC, Raritan, NJ DANIEL HAYES, Clinical Director of the Breast Oncology Program, Stuart B. Padnos Professor in Breast Cancer Research, University of Michigan, Ann Arbor, MI 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 NUSSBAUM, Chief, Division of Medical Genetics, Department of Medicine and Institute of Human Genetics, University of California, San Francisco, School of Medicine VICTORIA PRATT, Chief Director, Molecular Genetics, Quest Diagnostics Nichols Institute, Chantilly, VA RONALD PRZYGODZKI, Associate Director for Genomic Medicine and Acting Director of Biomedical Laboratory Research and Development, Office of Research and Development, Department of Veterans Affairs, Washington, DC DANIEL WATTENDORF, Deputy Chief, Medical Innovations, Department of the Air Force; Program Manager, DARPA/Defense Sciences Office, Arlington, VA IOM Staff ADAM C. BERGER, Project Director SARAH H. BEACHY, Christine Mirzayan Science and Technology Policy Graduate Fellow (August to November 2011) CLAIRE F. GIAMMARIA, Research Associate TONIA E. DICKERSON, Senior Program Assistant 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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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 EUAN ANGUS ASHLEY, representative of the American Heart Association; Director, Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Palo Alto, CA PAUL R. BILLINGS, Chief Medical Officer, Life Technologies, Carlsbad, CA BRUCE BLUMBERG, 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 JOANN A. BOUGHMAN, Executive Vice President, American Society of Human Genetics, Bethesda, MD C. THOMAS CASKEY, Professor, Baylor College of Medicine, Houston, TX SARA COPELAND, Acting Chief, Genetic Services Branch, Health Resources and Services Administration, Rockville, MD 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 RICHARD J. HODES, Director, National Institute on Aging, Bethesda, MD 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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SHARON KARDIA, Professor and Chair of Epidemiology; Director, Public Health Genetics Program; Director, Life Science and Society Program; Co-Director, Center for Public Health and Community Genomics, University of Michigan School of Public Health, Ann Arbor, MI MOHAMED KHAN, representative of the American Medical Association; Leader of Radiation Oncology, Vancouver Cancer Centre, BC Cancer Agency, Vancouver, BC, Canada MUIN KHOURY, Director, National Office of Public Health Genomics, Centers for Disease Control and Prevention, Atlanta, GA THOMAS LEHNER, Director, Office of Genomics Research Coordination, National Institute of Mental Health, Bethesda, MD DEBRA LEONARD, representative of the College of American Pathologists; Professor and Vice Chair for Laboratory Medicine; Director of the Clinical Laboratories; Director of the Pathology Residency Training Program, Weill Cornell Medical Center of Cornell University, New York, NY MICHELE A. LLOYD-PURYEAR, representative of the Office of Rare Diseases Research; Senior Medical and Scientific Advisor, National Institute of Child Health & Human Development, Bethesda, MD ELIZABETH MANSFIELD, Director of the Personalized Medicine Staff, Office of In Vitro Diagnostic Device Evaluation and Safety, Center for Devices and Radiological Health, U.S. 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 MICHELLE A. PENNY, Senior Director, Translational Medicine Group, Eli Lilly and Company, Indianapolis, IN AIDAN POWER, Vice President and Global Head of Molecular Medicine, Pfizer Inc., Groton, CT VICTORIA M. PRATT, Chief Director, Molecular Genetics, Quest Diagnostics Nichols Institute, Chantilly, VA RONALD PRZYGODZKI, Associate Director for Genomic Medicine and Acting Director of Biomedical Laboratory Research and Development, Department of Veterans Affairs, Washington, DC viii

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ALLEN D. ROSES, President and Chief Operating Officer, Cabernet, Shiraz and Zinfandel Pharmaceuticals; and 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 JOAN A. SCOTT, Executive Director, National Coalition for Health Professional Education in Genetics, Lutherville, MD 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 and Genomics, Bethesda, MD DANIEL WATTENDORF, Deputy Chief, Medical Innovations, Department of the Air Force; Program Manager, DARPA/Defense Sciences Office, Arlington, VA CATHERINE A. WICKLUND, Past President, National Society of Genetic Counselors; Director, Graduate Program in Genetic Counseling; Associate Professor, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL IOM Staff ADAM C. BERGER, Project Director SEAN P. DAVID, James C. Puffer, M.D./American Board of Family Medicine Fellow SARAH H. BEACHY, Christine Mirzayan Science and Technology Policy Graduate Fellow (August to November 2011) 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: Louis I. Hochheiser, Chief Medical Leader, Humana Inc., Jackson, WY Stanley Lapidus, Founder, President, and Chief Executive Officer, SynapDx Corp., Southborough, MA Ellen Sigal, Chairperson and Founder, Friends of Cancer Research, Washington, DC Although the reviewers listed above have provided many constructive comments and suggestions, they did not see the final draft of the report before its release. The review of this report was overseen by Harold J. 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. xi

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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 Facilitating the Development and Utilization of Genome-Based Diagnostic Technologies and the development of the workshop summary report titled Genome-Based Diagnostics: Clarifying Pathways to Clinical Use. Federal sponsors are the Centers for Disease Con- trol and Prevention; Department of the Air Force; Department of Veterans Affairs; Health Resources and Services Administration; National Cancer Institute; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; National Institute of Mental Health; National Institute on Aging; and Office of Rare Diseases Research. Nonfederal spon- sorship was provided by the American College of Medical Genetics and Genomics; American Heart Association; American Medical Association; American Nurses Association; American Society of Human Genetics; Blue Cross and Blue Shield Association; College of American Pathologists; Eli Lilly and Company; Genetic Alliance; Johnson & Johnson; The Kaiser Per- manente Program Offices Community Benefit II at the East Bay Community Foundation; Life Technologies; National Coalition for Health Professional Education in Genetics; National Society of Genetic Counselors; and Pfizer Inc. The Roundtable wishes to express its gratitude to the expert speakers whose presentations helped outline the challenges and opportunities in developing clinically useful genomic diagnostic tests. The Roundtable also wishes to thank the members of the planning committee for their work in developing an excellent workshop agenda. The project director would like to thank project staff who worked diligently to develop both the workshop and the resulting summary. xiii

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Contents ABBREVIATIONS AND ACRONYMS xix 1 INTRODUCTION 1 2 CALLS FOR CHANGE 5 A Consolidated System of Review and Approval for Genomic Diagnostic Tests, 6 Perspective from Venture Capital, 11 3 TEST DEVELOPERS 17 Regulatory Clarity in a Competitive Marketplace, 18 Improving the Efficiency of Test Development, 20 Overcoming Obstacles to Test Development, 21 Principles for Success, 23 4 PATIENTS 29 Policy Positions, 30 Issues of Concern, 30 5 PAYERS 33 Progressive Regulation and Reimbursement, 33 The Need for Standards, 36 From Evidence-Based to Critical Reasoning Medicine, 37 xv

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xvi CONTENTS 6 REGULATION, REIMBURSEMENT, AND PUBLIC HEALTH 39 A 21st-Century Oversight System, 40 FDA Review, 43 Coverage by CMS, 45 7 DISCUSSION OF MAJOR PROPOSALS 49 Eliminating the LDT Pathway, 49 Consolidating Offices Within FDA, 52 Collaboration Between FDA and CMS, 53 Progressive Approval and Reimbursement Processes, 54 Arriving at a Collective Social Judgment, 57 Final Remarks, 58 REFERENCES 61 APPENDIXES A WORKSHOP AGENDA 63 B SPEAKER BIOGRAPHICAL SKETCHES 69 C STATEMENT OF TASK 77 D REGISTERED ATTENDEES 79

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Table, Figures, and Boxes TABLE 2-1 Comparison of CLIA and FDA Regulatory Pathways, 8 FIGURES 2-1 Undervaluation of tumor markers leads to a vicious cycle in which incentives do not exist to increase the valuation, 7 2-2 Three pathways for generating high-quality evidence of clinical utility, 9 2-3 Highly valued tumor biomarkers lead to a virtuous cycle in which markers are continually improved, 12 2-4 Venture capital investments in U.S. companies from 1970 to 2010, 13 2-5 Venture capital investments in the life sciences and health care have declined significantly in recent years, 14 3-1 Little significant benefit is seen from use of chemotherapy in addition to tamoxifen treatment for patients with lymph node– negative, estrogen receptor–positive breast cancer, 24 6-1 The public health genomics model allows for a balance of the translational research (T0 through T4) needed to convert discoveries into better health, 40 xvii

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xviii TABLE, FIGURES, AND BOXES 6-2 An analysis of 2007 National Cancer Institute cancer genetics and genomics grants indicates very few supported research studies in later translational stages, with the majority falling into discovery or early translation, 41 BOXES 1-1 Pathways to Approval and Use, 4 2-1 Definitions of Validity and Utility, 8 7-1 Major Proposals Made by Individual Speakers, 50

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Abbreviations and Acronyms AHRQ Agency for Healthcare Research and Quality BRCA1 breast cancer type 1 BRCA2 breast cancer type 2 CAP College of American Pathologists CDC Centers for Disease Control and Prevention CDER Center for Drug Evaluation and Research CDRH Center for Devices and Radiological Health CED coverage with evidence development CLIA Clinical Laboratory Improvement Amendments CMS Centers for Medicare & Medicaid Services EGAPP Evaluation of Genomic Applications in Practice and Prevention FDA U.S. Food and Drug Administration GAPPNet Genomic Applications Practice and Prevention Network GP general partner IDE investigational device exemption IND Investigational New Drug IOM Institute of Medicine IRB institutional review board xix

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xx ABBREVIATIONS AND ACRONYMS LDT laboratory-developed test LP limited partner NCCS National Coalition for Cancer Survivorship NIH National Institutes of Health NVCA National Venture Capital Association ODAC Oncologic Drugs Advisory Committee PMA premarket approval PSA prostate-specific antigen RCT randomized controlled trial SACGHS Secretary’s Advisory Committee on Genetics, Health, and Society USPSTF U.S. Preventive Services Task Force