REFINING PROCESSES FOR THE CO-DEVELOPMENT
OF GENOME-BASED THERAPEUTICS AND
COMPANION DIAGNOSTIC TESTS

WORKSHOP SUMMARY

Sarah H. Beachy, Samuel G. Johnson, 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.

www.nap.edu



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Sarah H. Beachy, Samuel G. Johnson, 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 workshop that is the subject of this workshop summary was approved by the Governing Board of the National Research Council, whose members are drawn from the coun- cils 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 Academy of Nursing (unnumbered contract); American College of Medical Genetics and Genomics (unnumbered contract); American Heart Association (unnumbered contract); American Medical Association (unnumbered contract); American Society of Human Genetics (unnumbered contract); Association for Molecular Pathology (­ nnumbered u contract); Blue Cross and Blue Shield Association (unnumbered contract); College of American Pathologists (unnumbered contract); Department of the Air Force (Contract No. FA7014- 0-P-0072); Department of Veterans Affairs (Contract No. VA248-P-1528); Eli Lilly and Company (­ nnumbered contract); Genetic Alliance (unnumbered contract); u Health Resources and Services Administration (Contract No. HHSH250201100119P and Contract No. HHSH25034017T); International Society for Cardiovascular Translational Research (unnumbered contract); Johnson & Johnson (unnumbered contract); The Kaiser ­ P ­ ermanente Program Offices Community Benefit II at the East Bay Community Foundation (Contract No. 20121257); Life Technologies (unnumbered contract); National Cancer Insti- tute (Contract No. HHSN263201200074I, TO#5); 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 and Contract No. HHSN263201200074I, TO#5); National Institute of Mental Health (Contract No. N01-OD-4-2139, TO#275 and Contract No. HHSN263201200074I, TO#5); National Institute of Nursing Research (Contract No. HHSN263201200074I, TO#5); National Institute on Aging (Contract No. N01-OD-4-2139, TO#275 and Contract No. HHSN263201200074I, TO#5); National Society of Genetic C ­ ounselors (unnumbered contract); Northrop Grumman Health IT (unnumbered contract); ­ Office of Rare Diseases Research (Contract No. N01-OD-4-2139, TO#275); Pfizer Inc. (unnumbered contract); and PhRMA (unnumbered contract). The views presented in this publication do not necessarily reflect the views of the organizations or agencies that provided support for the activity. International Standard Book Number-13:  978-0-309-29821-6 International Standard Book Number-10:  0-309-29821-0 Additional copies of this workshop summary are available for sale from the National A ­ cademies 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 2014 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). 2014. Refining processes for the co-­ evelopment d of genome-based therapeutics and companion diagnostic tests: 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. C. D. Mote, Jr., 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 Coun- cil is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. C. D. Mote, Jr., are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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PLANNING COMMITTEE1 Debra G. B. Leonard (Co-Chair), Former 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, Technology Innovation and Strategy, Veridex, LLC, Raritan, NJ PHILLIP J. BROOKS, Health Scientist Administrator, Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health, 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 VICTORIA M. PRATT, Former 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 DEREK T. SCHOLES, Chief, Policy and Program Analysis Branch, National Human Genome Research Institute, Bethesda, MD PAMELA SWATKOWSKI, Director, Regulatory Affairs, Abbott Molecular, Inc., Des Plaines, IL Fellows Sean P. david, James C. Puffer, M.D./American Board of Family Medicine Fellow samuel G. johnson, American Association of Colleges of Pharmacy/ American College of Clinical Pharmacy Anniversary Fellow IOM Staff ADAM C. BERGER, Project Director TONIA E. DICKERSON, Senior Program Assistant Andrew M. Pope, Director, Board on Health Sciences Policy 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 (Co-Chair until June 2013), Professor and Chair, Department of Bioethics and Humanities, University of Washington, Seattle Geoffrey Ginsburg (Co-Chair from June 2013), Director, Center for Genomic Medicine, Institute for Genomic Sciences and Policy, Duke University, Durham, NC Sharon Terry (Co-Chair), President and Chief Executive Officer, Genetic Alliance, Washington, DC 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, Formerly Executive Vice President, American Society of Human Genetics, Bethesda, MD PAMELA BRADLEY, Staff Fellow, Personalized Medicine Staff, Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, MD PHILIP J. BROOKS, Health Scientist Administrator, Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD ANN CASHION, Acting Scientific Director, National Institute of Nursing Research, National Institutes of Health, Bethesda, MD C. THOMAS CASKEY, Professor, Baylor College of Medicine, Houston, TX SARA COPELAND, Former Acting Chief, Genetic Services Branch, Health Resources and Services Administration, Rockville, 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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ROBERT B. DARNELL, President and Scientific Director, New York Genome Center; Investigator, Howard Hughes Medical Institute, Heilbrunn Cancer Professor and Senior Physician, Head, Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, NY MICHAEL J. DOUGHERTY, Director of Education, American Society of Human Genetics, Bethesda, MD VICTOR DZAU, President and Chief Executive Officer, Duke University Health System; Chancellor for Health Affairs, Duke University, Durham, NC W. GREGORY FEERO, Contributing Editor, Journal of the American Medical Association, Chicago, IL ANDREW N. FREEDMAN, Branch Chief, Clinical and Translational Epidemiology Branch, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, MD JENNIFER L. HALL, Representative of the International Society for Cardiovascular Translational Research; Associate Professor of Medicine, University of Minnesota, Minneapolis Richard J. Hodes, Director, National Institute on Aging, Bethesda, MD Sharon Kardia, Professor and Chair of Epidemiology; Director, Public Health Genetics Program; Director, Life Science and Society Program; Codirector, Center for Public Health and Community Genomics, University of Michigan School of Public Health, Ann Arbor Mohamed Khan, Representative of the American Medical Association; Leader of Radiation Oncology, Vancouver Cancer Centre, BC Cancer Agency, Vancouver, British Columbia, Canada Muin Khoury, Director, National Office of Public Health Genomics, Centers for Disease Control and Prevention, Atlanta, GA GABRIELA LAVEZZARI, Assistant Vice President, Scientific Affairs, PhRMA, Washington, DC Thomas Lehner, Director, Office of Genomics Research Coordination, National Institute of Mental Health, Bethesda, MD Debra G. B. Leonard, Representative of the College of American Pathologists; Professor and Chair of Pathology and Physician Leader of Pathology and Laboratory Medicine, Fletcher Allen Health Care, University of Vermont College of Medicine, University of Vermont, Burlington MICHELE A. LLOYD-PURYEAR, Representative of the Office of Rare Diseases Research; Former Senior Medical and Scientific Advisor, National Institute of Child Health & Human Development, Bethesda, MD TERI A. MANOLIO, Director, Division of Genomic Medicine, National Human Genome Research Institute, Rockville, MD viii

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ELIZABETH MANSFIELD, Director of the Personalized Medicine Staff, Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, MD KATHRYN McLAUGHLIN, Program Officer, National Hemophilia Program, Genetic Services Branch, Health Resources and Services Administration, Rockville, MD KELLY McVEARRY, Former Senior Scientific Advisor, Health Solutions, Northrop Grumman Information Systems, Rockville, MD GARRY NEIL, Former 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 Olufunmilayo F. olopade, Walter L. Palmer Distinguished Service Professor of Medicine; Director, Center for Clinical Cancer Genetics; Associate Dean for Global Health, The University of Chicago, IL MICHELLE A. PENNY, Senior Director, Translational Medicine Group, Eli Lilly and Company, Indianapolis, IN AIDAN POWER, Vice President and Head PharmaTx Precision Medicine, Pfizer Inc., Groton, CT VICTORIA M. PRATT, Representative of the Association for Molecular Pathology; Associate Professor of Clinical, Medical and Molecular Genetics and Director, Pharmacogenomics Diagnostic Laboratory, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis ronald przygodzki, Associate Director for Genomic Medicine and Acting Director of Biomedical Laboratory Research and Development, Department of Veterans Affairs, Washington, DC 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, Chief, Genetic Services Branch, Division of Services for Children with Special Needs, Maternal and Child Health Bureau, Rockville, MD ix

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SAM SHEKAR, Chief Medical Officer, Health IT Program, Northrop Grumman Information Systems, McLean, VA KATHERINE JOHANSEN TABER, Senior Scientist, Genetics and Molecular Medicine, American Medical Association, Chicago, IL David Veenstra, Professor, Pharmaceutical Outcomes Research and Policy Program, Department of Pharmacy, University of Washington, Seattle 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, Defense Advanced Research Projects Agency/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 JANET K. WILLIAMS, Representative of the American Academy of Nursing; Professor of Nursing, University of Iowa College of Nursing, Iowa City Fellows Sean P. david, James C. Puffer, M.D./American Board of Family Medicine Fellow SAMUEL G. JOHNSON, American Association of Colleges of Pharmacy/ American College of Clinical Pharmacy Anniversary Fellow IOM Staff ADAM C. BERGER, Project Director SARAH H. BEACHY, Associate Program Officer TONIA E. DICKERSON, Senior Program Assistant (until January 2014) MEREDITH HACKMANN, Senior Program Assistant (from January 2014) Board on Health Sciences Policy Staff Andrew M. Pope, Director DONNA RANDALL, Administrative Assistant x

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Reviewers This workshop summary 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 workshop summary as sound as possible and to ensure that the workshop summary meets institutional standards for objectivity, evidence, and respon- siveness 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 workshop summary: Joanne Armstrong, Aetna Walter H. Koch, Roche Molecular Systems, Inc. Kenneth Offit, Department of Human Genetics, Memorial Sloan- Kettering Cancer Center Sheila D. Walcoff, Goldbug Strategies LLC Although the reviewers listed above have provided many constructive comments and suggestions, they did not see the final draft of the work- shop summary before its release. The review of this workshop summary was overseen by Harold Fallon. Appointed by the Institute of Medicine, he was responsible for making certain that an independent examination of this workshop summary was carried out in accordance with institu- tional procedures and that all review comments were carefully considered. Responsibility for the final content of this workshop summary rests entirely with the rapporteurs 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 Refining Processes for the Co-­ evelopment D of Genome-Based Therapeutics and Companion Diagnostic Tests and to the development of the workshop summary report. Federal sponsors are the 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 Insti- tute; National Institute of Mental Health; National Institute of Nursing Research; National Institute on Aging; and Office of Rare Diseases Research. Nonfederal sponsorship was provided by the American Academy of Nurs- ing; American College of Medical Genetics and Genomics; American Heart Association; American Medical Association; American Society of Human Genetics; Association for Molecular Pathology; Blue Cross and Blue Shield Association; College of American Pathologists; Eli Lilly and Company; Genetic Alliance; International Society for Cardiovascular Translational ­ Research; Johnson & Johnson; The Kaiser Permanente Program Offices ­ Community Benefit II at the East Bay Community Foundation; Life Tech- nologies; National Coalition for Health Professional Education in Genetics; National Society of Genetic Counselors; Northrop Grumman Health IT; Pfizer Inc.; and PhRMA. The Roundtable wishes to express its gratitude to the expert speakers ­ whose presentations helped outline the challenges in as well as the oppor- tunities to co-developing genomic-based therapeutics and companion diag- xiii

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xiv ACKNOWLEDGMENTS nostic 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.

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Contents ABBREVIATIONS AND ACRONYMS xix 1 INTRODUCTION 1 Workshop Themes, 4 2 REGULATORY PERSPECTIVES 7 Overview of Co-Development and Companion Diagnostic Policy, 8 Understanding Co-Development, 12 Next-Generation Sequencing, 15 3 PERSPECTIVES FROM PATIENTS, PROVIDERS, AND LABORATORY REPRESENTATIVES 19 Focus on Patients, 20 Use of Tests in Oncology, 21 Challenges for Clinical Laboratories, 22 Implications of Next-Generation Sequencing, 24 Direct-to-Consumer Testing, 27 4 PERSPECTIVES OF DIAGNOSTIC TEST AND PHARMACEUTICAL DEVELOPERS 29 Developing the Evidence for Validity and Utility, 30 Leveling the Playing Field, 32 Areas for Consideration, 33 xv

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xvi CONTENTS Considerations for IVDs and LDTs, 34 Test Performance in Use, 36 Test Registries, 39 In-House Diagnostic Units, 39 5 PERSPECTIVES OF PAYERS AND REGULATORS 41 Allow the Current System to Work, 42 Evaluating Two Systems, 42 Test Pricing, 45 Reimbursement of Next-Generation Sequencing, 48 6 CONCLUDING OBSERVATIONS 49 Coordinating Regulatory Pathways, 49 Generating Evidence for Test Value, 52 Value-Based Pricing, 53 Next-Generation Sequencing, 54 REFERENCES 55 APPENDIXES A WORKSHOP AGENDA 57 B SPEAKER BIOGRAPHICAL SKETCHES 63 C STATEMENT OF TASK 75 D REGISTERED ATTENDEES 77

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Boxes, Figures, and Tables BOXES 1-1 Overview of Companion Diagnostic Test Regulation, 3 1-2 Concerns Identified by Individual Stakeholders and Potential Solutions to the Current Co-Development Process, 5 6-1 Possible Solutions for Co-Development Challenges Suggested by Individual Speakers, 50 6-2 Goals for Companion Diagnostics Identified by Individual Speakers, 51 FIGURES 2-1 Integrating regulatory agencies and payers for product development, 16 4-1 Proposed payment model for connecting the costs of co-developed companion diagnostics to those of the related drug, 37 TABLES 2-1 FDA-Approved Companion Diagnostic Devices, 9 5-1 A Perspective on Current Requirements for IVDs and LDTs, 43 5-2 A Perspective on Possible Solutions from AdvaMed and ACLA, 44 xvii

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Abbreviations and Acronyms ACLA American Clinical Laboratory Association ACO accountable care organization AdvaMed Advanced Medical Technology Association ASCO American Society of Clinical Oncology CAP College of American Pathologists CISH chromogenic in situ hybridization CLIA Clinical Laboratory Improvement Amendments CMS Centers for Medicare & Medicaid Services EGFR epidermal growth factor receptor EQA external quality assurance FDA U.S. Food and Drug Administration FISH fluorescence in situ hybridization HER2 human epidermal growth factor receptor 2 IHC immunohistochemistry IOM Institute of Medicine IVD in vitro diagnostic LDT laboratory-developed test xix

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xx ABBREVIATIONS AND ACRONYMS NGS next-generation sequencing NSCLC non-small-cell lung cancer PCR polymerase chain reaction RCT randomized controlled trial