GENOME-BASED THERAPEUTICS

Targeted Drug Discovery and Development

WORKSHOP SUMMARY

Adam C. Berger and Steve Olson, 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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Adam C. Berger and Steve Olson, 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 Society of Human Genetics (unnumbered contract); Blue Cross and Blue Shield Association (unnumbered contract); Centers for Disease Control and Preven- tion (Contract No. 200-2011-38807); College of American Pathologists (unnumbered con- tract); 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); Johnson & Johnson (unnumbered contract); Kaiser Permanente Program Offices Community Benefit II at the East Bay Com- munity 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 necessarily reflect the views of the organizations or agencies that provided support for the project. International Standard Book Number-13: 978-0-309-26024-4 International Standard Book Number-10: 0-309-26024-8 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 therapeutics: T argeted drug discovery and development: Workshop summary. Washington, DC: The National Acad- emies 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 GEOFFREY GINSBURG (Chair), Director, Center for Genomic Medicine, Institute for Genomic Sciences and Policy, Duke University, Durham, NC THOMAS LEHNER, Director, Office of Genomics Research Coordination, National Institute of Mental Health, Bethesda, MD GARRY NEIL, Corporate Vice President, Corporate Office of Science and Technology, Johnson & Johnson, New Brunswick, NJ 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 ALLEN D. ROSES, President and Chief Operating Officer, Cabernet, Shiraz and Zinfandel Pharmaceuticals; and JeffersonPilot 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 SHARON TERRY, President and Chief Executive Officer, Genetic Alliance, Washington, DC 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 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), Professor and Chair, Department of Bioethics and Humanities, University of Washington, Seattle 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, 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 VICTOR DZAU, President and Chief Executive Officer, Duke University Health System; Chancellor for Health Affairs, Duke University, Durham, NC 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 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 and Human Development 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 JeffersonPilot 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 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, 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: Jeffrey A. Bluestone, Executive Vice Chancellor and Provost, University of California, San Francisco Walter M. Capone, Chief Operating Officer, Multiple Myeloma Research Foundation, Norwalk, CT Steven E. Hyman, Harvard Distinguished Service Professor; P rofessor of Stem Cell and Regenerative Biology, The Broad Institute, Cambridge, MA Gary Palmer, Senior Vice President, Medical Affairs and Commercial Development, Foundation Medicine, Inc., Cambridge, MA 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 Melvin Worth. xi

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xiiREVIEWERS 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 comments 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 plan- ning and conduct of the workshop New Paradigms in Drug Discovery: How Genomic Data Are Being Used to Revolutionize the Drug Discovery and Development Process and the development of the workshop summary report titled Genome-Based Therapeutics: Targeted Drug Discovery and Develop- ment. Federal sponsors are the Centers for Disease Control and Preven- tion; 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 on Aging; and Office of Rare Diseases Research. Nonfederal sponsorship was provided by the American College of Medical Genetics and Genomics; the Ameri- can Heart Association; the American Medical Association; the American Society of Human Genetics; the Blue Cross and Blue Shield Association; the College of American Pathologists; Eli Lilly and Company; the Genetic Alliance; Johnson & Johnson; the Kaiser Permanente Program Offices Com- munity Benefit II at the East Bay Community Foundation; Life Technologies; the National Coalition for Health Professional Education in Genetics; the 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 in as well as the opportu- nities for genomics-guided strategies for drug development. 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 work- shop and the resulting summary. xiii

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Contents ABBREVIATIONS AND ACRONYMS xix 1INTRODUCTION 1 Structure of the Report, 2 2 THE CURRENT LANDSCAPE 5 Great Expectations, 6 Current Use and Potential, 6 The Economic Challenge, 12 Challenges for Genomic-Based Approaches, 14 3 CASE STUDIES 17 The Development of Crizotinib for Treatment of Non-Small-Cell Lung Cancer, 18 Use of Genetics to Inform Drug Development for the Treatment of Schizophrenia, 22 A Genetic Approach to the Treatment of Cystic Fibrosis, 24 4 EMERGING TECHNOLOGIES IN DRUG DEVELOPMENT 29 Large-Scale Whole-Genome Sequencing, 30 The Value of Clinical Next-Generation Sequencing to Drug Developers, 32 The Uses of Genomic Information, 34 xv

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xviCONTENTS 5 EVOLVING PARADIGMS 37 Foundations and Drug Development: An Example, 38 Genomics and Regulatory Science, 39 Pharmacy Benefit Management and Pharmacogenomics, 41 Repurposing of Drugs, 44 6 FORGING COLLABORATIVE STRATEGIES FOR THE DEVELOPMENT OF PERSONALIZED MEDICINE 47 The Need for Collaboration, 48 FDA Initiatives, 49 NCATS Initiatives, 50 Biospecimens and Databases, 51 Reducing Health Disparities, 53 Patient and Physician Education, 54 An Emphasis on the Science, 54 REFERENCES55 APPENDIXES A WORKSHOP AGENDA 59 B SPEAKER BIOGRAPHICAL SKETCHES 65 C STATEMENT OF TASK 81 D REGISTERED ATTENDEES 83

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Table, Figures, and Boxes TABLE 2-1 Pharmacogenomic Biomarkers in Drug Labels, 8 FIGURES 2-1 A number of factors influence the market potential for targeted therapeutics with the prospect of reduced market size leading to increased market share, 11 2-2 The number of new drugs approved per billion dollars spent has declined steadily on a logarithmic scale for more than a half- century, 13 3-1 The development of crizotinib proceeded rapidly from compound identification to target discovery to clinical results to FDA approval, 19 3-2 The development of the diagnostic for ALK alterations also proceeded rapidly from a Phase I laboratory-developed test to PMA approval, 21 3-3 Administration of ivacaftor produced a rapid and sustained improvement in forced expiratory volume (FEV), which is a measure of lung function, 25 3-4 Approximately 5 percent of people with CFTR mutations have gating mutations such as G551D, 26 xvii

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xviii TABLE, FIGURES, AND BOXES 5-1 In the current paradigm of drug discovery and development, the approval of a drug rigidly separates the domains of regulators and payers, 42 5-2 In the future, the responsibilities of regulators and payers could overlap, resulting in a dynamic interplay between evidence generation and drug approval, 43 BOXES 1-1 Workshop Objectives, 2 2-1 Definition, 10

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Abbreviations and Acronyms ALK anaplastic lymphoma kinase CDER Center for Drug Evaluation and Research CDRH Center for Devices and Radiological Health CFTR cystic fibrosis transmembrane conductance regulator CLL chronic lymphocytic leukemia CMS Centers for Medicare & Medicaid Services DARPA Defense Advanced Research Projects Agency FDA U.S. Food and Drug Administration FEV forced expiratory volume FFPE formalin-fixed paraffin-embedded FISH fluorescence in situ hybridization GWAS genome-wide association studies IUO investigational use only MMRC Multiple Myeloma Research Consortium MMRF Multiple Myeloma Research Foundation NCATS National Center for Advancing Translational Sciences NIH National Institutes of Health NPC NCATS Pharmaceutical Collection xix

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xx ABBREVIATIONS AND ACRONYMS NSCLC non-small-cell lung cancer PwCPricewaterhouseCoopers SNP single nucleotide polymorphism