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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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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-
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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.
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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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Upon the authority of the charter granted to it by the Congress in 1863, the Acad-
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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
