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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
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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
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sharing with the National Academy of Sciences the responsibility for advising the
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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-
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The National Research Council was organized by the National Academy of Sci-
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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
