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EVOLUTION OF TRANSLATIONAL
OMICS
Lessons Learned and the Path Forward
Committee on the Review of Omics-Based Tests for
Predicting Patient Outcomes in Clinical Trials
Board on Health Care Services
Board on Health Sciences Policy
Christine M. Micheel, Sharyl J. Nass, and Gilbert S. Omenn, Editors
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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. The members of the committee responsible for the report were chosen for their
special competences and with regard for appropriate balance.
This study was supported by Contract Nos. HHSN261200900003C (National Cancer Insti-
tute); HHSF223201010692P and HHSF22301018T (Food and Drug Administration); and
200-2011-38807 and 200-2005-13434 (Centers for Disease Control and Prevention). This
study was also supported by the U.S. Department of Veterans Affairs, the American Society
for Clinical Pathology, and the College of American Pathologists. Any opinions, findings,
conclusions, or recommendations expressed in this publication are those of the author(s) and
do not necessarily reflect the view of the organizations or agencies that provided support for
this project.
International Standard Book Number 13: 978-0-309-22418-5
International Standard Book Number 10: 0-309-22418-7
Additional copies of this report are available from the National Academies Press, 500 Fifth
Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://
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For more information about the Institute of Medicine, visit the IOM home page at: www.
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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. Evolution of Translational Omics:
Lessons Learned and the Path Forward. 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-
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sharing with the National Academy of Sciences the responsibility for advising the
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ing programs aimed at meeting national needs, encourages education and research,
and recognizes the superior achievements of engineers. Dr. Charles M. Vest 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
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Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively,
of the National Research Council.
www.national-academies.org
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COMMITTEE ON THE REVIEW OF OMICS-BASED TESTS FOR
PREDICTING PATIENT OUTCOMES IN CLINICAL TRIALS
GILBERT S. OMENN (Chair), Professor of Internal Medicine, Human
Genetics and Public Health; Director, University of Michigan Center
for Computational Medicine and Bioinformatics, University of
Michigan Medical School, Ann Arbor
CATHERINE D. DEANGELIS, Professor of Pediatrics, Johns Hopkins
School of Medicine, Professor of Health Policy and Management,
Johns Hopkins School of Public Health, and Editor-in-Chief Emerita,
Journal of the American Medical Association, Baltimore, MD
DAVID L. DEMETS, Professor of Statistics and Biostatistics, University
of Wisconsin, Madison
THOMAS R. FLEMING, Professor of Biostatistics, Statistics, University
of Washington, Seattle
GAIL GELLER, Professor of Medicine, Berman Institute of Bioethics,
Johns Hopkins University, Baltimore, MD
JOE GRAY, Gordon Moore Endowed Chair, Department of Biomedical
Engineering, Center for Spatial Systems Biomedicine, Oregon Health
& Science University Knight Cancer Institute, Portland
DANIEL F. HAYES, Clinical Director of the Breast Oncology Program,
and Stuart B. Padnos Professor of Breast Cancer Research, University
of Michigan Comprehensive Cancer Center, Ann Arbor
I. CRAIG HENDERSON, Adjunct Professor of Medicine, University of
California, San Francisco and Helen Diller Family Comprehensive
Cancer Center
LARRY KESSLER, Professor and Chair, Department of Health Services,
University of Washington School of Public Health, Seattle
STANLEY LAPIDUS, Founder, President, and CEO, SynapDx
Corporation, Southborough, MA
DEBRA G. B. LEONARD, Professor and Vice Chair for Laboratory
Medicine, and Director of the Clinical Laboratories, Weill Medical
College of Cornell University, New York, NY
HAROLD L. MOSES, Director Emeritus, Hortense B. Ingram Professor
of Molecular Oncology, and Professor of Cancer Biology, Medicine,
and Pathology, Vanderbilt-Ingram Cancer Center, Nashville, TN
WILLIAM PAO, Associate Professor of Medicine, Cancer Biology, and
Pathology, Microbiology, Immunology, Ingram Associate Professor of
Cancer Research, Director of the Division of Hematology/Oncology,
and Director of Personalized Cancer Medicine, Vanderbilt University
School of Medicine, Nashville, TN
v
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REBECCA D. PENTZ, Professor of Hematology and Oncology in
Research Ethics, Emory School of Medicine, Atlanta, GA
NATHAN D. PRICE, Associate Professor, Institute for Systems Biology,
Seattle, WA
JOHN QUACKENBUSH, Professor of Computational Biology and
Bioinformatics, Dana-Farber Cancer Institute, Boston, MA
ELDA RAILEY, Cofounder, Research Advocacy Network, Plano, TX
DAVID RANSOHOFF, Professor of Medicine, Clinical Professor of
Epidemiology, University of North Carolina, School of Medicine and
Gillings School of Global Public Health, Chapel Hill
E. ALBERT REECE, Vice President for Medical Affairs, University of
Maryland, and John Z. and Akiko K. Bowers Distinguished Professor
and Dean, University of Maryland School of Medicine, Baltimore
DANIELA M. WITTEN, Assistant Professor of Biostatistics, University
of Washington, Seattle
Staff
CHRISTINE M. MICHEEL, Study Director (through November 2011)
SHARYL J. NASS, Director, National Cancer Policy Forum; Study
Director (from December 2011)
LAURA LEVIT, Program Officer (from June 2011)
ERIN BALOGH, Associate Program Officer
SARAH DOMNITZ, Christine Mirzayan Science and Technology Policy
Graduate Fellow (from August to December 2011)
JULIA E. DOOHER, Christine Mirzayan Science and Technology Policy
Graduate Fellow (from January to May 2011)
NIHARIKA SATHE, Research Assistant (from June 2011)
MICHAEL PARK, Senior Program Assistant
PATRICK BURKE, Financial Associate
ROGER HERDMAN, Director, Board on Health Care Services
ANDREW POPE, Director, Board on Health Sciences Policy
Consultant
JOHN BAILAR, Scholar in Residence
vi
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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 deliberative process. We wish to thank the following
individuals for their review of this report:
Wylie Burke, Professor and Chair, Department of Bioethics and
Humanities, University of Washington
Adam M. Clarke, Founder, MedTran Health Strategies, LLC
Susan S. Ellenberg, Professor of Biostatistics, Associate Dean for Clinical
Research, Perelman School of Medicine, University of Pennsylvania
Charis Eng, ACS Clinical Research Professor, Chair, and Director,
Genomic Medicine Institute, Cleveland Clinic Foundation, Case
Western Reserve University School of Medicine
Marcus Feldman, Professor of Biology, Stanford University
David B. Flannery, Chief of Medical Genetics, Professor of Pediatrics,
Vice Chair for Administration of the Department of Pediatrics,
Georgia Health Sciences University
Stephen Friend, President and CEO, Sage Bionetworks
vii
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viii REVIEWERS
Larry Gold, Chairman and Chief Executive Officer, SomaLogic, Inc.
Steven Goodman, Associate Dean for Clinical and Translational
Research, Professor of Medicine & Health Research and Policy,
Stanford University School of Medicine
Robert Gray, Professor of Biostatistics, Dana Farber Cancer Institute
Stephen Grubbs, Principal Investigator, Delaware Christiana Care
Community Clinical Oncology Program
David Korn, Vice Provost for Research, Professor of Pathology,
Harvard University
Marc Ladanyi, William J. Ruane Chair in Molecular Oncology,
Memorial Sloan-Kettering Cancer Center
Bernard Lo, Professor of Medicine and Director, Program in Medical
Ethics, University of California, San Francisco
David Madigan, Professor of Statistics, Columbia University
Bettie Sue Siler Masters, The Robert A. Welch Distinguished
Professor in Chemistry, University of Texas Health Science Center
at San Antonio
Charles E. Phelps, Provost Emeritus, Professor of Political Science
and of Economics, University of Rochester
Dan Roden, Professor of Medicine, William Stokes Chair in
Experimental Therapeutics, Professor of Pharmacology,
Vanderbilt University Medical Center
Larry Shapiro, Executive Vice Chancellor for Medical Affairs and
Dean, Washington University School of Medicine
Peter Shields, Professor and Chief, Deputy Director, Comprehensive
Cancer Center and Professor, College of Medicine, The Ohio
State University Medical Center
Steve Teutsch, Chief Science Officer, Los Angeles County Public Health
David Wong, Professor of Bioengineering, Director of the Dental
Research Institute, University of California, Los Angeles
Although the reviewers listed above have provided many constructive
comments and suggestions, they were not asked to endorse the conclusions
or recommendations, nor did they see the final draft of the report before
its release. The review of this report was overseen by Kristine Gebbie,
Adjunct Professor, Flinders University School of Nursing and Midwifery
and Lawrence D. Brown, Professor, Department of Statistics, The Wharton
School, University of Pennsylvania. Appointed by the Institute of Medicine
and the National Research Council, they were 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 authoring committee and the institution.
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Acknowledgments
The committee is grateful to many individuals who provided valu-
able input and information for the study, either through formal presenta-
tions or through informal communications with study staff and committee
members:
Patrick Anquetil, SynapDx
Keith Baggerly, MD Anderson Cancer Center
John Bailar, Institute of Medicine
William Barry, Duke University
Robert Becker, Food and Drug Administration
Robert Califf, Duke University
Ned Calonge, The Colorado Trust
Michael Cuffe, Duke University
Jeffrey Drazen, New England Journal of Medicine
John Falletta, Duke University
Geoffrey Ginsburg, Duke University
Alberto Gutierrez, Food and Drug Administration
Scott Henderson, Vermillion
Michael Kelley, Duke University
Katrina Kelner, Translational Medicine and Science
Véronique Kiermer, Nature Publishing
Sally Kornbluth, Duke University
Sumithra Mandrekar, Mayo Clinic
Anne-Marie Mazza, The National Academies
Ross McKinney, Duke University
ix
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x ACKNOWLEDGMENTS
Lisa McShane, National Cancer Institute
Stephen A. Merrill, The National Academies
Mitch Nelles, XDx
Joseph Nevins, Duke University
Nicole Osmer, Nicole Osmer Healthcare Communications
Harold Paz, Pennsylvania State University
Charles Perou, The University of North Carolina at Chapel Hill
Peter Pronovost, Johns Hopkins University
William Sellers, Novartis Institutes for BioMedical Research
Steven Shak, Genomic Health
Richard Simon, National Cancer Institute
Ed Stevens, Pathwork Diagnostics
Susan Su, United States Patent and Trademark Office
Paul Uhlir, The National Academies
Laura van ‘t Veer, Helen Diller Family Comprehensive Cancer Center
Pablo Whaley, United States Patent and Trademark Office
Scott Zeger, Johns Hopkins University
We thank the National Cancer Institute, the Food and Drug Adminis-
tration, the Centers for Disease Control and Prevention, the U.S. Depart-
ment of Veterans Affairs, the American Society for Clinical Pathology, and
the College of American Pathologists for supporting this study.
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Contents
BOXES, FIGURES, AND TABLES xiii
SUMMARY 1
1 INTRODUCTION 17
Origin of the Task, 18
Committee Appointment and Charge, 20
Engagement of Stakeholders and Implementation of the
Recommendations, 29
Organization of the Report, 30
References, 30
2 OMICS-BASED CLINICAL DISCOVERY:
SCIENCE, TECHNOLOGY AND APPLICATIONS 33
Types of Omics Data, 34
Emerging Omics Technologies and Data Analysis
Techniques, 37
Statistics and Bioinformatics Development of Omics-Based
Tests, 41
Completion of the Discovery Phase of Omics-Based Test
Development, 57
Summary and Recommendation, 58
References, 59
xi
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xii CONTENTS
3 BEST PRACTICES FOR OMICS-BASED TEST VALIDATION
PRIOR TO USE FOR PATIENT MANAGEMENT DECISIONS
IN A CLINICAL TRIAL SETTING 65
Background, 68
Test Validation Phase, 70
Preparation for Investigational Use of the Validated Test, 75
Funding for Validation of a Candidate Omics-Based Test in a
CLIA-Certified Clinical Laboratory, 76
Summary and Recommendation, 77
References, 78
4 EVALUATION OF OMICS-BASED TESTS FOR CLINICAL
UTILITY AND USE 79
Background, 79
Evaluation for Clinical Utility and Use Stage, 82
Summary and Recommendation, 101
References, 102
5 RESPONSIBLE PARTIES 105
Intrainstitutional Parties, 107
Funders, 129
FDA, 136
Journals, 140
Summary and Recommendations, 149
References, 153
6 LESSONS FROM THE CASE STUDIES 163
Methods, 164
Lessons Learned from the Case Studies, 168
Concluding Remarks, 179
References, 179
APPENDIXES
A Case Studies 183
B Gene Expression–Based Tests Developed at Duke University
239
and Used in Clinical Trials
C Introduction to Biomarkers 281
D Reporting Guidelines 289
E Committee Member and Staff Biographies 301
F Information Gathering Sessions and Speakers 319
ACRONYMS AND ABBREVIATIONS 323
GLOSSARY 327
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Boxes, Figures, and Tables
BOXES
S-1 Development and Evaluation Process Recommendations, 8
S-2 Recommendations on Appropriate Actions to Ensure Adoption
and Adherence, 10
1-1 Committee Statement of Task, 20
1-2 Important Definitions, 22
2-1 Considerations in Data and Information Sharing, 52
5-1 Themes from the Case Studies for Investigators, 109
5-2 Themes from the Case Studies for Institutions, 116
5-3 Examples of Institutional Oversight Bodies, 119
5-4 Clinical Trial Management Systems (CTMSs), 121
5-5 Themes from the Case Studies for Funders, 131
5-6 Themes from the Case Studies for FDA, 137
5-7 Themes from the Case Studies for Journals, 141
5-8 Lessons from the Banking Industry on Data and Code
Sharing, 145
D-1 Example of a Reporting Guideline Checklist: The REMARK
Checklist, 294
D-2 The EQUATOR Network, 296
xiii
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xiv BOXES, FIGURES, AND TABLES
FIGURES
S-1 Omics-based test development process, 6
1-1 The steps of the biomarker evaluation are interdependent, 27
2-1 Omics-based test development process, highlighting the discovery
phase, 35
3-1 Omics-based test development process, highlighting the test
validation phase, 66
4-1 Omics-based test development process, highlighting the evaluation
for clinical utility and use stage, 80
4-2 Two clinical trial designs in which the test is not used to direct
therapy, 96
4-3 Enrichment design, 99
4-4 Example of a test-guided strategy versus standard of care, 100
4-5 Example of a test-guided strategy versus non-guided strategy with
randomized treatment design, 101
A-1 Venn diagrams illustrating overlap in patient blood samples used
for AlloMap development, 219
TABLES
1-1 Categories of Biomarker Use, 25
1-2 Use of Biomarkers in Clinical Practice, 26
4-1 Examples of Clinical Study Designs for Test Assessment, 88
6-1 Overview of Commercially Available Omics-Based Tests, 165
6-2 Data Availability, 170
6-3 Statistical and Bioinformatics Validation Considerations, 173
6-4 Choice of Trial Designs for Clinical/Biological Validation, 177
A-1 Archival Tissue Used in the Development of Oncotype DX
Computational Model and Gene List, 188
A-2 Clinical/Biological Validation Studies for Oncotype DX, 190
A-3 Clinical/Biological Validation Studies for MammaPrint, 198
A-4 FDA 510(k) Clearances for MammaPrint, 202
A-5 Clinical/Biological Validation Studies for the Tissue of
Origin Test, 207
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xv
BOXES, FIGURES, AND TABLES
A-6 Performance Characteristics for OVA1 Applied to Pre- and
Postmenopausal Subjects Evaluated by Non-Gynecologic
Oncologist Physicians, 212
A-7 Clinical/Biological Validation Studies for AlloMap, 220
B-1 Clinical Trials Related to Duke University Gene Expression–Based
Tests and the Clinical Trials Listed in the Institute of Medicine
Committee’s Statement of Task, 241
B-2 Time Line of Events Surrounding the Duke Gene Expression–Based
Tests, 269
D-1 Reporting Standards Used in Omics Research, 292
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