BIOMARKER TESTS
FOR MOLECULARLY
TARGETED THERAPIES
Key to Unlocking Precision Medicine
Committee on Policy Issues in the Clinical Development and Use of
Biomarkers for Molecularly Targeted Therapies
Laurene A. Graig, Jonathan K. Phillips, and Harold L. Moses, Editors
Board on Health Care Services
Institute of Medicine
THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu
THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001
This study was supported by Contracts 200-2011-38807,TO#27 (Centers for Disease Control and Prevention), 185616 (Janssen Diagnostics), HHSN2632012000741 (National Cancer Institute), NGC19399 (Novartis), and OPP-3028.0 (Susan G. Komen). The study was also supported by the American Society for Radiation Oncology, American Society of Clinical Oncology, Breast Cancer Research Foundation, College of American Pathologists, Gilead Sciences, Inc., Pfizer Inc., and Quest Diagnostics. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.
International Standard Book Number-13: 978-0-309-38134-5
International Standard Book Number-10: 0-309-38134-7
Digital Object Identifier: 10.17226/21860
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.
Copyright 2016 by the National Academy of Sciences. All rights reserved.
Printed in the United States of America
Cover credit: Original art reproduced by permission from Michael Guy.
Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2016. Biomarker tests for molecularly targeted therapies: Key to unlocking precision medicine. Washington, DC: The National Academies Press. doi: 10.17226/21860.
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COMMITTEE ON POLICY ISSUES IN THE CLINICAL DEVELOPMENT AND USE OF BIOMARKERS FOR MOLECULARLY TARGETED THERAPIES
HAROLD L. MOSES (Chair), Ingram Professor of Cancer Research, Professor and Chair, Department of Cancer Biology, Professor of Medicine and Professor of Pathology, Microbiology, and Immunology, Director-Emeritus, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University Medical Center
JOHN M. CARETHERS, John G. Searle Professor and Chair, Department of Internal Medicine, Professor of Human Genetics, University of Michigan Health System
MOLLY COOKE, Professor of Medicine and Director of Education, Global Health Sciences, University of California, San Francisco
GARRET A. FITZGERALD, Professor of Medicine and Pharmacology, McNeil Professor in Translational Medicine and Therapeutics, Chair, Department of Pharmacology, Director, Institute for Translational Medicine & Therapeutics, Perelman School of Medicine, University of Pennsylvania
FELIX W. FRUEH, Executive Partner, Opus Three LLC
DEBRA LEONARD, Professor and Chair of Pathology & Laboratory Medicine, University of Vermont Medical Center, University of Vermont College of Medicine
GARY H. LYMAN, Co-Director, Hutchinson Institute for Cancer Outcomes Research, Public Health Sciences and Clinical Research Divisions, Fred Hutchinson Cancer Research Center, Professor of Medicine, Public Health, and Pharmacy, University of Washington
ROBERT L. NUSSBAUM, Chief Medical Officer, Invitae; Professor Emeritus and Volunteer Clinical Professor, University of California San Francisco School of Medicine
REBECCA D. PENTZ, Professor of Research Ethics, Winship Cancer Institute, Emory University School of Medicine
EDITH A. PEREZ,1 Vice President and Head of the BioOncology Medical Unit, US Medical Affairs, Genentech; Deputy Director at Large, Mayo Clinic Cancer Center, Director, Breast Cancer Translational Genomics Program, Serene M. and Frances C. Durling Professor of Medicine, Division of Hematology/Oncology, Mayo Clinic
JANE PERLMUTTER, Independent Consultant, Gemini Group
___________________
1 Through August 2015.
VICTORIA M. PRATT, Director, Pharmacogenomics Laboratory, Department of Medical and Molecular Genetics, Indiana University School of Medicine
YU SHYR, Harold L. Moses Chair in Cancer Research, Director, Vanderbilt Center for Quantitative Sciences, Director, Vanderbilt Technologies for Advanced Genomics, Analysis and Research Design, Professor, Department of Biostatistics, Biomedical Informatics, Cancer Biology, and Health Policy, Vanderbilt University
SEAN TUNIS, Founder, President and CEO, Center for Medical Technology Policy
TRACEY F. WEISBERG, President, New England Cancer Specialists
Study Staff
LAURENE GRAIG, Study Director
JONATHAN PHILLIPS, Research Associate
SARAH E. DE LEO, Christine Mirzayan Science and Technology Policy Graduate Fellow (from January to July 2015)
NOA NIR, Senior Program Assistant (from April 2015)
CELYNNE BALATBAT, Senior Program Assistant (until April 2015)
PATRICK BURKE, Financial Associate
SHARYL NASS, Director, National Cancer Policy Forum; Director, Board on Health Care Services
ADAM C. BERGER, Director, Roundtable on Translating Genomic-Based Research for Health (until August 2015)
ANDREW M. POPE, Director, Board on Health Sciences Policy
Reviewers
This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. 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:
JAMES BURNS, Sanofi
PAMELA B. DAVIS, Case Western Reserve University School of Medicine
NITA A. FARAHANY, Duke University
JOE GRAY, Oregon Health and Science University
ROBERT GREEN, Flatiron Health, Inc.
JAY L. HESS, Indiana University
LOUIS JACQUES, ADVI Consulting
LARRY KESSLER, University of Washington
FEDERICO A. MONZON, Castle Biosciences
TUDOR OPREA, University of New Mexico
JOHN PFEIFER, Washington University School of Medicine in St. Louis
ELDA RAILEY, Research Advocacy Network
SCOTT RAMSEY, Fred Hutchinson Cancer Research Center
CHARLES SAWYERS, Memorial Sloan Kettering Cancer Center
HAROLD VARMUS, Weill Cornell Medical College
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 LESLIE Z. BENET, University of California, San Francisco, and HUDA AKIL, University of Michigan. 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.
Acknowledgments
The committee is grateful to many individuals who provided valuable input and information for the study, either through formal presentations or through informal communication with study staff and committee members:
Amy Abernethy, M.D., Ph.D., Flatiron Health
Samuel Aronson, M.A., Partners Healthcare
Robert Califf, M.D., Food and Drug Administration
Brian Carey, J.D., Foley Hoag, LLP
Joseph Chin, M.D., M.S., Centers for Medicare & Medicaid Services
Jeff Chodakewitz, M.D., Vertex Pharmaceuticals
Stephen Friend, M.D., Ph.D., Sage Bionetworks
Sarah Garcia, Ph.D., Personalis, Inc.
Levi Garraway, M.D., Ph.D., Harvard Medical School
Curtis Hanson, M.D., Mayo Clinic
Daniel F. Hayes, M.D., University of Michigan Comprehensive Cancer Center
Jonathan W. Heusel, M.D., Ph.D., Washington University School of Medicine
Clifford Hudis, M.D., Memorial Sloan Kettering Cancer Center
Louis Jacques, M.D., ADVI Consulting
Elaine Jeter, M.D., Palmetto GBA
Simon Mallal, M.D., Vanderbilt University Medical Center
Elizabeth Mansfield, Ph.D., Food and Drug Administration
Robert McDonough, M.D., Aetna
Laurence Meyer, M.D., Ph.D., University of Utah
Lincoln Nadauld, M.D., Intermountain Healthcare
Lee Newcomer, M.D., M.H.A., UnitedHealthcare
Marisa Papaluca, Ph.D., European Medicines Agency
Sharon Plon, M.D., Ph.D., Baylor College of Medicine
Paul Radensky, M.D., McDermott, Will & Emory
Scott Ramsey, M.D., Ph.D., Fred Hutchinson Cancer Research Center
Alan Rosenberg, M.D., Anthem
William Stead, M.D., Vanderbilt University School of Medicine
Shawn Sweeney, Ph.D., American Association for Cancer Research
Suzanne Topalian, M.D., Johns Hopkins Medicine
John Wagner, M.D., Ph.D., Takeda Pharmaceuticals
Sheila D. Walcoff, J.D., Goldbug Strategies, LLC
Catherine A. Wicklund, M.S., CGC, Northwestern University Feinberg School of Medicine
Robert Wildin, M.D., National Institutes of Health
Marc Williams, M.D., Geisinger Health System
Janet Woodcock, M.D., Food and Drug Administration
In addition, we thank the individuals who spoke at the November 2014 National Cancer Policy Forum workshop Policy Issues in the Development and Adoption of Biomarkers for Molecularly Targeted Cancer Therapies. Workshop presentations and discussions informed committee deliberations. Speakers included:
Garnet Anderson, Ph.D., Fred Hutchinson Cancer Research Center
Dane Dickson, M.D., Palmetto GBA, Teton Cancer Institute
David Eberhard, M.D., Ph.D., University of North Carolina at Chapel Hill
Bill Gradishar, M.D., Northwestern University
Neil Hayes, M.D., M.S., M.P.H., University of North Carolina at Chapel Hill
Roy Herbst, M.D., Ph.D., Yale University
Matthias Holdhoff, M.D., Ph.D., Johns Hopkins University
Bruce Johnson, M.D., Dana-Farber Cancer Institute
Mia Levy, M.D., Ph.D., Vanderbilt University Medical Center
David Litwack, Ph.D., Food and Drug Administration
Patricia Lo Russo, D.O., Yale University
Karen Long, B.S., Abbott Molecular
Jennifer Malin, M.D., Ph.D., Wellpoint
Anne-Marie Martin, Ph.D., GlaxoSmithKline
Donna Messner, Ph.D., Center for Medical Technology Policy
Federico Monzon, M.D., Invitae
Kathryn Phillips, Ph.D., University of California, San Francisco
Richard Schilsky, M.D., American Society of Clinical Oncology
Adrian Senderowicz, M.D., Ignyta, Inc.
Lilian Siu, M.D., Princess Margaret Hospital, Ontario Cancer Institute
David Solit, M.D., Memorial Sloan Kettering Cancer Center
Sean Tunis, M.D., M.Sc., Center for Medical Technology Policy
Mickey Williams, Ph.D., National Cancer Institute
Funding for this study was provided by the American Society for Radiation Oncology, American Society of Clinical Oncology, Breast Cancer Research Foundation, Centers for Disease Control and Prevention, College of American Pathologists, Gilead Sciences, Janssen Diagnostics, National Cancer Institute, Novartis, Pfizer Inc., Quest Diagnostics, and Susan G. Komen. The committee appreciates the support of these sponsors for the development of this study and report.
Many individuals within the National Academies of Sciences, Engineering, and Medicine were helpful to the study staff. We would like to thank Erin Balogh, Clyde Behney, Jill Eden, Chelsea Frakes, Greta Gorman, Ellen Kimmel, Tracy Lustig, Fariha Mahmud, Sharyl Nass, Bettina Ritter, Patti Simon, Mark Stewart, and Jennifer Walsh.
Finally, we would also like to thank Laura Penny for her copyediting and Ian Graig for his assistance with report graphics.
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3 SUPPORTIVE POLICY ENVIRONMENT FOR BIOMARKER TESTS FOR MOLECULARLY TARGETED THERAPIES
Evidentiary Standards of Clinical Utility
Creating a Supportive Policy Environment for Biomarker Tests for Molecularly Targeted Therapies
4 SUPPORTING DATA INFRASTRUCTURE FOR BIOMARKER TESTS FOR MOLECULARLY TARGETED THERAPIES
5 PROCESSES TO IMPROVE PATIENT CARE
Current Challenges in Test Result Interpretation
Equity in Access to Testing and Expertise
Specimen Acquisition and Quality
A COMMITTEE MEMBER AND STAFF BIOGRAPHIES
B CODING: PAYMENT INFRASTRUCTURE FOR BIOMARKER TESTS FOR MOLECULARLY TARGETED THERAPIES
Boxes, Figures, and Tables
BOXES
S-1 Goals for Advancing Appropriate Use of Biomarker Tests for Molecularly Targeted Therapies
1-1 Precision Medicine Defined
1-3 Precision Medicine Initiative
1-4 Evolving Evidence for Biomarker Tests for Molecularly Targeted Therapies
2-1 At a Glance: Selected Examples of Learning Health Care Systems
2-2 Characteristics of a Learning Health Care System
3-1 Defining Validity and Utility of Biomarker Tests for Molecularly Targeted Therapies
3-2 Regulatory Pathways for Medical Devices
3-3 Selected Stakeholder Perspectives on FDA Draft Guidance on LDT Oversight
4-1 Pilot Projects Integrating Electronic Health Records (EHRs) and Genomic Data
4-2 Examples of Clinical Trials of Biomarker Test-Driven Molecularly Targeted Therapy
4-5 Comparative Effectiveness Research
5-1 Pharmacogenomic Biomarker Tests
5-3 Biomedical Imaging and Radiation Therapy
5-4 Advertising and Marketing Claims
FIGURES
S-1 Rapid learning system for biomarker tests for molecularly targeted therapies
S-2 Interrelationship of components of rapid learning system for biomarker tests
S-3 Overview of responsibility for implementation of committee recommendations
S-4 FDA–CMS Integrated Review Process
1-2 Recommended development and evaluation process for omics-based tests
2-1 Rapid learning system for biomarker tests for molecularly targeted therapies
3-1 Policy issues at the intersection of multiple health care stakeholders’ interests
3-2 ACCE Model process for evaluating genetic tests
3-3 FDA–CMS Integrated Review Process
3-4a Mock label for a biomarker test directing molecularly targeted therapy for leukemia
3-4b Mock label for a biomarker test directing molecularly targeted therapy for cystic fibrosis
TABLES
1-1 Clinical Uses of Biomarkers
3-1 Examples of Study Designs to Assess the Clinical Utility of a Biomarker Test
4-1 Examples of Web-Based Resources to Assist Patients with Shared Decision Making
4-2 Existing Data Resources for Assessing Clinical Significance of Biomarkers
5-1 IOM Standards for Development of Trustworthy CPGs
5-2 NCCN Guidelines for Clinical Use of Predictive Biomarker Tests in Common Cancers
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Acronyms
| AABB |
American Association of Blood Banks |
| AACR |
American Association for Cancer Research |
| AAFP |
American Academy of Family Physicians |
| ABL1 |
Abelson murine leukemia viral oncogene homolog 1 |
| ABMS |
American Board of Medical Specialties |
| ACC |
American College of Cardiology |
| ACCE |
analytic validity, clinical validity, clinical utility, and ethical/legal/social implications |
| ACGME |
Accreditation Council for Graduate Medical Education |
| ACLA |
American Clinical Laboratory Association |
| ACMG |
American College of Medical Genetics and Genomics |
| ACP |
American College of Physicians |
| ADLT |
advanced diagnostic laboratory test |
| AHA |
American Hospital Association; American Heart Association |
| AHLA |
American Health Lawyers Association |
| AHRQ |
Agency for Healthcare Research & Quality |
| ALK |
anaplastic lymphoma kinase |
| AMA |
American Medical Association |
| AMIA |
American Medical Informatics Association |
| AMP |
Association for Molecular Pathology |
| ASCO |
American Society of Clinical Oncology |
| ASCP |
American Society for Clinical Pathology |
| ASTRO |
American Society for Radiation Oncology |
| ATA |
American Telemedicine Association |
| AV |
analytic validity |
| BCBSA |
Blue Cross and Blue Shield Association |
| BCR |
breakpoint cluster region |
| BRAF |
B-RAF proto-oncogene, serine/threonine kinase |
| BRCA |
breast cancer susceptibility gene |
| CancerLinQ |
Cancer Learning Intelligence Network for Quality |
| CAP |
College of American Pathologists |
| CCHPCA |
Center for Connected Health Policy |
| CDC |
Centers for Disease Control and Prevention |
| CDD |
coverage with data development |
| CDE |
common data element |
| CDER |
Center for Drug Evaluation and Research |
| CDRH |
Center for Devices and Radiological Health |
| CDSS |
clinical decision support system |
| CE |
continuing education |
| CED |
coverage with evidence development |
| CER |
comparative effectiveness research |
| CEU |
Continuing Education Unit |
| CF |
cystic fibrosis |
| CFTR |
cystic fibrosis transmembrane conductance regulator |
| CI |
confidence interval |
| CLEP |
Clinical Laboratory Evaluation Program |
| CLFS |
Clinical Laboratory Fee Schedule |
| CLIA |
Clinical Laboratory Improvement Amendments of 1988 |
| CLIAC |
Clinical Laboratory Improvement Advisory Committee |
| CME |
Continuing Medical Education |
| CMS |
Centers for Medicare & Medicaid Services |
| CMTP |
Center for Medical Technology Policy |
| COI |
conflict of interest |
| COLA |
Commission on Office Laboratory Accreditation |
| COSMIC |
Catalogue of Somatic Mutations in Cancer |
| CPG |
clinical practice guideline |
| CPT® |
Current Procedural Terminology |
| CU |
clinical utility |
| CV |
clinical validity |
| DNA |
deoxyribonucleic acid |
| DoD |
Department of Defense |
| DTWG |
Diagnostic Test Working Group |
| EGAPP |
Evaluation of Genomic Applications in Practice and Prevention |
| EGFR |
epidermal growth factor receptor |
| EHR |
electronic health record |
| eMERGE |
Electronic Medical Records and Genomics |
| ER |
estrogen receptor |
| FACT |
Foundation for the Accreditation of Cellular Therapy |
| FAERS |
FDA’s Adverse Event Reporting System |
| FDA |
Food and Drug Administration |
| FDCA |
Federal Food, Drug, and Cosmetic Act |
| FISH |
fluorescence in situ hybridization |
| FTC |
Federal Trade Commission |
| GA4GH |
Global Alliance for Genomics and Health |
| GAO |
Government Accountability Office |
| GDG |
guideline developing group |
| GENIE |
Genomics Evidence Neoplasia Information Exchange |
| GINA |
Genetic Information Nondiscrimination Act of 2008 |
| GPC |
Green Park Collaborative |
| GTR |
Genetic Testing Registry |
| GWAS |
genome-wide association study |
| HCPCS |
Healthcare Common Procedure Coding System |
| HELP |
Senate Committee on Health, Education, Labor & Pensions |
| HER2 |
human epidermal growth factor receptor 2 |
| HGVS |
Human Genome Variation Society |
| HHS |
Department of Health and Human Services |
| HIV/AIDS |
human immunodeficiency virus/acquired immune deficiency syndrome |
| HLA |
human leukocyte antigen |
| HMO |
health maintenance organization |
| HNSCC |
head and neck squamous cell carcinoma |
| HPV |
human papillomavirus |
| HRSA |
Health Resources and Services Administration |
| ICD |
International Classification of Diseases |
| IHC |
immunohistochemistry |
| IOM |
Institute of Medicine |
| ISPOR |
International Society for Pharmacoeconomics and Outcomes Research |
| IT |
information technology |
| IVCT |
in vitro clinical test |
| IVD |
in vitro diagnostic |
| KRAS |
kirsten rat sarcoma viral oncogene homolog |
| LCD |
local coverage determination |
| LDP |
laboratory-developed procedure |
| LDT |
laboratory-developed test |
| LDTS |
laboratory-developed testing service |
| LIS |
laboratory information system |
| MAC |
Medicare Administrative Contractor |
| MED-C |
Molecular Evidence Development Consortium |
| MedPAC |
Medicare Payment Advisory Commissions |
| MMWR |
Morbidity and Mortality Weekly Report |
| MOC |
Maintenance of Certification |
| MoPath |
Molecular Pathology |
| MVP |
Million Veterans Program |
| NASEM |
The National Academies of Sciences, Engineering, and Medicine |
| NCCN |
National Comprehensive Cancer Network |
| NCD |
national coverage determination |
| NCI |
National Cancer Institute |
| NCPF |
National Cancer Policy Forum |
| NGS |
next-generation sequencing |
| NGTS |
next-generation tumor sequencing |
| NHGRI |
National Human Genome Research Institute |
| NIH |
National Institutes of Health |
| NLM |
National Library of Medicine |
| NLP |
natural language processing |
| NQF |
National Quality Forum |
| NRC |
National Research Council |
| NSCLC |
non-small-cell lung carcinoma |
| NYSDOH |
New York State Department of Health |
| OIG |
Office of the Inspector General |
| ONC |
Office of the National Coordinator for Health Information Technology |
| OSTP |
Office of Science and Technology Policy |
| PAMA |
Protecting Access to Medicare Act of 2014 |
| PBRSA |
performance-based risk-sharing arrangement |
| PCAST |
President’s Council of Advisors on Science and Technology |
| PCORI |
Patient-Centered Outcomes Research Institute |
| PCORNet |
National Patient-Centered Clinical Research Network |
| PCTF |
Payer Communication Task Force |
| PD-1 |
programmed cell death protein 1 |
| PET |
positron emission tomography |
| PFS |
physician fee schedule |
| PGR |
progesterone receptor |
| PGRN |
Pharmacogenomics Research Network |
| PheWAS |
phenome-wide association study |
| PIK3CA |
phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha |
| PMA |
premarket approval |
| PMC |
Personalized Medicine Coalition |
| PMI |
Precision Medicine Initiative |
| PROMIS |
Patient Reported Outcomes Measurement Information System |
| PT |
proficiency testing |
| PTEN |
phosphatase and tensin homolog |
| RCT |
randomized controlled trial |
| RNA |
ribonucleic acid |
| RUSP |
Recommended Uniform Screening Panel |
| SACGHS |
Secretary’s Advisory Committee on Genetics, Health, and Society |
| SACHDNC |
Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children |
| SNOMED CT |
Systematized Nomenclature of Medicine’s Clinical Terms |
| SNP |
single-nucleotide polymorphism |
| TAPUR |
Targeted Agents and Profiling Utilization Registry |
| TCGA |
The Cancer Genome Atlas |
| VA |
Department of Veterans Affairs |
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