Cancer Biomarkers

The Promises and Challenges of Improving Detection and Treatment

Committee on Developing Biomarker-Based Tools for Cancer Screening, Diagnosis, and Treatment

Sharyl J. Nass and Harold L. Moses, Editors

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.
www.nap.edu



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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment Cancer Biomarkers The Promises and Challenges of Improving Detection and Treatment Committee on Developing Biomarker-Based Tools for Cancer Screening, Diagnosis, and Treatment Sharyl J. Nass and Harold L. Moses, Editors INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. 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. HHSH25056133, HHSN261200611002C, 200-2005-13434, HHSM-500-2005-00179P, HHSP23320042509XI, and 223-01-2460 between the National Academy of Sciences and the Department of Health and Human Services. 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: 978-0-309-10386-2 (Book) International Standard Book Number 10: 0-309-10386-X (Book) International Standard Book Number 13: 978-0-309-66711-1 (PDF) International Standard Book Number 10: 0-309-66711-9 (PDF) Library of Congress Control Number 2007921549 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2007 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.

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Advising the Nation. Improving Health.

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine 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 Academy 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 engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf 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 Institute 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 Sciences 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 Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment COMMITTEE ON DEVELOPING BIOMARKER-BASED TOOLS FOR CANCER SCREENING, DIAGNOSIS, AND TREATMENT HAROLD L. MOSES, MD (Chair), Professor of Cancer Biology, Medicine, and Pathology, Director Emeritus, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University Medical Center DAVID CARBONE, MD, Professor of Medicine, Hematology-Oncology Division, Vanderbilt University LELAND HARTWELL, PhD, President and Director, Fred Hutchinson Cancer Research Center JUDITH K. HELLERSTEIN, PhD, Associate Professor of Economics, University of Maryland, College Park ROBERT S. MCDONOUGH, MD, JD, Medical Director, Clinical Policy Unit, Aetna DAVID R. PARKINSON, MD, Senior Vice President, Oncology Research and Development, Biogen Idec EDITH A. PEREZ, MD, Director, Cancer Clinical Study Unit, Mayo Clinic SCOTT RAMSEY, MD, PhD, Full Member, Fred Hutchinson Cancer Research Center CHARLES L. SAWYERS, MD, Chairman, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center HOWARD SCHULMAN, PhD, Vice-President, Pharmaceutical Product Development, Inc., Biomarker Discovery Sciences MARGARET R. SPITZ, MD, Chair of Epidemiology, M.D. Anderson Cancer Center Staff SHARYL NASS, PhD, Study Director ALIZA NORWOOD, Research Assistant MARY ANN PRYOR, Senior Program Assistant JULIE WILTSHIRE, Financial Associate

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment 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 NRC’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: Gerard Anderson, PhD, Johns Hopkins Bloomberg School of Public Health Stanley Hefta, PhD, Bristol-Myers Squibb Hedvig Hricak, MD, PhD, Memorial Sloan-Kettering Cancer Center Carolyn D. Jones, JD, MPH, AdvaMed Lawrence A. Loeb, MD, PhD, University of Washington Beverly S. Mitchell, MD, Stanford University Medical Center Scott D. Patterson, PhD, Amgen, Inc. Eric Schadt, PhD, Rosetta Inpharmatics, LLC Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclu-

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment sions or recommendations nor did they see the final draft of the report before its release. The review of this report was overseen by Melvin Worth, MD, Scholar-in-Residence at the Institute of Medicine, and Gilbert S. Omenn, MD, PhD, University of Michigan Medical School. Appointed by the National Research Council and the Institute of Medicine, 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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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment Acknowledgments The Committee is grateful to many individuals who provided valuable input and information for the study, either through formal presentations or through informal communications with study staff and Committee members. In addition to the speakers, moderators, and invited discussants at the IOM workshop on developing biomarkers, as noted in the appendix, contributors to the study include Peter Bach (Centers for Medicare and Medicaid Services), Carol Bigelow (Centers for Disease Control and Prevention), Ellen Feigal (The Critical Path Institute), Arthur Holden (Pharmaceutical Biomedical Research Consortium), Gail Javitt (Center for Genetics and Public Policy), Dan McGowan (SEMATECH Media Relations), Barbara Mittleman (NIH Office of Science Policy), Greg Raab (Raab and Associates, Inc.), Wolf Rogowski (Institute of Health Economics and Health Care Management), Todd Skaar and David Flockhart (Indiana University), Sudhir Srivastava and Donald Johnsey (NCI Cancer Biomarkers Research Group), Sean Tunis (Health Technology Center), Judith Wagner (IOM Scholar in Residence), Sidney Wolfe (Public Citizen’s Health Research Group), and Janet Woodcock (Food and Drug Administration). In addition, Margie Patlak assisted the committee by preparing some written background material on FDA oversight, CLIA, and the evaluation and adoption of clinical diagnostics for the report.

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment Contents     SUMMARY   1      Methods, Tools, and Resources Needed to Discover and Develop Biomarkers,   4      Guidelines, Standards, Oversight, and Incentives Needed for Biomarker Development,   10      Methods and Processes Needed for Clinical Evaluation and Adoption,   14 1   INTRODUCTION   19      Committee Charge,   25      Framework of the Report,   25 2   METHODS, TOOLS, AND RESOURCES NEEDED TO DISCOVER AND DEVELOP BIOMARKERS   29      Overview of the Biomarker Discovery and Development Process,   29      The Need for New, Innovative Technologies,   34      The Importance of Biorepositories,   42      The Role of Consortia,   48      Demonstration Projects to Develop Biomarkers for Drugs Already Approved,   54      The Need for Pathway Biomarkers,   59      The Need for Support of Translational Research Activities,   62      Summary and Conclusions,   64

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment 3   GUIDELINES, STANDARDS, OVERSIGHT, AND INCENTIVES NEEDED FOR BIOMARKER DEVELOPMENT   73      Review of Current FDA Oversight for Biomarker Tests,   73      CMS Oversight of Clinical Laboratory Performance,   79      The Need for Consistency and Transparency,   82      A Special Challenge of Pharmacogenomics—Codeveloping Diagnostic-Therapeutic Combinations,   99      Summary and Conclusions,   106 4   METHODS AND PROCESS NEEDED FOR CLINICAL ADOPTION AND EVALUATION OF BIOMARKER-BASED DIAGNOSTICS   114      The Challenge of Assessing Clinical Value,   115      Evidence for Coverage,   117      Cost-Effectiveness Analysis,   123      Reimbursement,   126      Summary and Conclusions,   130     ACRONYMS AND GLOSSARY   135 APPENDIX   Developing Biomarker-Based Tools for Cancer Screening, Diagnosis, and Treatment: The State of the Science, Evaluation, Implementation, and Economics, Workshop Summary   145

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment Boxes, Figure, and Tables BOXES S-1   Summary of Recommendations to Develop Biomarker-Based Tools for Cancern,   2 1-1   Biomarkers of Hematologic Cancers,   20 2-1   Overview of DARPA,   40 2-2   Examples of Current NCI-Supported Specimen Resources,   42 2-3   The Multiple Myeloma Research Consortium Tissue and Data Banks,   46 2-4   SEMATECH: A Successful Public–Private Partnership in the Semiconductor Industry,   50 2-5   The SNP Consortium,   52 2-6   Critical Path Institute,   54 2-7   Pharmaceutical Biomarker Research Consortium,   56 2-8   Tamoxifen Therapy and the CYP2D6 Gene,   60 3-1   Premarket Approval and Premarket Notification at the FDA,   74 3-2   FDA Regulation of Analyte-Specific Reagents,   76 3-3   Overview of CLIA Regulation of High-and Moderate-Complexity Tests,   80

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Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment 3-4   Examples of Standards and Guidelines for the Development and Use of Biomarkers,   86 3-5   Estrogen Receptor—The Classic Cancer Biomarker,   96 3-6   Herceptin/HercepTest Development and Approval,   98 3-7   EGFR Inhibitors—The Quest for Targeting Biomarkers,   102 4-1   Assessing the Value of OncotypeDX and MammaPrint,   118 FIGURE 2-1   EDRN informatics infrastructure,   44 TABLES 1-1   Use of Cancer Biomarkers in Patient Care,   23 1-2   Use of Biomarkers in Drug Development,   24 2-1   Examples of Biomarker Categories and High-Throughput Methods of Discovery,   30 2-2   Biomarker Validation and Qualification Requires Demonstration of Fitness for a Specified Purpose,   32