ACCELERATING THE DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY
Workshop Summary
Steve Olson, Sally Robinson, and Robert Giffin, Rapporteurs
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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 the American Diabetes Association; the American Society for Microbiology; Amgen, Inc.; the Association of American Medical Colleges; AstraZeneca Pharmaceuticals; Blue Cross Blue Shield Association; the Burroughs Wellcome Fund; Department of Health and Human Services (Contract Nos. N01-OD-4-2139 and 223-01-2460); the Doris Duke Charitable Foundation; Eli Lilly & Co.; Entelos Inc.; Genentech; GlaxoSmithKline; the March of Dimes Foundation; Merck & Co., Inc.; Pfizer Inc.; and UnitedHealth Group. 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.
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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.
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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.
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PLANNING COMMITTEE FOR ASSESSING AND ACCELERATING THE DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY: A WORKSHOP
Robert Califf (Workshop Chair),
Duke University Medical Center, North Carolina
Garret A. FitzGerald,
University of Pennsylvania School of Medicine
Marlene Haffner,
Amgen, Inc., Washington, DC
Ronald L. Krall,
GlaxoSmithKline, Pennsylvania
William B. Mattes,
Critical Path Institute, Maryland
Aidan Power,
Pfizer Inc., Connecticut
Janet Woodcock,
U.S. Food and Drug Administration, Maryland
Study Staff
Robert B. Giffin, Director
Sally Robinson, Program Officer
Andrea Rebholz, Senior Program Assistant
Genea S. Vincent, Senior Program Assistant
Rona Briere, Consulting Editor
FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION1
Gail H. Cassell (Co-Chair),
Eli Lilly and Company, Indiana
Jeffrey M. Drazen (Co-Chair),
New England Journal of Medicine, Massachusetts
Barbara Alving,
National Center for Research Resources, Maryland
Hal Barron,
Genentech, California
Leslie Z. Benet,
University of California, San Francisco
Catherine Bonuccelli,
AstraZeneca Pharmaceuticals, Delaware
Linda Brady,
National Institute of Mental Health, Maryland
Robert M. Califf,
Duke University Medical Center, North Carolina
Scott Campbell,
American Diabetes Association, Virginia
C. Thomas Caskey,
University of Texas-Houston Health Science Center
Peter B. Corr,
Celtic Therapeutics, New York
James H. Doroshow,
National Cancer Institute, Maryland
Paul R. Eisenberg,
Amgen, Inc., California
Garret A. FitzGerald,
University of Pennsylvania School of Medicine
Elaine K. Gallin,
The Doris Duke Charitable Foundation, New York
Steven K. Galson,
Office of the Surgeon General, U.S. Department of Health and Human Services, Maryland
Mikhail Gishizky,
Entelos, Inc., California
Stephen Groft,
National Institutes of Health, Maryland
Edward W. Holmes,
National University of Singapore
Peter K. Honig,
Merck & Co., Inc., Pennsylvania
A. Jacqueline Hunter,
GlaxoSmithKline, United Kingdom
Michael Katz,
March of Dimes Foundation, New York
Jack D. Keene,
Duke University Medical Center, North Carolina
Ronald L. Krall,
GlaxoSmithKline, Pennsylvania
Musa Mayer,
AdvancedBC.org, New York
Mark B. McClellan,
Brookings Institution, Washington, DC
Carol Mimura,
University of California, Berkeley
Amy P. Patterson,
National Institutes of Health, Maryland
Janet Shoemaker,
American Society for Microbiology, Washington, DC
Lana Skirboll,
National Institutes of Health, Maryland
Nancy S. Sung,
Burroughs Wellcome Fund, North Carolina
Irena Tartakovsky,
Association of American Medical Colleges, Washington, DC
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:
Mark Avigan, U.S. Food and Drug Administration, U.S. Department of Health and Human Services
Jacqueline Hunter, GlaxoSmithKline
Neil Kaplowitz, USC Research Center for Liver Diseases, Keck School of Medicine, University of Southern California
Dan M. Roden, Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine
Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the final draft of the report before its release. The review of this report was overseen by Dr. Johanna T. Dwyer, Tufts University School of Medicine & Friedman School of Nutrition Science & Policy, Frances Stern Nutrition Center, Tufts-
New England Medical Center. Appointed by the Institute of Medicine, she 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 authors and the institution.
Preface
Biomarkers are central to the future of medicine. By providing a measure of a biological state, they can indicate normal biological processes, pathogenic processes, or responses to an intervention or perturbation in the environment. They can be used to monitor the on-target and off-target effects of medical interventions, including treatments for disease; they can be used in diagnostic and prognostic tests; and they can define the individuals and populations most likely to respond to therapy. At the broadest level, they can provide insight into biological pathways and networks.
It is also important to recognize that biomarkers have limitations. In isolation, they reveal just one aspect of complex biological systems. Therefore, they may or may not be correlated with clinical outcomes, since other biological systems may override the particular marker being measured. The work needed to understand the relation of a biomarker to either a clinical outcome or a biological system can be enormous. Yet biomarkers are most powerful when they are linked with knowledge about biological systems, with empirical data about diagnostic and therapeutic trials, or with clinical outcomes derived from large populations. The power of modern biology comes from the ability to integrate disparate bases of knowledge, leading to better decisions.
As the cost of developing drugs has risen and the number of new drugs approved for use has fallen, many people have looked to the development of biomarkers as a way to cut costs, enhance safety, and provide a more focused and rational pathway to drug development. Accordingly, greater regulatory emphasis has been placed on the development and use of biomarkers in drug development, which has increased the urgency of accel-
erating preclinical and clinical research on these markers and establishing evidentiary standards for their use. Biomarker advocates tend to emphasize the progress that has been made, while many drug development teams and experts in clinical effectiveness are skeptical. In fact, both perspectives have merit, and the workshop summarized in this report provided some reassurance that biomarkers, placed in proper perspective, will advance both biomedical science and the pragmatic science of developing drugs that improve human health. At the same time, the workshop also demonstrated the inability of current biomarkers to substitute fully for actual measurement of the risks and benefits of interventions since multiple biological networks and pathways are always in play.
The workshop’s final sessions considered the increased complexity of validating and qualifying multimarker panels of biomarkers. Until recently, biomarkers had been developed one at a time. But the advent of large-scale genomic, proteomic, metabolomic, and advanced imaging technologies is changing the environment in which biomarkers are identified and assessed. In the final session, speakers explored the potential for applying cutting-edge scientific technologies to enhance the prediction and detection of drug-induced toxicity, discussed the integration of systems biology and computational biology into toxicity assessments early in drug development, and considered the regulatory and scientific challenges involved in the development and use of multimarker panels.
The workshop was not designed to produce consensus on future steps that should be taken, but in the course of the discussion, numerous ideas arose that can provide insight into measures that might be useful. The workshop challenged participants to consider how each individual and group might contribute to advancing this work, and the workshop organizers hope that this publication will do the same for a broader group of readers.
Robert Califf
Workshop Chair
Tables, Figures, and Boxes
TABLES
3-1 |
Strengths and Weakness of the QTc Interval as a Safety Biomarker, |
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4-1 |
Promising Translational Biomarkers of Acute Kidney Injuries, |
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4-2 |
Current Deficiencies, Needs, and Proposals to Address Kidney Safety Issues in Early Drug Development, |
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5-1 |
Regulatory Actions on Approved Drugs Due to Hepatotoxicity, 1995–2008, |
FIGURES
2-1 |
The number of new molecular entities (NMEs) submitted to the FDA has fallen since the mid-1990s, |
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5-1 |
Acute idiosyncratic hepatocellular injury, |
BOXES