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ACCELERATING THE DEVELOPMENT OF
BIOMARKERS FOR DRUG SAFETY
Workshop Summar y
Steve Olson, Sally Robinson, and Robert Giffin, Rapporteurs
Forum on Drug Discovery, Development, and Translation
Board on Health Sciences Policy
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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 Govern-
ing Board of the National Research Council, whose members are drawn from the
councils of the National Academy of Sciences, the National Academy of Engineer-
ing, 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 Col-
leges; AstraZeneca Pharmaceuticals; Blue Cross Blue Shield Association; the Bur-
roughs 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 Foun-
dation; 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.
International Standard Book Number-13: 978-0-309-13124-7
International Standard Book Number-10: 0-309-13124-3
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
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Copyright 2009 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). 2009. Accelerating the Develop-
ment of Biomarkers for Drug Safety: 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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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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The National Research Council was organized by the National Academy of Sciences
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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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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
v
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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
1 IOM 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.
vi
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Jorge A. Tavel, National Institute of Allergy and Infectious Diseases,
Maryland
Joanne Waldstreicher, Johnson & Johnson, New Jersey
Janet Woodcock, U.S. Food and Drug Administration, Maryland
Raymond L. Woosley, Critical Path Institute, Arizona
vii
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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:
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-
ix
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x REVIEWERS
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.
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Preface
Biomarkers are central to the future of medicine. By providing a mea-
sure 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 indi-
viduals 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. There-
fore, 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 bio-
markers in drug development, which has increased the urgency of accel-
xi
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xii PREFACE
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 measure-
ment 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 develop-
ment, 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 orga-
nizers hope that this publication will do the same for a broader group of
readers.
Robert Califf
Workshop Chair
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Contents
1 INTRODUCTION 1
Workshop Purpose, Scope, and Objectives, 2
Crosscutting Issues, 3
Organization of the Report, 5
References, 5
2 OVERVIEW OF KEY ISSUES 6
Predictions Based on Biomarkers, 9
Validation vs. Qualification, 10
Mechanisms vs. Patterns, 11
Regulatory Approval of Biomarkers, 12
Regulation of Single Biomarkers vs. Panels of Biomarkers, 13
Measures of Success, 13
An Example: Biomarkers for Toxicity of Psychiatric Drugs, 14
References, 16
3 CARDIAC SAFETY BIOMARKERS 17
The Regulatory Response, 19
Responses of Drug Developers, 20
Effects on Physician Decision Making, 21
Other Cardiac Safety Biomarkers, 22
The Cardiac Safety Research Consortium, 24
Lessons Learned, 26
Highlights of the Breakout Discussion, 26
References, 28
xiii
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xiv CONTENTS
4 ASSESSING AND PREDICTING KIDNEY SAFETY 29
The Current State, 30
A Vision of the Future, 37
Highlights of the Breakout Discussion, 39
References, 41
5 BIOMARKERS OF ACUTE IDIOSYNCRATIC
HEPATOCELLULAR INJURY IN CLINICAL TRIALS 42
Acute Idiosyncratic Hepatocellular Injury (AIHI), 43
Current State of Biomarkers for AIHI, 45
Potential New Biomarkers for AIHI, 50
Highlights of the Breakout Discussion, 52
References, 55
6 FUTURE CONSIDERATIONS 58
Creating Incentives for Collaboration, 58
Moving Forward Without Understanding Mechanisms, 61
Dealing with Different Levels of Risk, 63
Reference, 64
APPENDIXES
A Workshop Agenda 65
B Speaker Biographies 71
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Tables, Figures, and Boxes
TAbLES
3-1 Strengths and Weakness of the QTc Interval as a Safety
Biomarker, 18
4-1 Promising Translational Biomarkers of Acute Kidney Injuries, 32
4-2 Current Deficiencies, Needs, and Proposals to Address Kidney Safety
Issues in Early Drug Development, 38
5-1 Regulatory Actions on Approved Drugs Due to Hepatotoxicity,
1995–2008, 44
FIGuRES
2-1 The number of new molecular entities (NMEs) submitted to the FDA
has fallen since the mid-1990s, 8
5-1 Acute idiosyncratic hepatocellular injury, 44
bOXES
2-1 The Toll of Mental Illness, 15
4-1 Initiatives to Advance Understanding of Kidney Safety
Biomarkers, 33
6-1 Systems Biology and Biomarker Development, 62
xv
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