FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION
TRANSFORMING CLINICAL RESEARCH IN THE UNITED STATES
CHALLENGES AND OPPORTUNITIES
WORKSHOP SUMMARY
Rebecca A. English, Yeonwoo Lebovitz, and Robert B. Giffin, Rapporteurs
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
THE NATIONAL ACADEMIES PRESS
Washington, D.C.
www.nap.edu
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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 Department of Health and Human Services (Contract Nos. N01-OD-4-2139 and 223001003T), the American Diabetes Association, the American Society for Microbiology, Amgen Inc., the Association of American Medical Colleges, AstraZeneca Pharmaceuticals, the Burroughs-Wellcome Fund, Celtic Therapeutics, LLLP, the Critical Path Institute, the Doris Duke Charitable Foundation, Eli Lilly & Co., Entelos Inc., Genentech, GlaxoSmithKline, Johnson & Johnson, Novartis Pharmaceuticals Corporation, and Pfizer Inc. 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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Suggested citation: IOM (Institute of Medicine). 2010. Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary. Washington, DC: The National Academies Press.
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. Charles M. Vest 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. Charles M. Vest are chair and vice chair, respectively, of the National Research Council.
PLANNING COMMITTEE FOR THE WORKSHOP ON TRANSFORMING CLINICAL RESEARCH IN THE UNITED STATES1
BARBARA ALVING,
National Center for Research Resources, Maryland
LINDA BRADY,
National Institute of Mental Health, Maryland
ROBERT CALIFF,
Duke University Medical Center, North Carolina
SCOTT CAMPBELL,
American Diabetes Association, Virginia
GAIL H. CASSELL,
Eli Lilly and Company, Indiana
JAMES H. DOROSHOW,
National Cancer Institute, Maryland
JEFFREY M. DRAZEN,
New England Journal of Medicine, Massachusetts
GARRET A. FITZGERALD,
University of Pennsylvania School of Medicine
PETER K. HONIG,
Merck Research Laboratories (retired), Pennsylvania
RONALD L. KRALL,
GlaxoSmithKline (retired), Pennsylvania
MUSA MAYER,
AdvancedBC.org, New York
IRENA TARTAKOVSKY,
Association of American Medical Colleges, Washington, DC
JORGE A. TAVEL,
National Institute of Allergy and Infectious Diseases, Maryland
IOM Staff
ANNE B. CLAIBORNE, Director (as of April 5, 2010)
ROBERT B. GIFFIN, Director (until February 26, 2010)
REBECCA A. ENGLISH, Research Associate
YEONWOO LEBOVITZ, Program Associate
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
Leslie Z. Benet,
University of California–San Francisco
Ann Bonham,
Association of American Medical Colleges, Washington, DC
Linda Brady,
National Institute of Mental Health, Maryland
Robert M. Califf,
Duke University Medical Center, North Carolina
Scott Campbell,
Foundation for the National Institutes of Health, Maryland
Peter B. Corr,
Celtic Therapeutics Management Company, LLP, New York
James H. Doroshow,
National Cancer Institute, Maryland
Paul R. Eisenberg,
Amgen, Inc., California
Gary L. Filerman,
ATLAS Research, Washington, DC
Garret A. FitzGerald,
University of Pennsylvania School of Medicine
Elaine K. Gallin,
The Doris Duke Charitable Foundation, New York
Steven K. Galson,
Science Applications International Corporation, Virginia
Harry B. Greenberg,
Stanford University School of Medicine, California
Stephen Groft,
National Institutes of Health, Maryland
Peter K. Honig,
AstraZeneca Pharmaceuticals, Delaware
Annalisa Jenkins,
Bristol-Myers Squibb, New Jersey
Michael Katz,
March of Dimes Foundation, New York
Jack D. Keene,
Duke University Medical Center, North Carolina
Ronald L. Krall,
GlaxoSmithKline (retired), Pennsylvania
Freda Lewis-Hall,
Pfizer, Inc., New York
William Matthew,
National Institute of Neurological Disorders and Stroke, Maryland
Mark B. McClellan,
Brookings Institution, Washington, DC
Carol Mimura,
University of California-Berkeley
John Orloff,
Novartis Pharmaceuticals Corporation, New Jersey
Amy Patterson,
National Institutes of Health, Maryland
Janet Shoemaker,
American Society for Microbiology, Washington, DC
Nancy S. Sung,
Burroughs Wellcome Fund, North Carolina
Jorge A. Tavel,
National Institute of Allergy and Infectious Diseases, Maryland
Janet Tobias,
Ikana Media, New York
Joanne Waldstreicher,
Johnson & Johnson, New Jersey
Janet Woodcock,
U.S. Food and Drug Administration, Maryland
Raymond Woosley,
The Critical Path Institute, Arizona
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 process. We wish to thank the following individuals for their review of this report:
Timothy Coetzee, Fast Forward, LLC, National Multiple Sclerosis Society
Marlene E. Haffner, Haffner Associates, LLC
Steven E. Kahn, Division of Metabolism, Endocrinology, and Nutrition, Seattle VA Puget Sound Health Care System
Michael S. Lauer, Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health
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 Alastair J.J. Wood, Symphony Capital, LLC. Appointed by the Institute of Medicine, he 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
Clinical trials are the way the medical field tests whether a new therapeutic product performs as expected and actually makes a difference in treating disease. Hundreds of innovative therapies are generated in laboratories, but few survive early development to reach the point of human testing. Clinical trials in patients suffering from a specific condition represent the crucial link between scientific discovery and medical utility.
To plan and execute a clinical trial today can take years and cost hundreds of millions of dollars. In the past, the United States was considered the best place to conduct clinical trials because of the right mix of clinical and scientific expertise and an understanding of the research process. However, many believe that the clinical research enterprise in the United States has failed to keep pace with that in the rest of the world because of this time and cost burden. To evaluate the state of clinical research in the United States and identify strategies for enhancing the effectiveness and efficiency of clinical trials, the Institute of Medicine’s Forum on Drug Discovery, Development, and Translation convened a public workshop on October 7–8, 2009, titled Transforming Clinical Research in the United States. Clinical trial experts from academic research centers, pharmaceutical companies, contract research organizations, government, nonprofit research networks, and patient advocacy groups came together to discuss their clinical trial successes and failures, the challenges they face in conducting clinical research, and strategies for improving the efficiency of clinical trials while maintaining the highest standards for the data generated.
The intent of the workshop was to engage stakeholders in an honest discussion of the state of clinical trials today and to gain an understanding
of what has and has not worked in planning and executing trials. The workshop was focused on four disease areas: cardiovascular disease, depression, cancer, and diabetes. Although “clinical research” is a generic term, a clinical trial in breast cancer, with 5-, 10-, or 15-year outcomes, is quite different from a clinical trial in cardiovascular disease, where the outcome of interest may occur in a month or less. The disease being studied also affects the kind of patients needed and how they are recruited and retained. Gaining an appreciation of the differences in clinical trials by disease helped generate ideas for improving the clinical research enterprise as a whole.
This workshop is part of a broader initiative of the Forum addressing different aspects of clinical research. Future Forum plans include the following: further examining regulatory, administrative, and structural barriers to the effective conduct of clinical research; developing a vision for a stable, continuously funded clinical research infrastructure in the United States; and considering strategies and collaborative activities to facilitate more robust public engagement in the clinical research enterprise.
As the starting point for the Forum’s work in the area of clinical research, it is our hope that this workshop summary will serve as a resource for all organizations and individuals seeking a greater understanding of how the clinical research enterprise works and how it can improve. The workshop showcased the best examples from clinical research conducted to date and developed novel ideas for organizing and conducting clinical trials. Ultimately, as the health care system moves forward, we hope our work can serve as a source of information and inspiration to those involved in clinical research as sponsors, investigators, clinicians, patients, and policy makers.
Jeffrey M. Drazen, Co-Chair
Forum on Drug Discovery, Development, and Translation
Tables, Figures, and Boxes
TABLES
3-1 |
Global Research Costs: Relative Cost Indexes of Payments to Clinical Trial Sites, |
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3-2 |
Breakdown of the Costs for a Large, Global Clinical Trial (14,000 patients, 300 sites), |
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7-1 |
Structure of Study Centers for a Government-Sponsored Randomized Controlled Trial (Diabetes Prevention Program [DPP]) and an Industry-Sponsored Randomized Controlled Trial (A Diabetes Progression Outcomes Trial [ADOPT]), |
FIGURES
2-1 |
Timeline reflecting the number of clinical trials registered on clinicaltrials. gov and regulatory changes affecting the database registration from 2001 to 2009, |
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2-2 |
Percentage of the 10,974 ongoing clinical trials and 2.8 million study subjects being sought by intervention being tested, |
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2-3 |
Number of the 8,386 clinical trials involving FDA-regulated products and 1.9 million study subjects being sought for these trials by phase of research, |
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2-4 |
Number of the 10,974 ongoing clinical trials and 2.8 million study subjects being sought by disease being studied, |
2-5 |
The proportion of clinical investigators from North America has decreased since 1997, while the proportion of investigators from Western Europe and the rest of the world has increased, |
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3-1 |
While the number of senior NIAID/NIH tenured investigators is relatively stable, the number of NIAID/NIH tenure-track principal investigators is decreasing, |
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4-1 |
Classification system for the spectrum of acute coronary syndromes that helps practitioners identify a study population more easily, |
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4-2 |
Timeline for the NIH-sponsored Occluded Artery Trial (OAT), |
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Figure in Box 5-1 |
STAR*D clinical trial results: remission rates by treatment level (monotherapy or combination treatment), |
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7-1 |
Study management structure for a government-sponsored randomized controlled trial (Diabetes Prevention Program [DPP]) and an industry-sponsored randomized controlled trial (A Diabetes Progression Outcomes Trial [ADOPT]), |
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7-2 |
Patient recruitment rates for four type 1 diabetes trials, |
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8-1 |
CTSAs include 46 institutions in 26 states, |
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8-2 |
Typical NIH clinical trial network with academic health center sites surrounding the hub of a data coordinating center, |
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8-3 |
A vision of an integrated clinical research system linking existing networks (patients, physicians, and scientists) to form communities of research and conduct clinical trials more effectively, |
BOXES
Acronyms
ACS acute coronary syndromes
ADA American Diabetes Association
ADOPT A Diabetes Outcome Progression Trial
AHA American Heart Association
AHRQ Agency for Healthcare Research and Quality
ARO academic research organization
ARRA American Recovery and Reinvestment Act of 2009
caBIG Cancer Biomedical Informatics Grid
CDER Center for Drug Evaluation and Research
CEC clinical events committee
CER comparative effectiveness research
CMS Centers for Medicare and Medicaid Services
CNS central nervous system
CRF case report form
CRN clinical research network
CRO contract research organization
CTA clinical trial agreement
CTEP Cancer Therapy Evaluation Program
CTSA Clinical and Translational Science Awards
CTTI Clinical Trials Transformation Initiative
DBSA Depression and Bipolar Support Alliance
DCRI Duke Clinical Research Institute
DMC data monitoring committee
DPP diabetes prevention program
DSMB data safety monitoring board
ECG electrocardiogram
ECOG Eastern Cooperative Oncology Group
FDA U.S. Food and Drug Administration
FDAAA Food and Drug Administration Amendments Act of 2007
FDAMA Food and Drug Administration Modernization Act of 1997
HAM-D Hamilton Depression Rating Scale
HHS U.S. Department of Health and Human Services
HIPAA Health Information Portability and Accountability Act
ICMJE International Committee of Medical Journal Editors
IECRN Inventory and Evaluation of Clinical Research Networks
IOM Institute of Medicine
IRB Institutional Review Board
ISIS International Study of Infarct Survival
JDRF Juvenile Diabetes Research Foundation
MI myocardial infarction
MTA material transfer agreement
NCI National Cancer Institute
NCRR National Center for Research Resources
NDA New Drug Application
NHLBI National Heart, Lung, and Blood Institute
NIA National Institute on Aging
NIAID National Institute of Allergy and Infectious Diseases
NIDDK National Institute of Diabetes and Digestive and Kidney Diseases
NIH National Institutes of Health
NIMH National Institute of Mental Health
NLM National Library of Medicine
OAT occluded artery trial
OPEN oncology patient enrollment network
PBRN Practice-Based Research Network
PCI percutaneous intervention
PCORI Patient-Centered Outcomes Research Institute
PhRMA Pharmaceutical Research and Manufacturers of America
PI principal investigator
RCT randomized controlled trial
RFA Request for Applications
SSRI selective serotonin reuptake inhibitor
STAR*D Sequenced Treatment Alternatives to Relieve Depression
STEMI ST segment elevation myocardial infarction
TIMI Thrombolysis in Myocardial Infarction Study Group
VA U.S. Department of Veterans Affairs
WHO World Health Organization