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Cooperative Group Program; John Mendelsohn; Harold L. Moses;
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 A NATIONAL CANCER
CLINICAL TRIALS SYSTEM
FOR THE 21ST CENTURY
Reinvigorating the NCI Cooperative Group Program

Committee on Cancer Clinical Trials and the

NCI Cooperative Group Program
Board on Health Care Services

Sharyl J. Nass, Harold L. Moses, and John Mendelsohn, Editors

Copyright © 2010. National Academies Press. All rights reserved.

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 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. HHSN261200611002C and 200-2005-13434

TO #1 between the National Academy of Sciences and the National Cancer Institute and the
Centers for Disease Control and Prevention, respectively. This study was also supported by
the American Cancer Society, the American Society of Clinical Oncology, the Association of
American Cancer Institutes, and C-Change. Any opinions, findings, conclusions, or recommen-
dations 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: 978-0-309-15186-3

International Standard Book Number 10: 0-309-15186-4

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.
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Copyright 2010 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). 2010. A National Cancer Clinical Trials Sys-
Copyright © 2010. National Academies Press. All rights reserved.

tem for the 21st Century: Reinvigorating the NCI Cooperative Group Program. Washington,
DC: The National Academies Press.

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 “Knowing is not enough; we must apply.
Willing is not enough; we must do.”
—Goethe
Copyright © 2010. National Academies Press. All rights reserved.

Advising the Nation. Improving Health.

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 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 Acad-
emy 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 engineer-
ing programs aimed at meeting national needs, encourages education and research,
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
the examination of policy matters pertaining to the health of the public. The Insti-
tute 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 Sci-
ences 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
Copyright © 2010. National Academies Press. All rights reserved.

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 Coun-
cil 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.

www.national-academies.org

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 COMMITTEE ON Cancer Clinical Trials and
the NCI Cooperative Group Program

john mendelsohn (Chair), President, University of Texas M.D.

Anderson Cancer Center
harold L. Moses (Vice-Chair), Professor of Cancer Biology,
Medicine and Pathology and Director Emeritus, Vanderbilt-Ingram
Comprehensive Cancer Center
Susan G. Arbuck, Consultant, Susan G. Arbuck MD LLC
Donald A. Berry, Head, Division of Quantitative Sciences, Professor
and Frank T. McGraw Memorial Chair for Cancer Research, and
Chair, Department of Biostatistics, University of Texas M.D. Anderson
Cancer Center
Michael A. Carducci, AEGON Professor in Prostate Cancer
Research, Professor in Oncology and Urology, Sidney Kimmel
Comprehensive Cancer Center, Johns Hopkins University School of
Medicine
David M. Dilts, Director of Clinical Research, Knight Cancer Institute
and Professor of Health Care Management, Oregon Health and
Science University
Susan S. Ellenberg, Professor of Biostatistics and Associate Dean for
Clinical Research, University of Pennsylvania School of Medicine
Gwen Fyfe, Independent Consultant
Stephen S. Grubbs, Principal Investigator, Delaware Christiana Care
Community Clinical Oncology Program, Helen F. Graham Cancer
Center
Hedvig Hricak, Chair, Department of Radiology, Memorial Sloan-
Kettering Cancer Center
Richard Kaplan, Associate Director, United Kingdom National
Cancer Research Network and United Kingdom Clinical Research
Copyright © 2010. National Academies Press. All rights reserved.

Network, and Senior Scientist, Medical Research Council Clinical

Trials Unit
Minetta C. Liu, Associate Professor of Medicine and Oncology,
Lombardi Comprehensive Cancer Center, Georgetown University
Hospital
Lee N. Newcomer, Senior Vice President, Oncology, United
HealthCare
Edith A. Perez, Serene M. and Frances C. Durling Professor of
Medicine, Division of Hematology/Oncology, Mayo Clinic Florida
Charles L. Sawyers, Investigator, Howard Hughes Medical Institute,
and Director, Human Oncology and Pathogenesis Program, Memorial
Sloan-Kettering Cancer Center

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 Richard L. Schilsky, Professor of Medicine and Section Chief,
Hematology/Oncology, University of Chicago Medical Center
Ellen V. Sigal, Chair and Founder, Friends of Cancer Research

Consultant
Michaele Chamblee Christian (retired), Division of Cancer
Treatment and Diagnosis, National Cancer Institute

Study Staff
Sharyl Nass, Study Director and Senior Program Officer
Erin Balogh, Research Associate
Sally CLUCHEY, Program Officer (July to September 2009)
Lisa Boyette, Christine Mirzayan Science and Technology Policy
Graduate Fellow (September to November 2009)
Sharon Murphy, Scholar in Residence
Michael Park, Senior Program Assistant
Patrick Burke, Financial Associate
Roger Herdman, Director, Board on Health Care Services
Copyright © 2010. National Academies Press. All rights reserved.

vi

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 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 thank the following individuals
for their review of this report:

Kenneth Anderson, Professor of Medicine, Harvard Medical

School, Medical Director, Kraft Family Blood Center, Dana-
Copyright © 2010. National Academies Press. All rights reserved.

Farber Cancer Institute, Boston, MA

James Atkins, Southeast Cancer Control Consortium, Inc.,
Winston-Salem, NC
Monica M. Bertagnolli, Professor of Surgery, Harvard
Medical School, Chief, Division of Surgical Oncology, Brigham
and Women’s Hospital, Boston, MA
Troyen A. Brennan, Executive Vice President, Chief Medical
Officer, CVS Caremark, Woonsocket, RI
Robert M. Califf, Vice Chancellor for Clinical Research, Duke
University Medical Center, Director, Duke Translational Medicine
Institute, Durham, NC

vii

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 viii REVIEWERS

Sanjiv Gambhir, Director, Molecular Imaging Program, Stanford

University, Stanford, CA
Perry Nisen, Senior Vice President, Oncology, GlaxoSmithKline,
Collegeville, PA
Nancy Roach, Founder and Board Chair, C3: Colorectal Cancer
Coalition, Alexandria, VA
William B. Rouse, Executive Director and Professor, Tennenbaum
Institute, Georgia Institute of Technology, Atlanta, GA
David Schoenfeld, Professor of Medicine, Harvard Medical
School, Professor of Biostatistics, Harvard School of Public
Health, Boston, MA

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 Harold J. Fallon, Dean
Emeritus, School of Medicine, University of Alabama at Birmingham.
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 authoring committee and the institution.
Copyright © 2010. National Academies Press. All rights reserved.

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 Preface

Clinical trials that test the safety and therapeutic benefit of drugs and
other treatments are essential for developing new and improved therapies
for patients with cancer. However, the system for conducting cancer clini-
cal trials in the United States is approaching a state of crisis. Changes are
urgently needed if we are to continue to make progress against the second
leading cause of death in this country. If the clinical trials system does not
improve its efficiency and effectiveness, the introduction of new treatments
for cancer will be delayed and patient lives will be lost unnecessarily.
For the past 50 years, the Clinical Trials Cooperative Group Program
supported by the National Cancer Institute (NCI) has played a critical
role in testing new cancer therapies. The Program comprises a network of
cancer centers and community oncology practices across the country that
develops cancer clinical trials and enrolls patients in those studies. More
Copyright © 2010. National Academies Press. All rights reserved.

than 25,000 patients and thousands of clinical investigators participate in

these clinical trials annually. The knowledge gained from the large-scale,
multicenter trials conducted by the Cooperative Groups has been instru-
mental in establishing the therapies that are now routinely used to treat
patients with cancer.
Cooperative Group trials have diminished the impact of cancer on
many fronts. Most obviously, they have identified superior treatment strat-
egies that have led to longer lives. Findings from pediatric cancer trials,
largely carried out by Cooperative Groups over the past four decades,
have boosted childhood cancer cure rates from less than 10 percent in the
1950s to nearly 80 percent today. Cooperative Groups have performed the
definitive studies of many of the standard treatments for adult cancers as

ix

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
  PREFACE

well and have played a major role in evaluating innovative therapies, such
as those targeted to tumors with specific genetic characteristics and those
designed to halt tumor growth by blocking the blood vessels that support
the tumor rather than by directly killing cancer cells.
In addition to identifying treatments that prolong life, the Coopera-
tive Groups have also given attention to the important issue of quality
of life. Many important studies have focused on minimizing the adverse
consequences of cancer treatments. A landmark example was the trial
demonstrating that breast-conserving surgery plus radiation was as effec-
tive at eradicating early-stage breast cancer as radical mastectomy. Other
Cooperative Group trials have shown that some less intensive regimens for
pediatric cancers could control cancer while reducing the risks of long-term
harms from the highly toxic therapies typically used to treat those cancers.
Finally, the Cooperative Groups have also addressed cancer prevention.
One important trial showed that by taking a drug such as tamoxifen, breast
cancer incidence could be reduced by 50 percent for women at high risk for
breast cancer over a 5-year period.
Publicly sponsored trials fill an important information void by conduct-
ing head-to-head comparisons of different treatment regimens, combining
treatments, and investigating whether drugs approved for the treatment of
one type of cancer can be used to effectively treat other types of cancer,
all of which are far less likely to be pursued by pharmaceutical companies.
However, the NCI Cooperative Group Program is falling short of its full
potential to improve the quality of care that cancer patients receive. An
accumulation of problems is hampering progress, just at a time when new
knowledge about the genetic and molecular underpinnings of cancer has
created opportunities for designing trials with new, targeted anticancer
agents. Increasingly, biomarkers (predictors of a response to a particular
therapeutic intervention) can be used to select which treatment strategy is
most likely to benefit individual patients.
One major problem is the complex system of designing, reviewing, and
Copyright © 2010. National Academies Press. All rights reserved.

initiating Cooperative Group clinical trials, which has become a lengthy

and redundant process typically requiring years to complete. In attempt-
ing to optimize the effectiveness and safety of trials, proposals often are
redrafted and recycled by multiple stakeholders from academic institutions,
federal agencies, institutional review boards, and industry. This results
in frustration and a perception that stakeholders are working at cross-
purposes. In addition, the system lacks an adequate process for prioritizing
trials and selecting those most likely to be successful. Finally, when there
are long delays in designing and initiating clinical trials, the slow accrual of
patients is often the result. Only about 60 percent of NCI-sponsored trials
are actually completed and published, which is a terrible waste of human
and financial resources.

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 PREFACE xi

Another major problem is the inadequacy of NCI funding for Coop-

erative Group clinical trials. As much as half of the cost of clinical trials
today are borne by the clinical investigators and clinical care providers who
design and carry out these important studies. Almost universally, investiga-
tors are compelled to seek supplemental support from outside sources, such
as pharmaceutical companies. The problem is further compounded by the
increased costs of trials because of the opportunity to measure biomark-
ers in a patient’s cancer and use them to predict and monitor appropriate
therapy. Added to these challenges is the relatively low value placed on
Cooperative Group trials by academic institutions in evaluating faculty
accomplishments and by the NCI in evaluating Cancer Center achieve-
ments; this discourages physician participation. Moreover, the nonexperi-
mental costs of care in clinical trials are not borne by some insurance plans,
which significantly hinders patient participation.
In this report, developed at the request of the director of the NCI, an
Institute of Medicine committee makes recommendations to address these
challenges. Stepping back to gain a comprehensive perspective, the com-
mittee took a broad look at the needs and goals of all stakeholders in the
current cancer clinical trials system and has made recommendations for
changes across the board that will improve the efficiency and effectiveness
of the system. Our goal was to preserve the historical strengths of the Coop-
erative Group Program while recommending improvements to components
that are not working well.
Some functions will need to be better integrated, and others must be
carried out in parallel rather than in series to reduce the amount of time lost
to repetitive steps. The report stresses the need to consolidate functions and
processes within the clinical trials network, streamline oversight, enhance
collaboration, select and prioritize trials more stringently, fully fund the
most innovative and promising studies, and open and complete trials with
greater speed. There must also be agreement on strict deadlines that should
be met at each step along the way. The committee further recommends
Copyright © 2010. National Academies Press. All rights reserved.

(with regret) that the number of trials be reduced if adequate funding to

pay for the highest-priority studies is not available.
Changing any particular component of the system will not suffice. All
participants and stakeholders, including physicians, patients, and health
care insurers, as well as the NCI and regulatory agencies, must reevaluate
their combined roles and their contributions to a successful, streamlined
process for carrying out Cooperative Group clinical trials that will improve
the care of patients with cancer. Collectively, implementation of the recom-
mendations presented in this report will lead to the faster approval and
adoption of new therapies, new discoveries upon which to base future
studies, and the accelerated translation of new knowledge into beneficial
therapies for patients with cancer. The committee also endorses recom-

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 xii PREFACE

mendations recently made by NCI’s Operational Efficiency Working Group,

which aim at achieving similar goals and which are incorporated as an
appendix to this report.
The members of the committee wish to express their gratitude to the
staff of the Institute of Medicine, with whom we have worked so closely
for more than a year. Special thanks are due to Sharyl Nass, whose skills
in assimilating information and formulating our proposals into systematic
recommendations are unparalleled in our collective experience, and to Erin
Balogh, who was instrumental in helping the committee draft the chapters
of the report. We hope that our report will stimulate and guide the Coop-
erative Group Clinical Trials Program to enhance its critical role in advanc-
ing treatments for patients with cancer.

John Mendelsohn, Chair

Committee on Cancer Clinical Trials and
the NCI Cooperative Group Program
Copyright © 2010. National Academies Press. All rights reserved.

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 Acknowledgments

The committee is grateful to many individuals who provided valu-

able input and information for the study, either through formal presenta-
tions or through informal communications with study staff and committee
members:
Jeffrey Abrams (NCI) Robert L. Comis (Coalition of
Carmen Joseph Allegra (University National Cancer Cooperative
of Florida—Gainesville) Groups)
Anna Barker (NCI) Carolyn Compton (NCI)
Robert Becker (FDA) Gregory Curt (AstraZeneca)
Clara D. Bloomfield (Ohio State Philip J. DiSaia (Gynecologic
University Comprehensive Oncology Group)
Cancer) James H. Doroshow (NCI)
Copyright © 2010. National Academies Press. All rights reserved.

Peter Bross (FDA) Laura J. Esserman (University of

Suanna Steeby Bruinooge California, San Francisco)
(American Society of Clinical Stanley R. Hamilton (University of
Oncology) Texas M.D. Anderson Cancer
Jan C. Buckner (North Central Center)
Cancer Treatment Group) Robert Justice (FDA)
Gregory Campbell (FDA) Patricia Keegan (FDA)
Renzo Canetta (Bristol-Myers Rebecca A. Kirch (American
Squibb) Cancer Society Cancer Action
Michael Carome (HHS) Network)
Deborah Collyar (Patient Laura Levit (Institute of Medicine)
Advocates in Research)

xiii

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 xiv ACKNOWLEDGMENTS

Allen Lichter (American Society of Daniel Sargent (Mayo Clinic

Clinical Oncology) Comprehensive Cancer Center)
Stuart Lutzker (Genentech) Joseph V. Simone (University of
Elizabeth Mansfield (FDA) Florida)
Daniel R. Masys (Vanderbilt Frank Smith (Children’s Oncology
University) Group)
Lynn Matrisian (NCI) Daniel C. Sullivan (Duke
Lynne McGrath (Novartis) University)
Margaret Mooney (NCI) Jeffrey Trent (TGen)
Maura O’Leary (Children’s Linda Weiss (NCI)
Oncology Group) David Wholley (The Biomarkers
Richard Pazdur (FDA) Consortium)
Sonia Pearson-White (The D. Lawrence Wickerham (National
Biomarkers Consortium) Surgical Adjuvant Breast and
Philip D. Porter (Hogan & Bowel Project)
Hartson, LLP) Grant Williams (Williams Cancer
Gregory Reaman (Children’s Drug Consulting, LLC)
Oncology Group) Celia Witten (FDA)
Laura Reese (Gynecologic Janet Woodcock (FDA)
Oncology Group)

The committee also thanks Margie Patlak for preparing background

information on costs and oversight of clinical trials by the Food and
Drug Administration, the National Institutes of Health, and the Office
for Human Research Protections. In addition, the committee wishes to
thank the speakers who contributed to the workshops preceding this study,
including Improving the Quality of Cancer Clinical Trials and Multi-Center
Phase III Clinical Trials and NCI Cooperative Groups.
Copyright © 2010. National Academies Press. All rights reserved.

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 Contents

Executive Summary 1

Overview of Conclusions and Recommendations 5

Goal I. Improve the Speed and Efficiency of the Design, Launch,
and Conduct of Clinical Trials, 10
Goal II. Incorporate Innovative Science and Trial Design into
Cancer Clinical Trials, 24
Goal III. Improve Prioritization, Selection, Support, and
Completion of Cancer Clinical Trials, 29
Goal IV. Incentivize the Participation of Patients and Physicians
in Clinical Trials, 35
Summary, 40
Copyright © 2010. National Academies Press. All rights reserved.

1 Introduction 41
Importance of Cancer Clinical Trials, 42
The Clinical Trials Cooperative Group Program, 43
Achievements of the Cooperative Group Program, 45
Childhood Cancer, 50
Adult Solid Tumors and Hematologic Malignancies, 51
Adjuvant Therapy for Solid Tumors, 53
Combined-Modality Therapy, 53
Cancer Prevention and Detection, 54
Negative Findings and Previously Unobserved Treatment
Risks, 54
Strengths of the Cooperative Group Program, 55

xv

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 xvi CONTENTS

Challenges Confronting the Cooperative Group Program, 64

Clinical Trial Costs Outstrip Program Funding, 65
Inefficient Group Processes and Burdensome Oversight, 65
Inadequate Patient and Physician Involvement in Cancer
Clinical Trials, 66
Movement of Industry Trials Overseas, 66
Origin of the Study, 67
Committee Appointment and Charge, 68
The Committee’s Vision for Cancer Clinical Trials in 2015, 69
The Committee’s Conclusions and Recommendations, 69
Organization of the Report, 70
References, 71

2 The Science of Developing Cancer Therapy 77

The Role of Cooperative Groups in Biomarker Development, 79
Challenges in Biomarker Development, 82
Biospecimen Collection, Storage, Annotation, and Access, 82
Lack of Funding for Biomarker Development Within the
Cooperative Group Program, 85
Lack of Standards for Biomarker Development and Use, 86
Uncertain Relevance of Primary Tissue for Patients with
Metastatic Disease, 87
Promises and Challenges of Combination Products, 88
Diagnostic-Therapeutic Combinations, 88
Combination Therapy, 90
Trial Design, 92
Comparative Effectiveness Research, 100
Biomedical Imaging as a Cancer Biomarker, 101
Role of Anatomic Imaging in Clinical Trials, 102
Biological Basis for Improved Cancer Imaging in Oncology, 103
Molecular Imaging and Its Potential Applications in Clinical
Copyright © 2010. National Academies Press. All rights reserved.

Trials, 104
Codeveloping Imaging Biomarkers and Cancer
Therapeutics: Theranostics and Beyond, 106
Validation and Standardization, 107
Summary, 108
References, 112

3 Operations, Oversight, and Funding of Cancer Clinical Trials 121

Organization of the Cooperative Group Program, 122
Oversight of Clinical Trials, 122
NCI Oversight of Cooperative Group Trials, 124
Trial Concept Selection, 124

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 CONTENTS xvii

Protocol Development, 128

Trial Operations, 129
Oversight of Trials by IRBs, 131
IRB Oversight of Multicenter Trials, 131
Informed Consent, 136
FDA Oversight of Cancer Clinical Trials, 138
FDA Data Requirements, 140
Operational Inefficiencies in Trial Development, Launch, and
Conduct, 142
Potential Ways to Improve Trial Quality and Efficiencies,
146
Other Informative Models and Ongoing Activities, 149
Cost of Cancer Clinical Trials, 152
Funding for Cancer Clinical Trials, 158
Overview of Federal Funding for Cancer Research, 158
Funding of the Cooperative Group Program, 162
Collaboration Among Stakeholders, 165
Collaborative Funding Mechanisms, 166
Contract Negotiations and Intellectual Property, 169
Grand Challenges to Stimulate Innovation, 171
Summary, 173
References, 181

4 Physician and Patient Participation in Cancer Clinical Trials 191

Clinical Investigator Participation, 192
Financial and Regulatory Barriers, 193
Participating Sites, 193
Individual Physicians, 194
Participation by Community Physicians, 196
Participation by Academic Clinicians, 198
Recognizing and Rewarding Clinical and Team
Copyright © 2010. National Academies Press. All rights reserved.

Research, 198
Ensuring the Clinical Investigator Pipeline, 201
Physician Awareness of Clinical Trials, 202
Physician Perspectives on Clinical Trials, 203
Ensuring Adequate Patient Accrual at Participating Sites, 203
Information on Clinical Trial Availability, 204
Eligibility Requirements, 206
Patient Advocate Involvement, 207
Participation Patterns, 209
Expanding Patient Access to Clinical Trials, 210
Patient Participation in Clinical Trials, 211
Insurance Coverage, 215

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 xviii CONTENTS

Employer-Sponsored Plans Subject to ERISA, 218

Medicare and Medicaid Coverage, 219
Third-Party Payment Policies and Clinical Trial
Participation, 221
Summary, 223
References, 228

Appendixes

A Previous and Ongoing Analyses Undertaken by NCI 235

B Committee Member and Staff Biographies 259

Acronyms 275

Glossary 279
Copyright © 2010. National Academies Press. All rights reserved.

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
 Executive Summary

Advances in biomedical research are yielding significant opportuni-

ties to improve cancer prevention, detection, and treatment. However, the
ability to translate biomedical discoveries into meaningful advances in
cancer care depends on an effective clinical trials system. Publicly funded
clinical trials play a vital role by addressing questions that are important
to patients but are less likely to be top priorities of industry, which has an
important primary focus on new drug development and Food and Drug
Administration (FDA) registration. For example, companies may have less
incentive to

• conduct clinical trials to compare the effectiveness of different

treatment options that are already approved for clinical use,
• combine novel therapies developed by different sponsors,
Copyright © 2010. National Academies Press. All rights reserved.

• develop therapies for rare diseases,

• determine optimal duration and dose of treatment with drugs in
clinical use,
• test multimodality therapies, such as radiation therapy, surgery, or
devices in combination with drugs,
• study screening and prevention strategies, or
• focus on rehabilitation and quality of life following therapy.

The National Cancer Institute (NCI) supports the largest U.S. network
for clinical trials of any type. The largest component of that network is the
Clinical Trials Cooperative Group Program, which comprises 10 Groups
that involve more than 3,100 institutions and 14,000 investigators who

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
  a national cancer clinical trials system

enroll more than 25,000 patients in clinical trials each year. The results of
Cooperative Group trials have steadily improved the care of patients with
cancer in the United States and worldwide for more than 50 years.
One of the Program’s strengths is the extensive involvement of physi-
cians and patients from the community setting. Participation by the diverse
patient populations treated in the community setting helps to ensure that
the results of clinical trials are meaningful to a broad segment of the U.S.
population and provides these patients with access to promising, innovative
therapies as they are developed and tested. The clinical trials conducted by
the Cooperative Groups also provide a valuable mechanism for the training
of clinical investigators.
However, despite these important contributions and a long record of
accomplishments, the Cooperative Group Program is at a critical juncture.
Numerous challenges threaten its ability to conduct the timely, large-scale,
innovative clinical trials needed to improve patient care. With many itera-
tive layers of oversight, the complex trials system has become inefficient and
cumbersome. The average time required to design, approve, and activate
a trial is 2 years and many of the trials undertaken are not completed.
Furthermore, since 2002 funding for the Cooperative Group Program has
decreased by 20 percent, whereas new knowledge of the molecular changes
underpinning cancer and the use of predictive biomarkers in cancer therapy
not only increase the potential impact of trials but also add to their com-
plexity and cost.
The director of NCI asked the Institute of Medicine (IOM) to conduct
a consensus study of cancer clinical trials and the Cooperative Group Pro-
gram and to develop recommendations on how to improve the system. To
address the charge, the IOM appointed a 17-member committee with a
broad range of expertise and experience.
The committee concluded that a robust, standing cancer clinical trials
network is essential to effectively translate discoveries into clinical benefits
for patients. There are hundreds of cancer therapies in development and a
Copyright © 2010. National Academies Press. All rights reserved.

continuous need for design and implementation of new clinical trials, so it

would be highly inefficient to fund and develop infrastructures and research
teams separately for each new trial. Thus, it is imperative to preserve and
strengthen the unique capabilities of the Cooperative Group Program as a
vital component in NCI’s translational continuum.
However, the current structure and processes of the entire clinical trials
system need to be redesigned to improve value by reducing redundancy and
improving the effectiveness and efficiency of trials. Numerous changes are
needed, including an evaluation and justification of the unique contribu-
tion of each Cooperative Group and a shift in the primary focus of NCI
from oversight to the facilitation of Cooperative Group trials. The Program

Institute, of Medicine, et al. A National Cancer Clinical Trials System for the 21st Century : Reinvigorating the NCI Cooperative
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