A NATIONAL CANCER CLINICAL TRIALS SYSTEM FOR THE 21ST CENTURY

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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

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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 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. iom.edu. 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- tem for the 21st Century: Reinvigorating the NCI Cooperative Group Program. 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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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 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

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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 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 v

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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 vi

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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 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- 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

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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.

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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 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

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x 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 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.

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xi PREFACE 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 (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-

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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

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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) 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

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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.

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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 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

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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 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

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xvii CONTENTS 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 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

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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