Developing a National Registry of Pharmacologic and Biologic Clinical Trials

Workshop Report

Committee on Clinical Trial Registries

Board on Health Sciences Policy

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary Developing a National Registry of Pharmacologic and Biologic Clinical Trials Workshop Report Committee on Clinical Trial Registries Board on Health Sciences Policy INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary 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 internal unrestricted funds. Any opinions, findings, or conclusions 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. ISBN 0-309-10078-X 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 2006 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.

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Advising the Nation. Improving Health.

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary 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. Wm.A.Wulf 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. Wm.A.Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary COMMITTEE ON CLINICAL TRIAL REGISTRIES PHILIP A.PIZZO (Chair), Stanford University School of Medicine, Stanford, California GAIL H.CASSELL, Eli Lilly and Company, Indianapolis, Indiana ELLEN WRIGHT CLAYTON, Vanderbilt University Medical School, Nashville, Tennessee DAVID R.COX, Perlegen Sciences, Mountain View, California NANCY DUBLER, Montefiore Medical Center and The Albert Einstein College of Medicine, Bronx, New York ROBERT GIBBONS, University of Illinois, Chicago LYNN R.GOLDMAN, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland BERNARD D.GOLDSTEIN, University of Pittsburgh, Pittsburgh, Pennsylvania MARTHA N.HILL, Johns Hopkins University School of Nursing, Baltimore, Maryland ALAN LESHNER, American Association for the Advancement of Science, Washington, D.C. DANIEL MASYS, Vanderbilt University Medical Center, Nashville, Tennessee JONATHAN D.MORENO, University of Virginia, Charlottesville E.ALBERT REECE, University of Arkansas, Little Rock MYRL WEINBERG, National Health Council, Washington, D.C. MICHAEL J.WELCH, Washington University School of Medicine, St. Louis, Missouri MARY WOOLLEY, Research!America, Alexandria, Virginia Study Staff ANDREW M.POPE, Study Director AMY HAAS, Administrative Assistant DAVID CODREA, Financial Associate JANICE MEHLER, Editor CORI VANCHIERI, Consultant

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary BOARD ON HEALTH SCIENCES POLICY* PHILIP A.PIZZO (Chair), Stanford University School of Medicine, Stanford, California LESLIE BENET, University of California, San Francisco DAVID BLUMENTHAL, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts GAIL H.CASSELL, Eli Lilly and Company, Indianapolis, Indiana ELLEN WRIGHT CLAYTON, Vanderbilt University Medical School, Nashville, Tennessee DAVID R.COX, Perlegen Sciences, Mountain View, California NANCY DUBLER, Montefiore Medical Center and The Albert Einstein College of Medicine, Bronx, New York ROBERT GIBBONS, University of Illinois, Chicago LYNN R.GOLDMAN, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland BERNARD D.GOLDSTEIN, University of Pittsburgh, Pittsburgh, Pennsylvania MARTHA N.HILL, Johns Hopkins University School of Nursing, Baltimore, Maryland ALAN LESHNER, American Association for the Advancement of Science, Washington, D.C. DANIEL MASYS, Vanderbilt University Medical Center, Nashville, Tennessee JONATHAN D.MORENO, University of Virginia, Charlottesville E.ALBERT REECE, University of Arkansas, Little Rock MYRL WEINBERG, National Health Council, Washington, D.C. MICHAEL J.WELCH, Washington University School of Medicine, St. Louis, Missouri MARY WOOLLEY, Research!America, Alexandria, Virginia IOM Staff ANDREW M.POPE, Board Director AMY HAAS, Board Assistant DAVID CODREA, Financial Associate *   IOM Boards do not review or approve individual reports and are not asked to endorse conclusions and recommendations. The responsibility for the content of the report rests with the authoring committee and the institution.

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary Independent Report 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 (NRC’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: George Lundberg, Medscape General Medicine Sherry Marts, Society for Women’s Health Research Harold Sox, Annals of Internal Medicine Sharon Terry, Genetic Alliance Alastair Wood, 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 Melvin Worth, Scholar in Residence, Institute of Medicine and Elaine Larson, Columbia University School of Nursing. Appointed by the NRC and the Institute of Medicine, they were 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 consid-

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary ered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary Foreword The Honorable John Porter Partner, Hogan & Hartson, LLP Keynote Presentation, June 27, 2005 What an exciting day this is for biomedical research and global health. This evening the Gates Foundation and the Foundation for the National Institutes of Health will announce its initial grants of approximately $450 million for research on diseases affecting people in the world’s poorest countries. These Grand Challenges in Global Health grants carry the promise of transforming health in places long mired in poverty, disease, and early death. All of us, I believe, are anxious to see real progress toward improved health and productivity of the people in the developing world. These grants should remind us that discovery alone is insufficient to improve human health. New pharmaceuticals, biologics, and devices must be tested for safety and efficacy, and clinical trials are the only way to translate from the laboratory to the health and well-being of individuals. In a free and democratic society like ours, public support for biomedical research funding is vital and public trust in the integrity and the processes of discovery and translation is the sine qua non of public support. It might be argued that the only trust and support that are really necessary are those of policy makers—the Administration and Congress. But it is remarkable how well public trust in a free society is reflected in the trust of the public’s elected representatives. Where the public trusts, their representatives generally also trust. Where the public lacks trust, so do their representatives. It works both ways. The vote several weeks ago in the House of Representatives on stem cell research was extremely significant, whether the President ultimately vetoes new stem cell lines or not. It reminded leaders that the leash on departing from public opinion can be a short one and that public trust in science in our country is still strong. Likewise, the vote last week in the

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary House on funding for public broadcasting was a strong slap on the wrist for its detractors and a timely reminder of where in our media the public’s trust most strongly resides. Elected representatives understand that they depart from where public trust lies at their peril. Public trust in America is based on public perception. Sometimes that perception is grounded in knowledge and evidence, but sometimes it is not. Yet, in politics and public policy, perception—true or false—is the reality. If we are to ensure that the reality is grounded in truth, we must work to plant knowledge and evidence in the minds of both the public and their elected representatives. Public perception is often formed through the lenses of the media. One example is the April 2002 cover of Time magazine. It showed a photo of a woman in a hospital gown inside a cage, with the headline that read “How Medical Testing Has Turned Millions of Us into Human Guinea Pigs.” Although the pictures, the captions, and the headlines are often provocative and even untrue, the articles are often well written in language people can understand. But how many see only the pictures, the captions, and the headlines? We are reminded how important it is to public perception—and therefore public trust and support—that we have science journalists who can translate the complexities of research into language that the lay reader can understand. These talents are vitally needed in a society with rapidly changing technologies. I wonder how many universities encourage study in this area and how much emphasis the scientific community places on urging the formal development of these important skills. Research!America is giving recognition to achievements in this area. How many other organizations give priority to this kind of recognition and encouragement? Misperception is not the only factor that may undermine public trust in science. Research fraud, negligence or incompetence, lack of transparency, poor patient education, and lack of standards and patient protections in clinical trials can undermine public trust in the process of translating discovery to improved human health. Most significantly, the bad news always makes page 1. All we need to remind us of the danger to translational research is to say “Tuskegee.” That episode more than 50 years ago continues to reverberate through the African-American community and to deter participation of African Americans in clinical trials today. Ask anyone involved in lupus or sickle cell research of the difficulties they encounter, and then ask yourself how important public trust is to the success and support of biomedical research and clinical trials.

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary Names like Enron, WorldCom, Tyco, ImClone—although not all related to research—remind us how fraud and corporate abuse undermine support for markets that depend on public confidence in the data regarding investments. Their lapses led to vast new government regulations deemed necessary to protect the integrity of our free enterprise economic system. In addition, thinking of the CIA or of the abuses of some by Catholic clergy and what those events have meant to those two institutions should reinforce the importance of public trust to the work of science. It is significant that the strategic direction of our nation’s largest federal medical health research agency, the National Institutes of Health (NIH), not only acknowledges the importance of public trust and support, but has identified strategies to build on both. Director Elias Zerhouni’s NIH Roadmap Initiative demonstrates an understanding of the importance of cultivating public engagement in research as well as the necessity of policy-maker support in sustaining our national investment. The NIH Roadmap is particularly noteworthy because it identifies “reengineering of the clinical research enterprise” as one of its three central themes. Dr. Zerhouni has shown great leadership in identifying the need for more rapid translation. He also recognizes that without public trust and participation, acceleration in the pace of discoveries in the life sciences simply will not be achieved. On June 21, 2005, The Wall Street Journal ran a front-page article on a new NIH program designed to bridge the gap between academic research and development in industry. This program has been designed to entice private companies to invest in higher risk research by offering to pay for and carry out early clinical trials of experimental drugs. The NIH project has begun with an invitation to drug makers to participate in a clinical trial network that would clear away some of the cost and risk of drug development for the companies while providing access to top government and academic scientists. This program explores and tests creative approaches that serve the public interest and thus helps to build public trust. The public expects and supports collaboration among industry, academia, and government—91 percent of respondents in a recent Research!America poll said exactly that. Clearly, we have moved a long way from support for the research enterprise, which alone was once a sufficient appeal to policy makers, to the health and health care of the American people. Yes, we still can and do argue that we must maintain U.S. technological leadership; that we

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary must meet the competition emerging from China and India and, increasingly, from Europe; and that investment in biomedical research is a major driver of our country’s economic growth. But the bottom line, the reason why accountability is stressed and why clinical trials are so important, is policy makers’ connection with and concern for the health and well-being of the American people. This is what drives support for research today and why the clinical trial process that is transparent, understood, and protective of the enrolled patient, and produces evidence with a high degree of confidence in its accuracy, is so important to the public trust. Development of a publicly accessible comprehensive clinical trial registry, it seems to me, would be a key component—but not the sole component—of efforts to build public trust in clinical research. This public trust will also require programs to ensure that the public understands what clinical research is; knows what is being done and why; understands what the risks and benefits are when participating in clinical trials; believes in and trusts the research institutions as well as the researchers themselves; and knows where to go, what to do, and how to do it to be an effective advocate for clinical research. Science, our educational system, and the media have, quite frankly, not done a very good job of educating the people and their representatives on the basics of science, on how research is conducted in the laboratory today, on the exciting blending of many disciplines working together toward discovery, on the need to continue research and development of the tools produced by the physical sciences that are vital to further life science advances, and on the absolute need for clinical trials to test discovery and protect the public at large. Research!America polling shows—uniformly across all jurisdictions—that the majority of the American people cannot name one place where research is conducted in the United States. The same probably would have been true of the U.S. Congress 10 years ago, but we can be proud that we have made some progress there. But much remains to be done. If public support depends on public trust, if public trust depends on public perception, and if public perception depends on truth and knowledge, scientists need to share their understanding, their passion, and their exciting research with the public. They need to work closely with science journalists, with policy makers, and with the people in their communities. If each one will do only a little more, I believe more young people in America will be inspired to pursue careers in science and research, the

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary public perception of science will be strengthened, and public support will increase for investments in research and the clinical trials necessary to protect and improve human health. At the base of it all is public trust.

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary Preface Medical journal editors, the pharmaceutical industry, and the World Health Organization have all proposed some form of clinical trial registry for drugs and biologics. Other organizations, including the American Medical Association and the Association of American Medical Colleges, have supported the creation of a registry. These proposals have several features in common, such as public accessibility, broad inclusion of clinical trials, and most of the key data elements. However, so far the parties have disagreed as to inclusion of other elements such as trial results and have not determined the mechanisms for implementation and compliance. To help make progress on this issue, the Institute of Medicine’s (IOM’s) Board on Health Sciences Policy (HSP) of the National Academies hosted discussions among interested parties, leading to this report. On December 1, 2004, HSP invited leaders from several of the major constituencies to discuss areas of common ground and unresolved issues (see Appendix A for participants). Following that meeting, the Board formed a committee, some of whose members held additional discussions with journal editors and pharmaceutical and biotech leaders about the merits and importance of specific elements to be included in a workable clinical trial registry for drugs and biologics. The IOM committee posted background material regarding these issues on its website prior to convening a workshop on June 27, 2005, in Washington, D.C. The 150 workshop participants included public advocate groups, medical journal editors, pharmaceutical representatives, government representatives, and others (see Appendix B for the agenda, speakers, and participants). This report summarizes the views expressed by workshop participants and includes background information to provide the context

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary for workshop discussion based on the committee’s planning work. It includes information and perspectives gathered prior to and at the workshop, describing progress made toward a national registry for clinical trials and points for further consideration. Chapter 1 is a summary of the issues surrounding creation of a clinical trial registry and the contributions of this project. Chapter 2 describes the importance of a national clinical trial registry, drawing together views expressed throughout this project. Chapter 3 describes diverse perspectives and activities toward creating a national clinical trial registry. Chapter 4, describing potential elements of a registry, intersperses background material with comments made by workshop participants. Chapter 5, on implementation issues, also includes background material interspersed with comments made by participants. Although the Committee on Clinical Trial Registries is responsible for the overall quality and accuracy of the report as a record of what transpired at the workshop, the views contained in this report are not necessarily those of the committee. The purpose of the workshop and the resulting report is to continue to elicit broad input to inform future efforts to build a clinical trial registry that supports the public health. Philip Pizzo, Chair Committee on Clinical Trial Registries

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary Contents 1   SUMMARY   1 2   THE NEED FOR CLINICAL TRIAL REGISTRIES   5      Widespread Agreement That Some Form of Registry Is Needed,   5      Diverse Expectations and Perceived Needs,   6 3   CURRENT REGISTRY ACTIVITIES   9      ClinicalTrials.gov: Current Clinical Trial Disclosure Requirements,   9      International Committee of Medical Journal Editors,   11      Joint Pharmaceutical Industry Position,   12      The World Health Organization Project,   13      Federal and State Legislation,   15      Summary of Features of Current and Proposed Registries,   15 4   CONTENT OF A CLINICAL TRIAL REGISTRY   19      Guiding Principles and Goals for Clinical Trial Registries,   19      Trials to Be Registered,   23      Delayed Disclosure of Information Available at the Initiation of Trials,   26      Timing and Content for Reporting Results of Trials,   32 5   IMPLEMENTATION ISSUES   35      Process for Selection of Uniform Standards,   35      Balanced Process for Determining What Information Should Be Protected,   36

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary      Mechanisms to Ensure Compliance and Protect Against Promotion of Unauthorized Use of a Drug in Registry Postings,   38      Responsibility for Developing and Managing the Registry,   42 6   CONCLUSION AND NEXT STEPS   43     REFERENCES   47     APPENDIXES     A   Participants and Invited Experts Between December 1, 2004, and June 27, 2005,   49 B   Workshop Agenda, Speakers, Panelists, and Participants: June 27, 2005,   51 C   Section 113 of the Food and Drug Administration Modernization Act of 1997 and Guidance for Industry: Information Programs on Clinical Trials for Serious or Life-Threatening Diseases and Conditions. U.S. Department of Health and Human Services. March 2002,   63 D   Published Journal Editorials,   81 E   Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases,   91 F   Illustrative Data Fields for the Results Summary,   95 G   Biographical Sketches of Committee Members,   97

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Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Summary List of Tables 3–1   Required Data Fields for the DHHS Clinical Trial Registry at ClinicalTrials.gov,   10 3–2   Data Fields Required by the ICMJE as a Condition of Publication,   11 3–3   WHO Minimum Data Set,   14 3–4   Comparison of Registry/Disclosure Policies,   16 4–1   Clinical Trial Registry Data Fields Discussed at IOM Meetings,   26 D-1   Minimal Registration Data Set,   86

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