Assuring Data Quality and Validity in Clinical Trials for Regulatory Decision Making

Workshop Report

Roundtable on Research and Development of Drugs, Biologics, and Medical Devices

Jonathan R. Davis, Vivian P. Nolan, Janet Woodcock, and Ronald W. Estabrook, Editors

Division of Health Sciences Policy

INSTITUTE OF MEDICINE

NATIONAL ACADEMY PRESS
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Assuring Data Quality and Validity in Clinical Trials for Regulatory Decision Making Workshop Report Roundtable on Research and Development of Drugs, Biologics, and Medical Devices Jonathan R. Davis, Vivian P. Nolan, Janet Woodcock, and Ronald W. Estabrook, Editors Division of Health Sciences Policy INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, DC

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NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, D.C. 20418 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 selected for their special competences and with regard for appropriate balance. The Institute of Medicine was chartered in 1970 by the National Academy of Sciences to enlist distinguished members of the appropriate professions in the examination of policy matters pertaining to the health of the public. In this, the Institute acts under both the Academy's 1863 congressional charter responsibility to be an adviser to the federal government and its own initiative in identifying issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine. Support for this project was provided by the American Medical Association, Baxter International Inc., Eli Lilly, Food and Drug Administration (Center for Biologics Evaluation and Research, Center for Devices and Radiological Health, and Center for Drug Evaluation and Research), the Health Industry Manufacturers Association, Hoffmann-LaRoche, Merck & Co., Inc., National Institutes of Health (Office of Rare Diseases and National Institute of Child Health and Human Development), Pfizer, Pharmaceutical Research and Manufacturers of America, and Wyeth-Ayerst. The views presented are those of the Institute of Medicine's Roundtable on Research and Development of Drugs, Biologics, and Medical Devices and are not necessarily those of the funding organizations. International Standard Book No. 0-309-06594-1 Additional copies of this report are available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, DC 20055. Call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP's on-line bookstore at www.nap.edu. For information about the Institute of Medicine, visit the IOM home page at http://www.national-academies.org. Copyright 1999 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 image adopted as a logotype by the Institute of Medicine is based on a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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ROUNDTABLE ON RESEARCH AND DEVELOPMENT OF DRUGS, BIOLOGICS, AND MEDICAL DEVICES RONALD W. ESTABROOK (Chair), Virginia Lazenby O'Hara Professor of Biochemistry, University of Texas Southwestern Medical Center, Dallas ARTHUR L. BEAUDET, Investigator, Howard Hughes Medical Institute, and Professor and Chair, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas (through February 1999) LESLIE Z. BENET, Professor and Chair, Department of Biopharmaceutical Sciences, School of Pharmacy, University of California at San Francisco D. BRUCE BURLINGTON, Director, Center for Devices and Radiological Health, Food and Drug Administration, Rockville, Maryland (through March 1999) ROBERT CALIFF, Director, Duke Clinical Research Institute, Durham, North Carolina MICHAEL D. CLAYMAN, Vice President, Global Regulatory Affairs, Lilly Research Laboratories, Indianapolis, Indiana RITA R. COLWELL, President, Maryland Biotechnology Institute, University of Maryland, College Park (through December 1997) ADRIAN L. EDWARDS, Private Practice, Internal Medicine/Cardiology, The New York and Presbyterian Hospitals, New York City DAVID W. FEIGAL, Director, Center for Devices and Radiological Health, Food and Drug Administration, Rockville, Maryland (from June 1999) STEPHEN GROFT, Director, Office of Rare Diseases Research, National Institutes of Health, Bethesda, Maryland ANNE B. JACKSON, Sarasota, Florida ROBERT I. LEVY, Senior Vice President, Science and Technology, American Home Products, Wyeth-Ayerst Research, Madison, New Jersey MICHAEL R. McGARVEY, Chief Medical Officer, Blue Cross and Blue Shield of New Jersey, Inc., Newark KSHITIJ MOJAN, Corporate Vice President for Research and Technical Services, Baxter Health Care Corporation, Roundlake, Illinois STUART L. NIGHTINGALE, Associate Commissioner, Health Affairs, Food and Drug Administration, Rockville, Maryland PAUL GRANT ROGERS, Partner, Hogan & Hartson, Washington, D.C. DANIEL SECKINGER, Group Vice President, Professional Standards, American Medical Association, Chicago Illinois (through December 1997) WHAIJEN SOO, Vice President, Clinical Sciences, Roche Pharmaceuticals, Hoffmann-La Roche, Inc., Nutley, New Jersey REED TUCKSON, Group Vice President, Professional Standards, American Medical Association, Chicago, Illinois (from October 1998) JANET WOODCOCK, Director, Center for Drug Evaluation and Research, Food and Drug Administration Rockville, Maryland

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SUMNER YAFFE, Director, Center for Research for Mothers and Children, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland KATHRYN ZOON, Director, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland Liaisons to the Roundtable C. THOMAS CASKEY, Senior Vice President for Research, Merck & Co., Inc., West Point, Pennsylvania JAMES S. BENSON, Executive Vice President, Technology and Regulatory Affairs, Health Industry Manufacturers Association, Washington, D.C. BRIAN J. MALKIN, Associate Director for Patents and Hearings, Office of Health Affairs, Food and Drug Administration, Rockville, Maryland BERT SPILKER, Senior Vice President, Scientific and Regulatory Affairs, Pharmaceutical Research and Manufacturers of America, Washington, D.C. Study Staff JONATHAN R. DAVIS, Senior Program Officer VIVIAN P. NOLAN, Research Associate CHRISTINA THACKER, Research Assistant (to July 1998) NICOLE AMADO, Project Assistant Division Staff ANDREW M. POPE, Division Director LINDA DEPUGH, Administrative Assistant JAMAINE TINKER, Financial Associate (to October 1998) CARLOS GABRIEL, Financial Associate (from February 1999)

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Preface The Roundtable The Institute of Medicine's (IOM's) Roundtable on Research and Development of Drugs, Biologics, and Medical Devices evolved from the Forum on Drug Development, which was established in 1986. The importance of maintaining a neutral setting for discussions regarding long-term and politically sensitive issues was determined by sponsor representatives and the IOM to justify the need to revise and enhance past efforts. The new Roundtable is intended to be a mechanism to convene a broad group of experts to conduct a dialogue and exchange information. The experts consist of individuals, including government officials (who serve in an ex officio capacity), who represent all sides of public policy issues related to the development of drugs, biologics, and medical devices. Members of the Roundtable bring expertise from areas of clinical medicine, pharmacology, health policy, health insurance, industrial management, and product development as they pertain to research and development of drugs, biologics, and medical devices. Each member's participation adds a unique perspective to discussion topics. Members are responsible for identifying areas of Roundtable focus and determining issues that can be further elucidated in subsequent workshops. These workshops provide the opportunity to assemble a broader group of experts in the area of interest. The goals of the Roundtable include the provision of an environment for the exchange of information and the identification of high-priority issues in the areas of product discovery and development. To achieve these goals the Roundtable convenes twice annually and holds at least one workshop annually. The Roundtable identifies opportunities and problems that are current and likely to be ongoing, or that are expected to arise within the next few years and develops approaches to exploiting opportunities or solving problems. Several issues that have been suggested by Roundtable members as possible discussion topics are listed below:

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medical devices, genomics and gene therapy, product development for special populations, and public education and risk assessment. To allow full and candid participation by all members, reports of Roundtable discussions and workshops identify approaches but do not make recommendations or endorse specific courses of action. Workshop Report and Its Organization In an effort to increase knowledge and understanding of the process of assuring data quality and validity in clinical trials, the IOM hosted a workshop to open a dialogue on the process to identify and discuss issues of mutual concern among industry, regulators, payers, and consumers. The presenters and panelists together developed strategies that could be used to address the issues that were identified. This IOM report of the workshop summarizes the present status and highlights possible strategies for making improvements to the education of interested and affected parties as well as facilitating future planning. This report is divided into two major sections: (1) presubmission and submission of clinical data and (2) regulatory review of these data by the Food and Drug Administration (Food and Drug Administration). The content of the presubmission of clinical data is derived from discussions of the actions frequently undertaken by representatives of the pharmaceutical and clinical research industries. These individuals gave presentations on data collection, which addressed such issues as documentation, investigator selection and training, data complexity, and the number of clinical trials conducted; monitoring, which addressed such issues as common practices of the industry and auditing by third parties; and data handling and cleanup, which addressed such issues as common practices of the industry, costs and time required for data handling and cleanup, and troubleshooting. The first section also addresses submission of clinical data to the FDA. Here, the issues addressed were specifically concerned with the preparations of marketing applications, such as similarities and differences in content requirements, time and cost estimates, and validation considerations. The second section on FDA regulatory review was based on presentations by representatives from the FDA. These presenters discussed paper auditing, clinical site review, and institutional review board auditing. They also addressed integrity assessments, common patterns and practices, and sanctions for noncompliance. The basic tenets of the workshop were exploration of reasonable standards that will result in better quality data without inflation of the process costs and that will assure that these standards result in accurate and reliable data. The following themes were addressed during the 2-day workshop:

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What are the benefits of assuring the quality of clinical data? Are they commensurate with the costs? What are the implications for cost and timing of clinical development? What are reasonable standards for data quality, and how could such standards be developed? How should adequate quality be defined? How much is considered enough data? How do other countries assure quality of clinical data? How can the system or process be improved (i.e., streamlining of data collection and maintenance of quality? How will automation of data collection, central monitoring, and remote data entry affect quality? How does austerity affect the management of clinical research programs? How will managed care and third-party payment policies affect these programs? The agenda for the workshop is included in Appendix A of this report. The main body of the report follows the agenda's general outline and is largely based on a verbatim transcript of the workshop. However, explanatory material has been added to the introduction, and moderator's summaries have been combined and streamlined for greater clarity. The report is organized as a topic-by-topic synthesis of exchanges during the workshop. The names of the individuals who made presentations on individual topics are identified for each section. These individuals have reviewed and approved the sections for accuracy. All Roundtable members have also had the opportunity to review the document, and those present at the workshop have indicated that the report accurately reflects the workshop discussions. The Roundtable asks the reader to remember that any single workshop is necessarily incomplete and that its proceedings can report only on what participants stated at the workshop. Therefore, this report cannot serve as an exhaustive exploration of its subject matter since the information reported in the text emerged in the workshop itself. At the same time that this report provides an account of individual presentations at the workshop, the dynamics of the Roundtable are such that the report also reflects a very important aspect of the Roundtable philosophy. That is, this report reflects the Roundtable's function as a convenor of representatives from different sectors for dialogue and their thoughts on which subject areas and research may merit further attention. However, the reader should understand that the material presented here expresses the views and opinions of those participating in the workshop and not the deliberations of a formally constituted IOM study committee.

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Acknowledgments On behalf of the Roundtable and the Institute of Medicine (IOM), warmest appreciation is expressed to the individuals and organizations who gave valuable time to provide information and advice to the Roundtable through participation in the workshop. Each of the following contributed greatly: Susan Alpert, Food and Drug Administration (FDA); Robert Califf, Duke Clinical Research Institute; Michaele Christian, National Institutes of Health; Michael Clayman, Eli Lilly & Company; Susan Ellenberg, FDA; Ronald Estabrook, University of Texas, Southwestern Medical Center at Dallas; William Fairweather, FDA; Frank Hurley, Quintiles Transnational Corporation; Charma Konnor, FDA; Kiyoshi Kuromiya, Critical Path AIDS Project; David Lepay, FDA; Robert Levy, American Home Products, Wyeth-Ayerst Research; Murray Lumpkin, FDA; Michael McGarvey, Blue Cross and Blue Shield of New Jersey, Inc.; Royer Meyer, American Association of Medical Colleges; Kristin O'Connor, Boehringer Ingleheim Pharmaceuticals; Nicholas Pelliccione, Schering Plough; Jim Phillips, Quintiles Transnational Corporation; John Schultz, Neuroclinical Trials Center, University of Virginia; Eleanor Segal, Chiron Corporation; Kenneth Shine, IOM; Jay Siegel, FDA; Whaijen Soo, Hoffmann-La Roche, Inc.; Frances Visco, National Breast Cancer Coalition; William Waggoner, Essex Institution Review Board; Janet Woodcock, FDA; and Stan Woollen, FDA. The other workshop attendees who also deserve special recognition participated as guests. These individuals are identified in Appendix C. All the workshop participants played an important part in this activity, especially in stimulating discussion and providing ideas. The Roundtable also wishes to thank the following individuals who participated in the workshop's organizing committee and working group and who contributed greatly to ensure the success of the workshop: Leslie Benet, Jim Benson, Bruce Burlington, Robert Levy, Paul Rogers, Daniel Seckinger,

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Whaijen Soo, Janet Woodcock, and Kathryn Zoon. Additionally, the Roundtable especially thanks Matthew J. Tarosky, Program Management Officer at FDA's Center for Drug Evaluation and Research, for assisting with the planning of the workshop and for providing assistance with the Glossary and Acronyms, which can be found in Appendix D. The Roundtable expresses much appreciation to the IOM staff who provided invaluable help in this activity. Andrew Pope directed the Roundtable at its inception and was instrumental in planning and organizing this workshop. Christina Thacker assisted with the workshop planning and logistics. Of particular note, Nicole Amado developed the Glossary and Acronyms list and provided comprehensive administrative support to facilitate the development of the report. During report review, Sue Barron, Claudia Carl, and Mike Edington provided valuable direction and technical assistance. Other professional staff also provided invaluable help. Paul Phelps, an independent writer, incorporated into the first draft the many pieces of written material presented during the workshop. The extensive commentary and suggestions made by the copy editor, Michael Hayes, are gratefully acknowledged. The Roundtable and IOM also wish to thank the sponsors that supported this activity. Financial support for this project was provided by the American Medical Association, Baxter International Inc., Eli Lilly, Food and Drug Administration (Center for Biologics Evaluation and Research, Center for Devices and Radiological Health, and Center for Drug Evaluation and Research), the Health Industry Manufacturers Association, Hoffmann-LaRoche, Merck & Co., Inc., National Institutes of Health (Office of Rare Diseases and National Institute of Child Health and Human Development), Pfizer, Pharmaceutical Research and Manufacturers of America, and Wyeth-Ayerst. This report has been reviewed 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 Institute of Medicine in making the published report as sound as possible and ensuring that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The contents of the review comments and the draft manuscript remain confidential to protect the integrity of the deliberative process. The Roundtable and IOM wish to thank the following individuals for their participation in the review process: Margaret Anderson, Society for the Advancement of Women's Health Research; Daniel L. Azarnoff, M.D., D.L. Azarnoff Associates; John J. Burns, Ph.D., Cornell University Medical College; Farley Cleghorn, Ph.D., University of Maryland; and Myron M. Levine, M.D., University of Maryland School of Medicine. Although these individuals provided many constructive comments and suggestions, responsibility for the final content of this report rests solely with the authoring committee and the Institute of Medicine.

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Contents     Executive Summary   1     Introduction   7     The Topic   7     Background   8     Overview of Issues   10     Presubmission and Submission   13     Data Collection   13     Monitoring: Industry Perspective   16     Monitoring: National Cancer Institute Perspective   17     Data Handling and Cleanup   19     Preparation and Content of Marketing Applications   21     Panel Discussion   22     FDA Regulatory Review   26     Paper Auditing   26     Clinical Site Review and Institutional Review Board Audits   27     Sanctions   31     Assessment of Drugs   33     Assessment of Devices   35     Panel Discussion   37     Summary of Issues   42

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    Directions for the Future   43     Development   44     Safety   44     Final Comments   45     Action   46     Education and Training   46     Communication   46     Definitions   47     Functional Quality   47     International Data   47     Appendixes     A   Workshop Agenda   51 B   Speakers and Panelists   56 C   Workshop Registrants   59 D   Glossary and Acronyms   68