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Small Clinical Trials

Issues and Challenges

Charles H. Evans, Jr., and Suzanne T. Ildstad, Editors

Committee on Strategies for Small-Number-Participant

Clinical Research Trials

Board on Health Sciences Policy

INSTITUTE OF MEDICINE

NATIONAL ACADEMY PRESS
Washington, D.C.



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Page i Small Clinical Trials Issues and Challenges Charles H. Evans, Jr., and Suzanne T. Ildstad, Editors Committee on Strategies for Small-Number-Participant Clinical Research Trials Board on Health Sciences Policy INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C.

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Page ii NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, DC 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 chosen for their special competences and with regard for appropriate balance. Support for this project was provided by the National Aeronautics and Space Administration. The views presented in this report are those of the Institute of Medicine Committee on Strategies for Small-Number-Participant Clinical Research Trials and are not necessarily those of the funding agency. International Standard Book Number 0-309-07333-2 Additional copies of this report are available from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, D.C. 20055. Call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP's home page at www.nap.edu. The full text of this report is available at books.nap.edu/catalog/10078.html. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2001 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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Page iii “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe ~ enlarge ~ INSTITUTE OF MEDICINE Shaping the Future for Health

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Page iv THE NATIONAL ACADEMIES National Academy of Sciences National Academy of Engineering Institute of Medicine National Research Council 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. Bruce M. Alberts 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. William 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. Kenneth I. Shine 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. Bruce M. Alberts and Dr. William A. Wulf are chairman and vice chairman, respectively, of the National Research Council.

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Page v COMMITTEE ON STRATEGIES FOR SMALL-NUMBER-PARTICIPANT CLINICAL RESEARCH TRIALS SUZANNE T. ILDSTAD (Chair), Director, Institute for Cellular Therapeutics, University of Louisville ROBERT M. CENTOR, Associate Dean and Director, Division of General Internal Medicine, University of Alabama ED DAVIS, Professor and Chair, Department of Biostatistics, University of North Carolina School of Public Health, Chapel Hill BRUCE LEVIN, Professor and Chairman, Division of Biostatistics, The Joseph L. Mailman School of Public Health, Columbia University, New York City EDWARD D. MILLER, Dean and Chief Executive Officer, The Johns Hopkins University School of Medicine, Baltimore INGRAM OLKIN, Professor of Statistics and Education, Stanford University, Stanford, CA DAVID J. TOLLERUD, Professor of Public Health and Director, Center for Environmental and Occupational Health, MCP Hahnemann University School of Public Health, Philadelphia PETER TUGWELL, Chair, Department of Medicine, University of Ottawa, Ottawa, Canada Institute of Medicine Board on Health Sciences Policy Liaison ROBERT D. GIBBONS, Professor of Biostatistics and Director, Center for Health Statistics, University of Illinois at Chicago Study Staff CHARLES H. EVANS, JR., Study Director and Senior Adviser, Biomedical and Clinical Research VERONICA A. SCHREIBER, Research Assistant TANYA LEE, Project Assistant Institute of Medicine Staff ANDREW POPE, Director, Board on Health Sciences Policy ALDEN CHANG, Administrative Assistant CARLOS GABRIEL, Financial Associate Consultant KATHI E. HANNA Copy Editor MICHAEL K. HAYES

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Page vii Reviewers The report was 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 to assist the authors and the Institute of Medicine in making the 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 content of the review comments and the draft manuscript remain confidential to protect the integrity of the deliberative process. The committee wishes to thank the following individuals for their participation in the report review process: GREGORY CAMPBELL, Director, Division of Biostatistics, Center for Devices and Radiological Health, Food and Drug Administration, Rockville, Maryland JOSEPH T. COYLE, Chairman, Department of Psychiatry, Harvard Medical School, Boston NANCY NEVELOFF DUBLER, Director, Division of Bioethics, Montefiore Medical Center, The Albert Einstein College of Medicine, Bronx, New York

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Page viii LAWRENCE M. FRIEDMAN, Director, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Maryland STEVEN N. GOODMAN, Associate Professor, Biostatistics and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland RODERICK LITTLE, Chair, Department of Biostatistics University of Michigan School of Public Health, Ann Arbor, Michigan DAVID MELTZER, Assistant Professor, Section General Internal Medicine, University of Chicago, Chicago, Illinois JANE W. NEWBURGER, Director Clinical Research, Children's Hospital, Harvard University, Boston, Massachusetts RICHARD L. SIMMONS, Medical Director, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania SCOTT L. ZEGER, Chair, Department of Biostatistics, Johns Hopkins University School of Public Health, Baltimore, Maryland 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 Joseph T. Coyle, M.D., Chair, Consolidated Department of Psychiatry, Harvard Medical School, Belmont, Massachusetts, who 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 editors.

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Page ix Preface The design and conduct of any type of clinical trial requires three considerations: first, the study should examine valuable and important biomedical research questions; second, it must be based on a rigorous methodology that can answer a specific research question being asked; and third, it must be based on a set of ethical considerations, adherence to which minimizes risks to individuals. Whenever possible standard trial designs should be used in clinical trials. Moreover, investigators should strive to design clinical trials that contain adequate statistical power. However, there are times when the number of experimental subjects is unavoidably small. For example, the rapid progress that is occurring in a variety of areas of science (e.g. biotechnology, organ transplantation, gene therapy, cellular therapies, bioartificial organs, and designer genes tailored to an individual) has resulted in the need for clinical trials with small numbers of participants and new approaches to optimization of the design and analysis of clinical trials when the number of experimental participants (the sample size) in unavoidably small. Clinical trials with small numbers of participants, however, must address broad sets of issues different from those that must be addressed in trials with large numbers of participants. It is in those circumstances of trials with small sample sizes that approaches to optimization of the study design and data interpretation pose greater challenges.

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Page x Clinical trials involving astronauts share characteristics with clinical trials of the new technologies mentioned above, as astronauts comprise a population with small numbers of subjects, and many variables that affect this group during space travel cannot be controlled on Earth. However, interventions that prevent potentially life-threatening conditions such as accelerated bone mineral density loss on long space missions must be explored if long missions in space are to be successful. Therefore, the National Aeronautics and Space Administration (NASA) asked the Institute of Medicine (IOM) to convene a panel of experts to recommend optimal approaches to the design, implementation, and evaluation of outcomes in clinical trials with small numbers of participants. NASA commissioned this fast-track study because the opportunity to plan for the next clinical trial during a space mission was rapidly approaching and important questions needed to be answered. A group of experts in statistics, clinical research study design, epidemiology, and pharmacology made a major effort to prepare what I believe will be a widely useful report. Robert Gibbons, a biostatistician and liaison from the IOM Board on Health Sciences Policy, participated throughout the study as a full committee member. A centerpiece of the committee's activity was an invitational workshop. Experts from the United States and Canada spent a full day providing additional information and expertise to the committee during the invitational workshop discussing future directions for small clinical trials with small numbers of participants. Their efforts were particularly important in helping the committee prepare this report. After careful consideration the committee developed recommendations for approaching the issues and challenges inherent in clinical trials with small sample sizes. Moreover, the design and implementation of future research in this newly developing area of clinical investigation will improve the ability of investigators to evaluate outcomes efficiently and in a cost-effective manner to allow advances in medicine to be available to patients with life-threatening diseases in an efficient manner. Finally, the IOM staff, led by Charles Evans, contributed significantly to the find outcome. We owe a tremendous gratitude to Kathi Hanna, a highly skilled science writer, and to Veronica Schreiber, the research assistant on the project, for their untiring efforts and assistance to the committee throughout all phases of the study. Suzanne T. Ildstad Committee Chair

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Page xi Contents EXECUTIVE SUMMARY 1     Abstract, 1     Introduction, 2     Charge to the Committee and Plan of Action, 4     Findings, 5     Recommendations, 7     Concluding Remarks, 10 1     INTRODUCTION 12     When the Standard Approach to Clinical Trials Is Not Feasible, 13     A Search for Alternatives, 15     IOM Committee Process and Statement of Task, 18     Organization of the Report, 19 2     DESIGN OF SMALL CLINICAL TRIALS 20     Key Concepts in Clinical Trial Design, 21     Traditional Clinical Trial Designs, 37     Special Design Issues For Small Trials, 41     Summary, 57     Recommendations, 57

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Page xii 3     STATISTICAL APPROACHES TO ANALYSIS OF SMALL CLINICAL TRIALS 60     Sequential Analysis, 61     Hierarchical Models, 67     Bayesian Analysis, 71     Decision Analysis, 73     Statistical Prediction, 77     Meta-Analysis: Synthesis of Results of Independent Studies, 80     Risk-Based Allocation, 86     Summary, 87     Recommendations, 89 4     GENERAL GUIDELINES 91 REFERENCES 94 APPENDIXES     A     Study Methods 105     B     Glossary of Statistical and Clinical Trials Terms 130     C     Selected Bibliography on Small Clinical Trials 177     D     Committee and Staff Biographies 201

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Page xiii Small Clinical Trials

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