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MEDICAL INNOVATION AT THE CROSSROADS VOLUME I dodern Methods of Clinical Investigation Annetine C. Gelijns Editor Committee on Technological Innovation in Medicine INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C. 1990

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NATIONAL ACADEMY PRESS ∑ 2101 Constitution Avenue, N.W. ∑ Washington, D.C. 20418 The Institute of Medicine was chartered in 1970 by the National Academy of Sciences to enlist dis- tinguished 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 advisor to the federal government and its own initiative in identifying issues of medical care, research, and education. The Committee on Technological Innovation in Medicine was established in 1988 by the Institute of Medicine to design a series of workshops that would (a) provide a more fundamental knowledge of the process by which biomedical research findings are translated into clinical prac- tice, and (b) address opportunities for improving the rationality and efficiency of this process. This volume consists of the proceedings of the first workshop in this series, "Improving the Translation of Research Findings into Clinical Practice: The Potential and Problems of Modern Methods of Clinical Investigation," held on May 3-4, 1989. This workshop and its proceedings were supported by the Howard Hughes Medical Institute and the National Center for Health Services Research of the Department of Health and Human Services (grant 5 RO9 HS055 26 02). The opinions and con- clusions expressed here are those of the authors and do not necessarily represent the views of the Howard Hughes Medical Institute, the Department of Health and Human Services, the National Academy of Sciences, or any of their constituent parts. Library of Congress Cataloging-in-Publication Data Modern methods of clinical investigation/Annetine C. Gelijns, editor ; Committee on Technological Innovation in Medicine, Institute of Medicine. p. cm. (Medical innovation at the crossroads; v. 1) Proceedings of a workshop held on May 3-4' 1989, supported by the Howard Hughes Medical Institute and the National Center for Health Services Research of the Department of Health and Human Services (grant 5 RO9 HS055 26 02). Includes bibliographical references. Includes index. ISBN 0-309-04286-0 1. Medicaltechnology EvaluationóCongresses. 2. Medical innovations- EvaluationóCongresses. 3. Medicalcare Technological innovations~ongresses. 4. Meta-analysis~ongresses. I. Gelijns, Annetine. II. Institute of Medicine (U.S.). Committee on Technological Innovation in Medicine. III. Howard Hughes Medical Institute. IV. National Center for Health Services Research. V. Series. [DNLM: 1. Evaluation Studiesócongresses. 2. Outcome end process Assessment (Health CareWcongresses. 3. Research Design- congresses. W 20.5 M689 1989] R855.2.M63 1990 610'.72ódc20 DNLM/DLC for Library of Congress Copyright (D 1990 by the National Academy of Sciences Printed in the United States of America 90-6195 CIP

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Committee on Technological Innovation in Medicine GERALD D. LAUBACH, Chair, President, Pfizer, Inc. SUSAN BARTLETT FOOTE, Associate Professor, School of Business Administration, University of California, Berkeley BEN L. HOLMES, Vice-President and General Manager, Medical Products Group, Hewlett-Packard Company WILLIAM N. HUBBARD, JR., Chair, Council on Health Care Technology, Institute of Medicine ROBERT I. LEVY, Chair, Forum on Drug Development and Regulation, Institute of Medicine, and President, Sandoz Research Institute KENNETH L. MELMON, Arthur L. Bloomfield Professor of Medicine and Pharmacology, Department of Medicine, Stanford University School of Medicine PAUL D. PARKMAN, Director, Center for Biologics Evaluation and Research, The Food and Drug Administration JOHN E. WENNBERG, Professor of Epidemiology, Department of Community and Family Medicine, Dartmouth Medical School . . .

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Acknowledgments The Committee on Technological Innovation in Medicine expresses its grati- tude to the authors for the high quality of the papers they prepared for this vol- ume. These papers were originally presented at the Institute of Medicine work- shop, "Improving the Translation of Research Findings into Clinical Practice: The Potential and Problems of Modern Methods of Clinical Investigation." The committee also recognizes the significant contributions of the moderators, panel discussants, and workshop participants who provided valuable insights into the issues discussed here. Special thanks are due to Paul Friedman, Dean for Academic Personnel at the University of California, San Diego, who pre- pared a written summary of the workshop discussions that was invaluable in the preparation of this volume. The committee also greatly appreciates the help provided by Frederick Telling, Vice-President for Planning and Policy at Pfizer, Inc. Finally, Edward Edelson is to be thanked for his skillful and expeditious editing of the papers in this volume. The committee expresses its gratitude to Samuel Thier, President of the Institute of Medicine, for his initiative on behalf of this committee's activities. The committee also is grateful for the substantive and organizational support of Enriqueta Bond, Executive Officer; Ruth Bulger, Director of the Health Sciences Policy Division; Steven Bongard, Director of the Forum on Drug Development; and Wallace Waterfall, Editor for the Institute of Medicine. The workshop and the publication of this volume would not have been possible without Holly Dawkins, who devoted considerable effort to the logistics of the meeting as well as to the preparation and review of several drafts of this manuscript. Cliff Goodman, Director of the Council on Health Care Technology, provided worthy administrative and substantive support of the v

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Vl ACKNOWLEDGMENTS committee's activities. Finally, we acknowledge a considerable debt to Annetine Gelijns, International Fellow of the Institute of Medicine and princi- pal staff officer to the committee, for her conceptualization of the workshop and the editing of this volume. The Committee on Technological Innovation in Medicine greatly appreci- ates the opportunity provided by the Howard Hughes Medical Institute and the National Center for Health Services Research and Technology Assessment (grant HS 055 26) to investigate the process of medical innovation. GERALD D. LAUBACH Chair Committee on Technological Innovation in Medicine

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Preface GERALD D. LAUBACH This volume summarizes the first of a series of Institute of Medicine (IOM) workshops whose intent is to critically examine the process by which biomedi- cal research is translated into actual benefits in medical practice. Contemporary biomedical research has given us a rich harvest of innova- tion new pharmaceuticals, biotechnology products, medical devices, and clin- ical proceduresówhich in the aggregate essentially define modern, cutting- edge medicine. As always, such success is accompanied by challenges and problems. Some critics believe that certain medical technologies have been adopted too quickly, at the peril of patients or their pocketbooks. As our expe- rience with AIDS has vividly demonstrated, others consider the pace of adop- tion to be far too slow, unnecessarily depriving patients of desperately needed medical advances. Cost has also become an important concern. The cost of biomedical research and development in general, and clinical investigation in particular, has escalated dramatically over the past two decades. Because the process of clinical assessment is such a critical determinant of the efficiency, effectiveness, and cost of developing medical technology, the IOM Committee on Technological Innovation in Medicine chose to devote its first workshop to an examination of the status and potential of newer tech- niques and methods in clinical evaluation. We were further encouraged to make this topic as our lead-off theme by two additional considerations. One of these is the fact that there now exists a considerable variety of relatively new techniques based on non-traditional statistical concepts, the availability of large medical data bases, and the like that suggest themselves as useful adjuncts to the process of clinical evaluation. But the appropriate application and ultimate power and usefulness of these methods are not entirely clear. . . V11

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. . . V111 PREFACE The second consideration underlying our choice is the notable broadening of the questions that are being asked of clinical evaluation. Society now seeks information about new biomedical technologies that goes beyond the traditional issues of safety and efficacy. In many cases, for example, a new pharmaceuti- cal might be appropriately evaluated not only against existing drugs for the same condition but also against alternative medical devices or procedures. Increasingly, we seek information about the longer-term impact of a medical intervention as it expresses itself in the real world of everyday clinical practice, as contrasted with the more focused and nearly ideal setting characteristic of controlled clinical trials. We ask, and indeed should ask, questions about rare and idiosyncratic consequences of medical interventionsóquestions that can only be practically answered through access to data bases accumulated after very large numbers of patient exposures. Here, again, newer methodologies present themselves as powerful additions to the more traditional techniques. Finally, the United States currently has a patchwork process of technology transfer in biomedicine. In particular, there is a concern that regulatory approaches developed over the past four decades may not be evolving suitably to keep up with the exponential growth in biomedical knowledge, more recent developments in the clinical evaluative sciences, and the changing economics of health care. Our regulatory system has grown more or less haphazardly, and one of its most notable features is a remarkable asymmetry across the different classes of technology. A new drug must undergo long and stringent testing to be approved for a given medical indication. But whereas this process of drug evaluation is closely regulated, the adoption of new clinical procedures essen- tially falls outside the regulatory scope unless the procedure should happen to use a new instrument, in which case regulatory agencies become involved to a limited degree, depending on the nature of the device. Powerful forces in con- temporary health policy, not least the concern about marked and inexplicable regional variations in medical practice, seem to be pressing toward a more con- sistent and even-handed assessment of all kinds of medical technology, includ- ing comparisons of alternative modalities of management for a given medical condition. The optimum approach and methodology for accomplishing this challenging task are yet to be defined. The papers presented at this workshop essentially address two questions about clinical evaluation: How well are we doing it? How can we improve it? They provide a rich variety of answers and other key insights, with examples drawn from clinical practice, evaluations, and statistical methodology. The clear sense that emerges is that we can do better, and that the tools for improve- ment are at hand. The committee held its second workshop in December 1989. It explored and analyzed the changing economics of technological innovation in medicine, drawing on experience in the United States, Europe, and Japan. At present, two

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PREFACE IX additional workshops on issues in medical innovation are being organized. Together, this series of workshops will offer a coherent body of study and analy- sis for improving our understanding of medical innovation. It is our hope that this work will encourage a more rational and efficient transfer of biomedical research findings into direct patient care.

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Contents LIST OF TABLES AND FIGURES LIST OF ABBREVIATIONS . 1. MEDICAL TECHNOLOGY DEVELOPMENT: AN INTRODUCTION TO THE INNOVATION-EVALUATION NEXUS Annetine C. Gelijns and Samuel 0. Thier 1 2. THE SELECTION OF ENDPOINTS IN EVALUATIVE RESEARCH John P. Bunker ............................................................ . X111 . . . XV11 16 ADVANCES IN HEALTH STATUS MEASUREMENT: THE POTENTL\L TO IMPROVE EXPERIMENTAL AND NON-EXPERIMENTAL DATA COLLECTION Marilyn Bergner 23 WHAT IS OUTCOMES RESEARCH? John E. Wennberg 33 5. STRENGTHS AND WEAKNESSES OF HEALTH INSURANCE DATA SYSTEMS FOR ASSESSING OUTCOMES Leslie L. Roos, Noralou P. Roos, Elliott S. Fisher, and Thomas A. Bubolz . .47

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. . X11 CONTENTS 6. PRESCRIPT ION-EVENT MONITORING: AN EXAMPLE OF TOTAL POPULATION POST-MARKETING DRUG SURVEILLANCE William H. W. Inman 68 7. THE ROLE OF DECISION ANALYSIS IN THE TRANSLATION OF RESEARCH FINDINGS INTO CLINICAL PRACTICE Albert G. Mulley, Jr. 78 8. META-ANALYSIS: A QUANTITATIVE APPROACH TO RESEARCH INTEGRATION Stephen B. Thacker 88 9. AN INTRODUCTION TO A BAYESIAN METHOD FOR META-ANALYSIS: THE CONFIDENCE PROFILE METHOD David M. Eddy, Vic Hasselblad, and Ross Shachter ~ ~ 10. SHOULD WE CHANGE THE RULES FOR EVALUATING MEDICAL TECHNOLOGIES? David M. Eddy ........................................................... 11. ATTITUDINAL FACTORS THAT INFLUENCE THE UTILIZATION OF MODERN EVALUATIVE METHODS Kenneth L. Melmon ...................................................... APPENDIXES COMPARING THE DEVELOPMENT OF DRUGS, DEVICES, AND CLINICAL PROCEDURES Annetine C. Gelijns .................................................... B. WORKSHOP AGENDA C. CONTRIBUTORS .101 117 135 ..147 202 ............................... 206

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List of Tables and Figures TABLES 3.1 Suggested domains of quality of life, 25 3.2 The dimensions of health status, 26 3.3 Comparison of the quality of general health measurements, 28 4.1 Members of the BPH assessment team, 34 4.2 Synopsis of BPH assessment: Prostatectomy versus watchful waiting, 36 5.1 Data requirements and types of studies using hospital data, 50 8.1 Accuracy of electronic fetal monitoring using Apgar score as measure of outcome, 93 8.2 Pooled data from six controlled trials assessing efficacy of routine elec- tronic fetal monitoring in labor, 94 9.1 Likelihood functions for various types of experimental designs, out- comes, and effect measures, 104 9.2 Results of a hypothetical randomized controlled clinical trial, 105 9.3 Results of a hypothetical randomized controlled clinical trial with dilu- tion, 107 9.4 Results of a hypothetical randomized controlled clinical trial with dilu- tion and uncertainty, 108 9.5 Results of two hypothetical randomized controlled clinical trials, 110 10.1 Susceptibility of various designs to biases, 125 A.1 Comparison of rationality/eff~ciency of technology development, 184 . . . x'~z

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XiV LIST OF TABLES AND FIGURES FIGURES 1.1 Small chemical differences but large clinical differences, 5 3.1 Overall Sickness Impact Profile (SIP) scores for different disease condi- tions or population groups, 31 4.1 Proposed trial of a trial: Preference design versus double-blind random- ized design, 40 5.1 Analytical effort involved to produce results for different types of data, 59 6.1 Variables in "the numbers game," 69 7.1 The role of decision analysis at the interface between clinical investiga- tion and clinical practice, 79 7.2 A simple decision tree, 80 7.3 A two-way sensitivity analysis that displays results of a decision analy- sis for men with symptoms of benign prostatic hyperplasia who are considering TARP, 81 7.4 The net cost per case of non-A non-B hepatitis prevented by use of a screening test as it varies with the sensitivity and specificity of the test, 84 7.5 Use of receiver operating characteristic (ROC) curves to define the chal- lenge region for a new diagnostic test, 85 7.6 Net medical care costs per case of hepatitis prevented by vaccination of susceptible populations with different annual attack rates, 86 9.1 Probability distribution A for an increase in five-year survival as a result of treatment' 106 9.2 Probability distribution B for an increase in five-year survival as a result of treatment, 108 9.3 Probability distribution C for an increase in five-year survival as a result of treatment, 109 9.4 Probability distribution D for an increase in five-year survival as a result of treatment, 110 9.5 Probability distribution E for an increase in five-year survival as a result of treatment, 111 9.6 Diagram of technology families, 113 10.1 Results of randomized controlled clinical trial of hypothetical treatment for hears attacks, 119 10.2 Probability distributions of effects of two hypothetical treatments for heart attacks, 120 10.3 Probability distributions of effects of a hypothetical treatment for heart attacks as estimated from two randomized controlled clinical trials, 121

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LIST OF TABLES AND FIGURES XV 10.4 Probability distributions of effects of a hypothetical treatment for heart attacks as estimated from two randomized controlled clinical trials, 122 10.5 Probability distributions of two controlled clinical trials of breast cancer screening taken at face value, 123 10.6 Probability distributions for Swedish randomized controlled clinical trial taken at face value and adjusted for biases, 131 10.7 Probability distributions for Swedish randomized controlled clinical trial taken at face value and adjusted for biases and for DOM case-control study taken at face value and adjusted for biases, 132 A.1 A linear model of the innovation chain, 148 A.2 An interactive model of research, development, and diffusion streams, 150 A.3 Origin of NCEs on which Beds have been filed by U.S.-owned firms, 176 A.4 Possible impediments to future drug development, 179

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List of Abbreviations AIDS Acquired Immune Deficiency Syndrome AUA American Urological Association BPH Benign Prostatic Hyperplasia CABG Coronary Artery Bypass Grafting CON Certificate of Need CSM Committee on Safety of Medicines (United Kingdom) DES Diethylstilbestrol DSRU Drug Safety Research Unit (United Kingdom) FDA Food and Drug Administration FD&CA Food, Drug, and Cosmetics Act GAO General Accounting Office GMP Good Manufacturing Practices HCFA Health Care Financing Administration IDE Investigational Device Exemption IMS Intercontinental Medical Statistics Limited IND Investigational New Drug IOM Institute of Medicine IRE Institutional Review Board MRI Magnetic Resonance Imaging NCE New Chemical Entity NDA New Drug Application NHLBI National Heart, Lung, and Blood Institute NIH National Institutes of Health NSAIDs Non-steroidal Anti-inflammatory Drugs PEM Prescription-Event Monitoring (United Kingdom) . . XV11

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LIST OF ABBREVIATIONS PMA Pre-marketing Application for Devices PMS Post-marketing Surveillance POARP Patient Outcomes Assessment Research Program PPA Prescription Pricing Authority (United Kingdom) PPS Prospective Payment System PICA Percutaneous Transluminal Coronary Angioplasty R&D Research and Development RCT Randomized Controlled Clinical Trial ROC Receiver Operating Characteristic :-PA Tissue Plasminogen Activator TARP Transurethral Resection of the Prostate xviii