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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 Evaluation—Congresses. 2. Medical
innovations- Evaluation—Congresses. 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 Studies—congresses. 2. Outcome end process
Assessment (Health CareWcongresses. 3. Research Design-
congresses. W 20.5 M689 1989]
R855.2.M63 1990
610'.72—dc20
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 procedures—which 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 interventions—questions 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
