Methods and applications of statistics in clinical trials. Volume 1, concepts, principles, trials, and design

994 Pages·2014·62.55 MB·English

Methods and Applications of
Statistics in Clinical Trials
Volume 1
WILEY SERIES IN METHODS AND APPLICATIONS
OF STATISTICS
Advisory Editor
N. Balakrishnan
McMaster University, Canada
The Wiley Series in Methods and Applications of Statistics is a unique grouping of research that
features classic contributions from Wiley's Encyclopedia of Statistical Sciences, Second Edition
(ESS, 2e) alongside newly written articles that explore various problems of interest and their intrin-
sic connection to statistics. The goal of this collection is to encompass an encyclopedic scope of
coverage within individual books that unify the most important and interesting applications of sta-
tistics within a specific field of study. Each book in the series successfully upholds the goals of
ESS, 2e by combining established literature and newly developed contributions written by leading
academics, researchers, and practitioners in a comprehensive and accessible format. The result is a
succinct reference that unveils modern, cutting-edge approaches to acquiring, analyzing, and pre-
senting data across diverse subject areas.
WILEY SERIES IN METHODS AND APPLICATIONS OF STATISTICS
Balakrishnan · Methods and Applications of Statistics in the Life and Health Sciences
Balakrishnan · Methods and Applications of Statistics in Business, Finance, and
Management Science
Balakrishnan · Methods and Applications of Statistics in Engineering, Quality Control, and the
Physical Sciences
Balakrishnan · Methods and Applications of Statistics in the Social and Behavioral Sciences
Balakrishnan · Methods and Applications of Statistics in the Atmospheric and Earth Sciences
Balakrishnan · Methods and Applications of Statistics in Clinical Trials, Volume 1: Concepts,
Principles, Trials, and Designs
Balakrishnan · Methods and Applications of Statistics in Clinical Trials, Volume 2: Planning,
Analysis, and Inferential Methods
Methods and Applications of
Statistics in Clinical Trials
Volume 1
Concepts, Principles, Trials, and Design
Edited by
N. Balakrishnan
McMaster University
Department of Mathematics and Statistics
Hamilton, Ontario, Canada
W I L EY
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Library of Congress Cataloging-in-Publication Data:
Methods and applications of statistics in clinical trials / [edited by] N. Balakrishnan.
1 online resource. — (Methods and applications of statistics)
Includes bibliographical references and index.
Description based on print version record and CIP data provided by publisher; resource not viewed.
ISBN 978-1-118-59591-6 (ePub) — ISBN 978-1-118-59592-3 (Adobe PDF) — ISBN 978-1-118-59596-1
(ePub) — ISBN 978-1-118-59597-8 (Adobe PDF) — ISBN 978-1-118-30473-0 (cloth)
I. Balakrishnan, N., 1956- editor of compilation.
[DNLM: 1. Clinical Trials as Topic. 2. Statistics as Topic. QV 771.4]
R853.C55
610.72'4—dc23 2013035130
Printed in the United States of America.
10 9 8 7 6 5 4 3 21
Contents
Contributors xxiii
Preface xxix
1 Absolute Risk Reduction 1
1.1 Introduction 1
1.2 Preliminary Issues 1
1.3 Point and Interval Estimates for a Single Proportion 2
1.4 An Unpaired Difference of Proportions 5
1.5 Number Needed to Treat 8
1.6 A Paired Difference of Proportions 10
References 11
Further Reading 12
2 Accelerated Approval 14
2.1 Introduction 14
2.2 Accelerated Development Versus Expanded Access in the U.S.A 14
2.3 Sorting the Terminology—Which FDA Initiatives Do What? 15
2.4 Accelerated Approval Regulations: 21 C.F.R. 314.500, 314.520, 601.40 . 16
2.5 Stages of Drug Development and FDA Initiatives 16
2.6 Accelerated Approval Regulations: 21 CFR 314.500, 314.520, 601.40 . . 17
2.7 Accelerated Approval with Surrogate Endpoints 18
2.8 Accelerated Approval with Restricted Distribution 20
2.9 Phase IV Studies/Post Marketing Surveillance 20
2.10 Benefit Analysis for Accelerated Approvals Versus Other Illnesses . .. 21
2.11 Problems, Solutions, and Economic Incentives 22
2.12 Future Directions 24
References 25
Further Reading 26
3 AIDS Clinical Trials Group (ACTG) 27
3.1 Introduction 27
3.2 A Brief Primer on HIV/AIDS 27
3.3 ACTG Overview 28
v
VZ Contents
3.4 ACTG Scientific Activities 29
3.5 Development of Potent Antiretroviral Therapy (ART) 29
3.6 Expert Systems and Infrastructure 36
References 37
4 Algorithm-Based Designs 40
4.1 Phase I Dose-Finding Studies 40
4.2 Accelerated Designs 43
4.3 Model-Based Approach in the Estimation of MTD 46
4.4 Exploring Algorithm-Based Designs With Prespecified Targeted Toxicity
Levels 48
References 51
5 Alpha-Spending Function 53
5.1 Introduction 53
5.2 Alpha Spending Function Motivation 54
5.3 The Alpha Spending Function 56
5.4 Application of the Alpha Spending Function 57
5.5 Confidence Intervals and Estimation 59
5.6 Trial Design 59
5.7 Conclusions 61
References 61
Further Reading 63
6 Application of New Designs in Phase I Trials 65
6.1 Introduction 65
6.2 Objectives of a Phase I Trial 65
6.3 Standard Designs and Their Shortcomings 66
6.4 Some Novel Designs 67
6.5 Discussion 72
References 72
Further Reading 73
7 ASCOT Trial 74
7.1 Introduction 74
7.2 Objectives 74
7.3 Study Design 74
7.4 Results 75
7.5 Discussion and Conclusions 77
References 78
8 Benefit/Risk Assessment in Prevention Trials 80
8.1 Introduction 80
8.2 Types of B/RAs Performed in Prevention Trials 81
8.3 Alternative Structures of the Benefit/Risk Algorithm used in Prevention
Trials 82
8.4 Methodological and Practical Issues with B/RA in Prevention Trials . . 84
References 87
Contents νίί
9 Biased Coin Randomization 90
9.1 Randomization Strategies for Overall Treatment Balance 90
9.2 The Biased Coin Randomization Procedure 91
9.3 Properties 92
9.4 Extensions to the Biased Coin Randomization 92
9.5 Adaptive Biased Coin Randomization 94
9.6 Urn Models 99
9.7 Treatment Balance for Covariates 102
9.8 Application of Biased Coin Designs to Response-Adaptive Randomization 103
References 104
10 Biological Assay, Overview 106
10.1 Introduction 106
10.2 Direct Dilution Assays 108
10.3 Indirect Dilution Assays 109
10.4 Indirect Quantal Assays 113
10.5 Stochastic Approximation in Bioassay 116
10.6 Radioimmunoassay 117
10.7 Dosimetry and Bioassay 118
10.8 Semiparametrics in Bioassays 119
10.9 Nonparametrics in Bioassays 119
10.10 Bioavailability and Bioequivalence Models 120
10.11 Pharmacogenomics in Modern Bioassays 121
10.12 Complexities in Bioassay Modeling and Analysis 122
References 122
Further Reading 124
11 Block Randomization 125
11.1 Introduction 125
11.2 Simple Randomization 125
11.3 Restricted Randomization Through the Use of Blocks 126
11.4 Schemes Using a Single Block for the Whole Trial 130
11.5 Use of Unequal and Variable Block Sizes 131
11.6 Inference and Analysis Following Blocked Randomization 134
11.7 Miscellaneous Topics Related to Blocked Randomization 135
References 136
Further Reading 138
12 Censored Data 139
12.1 Introduction 139
12.2 Independent Censoring 140
12.3 Likelihoods: Noninformative Censoring 143
12.4 Other Kinds of Incomplete Observation 143
References 144
viii Contents
13 Clinical Data Coordination 146
13.1 Introduction 146
13.2 Study Initiation 147
13.3 Study Conduct 151
13.4 Study Closure 158
13.5 Summary 161
References 162
14 Clinical Data Management 164
14.1 Introduction 164
14.2 How Has Clinical Data Management Evolved? 165
14.3 Electronic Data Capture 166
14.4 Regulatory Involvement with Clinical Data Management 167
14.5 Professional Societies 167
14.6 Look to the Future 168
14.7 Conclusion 169
References 169
15 Clinical Significance 170
15.1 Introduction 170
15.2 Historical Background 170
15.3 Article Outline 171
15.4 Design and Methodology 171
15.5 Examples 181
15.6 Recent Developments 181
15.7 Concluding Remarks 185
References 185
16 Clinical Trial Misconduct 191
16.1 The Scope of this Article 191
16.2 Why Does Research Misconduct Matter? 191
16.3 Early Cases 192
16.4 Definition 193
16.5 Intent 194
16.6 What Scientific Misconduct was Not 194
16.7 The Process 194
16.8 The Past Decade 195
16.9 Lessons from the U.S. Experience 196
16.10 Outside the United States 197
16.11 Scientific Misconduct During Clinical Trials 198
16.12 Audit 198
16.13 Causes 199
16.14 Prevalence 200
16.15 Peer Review and Misconduct 200
16.16 Retractions 201
16.17 Prevention 201
References 202