Methods_and_applications_of_statistics in clinical trial 1.pdf

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 Wileys 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 WILEY Copyright 2014 by John Wiley&Sons,Inc.All rights reserved.Published by John Wiley&Sons,Inc.,Hoboken,New Jersey.All rights reserved.Published simultaneously in Canada.No part of this publication may be reproduced,stored in a retrieval system,or transmitted in any form or by any means,electronic,mechanical,photocopying,recording,scanning,or otherwise,except as permitted under Section 107 or 108 of the 1976 United States Copyright Act,without either the prior written permission of the Publisher,or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center,Inc.,222 Rosewood Drive,Danvers,MA 01923,(978)750-8400,fax(978)750-4470,or on the web at .Requests to the Publisher for permission should be addressed to the Permissions Department,John Wiley&Sons,Inc.,111 River Street,Hoboken,NJ 07030,(201)748-6011,fax(201)748-6008,or online at http:/ of Liability/Disclaimer of Warranty:While the publisher and author have used their best efforts in preparing this book,they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose.No warranty may be created or extended by sales representatives or written sales materials.The advice and strategies contained herein may not be suitable for your situation.You should consult with a professional where appropriate.Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages,including but not limited to special,incidental,consequential,or other damages.For general information on our other products and services or for technical support,please contact our Customer Care Department within the United States at(800)762-2974,outside the United States at(317)572-3993 or fax(317)572-4002.Wiley also publishes its books in a variety of electronic formats.Some content that appears in print may not be available in electronic format.For information about Wiley products,visit our web site at .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 610.724dc23 2013035130 Printed in the United States of America.10 9 8 7 6 5 4 3 2 1 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 TerminologyWhich 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 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 Contents ix 17 Clinical Trials,Early Cancer and Heart Disease 205 17.1 Introduction 205 17.2 Developments in Clinical Trials at the National Cancer Institute(NCI)205 17.3 Developments in Clinical Trials at the National Heart,Lung,and Blood Institute(NHLBI)209 References 213 18 Cluster Randomization 216 18.1 Introduction 216 18.2 Examples of Cluster Randomization Trials 217 18.3 Principles of Experimental Design 218 18.4 Experimental and Quasi-Experimental Designs 219 18.5 The Effect of Failing to Replicate 220 18.6 Sample Size Estimation 221 18.7 Cluster Level Analyses 222 18.8 Individual Level Analyses 223 18.9 Incorporating Repeated Assessments 225 18.10 Study Reporting 226 18.11 Meta-Analysis 227 References 228 19 Coherence in Phase I Clinical Trials 230 19.1 Introduction 230 19.2 Coherence:Definitions and Organization 230 19.3 Coherent Designs 232 19.4 Compatible Initial Design 233 19.5 Group Coherence 234 19.6 Real-Time Coherence 235 19.7 Discussion 238 References 238 20 Compliance and Survival Analysis 240 20.1 Compliance:Cause and Effect 240 20.2 All-or-Nothing Compliance 241 20.3 More General Exposure Patterns 242 20.4 Other Structural Modeling Options 242 References 244 21 Composite Endpoints in Clinical Trials 246 21.1 Introduction 246 21.2 The Rationale for Composite Endpoints 246 21.3 Formulation of Composite Endpoints 247 21.4 Examples 248 21.5 Interpreting Composite Endpoints 250 21.6 Conclusions 251 References 251 X Contents 22 Confounding 252 22.1 Introduction 252 22.2 Confounding as a Bias in Effect Estimation 252 22.3 Confounding and Noncollapsibility 258 22.4 Confounding in Experimental Design 260 References 261 23 Control Groups 263 23.1 Introduction 263 23.2 History 263 23.3 Ethics 264 23.4 Types of Control Groups:Historical Controls 266 23.5 Types of Control Groups:Randomized Controls 268 23.6 Conclusion 271 References 271 24 Coronary Drug Project 273 24.1 Introduction 273 24.2 Objectives 273 24.3 Study Design and Methods 273 24.4 Results 275 24.5 Conclusions and Lessons Learned 281 References 282 Further Reading 284 25 Covariates 285 25.1 Universal Character of Covariates 285 25.2 Use of Covariates in Clinical Trials 286 25.3 Continuous Covariates:Categorization or Functional Form?293 25.4 Reporting and Summary Assessment of Prognostic Markers 295 References 296 26 Crossover Design 300 26.1 Introduction 300 26.2 The Two-Period,Two-Treatment Design 301 26.3 Higher Order Designs 304 26.4 Model-Based Analyses 307 References 308 27 Crossover Trials 310 27.1 Introduction 310 27.2 2 x 2 Crossover Trial 312 27.3 Higher-Order Designs for Two Treatments 312 27.4 Designs for Three or More Treatments 312 27.5 Analysis of Continuous Data 314 27.6 Analysis of Discrete Data 315 27.7 Concluding Remarks 317 References.317 Contents XI 28 Diagnostic Studies 320 28.1 Introduction 320 28.2 Diagnostic Studies 320 28.3 Reliability 324 28.4 Validity 331 References 338 Further Reading 339 29 DNA Bank 340 29.1 Definition and Objectives of DNA Biobanks 340 29.2 Types of DNA Biobanks 343 29.3 Types of Samples Stored 344 29.4 Quality Assurance and Quality Control in DNA Biobanks 345 29.5 Ethical Issues 346 29.6 Current Biobank Initiatives 348 29.7 Conclusions 350 References 350 30 Up-and-Down and Escalation Designs 353 30.1 Introduction 353 30.2 Up-and-Down Designs 353 30.3 Escalation Designs 357 30.4 Comparing U&D,Escalation and Model-Based Designs 359 References 359 Further Reading 361 31 Dose Ranging Crossover Designs 362 31.1 Introduction 362 31.2 Titration Designs and Extension Studies 369 31.3 Randomized Designs 373 31.4 Discussion and Conclusion 376 References 379 Further Reading 382 32 Flexible Designs 383 32.1 Introduction 383 32.2 The General Framework 384 32.3 Conditional Power and Sample Size Reassessment 387 32.4 Extending the Flexibility to the Choice of the Number of Stages.392 32.5 Selection of the Test Statistic 393 32.6 More General Adaptations and Multiple Hypotheses Testing 393 32.7 An Example 395 32.8 Conclusion 395 References 396 X Contents 33 Gene Therapy 399 33.1 Introduction 399 33.2 Requirements for Successful Therapeutic Intervention 399 33.3 Pre-Clinical Research 402 33.4 Translational Challenges of Gene Therapy Trials 404 33.5 Clinical Trials 407 33.6 Lessons Learned 408 33.7 The Way Forward 411 References 411 Further Reading 422 34 Global Assessment Variables 423 34.1 Introduction 423 34.2 Scientific Questions for Multiple Outcomes 423 34.3 General Comments on the GST 424 34.4 Recoding Outcome Measures 424 34.5 Types of Global Statistical Tests(GSTs)425 34.6 Other Considerations 428 34.7 Other Methods 430 34.8 Examples of the Application of GST 434 34.9 Conclusions 435 References 435 35 Good Clinical Practice(GCP)438 35.1 Introduction 438 35.2 Human Rights and Protections 438 35.3 Informed Consent 439 35.4 Investigational Protocol 439 35.5 Investigators Brochure 440 35.6 Inves