41.Design and Analysis of Clinical Trials- Concepts and Methodologies ( PDFDrive.com )

Design and Analysis of Clinical Trials WILEY SERIES IN PROBABILITY AND STATISTICS Established by WALTER A SHEWHART and SAMUEL S WILKS Editors: David J Balding, Noel A C Cressie, Garrett M Fitzmaurice, Harvey Goldstein, Iain M Johnstone, Geert Molenberghs, David W Scott, Adrian F M Smith, Ruey S Tsay, Sanford Weisberg Editors Emeriti: Vic Barnett, J Stuart Hunter, Joseph B Kadane, Jozef L Teugels A complete list of the titles in this series appears at the end of this volume Design and Analysis of Clinical Trials Concepts and Methodologies Third Edition SHEIN-CHUNG CHOW Department of Biostatistics and Bioinformatics Duke University Durham, North Carolina JEN-PEI LIU National Taiwan University Taipei, Taiwan National Health Research Institutes Zhunan, Taiwan C 2014 by John Wiley & Sons, Inc All rights reserved Copyright  Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, 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Chow, Shein-Chung, 1955Design and analysis of clinical trials: concepts and methodologies / Shein-Chung Chow, Jen-Pei Liu – 3rd ed p.cm Includes index ISBN 978-0470-88765-3 (cloth) Clinical trials–Methodology Clinical trials–Statistical methods I Liu, Jen-Pei, 1952–II Title R853.S7C48 2014 610.72 4–dc23 2012020270 Printed in the United States of America 10 Contents Preface xi PART I PRELIMINARIES Introduction 1.1 1.2 1.3 1.4 1.5 1.6 1.7 What are Clinical Trials?, History of Clinical Trials, Regulatory Process and Requirements, 10 Investigational New Drug Application, 17 New Drug Application, 24 Clinical Development and Practice, 31 AIMS and Structure of the Book, 42 Basic Statistical Concepts 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 45 Introduction, 45 Uncertainty and Probability, 46 Bias and Variability, 49 Confounding and Interaction, 57 Descriptive and Inferential Statistics, 66 Hypotheses Testing and p-Values, 68 Clinical Significance and Clinical Equivalence, 75 Reproducibility and Generalizability, 79 Basic Design Considerations 3.1 3.2 3.3 3.4 3.5 85 Introduction, 85 Goals of Clinical Trials, 86 Target Population and Patient Selection, 90 Selection of Controls, 97 Statistical Considerations, 105 v vi CONTENTS 3.6 3.7 Other Issues, 112 Discussion, 115 Randomization and Blinding 4.1 4.2 4.3 4.4 4.5 4.6 4.7 117 Introduction, 117 Randomization Models, 118 Randomization Methods, 124 Implementation of Randomization, 144 Generalization of Controlled Randomized Trials, 149 Blinding, 153 Discussion, 160 PART II DESIGNS AND THEIR CLASSIFICATIONS Designs for Clinical Trials 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 5.10 Introduction, 165 Parallel Group Designs, 167 Clustered Randomized Designs, 172 Crossover Designs, 177 Titration Designs, 185 Enrichment Designs, 191 Group Sequential Designs, 195 Placebo-Challenging Designs, 197 Blinded Reader Designs, 203 Discussion, 207 Designs for Cancer Clinical Trials 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 211 Introduction, 211 General Considerations for Phase I Cancer Clinical Trials, 213 Single-Stage Up-and-Down Phase I Designs, 214 Two-Stage Up-and-Down Phase I Designs, 217 Continual Reassessment Method Phase I Designs, 219 Optimal and Flexible Multiple-Stage Designs, 222 Randomized Phase II Designs, 229 Discussion, 232 Classification of Clinical Trials 7.1 7.2 7.3 7.4 165 Introduction, 237 Multicenter Trials, 238 Superiority Trials, 245 Active Control and Equivalence/Noninferiority Trials, 248 237 vii CONTENTS 7.5 7.6 7.7 7.8 7.9 7.10 Dose–Response Trials, 261 Combination Trials, 266 Bridging Studies and Global Trials, 278 Vaccine Clinical Trials, 285 QT Studies, 291 Discussion, 299 PART III ANALYSIS OF CLINICAL DATA Analysis of Continuous Data 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 10 389 Introduction, 389 Estimation of the Survival Function, 391 Comparison Between Survival Functions, 399 Cox’s Proportional Hazard Model, 405 Calendar Time and Information Time, 419 Group Sequential Methods, 424 Discussion, 438 Sample Size Determination 11.1 11.2 343 Introduction, 343 Statistical Inference for One Sample, 345 Inference of Independent Samples, 358 Ordered Categorical Data, 364 Combining Categorical Data, 368 Model-Based Methods, 374 Repeated Categorical Data, 382 Discussion, 387 Censored Data and Interim Analysis 10.1 10.2 10.3 10.4 10.5 10.6 10.7 11 Introduction, 305 Estimation, 306 Test Statistics, 310 Analysis of Variance, 316 Analysis of Covariance, 323 Nonparametric Methods, 325 Repeated Measures, 332 Discussion, 341 Analysis of Categorical Data 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 305 Introduction, 441 Basic Concept, 442 441 viii CONTENTS 11.3 11.4 11.5 11.6 11.7 11.8 11.9 11.10 11.11 11.12 Two Samples, 447 Multiple Samples, 456 Censored Data, 459 Dose–Response Studies, 464 Crossover Designs, 471 Equivalence and Noninferiority Trials, 481 Multiple-Stage Design in Cancer Trials, 490 Multinational Trials, 490 Comparing Variabilities, 500 Discussion, 517 PART IV ISSUES IN EVALUATION 12 Issues in Efficacy Evaluation 12.1 12.2 12.3 12.4 12.5 12.6 12.7 12.8 12.9 12.10 13 Introduction, 521 Baseline Comparison, 523 Intention-to-Treat Principle and Efficacy Analysis, 528 Adjustment for Covariates, 536 Multicenter Trials, 541 Multiplicity, 548 Data Monitoring, 558 Use of Genetic Information for Evaluation of Efficacy, 564 Sample Size Reestimation, 570 Discussion, 572 Safety Assessment 13.1 13.2 13.3 13.4 13.5 13.6 13.7 521 573 Introduction, 573 Extent of Exposure, 574 Coding of Adverse Events, 582 Analysis of Adverse Events, 595 Analysis of Laboratory Data, 602 Analysis of QT/QTc Prolongation, 610 Discussion, 615 PART V RECENT DEVELOPMENT 14 Biomarkers and Targeted Clinical Trials 14.1 14.2 Introduction, 619 Concepts and Strategies, 620 619 ... composed of 12 major offices These offices include Office of Management, Office of Communications, Office of Compliance, Office of Planning and Informatics, Office of Regulatory Policy, Office of Executive... M.D (DBNRS) (DBNR) OFFICE OF NEWDRUGS DIRECTOR John K Jankins, M.D (DBNB) OFFICE OF MANAGEMENT DIRECTOR Melanie Keller OFFICE OF DRUG EVALUATION I DIRECTOR Robert J, Temple, M.D (Acting) (DBNRA)... Mohab M Nasr, Ph.D (DBNSC) (DBNSB) OFFICE OF GENERIC DRUGS DIRECTOR Keth Webber, Ph.D (Actirig) (DBNS) OFFICE OF PHARMACEUTICAL SCIENCE DIRECTOR Helen N Wirkle (DBNC) OFFICE OF COMMUNICATION DIRECTOR