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Preface xi <p>PART I PRELIMINARIES</p> <p>1 Introduction 3</p> <p>1.1 What are Clinical Trials?, 3</p> <p>1.2 History of Clinical Trials, 4</p> <p>1.3 Regulatory Process and Requirements, 10</p> <p>1.4 Investigational New Drug Application, 17</p> <p>1.5 New Drug Application, 24</p> <p>1.6 Clinical Development and Practice, 31</p> <p>1.7 AIMS and Structure of the Book, 42</p> <p>2 Basic Statistical Concepts 45</p> <p>2.1 Introduction, 45</p> <p>2.2 Uncertainty and Probability, 46</p> <p>2.3 Bias and Variability, 49</p> <p>2.4 Confounding and Interaction, 57</p> <p>2.5 Descriptive and Inferential Statistics, 66</p> <p>2.6 Hypotheses Testing and p-Values, 68</p> <p>2.7 Clinical Significance and Clinical Equivalence, 75</p> <p>2.8 Reproducibility and Generalizability, 79</p> <p>3 Basic Design Considerations 85</p> <p>3.1 Introduction, 85</p> <p>3.2 Goals of Clinical Trials, 86</p> <p>3.3 Target Population and Patient Selection, 90</p> <p>3.4 Selection of Controls, 97</p> <p>3.5 Statistical Considerations, 105</p> <p>3.6 Other Issues, 112</p> <p>3.7 Discussion, 115</p> <p>4 Randomization and Blinding 117</p> <p>4.1 Introduction, 117</p> <p>4.2 Randomization Models, 118</p> <p>4.3 Randomization Methods, 124</p> <p>4.4 Implementation of Randomization, 144</p> <p>4.5 Generalization of Controlled Randomized Trials, 149</p> <p>4.6 Blinding, 153</p> <p>4.7 Discussion, 160</p> <p>PART II DESIGNS AND THEIR CLASSIFICATIONS</p> <p>5 Designs for Clinical Trials 165</p> <p>5.1 Introduction, 165</p> <p>5.2 Parallel Group Designs, 167</p> <p>5.3 Clustered Randomized Designs, 172</p> <p>5.4 Crossover Designs, 177</p> <p>5.5 Titration Designs, 185</p> <p>5.6 Enrichment Designs, 191</p> <p>5.7 Group Sequential Designs, 195</p> <p>5.8 Placebo-Challenging Designs, 197</p> <p>5.9 Blinded Reader Designs, 203</p> <p>5.10 Discussion, 207</p> <p>6 Designs for Cancer Clinical Trials 211</p> <p>6.1 Introduction, 211</p> <p>6.2 General Considerations for Phase I Cancer Clinical Trials, 213</p> <p>6.3 Single-Stage Up-and-Down Phase I Designs, 214</p> <p>6.4 Two-Stage Up-and-Down Phase I Designs, 217</p> <p>6.5 Continual Reassessment Method Phase I Designs, 219</p> <p>6.6 Optimal and Flexible Multiple-Stage Designs, 222</p> <p>6.7 Randomized Phase II Designs, 229</p> <p>6.8 Discussion, 232</p> <p>7 Classification of Clinical Trials 237</p> <p>7.1 Introduction, 237</p> <p>7.2 Multicenter Trials, 238</p> <p>7.3 Superiority Trials, 245</p> <p>7.4 Active Control and Equivalence/Noninferiority Trials, 248</p> <p>7.5 Dose–Response Trials, 261</p> <p>7.6 Combination Trials, 266</p> <p>7.7 Bridging Studies and Global Trials, 278</p> <p>7.8 Vaccine Clinical Trials, 285</p> <p>7.9 QT Studies, 291</p> <p>7.10 Discussion, 299</p> <p>PART III ANALYSIS OF CLINICAL DATA</p> <p>8 Analysis of Continuous Data 305</p> <p>8.1 Introduction, 305</p> <p>8.2 Estimation, 306</p> <p>8.3 Test Statistics, 310</p> <p>8.4 Analysis of Variance, 316</p> <p>8.5 Analysis of Covariance, 323</p> <p>8.6 Nonparametric Methods, 325</p> <p>8.7 Repeated Measures, 332</p> <p>8.8 Discussion, 341</p> <p>9 Analysis of Categorical Data 343</p> <p>9.1 Introduction, 343</p> <p>9.2 Statistical Inference for One Sample, 345</p> <p>9.3 Inference of Independent Samples, 358</p> <p>9.4 Ordered Categorical Data, 364</p> <p>9.5 Combining Categorical Data, 368</p> <p>9.6 Model-Based Methods, 374</p> <p>9.7 Repeated Categorical Data, 382</p> <p>9.8 Discussion, 387</p> <p>10 Censored Data and Interim Analysis 389</p> <p>10.1 Introduction, 389</p> <p>10.2 Estimation of the Survival Function, 391</p> <p>10.3 Comparison Between Survival Functions, 399</p> <p>10.4 Cox’s Proportional Hazard Model, 405</p> <p>10.5 Calendar Time and Information Time, 419</p> <p>10.6 Group Sequential Methods, 424</p> <p>10.7 Discussion, 438</p> <p>11 Sample Size Determination 441</p> <p>11.1 Introduction, 441</p> <p>11.2 Basic Concept, 442</p> <p>11.3 Two Samples, 447</p> <p>11.4 Multiple Samples, 456</p> <p>11.5 Censored Data, 459</p> <p>11.6 Dose–Response Studies, 464</p> <p>11.7 Crossover Designs, 471</p> <p>11.8 Equivalence and Noninferiority Trials, 481</p> <p>11.9 Multiple-Stage Design in Cancer Trials, 490</p> <p>11.10 Multinational Trials, 490</p> <p>11.11 Comparing Variabilities, 500</p> <p>11.12 Discussion, 517</p> <p>PART IV ISSUES IN EVALUATION</p> <p>12 Issues in Efficacy Evaluation 521</p> <p>12.1 Introduction, 521</p> <p>12.2 Baseline Comparison, 523</p> <p>12.3 Intention-to-Treat Principle and Efficacy Analysis, 528</p> <p>12.4 Adjustment for Covariates, 536</p> <p>12.5 Multicenter Trials, 541</p> <p>12.6 Multiplicity, 548</p> <p>12.7 Data Monitoring, 558</p> <p>12.8 Use of Genetic Information for Evaluation of Efficacy, 564</p> <p>12.9 Sample Size Reestimation, 570</p> <p>12.10 Discussion, 572</p> <p>13 Safety Assessment 573</p> <p>13.1 Introduction, 573</p> <p>13.2 Extent of Exposure, 574</p> <p>13.3 Coding of Adverse Events, 582</p> <p>13.4 Analysis of Adverse Events, 595</p> <p>13.5 Analysis of Laboratory Data, 602</p> <p>13.6 Analysis of QT/QTc Prolongation, 610</p> <p>13.7 Discussion, 615</p> <p>PART V RECENT DEVELOPMENT</p> <p>14 Biomarkers and Targeted Clinical Trials 619</p> <p>14.1 Introduction, 619</p> <p>14.2 Concepts and Strategies, 620</p> <p>14.3 Biomarker Development and Validation, 623</p> <p>14.4 Designs of Targeted Clinical Trials, 630</p> <p>14.5 Analyses of Targeted Clinical Trials, 640</p> <p>14.6 Discussion, 647</p> <p>15 Trials for Evaluating Accuracy of Diagnostic Devices 649</p> <p>15.1 Introduction, 649</p> <p>15.2 Study Design, 651</p> <p>15.3 Measures of Diagnostic Accuracy, 656</p> <p>15.4 Reporting Results, 663</p> <p>15.5 Sample Size Estimation, 672</p> <p>15.6 Discussion, 675</p> <p>16 Statistical Methods in Translational Medicine 677</p> <p>16.1 Introduction, 677</p> <p>16.2 Biomarker Development, 678</p> <p>16.3 Bench-to-Bedside, 682</p> <p>16.4 Animal Model Versus Human Model, 689</p> <p>16.5 Translation in Study Endpoints, 691</p> <p>16.6 Bridging Studies, 696</p> <p>16.7 Discussion, 699</p> <p>16.8 Appendix, 700</p> <p>17 Adaptive Clinical Trial Designs 703</p> <p>17.1 Introduction, 703</p> <p>17.2 What Is Adaptive Design?, 704</p> <p>17.3 Well-Understood and Less Well-Understood Designs, 709</p> <p>17.4 Clinical/Statistical and Regulatory Perspectives, 713</p> <p>17.5 Impact of Protocol Amendments, 716</p> <p>17.6 Challenges in By-Design Adaptations, 721</p> <p>17.7 Obstacles of Retrospective Adaptations, 727</p> <p>17.8 Discussion, 729</p> <p>18 Traditional Chinese Medicine 733</p> <p>18.1 Introduction, 733</p> <p>18.2 Fundamental Differences, 734</p> <p>18.3 Basic Considerations of TCM Clinical Trials, 741</p> <p>18.4 Other Issues in TCM Research and Development, 744</p> <p>18.5 Consortium for Globalization of Traditional Chinese Medicine, 751</p> <p>18.6 Discussion, 752</p> <p>PART VI CONDUCT OF CLINICAL TRIALS</p> <p>19 Preparation and Implementation of a Clinical Protocol 755</p> <p>19.1 Introduction, 755</p> <p>19.2 Structure and Components of a Protocol, 756</p> <p>19.3 Points to be Considered and Common Pitfalls During Development</p> <p>and Preparation of a Protocol, 762</p> <p>19.4 Common Departures for Implementation of a Protocol, 765</p> <p>19.5 Monitoring, Audit, and Inspection, 771</p> <p>19.6 Quality Assessment of a Clinical Trial, 775</p> <p>19.7 Discussion, 777</p> <p>20 Data Management of a Clinical Trial 779</p> <p>20.1 Introduction, 779</p> <p>20.2 Regulatory Requirements, 781</p> <p>20.3 Development of Case Report Forms, 783</p> <p>20.4 Database Development, 787</p> <p>20.5 Data Entry, Query, and Correction, 788</p> <p>20.6 Data Validation and Quality, 791</p> <p>20.7 Database Lock, Archive, and Transfer, 792</p> <p>20.8 Critical Issues, 795</p> <p>References 799</p> <p>Appendix A 845</p> <p>Index 851</p>

<p>?In summary, this third edition is an impressive expansion beyond a remarkable second edition. This book would be good reference for biostatisticians, clinical researchers, and pharmaceutical scientists in clinical research and development.? (<i>Journal of Biopharmaceutical Statistics</i>, 1 July 2014)</p><p>"<i>Design and Analysis of Clinical Trials: Concepts and Methodologies, Third Edition</i> is a grand feast for biostatisticians. It stands ready to satisfy the appetite of any pharmaceutical scientist with a respectable statistical appetite...Essential reading for clinical research professionals." (<i>Journal of Clinical Research Best Practice</i> February 2014)</p>

<p><b>SHEIN-CHUNG CHOW, PhD,</b> is Professor in the Department of Biostatistics and Bioinformatics at Duke University School of Medicine.</p> <p><b>JEN-PEI LIU, PhD,</b> is Professor in the Department of Agronomy and Institute of Epidemiology and Preventive Medicine at the National Taiwan University. He has authored multiple articles and books on clinical trials and been involved in clinical trials as a biostatistician for more than twenty-five years.</p>

<p>Praise for the <i>Second Edition</i></p> <p><i>". . . a grand feast for biostatisticians. It stands ready to satisfy the appetite of any pharmaceutical scientist with a respectable statistical appetite."<br /> </i>—Journal of Clinical Research Best Practices</p> <p>The <i>Third Edition</i> of <i>Design and Analysis of Clinical Trials</i> provides complete, comprehensive, and expanded coverage of recent health treatments and interventions. Featuring a unified presentation, the book provides a well-balanced summary of current regulatory requirements and recently developed statistical methods as well as an overview of the various designs and analyses that are utilized at different stages of clinical research and development. Additional features of this <i>Third Edition</i> include:</p> <ul> <li>New chapters on biomarker development and target clinical trials, adaptive design, trials for evaluating diagnostic devices, statistical methods for translational medicine, and traditional Chinese medicine</li> <li>A balanced overview of current and emerging clinical issues as well as newly developed statistical methodologies</li> <li>Practical examples of clinical trials that demonstrate everyday applicability, with illustrations and examples to explain key concepts</li> <li>New sections on bridging studies and global trials, QT studies, multinational trials, comparative effectiveness trials, and the analysis of QT/QTc prolongation</li> <li>A complete and balanced presentation of clinical and scientific issues, statistical concepts, and methodologies for bridging clinical and statistical disciplines</li> <li>An update of each chapter that reflects changes in regulatory requirements for the drug review and approval process and recent developments in statistical design and methodology for clinical research and development</li> </ul> <p><i>Design and Analysis of Clinical Trials, Third Edition</i> continues to be an ideal clinical research reference for academic, pharmaceutical, medical, and regulatory scientists/researchers, statisticians, and graduate-level students.</p>

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