Preface xi PART I PRELIMINARIES 1 Introduction 3 1.1 What are Clinical Trials?, 3 1.2 History of Clinical Trials, 4 1.3 Regulatory Process and Requirements, 10 1.4 Investigational New Drug Application, 17 1.5 New Drug Application, 24 1.6 Clinical Development and Practice, 31 1.7 AIMS and Structure of the Book, 42 2 Basic Statistical Concepts 45 2.

1 Introduction, 45 2.2 Uncertainty and Probability, 46 2.3 Bias and Variability, 49 2.4 Confounding and Interaction, 57 2.5 Descriptive and Inferential Statistics, 66 2.6 Hypotheses Testing and p-Values, 68 2.7 Clinical Significance and Clinical Equivalence, 75 2.8 Reproducibility and Generalizability, 79 3 Basic Design Considerations 85 3.

1 Introduction, 85 3.2 Goals of Clinical Trials, 86 3.3 Target Population and Patient Selection, 90 3.4 Selection of Controls, 97 3.5 Statistical Considerations, 105 3.6 Other Issues, 112 3.7 Discussion, 115 4 Randomization and Blinding 117 4.1 Introduction, 117 4.

2 Randomization Models, 118 4.3 Randomization Methods, 124 4.4 Implementation of Randomization, 144 4.5 Generalization of Controlled Randomized Trials, 149 4.6 Blinding, 153 4.7 Discussion, 160 PART II DESIGNS AND THEIR CLASSIFICATIONS 5 Designs for Clinical Trials 165 5.1 Introduction, 165 5.2 Parallel Group Designs, 167 5.

3 Clustered Randomized Designs, 172 5.4 Crossover Designs, 177 5.5 Titration Designs, 185 5.6 Enrichment Designs, 191 5.7 Group Sequential Designs, 195 5.8 Placebo-Challenging Designs, 197 5.9 Blinded Reader Designs, 203 5.10 Discussion, 207 6 Designs for Cancer Clinical Trials 211 6.

1 Introduction, 211 6.2 General Considerations for Phase I Cancer Clinical Trials, 213 6.3 Single-Stage Up-and-Down Phase I Designs, 214 6.4 Two-Stage Up-and-Down Phase I Designs, 217 6.5 Continual Reassessment Method Phase I Designs, 219 6.6 Optimal and Flexible Multiple-Stage Designs, 222 6.7 Randomized Phase II Designs, 229 6.8 Discussion, 232 7 Classification of Clinical Trials 237 7.

1 Introduction, 237 7.2 Multicenter Trials, 238 7.3 Superiority Trials, 245 7.4 Active Control and Equivalence/Noninferiority Trials, 248 7.5 Dose-Response Trials, 261 7.6 Combination Trials, 266 7.7 Bridging Studies and Global Trials, 278 7.8 Vaccine Clinical Trials, 285 7.

9 QT Studies, 291 7.10 Discussion, 299 PART III ANALYSIS OF CLINICAL DATA 8 Analysis of Continuous Data 305 8.1 Introduction, 305 8.2 Estimation, 306 8.3 Test Statistics, 310 8.4 Analysis of Variance, 316 8.5 Analysis of Covariance, 323 8.6 Nonparametric Methods, 325 8.

7 Repeated Measures, 332 8.8 Discussion, 341 9 Analysis of Categorical Data 343 9.1 Introduction, 343 9.2 Statistical Inference for One Sample, 345 9.3 Inference of Independent Samples, 358 9.4 Ordered Categorical Data, 364 9.5 Combining Categorical Data, 368 9.6 Model-Based Methods, 374 9.

7 Repeated Categorical Data, 382 9.8 Discussion, 387 10 Censored Data and Interim Analysis 389 10.1 Introduction, 389 10.2 Estimation of the Survival Function, 391 10.3 Comparison Between Survival Functions, 399 10.4 Cox''s Proportional Hazard Model, 405 10.5 Calendar Time and Information Time, 419 10.6 Group Sequential Methods, 424 10.

7 Discussion, 438 11 Sample Size Determination 441 11.1 Introduction, 441 11.2 Basic Concept, 442 11.3 Two Samples, 447 11.4 Multiple Samples, 456 11.5 Censored Data, 459 11.6 Dose-Response Studies, 464 11.7 Crossover Designs, 471 11.

8 Equivalence and Noninferiority Trials, 481 11.9 Multiple-Stage Design in Cancer Trials, 490 11.10 Multinational Trials, 490 11.11 Comparing Variabilities, 500 11.12 Discussion, 517 PART IV ISSUES IN EVALUATION 12 Issues in Efficacy Evaluation 521 12.1 Introduction, 521 12.2 Baseline Comparison, 523 12.3 Intention-to-Treat Principle and Efficacy Analysis, 528 12.

4 Adjustment for Covariates, 536 12.5 Multicenter Trials, 541 12.6 Multiplicity, 548 12.7 Data Monitoring, 558 12.8 Use of Genetic Information for Evaluation of Efficacy, 564 12.9 Sample Size Reestimation, 570 12.10 Discussion, 572 13 Safety Assessment 573 13.1 Introduction, 573 13.

2 Extent of Exposure, 574 13.3 Coding of Adverse Events, 582 13.4 Analysis of Adverse Events, 595 13.5 Analysis of Laboratory Data, 602 13.6 Analysis of QT/QTc Prolongation, 610 13.7 Discussion, 615 PART V RECENT DEVELOPMENT 14 Biomarkers and Targeted Clinical Trials 619 14.1 Introduction, 619 14.2 Concepts and Strategies, 620 14.

3 Biomarker Development and Validation, 623 14.4 Designs of Targeted Clinical Trials, 630 14.5 Analyses of Targeted Clinical Trials, 640 14.6 Discussion, 647 15 Trials for Evaluating Accuracy of Diagnostic Devices 649 15.1 Introduction, 649 15.2 Study Design, 651 15.3 Measures of Diagnostic Accuracy, 656 15.4 Reporting Results, 663 15.

5 Sample Size Estimation, 672 15.6 Discussion, 675 16 Statistical Methods in Translational Medicine 677 16.1 Introduction, 677 16.2 Biomarker Development, 678 16.3 Bench-to-Bedside, 682 16.4 Animal Model Versus Human Model, 689 16.5 Translation in Study Endpoints, 691 16.6 Bridging Studies, 696 16.

7 Discussion, 699 16.8 Appendix, 700 17 Adaptive Clinical Trial Designs 703 17.1 Introduction, 703 17.2 What Is Adaptive Design?, 704 17.3 Well-Understood and Less Well-Understood Designs, 709 17.4 Clinical/Statistical and Regulatory Perspectives, 713 17.5 Impact of Protocol Amendments, 716 17.6 Challenges in By-Design Adaptations, 721 17.

7 Obstacles of Retrospective Adaptations, 727 17.8 Discussion, 729 18 Traditional Chinese Medicine 733 18.1 Introduction, 733 18.2 Fundamental Differences, 734 18.3 Basic Considerations of TCM Clinical Trials, 741 18.4 Other Issues in TCM Research and Development, 744 18.5 Consortium for Globalization of Traditional Chinese Medicine, 751 18.6 Discussion, 752 PART VI CONDUCT OF CLINICAL TRIALS 19 Preparation and Implementation of a Clinical Protocol 755 19.

1 Introduction, 755 19.2 Structure and Components of a Protocol, 756 19.3 Points to be Considered and Common Pitfalls During Development and Preparation of a Protocol, 762 19.4 Common Departures for Implementation of a Protocol, 765 19.5 Monitoring, Audit, and Inspection, 771 19.6 Quality Assessment of a Clinical Trial, 775 19.7 Discussion, 777 20 Data Management of a Clinical Trial 779 20.1 Introduction, 779 20.

2 Regulatory Requirements, 781 20.3 Development of Case Report Forms, 783 20.4 Database Development, 787 20.5 Data Entry, Query, and Correction, 788 20.6 Data Validation and Quality, 791 20.7 Database Lock, Archive, and Transfer, 792 20.8 Critical Issues, 795 References 799 Appendix A 845 Index 851.