Design and Analysis of Clinical Trials

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