Preface to the First Edition.

1. Introduction.

1.1 What are Clinical Trials?

1.2 History of Clinical Trials.

1.3 Regulatory Process and Requirements.

1.4 Investigational New Drug Application.

1.5 New Drug Application.

1.6 Clinical Development and Practice.

1.7 Aims and Structure of the Book.

2. Basic Statistical Concepts.

2.1 Introduction.

2.2 Uncertainty and Probability.

2.3 Bias and Variability.

2.4 Confounding and Interaction.

2.5 Descriptive and Inferential Statistics.

2.6 Hypothesis Testing and p-Values.

2.7 Clinical Significance and Clinical Equivalence.

2.8 Reproducibility and Generalizability.

3. Basic Design Considerations.

3.1 Introduction.

3.2 Goals of Clinical Trials.

3.3 Target Population and Patient Selection.

3.4 Selection of Controls.

3.5 Statistical Considerations.

3.6 Other Issues.

3.7 Discussion.

4. Randomization and Blinding.

4.1 Introduction.

4.2 Randomization Models.

4.3 Randomization Methods.

4.4 Implementation of Randomization.

4.5 Generalization of Controlled Randomized Trials.

4.6 Blinding.

4.7 Discussion.

5. Designs for Clinical Trials.

5.1 Introduction.

5.2 Parallel Group Designs.

5.3 Cluster Randomized Designs.

5.4 Crossover Designs.

5.5 Titration Designs.

5.6 Enrichment Designs.

5.7 Group Sequential Designs.

5.8 Placebo-Challenging Design.

5.9 Blinded Reader Designs.

5.10 Discussion.

6. Designs for Cancer Clinical Trials.

6.1 Introduction.

6.2 General Considerations for Phase I Cancer Clinical Trials.

6.3 Single-Stage Up-and-Down Phase I Designs.

6.4 Two-Stage Up-and-Down Phase I Designs.

6.5 Continual Reassessment Method Phase I Designs.

6.6 Optimal/Flexible Multiple-Stage Designs.

6.7 Randomized Phase II Designs.

6.8 Discussion.

7. Classification of Clinical Trials.

7.1 Introduction.

7.2 Multicenter Trial.

7.3 Superiority Trials.

7.4 Active Control and Equivalence/Noninferiority Trials.

7.5 Dose-Response Trials.

7.6 Combination Trials.

7.7 Bridging Studies.

7.8 Vaccine Clinical Trials.

7.9 Discussion.

8. Analysis of Continuous Data.

8.1 Introduction.

8.2 Estimation.

8.3 Test Statistics.

8.4 Analysis of Variance.

8.5 Analysis of Covariance.

8.6 Nonparametrics.

8.7 Repeated Measures.

8.8 Discussion.

9. Analysis of Categorical Data.

9.1 Introduction.

9.2 Statistical Inference for One Sample.

9.3 Inference of Independent Samples.

9.4 Ordered Categorical Data.

9.5 Combining Categorical Data.

9.6 Model-Based Methods.

9.7 Repeated Categorical Data.

9.8 Discussion.

10. Censored Data and Interim Analysis.

10.1 Introduction.

10.2 Estimation of the Survival Function.

10.3 Comparison between Survival Functions.

10.4 Cox’s Proportional Hazard Model.

10.5 Calendar Time and Information Time.

10.6 Group Sequential Methods.

10.7 Discussion.

11. Sample Size Determination.

11.1 Introduction.

11.2 Basic Concept.

11.3 Two Samples.

11.4 Multiple Samples.

11.5 Censored Data.

11.6 Dose-Response Studies.

11.7 Crossover Designs.

11.8 Equivalence and Noninferiority Trials.

11.9 Multiple-Stage Design in Cancer Trials.

11.10 Comparing Variabilities.

11.11 Discussion.

12. Issues in Efficacy Evaluation.

12.1 Introduction.

12.2 Baseline Comparison.

12.3 Intention-to-Treat Principle and Efficacy Analysis.

12.4 Adjustment for Covariates.

12.5 Multicenter Trials.

12.6 Multiplicity.

12.7 Data Monitoring.

12.8 Use of Genetic Information for Evaluation of Efficacy.

12.9 Sample Size Re-estimation.

12.10 Discussion.

13. Safety Assessment.

13.1 Introduction.

13.2 Extent of Exposure.

13.3 Coding of Adverse Events.

13.4 Analysis of Adverse Events.

13.5 Analysis of Laboratory Data.

13.6 Discussion.

14. Preparation and Implementation of a Clinical Protocol.

14.1 Introduction.

14.2 Structure and Components of a Protocol.

14.3 Points to Be Considered and Common Pitfalls during Development and Preparation of a Protocol.

14.4 Common Departures for Implementation of a Protocol.

14.5 Monitoring, Audit, and Inspection, 617

14.6 Quality Assessment of a Clinical Trial.

14.7 Discussion.

15. Clinical Data Management.

15.1 Introduction.

15.2 Regulatory Requirements.

15.3 Development of Case Report Forms.

15.4 Database Development.

15.5 Data Entry, Query, and Correction.

15.6 Data Validation and Quality.

15.7 Database Lock, Archive, and Transfer.

15.8 Discussion.

Bibliography.

Appendices.

Index.