Design and Analysis of Clinical Trials

SHEIN-CHUNG CHOW, PhD, is Professor in the Department of Biostatistics and Bioinformatics at Duke University School of Medicine.JEN-PEI LIU, PhD, 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.

• Preface xi PART I PRELIMINARIES1 Introduction 31.1 What are Clinical Trials?, 31.2 History of Clinical Trials, 41.3 Regulatory Process and Requirements, 101.4 Investigational New Drug Application, 171.5 New Drug Application, 241.6 Clinical Development and Practice, 311.7 AIMS and Structure of the Book, 422 Basic Statistical Concepts 452.1 Introduction, 452.2 Uncertainty and Probability, 462.3 Bias and Variability, 492.4 Confounding and Interaction, 572.5 Descriptive and Inferential Statistics, 662.6 Hypotheses Testing and p-Values, 682.7 Clinical Significance and Clinical Equivalence, 752.8 Reproducibility and Generalizability, 793 Basic Design Considerations 853.1 Introduction, 853.2 Goals of Clinical Trials, 863.3 Target Population and Patient Selection, 903.4 Selection of Controls, 973.5 Statistical Considerations, 1053.6 Other Issues, 1123.7 Discussion, 1154 Randomization and Blinding 1174.1 Introduction, 1174.2 Randomization Models, 1184.3 Randomization Methods, 1244.4 Implementation of Randomization, 1444.5 Generalization of Controlled Randomized Trials, 1494.6 Blinding, 1534.7 Discussion, 160PART II DESIGNS AND THEIR CLASSIFICATIONS5 Designs for Clinical Trials 1655.1 Introduction, 1655.2 Parallel Group Designs, 1675.3 Clustered Randomized Designs, 1725.4 Crossover Designs, 1775.5 Titration Designs, 1855.6 Enrichment Designs, 1915.7 Group Sequential Designs, 1955.8 Placebo-Challenging Designs, 1975.9 Blinded Reader Designs, 2035.10 Discussion, 2076 Designs for Cancer Clinical Trials 2116.1 Introduction, 2116.2 General Considerations for Phase I Cancer Clinical Trials, 2136.3 Single-Stage Up-and-Down Phase I Designs, 2146.4 Two-Stage Up-and-Down Phase I Designs, 2176.5 Continual Reassessment Method Phase I Designs, 2196.6 Optimal and Flexible Multiple-Stage Designs, 2226.7 Randomized Phase II Designs, 2296.8 Discussion, 2327 Classification of Clinical Trials 2377.1 Introduction, 2377.2 Multicenter Trials, 2387.3 Superiority Trials, 2457.4 Active Control and Equivalence/Noninferiority Trials, 2487.5 Dose–Response Trials, 2617.6 Combination Trials, 2667.7 Bridging Studies and Global Trials, 2787.8 Vaccine Clinical Trials, 2857.9 QT Studies, 2917.10 Discussion, 299PART III ANALYSIS OF CLINICAL DATA8 Analysis of Continuous Data 3058.1 Introduction, 3058.2 Estimation, 3068.3 Test Statistics, 3108.4 Analysis of Variance, 3168.5 Analysis of Covariance, 3238.6 Nonparametric Methods, 3258.7 Repeated Measures, 3328.8 Discussion, 3419 Analysis of Categorical Data 3439.1 Introduction, 3439.2 Statistical Inference for One Sample, 3459.3 Inference of Independent Samples, 3589.4 Ordered Categorical Data, 3649.5 Combining Categorical Data, 3689.6 Model-Based Methods, 3749.7 Repeated Categorical Data, 3829.8 Discussion, 38710 Censored Data and Interim Analysis 38910.1 Introduction, 38910.2 Estimation of the Survival Function, 39110.3 Comparison Between Survival Functions, 39910.4 Cox’s Proportional Hazard Model, 40510.5 Calendar Time and Information Time, 41910.6 Group Sequential Methods, 42410.7 Discussion, 43811 Sample Size Determination 44111.1 Introduction, 44111.2 Basic Concept, 44211.3 Two Samples, 44711.4 Multiple Samples, 45611.5 Censored Data, 45911.6 Dose–Response Studies, 46411.7 Crossover Designs, 47111.8 Equivalence and Noninferiority Trials, 48111.9 Multiple-Stage Design in Cancer Trials, 49011.10 Multinational Trials, 49011.11 Comparing Variabilities, 50011.12 Discussion, 517PART IV ISSUES IN EVALUATION12 Issues in Efficacy Evaluation 52112.1 Introduction, 52112.2 Baseline Comparison, 52312.3 Intention-to-Treat Principle and Efficacy Analysis, 52812.4 Adjustment for Covariates, 53612.5 Multicenter Trials, 54112.6 Multiplicity, 54812.7 Data Monitoring, 55812.8 Use of Genetic Information for Evaluation of Efficacy, 56412.9 Sample Size Reestimation, 57012.10 Discussion, 57213 Safety Assessment 57313.1 Introduction, 57313.2 Extent of Exposure, 57413.3 Coding of Adverse Events, 58213.4 Analysis of Adverse Events, 59513.5 Analysis of Laboratory Data, 60213.6 Analysis of QT/QTc Prolongation, 61013.7 Discussion, 615PART V RECENT DEVELOPMENT14 Biomarkers and Targeted Clinical Trials 61914.1 Introduction, 61914.2 Concepts and Strategies, 62014.3 Biomarker Development and Validation, 62314.4 Designs of Targeted Clinical Trials, 63014.5 Analyses of Targeted Clinical Trials, 64014.6 Discussion, 64715 Trials for Evaluating Accuracy of Diagnostic Devices 64915.1 Introduction, 64915.2 Study Design, 65115.3 Measures of Diagnostic Accuracy, 65615.4 Reporting Results, 66315.5 Sample Size Estimation, 67215.6 Discussion, 67516 Statistical Methods in Translational Medicine 67716.1 Introduction, 67716.2 Biomarker Development, 67816.3 Bench-to-Bedside, 68216.4 Animal Model Versus Human Model, 68916.5 Translation in Study Endpoints, 69116.6 Bridging Studies, 69616.7 Discussion, 69916.8 Appendix, 70017 Adaptive Clinical Trial Designs 70317.1 Introduction, 70317.2 What Is Adaptive Design?, 70417.3 Well-Understood and Less Well-Understood Designs, 70917.4 Clinical/Statistical and Regulatory Perspectives, 71317.5 Impact of Protocol Amendments, 71617.6 Challenges in By-Design Adaptations, 72117.7 Obstacles of Retrospective Adaptations, 72717.8 Discussion, 72918 Traditional Chinese Medicine 73318.1 Introduction, 73318.2 Fundamental Differences, 73418.3 Basic Considerations of TCM Clinical Trials, 74118.4 Other Issues in TCM Research and Development, 74418.5 Consortium for Globalization of Traditional Chinese Medicine, 75118.6 Discussion, 752PART VI CONDUCT OF CLINICAL TRIALS19 Preparation and Implementation of a Clinical Protocol 75519.1 Introduction, 75519.2 Structure and Components of a Protocol, 75619.3 Points to be Considered and Common Pitfalls During Developmentand Preparation of a Protocol, 76219.4 Common Departures for Implementation of a Protocol, 76519.5 Monitoring, Audit, and Inspection, 77119.6 Quality Assessment of a Clinical Trial, 77519.7 Discussion, 77720 Data Management of a Clinical Trial 77920.1 Introduction, 77920.2 Regulatory Requirements, 78120.3 Development of Case Report Forms, 78320.4 Database Development, 78720.5 Data Entry, Query, and Correction, 78820.6 Data Validation and Quality, 79120.7 Database Lock, Archive, and Transfer, 79220.8 Critical Issues, 795References 799Appendix A 845Index 851

�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.�  (Journal of Biopharmaceutical Statistics, 1 July 2014)"Design and Analysis of Clinical Trials: Concepts and Methodologies, Third Edition 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." (Journal of Clinical Research Best Practice February 2014)