Design and Analysis of Clinical Trials -- Contents -- Preface -- PART I Preliminaries -- CHAPTER 1 Introduction -- 1.1 WHAT ARE CLINICAL TRIALS? -- 1.2 HISTORY OF CLINICAL TRIALS -- 1.3 REGULATORY PROCESS AND REQUIREMENTS -- 1.3.1 The Food and Drug Administration -- 1.3.2 FDA Regulations for Clinical Trials -- 1.3.3 Phases of Clinical Development -- 1.4 INVESTIGATIONAL NEW DRUG APPLICATION -- 1.4.1 Clinical Trial Protocol -- 1.4.2 Institutional Review Board -- 1.4.3 Safety Report -- 1.4.4 Treatment IND -- 1.4.5 Withdrawal and Termination of an IND -- 1.4.6 Communication with the FDA -- 1.5 NEW DRUG APPLICATION -- 1.5.1 Expanded Access -- 1.5.2 Abbreviated New Drug Application -- 1.5.3 Supplemental New Drug Application -- 1.5.4 Advisory Committee -- 1.6 CLINICAL DEVELOPMENT AND PRACTICE -- 1.6.1 Clinical Development Plan -- 1.6.2 Good Clinical Practice -- 1.7 AIMS AND STRUCTURE OF THE BOOK -- CHAPTER 2 Basic Statistical Concepts -- 2.1 INTRODUCTION -- 2.2 UNCERTAINTY AND PROBABILITY -- 2.2.1 Uncertainty -- 2.2.2 Probability -- 2.3 BIAS AND VARIABILITY -- 2.3.1 Bias -- 2.3.2 Variability -- 2.4 CONFOUNDING AND INTERACTION -- 2.4.1 Confounding -- 2.4.2 Interaction -- 2.5 DESCRIPTIVE AND INFERENTIAL STATISTICS -- 2.6 HYPOTHESES TESTING AND p-VALUES -- 2.6.1 p-Values -- 2.6.2 One-Sided Versus Two-Sided Hypotheses -- 2.7 CLINICAL SIGNIFICANCE AND CLINICAL EQUIVALENCE -- 2.8 REPRODUCIBILITY AND GENERALIZABILITY -- 2.8.1 Reproducibility -- 2.8.2 Generalizability -- CHAPTER 3 Basic Design Considerations -- 3.1 INTRODUCTION -- 3.2 GOALS OF CLINICAL TRIALS -- 3.3 TARGET POPULATION AND PATIENT SELECTION -- 3.3.1 Eligibility Criteria -- 3.3.2 Patient Selection Process -- 3.3.3 Ethical Considerations -- 3.4 SELECTION OF CONTROLS -- 3.4.1 Placebo Concurrent Control -- 3.4.2 Dose-Response Concurrent Control -- 3.4.3 Active (Positive) Concurrent Control.

3.4.4 No Treatment Concurrent Control -- 3.4.5 Historical Control -- 3.5 STATISTICAL CONSIDERATIONS -- 3.5.1 Efficacy and Safety Assessment -- 3.5.2 Sample Size Estimation -- 3.5.3 Interim Analysis and Data Monitoring -- 3.5.4 Statistical and Clinical Inference -- 3.6 OTHER ISSUES -- 3.6.1 Single Site Versus Multisites -- 3.6.2 Treatment Duration -- 3.6.3 Patient Compliance -- 3.6.4 Missing Value and Dropout -- 3.7 DISCUSSION -- CHAPTER 4 Randomization and Blinding -- 4.1 INTRODUCTION -- 4.2 RANDOMIZATION MODELS -- 4.2.1 Population Model -- 4.2.2 Invoked Population Model -- 4.2.3 Randomization Model -- 4.2.4 Stratification -- 4.3 RANDOMIZATION METHODS -- 4.3.1 Complete Randomization -- 4.3.2 Permuted-Block Randomization -- 4.3.3 Adaptive Randomization -- 4.4 IMPLEMENTATION OF RANDOMIZATION -- 4.4.1 Generation, Labeling, and Packaging -- 4.4.2 Random Assignment -- 4.5 GENERALIZATION OF CONTROLLED RANDOMIZED TRIALS -- 4.6 BLINDING -- 4.7 DISCUSSION -- PART II Designs and Their Classifications -- CHAPTER 5 Designs for Clinical Trials -- 5.1 INTRODUCTION -- 5.2 PARALLEL GROUP DESIGNS -- 5.2.1 Run-in Periods -- 5.2.2 Examples of Parallel Group Design in Clinical Trials -- 5.3 CLUSTERED RANDOMIZED DESIGNS -- 5.4 CROSSOVER DESIGNS -- 5.4.1 Higher-Order Crossover Designs -- 5.4.2 Williams Designs -- 5.4.3 Balanced Incomplete Block Design -- 5.4.4 Examples of Crossover Design in Clinical Trials -- 5.5 TITRATION DESIGNS -- 5.5.1 Standard Titration Design -- 5.5.2 Forced Dose-Escalation Design -- 5.6 ENRICHMENT DESIGNS -- 5.7 GROUP SEQUENTIAL DESIGNS -- 5.8 PLACEBO-CHALLENGING DESIGNS -- 5.8.1 Statistical Model and Inferences -- 5.9 BLINDED READER DESIGNS -- 5.10 DISCUSSION -- CHAPTER 6 Designs for Cancer Clinical Trials -- 6.1 INTRODUCTION -- 6.2 GENERAL CONSIDERATIONS FOR PHASE ICANCER CLINICAL TRIALS -- 6.3 SINGLE-STAGE UP-AND-DOWN PHASE I DESIGNS.

6.3.1 Design A-Standard Dose-Escalation Design -- 6.3.2 Design B -- 6.3.3 Design D -- 6.4 TWO-STAGE UP-AND-DOWN PHASE I DESIGNS -- 6.4.1 Design BD -- 6.4.2 Accelerated Titration Designs -- 6.5 CONTINUAL REASSESSMENT METHOD PHASE I DESIGNS -- 6.6 OPTIMAL AND FLEXIBLE MULTIPLE-STAGE DESIGNS -- 6.6.1 Single-Arm Trials -- 6.6.2 Multiple-Arm Trials -- 6.7 RANDOMIZED PHASE II DESIGNS -- 6.8 DISCUSSION -- CHAPTER 7 Classification of Clinical Trials -- 7.1 INTRODUCTION -- 7.2 MULTICENTER TRIALS -- 7.2.1 Treatment-by-Center Interaction -- 7.2.2 Practical Issues -- 7.3 SUPERIORITY TRIALS -- 7.4 ACTIVE CONTROL AND EQUIVALENCE/NONINFERIORITY TRIALS -- 7.4.1 Primary Objectives -- 7.4.2 Issues in Active Control Equivalence Trials -- 7.4.3 Interpretation of the Results of Active Control Trials -- 7.4.4 Equivalence/Noninferiority Limits -- 7.4.5 Statistical Methods -- 7.5 DOSE-RESPONSE TRIALS -- 7.5.1 Randomized Parallel Dose-Response Designs -- 7.5.2 Crossover Dose-Response Design -- 7.5.3 Forced Titration (Dose-Escalation) Design -- 7.5.4 Optional Titration Design (Placebo-Controlled Titration to Endpoint) -- 7.6 COMBINATION TRIALS -- 7.6.1 Fixed-Combination Prescription Drugs -- 7.6.2 Multilevel Factorial Design -- 7.6.3 Global Superiority of Combination Drugs -- 7.6.4 Method of Response Surface -- 7.7 BRIDGING STUDIES AND GLOBAL TRIALS -- 7.7.1 Introduction -- 7.7.2 Ethnic Sensitivity and Necessity of Bridging Studies -- 7.7.3 Types of Bridging Studies -- 7.7.4 Assessment of Similarity Based on Bridging Evidence -- 7.8 VACCINE CLINICAL TRIALS -- 7.8.1 Basic Design and Statistical Considerations -- 7.8.2 Types of Vaccine Immunogenicity Trials -- 7.8.3 Statistical Methods -- 7.9 QT STUDIES -- 7.9.1 Study Designs and Models -- 7.9.2 Power and Sample Size Calculation -- 7.9.3 Allocation Optimization -- 7.9.4 Remarks -- 7.10 DISCUSSION.

PART III Analysis of Clinical Data -- CHAPTER 8 Analysis of Continuous Data -- 8.1 INTRODUCTION -- 8.2 ESTIMATION -- 8.3 TEST STATISTICS -- 8.3.1 Paired t Test -- 8.3.2 Two-Sample t Test -- 8.4 ANALYSIS OF VARIANCE -- 8.4.1 One-Way Classification -- 8.4.2 Simultaneous Confidence Intervals -- 8.4.3 Two-Way Classification -- 8.5 ANALYSIS OF COVARIANCE -- 8.6 NONPARAMETRIC METHODS -- 8.6.1 Wilcoxon Signed Rank Test -- 8.6.2 Wilcoxon Rank Sum Test -- 8.6.3 Kruskal-Wallis Test -- 8.7 REPEATED MEASURES -- 8.7.1 Assessment of Overall Average Effect Across Time -- 8.7.2 Detection of Time Effect -- 8.7.3 Treatment-by-Time Interaction -- 8.7.4 Method of Generalized Estimating Equations (GEEs) -- 8.8 DISCUSSION -- CHAPTER 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 -- CHAPTER 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 -- CHAPTER 11 Sample Size Determination -- 11.1 INTRODUCTION -- 11.2 BASIC CONCEPT -- 11.2.1 Study Objectives and Hypotheses -- 11.2.2 Type I and Type II Errors -- 11.2.3 Precision Analysis -- 11.2.4 Power Analysis -- 11.3 TWO SAMPLES -- 11.3.1 One-Sample Test for Mean -- 11.3.2 Two-Sample Test for Comparing Means -- 11.4 MULTIPLE SAMPLES -- 11.4.1 Sample Size Calculations for Analysis of Variance Models -- 11.4.2 Sample Size Calculations for Generalized Linear Models -- 11.5 CENSORED DATA -- 11.6 DOSE-RESPONSE STUDIES -- 11.6.1 Dose-Response Relationship.

11.6.2 Minimum Effective Dose -- 11.7 CROSSOVER DESIGNS -- 11.7.1 Point Hypotheses for Equality -- 11.7.2 Interval Hypotheses for Equivalence -- 11.7.3 Higher-Order Crossover Designs -- 11.8 EQUIVALENCE AND NONINFERIORITY TRIALS -- 11.8.1 Independent Binary Endpoints -- 11.8.2 Paired Binary Endpoints -- 11.8.3 Independent Censored Endpoints -- 11.9 MULTIPLE-STAGE DESIGN IN CANCER TRIALS -- 11.10 MULTINATIONAL TRIALS -- 11.10.1 Selection of the Number of Sites -- 11.10.2 Sample Size Calculation and Allocation -- 11.11 COMPARING VARIABILITIES -- 11.11.1 Comparing Intrasubject Variabilities -- 11.11.2 Comparing Intersubject Variabilities -- 11.12 DISCUSSION -- PART IV Issues in Evaluation -- CHAPTER 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 -- 12.6.1 Multiple Comparisons -- 12.6.2 Multiple Endpoints -- 12.6.3 Subgroup Analysis -- 12.7 DATA MONITORING -- 12.7.1 Definition and Objectives -- 12.7.2 Regulatory Concerns -- 12.7.3 Early and Late Stages of Drug Development -- 12.7.4 Administrative Interim Analyses -- 12.7.5 Data Monitoring Committee -- 12.8 USE OF GENETIC INFORMATION FOR EVALUATION OF EFFICACY -- 12.9 SAMPLE SIZE REESTIMATION -- 12.10 DISCUSSION -- CHAPTER 13 Safety Assessment -- 13.1 INTRODUCTION -- 13.2 EXTENT OF EXPOSURE -- 13.2.1 Risk of Exposure -- 13.2.2 Absorbing Events -- 13.2.3 Recurring Events with Negligible Duration -- 13.2.4 Recurring Events with Nonnegligible Duration -- 13.2.5 Laboratory Data -- 13.3 CODING OF ADVERSE EVENTS -- 13.3.1 Definitions of Adverse Events -- 13.3.2 COSTART -- 13.3.3 MedDRA -- 13.3.4 Common Toxicity Criteria -- 13.4 ANALYSIS OF ADVERSE EVENTS -- 13.4.1 Adverse Event Data Listing -- 13.4.2 Summary Tables of Adverse Events.

13.4.3 Graphical Presentation.