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| Preface | |
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| Preliminaries | |
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| Introduction | |
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| What are Clinical Trials? | |
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| History of Clinical Trials | |
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| Regulatory Process and Requirements | |
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| Investigational New Drug Application | |
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| New Drug Application | |
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| Clinical Development and Practice | |
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| ATMS and Structure of the Book | |
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| Basic Statistical Concepts | |
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| Introduction | |
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| Uncertainty and Probability | |
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| Bias and Variability | |
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| Confounding and Interaction | |
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| Descriptive and Inferential Statistics | |
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| Hypotheses Testing and p-Values | |
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| Clinical Significance and Clinical Equivalence | |
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| Reproducibility and Generalizability | |
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| Basic Design Considerations | |
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| Introduction | |
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| Goals of Clinical Trials | |
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| Target Population and Patient Selection | |
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| Selection of Controls | |
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| Statistical Considerations | |
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| Other Issues | |
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| Discussion | |
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| Randomization and Blinding | |
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| Introduction | |
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| Randomization Models | |
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| Randomization Methods | |
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| Implementation of Randomization | |
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| Generalization of Controlled Randomized Trials | |
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| Blinding | |
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| Discussion | |
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| Designs and their Classifications | |
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| Designs for Clinical Trials | |
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| Introduction | |
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| Parallel Group Designs | |
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| Clustered Randomized Designs | |
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| Crossover Designs | |
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| Titration Designs | |
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| Enrichment Designs | |
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| Group Sequential Designs | |
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| Placebo-Challenging Designs | |
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| Blinded Reader Designs | |
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| Discussion | |
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| Designs for Cancer Clinical Trials | |
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| Introduction | |
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| General Considerations for Phase I Cancer Clinical Trials | |
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| Single-Stage Up-and-Down Phase I Designs | |
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| Two-Stage Up-and-Down Phase I Designs | |
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| Continual Reassessment Method Phase I Designs | |
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| Optimal and Flexible Multiple-Stage Designs | |
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| Randomized Phase II Designs | |
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| Discussion | |
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| Classification of Clinical Trials | |
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| Introduction | |
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| Multicenter Trials | |
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| Superiority Trials | |
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| Active Control and Equivalence/Noninferiority Trials | |
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| Dose-Response Trials | |
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| Combination Trials | |
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| Bridging Studies and Global Trials | |
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| Vaccine Clinical Trials | |
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| QT Studies | |
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| Discussion | |
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| Analysis of Clinical Data | |
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| Analysis of Continuous Data | |
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| Introduction | |
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| Estimation | |
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| Test Statistics | |
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| Analysis of Variance | |
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| Analysis of Covariance | |
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| Nonparametric Methods | |
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| Repeated Measures | |
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| Discussion | |
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| Analysis of Categorical Data | |
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| Introduction | |
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| Statistical Inference for One Sample | |
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| Inference of Independent Samples | |
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| Ordered Categorical Data | |
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| Combining Categorical Data | |
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| Model-Based Methods | |
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| Repeated Categorical Data | |
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| Discussion | |
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| Censored Data and Interim Analysis | |
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| Introduction | |
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| Estimation of the Survival Function | |
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| Comparison Between Survival Functions | |
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| Cox's Proportional Hazard Model | |
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| Calendar Time and Information Time | |
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| Group Sequential Methods | |
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| Discussion | |
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| Sample Size Determination | |
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| Introduction | |
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| Basic Concept | |
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| Two Samples | |
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| Multiple Samples | |
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| Censored Data | |
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| Dose-Response Studies | |
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| Crossover Designs | |
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| Equivalence and Noninferiority Trials | |
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| Multiple-Stage Design in Cancer Trials | |
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| Multinational Trials | |
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| Comparing Variabilities | |
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| Discussion | |
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| Issues in Evaluation | |
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| Issues in Efficacy Evaluation | |
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| Introduction | |
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| Baseline Comparison | |
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| Intention-to-Treat Principle and Efficacy Analysis | |
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| Adjustment for Covariates | |
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| Multicenter Trials | |
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| Multiplicity | |
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| Data Monitoring | |
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| Use of Genetic Information for Evaluation of Efficacy | |
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| Sample Size Reestimation | |
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| Discussion | |
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| Safety Assessment | |
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| Introduction | |
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| Extent of Exposure | |
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| Coding of Adverse Events | |
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| Analysis of Adverse Events | |
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| Analysis of Laboratory Data | |
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| Analysis of QT/QTc Prolongation | |
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| Discussion | |
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| Recent Development | |
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| Biomarkers and Targeted Clinical Trials | |
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| Introduction | |
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| Concepts and Strategies | |
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| Biomarker Development and Validation | |
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| Designs of Targeted Clinical Trials | |
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| Analyses of Targeted Clinical Trials | |
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| Discussion | |
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| Trials for Evaluating Accuracy of Diagnostic Devices | |
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| Introduction | |
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| Study Design | |
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| Measures of Diagnostic Accuracy | |
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| Reporting Results | |
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| Sample Size Estimation | |
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| Discussion | |
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| Statistical Methods in Translational Medicine | |
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| Introduction | |
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| Biomarker Development | |
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| Bench-to-Bedside | |
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| Animal Model Versus Human Model | |
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| Translation in Study Endpoints | |
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| Bridging Studies | |
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| Discussion | |
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| Appendix | |
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| Adaptive Clinical Trial Designs | |
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| Introduction | |
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| What Is Adaptive Design? | |
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| Well-Understood and Less Well-Understood Designs | |
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| Clinical/Statistical and Regulatory Perspectives | |
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| Impact of Protocol Amendments | |
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| Challenges in By-Design Adaptations | |
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| Obstacles of Retrospective Adaptations | |
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| Discussion | |
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| Traditional Chinese Medicine | |
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| Introduction | |
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| Fundamental Differences | |
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| Basic Considerations of TCM Clinical Trials | |
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| Other Issues in TCM Research and Development | |
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| Consortium for Globalization of Traditional Chinese Medicine | |
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| Discussion | |
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| Conduct of Clinical Trials | |
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| Preparation and Implementation of a Clinical Protocol | |
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| Introduction | |
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| Structure and Components of a Protocol | |
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| Points to be Considered and Common Pitfalls During Development and Preparation of a Protocol | |
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| Common Departures for Implementation of a Protocol | |
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| Monitoring, Audit, and Inspection | |
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| Quality Assessment of a Clinical Trial | |
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| Discussion | |
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| Data Management of a Clinical Trial | |
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| Introduction | |
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| Regulatory Requirements | |
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| Development of Case Report Forms | |
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| Database Development | |
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| Data Entry, Query, and Correction | |
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| Data Validation and Quality | |
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| Database Lock, Archive, and Transfer | |
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| Critical Issues | |
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| References | |
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| Appendix A | |
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| Index | |