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Praise for the Second Edition: "...a grand feast for biostatisticians. It stands ready to satisfy the appetite of any pharmaceutical scientist with a respectable statistical appetite." --Journal of Clinical Research Best Practices The Third Edition of Design and Analysis of Clinical Trials provides complete, comprehensive, and expanded coverage of recent health treatments and interventions. Featuring a unified presentation, the book provides a well-balanced summary of current regulatory requirements and recently developed statistical methods as well as an overview of the various designs and…mehr
Praise for the Second Edition: "...a grand feast for biostatisticians. It stands ready to satisfy the appetite of any pharmaceutical scientist with a respectable statistical appetite." --Journal of Clinical Research Best Practices The Third Edition of Design and Analysis of Clinical Trials provides complete, comprehensive, and expanded coverage of recent health treatments and interventions. Featuring a unified presentation, the book provides a well-balanced summary of current regulatory requirements and recently developed statistical methods as well as an overview of the various designs and analyses that are utilized at different stages of clinical research and development. Additional features of this Third Edition include: * New chapters on biomarker development and target clinical trials, adaptive design, trials for evaluating diagnostic devices, statistical methods for translational medicine, and traditional Chinese medicine * A balanced overview of current and emerging clinical issues as well as newly developed statistical methodologies * Practical examples of clinical trials that demonstrate everyday applicability, with illustrations and examples to explain key concepts * New sections on bridging studies and global trials, QT studies, multinational trials, comparative effectiveness trials, and the analysis of QT/QTc prolongation * A complete and balanced presentation of clinical and scientific issues, statistical concepts, and methodologies for bridging clinical and statistical disciplines * An update of each chapter that reflects changes in regulatory requirements for the drug review and approval process and recent developments in statistical design and methodology for clinical research and development Design and Analysis of Clinical Trials, Third Edition continues to be an ideal clinical research reference for academic, pharmaceutical, medical, and regulatory scientists/researchers, statisticians, and graduate-level students.
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.
Inhaltsangabe
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
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
Rezensionen
"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)
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