Clinical Trials

Steven Piantadosi, MD, PhD, is Professor in Residence at Brigham and Women’s Hospital and Harvard Medical School. He is one of the world’s leading experts on the design and analysis of clinical trials. Dr. Piantadosi has been engaged with clinical trials for over 4 decades and taught the subject for more than 30 years. His research has focused on cancer but has involved many other therapeutic areas as well. He has published over 275 papers on research results, clinical applications, and trial methodology. Dr. Piantadosi has held leadership roles with national cooperative oncology groups, including the Alliance, a National Clinical Trials Network collaboration. He has also served as a member of numerous advisory and clinical trial monitoring committees.

• Preface xxiAbout the Companion website xxv1 Preliminaries 11.1 Introduction 11.2 Deconstruction 21.3 A Clinical Trial is a Test of Treatment Under Controlled Conditions 31.4 Audience 31.5 Scope 41.6 Other Sources of Knowledge 51.8 Programs Examples and Data 81.9 Summary 92 Clinical Trials as Research 102.1 Introduction 102.2 Research 122.3 Defining Clinical Trials 172.4 Practicalities of Usage 242.5 Non-Experimental Designs 302.6 Summary 342.7 Questions for Discussion 343 Why Clinical Trials Are Ethical 353.1 Introduction 353.2 Duality is Ever Present 383.3 Historically Derived Principles of Ethics 463.4 Contemporary Foundational Principles 523.5 Methodologic Reflections 573.6 Professional Conduct 623.7 Summary 673.8 Questions for Discussion 674 Contexts for Clinical Trials 694.1 Introduction 694.2 Drugs 724.3 Devices 754.4 Prevention 774.5 Complementary and Alternative Medicine 834.6 Surgery and Skill-Dependent Therapies 904.7 A Brief View of Some Other Contexts 1004.8 Summary 1034.9 Questions for Discussion 1045 Measurement 1055.1 Introduction 1055.2 Objectives 1075.3 Measurement Design 1095.4 Surrogate Outcomes 1265.5 Summary 1325.6 Questions for Discussion 1326 Random Error and Bias 1336.1 Introduction 1336.2 Bias in Clinical Trials 1406.3 Statistical Bias 1456.4 Summary 1496.5 Questions for Discussion 1507 Statistical Perspectives 1517.1 Introduction 1517.2 Differences in Statistical Perspectives 1527.3 Frequentist 1557.4 Bayesian 1577.5 Likelihood 1617.6 Statistics Issues 1647.7 Summary 1657.8 Questions for Discussion 1668 Experiment Design in Clinical Trials 1678.1 Introduction 1678.2 Trials as Simple Experiment Designs 1688.3 Goals of Experiment Design 1718.4 Design Concepts 1738.5 Design Features 1768.6 Special Design Issues 1818.7 Importance of Protocol Documents 1868.8 Summary 1938.9 Questions for Discussion 1939 Trial Cohorts 1959.1 Introduction 1959.2 Cohort Definition and Selection 1969.3 Modeling Accrual 2029.4 Inclusiveness Representation and Interactions 2059.5 Summary 2119.6 Questions for Discussion 21110 Development Paradigms 21310.1 Introduction 21310.2 Pipeline Principles and Problems 21610.3 A Simple Quantitative Pipeline 21910.4 Late Failures 22410.5 Summary 23010.6 Questions for Discussion 23111 Translational Clinical Trials 23211.1 Introduction 23211.2 Inferential Paradigms 23611.3 Evidence and Theory 23911.4 Translational Trials Defined 24111.5 Information from Translational Trials 24411.6 Summary 25211.7 Questions for Discussion 25212 Early Development and Dose Finding 25312.1 Introduction 25312.2 Essential Concepts 25412.3 Dose Ranging 26012.4 Bayesian Optimal Interval (BOIN) Design 26612.5 Model-Guided Dose Finding 26712.6 General Dose-Finding Issues 27612.7 Summary 28412.8 Questions for Discussion 28613 Middle Development 28713.1 Introduction 28713.2 Characteristics of Middle Development 28913.3 Design Issues 29113.4 Middle Development Distills True Positives 29313.5 Futility and Non-superiority Designs 29513.6 Dose Efficacy Questions 29813.7 Randomized Comparisons 29913.8 Cohort Mixtures 30413.9 Summary 30613.10 Questions for Discussion 30714 Comparative Trials 30814.1 Introduction 30814.2 Elements of Reliability 30914.3 Biomarker-Based Comparative Designs 31314.4 Other Comparative Designs 31714.5 Summary 32014.6 Questions for Discussion 32115 Adaptive Design Features 32215.1 Introduction 32215.2 Some Familiar Adaptations 32515.3 Biomarker Adaptive Trials 33015.4 Re-Designs 33115.5 Seamless Designs 33215.6 Barriers to AD 33315.7 Adaptive Design Case Study 33315.8 Summary 33415.9 Questions for Discussion 33416 Precision Sample Size and Power 33516.1 Introduction 33516.2 Principles 33616.3 Early Developmental Trials 33916.4 Simple Estimation Designs 34116.5 Event Rates 35216.6 Stages 35516.7 Comparative Trials 35816.8 Expanded Safety Trials 37716.9 Other Considerations 38016.10 Summary 38616.11 Questions for Discussion 38717 Treatment Allocation 38917.1 Introduction 38917.2 Randomization 39017.3 Constrained Randomization 39517.4 Adaptive Allocation 39817.5 Other Issues Regarding Randomization 40117.6 Unequal Treatment Allocation 40617.7 Randomization Before Consent 41017.8 Summary 41017.9 Questions for Discussion 41118 Monitoring Treatment Effects 41218.1 Introduction 41218.2 Administrative Issues in Trial Monitoring 41518.3 Organizational Issues Related to Monitoring 42218.4 Statistical Methods for Monitoring 42818.5 Summary 44718.6 Questions for Discussion 44819 Counting Subjects and Events 45019.1 Introduction 45019.2 Imperfection and Validity 45119.3 Treatment Nonadherence 45219.4 Protocol Nonadherence 45519.5 Data Imperfections 45719.6 Summary 46119.7 Questions for Discussion 46120 Estimating Clinical Effects 46220.1 Introduction 46220.2 Dose-Finding and Pharmacokinetic Trials 46520.3 Middle Development Studies 47020.4 Randomized Comparative Trials 47520.5 Problems With P-Values 48320.6 Strength of Evidence Through Support Intervals 48720.7 Special Methods of Analysis 48820.8 Vaccine Trials 49420.9 Exploratory Analyses 49620.10 Summary 50420.11 Questions for Discussion 50421 Generalizing Results From Clinical Trials 50821.1 Introduction 50821.2 Laboratory Lessons 51021.3 Sample-Based Generalization 51021.4 Reconciling New Findings with Old Data 51221.5 Fit for Purpose Data 51321.6 Shared Biology 51421.7 Learning from Harmful Effects 51521.8 Pandemic 51621.9 Summary 51721.10 Questions for Discussion 51722 Prognostic Factor Analyses 51822.1 Introduction 51822.2 Model-Based Methods 52022.3 Adjusted Analyses of Comparative Trials 53122.4 Pfas Without Models 53422.5 Summary 53822.6 Questions for Discussion 53823 Factorial Designs 53923.1 Introduction 53923.2 Characteristics of Factorial Designs 54023.3 Treatment Interactions 54223.4 Examples of Factorial Designs 54623.5 Partial Fractional and Incomplete Factorials 54723.6 Summary 54823.7 Questions for Discussion 54824 Crossover Designs 55024.1 Introduction 55024.2 Advantages and Disadvantages 55224.3 Analysis 55524.4 Crossover Case Study 55924.5 Summary 55924.6 Questions for Discussion 56025 Operating Characteristics 56125.1 Introduction 56125.2 Calculated Operating Characteristics 56225.3 Operating Characteristics by Simulation 56525.4 Summary 57125.5 Questions for Discussion 57226 Meta-Analyses 57326.1 Introduction 57326.2 A Sketch of Meta-Analysis Methods 57526.3 Other Issues 57926.4 Summary 58026.5 Questions for Discussion 58027 Reporting and Authorship 58127.1 Introduction 58127.2 General Issues in Reporting 58227.3 Clinical Trial Reports 58527.4 Authorship 59327.5 Other Issues in Disseminating Results 59627.6 Summary 59727.7 Questions for Discussion 59828 Misconduct and Fraud in Clinical Research 59928.1 Introduction 59928.2 Research Practices 60428.3 Approach to Allegations of Misconduct 60628.4 Characteristics of Some Misconduct Cases 60828.5 Lessons 61528.6 Clinical Investigator Responsibilities 61628.7 Summary 61828.8 Questions for Discussion 61929 Clinical Trials in the COVID-19 Pandemic 62029.1 Introduction 62029.2 Epidemic Models 62229.3 Testing 62429.4 Useless Well-Liked Drugs 62629.5 Impact of Covid-19 on Clinical Trials 62729.6 Designing Trials to Test Covid-19 Treatments 62829.7 Ethics Takes a Detour 63129.8 Vaccine Trials 63729.9 Summary 64129.10 Questions for Discussion 64130 Real-World Clinical Trials 64230.1 Introduction 64230.2 Point-of-Care Data 64330.3 Whither Clinical Trials? 64630.4 Summary 64730.5 Questions for Discussion 647Appendix A Notation and Terminology 648References 662Index 741