Clinical Trials

Preface xxi About the Companion website xxv 1 Preliminaries 1 1.1 Introduction 1 1.2 Deconstruction 2 1.3 A Clinical Trial is a Test of Treatment Under Controlled Conditions 3 1.4 Audience 3 1.5 Scope 4 1.6 Other Sources of Knowledge 5 1.8 Programs Examples and Data 8 1.9 Summary 9 2 Clinical Trials as Research 10 2.1 Introduction 10 2.2 Research 12 2.3 Defining Clinical Trials 17 2.4 Practicalities of Usage 24 2.5 Non-Experimental Designs 30 2.6 Summary 34 2.7 Questions for Discussion 34 3 Why Clinical Trials Are Ethical 35 3.1 Introduction 35 3.2 Duality is Ever Present 38 3.3 Historically Derived Principles of Ethics 46 3.4 Contemporary Foundational Principles 52 3.5 Methodologic Reflections 57 3.6 Professional Conduct 62 3.7 Summary 67 3.8 Questions for Discussion 67 4 Contexts for Clinical Trials 69 4.1 Introduction 69 4.2 Drugs 72 4.3 Devices 75 4.4 Prevention 77 4.5 Complementary and Alternative Medicine 83 4.6 Surgery and Skill-Dependent Therapies 90 4.7 A Brief View of Some Other Contexts 100 4.8 Summary 103 4.9 Questions for Discussion 104 5 Measurement 105 5.1 Introduction 105 5.2 Objectives 107 5.3 Measurement Design 109 5.4 Surrogate Outcomes 126 5.5 Summary 132 5.6 Questions for Discussion 132 6 Random Error and Bias 133 6.1 Introduction 133 6.2 Bias in Clinical Trials 140 6.3 Statistical Bias 145 6.4 Summary 149 6.5 Questions for Discussion 150 7 Statistical Perspectives 151 7.1 Introduction 151 7.2 Differences in Statistical Perspectives 152 7.3 Frequentist 155 7.4 Bayesian 157 7.5 Likelihood 161 7.6 Statistics Issues 164 7.7 Summary 165 7.8 Questions for Discussion 166 8 Experiment Design in Clinical Trials 167 8.1 Introduction 167 8.2 Trials as Simple Experiment Designs 168 8.3 Goals of Experiment Design 171 8.4 Design Concepts 173 8.5 Design Features 176 8.6 Special Design Issues 181 8.7 Importance of Protocol Documents 186 8.8 Summary 193 8.9 Questions for Discussion 193 9 Trial Cohorts 195 9.1 Introduction 195 9.2 Cohort Definition and Selection 196 9.3 Modeling Accrual 202 9.4 Inclusiveness Representation and Interactions 205 9.5 Summary 211 9.6 Questions for Discussion 211 10 Development Paradigms 213 10.1 Introduction 213 10.2 Pipeline Principles and Problems 216 10.3 A Simple Quantitative Pipeline 219 10.4 Late Failures 224 10.5 Summary 230 10.6 Questions for Discussion 231 11 Translational Clinical Trials 232 11.1 Introduction 232 11.2 Inferential Paradigms 236 11.3 Evidence and Theory 239 11.4 Translational Trials Defined 241 11.5 Information from Translational Trials 244 11.6 Summary 252 11.7 Questions for Discussion 252 12 Early Development and Dose Finding 253 12.1 Introduction 253 12.2 Essential Concepts 254 12.3 Dose Ranging 260 12.4 Bayesian Optimal Interval (BOIN) Design 266 12.5 Model-Guided Dose Finding 267 12.6 General Dose-Finding Issues 276 12.7 Summary 284 12.8 Questions for Discussion 286 13 Middle Development 287 13.1 Introduction 287 13.2 Characteristics of Middle Development 289 13.3 Design Issues 291 13.4 Middle Development Distills True Positives 293 13.5 Futility and Non-superiority Designs 295 13.6 Dose Efficacy Questions 298 13.7 Randomized Comparisons 299 13.8 Cohort Mixtures 304 13.9 Summary 306 13.10 Questions for Discussion 307 14 Comparative Trials 308 14.1 Introduction 308 14.2 Elements of Reliability 309 14.3 Biomarker-Based Comparative Designs 313 14.4 Other Comparative Designs 317 14.5 Summary 320 14.6 Questions for Discussion 321 15 Adaptive Design Features 322 15.1 Introduction 322 15.2 Some Familiar Adaptations 325 15.3 Biomarker Adaptive Trials 330 15.4 Re-Designs 331 15.5 Seamless Designs 332 15.6 Barriers to AD 333 15.7 Adaptive Design Case Study 333 15.8 Summary 334 15.9 Questions for Discussion 334 16 Precision Sample Size and Power 335 16.1 Introduction 335 16.2 Principles 336 16.3 Early Developmental Trials 339 16.4 Simple Estimation Designs 341 16.5 Event Rates 352 16.6 Stages 355 16.7 Comparative Trials 358 16.8 Expanded Safety Trials 377 16.9 Other Considerations 380 16.10 Summary 386 16.11 Questions for Discussion 387 17 Treatment Allocation 389 17.1 Introduction 389 17.2 Randomization 390 17.3 Constrained Randomization 395 17.4 Adaptive Allocation 398 17.5 Other Issues Regarding Randomization 401 17.6 Unequal Treatment Allocation 406 17.7 Randomization Before Consent 410 17.8 Summary 410 17.9 Questions for Discussion 411 18 Monitoring Treatment Effects 412 18.1 Introduction 412 18.2 Administrative Issues in Trial Monitoring 415 18.3 Organizational Issues Related to Monitoring 422 18.4 Statistical Methods for Monitoring 428 18.5 Summary 447 18.6 Questions for Discussion 448 19 Counting Subjects and Events 450 19.1 Introduction 450 19.2 Imperfection and Validity 451 19.3 Treatment Nonadherence 452 19.4 Protocol Nonadherence 455 19.5 Data Imperfections 457 19.6 Summary 461 19.7 Questions for Discussion 461 20 Estimating Clinical Effects 462 20.1 Introduction 462 20.2 Dose-Finding and Pharmacokinetic Trials 465 20.3 Middle Development Studies 470 20.4 Randomized Comparative Trials 475 20.5 Problems With P-Values 483 20.6 Strength of Evidence Through Support Intervals 487 20.7 Special Methods of Analysis 488 20.8 Vaccine Trials 494 20.9 Exploratory Analyses 496 20.10 Summary 504 20.11 Questions for Discussion 504 21 Generalizing Results From Clinical Trials 508 21.1 Introduction 508 21.2 Laboratory Lessons 510 21.3 Sample-Based Generalization 510 21.4 Reconciling New Findings with Old Data 512 21.5 Fit for Purpose Data 513 21.6 Shared Biology 514 21.7 Learning from Harmful Effects 515 21.8 Pandemic 516 21.9 Summary 517 21.10 Questions for Discussion 517 22 Prognostic Factor Analyses 518 22.1 Introduction 518 22.2 Model-Based Methods 520 22.3 Adjusted Analyses of Comparative Trials 531 22.4 Pfas Without Models 534 22.5 Summary 538 22.6 Questions for Discussion 538 23 Factorial Designs 539 23.1 Introduction 539 23.2 Characteristics of Factorial Designs 540 23.3 Treatment Interactions 542 23.4 Examples of Factorial Designs 546 23.5 Partial Fractional and Incomplete Factorials 547 23.6 Summary 548 23.7 Questions for Discussion 548 24 Crossover Designs 550 24.1 Introduction 550 24.2 Advantages and Disadvantages 552 24.3 Analysis 555 24.4 Crossover Case Study 559 24.5 Summary 559 24.6 Questions for Discussion 560 25 Operating Characteristics 561 25.1 Introduction 561 25.2 Calculated Operating Characteristics 562 25.3 Operating Characteristics by Simulation 565 25.4 Summary 571 25.5 Questions for Discussion 572 26 Meta-Analyses 573 26.1 Introduction 573 26.2 A Sketch of Meta-Analysis Methods 575 26.3 Other Issues 579 26.4 Summary 580 26.5 Questions for Discussion 580 27 Reporting and Authorship 581 27.1 Introduction 581 27.2 General Issues in Reporting 582 27.3 Clinical Trial Reports 585 27.4 Authorship 593 27.5 Other Issues in Disseminating Results 596 27.6 Summary 597 27.7 Questions for Discussion 598 28 Misconduct and Fraud in Clinical Research 599 28.1 Introduction 599 28.2 Research Practices 604 28.3 Approach to Allegations of Misconduct 606 28.4 Characteristics of Some Misconduct Cases 608 28.5 Lessons 615 28.6 Clinical Investigator Responsibilities 616 28.7 Summary 618 28.8 Questions for Discussion 619 29 Clinical Trials in the COVID-19 Pandemic 620 29.1 Introduction 620 29.2 Epidemic Models 622 29.3 Testing 624 29.4 Useless Well-Liked Drugs 626 29.5 Impact of Covid-19 on Clinical Trials 627 29.6 Designing Trials to Test Covid-19 Treatments 628 29.7 Ethics Takes a Detour 631 29.8 Vaccine Trials 637 29.9 Summary 641 29.10 Questions for Discussion 641 30 Real-World Clinical Trials 642 30.1 Introduction 642 30.2 Point-of-Care Data 643 30.3 Whither Clinical Trials? 646 30.4 Summary 647 30.5 Questions for Discussion 647 Appendix A Notation and Terminology 648 References 662 Index 741