Clinical Trials: A Methodologic Perspective

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