Description
Integrate RCTs and real-world evidence for stronger regulatory submissions
Since the passage of the 21st Century Cures Act, the landscape of clinical research has transformed dramatically. Today, the integration of real-world data (RWD) and real-world evidence (RWE) with traditional randomized controlled trials (RCTs) is not just innovative - it is essential for modern drug development and regulatory decision-making.
This comprehensive volume bridges the methodologies of conventional RCTs and emerging RWE studies, offering systematic approaches for leveraging diverse data sources throughout the clinical development lifecycle. Grounded in regulatory statistics yet forward-looking in scope, the book explores Stein's continuum of study designs - from traditional RCTs to pragmatic trials and observational studies - and demonstrates how RWD can enhance trial feasibility, inform outcome selection, provide external controls for single-arm trials, and strengthen post-approval safety monitoring.
Readers will find detailed explorations of:
- A history of clinical trials, evidence-based medicine, and the regulatory frameworks governing drug approval
- Treatment switching and estimands in RWE studies
- Advanced analytical considerations including precision medicine, vaccine effectiveness, safety evaluation, and sensitivity analysis
- Practical roadmaps for designing robust RWE studies
- Artificial intelligence and machine learning in clinical research
Designed as both a reference and a graduate-level textbook, this book serves clinical researchers such as clinicians and biostatisticians, regulatory professionals, public health scientists, and industry practitioners seeking to harness the power of RWD and RWE to generate credible, actionable evidence for modern medicine.
Table of Contents
Preface xvii
Acknowledgments xxi
Acronyms xxiii
CHAPTER 1 Introduction 1
1.1 Medical Product Development Pathway 1
1.2 Development of Evidence-Based Medicine 2
1.3 The 21st Century Cures Act 4
1.4 Regulatory Guidance and Related Documents 4
1.5 Discussion and Summary 8
1.6 Supplements 9
CHAPTER 2 A Brief History and Critical Components of Clinical Trials 10
2.1 Lady Tasting Tea 10
2.2 Alpha 12
2.3 Permutation Test 13
2.4 Selection of Control 16
2.5 Parallel Versus Crossover Trials 19
2.6 Blinding 20
2.7 Process of a Clinical Trial 21
2.8 Supplements 26
CHAPTER 3 Clinical Development Process of a New Drug 27
3.1 Clinical Development Plan 27
3.2 Phase I Clinical Trials 31
3.3 Phase II Clinical Trials 36
3.4 Phase III Trials 44
3.5 New Drug Application (NDA) 49
3.6 Phase IV Studies 50
3.7 Supplements 51
CHAPTER 4 Design Considerations for Phase III Confirmatory Trials 52
4.1 Drug Label 52
4.2 Selection of Primary Indication 53
4.3 Multi-Regional Clinical Trials (MRCT) 54
4.4 Selection of Endpoint(s) 56
4.5 Selection of Control 57
4.6 Selection of Dose(s) 61
4.7 Additional Considerations 63
4.8 Supplements 67
CHAPTER 5 Regulatory Submission and Approval 69
5.1 International Council of Harmonisation (ICH) 69
5.2 Prescription Drug User Fee Act (PDUFA) 71
5.3 Pre-submission Meetings 72
5.4 Common Technical Documents and Submission 73
5.5 Advisory Committee Meetings 75
5.6 Supplements 77
CHAPTER 6 Overview on Use of RWD and RWE in Regulatory Setting 79
6.1 Categories of RWD and External Data 79
6.2 Supporting Trial Design and Conduct 80
6.3 Using RWD and RWE to Support Product Approval 83
6.4 Fulfilling Post-marketing Requirements and Commitments 88
6.5 Discussion and Summary 89
6.6 Supplements 89
CHAPTER 7 Single-Arm Trials 91
7.1 Necessary Conditions 92
7.2.1 Well-Understood Natural History of the Rare Diseases 92
7.3 Other Considerations 98
7.4 Examples 101
7.5 Conclusion and Summary 104
7.6 Supplements 105
CHAPTER 8 Externally Controlled Trials 107
8.1 Types of External Controls 107
8.2 External Data as a Sole Control Group 111
8.3 External Data to Augment Concurrent Controls in RCTs 114
8.4 Assessment of Fit-for-Use External Data 115
8.5 General Considerations in Using External Controls 117
8.6 A Targeted-Learning Roadmap for Causal Inference in ECTs 118
8.7 Discussion and Summary 123
8.8 Supplements 124
CHAPTER 9 Master Protocols 126
9.1 Types and Features of Master Protocols 126
9.2 Estimands in Master Protocols 128
9.3 Multiplicity 129
9.4 Master Protocols Using External Controls 130
9.5 Case Studies for ECTs 134
9.6 Discussion and Summary 137
9.7 Supplements 137
CHAPTER 10 Decentralized Clinical Trials 139
10.1 Elements of DCTs 140
10.2 Regulatory Guidance and Framework on DCTs 144
10.3 Statistical Challenges and Considerations 145
10.4 Examples 154
10.5 Discussion and Summary 156
10.6 Supplements 157
CHAPTER 11 Drug Development for Rare Diseases 159
11.1 Regulatory Guidance for Rare Diseases 160
11.2 Challenges in Rare Disease Drug Development 163
11.3 Strategies to Address the Challenges 168
11.4 Use of RWD and RWE in Rare Disease Drug Development 174
11.5 Case Studies 180
11.6 Discussion and Summary 182
11.7 Supplements 183
CHAPTER 12 Time-to-Event Analysis with Treatment Switches 185
12.1 Scenarios of Treatment Switching 185
12.2 Study Designs Incorporating Treatment Switching 187
12.3 Strategies to Handle Treatment Switching 189
12.4 Analytical Methods Handling Treatment Switching 190
12.5 Considerations for Study Conduct and Data Analysis 195
12.6 Communication with Regulatory Agencies 196
12.7 Case Studies 197
12.8 Discussion and Summary 199
12.9 Supplements 200
CHAPTER 13 Precision Medicine 201
13.1 Regulatory Activities and Approvals 202
13.2 Biomarkers 205
13.3 Study Designs in Precision Medicine Development 211
13.4 Analytic Methods and Applications 224
13.5 Optimal Treatment Regimes 235
13.6 Discussion and Summary 246
13.7 Supplements 248
CHAPTER 14 Vaccine Effectiveness Studies 251
14.1 General Considerations in Vaccine Development 252
14.2 Immune Response, Immunogenicity, and Early-Phase Clinical Development 254
14.3 Endpoints, Study Population, and Other Design Considerations in Late-Phase Trials 257
14.4 Assessing Vaccine Effectiveness Using Real-World Data and Evidence 264
14.5 Vaccine Safety 265
14.6 Discussion and Summary 266
14.7 Supplements 267
CHAPTER 15 Sensitivity Analyses in Clinical Trials 269
15.1 Primary, Supplementary, Sensitivity, and Exploratory Analyses 269
15.2 Rationales for Sensitivity Analysis 272
15.3 Considerations for Sensitivity Analysis 272
15.4 Methods for Sensitivity Analyses 274
15.5 Summary and Conclusion 278
15.6 Supplements 279
CHAPTER 16 Safety Evaluation 282
16.1 Safety Databases 282
16.2 Statistical Methods for Analysis of Spontaneous Adverse Event Reports 284
16.3 A Case Study—Sequential Monitoring in Pragmatic Trials 296
16.4 Discussion and Summary 299
16.5 Supplements 300
CHAPTER 17 Estimands in RWE Studies 302
17.1 Frameworks for Defining Estimands 302
17.2 Estimands in RWE Studies 307
17.3 Examples of Estimands in TCTs and RWE Studies 312
17.4 Discussion and Summary 319
17.5 Supplements 319
CHAPTER 18 A Roadmap for Formulating RWE Studies 321
18.1 Who Are the Stakeholders and What Are Their Research Questions? 321
18.2 What Are the Study Objectives, Designs, and Analytic Methods? 322
18.3 What Are the Fit-for-Purpose RWD Sources? 322
18.4 What Are the Treatment Regimes of Interest? 322
18.5 What Are the Possible Intercurrent Events? 322
18.6 A Roadmap for Choosing an Appropriate Estimand and RWE Study Design 323
18.7 Discussion and Summary 323
18.8 Supplements 325
CHAPTER 19 Artificial Intelligence and Machine Learning in Clinical Studies 326
19.1 Study Design and Planning 327
19.2 Study Conduct 330
19.3 Data Analytics 336
19.4 Prediction of Clinical Trial Outcomes 346
19.5 Discussion and Summary 354
19.6 Supplements 355
Bibliography 361
Index 429
