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Clinical Trials in the Era of Real-World Evidence
Jie Chen (Author), Naitee Ting (Author), Feinan Lu (Author)
9781394369652, Wiley
Paperback / softback, published 6 May 2026
464 pages
24.6 x 20.3 x 3 cm, 0.885 kg
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: 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.
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 Desirable Conditions 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
Subject Areas: Medicine: general issues [MB]
