Preface xix Acknowledgments xxiii Acronyms xxv 1 Introduction 1 1.1 Medical Product Development Pathway 1 1.2 Development of Evidence-Based Medicine 3 1.3 The 21st Century Cures Act 4 1.4 Regulatory Guidance 5 1.4.1 Guidance and related documents by the FDA 5 1.4.
2 Guidance and related documents by the EMA 6 1.4.3 Guidance and related documents by the NMPA 6 1.4.4 Guidance and related documents by the ICH 7 1.4.5 Guidance and related documents by the MHLW of Japan 7 1.4.
6 Guidance and related documents by other regulatory agencies 8 1.5 Discussion and Summary 9 1.6 Supplements 11 2 A Brief History and Critical Components of Clinical Trials 13 2.1 Lady Tasting Tea 14 2.2 Alpha 15 2.3 Permutation Test 17 2.4 Selection of Control 21 2.5 Parallel vs crossover trials 25 2.
6 Blinding 25 2.7 Process of a Clinical Trial 27 2.7.1 Clinical trial design stage 27 2.7.2 Trial monitoring or study conduct stage 31 2.7.3 Analysis and reporting stage 32 2.
8 Supplements 33 3 Clinical Development Process of a New Drug 35 3.1 Clinical Development Plan 35 3.1.1 Clinical development phases 36 3.1.2 Documents for regulatory submission 37 3.1.3 Target product profile 38 3.
1.4 Oncology drug development 39 3.2 Phase I Clinical Trials 40 3.2.1 Pharmacokinetics (PK) 40 3.2.2 Tolerability 43 3.3 Phase II Clinical Trials 46 3.
3.1 Proof of Concept (PoC) trials 48 3.3.2 Dose-ranging trials 50 3.3.3 Combined PoC and dose ranging 52 3.3.4 Example--A Phase II osteoarthritis (OA) trial 54 3.
4 Phase III Trials 57 3.4.1 Example--Late developed AE (Proteinuria) 61 3.5 New Drug Application (NDA) 63 3.6 Phase IV Studies 64 3.7 Supplements 65 4 Design Considerations for Phase III Confirmatory Trials 67 4.1 Drug Label 67 4.2 Selection of Primary Indication 68 4.
3 Multi-Regional Clinical Trials (MRCT) 70 4.4 Selection of Endpoint(s) 72 4.5 Selection of Control 74 4.6 Selection of Dose(s) 78 4.6.1 Drug efficacy considerations 79 4.6.2 Drug safety concerns 80 4.
7 Additional Considerations 81 4.7.1 Vaccines or drugs for prevention 83 4.7.2 Drugs treating non-life-threatening diseases 84 4.7.3 Drugs treating life-threatening diseases 85 4.8 Supplementary 86 5 Regulatory Submission and Approval 89 5.
1 International Council of Harmonisation (ICH) 90 5.2 Prescription Drug User Fee Act (PDUFA) 91 5.3 Pre-Submission Meetings 93 5.3.1 End of phase II meeting 93 5.3.2 Pre-NDA/BLA meeting 94 5.4 Common Technical Documents and Submission 94 5.
5 Advisory Committee Meetings 97 5.6 Supplements 100 6 Overview on Use of RWD and RWE in Regulatory Setting 103 6.1 Categories of RWD and External Data 103 6.2 Trial Design and Conduct 104 6.2.1 Evidence synthesis 104 6.2.2 Use of external data in trial design and conduct 107 6.
2.3 External data as external controls in trial design 107 6.3 Using RWD and RWE to Support Product Approval 108 6.3.1 Serving as external controls 109 6.3.2 Supporting population extrapolation 109 6.3.
3 Supporting label expansion to different indications 112 6.3.4 Serving as sole evidence 112 6.3.5 Supporting other label modifications 113 6.4 PMRs and PMCs 114 6.5 Discussion and Summary 115 6.6 Supplements 115 7 Single-Arm Trials 119 7.
1 Necessary Conditions 120 7.1.1 Life-threatening or serious conditions with no efficacious treatments 120 7.1.2 Rare diseases 120 7.2 Desirable Conditions 121 7.2.1 Well-understood natural history of the rare diseases 121 7.
2.2 Well-understood mechanism of action of the drug 121 7.2.3 Adequate dose optimization 122 7.2.4 Substantial treatment effects 124 7.2.5 Translation of SEs into clinical benefits 125 7.
2.6 Favorable benefit-risk profile 126 7.2.7 Totality of evidence 127 7.2.8 Planning/initiation of confirmatory trials 128 7.3 Other Considerations 128 7.3.
1 Well-defined estimands 128 7.3.2 Adaptive designs 129 7.3.3 External controls 129 7.3.4 Communication with regulatory agencies 130 7.4 Examples 131 7.
4.1 Blinatumomab for relapsed/refractory B-cell acute lym- phoblastic leukemia 131 7.4.2 Retifanlimab for locally advanced or metastatic squa- mous carcinoma of the anal canal 133 7.4.3 PI3K inhibitor for hematologic malignancies 134 7.5 Conclusion and Summary 136 7.6 Supplements 136 8 Externally Controlled Trials 139 8.
1 Types of External Controls 139 8.1.1 Historical control 140 8.1.2 Contemporaneous control 141 8.1.3 Non-concurrent control 142 8.1.
4 Historical-contemporaneous control 142 8.1.5 Synthetic control 143 8.1.6 Hybrid control 143 8.1.7 Virtual control 144 8.2 External Data as a Sole Control Group 145 8.
2.1 Selection of covariates 145 8.2.2 Choice of distance metrics 146 8.2.3 Matching 146 8.3 External data to augment concurrent controls in RCTs 148 8.4 Assessment of fit-for-use external data 149 8.
5 General Considerations--External Controls 151 8.6 Targeted-Learning Roadmap 153 8.6.1 Step 0: Clearly defined research question 154 8.6.2 Step 1: Observed data and its generating mechanism 154 8.6.3 Step 2: Statistical model and targeted statistical esti- mand (parameter) 155 8.
6.4 Step 3: Causal model and causal estimand 155 8.6.5 Step 4: Statistical estimand versus causal identifiability 156 8.6.6 Step 5: Estimation of statistical estimand 157 8.6.7 Step 6: Result interpretation and sensitivity analysis 158 8.
7 Discussion and Summary 159 8.8 Supplements 161 9 Master Protocols 163 9.1 Types and Features of Master Protocols 163 9.2 Estimands in Master Protocols 165 9.3 Multiplicity 167 9.4 Master Protocols Using External Controls 168 9.4.1 Estimands in master protocols using EDE 169 9.
4.2 Special considerations for different types of master pro- tocols using EDE 172 9.5 Case Studies for ECTs 173 9.5.1 MASTER KEY project 173 9.5.2 MORPHEUS 174 9.6 Discussion and Summary 176 9.
7 Supplements 177 10 Decentralized Clinical Trials 179 10.1 Elements of DCTs 180 10.1.1 DHTs 180 10.1.2 Participant screening, recruitment, and retention 182 10.1.3 Dispensing medication 183 10.
1.4 Remote data acquisition 183 10.1.5 Outcome/endpoint assessment and data acquisition 184 10.2 Regulatory Guidance and Framework on DCTs 185 10.3 Statistical Challenges and Considerations 186 10.3.1 Estimands 186 10.
3.2 Trial design 188 10.3.3 Data management plan 191 10.3.4 Statistical analysis plan 192 10.3.5 Missing data 193 10.
3.6 Study conduct 194 10.3.7 Reporting and monitoring of safety events 196 10.3.8 Other considerations 197 10.4 Examples 198 10.4.
1 Decentralization by necessity 198 10.4.2 Decentralization for operational benefits 198 10.4.3 Decentralization to address unique scientific questions 199 10.4.4 Decentralization for validation of endpoints 200 10.4.
5 Decentralization for validation of DCT platform 200 10.5 Discussion and Summary 200 10.6 Supplements 201 11 Drug Development for Rare Diseases 203 11.1 Regulatory Guidance 204 11.1.1 Guidance and related documents by the FDA 204 11.1.2 Guidance and related documents by other agencies 206 11.
2 Challenges in Rare Disease Drug Development 209 11.2.1 Study design 209 11.2.2 Study conduct 211 11.2.3 Statistical analyses 212 11.2.
4 Ultra rare diseases 213 11.2.5 Others challenges 213 11.3 Strategies to Address the Challenges 214 11.3.1 An overall development strategy 214 11.3.2 Trial design 215 11.
3.3 Trial conduct 218 11.3.4 Statistical analyses 219 11.3.5 Ultra rare diseases 220 11.3.6 Other considerations 220 11.
4 Use of RWD and RWE 221 11.4.1 Natural history studies 221 11.4.2 Trial design 223 11.4.3 Trial conduct 225 11.4.
4 Analytical methods for data analysis 226 11.4.5 Model-informed drug discovery and development and in silico trials 227 11.4.6 Collaborative efforts 227 11.5 Case Studies 228 11.5.1 NHS to support product effectiveness 228 11.
5.2 Use of RWD/RWE to support regulatory decisions in various settings 228 11.6 Discussion and Summary 230 11.7 Supplements 232 12 Time-to-Event Analysis with Treatment Switches 235 12.1 Scenarios of Treatment Switching 236 12.1.1 Control group to receive new treatment 236 12.1.
2 Treatment group to receive control drug 236 12.1.3 Control and treatment groups to receive other drugs 238 12.2 Study Designs 238 12.3 Strategies to Handle Treatment Switching 240 12.3.1 Treatment policy strategy 240 12.3.
2 Hypothetical strategy 240 12.3.3 Principal stratum strategy 241 12.3.4 Composite variable strategy 241 12.3.5 While-on-treatment strategy 241 12.4 Analytical Methods 242 12.
4.1 Counterfactual methods 242 12.4.2 Non-counterfactual methods 243 12.4.3 Choice of appropriate methods for adjusting treatment switching 245 12.5 Considerations 247 12.