Randomised Clinical Trials

Preface xiii Part I Basic Considerations 1 1 Introduction 3 1.1 Introduction 3 1.2 Some completed trials 4 1.3 Choice of design 13 1.4 Practical constraints 18 1.5 Influencing clinical practice 20 1.6 History 20 1.7 How do trials arise? 22 1.8 Ethical considerations 24 1.9 Regulatory requirements 24 1.10 Focus 25 1.11 Further reading 25 2 Design Features 27 2.1 Introduction 27 2.2 The research question 29 2.3 Patient selection 30 2.4 The consent process 32 2.5 Choice of interventions 33 2.6 Choice of design 35 2.7 Assigning the interventions 37 2.8 Making the assessments 38 2.9 Analysis and reporting 38 2.10 Technical details 42 2.11 Guidelines 43 2.12 Further reading 44 3 The Trial Protocol 45 3.1 Introduction 45 3.2 Abstract 47 3.3 Background 49 3.4 Research objectives 49 3.5 Design 52 3.6 Intervention details 53 3.7 Eligibility 56 3.8 Randomisation 58 3.9 Assessment and data collection 61 3.10 Statistical considerations 63 3.11 Ethical issues 66 3.12 Organisational structure 69 3.13 Publication policy 69 3.14 Trial forms 70 3.15 Appendices 71 3.16 Regulatory requirements 72 3.17 Guidelines 74 3.18 Protocols 74 4 Measurement and Data Capture 77 4.1 Introduction 77 4.2 Types of measures 78 4.3 Measures and endpoints 80 4.4 Making the observations 91 4.5 Baseline measures 92 4.6 Data recording 93 4.7 Technical notes 101 4.8 Guidelines 101 5 Randomisation 103 5.1 Introduction 103 5.2 Rationale 104 5.3 Mechanics 104 5.4 Application 113 5.5 Carrying out randomisation 115 5.6 Documentation 119 5.7 Unacceptable methods 120 5.8 Guidelines 120 6 Trial Initiation 121 6.1 Introduction 121 6.2 Trial organisation 122 6.3 Data collection and processing 130 6.4 Internal data monitoring 132 6.5 Ethical and regulatory requirements 133 6.6 Launching the trial 134 6.7 Trial registries 134 6.8 Guidelines 135 7 Trial Conduct and Completion 137 7.1 Introduction 137 7.2 Regular feedback 137 7.3 Publicity 141 7.4 Protocol modifications 142 7.5 Preparing the publication(s) 142 7.6 The next trial? 145 7.7 Protocol 146 8 Basics for Analysis 147 8.1 Introduction 147 8.2 The standard Normal distribution 148 8.3 Confidence intervals 149 8.4 Statistical tests 150 8.5 Examples of analysis 152 8.6 Regression methods 169 8.7 Other issues 179 8.8 Practice 182 8.9 Technical details 183 9 Trial Size 185 9.1 Introduction 185 9.2 Significance level and power 186 9.3 The fundamental equation 188 9.4 Specific situations 190 9.5 Practical considerations 198 9.6 Further topics 203 9.7 Guideline 206 9.8 Software 206 10 Data and Safety Monitoring 209 10.1 Introduction 209 10.2 The DSMB 211 10.3 Early reviews 214 10.4 Interim reviews 219 10.5 Protocols 228 11 Reporting 229 11.1 Introduction 229 11.2 Publication 230 11.3 Responsibilities 233 11.4 Background 235 11.5 Methods 236 11.6 Findings 248 11.7 When things go wrong 258 11.8 Conclusions 259 11.9 Guidelines 260 Part II Adaptions of the Basic Design 263 12 More Than Two Interventions 265 12.1 Introduction 265 12.2 Unstructured comparisons 266 12.3 Comparisons with placebo (or standard) 270 12.4 Dose-response designs 275 12.5 Factorial trials 280 12.6 Complex structure comparisons 289 13 Paired and Matched Designs 293 13.1 Matched-pair trials 293 13.2 Cross-over trials 305 13.3 Split-mouth designs 311 13.4 Guidelines 317 14 Repeated Measures Design 319 14.1 Introduction 319 14.2 Simplified analysis 322 14.3 Regression models 329 14.4 Auto-correlation 331 14.5 Accounting for auto-correlation 334 14.6 The design effect (DE) 338 14.7 Trial size 344 14.8 Practicalities 347 14.9 Reporting 350 14.10 Matched organs receiving the same intervention 354 15 Non-Inferiority and Equivalence Trials 357 15.1 Introduction 357 15.2 Non-inferiority 358 15.3 Analysis 361 15.4 Trial size 366 15.5 Equivalence 370 15.6 Reporting 373 15.7 Practical Issues 373 15.8 Guidelines 373 16 Cluster Designs 375 16.1 Design features 375 16.2 Procedures 376 16.3 Regression models 379 16.4 Intra-class correlation 380 16.5 Trial size 381 16.6 Analysis 386 16.7 Practicalities 388 16.8 Reporting 388 16.9 Further reading 389 17 Stepped Wedge Designs 391 17.1 Introduction 391 17.2 Notation 392 17.3 Basic structure 396 17.4 Randomisation 398 17.5 Cross-sectional design 398 17.6 Closed cohort design 408 17.7 Practicalities 413 Part III Further Topics 415 18 Genomic Targets 417 18.1 Introduction 417 18.2 Predictive markers 418 18.3 Enrichment design 420 18.4 Biomarker-Stratified Designs 422 18.5 Adaptive threshold designs 431 19 Feasibility and Pilot Studies 435 19.1 Introduction 435 19.2 Feasibility studies 436 19.3 External-pilot studies 437 19.4 Considerations across external-pilot and main trial 444 19.5 Internal-pilot studies 445 19.6 Other preliminary studies 447 19.7 Reporting 449 20 Further Topics 451 20.1 Introduction 451 20.2 Adaptive approaches 452 20.3 Large simple trials 461 20.4 Bayesian methods 463 20.5 Interim analyses 467 20.6 Zelen randomised consent designs 472 20.7 Systematic overviews 476 Statistical Tables 483 Glossary 493 References 503 Index 523