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Randomised Clinical Trials. Design, Practice and Reporting. Edition No. 2

  • Book

  • 560 Pages
  • May 2021
  • John Wiley and Sons Ltd
  • ID: 5838464

Randomised Clinical Trials: Design, Practice and Reporting provides a detailed overview of the methodology for conducting clinical trials, including developing protocols, data capture, randomisation, analysis and reporting. Assuming no prior background, this user-friendly resource describes the statistical, regulatory, and practical components required for conducting randomised clinical trials. Numerous examples and case studies from industry, academia, and the research literature help readers understand each stage of the clinical trial process.

This second edition contains extensively revised material throughout, including new chapters covering designs for repeated measures, non-inferiority, cluster and stepped wedge trials. Other new chapters describe data and safety monitoring, biomarker studies, and feasibility studies. Updated and expanded sections discuss situations where multiple organs, different body locations or competing risks are involved, subgroup analysis, and multiple outcomes. Written by an author team with extensive experience in conducting clinical trials, this book:

  • Provides comprehensive coverage of randomised clinical trials, ranging from basic to advanced
  • Features several new chapters, updated case studies and examples, and references to changes in regulations
  • Explains basic randomised trials, including the parallel two-group controlled trial with a single outcome measure
  • Covers paired trial designs and trials with more than two interventions
  • Includes a chapter on miscellaneous topics such as adaptive designs, large simple trials, Bayesian methods for very small trials, alpha-spending functions and the predictive probability test

Randomised Clinical Trials is essential reading for clinicians, nurses, data managers, and medical statisticians involved in clinical trials, and for health practitioners responsible for direct patient care in a clinical trial setting.

Table of Contents

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

Authors

David Machin Medical Research Council Cancer Trials Office, Cambridge. Peter M. Fayers Medical Research Council Clinical Trials Unit, London, UK. Bee Choo Tai Associate Professor, Dept of Epidemiology and Public Health, National University of Singapore, Singapore.