Randomized Clinical Trials

David Machin, Medical Statistics Group, School of Health andRelated Sciences, University of Sheffield, UK and Children's Cancerand Leukaemia Group, University of Leicester, UK Peter M Fayers, Department of Public Health, Universityof Aberdeen, UK and Faculty of Medicine, Norwegian University ofScience and Technology, Trondheim, Norway

Preface. 1 Introduction. 1.1 Introduction. 1.2 Some completed trials. 1.3 Choice of design. 1.4 Practical constraints. 1.5 Influencing clinical practice. 1.6 History. 1.7 How trials arise. 1.8 Ethical considerations. 1.9 Regulatory requirements. 1.10 Focus. 1.11 Further reading. 2 Design Features. 2.1 Introduction. 2.2 The research question. 2.3 Patient selection. 2.4 The consent process. 2.5 Choice of interventions. 2.6 Choice of design. 2.7 Assigning the interventions. 2.8 Making the assessments. 2.9 Analysis and reporting. 2.10 Technical details. 2.11 Guidelines. 2.12 Further reading. 3 The Trial Protocol. 3.1 Introduction. 3.2 Protocol abstract. 3.3 Protocol background. 3.4 Protocol research objectives. 3.5 Protocol design. 3.6 Protocol intervention details. 3.7 Protocol eligibility. 3.8 Protocol randomization. 3.9 Protocol assessment and data collection. 3.10 Protocol statistical considerations. 3.11 Protocol ethical issues. 3.12 Protocol organizational structure. 3.13 Protocol publication policy. 3.14 Protocol trial forms. 3.15 Protocol appendices. 3.16 Regulatory requirements. 3.17 Guidelines. 3.18 Protocols. 4 Measurement and Data Capture. 4.1 Introduction. 4.2 Measures and endpoints. 4.3 Making the observations. 4.4 Baseline measures. 4.5 Types of measures. 4.6 Data recording. 4.7 Technical notes. 4.8 Guidelines. 5 Randomization. 5.1 Introduction. 5.2 Rationale. 5.3 Mechanics. 5.4 Application. 5.5 Carrying out randomization. 5.6 Documentation. 5.7 Unacceptable methods. 5.8 Software. 5.9 Guidelines. 6 Trial Initiation. 6.1 Introduction. 6.2 Trial organization. 6.3 Data collection and processing. 6.4 Data monitoring. 6.5 Ethical and regulatory requirements. 6.6 Launching the trial. 6.7 Trial registries. 6.8 Guidelines. 7 Trial Conduct. 7.1 Introduction. 7.2 Regular feedback. 7.3 Publicity. 7.4 Data monitoring committees. 7.5 Protocol modifications. 7.6 Preparing the publication(s). 7.7 The next trial? 7.8 Protocols. 8 Basics of Analysis. 8.1 Introduction. 8.2 Confidence intervals. 8.3 Statistical tests. 8.4 Examples of analysis. 8.5 Other issues. 8.6 Practice. 8.7 Technical details. 9 Trial Size. 9.1 Introduction. 9.2 Significance level and power. 9.3 The fundamental equation. 9.4 Specific situations. 9.5 Practical considerations. 9.6 Further topics. 9.7 Other methods and software. 9.8 Guideline. 10 Reporting. 10.1 Introduction. 10.2 Publication guidelines. 10.3 Responsibilities. 10.4 Background. 10.5 Methods. 10.6 Findings. 10.7 When things go wrong. 10.8 Conclusions. 10.9 Guidelines. 11 Adaptations of the Basic Design. 11.1 Introduction. 11.2 Repeated measures. 11.3 Cluster-randomized trials. 11.4 Non-inferiority trials. 11.5 Guidelines. 12 Paired Designs. 12.1 Cross-over trials. 12.2 Split-mouth designs. 12.3 Paired organs. 13 More Than Two Interventions. 13.1 Introduction. 13.2 Unstructured comparisons. 13.3 Comparisons with placebo (or standard). 13.4 Dose response designs. 13.5 Factorial trials. 14 Further Topics. 14.1 Introduction. 14.2 Adaptive approaches. 14.3 Large simple trials. 14.4 Bayesian methods. 14.5 Zelen randomized-consent designs. 14.6 Systematic overviews. 14.7 Conclusion. Statistical Tables. Glossary. References. Index.