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<p>Preface ix</p> <p>Foreword xi</p> <p><b>1 Fundamental concepts 1</b></p> <p>1.1 What is a clinical trial? 1</p> <p>1.2 Early trials 2</p> <p>1.3 Why clinical trials are needed 3</p> <p>1.4 Alternatives to clinical trials 3</p> <p>1.5 Types of clinical trials 5</p> <p>1.6 Key design features 7</p> <p>1.7 Summary points 13</p> <p><b>2 Types of outcome measures and understanding them 15</b></p> <p>2.1 Clinical trial outcome measures (endpoints) 15</p> <p>2.2 ‘True’ versus surrogate outcome measures 16</p> <p>2.3 Types of outcomes 18</p> <p>2.4 Counting people 18</p> <p>2.5 Taking measurements on people 19</p> <p>2.6 Time-to-event measures 21</p> <p>2.7 Patient-reported outcome measures (PROMs) 25</p> <p>2.8 Summary points 27</p> <p><b>3 Phase I trials 29</b></p> <p>3.1 Trial objectives 29</p> <p>3.2 Types of participants 30</p> <p>3.3 Outcome measures 30</p> <p>3.4 Designs 32</p> <p>3.5 Conducting the trial 37</p> <p>3.6 Statistical analysis and reporting the trial results 37</p> <p>3.7 Summary points 39</p> <p><b>4 Phase II trials 41</b></p> <p>4.1 Trial objectives 41</p> <p>4.2 Designs 41</p> <p>4.3 Outcome measures 48</p> <p>4.4 Estimating study size 48</p> <p>4.5 Stopping early for toxicity 50</p> <p>4.6 Statistical analyses 51</p> <p>4.7 Interpreting phase II studies 55</p> <p>4.8 Summary points 56</p> <p><b>5 Phase III trials: design 59</b></p> <p>5.1 Trial objectives 59</p> <p>5.2 Designs 59</p> <p>5.3 Inclusion and exclusion criteria 62</p> <p>5.4 Experimental/investigational treatment group 64</p> <p>5.5 Control (comparator) group 64</p> <p>5.6 Randomisation and allocating participants 65</p> <p>5.7 Blinding (placebo) 66</p> <p>5.8 Outcome measures 66</p> <p>5.9 Participant follow-up 68</p> <p>5.10 Estimating study size 69</p> <p>5.11 Non-inferiority and equivalence 72</p> <p>5.12 Multiplicity: multiple treatment arms or multiple outcome measures 74</p> <p>5.13 Participants who switch trial interventions (crossover) 75</p> <p>5.14 Summary points 76</p> <p><b>6 Phase III trials – fundamental aspects of analysis and interpretation 79</b></p> <p>6.1 Efficacy 79</p> <p>6.2 Safety toxicity and adverse events 96</p> <p>6.3 Adherence (compliance) 98</p> <p>6.4 Health‐related quality of life (QoL) 99</p> <p>6.5 Intention‐to‐treat and per‐protocol analyses 102</p> <p>6.6 Summary points 103</p> <p><b>7 Randomised trials – additional aspects of analysis and interpretation 107</b></p> <p>7.1 Non-inferiority and equivalence trials 107</p> <p>7.2 Composite outcome measures 110</p> <p>7.3 Subgroup (subset) analyses 111</p> <p>7.4 Crossover trials 115</p> <p>7.5 Factorial trials 115</p> <p>7.6 Cluster randomised trial 117</p> <p>7.7 Repeated measures 117</p> <p>7.8 Multiple endpoints 117</p> <p>7.9 Dealing with missing outcome data 119</p> <p>7.10 Translational research 120</p> <p><b>8 Commercial trials of medicinal products; other types of interventions; health economic analysis 127</b></p> <p>8.1 Commercial trials of medicines (drugs) 127</p> <p>8.2 Other types of interventions 135</p> <p>Surgical techniques 137</p> <p>Radiotherapy and radioactive substances 139</p> <p>Behavioural/lifestyle interventions 139</p> <p>Medical devices 141</p> <p>Cell and gene therapy 142</p> <p>8.3 Health economic analyses 144</p> <p><b>9 Systematic reviews and meta-analyses; and real-world evidence 147</b></p> <p>9.1 Systematic reviews of randomised controlled trials (direct comparisons) 147</p> <p>9.2 Meta-analyses based on indirect comparisons 154</p> <p>9.3 Real-world evidence and real-world data 159</p> <p>9.4 Summary points 166</p> <p><b>10 Conducting and reporting trials 169</b></p> <p>10.1 Working group and key roles 169</p> <p>10.2 Estimate and secure funding 170</p> <p>10.3 Patient and Public Involvement and Engagement (PPIE) 171</p> <p>10.4 Essential trial documents 171</p> <p>Trial protocol 171</p> <p>Participant/Patient Information Sheet (PIS) and Consent Form 172</p> <p>Case report forms (CRFs) 175</p> <p>Electronic database (randomisation system) 176</p> <p>Standard operating procedures (SOPs) 176</p> <p>Investigator’s Brochure (IB) 177</p> <p>Trial Master File (TMF) 177</p> <p>10.5 Ethics and regulatory approvals 177</p> <p>10.6 Trial set up 179</p> <p>Register the trial 179</p> <p>Contracts and agreements 179</p> <p>Assess site feasibility 181</p> <p>Site initiation and activation 181</p> <p>Handling and distribution of trial drugs 181</p> <p>Handling and shipping of biospecimens or imaging scans 182</p> <p>10.7 Conducting the trial 182</p> <p>10.8 Monitoring the trial and suspension/early stopping 184</p> <p>Safety monitoring and reporting 185</p> <p>10.9 End of trial 188</p> <p>10.10 Reporting and publishing trials 190</p> <p>10.11 Regulations and guidance associated with conducting trials 191</p> <p>10.12 Why trials ‘fail’ 194</p> <p>Clinical trial critical appraisal checklist 199</p> <p>Glossary of abbreviations used in clinical trials 201</p> <p>Further reading 205</p> <p>Index 207</p>

<p><b>Allan Hackshaw</b> is Professor of Epidemiology and Medical Statistics and Deputy Director, CRUK Cancer Trials Centre, University College London, United Kingdom.

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