Contents

1 Introduction 1

2 The public perspective 5

2.1 Introduction 5

2.2 Barriers to taking part in trials 6

2.3 Informed consent 8

2.3.1 Public opinion concerning consent 9

2.3.2 How much information should be disclosed? 10

2.3.3 Explaining randomization andrationale for trials 10

2.3.4 Patient information sheets 12

2.4 Informing participants about the results of trials 14

2.5 Involving the public in designing trials and setting research agendas 15

2.5.1 NCI directors consumer liaison group 16

2.6 Education and raising public awareness of trials 18

2.7 Conclusions 20 References 21

3 What type of trial is needed? 25

3.1 Introduction 25

3.1.1 Phases of clinical trials 25

3.2 Phase I - Clinical pharmacology and toxicity 26

3.3 Phase II - Initial investigation of treatment activity 26

3.3.1 General aim 26

3.3.2 The importance of prospective conduct 27

3.3.3 Common phase II designs 27

3.3.4 Choice of design 30

3.3.5 Limitations of conventional phase II trials 30

3.4 Phase III - Full-scale comparative treatment evaluation 31

3.4.1 The importance of randomization 32

3.4.2 Non-randomized comparisons - an introduction 32

3.4.3 Historical controls 33

3.4.4 Concurrent controls 36

3.5 Phase IV - Post-marketing surveillance 37

3.6 'Positioning'your trial 37

3.7 Conclusion 42 References 42

4 Design issues for randomized trials 44

4.1 Introduction 44

4.2 Key design decisions 44

4.2.1 Choice of arms 44

4.2.2 Efficacy, equivalence or non-inferiority? 46

4.2.3 Explanatory or pragmatic? 47

4.3 Timing of randomization and consent 53

4.3.1 Problems with the conventional order of events 52

4.3.2 Alternative randomization procedures 53

4.4 Unit of randomization - individuals or groups? 55

4.4.1 What are the advantages of cluster randomization? 56

4.4.2 What are the disadvantages of cluster randomization? 57

4.4.3 Further reading 57

4.5 Designs for randomized trials 58

4.5.1 Introduction 58

4.5.2 Parallel groups 58

4.5.3 Factorial designs 59

4.5.4 Cross-over trials 63

4.6 Sequential randomizations within and between trials 64

4.7 Allocation methods for randomized trials 68

4.7.1 Introduction 68

4.7.2 Simple (pure) randomization 69

4.7.3 Block randomization (random permuted blocks) 70

4.7.4 Stratified randomization 71

4.7.5 Minimization 73

4.7.6 Sealed envelope randomization 76

4.7.7 Practical issues 76

4.8 Allocation concealment - blinding/masking 77

4.8.1 Definitions 77

4.8.2 Placebos 78

4.8.3 Practicalities of using placebos or blinded treatments 79

4.8.4 General guidance 79

4.9 Conclusion 80 References 80

5 Trial size 83

5.1 Introduction 83

5.2 Outcome measures 84

5.3 Basic considerations 86

5.3.1 What size of type I error is acceptable? 87

5.3.2 What size of type II error is acceptable? 89

5.3.3 What do you expect of the control arm? 90

5.3.4 What size of difference between treatments is important? 91

5.3.5 Allocation ratios 99

5.4 Calculating sample sizes 100

5.4.1 Continuous data 101

5.4.2 Binary data 104

5.4.3 Survival data 104

5.4.4 Non-compliers and drop-outs 106

5.4.5 Phase II trials 106

5.5 The perfect and the practicable 109

5.6 Changing sample sizes mid-trial 111

5.7 Sample size tables and software 112

5.8 Conclusions 114 References 114

6 Quality of life in clinical trials 116

6.1 Introduction 116

6.2 The rationale behind the assessment of QL in randomized clinical trials in cancer 117

6.2.1 What is quality of life? 117

6.2.2 Why measure QL? 118

6.2.3 Who should assess quality of life? 119

6.2.4 Conditions for patient-completed questionnaires 120

6.2.5 Response shift 121

6.3 Implementation of QL into trials 122

6.3.1 Which trials should include a QL assessment? 122

6.3.2 The importance of setting hypotheses 124

6.3.3 Identifying key symptoms 125

6.3.4 Identifying key timepoints 127

6.3.5 How many patients are required? 128

6.4 Choosing the questionnaire 129

6.4.1 Single global question and psychometrics 130

6.4.2 Development of QL questionnaires 131

6.4.3 Types of questionnaires 134

6.4.4 Weighting 136

6.4.5 Adding trial-specific questions 137

6.4.6 Translations 137

6.4.7 Choosing a questionnaire 137

6.5 Practical administration issues 138

6.5.1 Local QL coordinator 138

6.5.2 Administration 139

6.5.3 How can good compliance be attained and maintained? 140

6.5.4 Guidelines for protocol writing 143

6.5.5 The future 145

6.6 Conclusions 145 References 145

7 Putting plans into practice 151

7.1 Introduction 151

7.2 What needs to be done? 151

7.3 International standards for conducting trials 152

7.4 Who does what? 152

7.4.1 The trial sponsor and trial funders 152

7.4.2 The trial management group 153

7.4.3 Principal investigator 154

7.4.4 Clinical advisers 155

7.4.5 Expert advisers and independent assessors 155

7.4.6 Medical statistician 156

7.4.7 Clinical trials manager 156

7.4.8 Collaborating centres 156

7.5 Developing and drafting an outline proposal 157

7.5.1 Title 157

7.5.2 The need for the trial 157

7.5.3 The design of the trial 158

7.5.4 The level of interest the trial is likely to attract 159

7.5.5 The costs of the trial and the funding requested 160

7.5.6 The research team 162

7.6 Preparing the trial protocol 162

7.6.1 Front cover 162

7.6.2 Inside front cover 162

7.6.3 Contents 162

7.6.4 Trial outline 163

7.6.5 Background 164

7.6.6 Aims 164

7.6.7 Eligibility criteria 164

7.6.8 Registration and randomization 164

7.6.9 Treatment regimens 165

7.6.10 Adverse effects of treatment 166

7.6.11 Relapse procedures 166

7.6.12 Assessments and investigations 166

7.6.13 Quality of life assessment 166

7.6.14 Outcome measures 166

7.6.15 Statistical considerations 167

7.6.16 Ethical considerations 167

7.6.17 Data access and quality assurance 168

7.6.18 Publication 168

7.6.19 References 168

7.6.20 Patient information sheet 168

7.6.21 Storage of tissue and biological samples 170

7.6.22 Patient consent form 171

7.6.23 Trial report forms 172

7.7 Trial-specific procedures 173

7.7.1 Trial personnel 174

7.7.2 Computer database 174

7.7.3 Registration and randomization 174

7.7.4 Enrolling new centres 178

7.7.5 Instructions for initial site visits by trial coordinating staff 178

7.7.6 Instructions for subsequent monitoring visits 178

111 Standard documents 179

7.7.8 Filing 179

7.7.9 Finance 179

7.7.10 Other instructions that may be relevant 180

7.8 Ethics 180

7.8.1 Ethics committees 180

7.8.2 Patients'consent 181

7.8.3 Obtaining consent from children and adolescents 181

7.8.4 Adult patients whose capacity to give consent is impaired 182

7.9 Collaboration between industrial and non-industrial partners 182

7.10 Collaboration between research groups 184

7.11 Conclusion 185 References 186

8 Conducting trials 187

8.1 Introduction 187

8.2 What needs to be done? 187

8.3 Launching the trial and recruiting centres 188

8.4 Promoting and publicizing the trial 189

8.5 Day-to-day conduct of the trial and data management 190

8.5.1 Obtaining, recording and checking data 190

8.5.2 Source data verification 190

8.5.3 Data entry checking 193

8.6 Maintaining good collaboration 194

8.6.1 Day-to-day contact between trial coordinators and collaborating centres 194

8.6.2 Regular collaborators'meetings 195

8.7 Conferring with patient advocacy groups 196

8.8 Conducting analyses 196

8.9 Preparing reports for presentation and publication 197

8.9.1 Style of authorship 197

8.9.2 Acknowledgements 198

8.9.3 Drafting reports 199

8.10 Independent data monitoring and supervision 199

8.10.1 Membership and functions of the data monitoring and ethics committee 200

8.10.2 Membership and functions of the trial steering committee 203

8.11 Computing and information technology 205

8.11.1 Communication 205

8.11.2 Randomization software 206

8.11.3 Clinical trials software 206

8.12 Data protection 207

8.12.1 Principles of data protection 208

8.12.2 Common-sense rules for protecting data 209

8.12.3 Encrypting data 209

8.12.4 Worldwide availability of data 209

8.13 Research misconduct 210

8.13.1 Definition of misconduct 211

8.13.2 Examples 211

8.13.3 Detecting possible misconduct and whistle-blowing 211

8.13.4 Prevention 212

8.14 Conclusion 212 References 213

9 Analysis 214

9.1 Introduction 214

9.2 Significance testing and estimation 215

9.2.1 Significance testing 215

9.2.2 Estimation 215

9.2.3 Differences and relationship between significance testing and estimation 216

9.3 Statistical methods 217

9.3.1 Binary data 217

9.3.2 More than two categories 222

9.3.3 Continuous data 224

9.3.4 Time-to-event data 226

9.3.5 Longitudinal data (repeated measures) 235

9.4 Practical guidance in analyzing the data from a randomized trial 235

9.4.1 Intention-to-treat analysis 235

9.4.2 Intention-to-treat analysis and equivalence trials 238

9.4.3 Patient characteristics 239

9.4.4 Treatment and compliance 240

9.4.5 Response 241

9.4.6 Toxicity 244

9.4.7 Time-to-event 245

9.4.8 Subgroup analysis 248

9.4.9 Quality of life (including longitudinal) data 252

9.5 Interim analyses 263

9.6 Conclusion 269 References 269

10 Reporting and interpreting results 272

10.1 Introduction 272

10.2 General principles 272

10.3 Structure and content of a trial report - CONSORT 272

10.3.1 The CONSORT guidelines - justification 273

10.3.2 Other points to include 279

10.4 Presenting results - relative or absolute measures? 279

10.5 Practical issues in reporting 280

10.5.1 Always publish 280

10.5.2 When should the first results be published? 281

10.5.3 How often should trial results be updated for publication? 281

10.5.4 Choosing an appropriate journal 282

10.5.5 The covering letter 282

10.5.6 Publishing data from sub-studies 283

10.6 Disseminating results 284

10.6.1 Conference presentations 284

10.6.2 Pressreleases 285

10.6.3 Informing the trial patients and/or their families 289

10.7 Interpreting trials 289

10.7.1 Is the result (or conclusion) falsely negative? 289

10.7.2 Is the result (or conclusion) falsely positive? 290

10.8 Conclusion 292 References 293

11 Systematic review and meta-analysis 294

11.1 Introduction 294 11.1.1 Definitions 295

11.2 Why we need systematic reviews and meta-analyses 295

11.2.1 Reducing the effect of random error 296

11.2.2 Reducing the effect of bias 297

11.2.3 Underlying assumptions of meta-analysis 297

11.3 Different types of meta-analysis 298

11.3.1 Comparing IPD and other approaches 298

11.3.2 Potential benefits of the IPD approach 300

11.3.3 Potential costs of the IPD approach 301

11.3.4 Choosing which approach is appropriate 301

11.4 Methodological principles of systematic review 302

11.4.1 Include only randomized trials 302

11.4.2 Include all randomized trials 303

11.4.3 Include trials once only 304

11.4.4 Include all and only randomized patients 305

11.5 Practical methods for systematic review and meta-analysis 306

11.5.1 Defining the question 307

11.5.2 Writing a protocol 308

11.5.3 Organizational structures 308

11.5.4 Identifying trials 310

11.5.5 Data collection 315

11.5.6 Data checking 319

11.5.7 Analyses 322

11.5.8 Reporting and disseminating results 331

11.6 Some statistical issues in meta-analysis 333

11.6.1 Fixed versus random effect model 333

11.6.2 Heterogeneity 333

11.6.3 Meta-regression 334

11.6.4 Investigating publication bias 334

11.7 Example of an IPD meta-analysis: Postoperative radiotherapy in non-small-cell lung cancer 336

11.8 The Cochrane collaboration 340

11.9 Conclusions 341 References 342

12 Benefits of an established trials centre and research group 346

12.1 Introduction 346

12.2 The characteristics of an established trials centre 346

12.3 International collaboration between trials centres 346

12.4 Coherent programmes of trials 348

12.4.1 Framing clinically relevant hypotheses 348

12.4.2 Example of a strategically planned programme of clinical research 348

12.5 Maintaining a network of collaborating centres 349

12.5.1 Collaborators' meetings 350

12.5.2 Planning group meetings 351

12.5.3 Newsletters and annual reports 351

12.6 Trials centre staff 351

12.6.1 Staff and expertise 351

12.6.2 Standard operating procedures 352

12.7 Links with patient advocacy groups 352

12.8 Long-term follow-up, ownership and retention of data 353

12.9 Methodological and trials-associated research 354

12.10 Conclusion 356 References 356

Index 359

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