Clinical Trials in Cancer: Principles and Practice (Oxford Medical Publications)

Contents......Page 10
1 Introduction......Page 20
2.1 Introduction......Page 24
2.2 Barriers to taking part in trials......Page 25
2.3 Informed consent......Page 27
2.3.1 Public opinion concerning consent......Page 28
2.3.3 Explaining randomization and rationale for trials......Page 29
2.3.4 Patient information sheets......Page 31
2.4 Informing participants about the results of trials......Page 33
2.5 Involving the public in designing trials and setting research agendas......Page 34
2.5.1 NCI directors consumer liaison group......Page 35
2.6 Education and raising public awareness of trials......Page 37
2.7 Conclusions......Page 39
References......Page 40
3.1.1 Phases of clinical trials......Page 44
3.3.1 General aim......Page 45
3.3.3 Common phase II designs......Page 46
3.3.5 Limitations of conventional phase II trials......Page 49
3.4 Phase III – Full-scale comparative treatment evaluation......Page 50
3.4.2 Non-randomized comparisons – an introduction......Page 51
3.4.3 Historical controls......Page 52
3.4.4 Concurrent controls......Page 55
3.6 'Positioning' your trial......Page 56
References......Page 61
4.2.1 Choice of arms......Page 63
4.2.2 Efficacy, equivalence or non-inferiority?......Page 65
4.2.3 Explanatory or pragmatic?......Page 66
4.3.1 Problems with the conventional order of events......Page 71
4.3.2 Alternative randomization procedures......Page 72
4.4 Unit of randomization – individuals or groups?......Page 74
4.4.1 What are the advantages of cluster randomization?......Page 75
4.4.3 Further reading......Page 76
4.5.2 Parallel groups......Page 77
4.5.3 Factorial designs......Page 78
4.5.4 Cross-over trials......Page 82
4.6 Sequential randomizations within and between trials......Page 83
4.7.1 Introduction......Page 87
4.7.2 Simple (pure) randomization......Page 88
4.7.3 Block randomization (random permuted blocks)......Page 89
4.7.4 Stratified randomization......Page 90
4.7.5 Minimization......Page 92
4.7.7 Practical issues......Page 95
4.8.1 Definitions......Page 96
4.8.2 Placebos......Page 97
4.8.4 General guidance......Page 98
References......Page 99
5.1 Introduction......Page 102
5.2 Outcome measures......Page 103
5.3 Basic considerations......Page 105
5.3.1 What size of type I error is acceptable?......Page 106
5.3.2 What size of type II error is acceptable?......Page 108
5.3.3 What do you expect of the control arm?......Page 109
5.3.4 What size of difference between treatments is important?......Page 110
5.3.5 Allocation ratios......Page 118
5.4 Calculating sample sizes......Page 119
5.4.1 Continuous data......Page 120
5.4.3 Survival data......Page 123
5.4.5 Phase II trials......Page 125
5.5 The perfect and the practicable......Page 128
5.6 Changing sample sizes mid-trial......Page 130
5.7 Sample size tables and software......Page 131
References......Page 133
6.1 Introduction......Page 135
6.2.1 What is quality of life?......Page 136
6.2.2 Why measure QL?......Page 137
6.2.3 Who should assess quality of life?......Page 138
6.2.4 Conditions for patient-completed questionnaires......Page 139
6.2.5 Response shift......Page 140
6.3.1 Which trials should include a QL assessment?......Page 141
6.3.2. The importance of setting hypotheses......Page 143
6.3.3 Identifying key symptoms......Page 144
6.3.4 Identifying key timepoints......Page 146
6.3.5 How many patients are required?......Page 147
6.4 Choosing the questionnaire......Page 148
6.4.1 Single global question and psychometrics......Page 149
6.4.2 Development of QL questionnaires......Page 150
6.4.3 Types of questionnaires......Page 153
6.4.4 Weighting......Page 155
6.4.7 Choosing a questionnaire......Page 156
6.5.1 Local QL coordinator......Page 157
6.5.2 Administration......Page 158
6.5.3 How can good compliance be attained and maintained?......Page 159
6.5.4 Guidelines for protocol writing......Page 162
References......Page 164
7.2 What needs to be done?......Page 170
7.4.1 The trial sponsor and trial funders......Page 171
7.4.2 The trial management group......Page 172
7.4.3 Principal investigator......Page 173
7.4.5 Expert advisers and independent assessors......Page 174
7.4.8 Collaborating centres......Page 175
7.5.2 The need for the trial......Page 176
7.5.3 The design of the trial......Page 177
7.5.4 The level of interest the trial is likely to attract......Page 178
7.5.5 The costs of the trial and the funding requested......Page 179
7.6.3 Contents......Page 181
7.6.4 Trial outline......Page 182
7.6.8 Registration and randomization......Page 183
7.6.9 Treatment regimens......Page 184
7.6.14 Outcome measures......Page 185
7.6.16 Ethical considerations......Page 186
7.6.20 Patient information sheet......Page 187
7.6.21 Storage of tissue and biological samples......Page 189
7.6.22 Patient consent form......Page 190
7.6.23 Trial report forms......Page 191
7.7 Trial-specific procedures......Page 192
7.7.3 Registration and randomization......Page 193
7.7.6 Instructions for subsequent monitoring visits......Page 197
7.7.9 Finance......Page 198
7.8.1 Ethics committees......Page 199
7.8.3 Obtaining consent from children and adolescents......Page 200
7.9 Collaboration between industrial and non-industrial partners......Page 201
7.10 Collaboration between research groups......Page 203
7.11 Conclusion......Page 204
References......Page 205
8.2 What needs to be done?......Page 206
8.3 Launching the trial and recruiting centres......Page 207
8.4 Promoting and publicizing the trial......Page 208
8.5.2 Source data verification......Page 209
8.5.3 Data entry checking......Page 212
8.6.1 Day-to-day contact between trial coordinators and collaborating centres......Page 213
8.6.2 Regular collaborators' meetings......Page 214
8.8 Conducting analyses......Page 215
8.9.1 Style of authorship......Page 216
8.9.2 Acknowledgements......Page 217
8.10 Independent data monitoring and supervision......Page 218
8.10.1 Membership and functions of the data monitoring and ethics committee......Page 219
8.10.2 Membership and functions of the trial steering committee......Page 222
8.11.1 Communication......Page 224
8.11.3 Clinical trials software......Page 225
8.12 Data protection......Page 226
8.12.1 Principles of data protection......Page 227
8.12.4 Worldwide availability of data......Page 228
8.13 Research misconduct......Page 229
8.13.3 Detecting possible misconduct and whistle-blowing......Page 230
8.14 Conclusion......Page 231
References......Page 232
9.1 Introduction......Page 233
9.2.2 Estimation......Page 234
9.2.3 Differences and relationship between significance testing and estimation......Page 235
9.3.1 Binary data......Page 236
9.3.2 More than two categories......Page 241
9.3.3 Continuous data......Page 243
9.3.4 Time-to-event data......Page 245
9.4.1 Intention-to-treat analysis......Page 254
9.4.2 Intention-to-treat analysis and equivalence trials......Page 257
9.4.3 Patient characteristics......Page 258
9.4.4 Treatment and compliance......Page 259
9.4.5 Response......Page 260
9.4.6 Toxicity......Page 263
9.4.7 Time-to-event......Page 264
9.4.8 Subgroup analysis......Page 267
9.4.9 Quality of life (including longitudinal) data......Page 271
9.5 Interim analyses......Page 282
References......Page 288
10.3 Structure and content of a trial report – CONSORT......Page 291
10.3.1 The CONSORT guidelines – justification......Page 292
10.4 Presenting results – relative or absolute measures?......Page 298
10.5.1 Always publish......Page 299
10.5.3 How often should trial results be updated for publication?......Page 300
10.5.5 The covering letter......Page 301
10.5.6 Publishing data from sub-studies......Page 302
10.6.1 Conference presentations......Page 303
10.6.2 Press releases......Page 304
10.7.1 Is the result (or conclusion) falsely negative?......Page 308
10.7.2 Is the result (or conclusion) falsely positive?......Page 309
10.8 Conclusion......Page 311
References......Page 312
11.1 Introduction......Page 313
11.2 Why we need systematic reviews and meta-analyses......Page 314
11.2.1 Reducing the effect of random error......Page 315
11.2.3 Underlying assumptions of meta-analysis......Page 316
11.3.1 Comparing IPD and other approaches......Page 317
11.3.2 Potential benefits of the IPD approach......Page 319
11.3.4 Choosing which approach is appropriate......Page 320
11.4 Methodological principles of systematic review......Page 321
11.4.2 Include all randomized trials......Page 322
11.4.3 Include trials once only......Page 323
11.4.4 Include all and only randomized patients......Page 324
11.5 Practical methods for systematic review and meta-analysis......Page 325
11.5.1 Defining the question......Page 326
11.5.3 Organizational structures......Page 327
11.5.4 Identifying trials......Page 329
11.5.5 Data collection......Page 334
11.5.6 Data checking......Page 338
11.5.7 Analyses......Page 341
11.5.8 Reporting and disseminating results......Page 350
11.6.2 Heterogeneity......Page 352
11.6.4 Investigating publication bias......Page 353
11.7 Example of an IPD meta-analysis: Postoperative radiotherapy in non-small-cell lung cancer......Page 355
11.8 The Cochrane collaboration......Page 359
11.9 Conclusions......Page 360
References......Page 361
12.3 International collaboration between trials centres......Page 365
12.4.2 Example of a strategically planned programme of clinical research......Page 367
12.5 Maintaining a network of collaborating centres......Page 368
12.5.1 Collaborators' meetings......Page 369
12.6.1 Staff and expertise......Page 370
12.7 Links with patient advocacy groups......Page 371
12.8 Long-term follow-up, ownership and retention of data......Page 372
12.9 Methodological and trials-associated research......Page 373
References......Page 375
C......Page 378
E......Page 379
I......Page 380
M......Page 381
P......Page 382
Q......Page 383
S......Page 384
T......Page 385
Z......Page 386