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

Clinical Trials in Cancer provides concise, accessible and practical information on the practicalities of planning, designing, conducting, analysing, reporting, and interpreting phase III clinical trials predominantly, but also single-arm and randomized phase II trials. The book shows clearly how recent developments and current thinking can be implemented. Information on the need to decide and measure realistic target differences in trials, the conduct and interpretation of interim analyses, patient advocacy, good clinical practice, the study of quality of life, the role of meta-analyses, and informed consent and other ethical issues are also covered. This book will prove invaluable for medical, statistical, and biological cancer researchers, health care professionals, and researchers in the pharmaceutical industry. Trial sponsors, principal investigators, members of data monitoring and trial supervisory committees, specialists invited to provide independent assessments, and many others involved in all aspects of research related to clinical trials should also find this book helpful. 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