Fundamentals of Clinical Trials

About the Authors......Page 5
Preface......Page 7
Acknowledgments......Page 11
Contents......Page 12
Chapter 1: Introduction to Clinical Trials......Page 21
 What Is a Clinical Trial?......Page 22
 Clinical Trial Phases......Page 24
  Phase I Studies......Page 25
  Phase II Studies......Page 27
  Phase III/IV Trials......Page 29
 Why Are Clinical Trials Needed?......Page 30
 Problems in the Timing of a Trial......Page 34
 Study Protocol......Page 35
 Appendices......Page 37
 References......Page 38
Chapter 2: Ethical Issues......Page 44
  Does the Question Require a Clinical Trial?......Page 46
  Randomization......Page 49
  Control Group......Page 50
  Protection from Conflicts of Interest......Page 52
  Informed Consent......Page 53
  Trials in Low- and Middle-Income Countries......Page 56
  Recruitment......Page 57
  Safety and Efficacy Monitoring......Page 58
  Early Termination for Other Than Scientific or Safety Reasons......Page 59
  Data Falsification......Page 60
  Publication Bias, Suppression, and Delays......Page 61
 References......Page 62
Chapter 3: What Is the Question?......Page 68
  Primary Question......Page 69
  Secondary Questions Regarding Benefit......Page 70
  Questions Regarding Harm......Page 71
  Ancillary Questions......Page 72
  Trials with Extensive Data Collection vs. Large, Simple......Page 73
  Comparative Effectiveness Trials......Page 74
 Intervention......Page 75
  Kinds of Response Variables......Page 76
  Specifying the Question......Page 79
  Biomarkers and Surrogate Response Variables......Page 81
 Changing the Question......Page 84
 General Comments......Page 85
 References......Page 86
 Fundamental Point......Page 91
 Definition of Study Population......Page 92
  Considerations in Defining the Study Population......Page 93
  Potential for Benefit......Page 94
  High Likelihood of Showing Benefit......Page 96
  Avoiding Adverse Effects......Page 98
  Avoiding Poor Adherers......Page 99
 Pharmacogenetics......Page 100
 Generalization......Page 101
 Recruitment......Page 103
 References......Page 104
Chapter 5: Basic Study Design......Page 107
 Overview......Page 108
 Randomized Control Trials......Page 110
 Nonrandomized Concurrent Control Studies......Page 112
  Strengths of Historical Control Studies......Page 113
  Limitations of Historical Control Studies......Page 114
  Role of Historical Controls......Page 118
 Cross-Over Designs......Page 120
 Withdrawal Studies......Page 121
 Factorial Design......Page 122
 Group Allocation Designs......Page 124
 Large, Simple and Pragmatic Clinical Trials......Page 125
 Studies of Equivalency and Noninferiority......Page 127
 Adaptive Designs......Page 132
 References......Page 133
 Fundamental Point......Page 140
 Fixed Allocation Randomization......Page 141
  Simple Randomization......Page 142
  Blocked Randomization......Page 143
  Stratified Randomization......Page 145
 Adaptive Randomization Procedures......Page 148
  Baseline Adaptive Randomization Procedures......Page 149
  Minimization......Page 150
  Response Adaptive Randomization......Page 152
 Mechanics of Randomization......Page 154
 Appendix: Adaptive Randomization Algorithm......Page 156
 References......Page 158
Chapter 7: Blinding......Page 163
  Unblinded......Page 164
  Single-Blind......Page 166
  Double-Blind......Page 167
  Triple-Blind......Page 169
 Protecting the Double-Blind Design......Page 170
  Matching of Drugs......Page 171
  Coding of Drugs......Page 173
  Official Unblinding......Page 174
  Inadvertent Unblinding......Page 175
  Assessment and Reporting of Blinding......Page 176
 Debriefing of Participants......Page 177
 References......Page 178
Chapter 8: Sample Size......Page 180
 Fundamental Point......Page 181
 Statistical Concepts......Page 182
  Two Independent Samples......Page 186
  Paired Dichotomous Response......Page 192
  Adjusting Sample Size to Compensate for Nonadherence......Page 193
 Sample Size Calculations for Continuous Response Variables......Page 194
  Two Independent Samples......Page 195
  Paired Data......Page 196
 Sample Size for Repeated Measures......Page 198
 Sample Size Calculations for ``Time to Failure´´......Page 199
 Sample Size for Testing ``Equivalency´´ or Noninferiority of Interventions......Page 203
 Sample Size for Cluster Randomization......Page 204
 Multiple Response Variables......Page 207
 Estimating Sample Size Parameters......Page 208
 References......Page 210
  Description of Trial Participants......Page 216
  Baseline Comparability......Page 217
  Controlling for Imbalances in the Analysis......Page 219
  Subgrouping......Page 220
  Screening for Participants......Page 222
  Regression Toward the Mean......Page 223
  Uncertainty About Qualifying Diagnosis......Page 225
  Contamination of the Intervention......Page 226
 Changes of Baseline Measurement......Page 227
 References......Page 228
 Fundamental Point......Page 230
  Selection of Study Sample......Page 231
  Common Recruitment Problems......Page 232
  Planning......Page 234
  Recruitment Sources......Page 236
 Conduct......Page 238
 Monitoring......Page 240
 Approaches to Lagging Recruitment......Page 244
 References......Page 245
Chapter 11: Data Collection and Quality Control......Page 248
 Fundamental Point......Page 249
  Major Types......Page 250
  Design of Protocol and Manual......Page 253
  Training and Certification......Page 254
  Techniques to Reduce Variability Including Central Adjudication of Events......Page 256
  Electronic Source Data......Page 258
 Quality Monitoring......Page 259
  Monitoring of Procedures......Page 261
  Monitoring of Drug Handling......Page 262
  Audits......Page 263
 References......Page 265
Chapter 12: Assessment and Reporting of Harm......Page 269
  Strengths......Page 270
  Limitations......Page 271
  Identification of Harm in Clinical Trials......Page 273
 Classification of Adverse Events......Page 274
 Ascertainment......Page 276
  Prespecified Adverse Events......Page 277
  Length of Follow-up......Page 278
  Standard Reporting......Page 280
  Post Hoc Analysis......Page 281
  Meta-analysis......Page 282
 Reporting of Harm......Page 283
 Scientific Journal Publication......Page 285
 Regulatory Considerations......Page 286
 Recommendations for Assessing and Reporting Harm......Page 287
 References......Page 288
 Fundamental Point......Page 292
  Primary Measures......Page 293
  Additional Measures......Page 294
 Uses of HRQL Measures......Page 295
 Design Issues......Page 297
  Type of Intervention......Page 298
  Frequency of Assessment (Acute Versus Chronic)......Page 299
  Protocol Considerations......Page 300
 Selection of HRQL Instruments......Page 301
  Types of Measures......Page 302
  Determining the Significance of HRQL Measures......Page 303
 Utility Measures/Preference Scaling and Comparative Effectiveness Research......Page 304
 References......Page 305
Chapter 14: Participant Adherence......Page 309
  Definitions......Page 310
 Medication Adherence......Page 311
  Design Factors......Page 312
  Participant Factors......Page 314
  Box 14.1: Women´s Health Initiative Brochure......Page 316
 Maintaining Good Participant Adherence......Page 318
 Box 14.2: Aspirin Myocardial Infarction Study Brochure......Page 320
 Adherence Monitoring......Page 323
 Dealing with Low Adherence......Page 326
 References......Page 327
 Fundamental Point......Page 331
 Estimation of the Survival Curve......Page 332
  Kaplan-Meier Estimate......Page 336
 Comparison of Two Survival Curves......Page 340
  Comparison of Median Survival Times......Page 341
  Total Curve Comparison......Page 342
  Generalizations......Page 347
  Covariate Adjusted Analysis......Page 349
 References......Page 352
Chapter 16: Monitoring Committee Structure and Function......Page 354
 Monitoring Committee......Page 357
 Repeated Testing for Significance......Page 361
 Decision for Early Termination......Page 363
 Decision to Extend a Trial......Page 374
 Accelerated Approval Paradigm......Page 378
 References......Page 379
 Fundamental Point......Page 384
 Classical Sequential Methods......Page 385
 Group Sequential Methods......Page 386
 Flexible Group Sequential Procedures: Alpha Spending Functions......Page 389
 Applications of Group Sequential Boundaries......Page 392
 Asymmetric Boundaries......Page 395
 Curtailed Sampling and Conditional Power Procedures......Page 397
 Other Approaches......Page 402
 Trend Adaptive Designs and Sample Size Adjustments......Page 403
 References......Page 406
Chapter 18: Issues in Data Analysis......Page 413
 Which Participants Should Be Analyzed?......Page 414
  Ineligibility......Page 416
  Nonadherence......Page 420
 Missing or Poor Quality Data......Page 424
 Competing Events......Page 431
 Composite Outcomes......Page 432
 Covariate Adjustment......Page 434
  Surrogates as a Covariate......Page 435
  Baseline Variables as Covariates......Page 438
 Subgroup Analyses......Page 441
 Not Counting Some Events......Page 448
 Comparison of Multiple Variables......Page 449
 Use of Cutpoints......Page 450
 Noninferiority Trial Analysis......Page 452
 Analysis Following Trend Adaptive Designs......Page 454
  Rationale and Issues......Page 455
  Statistical Methods......Page 459
  Analysis for Harmful Effects......Page 461
 References......Page 463
  Planning......Page 473
  Scheduling of Closeout Visits......Page 474
  Final Response Ascertainment......Page 475
 Transfer of Post-trial Care......Page 478
  Cleanup and Verification......Page 479
  Storage......Page 480
 Dissemination of Results......Page 481
 Post Study Follow-up......Page 483
 References......Page 485
Chapter 20: Reporting and Interpreting of Results......Page 488
 Guidelines for Reporting......Page 489
  Authorship......Page 491
  Presentation of Data......Page 492
 Interpretation......Page 493
 Publication Bias......Page 494
  Blinding......Page 496
  What Are the Limitations?......Page 497
 What Kinds of Analyses?......Page 498
 How Do the Findings Compare with Those from Other Studies?......Page 500
 What Are the Clinical Implications of the Findings?......Page 501
 Data Sharing......Page 502
 References......Page 503
Chapter 21: Multicenter Trials......Page 509
 Reasons for Multicenter Trials......Page 510
 Conduct of Multicenter Trials......Page 512
 Globalization of Trials......Page 519
 Large, Simple Trials......Page 522
 References......Page 523
Chapter 22: Regulatory Issues......Page 527
 Fundamental Point......Page 528
  History......Page 529
  Trial Phases......Page 531
 Pretrial Requirements......Page 533
 Conduct......Page 534
  Interventions: Drugs......Page 536
  Interventions: Devices......Page 537
  Interventions: Biologics......Page 540
 Post-trial Requirements......Page 541
  Documents for FDA submission......Page 542
  Post-approval Issues and Postmarketing Investigations......Page 543
  U.S. Food and Drug Administration......Page 545
 References......Page 546
ERRATUM......Page 551
Index......Page 553