دانلود کتاب Design and Analysis of Clinical Trials: Concepts and Methodologies

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Design and Analysis of Clinical Trials......Page 3
Contents......Page 7
Preface......Page 13
PART I Preliminaries......Page 15
1.1 WHAT ARE CLINICAL TRIALS?......Page 17
1.2 HISTORY OF CLINICAL TRIALS......Page 18
1.3.1 The Food and Drug Administration......Page 24
1.3.2 FDA Regulations for Clinical Trials......Page 27
1.3.3 Phases of Clinical Development......Page 29
1.4 INVESTIGATIONAL NEW DRUG APPLICATION......Page 31
1.4.1 Clinical Trial Protocol......Page 33
1.4.2 Institutional Review Board......Page 36
1.4.5 Withdrawal and Termination of an IND......Page 37
1.5 NEW DRUG APPLICATION......Page 38
1.5.1 Expanded Access......Page 40
1.5.2 Abbreviated New Drug Application......Page 43
1.5.3 Supplemental New Drug Application......Page 44
1.6.1 Clinical Development Plan......Page 45
1.6.2 Good Clinical Practice......Page 47
1.7 AIMS AND STRUCTURE OF THE BOOK......Page 56
2.1 INTRODUCTION......Page 59
2.2.1 Uncertainty......Page 60
2.2.2 Probability......Page 61
2.3.1 Bias......Page 63
2.3.2 Variability......Page 68
2.4 CONFOUNDING AND INTERACTION......Page 71
2.4.1 Confounding......Page 72
2.4.2 Interaction......Page 75
2.5 DESCRIPTIVE AND INFERENTIAL STATISTICS......Page 80
2.6 HYPOTHESES TESTING AND p-VALUES......Page 82
2.6.1 p-Values......Page 84
2.6.2 One-Sided Versus Two-Sided Hypotheses......Page 86
2.7 CLINICAL SIGNIFICANCE AND CLINICAL EQUIVALENCE......Page 89
2.8 REPRODUCIBILITY AND GENERALIZABILITY......Page 93
2.8.1 Reproducibility......Page 94
2.8.2 Generalizability......Page 95
3.1 INTRODUCTION......Page 99
3.2 GOALS OF CLINICAL TRIALS......Page 100
3.3.1 Eligibility Criteria......Page 104
3.3.2 Patient Selection Process......Page 108
3.3.3 Ethical Considerations......Page 110
3.4 SELECTION OF CONTROLS......Page 111
3.4.1 Placebo Concurrent Control......Page 112
3.4.2 Dose–Response Concurrent Control......Page 115
3.4.3 Active (Positive) Concurrent Control......Page 117
3.4.4 No Treatment Concurrent Control......Page 118
3.5.1 Efficacy and Safety Assessment......Page 119
3.5.2 Sample Size Estimation......Page 121
3.5.3 Interim Analysis and Data Monitoring......Page 122
3.5.4 Statistical and Clinical Inference......Page 124
3.6 OTHER ISSUES......Page 126
3.6.3 Patient Compliance......Page 127
3.6.4 Missing Value and Dropout......Page 128
3.7 DISCUSSION......Page 129
4.1 INTRODUCTION......Page 131
4.2 RANDOMIZATION MODELS......Page 132
4.2.2 Invoked Population Model......Page 133
4.2.3 Randomization Model......Page 134
4.2.4 Stratification......Page 136
4.3 RANDOMIZATION METHODS......Page 138
4.3.1 Complete Randomization......Page 142
4.3.2 Permuted-Block Randomization......Page 147
4.3.3 Adaptive Randomization......Page 151
4.4.1 Generation, Labeling, and Packaging......Page 158
4.4.2 Random Assignment......Page 160
4.5 GENERALIZATION OF CONTROLLED RANDOMIZED TRIALS......Page 163
4.6 BLINDING......Page 167
4.7 DISCUSSION......Page 174
PART II Designs and Their Classifications......Page 177
5.1 INTRODUCTION......Page 179
5.2 PARALLEL GROUP DESIGNS......Page 181
5.2.1 Run-in Periods......Page 183
5.2.2 Examples of Parallel Group Design in Clinical Trials......Page 184
5.3 CLUSTERED RANDOMIZED DESIGNS......Page 186
5.4 CROSSOVER DESIGNS......Page 191
5.4.1 Higher-Order Crossover Designs......Page 192
5.4.2 Williams Designs......Page 195
5.4.4 Examples of Crossover Design in Clinical Trials......Page 196
5.5.1 Standard Titration Design......Page 199
5.5.2 Forced Dose-Escalation Design......Page 203
5.6 ENRICHMENT DESIGNS......Page 205
5.7 GROUP SEQUENTIAL DESIGNS......Page 209
5.8 PLACEBO-CHALLENGING DESIGNS......Page 211
5.8.1 Statistical Model and Inferences......Page 212
5.9 BLINDED READER DESIGNS......Page 217
5.10 DISCUSSION......Page 221
6.1 INTRODUCTION......Page 225
6.2 GENERAL CONSIDERATIONS FOR PHASE ICANCER CLINICAL TRIALS......Page 227
6.3 SINGLE-STAGE UP-AND-DOWN PHASE I DESIGNS......Page 228
6.3.1 Design A—Standard Dose-Escalation Design......Page 229
6.4 TWO-STAGE UP-AND-DOWN PHASE I DESIGNS......Page 231
6.4.2 Accelerated Titration Designs......Page 232
6.5 CONTINUAL REASSESSMENT METHOD PHASE I DESIGNS......Page 233
6.6.1 Single-Arm Trials......Page 236
6.6.2 Multiple-Arm Trials......Page 240
6.7 RANDOMIZED PHASE II DESIGNS......Page 243
6.8 DISCUSSION......Page 246
7.1 INTRODUCTION......Page 251
7.2 MULTICENTER TRIALS......Page 252
7.2.1 Treatment-by-Center Interaction......Page 253
7.2.2 Practical Issues......Page 255
7.3 SUPERIORITY TRIALS......Page 259
7.4.1 Primary Objectives......Page 262
7.4.2 Issues in Active Control Equivalence Trials......Page 263
7.4.3 Interpretation of the Results of Active Control Trials......Page 267
7.4.4 Equivalence/Noninferiority Limits......Page 269
7.4.5 Statistical Methods......Page 272
7.5 DOSE–RESPONSE TRIALS......Page 275
7.5.1 Randomized Parallel Dose–Response Designs......Page 276
7.5.3 Forced Titration (Dose-Escalation) Design......Page 278
7.5.4 Optional Titration Design (Placebo-Controlled Titration to Endpoint)......Page 279
7.6 COMBINATION TRIALS......Page 280
7.6.1 Fixed-Combination Prescription Drugs......Page 282
7.6.2 Multilevel Factorial Design......Page 285
7.6.3 Global Superiority of Combination Drugs......Page 287
7.6.4 Method of Response Surface......Page 291
7.7.1 Introduction......Page 292
7.7.2 Ethnic Sensitivity and Necessity of Bridging Studies......Page 293
7.7.4 Assessment of Similarity Based on Bridging Evidence......Page 296
7.8.1 Basic Design and Statistical Considerations......Page 299
7.8.2 Types of Vaccine Immunogenicity Trials......Page 300
7.8.3 Statistical Methods......Page 302
7.9 QT STUDIES......Page 305
7.9.1 Study Designs and Models......Page 306
7.9.2 Power and Sample Size Calculation......Page 307
7.9.3 Allocation Optimization......Page 311
7.9.4 Remarks......Page 312
7.10 DISCUSSION......Page 313
PART III Analysis of Clinical Data......Page 317
8.1 INTRODUCTION......Page 319
8.2 ESTIMATION......Page 320
8.3 TEST STATISTICS......Page 324
8.3.1 Paired t Test......Page 326
8.3.2 Two-Sample t Test......Page 327
8.4.1 One-Way Classification......Page 330
8.4.2 Simultaneous Confidence Intervals......Page 332
8.4.3 Two-Way Classification......Page 334
8.5 ANALYSIS OF COVARIANCE......Page 337
8.6 NONPARAMETRIC METHODS......Page 339
8.6.1 Wilcoxon Signed Rank Test......Page 340
8.6.2 Wilcoxon Rank Sum Test......Page 341
8.6.3 Kruskal–Wallis Test......Page 345
8.7.1 Assessment of Overall Average Effect Across Time......Page 346
8.7.2 Detection of Time Effect......Page 348
8.7.3 Treatment-by-Time Interaction......Page 349
8.7.4 Method of Generalized Estimating Equations (GEEs)......Page 351
8.8 DISCUSSION......Page 355
9.1 INTRODUCTION......Page 357
9.2 STATISTICAL INFERENCE FOR ONE SAMPLE......Page 359
9.3 INFERENCE OF INDEPENDENT SAMPLES......Page 372
9.4 ORDERED CATEGORICAL DATA......Page 378
9.5 COMBINING CATEGORICAL DATA......Page 382
9.6 MODEL-BASED METHODS......Page 388
9.7 REPEATED CATEGORICAL DATA......Page 396
9.8 DISCUSSION......Page 401
10.1 INTRODUCTION......Page 403
10.2 ESTIMATION OF THE SURVIVAL FUNCTION......Page 405
10.3 COMPARISON BETWEEN SURVIVAL FUNCTIONS......Page 413
10.4 COX’S PROPORTIONAL HAZARD MODEL......Page 419
10.5 CALENDAR TIME AND INFORMATION TIME......Page 433
10.6 GROUP SEQUENTIAL METHODS......Page 438
10.7 DISCUSSION......Page 452
11.1 INTRODUCTION......Page 455
11.2.1 Study Objectives and Hypotheses......Page 456
11.2.2 Type I and Type II Errors......Page 458
11.2.3 Precision Analysis......Page 459
11.2.4 Power Analysis......Page 460
11.3.1 One-Sample Test for Mean......Page 461
11.3.2 Two-Sample Test for Comparing Means......Page 462
11.4.1 Sample Size Calculations for Analysis of Variance Models......Page 470
11.4.2 Sample Size Calculations for Generalized Linear Models......Page 472
11.5 CENSORED DATA......Page 473
11.6.1 Dose–Response Relationship......Page 478
11.6.2 Minimum Effective Dose......Page 480
11.7.1 Point Hypotheses for Equality......Page 485
11.7.2 Interval Hypotheses for Equivalence......Page 487
11.7.3 Higher-Order Crossover Designs......Page 492
11.8 EQUIVALENCE AND NONINFERIORITY TRIALS......Page 495
11.8.1 Independent Binary Endpoints......Page 496
11.8.2 Paired Binary Endpoints......Page 498
11.8.3 Independent Censored Endpoints......Page 500
11.10 MULTINATIONAL TRIALS......Page 504
11.10.1 Selection of the Number of Sites......Page 505
11.10.2 Sample Size Calculation and Allocation......Page 511
11.11 COMPARING VARIABILITIES......Page 514
11.11.1 Comparing Intrasubject Variabilities......Page 515
11.11.2 Comparing Intersubject Variabilities......Page 523
11.12 DISCUSSION......Page 531
PART IV Issues in Evaluation......Page 533
12.1 INTRODUCTION......Page 535
12.2 BASELINE COMPARISON......Page 537
12.3 INTENTION-TO-TREAT PRINCIPLE AND EFFICACY ANALYSIS......Page 542
12.4 ADJUSTMENT FOR COVARIATES......Page 550
12.5 MULTICENTER TRIALS......Page 555
12.6 MULTIPLICITY......Page 562
12.6.1 Multiple Comparisons......Page 564
12.6.2 Multiple Endpoints......Page 566
12.6.3 Subgroup Analysis......Page 571
12.7.2 Regulatory Concerns......Page 572
12.7.3 Early and Late Stages of Drug Development......Page 574
12.7.5 Data Monitoring Committee......Page 575
12.8 USE OF GENETIC INFORMATION FOR EVALUATION OF EFFICACY......Page 578
12.9 SAMPLE SIZE REESTIMATION......Page 584
12.10 DISCUSSION......Page 586
13.1 INTRODUCTION......Page 587
13.2 EXTENT OF EXPOSURE......Page 588
13.2.1 Risk of Exposure......Page 589
13.2.2 Absorbing Events......Page 590
13.2.3 Recurring Events with Negligible Duration......Page 591
13.2.4 Recurring Events with Nonnegligible Duration......Page 592
13.2.5 Laboratory Data......Page 593
13.3.1 Definitions of Adverse Events......Page 596
13.3.2 COSTART......Page 600
13.3.3 MedDRA......Page 602
13.3.4 Common Toxicity Criteria......Page 607
13.4.1 Adverse Event Data Listing......Page 609
13.4.2 Summary Tables of Adverse Events......Page 610
13.4.4 Analysis of Adverse Events......Page 611
13.5.2 Combinability of Laboratory Data......Page 616
13.5.3 Clinically Significant Changes......Page 618
13.5.4 Shift Analysis......Page 619
13.6 ANALYSIS OF QT/QTc PROLONGATION......Page 624
13.6.1 Test Under Parallel Group Design......Page 625
13.6.2 Test Under Crossover Design......Page 627
13.6.4 Remarks......Page 628
13.7 DISCUSSION......Page 629
PART V Recent Development......Page 631
14.1 INTRODUCTION......Page 633
14.2 CONCEPTS AND STRATEGIES......Page 634
14.3.1 Classifier, Prognostic, and Predictive Biomarkers......Page 637
14.3.2 Biomarker Development......Page 639
14.3.3 Analytical Validation......Page 641
14.3.4 Clinical Validation......Page 642
14.4.1 Considerations for Phase I Trials......Page 644
14.4.2 Considerations for Phase II Trials......Page 645
14.4.3 Considerations for Phase III Trials......Page 648
14.5.1 Biomarker as a Covariate Versus a Stratification Factor......Page 654
14.5.2 Treatment-by-Biomarker Interaction Versus Separate Analysis......Page 655
14.5.3 Impact of the Measurement and Classification Error......Page 657
14.6 DISCUSSION......Page 661
15.1 INTRODUCTION......Page 663
15.2 STUDY DESIGN......Page 665
15.3 MEASURES OF DIAGNOSTIC ACCURACY......Page 670
15.4 REPORTING RESULTS......Page 677
15.5 SAMPLE SIZE ESTIMATION......Page 686
15.6 DISCUSSION......Page 689
16.1 INTRODUCTION......Page 691
16.2 BIOMARKER DEVELOPMENT......Page 692
16.2.1 Optimal Variable Screening......Page 693
16.2.2 Model Selection and Validation......Page 694
16.2.3 Remarks......Page 695
16.3.1 One-Way Translational Process......Page 696
16.3.2 Two-Way Translational Process......Page 701
16.4 ANIMAL MODEL VERSUS HUMAN MODEL......Page 703
16.5.1 Power Analysis and Sample Size Calculation......Page 705
16.5.2 Remarks......Page 709
16.6 BRIDGING STUDIES......Page 710
16.6.1 Test for Consistency......Page 711
16.6.3 Test for Similarity......Page 712
16.7 DISCUSSION......Page 713
16.8 APPENDIX......Page 714
17.1 INTRODUCTION......Page 717
17.2 WHAT IS ADAPTIVE DESIGN?......Page 718
17.2.2 Type of Adaptive Designs......Page 719
17.3.1 Well-Understood Designs......Page 723
17.3.2 LessWell-Understood Designs......Page 724
17.4.1 Clinical Operation Perspectives......Page 727
17.4.3 Regulatory Perspectives......Page 729
17.5.1 Moving Target Patient Population......Page 730
17.5.2 Statistical Inference with Covariate Adjustment......Page 731
17.5.3 Bayesian Approach......Page 733
17.6.1 Adaptive Group Sequential Design......Page 735
17.6.2 Adaptive Dose-Finding Design......Page 737
17.6.3 Adaptive Seamless Designs......Page 739
17.6.4 Remarks......Page 740
17.7 OBSTACLES OF RETROSPECTIVE ADAPTATIONS......Page 741
17.8 DISCUSSION......Page 743
18.1 INTRODUCTION......Page 747
18.2 FUNDAMENTAL DIFFERENCES......Page 748
18.2.1 Medical Theory/Mechanism and Practice......Page 749
18.2.2 Techniques of Diagnosis......Page 752
18.2.3 Treatment......Page 753
18.2.4 Remarks......Page 754
18.3.1 Study Design......Page 755
18.3.2 Validation of Quantitative Instrument......Page 756
18.3.4 Matching Placebo......Page 757
18.4 OTHER ISSUES IN TCM RESEARCH AND DEVELOPMENT......Page 758
18.4.1 Test for Consistency......Page 759
18.4.2 Stability Analysis......Page 761
18.4.3 Animal Studies......Page 763
18.4.5 Indication/Label......Page 764
18.5 CONSORTIUM FOR GLOBALIZATION OF TRADITIONALCHINESE MEDICINE......Page 765
18.6 DISCUSSION......Page 766
PART VI Conduct of Clinical Trials......Page 767
19.1 INTRODUCTION......Page 769
19.2 STRUCTURE AND COMPONENTS OF A PROTOCOL......Page 770
19.3 POINTS TO BE CONSIDERED AND COMMON PITFALLS DURINGDEVELOPMENT AND PREPARATION OF A PROTOCOL......Page 776
19.4 COMMON DEPARTURES FOR IMPLEMENTATION OF A PROTOCOL......Page 779
19.5 MONITORING, AUDIT, AND INSPECTION......Page 785
19.6 QUALITY ASSESSMENT OF A CLINICAL TRIAL......Page 789
19.7 DISCUSSION......Page 791
20.1 INTRODUCTION......Page 793
20.2.1 Part 11 Compliance......Page 795
20.2.3 FDA Guidance on Bioresearch Monitoring—Compliance ProgramGuidance Manual......Page 796
20.3 DEVELOPMENT OF CASE REPORT FORMS......Page 797
20.3.1 CRF Design......Page 798
20.3.2 CRF Flow and Tracking......Page 799
20.4.2 Data Edit Check Specifications......Page 801
20.5.1 Data Entry and Verification......Page 802
20.5.2 Data Query......Page 803
20.6 DATA VALIDATION AND QUALITY......Page 805
20.7.2 Database Transfer......Page 806
20.8.2 Electronic Data Capture......Page 809
20.8.4 Global Database and System......Page 810
20.8.5 Role of the Statistician in the Data Management Process......Page 811
References......Page 813
Appendix A......Page 859
Index......Page 865
Wiley Series in Probability and Statistics......Page 885