Classical and Adaptive Clinical Trial Designs Using ExpDesign Studio

CLASSICAL AND ADAPTIVE CLINICAL TRIAL DESIGNS USING EXPDESIGN STUDIO™......Page 4
CONTENTS......Page 8
Preface......Page 16
Self-Study and Practice Guide......Page 20
1.1 Introduction......Page 22
1.2 How to Design a Trial Using ExpDesign Studio......Page 24
1.2.2 How to Design a Group Sequential Trial......Page 25
1.2.3 How to Design an Adaptive Trial......Page 26
1.2.4 How to Run Adaptive Trial Simulations......Page 28
1.2.5 How to Design a Multistage Trial......Page 30
1.2.6 How to Design a Dose-Escalation Trial......Page 31
1.3 ExpDesign Menus......Page 32
2.2 Classical Clinical Trial Design......Page 35
2.2.3 Confirmatory Trials......Page 36
2.2.7 Trials to Show Equivalence or Noninferiority......Page 37
2.2.10 Crossover Design......Page 38
2.3.1 Balanced Versus Unbalanced Designs......Page 39
2.3.2 Crossover Versus Parallel Designs......Page 40
2.3.4 Bioavailability Versus Bioequivalence Designs......Page 42
2.3.5 Equivalence Versus Bioequivalence......Page 43
2.4 Adaptive Clinical Trial Design......Page 44
2.4.1 Group Sequential Design......Page 45
2.4.4 Response-Adaptive Randomization Design......Page 46
2.4.7 Multistage Design of Single-Arm Trials......Page 47
3.1.1 Hypothesis Test......Page 48
3.1.2 Importance of Sample-Size Calculation......Page 49
3.1.4 Avoiding Under- or Overpowered Designs......Page 50
3.2.2 Testing the Proportion Difference Between Two Groups......Page 51
3.2.3 Testing the Survival Difference Between Two Groups......Page 52
3.2.4 Testing the Survival Difference with a Follow-up Period......Page 53
3.2.5 Exact Test for a One-Sample Proportion......Page 54
3.2.7 Noninferiority Test for Two Means......Page 56
3.2.8 Bioequivalence Test for Two Means......Page 57
3.2.9 Bioequivalence Test for Two Means of Lognormal Data......Page 58
3.2.10 Equivalence Test Based on the Ratio of Two Means......Page 59
3.2.12 Mantel–Haenszel Test for an Odds Ratio with Two Strata......Page 60
3.2.14 One-Way ANOVA for Parallel Groups......Page 62
3.2.15 Dose–Response Trial for a Myocardial Infarction......Page 63
3.3.1 Large-Sample-Size Calculation for Classical Design......Page 64
3.3.2 Commonly Used Terms and Their Mathematical Expressions......Page 66
3.3.3 Relationship Between Enrollment Rate and Number of Events......Page 69
4.2 Basics of Group Sequential Design......Page 72
4.3 How to Design Sequential Trials Using ExpDesign......Page 74
4.3.1 Design Featuring Early Efficacy Stopping for Two Means......Page 75
4.3.2 Design Featuring Early Futility Stopping for a Proportion......Page 77
4.3.3 Design Featuring Early Stopping for a Survival Endpoint......Page 79
4.3.4 Design Featuring Early Stopping for Paired Proportions......Page 81
4.4.1 Need for Trial Monitoring......Page 83
4.4.2 Techniques for Monitoring a Sequential Trial......Page 84
4.4.3 How to Monitor a Trial Using ExpDesign......Page 85
4.5.1 Unified Formulation for Sequential Trial Design......Page 89
4.5.2 Calculation of Conditional Probability......Page 93
4.5.3 Conditional and Predictive Power and RCI for Trial Monitoring......Page 94
4.5.4 Bias-Adjusted Estimates......Page 95
5.2 Basics of Adaptive Design Methods......Page 96
5.3 How To Design a Sample-Size Reestimation Trial Using ExpDesign......Page 98
5.3.3 Adaptive Design for an Acute Ischemic Stroke Trial......Page 99
5.3.4 Adaptive Design for an Asthma Study......Page 102
5.3.5 Adaptive Design for an Oncology Trial......Page 105
5.3.6 Noninferiority Design with a Binary Endpoint......Page 107
5.4.2 Seamless Design of an Asthma Trial......Page 111
5.5.1 Biomarker Classifications......Page 114
5.5.2 Biomarker-Adaptive Design......Page 115
5.6 How to Design a Play-the-Winner Trail Using ExpDesign......Page 116
5.6.1 Randomized Play-the-Winner Design......Page 117
5.6.2 Adaptive Randomization with a Normal Endpoint......Page 119
6.2 Error-Spending Approach......Page 124
6.3 How to Recalculate Stopping Boundaries Using ExpDesign......Page 126
6.4 Conditional Power and the Futility Index......Page 130
6.5.1 Calculating Conditional Power Using ExpDesign......Page 133
6.5.2 Reestimating Sample Size Using ExpDesign......Page 134
6.6.1 Changes in Number and Timing of the Analyses......Page 135
6.6.3 Conditional Power and Sample-Size Reestimation......Page 140
7.1.1 Introduction......Page 144
7.1.2 How to Design a Multistage Design Using ExpDesign......Page 145
7.2.1 Introduction......Page 150
7.2.2 Bayesian Continual Reassessment Method......Page 155
7.2.3 How to Design a Dose-Escalation Trial Using ExpDesign......Page 156
7.3 Dose-Escalation Trial Monitoring Using CRM......Page 162
7.4.1 Decision Tree for a Multistage Trial......Page 164
7.4.2 Two-Stage Design......Page 165
7.4.3 Three-Stage Design......Page 166
7.5.1 Probability Model for Dose–Response......Page 167
7.5.5 Assignment of the Next Patient......Page 168
8.1 Adjusting the Critical Region Method......Page 170
8.2 Classical Design with Two Parallel Treatment Groups......Page 172
8.3 Flexible Design with Sample-Size Reestimation......Page 178
8.4 Design with Random-Play-the-Winner Randomization......Page 181
8.5 Group Sequential Design with One Interim Analysis......Page 182
8.6 Design Permitting Early Stopping and Sample-Size Reestimation......Page 183
8.8 Multigroup Trial with Response-Adaptive Randomization......Page 186
8.9 Adaptive Design Featuring Dropping Losers......Page 187
8.11 Dose-Escalation Design for an Oncology Trial......Page 189
9.1 ExpDesign Probability Functions......Page 193
9.2.2 How to Generate a Random Univariate Using ExpDesign......Page 198
9.2.3 How to Generate a Random Multivariate Using ExpDesign......Page 200
9.2.4 How to Generate a Random Multibinomial Using ExpDesign......Page 202
9.3 ExpDesign Toolkits......Page 203
9.3.1 Graphic Calculator......Page 204
9.3.3 Confidence Interval Calculator......Page 206
10.1.1 One/Paired-Sample Hypothesis Test for the Mean......Page 208
10.1.2 One/Paired-Sample Hypothesis Test for the Proportion......Page 210
10.1.3 One/Paired-Sample Hypothesis Test for Others......Page 211
10.1.4 Paired-Sample Equivalence Test for the Mean......Page 213
10.1.6 One-Sample Confidence Interval for the Mean......Page 214
10.1.7 One-Sample Confidence Interval for the Proportion......Page 216
10.2.1 Two-Sample Hypothesis Test for the Mean......Page 217
10.2.2 Two-Sample Hypothesis Test for the Proportion......Page 220
10.2.3 Two-Sample Hypothesis Test for Others......Page 223
10.2.4 Two-Sample Equivalence/Noninferiority Test for the Mean......Page 226
10.2.6 Two-Sample Equivalence/Noninferiority Test for Survival......Page 228
10.2.8 Two-Sample Confidence Interval for the Proportion......Page 229
10.3.1 Multisample Hypothesis Test for the Mean......Page 230
10.3.2 Multisample Hypothesis Test for the Proportion......Page 232
10.3.3 Multisample Hypothesis Test for Others......Page 233
10.3.4 Multisample Confidence Interval for Others......Page 234
Afterword......Page 235
Appendix A: Validation of ExpDesign Studio......Page 236
A.1.2 Statistical Outcome Validation......Page 237
A.2 Validation of the Classical Design Module......Page 238
A.3.2 Power and Sample-Size Validation......Page 242
A.4.1 Stopping Boundary and Type I Error Rate Validation......Page 245
A.5 Validation of the Multistage Design Module......Page 247
A.8 Validation of the Randomizor......Page 249
A.9 Validation of the ExpDesign Toolkits......Page 250
A.10.2 Traditional 3 + 3 Escalation Design Validation......Page 252
A.10.3 SAS Program for CRM Validation......Page 253
Appendix B: Sample-Size Calculation Methods: Classical Design......Page 256
References......Page 261
Index......Page 272
System Requirements, Software Installation, and Software License Agreement......Page 280