Advances in Clinical Trial Biostatistics

ADVANCES IN CLINICAL TRIAL B IOSTATISTI CS......Page 1
SERIES INTRODUCTION......Page 4
PREFACE......Page 6
5. DESIGN AND ANALYSIS OF CLUSTER RANDOMIZATION TRIALS......Page 8
12. STATISTICAL ISSUES EMERGING FROM CLINICAL TRIALS IN HIV INFECTION......Page 9
CONTRIBUTORS......Page 10
CONTENTS......Page 0
1.1. GOAL AND DEFINITIONS......Page 13
1.2. DEFINITION OF DOSE......Page 15
1.4. EXAMPLES......Page 16
2. GENERAL BAYESIAN METHODOLOGY......Page 17
2.1. FORMULATION OF THE PROBLEM......Page 18
2.2. DOSE-TOXICITY MODEL......Page 20
2.3. PRIOR DISTRIBUTION......Page 23
2.4. POSTERIOR DISTRIBUTION......Page 28
2.5. LOSS FUNCTION......Page 29
3.1. MAXIMUM LIKELIHOOD......Page 35
3.3. RAPID INITIAL ESCALATION......Page 36
3.5. MULTINOMIAL AND CONTINUOUS RESPONSE MEASURES......Page 37
3.6. DESIGNS FOR DRUG COMBINATIONS......Page 40
3.7. INCORPORATION OF COVARIATE INFORMATION......Page 41
3.8. MONITORING SAFETY AND EFFICACY IN PHASE I AND II TRIALS......Page 44
4. STATISTICAL CONSIDERATIONS......Page 47
REFERENCES......Page 48
1. INTRODUCTION......Page 52
2. A PHASE I/II DESIGN FOR PBSC TRANSPLANTATION TRIALS......Page 54
3. BAYESIAN STOPPING RULE FOR SAFETY......Page 56
4. A PHASE II TRIAL DESIGN WITH AN INTERMEDIATE ENDPOINT AND BAYESIAN STOPPING RULES FOR EARLY FAILURE......Page 58
5. A PHASE II DESIGN WITH MULTIPLE PRIORITIZED ENDPOINTS......Page 60
6. DISCUSSION......Page 61
REFERENCES......Page 62
1. INTRODUCTION......Page 64
2.1. TESTING THE NULL HYPOTHESIS OF EQUIVALENCE......Page 66
2.2. TESTING A NONNULL HYPOTHESIS......Page 67
2.3. CONFIDENCE INTERVALS......Page 68
2.4. SPECIFICATION OF "DELTA"......Page 70
3.1. ANALYSIS......Page 71
3.2. DESIGN......Page 74
4. CONCLUSION......Page 76
REFERENCES......Page 77
1. INTRODUCTION......Page 78
2.1. CONTINUOUS OUTCOME CASE......Page 79
2.2. EXAMPLE: DASH......Page 81
2.3. THE DICHOTOMOUS OUTCOME CASE......Page 82
2.4. DASH EXAMPLE EMBELLISHED......Page 83
3. SAMPLE SIZE REESTIMATION BASED ON TREATMENT EFFECT......Page 84
3.1. EXAMPLE......Page 88
REFERENCES......Page 91
1. INTRODUCTION......Page 93
2.1. UNIT OF RANDOMIZATION AND ANALYSIS......Page 94
2.2. SAMPLING METHODOLOGY AND HANDLING OF PARTICIPANT MIGRATION......Page 96
2.3. SOME FURTHER CONSIDERATIONS......Page 97
3.1. UNADJUSTED ANALYSES......Page 98
3.2. ADJUSTED ANALYSES......Page 101
4. SAMPLE SIZE CALCULATION......Page 104
5. EXAMPLE: THE CATCH TRIAL......Page 105
6. SUMMARY......Page 107
REFERENCES......Page 108
1. INTRODUCTION AND NOTATION......Page 111
2. SOME HYPOTHESIS TESTS FOR MULTIPLE ENDPOINTS......Page 112
2.1. BONFERRONI METHODS......Page 113
2.3. LINEAR COMBINATIONS OF ENDPOINTS......Page 114
2.4. WALD-TYPE TEST FOR MULTIPLE BINARY OUTCOMES......Page 115
2.5. LIKELIHOOD RATIO TESTS......Page 116
2.6. NONPARAMETRIC TESTS......Page 117
3. A STEP-DOWN CLOSED PROCEDURE FOR DETERMINING WHICH ENDPOINTS DIFFER FOLLOWING A GLOBAL TEST......Page 118
3.2. A PROCEDURE WITH WEAK CONTROL OF THE OVERALL TYPE I ERROR......Page 119
4.3. STEP-DOWN PROCEDURES FOR GROUP SEQUENTIAL TRIALS WITH MULTIPLE PRIMARY ENDPOINTS......Page 120
5. AN EXAMPLE: THE NINDS STROKE TRIAL......Page 123
6. EXTENSIONS TO MORE THAN TWO SAMPLES......Page 125
7. DISCUSSION......Page 126
REFERENCES......Page 127
1. INTRODUCTION......Page 130
2. STANDARD APPROACHES......Page 131
2.1. POWER OF TESTS OF INTERACTION......Page 135
2.2. MULTIPLICITY......Page 136
3.1. TESTS OF QUALITATIVE INTERACTION......Page 140
3.2. MULTIVARIATE APPROACHES TO INTERACTION......Page 142
4. AVID TRIAL......Page 144
REFERENCES......Page 147
1. INTRODUCTION......Page 149
2. DPT FRAMEWORK......Page 150
3.1. ESTIMATION OF "Y"......Page 153
3.2. TESTS......Page 154
3.3. EXAMPLES......Page 155
4. STRATIFIED DATA......Page 157
4.1. ESTIMATION OF "Y"......Page 158
4.2. FEATURES......Page 160
4.3. EXAMPLE 3: PROSTATE CANCER CLINICAL TRIAL......Page 161
5.1. RANK TESTS......Page 162
5.2. PAIRED T TEST......Page 163
6. ALTERNATIVE METHODS......Page 164
REFERENCES......Page 166
1. INTRODUCTION......Page 169
2. RANDOMIZED TRIAL OF TWO REGIMENS OF CHEMOTHERAPY IN OPERABLE OSTEOSARCOMA: A BAYESIAN PERSPECTIVE ON A TRIAL OF THE EUROPEAN OSTEOSARCOMA INTERGROUP......Page 170
2.1. BACKGROUND......Page 171
2.2. PATIENTS AND METHODS......Page 172
2.3. RESULTS......Page 181
2.4. INTERPRETATION......Page 188
2.5. DISCUSSION*......Page 192
3. EPILOGUE......Page 193
REFERENCES......Page 194
1. INTRODUCTION......Page 197
2.1. POTENTIAL OUTCOMES......Page 200
2.2. LOCAL AVERAGE TREATMENT EFFICACY (LATE)......Page 202
3.1. ‘‘NULL’’ VERSUS ‘‘FULL’’ COMPLIANCE......Page 205
3.2. NULL, PARTIAL, AND FULL COMPLIANCE......Page 209
4.1. THE MODEL AND SEMIPARAMETRIC ESTIMATION......Page 212
4.2. EFFICIENCY......Page 213
4.3. IMPLEMENTATION: AN EXAMPLE......Page 214
5. STRUCTURAL DISTRIBUTION MODELS......Page 215
6. DISCUSSION......Page 216
REFERENCES......Page 217
1. INTRODUCTION......Page 220
2.1. SIMPLE UNIVARIATE ANALYSES OF SUMMARY MEASURES......Page 222
2.2. LONGITUDINAL METHODS FOR GAUSSIAN DATA......Page 223
2.3. LONGITUDINAL METHODS FOR DISCRETE DATA......Page 224
3. MISSINGNESS IN LONGITUDINAL CLINICAL TRIALS: TERMINOLOGY......Page 226
5.1. ANALYSES ON SUMMARY MEASURES......Page 227
5.2. SELECTION VERSUS PATTERN MIXTURE MODELS......Page 229
5.3. SHARED RANDOM EFFECTS MODELS AND INFORMATIVE MISSINGNESS......Page 230
6. ANALYZING LONGITUDINAL GAUSSIAN DATA WITH MISSINGNESS: IPPB TRIAL......Page 233
7. ANALYZING LONGITUDINAL BINARY DATA WITH MISSINGNESS: OPIATE TRIAL......Page 235
8. ANALYZING LONGITUDINAL COUNT DATA WITH DROPOUT: EPILEPSY CLINICAL TRIAL......Page 238
9. CONCLUSIONS......Page 239
REFERENCES......Page 240
1. INTRODUCTION......Page 244
2. ANALYSIS OF MULTIPLE EVENTS......Page 253
2.1. MARGINAL MODELS......Page 254
2.2. FRAILTY MODELS......Page 256
2.3. CONDITIONAL AND MULTISTATE MODELS......Page 257
3.1. SURROGACY......Page 259
3.2. ANALYSIS OF BIOLOGICAL MARKERS AS CONTINUOUS VARIABLES......Page 262
3.3. ANALYSIS OF BIOLOGICAL MARKERS AS FAILURE TIME DATA......Page 264
4. ADJUSTING FOR CHANGES FROM ALLOCATED TREATMENT......Page 267
5. CONCLUSIONS......Page 271
REFERENCES......Page 272