An Introduction to Statistics in Early Phase Trials

Summary of Early Phase Trial Objectives......Page 5
Further Issues with Pharmacokinetic Analysis......Page 17
2.3.1.1 Compartmental Approach for Intravenous Dose: Single Compartment......Page 19
Compartmental Approach for Intravenous Dose: Two Compartments......Page 21
Compartmental Approach for Extravascular Dose: Single Compartment......Page 23
Noncompartmental Approach for Extravascular Dose with Single Compartment......Page 26
Repeat Dose......Page 29
Simple Compartmental Analysis Model......Page 32
Summarizing Pharmacokinetic Data......Page 35
Population Approaches......Page 37
Minimum Sample Size Required......Page 40
Type I and Type II Error......Page 41
Evaluable Sample Size......Page 42
Parallel-Group Trials......Page 43
Crossover Trials......Page 44
Parallel-Group Trials......Page 47
Crossover Trials......Page 48
Parallel-Group Trials......Page 49
Crossover Trials......Page 50
Worked Example: Precision Sample Size Calculations......Page 52
Precision about the Mean......Page 53
Precision about the Variance......Page 54
Reason 3: Regulatory Considerations......Page 55
Crossover Trials......Page 57
Two-Period AB/BA Design......Page 58
Paired t-tests......Page 59
Worked Example 4.1......Page 60
Worked Example 4.2......Page 61
Analysis of Variance ANOVA......Page 63
What is Good about Crossover Trials......Page 64
What is Bad about Crossover Trials......Page 67
Not all Investigations are Made on All Subjects but Everyone Receives Placebo and Active Control......Page 72
How to Analyse......Page 74
Precision-Based Trials......Page 75
Even Number of Treatments......Page 76
Worked Example 5.1......Page 77
Sample Size......Page 78
Even Number of Treatments in Odd Number of Periods......Page 79
Number of Periods Two or More Less than the Number of Treatments......Page 80
Worked Example 5.2......Page 81
Worked Example 5.3......Page 83
Analysis of First-Time-into-Man Studies......Page 87
Placebo Interrupting Design......Page 90
Summarizing the Data......Page 91
Placebo-Interrupting Design: Last Dose Carried Forward......Page 94
Interlocking-Cohort Placebo-Interrupting Design......Page 95
Interlocking-Cohort Placebo-Replacing Design......Page 96
Placebo-Interrupting Design......Page 101
Interlocking-Cohort Placebo-Replacing Design......Page 103
Analysis 2: Power Method......Page 106
Worked Example 6.1......Page 107
Additional Analyses......Page 109
Utility of Bayesian Methods......Page 112
Worked Example 7.1......Page 116
Worked Example 7.2......Page 118
Which design?......Page 124
C33D......Page 126
‘Best-of-5’......Page 128
Storer Design......Page 129
Dose-Response Model......Page 130
Determining the Probability of DLT......Page 131
Determining q......Page 133
Bayes and Maximum Likelihood......Page 134
Example 8.1......Page 135
Adaptive Designs in Bioequivalence Assessment......Page 138
Japan......Page 142
Narrow Therapeutic Index......Page 143
Summary of Assessing Bioequivalence......Page 144
General Case of Ratio Not Equalling Unity......Page 145
Special case of the ratio equalling unity......Page 146
Worked Example 9.1: Sample Size Calculation......Page 149
Worked Example 9.2: Descriptive Plots......Page 151
Paired Agreement Plots......Page 154
Worked Example 9.3: Paired Agreement Plots......Page 155
Worked Example 9.4: Mean-Difference-versus-Total Plots......Page 156
Formal Assessment of Bioequivalence......Page 158
Worked Example 9.6: Reinterrogation of the Sample Size Calculations......Page 159
Worked Example 9.7: Group Sequential......Page 162
Utility of Adaptive Designs in the Assessment of Bioequivalence......Page 165
Relative Potency......Page 167
Design of Dose-Proportionality Studies......Page 168
Analysis 2: Power Method......Page 169
Introduction......Page 170
Design of Repeat-Dose Studies......Page 171
Analysis of Repeat-Dose Studies......Page 172
Introduction......Page 173
Design and Analysis of Drug Interaction Studies......Page 174
Hepatic Impairment......Page 175
Renal Impairment......Page 176
Introduction......Page 177
Study Design......Page 178
Design......Page 180
Data Analysis......Page 181
Analysis......Page 182
Trial Reporting......Page 184
Choice of design......Page 185
Statistical analysis......Page 186
Full Study Report......Page 187
Abbreviated Study Report......Page 188
Study Synopses......Page 191
Powered Assessment......Page 194
Titrate to Target Concentration......Page 199
Overlapping Confidence Intervals......Page 200
Worked Example 12.1......Page 203
Bonferroni and Dunnett’s Methods......Page 205
Holm or Hochberg Procedures......Page 206
Gate Keeping through Sequential Testing......Page 207
Randomized Phase II Trials......Page 208
Fleming-A’Hern......Page 210
Gehan......Page 211
Simon Optimal and Minimax......Page 212
Case and Morgan......Page 213
Bryant and Day......Page 214
Overview of the Bayesian Approach......Page 215
Bayesian Single and Dual Threshold......Page 216
Simon, Wittes and Ellenberg SWE Design......Page 218
Application of the Results......Page 220
Inference in Estimation of a Future Trial Effect......Page 222
Worked Example 14.2......Page 225
Binary Data......Page 228
Exact Confidence Intervals......Page 229
Worked Example 15.1: Calculating Confidence Intervals for a Single Proportion......Page 230
Worked Example 15.2: Constructing a Prior Response......Page 232
Anticipated Response......Page 233
Effect of Sample Size on Posterior Distribution......Page 234
Effect of Prior on Posterior Distribution......Page 235
Go/No-Go Criteria......Page 236
Worked Example 15.5: Construction of a Go/No-Go Criterion......Page 238
Worked Example 15.6: Reconstruction of a Go/No-Go Criterion......Page 241
Appendix......Page 242
References......Page 247
Index......Page 252