Design of adaptive multi-arm multi-stage clinical trials
Ghosh, Pranab Kumar
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Two-arm group sequential designs have been widely used for over forty years, especially for studies with mortality endpoints. The natural generalization of such designs to trials with multiple treatment arms and a common control (MAMS designs) has, however, been implemented rarely. While the statistical methodology for this extension is clear, the main limitation has been an efficient way to perform the computations. Past efforts were hampered by algorithms that were computationally explosive. With the increasing interest in adaptive designs, platform designs, and other innovative designs that involve multiple comparisons over multiple stages, the importance of MAMS designs is growing rapidly. This dissertation proposes a group sequential approach to design MAMS trial where the test statistic is the maximum of the cumulative score statistics for each pair-wise comparison, and is evaluated at each analysis time point with respect to efficacy and futility stopping boundaries while maintaining strong control of the family wise error rate (FWER). In this dissertation we start with a break-through algorithm that will enable us to compute MAMS boundaries rapidly. This algorithm will make MAMS design a practical reality. For designs with efficacy-only boundaries, the computational effort increases linearly with number of arms and number of stages. For designs with both efficacy and futility boundaries the computational effort doubles with successive increases in number of stages. Previous attempts to obtain MAMS boundaries were confined to smaller problems because their computational effort grew exponentially with number of arms and number of stages. We will next extend our proposed group sequential MAMS design to permit adaptive changes such as dropping treatment arms and increasing the sample size at each interim analysis time point. In order to control the FWER in the presence of these adaptations the early stopping boundaries must be re-computed by invoking the conditional error rate principle and the closed testing principle. This adaptive MAMS design is immensely useful in phase~2 and phase~3 settings. An alternative to the group sequential approach for MAMS design is the p-value combination approach. This approach has been in place for the last fifteen years.This alternative MAMS approach is based on combining independent p-values from the incremental data of each stage. Strong control of the FWER for this alternative approach is achieved by closed testing. We will compare the operating characteristics of the two approaches both analytically and empirically via simulation. In this dissertation we will demonstrate that the MAMS group sequential approach dominates the traditional p-value combination approach in terms of statistical power.