Planning and analyzing adaptive group sequential survival trials.

Abstract

The use of adaptive methods has experienced increasing interest in the current literature on group sequential designs. Group sequential analysis in survival trials usually apply the error spending function approach due to the unpredictable amount of information available in an interim analysis. An alternative way is to apply adaptive methods where additionally the maximum amount of information and other designing parameters can be changed based on the information available at the interim stage. In this paper, it is shown how the inverse normal method can be used within a survival design using the log-rank test for comparing two survival functions. This method allows for many kinds of design modifications. In case of no modifications, the inverse normal method coincides with the commonly used analysis strategy. It is straightforward to specify effect estimates. Confidence intervals for the hazard ratio that can be calculated at each stage of the trial and intervals that can only be computed by the end of the trial are proposed. The latter also enables the calculation of median unbiased estimates. Overall p-values can be defined analogously. Properties of the analyses techniques are investigated and compared with alternative approaches. It is shown that the proposed analysis technique might help to rescue an underpowered study and opens the way to other types of changes in design. The proposed technique is implemented in the software ADDPLAN Adaptive Design, Plans and Analyses (http://www.addplan.com).