Adaptive trial design: a general methodology for censored time to event data.

Adaptive designs allow a clinical trial design to be changed according to interim findings without inflating type I error. The Inverse Normal method can be considered as an adaptive generalization of classical group sequential designs. The use of the Inverse Normal method for censored survival data was demonstrated only for the logrank statistic. However, the logrank statistic is inefficient in the presence of nuisance covariates affecting survival. We demonstrate, how the Inverse Normal method can be applied to Cox regression analysis. The required independence between test statistics of the different stages of the trial can be obtained by two different approaches. One is using the independent increment structure of the score process. The other uses right censoring and left truncating to divide individuals follow-up into per-stage data. Simulation studies show, that performance of the adaptive design does not depend on the method used for obtaining independence. Either way, an adaptive Cox regression analyis is more efficient than an adaptive logrank analysis if nuisance covariates affect survival.