Studentized permutation method for comparing two restricted mean survival times with small sample from randomized trials

Recent observations, especially in cancer immunotherapy clinical trials with time-to-event outcomes, show that the commonly used proportional hazard assumption is often not justifiable, hampering an appropriate analysis of the data by hazard ratios. An attractive alternative advocated is given by the restricted mean survival time (RMST), which does not rely on any model assumption and can always be interpreted intuitively. Since methods for the RMST based on asymptotic theory suffer from inflated type-I error under small sample sizes, a permutation test was proposed recently leading to more convincing results in simulations. However, classical permutation strategies require an exchangeable data setup between comparison groups which may be limiting in practice. Besides, it is not possible to invert related testing procedures to obtain valid confidence intervals, which can provide more in-depth information. In this paper, we address these limitations by proposing a studentized permutation test as well as respective permutation-based confidence intervals. In an extensive simulation study, we demonstrate the advantage of our new method, especially in situations with relatively small sample sizes and unbalanced groups. Finally, we illustrate the application of the proposed method by re-analyzing data from a recent lung cancer clinical trial.