Sample size calculation for two-arm trials with time-to-event endpoint for nonproportional hazards using the concept...

Sample size calculations for two-arm clinical trials with a time-to-event endpoint have traditionally used the assumption of proportional hazards (PH) or the assumption of exponentially distributed survival times. Available software provides methods for sample size calculation using a nonparametric logrank test, Schoenfeld's formula for Cox PH model, or parametric calculations specific to the exponential distribution. In cases where the PH assumption is not valid, the first-choice method is to compute sample size assuming a piecewise linear survival curve (Lakatos approach) for both the control and treatment arms with judiciously chosen cut-points. Recent advances in literature have used the assumption of Weibull distributed times for single-arm trials, and, newer methods have emerged that allow sample size calculations for two-arm trials using the assumption of proportional time (PT) while considering non-PH. These methods, however, always assume an instantaneous effect of treatment relative to control requiring that the effect size be defined by a single number whose magnitude is preserved throughout the trial duration. Here, we consider the scenarios where the hypothesized benefit of treatment relative to control may not be constant giving rise to the notion of Relative Time (RT). By assuming that survival times for control and treatment arm come from two different Weibull distributions with different location and shape parameters, we develop the methodology for sample size calculation for specific cases of both non-PH and non-PT. Simulations are conducted to assess the operation characteristics of the proposed method and a practical example is discussed.