Adaptive weight selection for time-to-event data under non-proportional hazards

TL;DR

This paper proposes an adaptive, multi-stage approach for time-to-event clinical trials that improves robustness under non-proportional hazards by combining flexible testing methods and survival curve extrapolation.

Contribution

It introduces a novel adaptive multi-stage design with combination tests and spline-based survival extrapolation for more flexible and robust analysis under uncertain effect patterns.

Findings

The method can save inconclusive trials.

It maintains high power under non-proportional hazards.

The approach is validated with real data and simulations.

Abstract

When planning a clinical trial for a time-to-event endpoint, we require an estimated effect size and need to consider the type of effect. Usually, an effect of proportional hazards is assumed with the hazard ratio as the corresponding effect measure. Thus, the standard procedure for survival data is generally based on a single-stage log-rank test. Knowing that the assumption of proportional hazards is often violated and sufficient knowledge to derive reasonable effect sizes is usually unavailable, such an approach is relatively rigid. We introduce a more flexible procedure by combining two methods designed to be more robust in case we have little to no prior knowledge. First, we employ a more flexible adaptive multi-stage design instead of a single-stage design. Second, we apply combination-type tests in the first stage of our suggested procedure to benefit from their robustness under uncertainty about the deviation pattern. We can then use the data collected during this period to choose a more specific single-weighted log-rank test for the subsequent stages. In this step, we employ Royston-Parmar spline models to extrapolate the survival curves to make a reasonable decision. Based on a real-world data example, we show that our approach can save a trial that would otherwise end with an inconclusive result. Additionally, our simulation studies demonstrate a sufficient power performance while maintaining more flexibility.