Dynamic path analysis for exploring treatment effect mediation processes in clinical trials with time-to-event endpoints.

Abstract

Why does a beneficial treatment effect on a longitudinal biomarker not translate into overall treatment benefit on survival, when the biomarker is in fact a prognostic factor of survival? In a recent exploratory data analysis in oncology, we were faced with this seemingly paradoxical result. To address this problem, we applied a theoretically principled methodology called dynamic path analysis, which allows us to perform mediation analysis with a longitudinal mediator and survival outcome. The aim of the analysis is to decompose the total treatment effect into a direct treatment effect and an indirect treatment effect mediated through a carefully constructed mediation path. The dynamic nature of the underlying methodology enables us to describe how these effects evolve over time, which can add to the mechanistic understanding of the underlying processes. In this paper, we present a detailed description of the dynamic path analysis framework and illustrate its application to survival mediation analysis using simulated and real data. The use case analysis provides clarity on the specific exploratory question of interest while the methodology generalizes to a wide range of applications in drug development where time-to-event is the primary clinical outcome of interest.