SEMINAR by Quentin Le Coënt (UCLouvain)

SEMINAR by Quentin Le Coënt (UCLouvain) on "Surrogate endpoints validation in clinical trials using joint modeling, mediation analysis and meta-analytic data"

Abstract :
In clinical research, surrogate (or intermediate) endpoints can be used instead of final endpoints to help speed up the evaluation of a new treatment or intervention. A common example is the use in oncology of the time-to-progression of a cancer as a surrogate of the overall survival. However, before any use putative surrogates must first be statistically assessed to be good surrogate.
In this work we propose the validation of surrogate endpoints using mediation analysis which aims at decomposing the effect of the treatment on the final endpoint into an indirect effect through the surrogate endpoint and a direct effect independent of it. A surrogate endpoint will be validated if most of the treatment effect corresponds to the indirect effect (the treatment therefore mainly operates through the surrogate).
We are particularly interested in the case where the final endpoint is a time-to-event and the surrogate endpoint is either also a time-to-event or a longitudinal biomarker. Joint models have been developed to properly take into account the relashionship between such endpoints. From these models the direct and indirect treatment effects can be derived whose causal interpretations can be established under given assumptions. Moreover, heterogeneous data from meta-analyses or multicenter studies can be used to strengthen the validation process.
We illustrate this approach with two examples in oncology: with a meta-analysis in resectable gastric cancer to evaluate the time-to-relapse as a surrogate for the overall survival and with a multicenter trial in locally advanced prostate cancer to evaluate the evolution over time of the prostate-specific antigen as a surrogate for the disease-free survival.