Subgroup analysis methods for time-to-event outcomes in heterogeneous randomized controlled trials

Non-significant randomized control trials can hide subgroups of good responders to experimental drugs, thus hindering subsequent development. Identifying such heterogeneous treatment effects is key for precision medicine and many post-hoc analysis methods have been developed for that purpose. While several benchmarks have been carried out to identify the strengths and weaknesses of these methods, notably for binary and continuous endpoints, similar systematic empirical evaluation of subgroup analysis for time-to-event endpoints are lacking. This work aims to fill this gap by evaluating several subgroup analysis algorithms in the context of time-to-event outcomes, by means of three different research questions: Is there heterogeneity? What are the biomarkers responsible for such heterogeneity? Who are the good responders to treatment? In this context, we propose a new synthetic and semi-synthetic data generation process that allows one to explore a wide range of heterogeneity scenarios with precise control on the level of heterogeneity. We provide an open source Python package, available on Github, containing our generation process and our comprehensive benchmark framework. We hope this package will be useful to the research community for future investigations of heterogeneity of treatment effects and subgroup analysis methods benchmarking.

FedECA: A Federated External Control Arm Method for Causal Inference with Time-To-Event Data in Distributed Settings

External control arms (ECA) can inform the early clinical development of experimental drugs and provide efficacy evidence for regulatory approval in non-randomized settings. However, the main challenge of implementing ECA lies in accessing real-world data or historical clinical trials. Indeed, data sharing is often not feasible due to privacy considerations related to data leaving the original collection centers, along with pharmaceutical companies' competitive motives. In this paper, we leverage a privacy-enhancing technology called federated learning (FL) to remove some of the barriers to data sharing. We introduce a federated learning inverse probability of treatment weighted (IPTW) method for time-to-event outcomes called FedECA which eases the implementation of ECA by limiting patients' data exposure. We show with extensive experiments that FedECA outperforms its closest competitor, matching-adjusted indirect comparison (MAIC), in terms of statistical power and ability to balance the treatment and control groups. To encourage the use of such methods, we publicly release our code which relies on Substra, an open-source FL software with proven experience in privacy-sensitive contexts.