Data-Driven Subgroup Identification in Confirmatory Clinical Trials.

Data-driven subgroup analysis plays an important role in clinical trials. This paper focuses on practical considerations in post-hoc subgroup investigations in the context of confirmatory clinical trials. The analysis is aimed at assessing the heterogeneity of treatment effects across the trial population and identifying patient subgroups with enhanced treatment benefit. The subgroups are defined using baseline patient characteristics, including demographic and clinical factors. Much progress has been made in the development of reliable statistical methods for subgroup investigation, including methods based on global models and recursive partitioning. The paper provides a review of principled approaches to data-driven subgroup identification and illustrates subgroup analysis strategies using a family of recursive partitioning methods known as the SIDES (subgroup identification based on differential effect search) methods. These methods are applied to a Phase III trial in patients with metastatic colorectal cancer. The paper discusses key considerations in subgroup exploration, including the role of covariate adjustment, subgroup analysis at early decision points and interpretation of subgroup search results in trials with a positive overall effect.