Specific Aspects and Significance of Subgroup Assessment in Confirmatory Clinical Trials

Patient subgroup analysis plays an important role in interpretation of confirmatory clinical trial results and is mandatory in most cases. The purpose of subgroup analysis is to assess the consistency (heterogeneity) of the treatment effect in subgroups of patients identified based on such characteristics as demographics, stage and severity of the underlying disease, presence of a certain genetic mutation, etc. However, existing methodological issues (the problem of multiple comparisons, detection of differences between subgroups by chance alone, etc.) make it difficult to carry out the analysis and often lead to controversial conclusions. The aim of the study was to analyse and summarise foreign regulatory approaches to subgroup analysis in confirmatory clinical trials, and to elaborate science-based requirements for subgroup analysis and interpretation of the results by clinical trial sponsors and experts when assessing the risk-benefit ratio of medicinal products for the purpose of their authorisation in Russia and the Eura sian Economic Union. This paper discusses the objectives of subgroup analysis and statistical approaches to its performance, provides relevant examples of such analysis from regulatory practice. It describes approaches to interpretation of subgroup analysis depending on the presence/absence of evidence supporting the primary hypothesis of the study, the nature of the experimental medicinal product’s heterogeneous effects in the subgroups, and selection of the subgroups. The paper highlights areas of concern in subgroup analysis, potential controversies in interpretation of the obtained results, and regulatory expectations. The recommendations presented in the paper can be used by experts in the assessment of the risk-benefit ratio, as well as by medicine developers in the preparation of clinical trial protocols and reports.