Tutorial on statistical considerations on subgroup analysis in confirmatory clinical trials.

Clinical trials target patients who are expected to benefit from a new treatment under investigation. However, the magnitude of the treatment benefit, if it exists, often depends on the patient baseline characteristics. It is therefore important to investigate the consistency of the treatment effect across subgroups to ensure a proper interpretation of positive study findings in the overall population. Such assessments can provide guidance on how the treatment should be used. However, great care has to be taken when interpreting consistency results. An observed heterogeneity in treatment effect across subgroups can arise because of chance alone, whereas true heterogeneity may be difficult to detect by standard statistical tests because of their low power. This tutorial considers issues related to subgroup analyses and their impact on the interpretation of findings of completed trials that met their main objectives. In addition, we provide guidance on the design and analysis of clinical trials that account for the expected heterogeneity of treatment effects across subgroups by establishing treatment benefit in a pre-defined targeted subgroup and/or the overall population.