Level of evidence for promising subgroup findings in an overall non-significant trial

Abstract

In drug development and drug licensing, it sometimes occurs that a new drug does not demonstrate effectiveness for the full study population, but there appears to be benefit in a relevant, pre-defined subgroup. This raises the question, how strong the evidence from such a subgroup is, and which confirmatory testing strategies are the most appropriate ones. Hence, we considered the type I error and the power of a subgroup result in a trial with non-significant overall results and of suitable replication strategies. In the case of a single trial, the inflation of the overall type I error is substantial and can be up to twice as large, especially in relatively small subgroups. This also increases to the risk of starting a replication trial that should not be done, if such a second trial is not already available. The overall type I error is almost controlled by using an appropriate replication strategy. This confirms the required cautious interpretation of promising subgroups, even in the case that overall trial results were perceived to be close to significance.