Interpretation of Subgroup Analyses in Clinical Trials

Abstract

The reliability of subgroup analyses is frequently misunderstood. While pivotal clinical trials are usually designed to assess the global efficacy of a new therapy, there is often strong interest in performing exploratory subgroup analyses to allow for possible tailoring of patient care in a manner that depends on levels of one or more covariates. Estimates of treatment effects in subgroups tend to be highly variable. False-positive and false-negative conclusions from exploratory subgroup analyses are likely to occur, due to the unreliability of these estimates arising from this variability and due to the multiplicity of testing which is inherent in this exploratory setting. Prominent examples, as well as computer simulation studies for trials with time-to-event endpoints, are cited to provide scientific insight into the reliability of subgroup analyses, and into the proper interpretation of findings from these analyses. Exploratory subgroup analyses usually do not provide definitive conclusions, but rather should be viewed as an important approach to generating hypotheses which must be confirmed by other trials.