Trials within trials: Confirmatory subgroup analyses in controlled clinical experiments

Subgroup analyses remain a popular and necessary component of controlled clinical trials. However, lack of prospective specification, inadequate sample size, inability to maintain power, and the cumulative effect of sampling error can complicate their interpretation. This article demonstrates that clinical trial design tools that would allow the medical community to draw confirmatory and not just exploratory conclusions from specific subgroup evaluations are available to methodologists. Distinct from the use of a treatment by subgroup interaction term, this methodology provides an evaluation of the effect of an intervention within a particular subgroup stratum prospectively declared to be of interest to the investigators. The necessary prespecification of stratum-specific type I error rates, when combined with (1) a stratum-specific event rate in the subgroup, (2) a stratum-specific primary endpoint, (3) a stratum-specific endpoint precision, and/or (4) a stratum-specific efficacy, satisfies the requirements for a subgroup stratum's "stand-alone" interpretation at the trial's conclusion.