Resampling in multiple-dose factorial designs.

Multiple-dose factorial designs may provide confirmatory evidence that (fixed) combination drugs are superior to either component drug alone. Moreover, a useful and safe range of dose combinations may be identified. In our study, we focus on (A) adjustments of the overall significance level made necessary by multiple testing, (B) improvement of conventional statistical methods with respect to power, distributional assumptions and dimensionality, and (C) construction of corresponding simultaneous confidence intervals. We propose novel resampling algorithms, which in a simple way take the correlation of multiple test statistics into account, thus improving power. Moreover, these algorithms can easily be extended to combinations of more than two component drugs and binary outcome data. Published data summaries from a blood pressure reduction trial are analysed and presented as a worked example. An implementation of the proposed methods is available online as an R package.