The role of a placebo-treated control group in combination drug trials

In order to satisfy regulatory requirements for fixed-dose combination drug products, clinical trials must demonstrate that each component contributes to the claimed effect of the combination. Thus, the comparisons of primary interest are usually of the combination versus combination minus one component, and do not involve placebo. However, a placebo-treated group can be useful for interpreting the primary comparisons and for clarifying the nature of effects in the presence of interactions. These points are illustrated by examples from various drug classes. Statistical analysis of combination drug trials, particularly the appropriateness of factorial analysis, is also discussed.