Statistical planning in confirmatory clinical trials with multiple treatment groups, multiple visits, and multiple endpoints.

Multiplicity issues can be multidimensional: A confirmatory clinical trial may be designed to have efficacy assessed with two or more primary endpoints, for multiple dose groups, and at several post-baseline visits. Controlling for multiplicity in this situation is challenging because there can be a hierarchy with respect to some but not all measurements. If the higher dose is considered more efficacious, multiplicity approach may evaluate the higher dose with higher priority through a fixed sequential testing framework for dose assessments in combination with a Hochberg approach for endpoints. The lower dose is only assessed when the higher dose has significant results, which reduces the power for detecting signals in the lower dose group. However, in some instances the higher dose may associate with tolerability or safety concerns that preclude regulatory approval. A real confirmatory clinical trial with such challenges is provided as an illustrative example. We discuss closed testing procedures based on multi-way averages of comparisons for this complex multiplicity situation through illustrative case analyses and a simulation study. Such strategies manage the higher dose and the lower dose with equal priority, and they enable evaluation of the multiple endpoints at multiple visits collectively with power being reasonably high. [ABSTRACT FROM PUBLISHER]