Penalty-based approaches to evaluating multiplicity adjustments in clinical trials: Advanced multiplicity problems.

Given the importance of addressing multiplicity issues in confirmatory clinical trials, several recent publications focused on the general goal of identifying most appropriate methods for multiplicity adjustment in each individual setting. This goal can be accomplished using the Clinical Scenario Evaluation approach. This approach encourages trial sponsors to perform comprehensive assessments of applicable analysis strategies such as multiplicity adjustments under all plausible sets of statistical assumptions using relevant evaluation criteria. This two-part paper applies a novel class of criteria, known as criteria based on multiplicity penalties, to the problem of evaluating the performance of several candidate multiplicity adjustments. The ultimate goal of this evaluation is to identify efficient and robust adjustments for each individual trial and optimally select parameters of these adjustments. Part II focuses on advanced settings with several sources of multiplicity, for example, clinical trials with several endpoints evaluated at two or more doses of an experimental treatment. A case study is given to illustrate a penalty-based approach to evaluating candidate multiple testing procedures in advanced multiplicity problems. [ABSTRACT FROM PUBLISHER]