title: Multiple testing procedures in two pivotal clinical trials for approval of a new pharmaceutical product.
abstract: We consider analysis of two identical pivotal trials with correlated multiple hypotheses evaluated by the fixed-sequence, weighted Holm, or fallback procedure. For approval, at least one hypothesis must be rejected in both studies. Various weights are considered for the fallback and weighted Holm procedure to provide separation in a single study. Evaluation of the procedures as closed tests distinguishes which has the highest power in different situations. No procedure is universally optimal. The best procedure depends on the power to reject the various hypotheses, something that is never known with certainty, and the goals of the analyses. If the most important goal is to demonstrate a difference on the first hypothesis or on all hypotheses, the fixed-sequence procedure performs best. However, the fixed sequence often has the highest chance of obtaining inconsistent results between the two independent studies, which makes it less appealing. The weighted Holm and fallback procedures are very similar, with various weighting schemes providing modest differentiation. The alpha exhaustive version of the fallback procedure often has higher power for some endpoints and lower power for other endpoints compared to the weighted Holm procedure, but the differences are rarely large.
authors.affiliation: Alcon Laboratories Ltd., Fort Worth, Texas 76134, USA. brian.wiens@alconlabs.com
authors.forename: Brian L
authors.initials: BL
authors.lastname: Wiens
mesh_terms: D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D017277:Drug Approval / Q000706:statistics & numerical data*; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000592:standards; D011336:Probability
chemical_list: D004364:Pharmaceutical Preparations