Applications of general multistage gatekeeping and graphical multiple testing strategies in a clinical trial setting

Multiplicity adjustment plays a critical role for testing multiple endpoints and/or multiple doses in clinical trials. Under the clinical trial setting, multiple hypotheses are usually grouped into primary and secondary families and hierarchically ordered between and within families. The determination of the order and grouping of the hypotheses depends on the objectives of the trial. In such scenarios, strong control of the family-wise error rate (FWER) can be achieved via either gatekeeping procedures or the graphical approach to sequential testing procedures. The aforementioned two types of procedures are related but are not completely overlapping. Both approaches are assessed in this manuscript, with a focus on the comparison and relationship between the two. In addition, the performance of various constructions of gatekeeping and graphical multiple comparison procedures (MCPs) under a typical clinical trial setting with multiple doses and multiple endpoints is studied.