title: Statistical considerations for testing multiple endpoints in group sequential or adaptive clinical trials.
abstract: Many clinical trials are designed with a fixed sample size or total number of events to detect a postulated size of treatment effect on a primary efficacy endpoint. When the trial is completed and the primary efficacy endpoint achieves statistical significance, formal statistical testing of other clinically important secondary endpoints often follows in order for the statistically and clinically significant results of these endpoints to be included in the label of the test pharmaceutical product. In conventional fixed designs without any interim analysis or trial extension, these endpoints are often tested in a pre-specified hierarchical order, following the closed testing principle. This testing strategy ensures a strong control of the overall type I error. However, when trials are conducted using a group-sequential design with interim analyses or can be extended using an adaptive design with an increase of sample size or total number of events, this conventional hierarchical testing strategy may violate the closure principle and the overall type I error rate may not be controlled in the strong sense.
authors.affiliation: Division of Biometrics I, OB/OTS/CDER, FDA, Silver Spring, Maryland 20993-0002, USA. hsienming.hung@fda.hhs.gov
authors.forename: H M James
authors.initials: HM
authors.lastname: Hung
authors.forename: Sue-Jane
authors.initials: SJ
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: O'Neill
mesh_terms: D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D023381:Endpoint Determination / Q000706:statistics & numerical data*; D006801:Humans; D011336:Probability; D012107:Research Design / Q000706:statistics & numerical data*; D018401:Sample Size