title: Impacts on type I error rate with inappropriate use of learn and confirm in confirmatory adaptive design trials.
abstract: A two-stage adaptive design trial is a single trial that combines the learning data from stage 1 (or phase II) and the confirming data in stage 2 (or phase III) for formal statistical testing. We call it a "Learn and Confirm" trial. The studywise type I error rate remains to be at issue in a "Learn and Confirm" trial. For studying multiple doses or multiple enpdoints, a "Learn and Confirm" adaptive design can be more attractive than a fixed design approach. This is because intuitively the learning data in stage 1 should not be subjected to type I error scrutiny if there is no formal interim analysis performed and only an adaptive selection of design parameters is made at stage 1. In this work, we conclude from extensive simulation studies that the intuition is most often misleading. That is, regardless of whether or not there is a formal interim analysis for making an adaptive selection, the type I error rates are always at risk of inflation. Inappropriate use of any "Learn and Confirm" strategy should not be overlooked.
authors.affiliation: OTS/CDER, US FDA, Silver Spring, MD 20993-0002, USA. suejane.wang@fda.hhs.gov
authors.forename: Sue-Jane
authors.initials: SJ
authors.lastname: Wang
authors.forename: H M
authors.initials: HM
authors.lastname: James Hung
authors.forename: Robert T
authors.initials: RT
authors.lastname: O'Neill
mesh_terms: D015415:Biomarkers; D002986:Clinical Trials as Topic / Q000379:methods*; D055808:Drug Discovery; D023381:Endpoint Determination; D006801:Humans; D009042:Motivation; D012107:Research Design; D018401:Sample Size; D016896:Treatment Outcome; D054928:Validation Studies as Topic
chemical_list: D015415:Biomarkers