title: Methodological issues with adaptation of clinical trial design.
abstract: Adaptation of clinical trial design generates many issues that have not been resolved for practical applications, though statistical methodology has advanced greatly. This paper focuses on some methodological issues. In one type of adaptation such as sample size re-estimation, only the postulated value of a parameter for planning the trial size may be altered. In another type, the originally intended hypothesis for testing may be modified using the internal data accumulated at an interim time of the trial, such as changing the primary endpoint and dropping a treatment arm. For sample size re-estimation, we make a contrast between an adaptive test weighting the two-stage test statistics with the statistical information given by the original design and the original sample mean test with a properly corrected critical value. We point out the difficulty in planning a confirmatory trial based on the crude information generated by exploratory trials. In regards to selecting a primary endpoint, we argue that the selection process that allows switching from one endpoint to the other with the internal data of the trial is not very likely to gain a power advantage over the simple process of selecting one from the two endpoints by testing them with an equal split of alpha (Bonferroni adjustment). For dropping a treatment arm, distributing the remaining sample size of the discontinued arm to other treatment arms can substantially improve the statistical power of identifying a superior treatment arm in the design. A common difficult methodological issue is that of how to select an adaptation rule in the trial planning stage. Pre-specification of the adaptation rule is important for the practicality consideration. Changing the originally intended hypothesis for testing with the internal data generates great concerns to clinical trial researchers.
authors.affiliation: Division of Biometrics I, OB/CDER/FDA, 10903 New Hampshire Avenue, BLDG 22 Rm 4238, HFD-710, Mail Stop 4105, Silver Spring, MD 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 T
authors.initials: RT
authors.lastname: O'Neill
mesh_terms: D002986:Clinical Trials as Topic / Q000379:methods*; D023381:Endpoint Determination; D006801:Humans; D012107:Research Design; D018401:Sample Size