Interim analysis incorporating short- and long-term binary endpoints

Niewczas, J. and Kunz, C.U. and König, F. (2019) Interim analysis incorporating short- and long-term binary endpoints. Biometrical Journal, 61 (3 (Spe). pp. 665-687. ISSN 0323-3847

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Designs incorporating more than one endpoint have become popular in drug development. One of such designs allows for incorporation of short-term information in an interim analysis if the long-term primary endpoint has not been yet observed for some of the patients. At first we consider a two-stage design with binary endpoints allowing for futility stopping only based on conditional power under both fixed and observed effects. Design characteristics of three estimators: using primary long-term endpoint only, short-term endpoint only, and combining data from both are compared. For each approach, equivalent cut-off point values for fixed and observed effect conditional power calculations can be derived resulting in the same overall power. While in trials stopping for futility the type I error rate cannot get inflated (it usually decreases), there is loss of power. In this study, we consider different scenarios, including different thresholds for conditional power, different amount of information available at the interim, different correlations and probabilities of success. We further extend the methods to adaptive designs with unblinded sample size reassessments based on conditional power with inverse normal method as the combination function. Two different futility stopping rules are considered: one based on the conditional power, and one from P-values based on Z-statistics of the estimators. Average sample size, probability to stop for futility and overall power of the trial are compared and the influence of the choice of weights is investigated.

Item Type:
Journal Article
Journal or Publication Title:
Biometrical Journal
Uncontrolled Keywords:
?? adaptive designscombination testconditional powerfutility stoppingsample size reassessmentstatistics and probabilitystatistics, probability and uncertaintygeneral medicinemedicine(all) ??
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Deposited On:
01 Mar 2019 13:45
Last Modified:
16 Jul 2024 10:58