Dataset Information

Interim evaluation of efficacy or futility in group-sequential trials with multiple co-primary endpoints.

ABSTRACT: We discuss group-sequential designs in superiority clinical trials with multiple co-primary endpoints, that is, when trials are designed to evaluate if the test intervention is superior to the control on all primary endpoints. We consider several decision-making frameworks for evaluating efficacy or futility, based on boundaries using group-sequential methodology. We incorporate the correlations among the endpoints into the calculations for futility boundaries and sample sizes as a function of other design parameters, including mean differences, the number of analyses, and efficacy boundaries. We investigate the operating characteristics of the proposed decision-making frameworks in terms of efficacy/futility boundaries, power, the Type I error rate, and sample sizes, while varying the number of analyses, the correlations among the endpoints, and the mean differences. We provide an example to illustrate the methods and discuss practical considerations when designing efficient group-sequential designs in clinical trials with co-primary endpoints.

SUBMITTER: Asakura K

PROVIDER: S-EPMC6222168 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

Interim evaluation of efficacy or futility in group-sequential trials with multiple co-primary endpoints.

Asakura Koko K Hamasaki Toshimitsu T Evans Scott R SR

Biometrical journal. Biometrische Zeitschrift 20161019 4

We discuss group-sequential designs in superiority clinical trials with multiple co-primary endpoints, that is, when trials are designed to evaluate if the test intervention is superior to the control on all primary endpoints. We consider several decision-making frameworks for evaluating efficacy or futility, based on boundaries using group-sequential methodology. We incorporate the correlations among the endpoints into the calculations for futility boundaries and sample sizes as a function of o ...[more]

PMID: 27757980

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Project description:In clinical trials, the opportunity for an early stop during an interim analysis (either for efficacy or for futility) may relevantly save time and financial resources. This is especially important, if the planning assumptions required for power calculation are based on a low level of evidence. For example, when including two primary endpoints in the confirmatory analysis, the power of the trial depends on the effects of both endpoints and on their correlation. Assessing the feasibility of such a trial is therefore difficult, as the number of parameter assumptions to be correctly specified is large. For this reason, so-called 'group sequential designs' are of particular importance in this setting. Whereas the choice of adequate boundaries to stop a trial early for efficacy has been broadly discussed in the literature, the choice of optimal futility boundaries has not been investigated so far, although this may have serious consequences with respect to performance characteristics.In this work, we propose a general method to construct 'optimal' futility boundaries according to predefined criteria. Further, we present three different group sequential designs for two endpoints applying these futility boundaries. Our methods are illustrated by a real clinical trial example and by Monte-Carlo simulations.By construction, the provided method of choosing futility boundaries maximizes the probability to correctly stop in case of small or opposite effects while limiting the power loss and the probability of stopping the study 'wrongly'. Our results clearly demonstrate the benefit of using such 'optimal' futility boundaries, especially compared to futility boundaries commonly applied in practice.As the properties of futility boundaries are often not considered in practice and unfavorably chosen futility boundaries may imply bad properties of the study design, we recommend assessing the performance of these boundaries according to the criteria proposed in here.

Dataset Information

Interim evaluation of efficacy or futility in group-sequential trials with multiple co-primary endpoints.

Publications

Interim evaluation of efficacy or futility in group-sequential trials with multiple co-primary endpoints.

Similar Datasets

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