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BMC Medical Research Methodology
Published in: BMC Medical Research Methodology 1/2017

Open Access 01-12-2017 | Research Article

Choice of futility boundaries for group sequential designs with two endpoints

Authors: Svenja Schüler, Meinhard Kieser, Geraldine Rauch

Published in: BMC Medical Research Methodology | Issue 1/2017

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.
Appendix
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Metadata
Title
Choice of futility boundaries for group sequential designs with two endpoints
Authors
Svenja Schüler
Meinhard Kieser
Geraldine Rauch
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Medical Research Methodology / Issue 1/2017
Electronic ISSN: 1471-2288
DOI
https://doi.org/10.1186/s12874-017-0387-4

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