Optimality criteria for futility stopping boundaries for group sequential designs with a continuous endpoint
Abstract Background In clinical trials with fixed study designs, statistical inference is only made when the trial is completed. In contrast, group sequential designs allow an early stopping of the trial at interim, either for efficacy when the treatment effect is significant or for futility when th...
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| Format: | Article |
| Language: | English |
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BMC
2020-11-01
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| Series: | BMC Medical Research Methodology |
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| Online Access: | http://link.springer.com/article/10.1186/s12874-020-01141-5 |
| _version_ | 1818253274939129856 |
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| author | Xieran Li Carolin Herrmann Geraldine Rauch |
| author_facet | Xieran Li Carolin Herrmann Geraldine Rauch |
| author_sort | Xieran Li |
| collection | DOAJ |
| description | Abstract Background In clinical trials with fixed study designs, statistical inference is only made when the trial is completed. In contrast, group sequential designs allow an early stopping of the trial at interim, either for efficacy when the treatment effect is significant or for futility when the treatment effect seems too small to justify a continuation of the trial. Efficacy stopping boundaries based on alpha spending functions have been widely discussed in the statistical literature, and there is also solid work on the choice of adequate futility stopping boundaries. Still, futility boundaries are often chosen with little or completely without theoretical justification, in particular in investigator initiated trails. Some authors contributed to fill this gap. In here, we rely on an idea of Schüler et al. (2017) who discuss optimality criteria for futility boundaries for the special case of trials with (multiple) time-to-event endpoints. Their concept can be adopted to define “optimal” futility boundaries (with respect to given performance indicators) for continuous endpoints. Methods We extend Schülers’ definition for “optimal” futility boundaries to the most common study situation of a single continuous primary endpoint compared between two groups. First, we introduce the analytic algorithm to derive these futility boundaries. Second, the new concept is applied to a real clinical trial example. Finally, the performance of a study design with an “optimal” futility boundary is compared to designs with arbitrarily chosen futility boundaries. Results The presented concept of deriving futility boundaries allows to control the probability of wrongly stopping for futility, that means stopping for futility even if the treatment effect is promizing. At the same time, the loss in power is also controlled by this approach. Moreover, “optimal” futility boundaries improve the probability of correctly stopping for futility under the null hypothesis of no difference between two groups. Conclusions The choice of futility boundaries should be thoroughly investigated at the planning stage. The sometimes met, arbitrary choice of futility boundaries can lead to a substantial negative impact on performance. Applying futility boundaries with predefined optimization criteria increases efficiency of group sequential designs. Other optimization criteria than proposed in here might be incorporated. |
| first_indexed | 2024-12-12T16:37:29Z |
| format | Article |
| id | doaj.art-46b8b46ed1ef4bacb00865c54f32cc79 |
| institution | Directory Open Access Journal |
| issn | 1471-2288 |
| language | English |
| last_indexed | 2024-12-12T16:37:29Z |
| publishDate | 2020-11-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Research Methodology |
| spelling | doaj.art-46b8b46ed1ef4bacb00865c54f32cc792022-12-22T00:18:38ZengBMCBMC Medical Research Methodology1471-22882020-11-012011810.1186/s12874-020-01141-5Optimality criteria for futility stopping boundaries for group sequential designs with a continuous endpointXieran Li0Carolin Herrmann1Geraldine Rauch2Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical EpidemiologyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical EpidemiologyCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical EpidemiologyAbstract Background In clinical trials with fixed study designs, statistical inference is only made when the trial is completed. In contrast, group sequential designs allow an early stopping of the trial at interim, either for efficacy when the treatment effect is significant or for futility when the treatment effect seems too small to justify a continuation of the trial. Efficacy stopping boundaries based on alpha spending functions have been widely discussed in the statistical literature, and there is also solid work on the choice of adequate futility stopping boundaries. Still, futility boundaries are often chosen with little or completely without theoretical justification, in particular in investigator initiated trails. Some authors contributed to fill this gap. In here, we rely on an idea of Schüler et al. (2017) who discuss optimality criteria for futility boundaries for the special case of trials with (multiple) time-to-event endpoints. Their concept can be adopted to define “optimal” futility boundaries (with respect to given performance indicators) for continuous endpoints. Methods We extend Schülers’ definition for “optimal” futility boundaries to the most common study situation of a single continuous primary endpoint compared between two groups. First, we introduce the analytic algorithm to derive these futility boundaries. Second, the new concept is applied to a real clinical trial example. Finally, the performance of a study design with an “optimal” futility boundary is compared to designs with arbitrarily chosen futility boundaries. Results The presented concept of deriving futility boundaries allows to control the probability of wrongly stopping for futility, that means stopping for futility even if the treatment effect is promizing. At the same time, the loss in power is also controlled by this approach. Moreover, “optimal” futility boundaries improve the probability of correctly stopping for futility under the null hypothesis of no difference between two groups. Conclusions The choice of futility boundaries should be thoroughly investigated at the planning stage. The sometimes met, arbitrary choice of futility boundaries can lead to a substantial negative impact on performance. Applying futility boundaries with predefined optimization criteria increases efficiency of group sequential designs. Other optimization criteria than proposed in here might be incorporated.http://link.springer.com/article/10.1186/s12874-020-01141-5Futility stopGroup sequential designContinuous endpoint |
| spellingShingle | Xieran Li Carolin Herrmann Geraldine Rauch Optimality criteria for futility stopping boundaries for group sequential designs with a continuous endpoint BMC Medical Research Methodology Futility stop Group sequential design Continuous endpoint |
| title | Optimality criteria for futility stopping boundaries for group sequential designs with a continuous endpoint |
| title_full | Optimality criteria for futility stopping boundaries for group sequential designs with a continuous endpoint |
| title_fullStr | Optimality criteria for futility stopping boundaries for group sequential designs with a continuous endpoint |
| title_full_unstemmed | Optimality criteria for futility stopping boundaries for group sequential designs with a continuous endpoint |
| title_short | Optimality criteria for futility stopping boundaries for group sequential designs with a continuous endpoint |
| title_sort | optimality criteria for futility stopping boundaries for group sequential designs with a continuous endpoint |
| topic | Futility stop Group sequential design Continuous endpoint |
| url | http://link.springer.com/article/10.1186/s12874-020-01141-5 |
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