Dataset Information

Interim Monitoring for Futility in Clinical Trials with Two Co-primary Endpoints Using Prediction.

ABSTRACT: We discuss using prediction as a flexible and practical approach for monitoring futility in clinical trials with two co-primary endpoints. This approach is appealing in that it provides quantitative evaluation of potential effect sizes and associated precision, and can be combined with flexible error-spending strategies. We extend prediction of effect size estimates and the construction of predicted intervals to the two co-primary endpoints case, and illustrate interim futility monitoring of treatment effects using prediction with an example. We also discuss alternative approaches based on the conditional and predictive powers, compare these methods and provide some guidance on the use of prediction for better decision in clinical trials with co-primary endpoints.

SUBMITTER: Asakura K

PROVIDER: S-EPMC7539647 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Interim Monitoring for Futility in Clinical Trials with Two Co-primary Endpoints Using Prediction.

Asakura Koko K Evans Scott R SR Hamasaki Toshimitsu T

Statistics in biopharmaceutical research 20191104 2

We discuss using prediction as a flexible and practical approach for monitoring futility in clinical trials with two co-primary endpoints. This approach is appealing in that it provides quantitative evaluation of potential effect sizes and associated precision, and can be combined with flexible error-spending strategies. We extend prediction of effect size estimates and the construction of predicted intervals to the two co-primary endpoints case, and illustrate interim futility monitoring of tre ...[more]

PMID: 33042476

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Project description:BackgroundGiven the inherent challenges of conducting randomized phase III trials in older cancer patients, single-arm phase II trials which assess the feasibility of a treatment that has already been shown to be effective in a younger population may provide a compelling alternative. Such an approach would need to evaluate treatment feasibility based on a composite endpoint that combines multiple clinical dimensions and to stratify older patients as fit or frail to account for the heterogeneity of the study population to recommend an appropriate treatment approach. In this context, stratified adaptive two-stage designs for binary or composite endpoints, initially developed for biomarker studies, allow to include two subgroups whilst maintaining competitive statistical performances. In practice, heterogeneity may indeed affect more than one dimension and incorporating co-primary endpoints, which independently assess each individual clinical dimension, would therefore appear quite pertinent. The current paper presents a novel phase II design for co-primary endpoints which takes into account the heterogeneity of a population. METHODS: We developed a stratified adaptive Bryant & Day design based on the Jones et al. and Parashar et al. algorithm. This two-stage design allows to jointly assess two dimensions (e.g. activity and toxicity) in two different subgroups. The operating characteristics of this new design were evaluated using examples and simulation comparisons with the Bryant & Day design in the context where the study population is stratified according to a pre-defined criterion.ResultsSimulation results demonstrated that the new design minimized the expected and maximum sample sizes as compared to parallel Bryant & Day designs (one in each subgroup), whilst controlling type I error rates and maintaining a competitive statistical power as well as a high probability of detecting heterogeneity.ConclusionsIn a heterogeneous population, this two-stage stratified adaptive phase II design provides a useful alternative to classical one and allows to identify a subgroup of interest without dramatically increasing sample size. As heterogeneity is not limited to older populations, this new design may also be relevant to other study populations such as children or adolescents and young adults or the development of targeted therapies based on a biomarker.

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 Monitoring for Futility in Clinical Trials with Two Co-primary Endpoints Using Prediction.

Publications

Interim Monitoring for Futility in Clinical Trials with Two Co-primary Endpoints Using Prediction.

Similar Datasets

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