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Futility stopping in clinical trials, optimality and practical considerations.

ABSTRACT: Stopping for futility is a useful tool in a clinical trial. It is widely used in single-arm trials in oncology and in many two-arm trials. We review three stopping rules for futility. We give recommendations for the optimal timing of futility looks in two-stage trials in terms of the information fraction and the probability of stopping under the alternative hypothesis. We discuss futility stopping in trials with substantial uncertainty about the variability of the outcome and in crossover trials.

SUBMITTER: Chang Y

PROVIDER: S-EPMC7954786 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Futility stopping in clinical trials, optimality and practical considerations.

Chang Yen Y Song Tianhao T Monaco Jane J Ivanova Anastasia A

Journal of biopharmaceutical statistics 20200914 6

Stopping for futility is a useful tool in a clinical trial. It is widely used in single-arm trials in oncology and in many two-arm trials. We review three stopping rules for futility. We give recommendations for the optimal timing of futility looks in two-stage trials in terms of the information fraction and the probability of stopping under the alternative hypothesis. We discuss futility stopping in trials with substantial uncertainty about the variability of the outcome and in crossover trials ...[more]

PMID: 32926648

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Project description:BackgroundIn 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.MethodsWe 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.ResultsThe 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.ConclusionsThe 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.

Project description:Limiting or withdrawing nonbeneficial medical care is considered ethically responsible throughout most of critical care and medical ethics literature. Practically, however, setting limits to treatment is often challenging. We review the literature to identify best practices for using the definition of futility as an anchoring concept to aid the ethical practice of ICU clinicians.Data sourcesSource data were obtained from a PubMed literature review.Study selectionEnglish language articles were chosen based on relevance to medical futility ethics, end-of-life care in the ICU, or communication and conflict mitigation strategies.Data extractionIndependent evaluation of selected articles for recurrent content themes as relevant to our clinical case were compared among authors and based on consensus, quantitative and qualitative data from these sources were referenced directly.Data synthesisWhen life-sustaining treatment is unlikely to achieve a meaningful benefit such as symptom improvement, continued care may be discordant with the patient's goals. Institutional and cultural norms, unconscious biases, and difficulty with navigating conflicts all influence how un(comfortable) clinicians feel in setting limits to futile care. Defining futility in light of the patient's goals and values, focusing on outcomes rather than interventions, and being proactive in communication with families are the staples of medically meaningful critical care. Palliative measures should be framed affirmatively, and clinicians should be transparent about the limits of medicine.ConclusionsClinicians have an ethical obligation not to provide futile care. To practice accordingly, we must clearly understand the nature and forms of futility. Armed with this understanding, our discussions with family and surrogates in the ICU should fundamentally comprise 1) eliciting the patient's values and goals, 2) communicating which interventions serve those values and goals and which do not, and 3) offering only those interventions whose likely outcomes are in line with said values and goals.

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Futility stopping in clinical trials, optimality and practical considerations.

Publications

Futility stopping in clinical trials, optimality and practical considerations.

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