Sample Size Reestimation in Stochastic Curtailment Tests With Time-to-Events Outcome in the Case of Nonproportional Hazards Utilizing Two Weibull Distributions With Unknown Shape Parameters.

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Pharmaceutical Statistics Pub Date : 2024-08-18 DOI:10.1002/pst.2429
Palash Sharma, Milind A Phadnis
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Abstract

Stochastic curtailment tests for Phase II two-arm trials with time-to-event end points are traditionally performed using the log-rank test. Recent advances in designing time-to-event trials have utilized the Weibull distribution with a known shape parameter estimated from historical studies. As sample size calculations depend on the value of this shape parameter, these methods either cannot be used or likely underperform/overperform when the natural variation around the point estimate is ignored. We demonstrate that when the magnitude of the Weibull shape parameters changes, unblinded interim information on the shape of the survival curves can be useful to enrich the final analysis for reestimation of the sample size. For such scenarios, we propose two Bayesian solutions to estimate the natural variations of the Weibull shape parameter. We implement these approaches under the framework of the newly proposed relative time method that allows nonproportional hazards and nonproportional time. We also demonstrate the sample size reestimation for the relative time method using three different approaches (internal pilot study approach, conditional power, and predictive power approach) at the interim stage of the trial. We demonstrate our methods using a hypothetical example and provide insights regarding the practical constraints for the proposed methods.

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在非比例危害的情况下,利用具有未知形状参数的两个 Weibull 分布,对具有时间到事件结果的随机缩尾试验进行样本量重估。
对于采用时间到事件终点的二期双臂试验,传统上采用对数秩检验法进行随机缩减试验。最近在设计时间到事件试验方面取得的进展是利用了从历史研究中估算出的已知形状参数的 Weibull 分布。由于样本量的计算取决于该形状参数的值,当忽略点估计值周围的自然变化时,这些方法要么无法使用,要么可能表现不佳或表现不佳。我们证明,当 Weibull 形状参数的大小发生变化时,有关生存曲线形状的非盲法临时信息可用于丰富最终分析,以重新估计样本量。针对这种情况,我们提出了两种贝叶斯解决方案来估计 Weibull 形状参数的自然变化。我们在新提出的允许非比例危害和非比例时间的相对时间法框架下实施了这些方法。我们还演示了在试验中期使用三种不同方法(内部试验研究法、条件功率法和预测功率法)对相对时间法的样本量进行重新估计。我们用一个假设的例子演示了我们的方法,并就所建议方法的实际限制提供了见解。
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来源期刊
Pharmaceutical Statistics
Pharmaceutical Statistics 医学-统计学与概率论
CiteScore
2.70
自引率
6.70%
发文量
90
审稿时长
6-12 weeks
期刊介绍: Pharmaceutical Statistics is an industry-led initiative, tackling real problems in statistical applications. The Journal publishes papers that share experiences in the practical application of statistics within the pharmaceutical industry. It covers all aspects of pharmaceutical statistical applications from discovery, through pre-clinical development, clinical development, post-marketing surveillance, consumer health, production, epidemiology, and health economics. The Journal is both international and multidisciplinary. It includes high quality practical papers, case studies and review papers.
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