论文标题
基于短期二进制结果的长期生存结果的III期试验设计
Design of phase III trials with long-term survival outcomes based on short-term binary results
论文作者
论文摘要
病理完全反应（PCR）是II期试验甚至加速批准新辅助癌症治疗的常见主要终点。如果被授予，通常需要进行两臂验证试验，以证明诸如总生存时间之类的事实结果的功效。但是，基于先前有关PCR效应的先前信息的后续III期试验的设计并不直接。旨在使用先前试验中的PCR信息设计将这种III期试验作为主要终点，我们考虑了一种混合模型，该模型既包含生存率和二进制终点。我们建议将臂之间的比较基于限制的平均生存时间的差异，并显示整个生存的效果大小和样本大小如何取决于二进制响应的概率以及每个治疗臂的响应状态的生存分布。此外，我们在不同方案下提供了样本量计算，并伴随着将所有计算实施的R软件包。我们通过一项模拟研究评估我们的建议，并通过新辅助乳腺癌试验说明了其应用。
Pathologic complete response (pCR) is a common primary endpoint for a phase II trial or even accelerated approval of neoadjuvant cancer therapy. If granted, a two-arm confirmatory trial is often required to demonstrate the efficacy with a time-to-event outcome such as overall survival. However, the design of a subsequent phase III trial based on prior information on the pCR effect is not straightforward. Aiming at designing such phase III trials with overall survival as primary endpoint using pCR information from previous trials, we consider a mixture model that incorporates both the survival and the binary endpoints. We propose to base the comparison between arms on the difference of the restricted mean survival times, and show how the effect size and sample size for overall survival rely on the probability of the binary response and the survival distribution by response status, both for each treatment arm. Moreover, we provide the sample size calculation under different scenarios and accompany them with an R package where all the computations have been implemented. We evaluate our proposal with a simulation study, and illustrate its application through a neoadjuvant breast cancer trial.
