论文标题
改进的加权日志秩检验,用于验证性试验,并具有很高的治疗切换
A modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching
论文作者
论文摘要
在验证性癌症临床试验中,总体生存(OS)通常是调节标准下意对于治疗(ITT)分析中的主要终点。肿瘤进行后,通常将分配给对照组的患者切换到实验治疗,或同一类中的另一种药物。与对照组相比,这种治疗转换可以稀释新药的相对疗效,从而导致统计能力降低。可以通过缩短随访期来减少估计偏差,但这可能导致信息和权力损失。取而代之的是,我们提出了一个改进的加权日志秩检验(MWLR),旨在通过在许多患者切换治疗时发生的下降加权事件来平衡这些因素。 由于应预先指定加权,并且处理切换的影响尚不清楚,因此我们预测危险比功能并使用它来计算MWLR的权重。该方法可能会合并以前试验中有关潜在危害比功能随时间推移的信息。 在转移性肾细胞癌患者中,依维莫司对安慰剂的记录1试验激励我们,安慰剂组中近80%的患者在疾病进展后接受了依维莫司。广泛的模拟表明,在现实情况下,新测试比标准对数秩检验的效率要高得多。
In confirmatory cancer clinical trials, overall survival (OS) is normally a primary endpoint in the intention-to-treat (ITT) analysis under regulatory standards. After the tumor progresses, it is common that patients allocated to the control group switch to the experimental treatment, or another drug in the same class. Such treatment switching may dilute the relative efficacy of the new drug compared to the control group, leading to lower statistical power. It would be possible to decrease the estimation bias by shortening the follow-up period but this may lead to a loss of information and power. Instead we propose a modified weighted log-rank test (mWLR) that aims at balancing these factors by down-weighting events occurring when many patients have switched treatment. As the weighting should be pre-specified and the impact of treatment switching is unknown, we predict the hazard ratio function and use it to compute the weights of the mWLR. The method may incorporate information from previous trials regarding the potential hazard ratio function over time. We are motivated by the RECORD-1 trial of everolimus against placebo in patients with metastatic renal-cell carcinoma where almost 80\% of the patients in the placebo group received everolimus after disease progression. Extensive simulations show that the new test gives considerably higher efficiency than the standard log-rank test in realistic scenarios.