Department of Medical Oncology, Thunder Bay Regional Health Sciences Centre and Northern Ontario School of Medicine, Thunder Bay, ON, Canada.
Division of Medical Oncology, Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada.
Lancet Oncol. 2019 Aug;20(8):1065-1069. doi: 10.1016/S1470-2045(19)30338-9. Epub 2019 Jul 8.
The fragility index of trial results-ie, the minimum number of changes from non-events to events resulting in loss of statistical significance-can provide a measure of confidence that a positive effect reported in a randomised controlled trial is real. We aimed to calculate the fragility index of randomised controlled trials supporting US Food and Drug Administration (FDA)-approved anticancer drugs.
This is a retrospective analysis of phase 3, randomised, controlled trials supporting anticancer drugs that were approved by the FDA between Jan 1, 2014, and Dec 31, 2018. Two-arm studies with 1:1 randomisation and significant positive results for a time-to-event outcome were eligible for the fragility index calculation, which involves the iterative addition of an event to the experimental group (defined as the group with the smaller number of events in positive trials) and concomitant subtraction of a non-event from that group, until positive significance (defined as p<0·05 by Fisher's exact test) is lost.
We identified 36 phase 3 randomised controlled trials, of which 17 (47%) were included in the fragility index analysis. The median fragility index was 2 (IQR 0-27). The fragility index was 2 or less in nine (53%) of 17 trials; for these trials, the fragility index was 1% or less of the total sample size. In five (29%) of 17 trials, the number lost to follow-up was more than the fragility index.
Many phase 3 randomised controlled trials supporting FDA-approved anticancer drugs have a low fragility index, challenging confidence for concluding their superiority over control treatments. Although not a measure of effect, the fragility index might provide an additional means of assessing the robustness of clinical trial data.
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试验结果的脆弱指数（即从非事件到事件的最小变化数，导致统计意义丧失）可以提供一种置信度的衡量标准，表明随机对照试验中报告的阳性效应是真实的。我们旨在计算支持美国食品和药物管理局（FDA）批准的抗癌药物的随机对照试验的脆弱指数。
这是一项回顾性分析，纳入了 2014 年 1 月 1 日至 2018 年 12 月 31 日期间获得 FDA 批准的支持抗癌药物的 3 期、随机、对照试验。符合脆弱指数计算条件的研究为：1:1 随机分组，生存结局有阳性结果且显著。脆弱指数的计算涉及到将事件逐次添加到实验组（定义为阳性试验中事件较少的组）并同时从该组中减去一个非事件，直到阳性意义（Fisher 确切检验 p<0·05）丧失。
我们确定了 36 项 3 期随机对照试验，其中 17 项（47%）纳入脆弱指数分析。中位数脆弱指数为 2（IQR 0-27）。17 项试验中有 9 项（53%）脆弱指数为 2 或更低；对于这些试验，脆弱指数为总样本量的 1%或更低。在 17 项试验中有 5 项（29%）的失访人数超过脆弱指数。
许多支持 FDA 批准的抗癌药物的 3 期随机对照试验的脆弱指数较低，这对得出其优于对照治疗的结论提出了挑战。尽管脆弱指数不是衡量效应的指标，但它可能为评估临床试验数据的稳健性提供另一种方法。
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