Wilson Brooke E, Desnoyers Alexandra, Nadler Michelle B, Tibau Ariadna, Amir Eitan
Princess Margaret Cancer Centre, Department of Medical Oncology, University of Toronto, Toronto, ON, Canada.
University of New South Wales, Kensington, NSW, Australia.
Cancer Med. 2021 Aug;10(16):5405-5414. doi: 10.1002/cam4.4029. Epub 2021 Jul 28.
It has been suggested that the results from fragile trials are less likely to translate into benefit in routine clinical practice.
We searched the Food and Drug Administration (FDA) archives to identify drug approvals for solid organ malignancies between 2010 and 2019. We calculated the Fragility Index (FI) supporting each approval, using methods to account for time-to-event. We compared FI and trial and approval characteristics using Mann-Whitney U and Kruskal-Wallis test. Using logistic regression, we examined study characteristics associated with withdrawal of consent or lost to follow-up (WCLFU) exceeding the calculated FI.
The median FI among 125 included studies was 23 (range 1-322). The FI was ≤10 in 35 studies (28%), 11-20 in 21 (17%), and >20 in 69 (55%). The median FI/Nexp was 7.7% (range 0.1-51.7%). The median FI was significantly lower among approvals processed through the accelerated vs regular pathway (5.5 vs 25, p = 0.001), but there was no difference in median FI/Nexp. The WCLFU exceeded FI in 42% of studies. Overall survival endpoints were more likely to have a WCLFU exceeding FI (OR 3.16, p = 0.003). WCLFU exceeding FI was also associated with a lesser magnitude of effect (median HR 0.69 vs 0.55, p < 0.001). In a sensitivity analysis including only studies with 1:1 randomization, 51% of studies had WCLFU >FI.
The median FI among all trials was 23, and WCLFU exceeded FI in 42%. Comparative trials in solid tumors supporting approval through the accelerated pathway are more fragile compared to trials approved through the regular pathway, an observation likely explained by a lower sample size in the experimental arm.
有人认为，脆弱试验的结果在常规临床实践中转化为益处的可能性较小。
我们检索了美国食品药品监督管理局（FDA）的档案，以确定2010年至2019年间实体器官恶性肿瘤的药物批准情况。我们使用考虑事件发生时间的方法计算支持每项批准的脆弱性指数（FI）。我们使用曼-惠特尼U检验和克鲁斯卡尔-沃利斯检验比较FI以及试验和批准的特征。使用逻辑回归，我们研究了与同意撤回或失访（WCLFU）超过计算出的FI相关的研究特征。
125项纳入研究的FI中位数为23（范围1 - 322）。35项研究（28%）的FI≤10，21项（17%）的FI为11 - 20，69项（55%）的FI>20。FI/Nexp的中位数为7.7%（范围0.1 - 51.7%）。通过加速途径与常规途径处理的批准中，FI中位数显著较低（分别为5.5和25，p = 0.001），但FI/Nexp中位数无差异。42%的研究中WCLFU超过了FI。总生存终点更有可能出现WCLFU超过FI的情况（比值比3.16，p = 0.003）。WCLFU超过FI还与较小的效应量相关（HR中位数0.69对0.55，p < 0.001）。在仅包括1:1随机化研究的敏感性分析中，51%的研究WCLFU>FI。
所有试验的FI中位数为23，42%的研究中WCLFU超过了FI。与通过常规途径批准的试验相比，支持通过加速途径批准的实体瘤比较试验更脆弱，这一观察结果可能是由于试验组样本量较小所致。
