Using numerical modeling and simulation to assess the ethical burden in clinical trials and how it relates to the proportion of responders in a trial sample.
Using numerical modeling and simulation to assess the ethical burden in clinical trials and how it relates to the proportion of responders in a trial sample.
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DOI：
10.1371/journal.pone.0258093
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Hommel M
中科院分区：
文献类型：
--
作者：
Boissel JP;Pérol D;Décousus H;Klingmann I;Hommel M
为了提出更精确的定义并探索如何减少随机对照临床试验（RCT）中的道德损失，我们着手识别那些无助于证明实验组的治疗优于对照组的试验参与者。随机对照试验于上世纪中叶出现，成为评估疗效的黄金标准，成为新疗法价值的基石，但其伦理基础仍存在争议。我们在随机对照试验中引入了不必要参与者的概念，即无信息参与者和无反应者的总和。与携带得出治疗疗效结论所需的所有信息的反应者相比，不提供信息的参与者被认为对试验中测量的疗效不提供信息。无论是否接受实验治疗，无反应者都会出现该事件。不必要的参与者承担着必须参加临床试验而无法从中受益的负担，其中可能包括经历副作用。因此，这些不必要的参与者带来了 RCT 方法固有的道德损失。相反，对实验治疗有反应的人在随机对照试验中承担了其全部功效。从文献中真实的安慰剂对照试验中观察到的比例开始，我们进行了随机对照试验的模拟，逐步将应答者的比例提高到 100%。我们表明，不必要的参与者数量稳步减少，直到 RCT 的道德损失达到最低限度。与此同时，试验的样本量减少了（大概其成本也减少了），尽管试验的统计功效有所增加，如比较两组之间的事件率的卡方增加所示。因此，我们预计增加随机对照试验中应答者的比例将有助于使它们在道德上更容易被接受，并减少假阴性结果。
In order to propose a more precise definition and explore how to reduce ethical losses in randomized controlled clinical trials (RCTs), we set out to identify trial participants who do not contribute to demonstrating that the treatment in the experimental arm is superior to that in the control arm. RCTs emerged mid-last century as the gold standard for assessing efficacy, becoming the cornerstone of the value of new therapies, yet their ethical grounds are a matter of debate. We introduce the concept of unnecessary participants in RCTs, the sum of non-informative participants and non-responders. The non-informative participants are considered not informative with respect to the efficacy measured in the trial in contrast to responders who carry all the information required to conclude on the treatment’s efficacy. The non-responders present the event whether or not they are treated with the experimental treatment. The unnecessary participants carry the burden of having to participate in a clinical trial without benefiting from it, which might include experiencing side effects. Thus, these unnecessary participants carry the ethical loss that is inherent to the RCT methodology. On the contrary, responders to the experimental treatment bear its entire efficacy in the RCT. Starting from the proportions observed in a real placebo-controlled trial from the literature, we carried out simulations of RCTs progressively increasing the proportion of responders up to 100%. We show that the number of unnecessary participants decreases steadily until the RCT’s ethical loss reaches a minimum. In parallel, the trial sample size decreases (presumably its cost as well), although the trial’s statistical power increases as shown by the increase of the chi-square comparing the event rates between the two arms. Thus, we expect that increasing the proportion of responders in RCTs would contribute to making them more ethically acceptable, with less false negative outcomes.
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自适应设计中的概述，障碍和未来的工作：来自国立卫生研究院资助的研讨会的观点。
DOI：
10.1177/1740774512461859
发表时间：
2012-12
期刊：
Clinical trials (London, England)
影响因子：
--
作者：
Coffey CS;Levin B;Clark C;Timmerman C;Wittes J;Gilbert P;Harris S
通讯作者：
Harris S
影响因子：
7.2
作者：
Boissel, Jean-Pierre;Cucherat, Michel;Leizorovicz, Alain
通讯作者：
Leizorovicz, Alain
影响因子：
2
作者：
LANG, JM;BURING, JE;HENNEKENS, CH
通讯作者：
HENNEKENS, CH
影响因子：
45.3
作者：
Ratain, Mark J.;Eisen, Tim;O'Dwyer, Peter J.
通讯作者：
O'Dwyer, Peter J.
影响因子：
3.7
作者：
van Rosmalen BV;Alldinger I;Cieslak KP;Wennink R;Clarke M;Ahmed Ali U;Besselink MG
通讯作者：
Besselink MG