Is "rescue" therapy ethical in randomized controlled trials?
Is "rescue" therapy ethical in randomized controlled trials?
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随机对照试验中的“救援”疗法是否符合伦理？
DOI：
10.1097/pcc.0b013e318198bd13
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发表时间：
2009
期刊：
影响因子：
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通讯作者：
EuniceKennedyShriverNationalInstituteofChildHeal
中科院分区：
文献类型：
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作者：
Holubkov,Richard;Dean,JMichael;Berger,John;Anand,KanwaljeetJS;Carcillo,Joseph;Meert,Kathleen;Zimmerman,Jerry;Newth,Christopher;Harrison,Rick;Willson,DouglasF;Nicholson,Carol;EuniceKennedyShriverNationalInstituteofChildHeal
目的：有一种普遍的观点认为，在儿童病情恶化时，儿科重症监护中的随机、安慰剂对照试验应包括“救援”疗法(活性药物的开放标签给药)。随机试验中与抢救治疗相关的伦理、概念和分析挑战可能被歪曲。设计：叙述性综述。方法：在一项假设性随机试验的背景下，检查抢救治疗的伦理基础、均衡概念和意向治疗分析，比较皮质类固醇和安慰剂在儿童感染性休克中的作用。结果：人们对抢救治疗的感知需要可能部分是出于挽救儿童生命的道德要求。然而，允许在试验中进行抢救治疗是错误的，与研究药物疗效的均衡不一致。如果抢救疗法被允许，意向治疗分析只能比较研究药物的立即使用和延迟使用。当抢救疗法是有益的时，观察到的治疗效果与研究药物的真实效果相比会大大降低，导致样本量增加，从而将更多的儿童置于危险之中(在我们的假设例子中，发生了18例安慰剂过量死亡)。对包含抢救疗法的试验的分析不能最终评估药物的总体疗效，也不能区分与用药时机有关的有益或有害的治疗效果。结论：尽管随机试验中的抢救疗法成分可能被认为是伦理上可取的，但救援疗法与完全均衡的不一致本身可能会引发重大的伦理问题。样本量的增加使更多的儿童面临参与研究的风险，包括死亡。研究人员应该意识到，用抢救疗法设计的临床试验不能确定治疗本身的益处或有害影响，只能评估延迟或立即提供治疗的效果。
Objective:There is a commonly held belief that randomized, placebo-controlled trials in pediatric critical care should incorporate “rescue” therapy (open-label administration of active drug) when a child’s condition is deteriorating. The ethical, conceptual, and analytic challenges related to rescue therapy in randomized trials can be misrepresented.Design:Narrative review.Methods:The ethical basis of rescue therapy, the equipoise concept, and intention-to-treat analysis are examined in the setting of a hypothetical randomized trial comparing corticosteroids vs. placebo in pediatric septic shock.Findings:The perceived need for rescue therapy may be partly motivated by the moral imperative to save a child’s life. However, allowing rescue therapy in a trial is misconceived and inconsistent with equipoise regarding the efficacy of the study drug. If rescue therapy is permitted, intention-to-treat analysis can only compare immediate vs. delayed use of the study drug. When rescue therapy is beneficial, the observed treatment effect is substantially diminished from true effect of the study drug, leading to increased sample size and thereby placing more children at risk (18 “excess” placebo-arm deaths occur in our hypothetical example). Analysis of a trial incorporating rescue therapy cannot definitively assess overall efficacy of the agent, or distinguish beneficial or harmful treatment effects related to timing of drug use.Conclusions:Although a rescue therapy component in a randomized trial may be perceived as ethically desirable, inconsistency of rescue therapy with full equipoise may itself raise significant ethical concerns. Increased sample sizes expose more children to the risks of study participation, including death. Researchers should be aware that clinical trials designed with rescue therapy cannot definitively determine the beneficial or harmful effects of a treatment per se, and can only assess the effects of delayed vs. immediate provision of the treatment.