Background/AimsEvaluating safety is as important as evaluating efficacy in a clinical trial, yet the tradition for safety analysis is rudimentary. This article explores more complex methodologies for safety evaluation, with the aim of improving the interpretability, as well as generalizability, of the results.MethodsFor studies where the analysis periods vary over the subjects, using the International Council for Harmonisation estimand framework, we construct a formal estimand that could be used in the setting of safety surveillance that answers the clinical question of ‘What is the magnitude of the increase in risk of experiencing an adverse event if the treatment is taken, as prescribed, for a specific period of time?’. Estimation methodologies for this estimand are also discussed.ResultsThe proposed estimand is similar to that found in the efficacy analyses of time to event data (e.g. in outcome studies), with the key difference of utilization of hypothetical intercurrent event strategy for the intercurrent event of treatment discontinuation. This is motivated by what we perceive to be a key difference for the safety objective compared to efficacy objectives, namely a desire for sensitivity (i.e. greater possibility of detecting a negative impact of the drug, if such exists) as opposed to the need to prove a positive effect of the drug in a conservative manner.ConclusionIt is valuable, and possible, to use the International Council for Harmonisation estimand framework not only for efficacy but also for safety evaluation, with the estimand driven by an interpretable, and relevant, clinical question.

中文翻译：

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后期临床试验的安全性估计，其中分析期因受试者而异

背景/目标在临床试验中评估安全性与评估疗效同样重要，但安全性分析的传统还很初级。本文探讨了更复杂的安全性评估方法，旨在提高结果的可解释性和普遍性。方法对于分析周期因受试者而异的研究，使用国际协调委员会估计框架，我们构建了一个可用于安全监测环境的正式估计，回答以下临床问题：“如果在特定时间内按照规定进行治疗，发生不良事件的风险增加的程度是多少？” 。还讨论了该估计值的估计方法。结果所提出的估计值与事件时间数据的功效分析（例如结果研究）中发现的估计值类似，主要区别在于针对治疗并发事件使用假设并发事件策略停产。这是由于我们认为安全性目标与功效目标相比的一个关键区别，即对敏感性的渴望（即检测药物的负面影响的可能性更大，如果存在的话），而不是需要证明结论使用国际协调委员会的估计框架不仅对于疗效而且对于安全性评估是有价值且可能的，该估计由可解释的相关临床问题驱动。