Objectives To evaluate how often the precise research question being addressed about an intervention (the estimand) is stated or can be determined from reported methods, and to identify what types of questions are being investigated in phase 2-4 randomised trials. Design Systematic review of the clarity of research questions being investigated in randomised trials in 2020 in six leading general medical journals. Data source PubMed search in February 2021. Eligibility criteria for selecting studies Phase 2-4 randomised trials, with no restrictions on medical conditions or interventions. Cluster randomised, crossover, non-inferiority, and equivalence trials were excluded. Main outcome measures Number of trials that stated the precise primary question being addressed about an intervention (ie, the primary estimand), or for which the primary estimand could be determined unambiguously from the reported methods using statistical knowledge. Strategies used to handle post-randomisation events that affect the interpretation or existence of patient outcomes, such as intervention discontinuations or uses of additional drug treatments (known as intercurrent events), and the corresponding types of questions being investigated. Results 255 eligible randomised trials were identified. No trials clearly stated all the attributes of the estimand. In 117 (46%) of 255 trials, the primary estimand could be determined from the reported methods. Intercurrent events were reported in 242 (95%) of 255 trials; but the handling of these could only be determined in 125 (49%) of 255 trials. Most trials that provided this information considered the occurrence of intercurrent events as irrelevant in the calculation of the treatment effect and assessed the effect of the intervention regardless (96/125, 77%)—that is, they used a treatment policy strategy. Four (4%) of 99 trials with treatment non-adherence owing to adverse events estimated the treatment effect in a hypothetical setting (ie, the effect as if participants continued treatment despite adverse events), and 19 (79%) of 24 trials where some patients died estimated the treatment effect in a hypothetical setting (ie, the effect as if participants did not die). Conclusions The precise research question being investigated in most trials is unclear, mainly because of a lack of clarity on the approach to handling intercurrent events. Clear reporting of estimands is necessary in trial reports so that all stakeholders, including clinicians, patients and policy makers, can make fully informed decisions about medical interventions. Systematic review registration PROSPERO CRD42021238053. The datasets used during the current study are available from the corresponding author at s.cro{at}imperial.ac.uk fon reasonable request.

中文翻译：

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评估随机试验中正在调查的问题的明确程度：对估计值的系统评价


目标 评估陈述或通过报告的方法确定有关干预措施（估计值）的精确研究问题的频率，并确定 2-4 期随机试验中正在调查哪些类型的问题。设计 对 2020 年六种领先的普通医学期刊中随机试验中正在调查的研究问题的清晰度进行系统审查。数据来源 PubMed 检索，2021 年 2 月。选择研究的资格标准 2-4 期随机试验，对医疗条件或干预措施没有限制。整群随机、交叉、非劣效性和等效性试验被排除在外。主要结果指标 陈述了有关干预措施的精确主要问题（即主要估计值）的试验数量，或者可以使用统计知识从报告的方法中明确确定主要估计值的试验数量。用于处理影响患者结果的解释或存在的随机化后事件的策略，例如干预中断或使用额外的药物治疗（称为并发事件），以及正在调查的相应类型的问题。结果 确定了 255 项合格的随机试验。没有试验清楚地说明被估量的所有属性。在 255 项试验中的 117 项（46%）中，主要估计值可以根据报告的方法确定。 255 项试验中有 242 项（95%）报告了并发事件；但这些处理方法只能在 255 项试验中的 125 项（49%）中确定。 大多数提供此信息的试验认为并发事件的发生与治疗效果的计算无关，并无论如何评估干预效果（96/125，77%）——也就是说，他们使用了治疗政策策略。 99 项因不良事件而导致治疗不依从的试验中，有 4 项 (4%) 评估了假设环境中的治疗效果（即，参与者尽管发生不良事件仍继续接受治疗的效果），24 项试验中有 19 项 (79%)一些死亡的患者在假设的环境中估计了治疗效果（即，假设参与者没有死亡的效果）。结论 大多数试验中正在调查的确切研究问题尚不清楚，主要是因为处理并发事件的方法缺乏明确性。试验报告中必须明确报告估计值，以便所有利益相关者，包括临床医生、患者和政策制定者，能够就医疗干预措施做出充分知情的决定。系统审评注册PROSPERO CRD42021238053。当前研究中使用的数据集可根据合理要求从 s.cro{at}imperial.ac.uk 的相应作者处获得。