Reporting of randomised trials using surrogate outcomes: development of extensions to the CONSORT 2010 and SPIRIT 2013 guidance statements

我们的目标：通过开发对当前报告清单的扩展，提高随机试验中替代结果的准确性和报告。这项研究的重要性：治疗有效性的证据理想地来自设计良好的随机对照试验，这些试验评估以患者为中心的结果，直接衡量患者的感觉、功能或生存情况。广泛采用的基于证据的SPIRIT(标准方案项目：介入试验建议)和CONSORT(报告试验综合标准)声明为报告随机试验的方案和结果提供了最低限度的建议。在推动患者更快获得治疗的过程中，代理终点越来越多地被用作随机试验的主要结果。替代终点成为以患者为中心的结果的“替代品”，例如，一种针对特定类型限制生命的癌症的新药试验最终寻求改善患者的生存，将在临床试验中评估肿瘤大小，而不是死亡(这将需要更长的时间才能发生)。基于替代终点的试验的优点是它们更短、更小、更便宜。然而，这类试验的一个重要的潜在不利方面是，这种疗法可能最终没有替代疗法所预测的好处，例如，该药物获得许可并根据肿瘤体积缩小(与安慰剂相比)的证据提供给患者，但事实证明并不能改善(甚至恶化)患者的死亡率。因此，建议使用替代终点的试验只使用已被证实(“确认”)的终点来预测以患者为中心的结果。然而，这似乎在实践中很少发生，导致从已发表的研究中得出潜在的误导性结论。因此，需要更好的报道。改进以替代终点为结果的试验报告将为SPIRIT和CONSORT标准的现有扩展增加价值。我们计划做什么：我们将采用与以前类似的方法来开发SPIRIT，并协调主要声明和扩展。我们已经对文献进行了范围审查，我们将使用这些文献来起草一长串项目，我们认为这些项目在报告替代终点试验时可能有用。然后我们将进行德尔菲法，这是一种旨在产生共识的量化方法，包括(1)在线调查和(2)虚拟共识会议。对于在线调查，我们将联系利益相关者，包括在替代终点试验的设计/实施/分析/报告方面具有经验的临床试验研究人员、知识用户、资助机构的代表、期刊编辑以及患者和公众参与代表。我们将从相关出版物和我们广泛的研究网络中确定个人。这项研究的最后阶段包括编写和传播《精神》和《协议书》延展指南和核对表，以及一份《解释和阐述》文件，其中提供如何使用核对表的更详细指导，以及礼宾和审判报告良好做法的范例。研究小组中的一位在担任试验方法学研究的非专业贡献者方面具有丰富的经验，他参与了这份申请的撰写，如果得到资助，他将帮助我们确保公众参与我们的研究。这项研究的好处：代理初级终点的配偶和精神扩展将有助于对赠款审查员、资助机构、试验方法学家、期刊编辑、审查员和读者(包括患者和公众成员)进行批判性评估和解释。这项研究的结果预计将减少对评估替代终点的方案和试验的不完整、不清楚或不准确的报告，从而限制关于治疗的长期安全性和有效性的错误结论。

OUR AIM: To improve the accuracy and reporting of surrogate outcomes in randomised trials through the development of an extension to current reporting checklists.WHY THIS RESEARCH IS IMPORTANT: Evidence for the effectiveness of treatments ideally comes from well-designed randomised controlled trials that assess patient-centred outcomes that directly measures how a patient feels, functions, or survives. Widely adopted and evidence-based, SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) statements provide minimum recommendations for reporting protocols and results of randomised trials. In drive to make treatments available more quickly to patients, surrogate endpoints are increasing used as the main outcomes in randomised trials. A surrogate endpoint becomes a 'substitute' for patient centred outcomes, e.g. a trial of a new drug for particular type of life-limiting cancer ultimately seeking to improve patient survival, will assess tumour size within the clinical trial instead of death (that would take much longer to occur). Advantages of trials based on a surrogate endpoint is that they are shorter, smaller, and less expensive. However, an important potential down-side of such trials is that the therapy may turn out not to have the benefit predicted by a surrogate, e.g. the drug is licensed and made available based to patients based on evidence of a reduction in tumour size (compared to placebo) but turns out not to improve (or even worsen) patient mortality. It is therefore recommended that trials using surrogate endpoints only use endpoints that have been proven ('validated') to predict patient centred outcomes. However, this infrequently seems to happen in practice leading to potential misleading conclusions drawn from published studies. Therefore, better reporting is needed. Improving the reporting of trials with surrogate endpoints as its outcome will add value to the existing extensions to SPIRIT and CONSORT Standards. WHAT WE PLAN TO DO: We will adopt similar methods as used previously to develop SPIRIT and CONSORT main statements and extensions. We have already conducted a scoping review of the literature that we will use to draw up a long list of items that we consider may be useful in reporting surrogate endpoints trials. We will then conduct a Delphi, a quantitative method aimed at generating consensus comprising (1) an online survey, and (2) a virtual consensus meeting. For the online survey, we will contact stakeholders including clinical trials researchers with experience in the design/conduct/analysis/reporting of surrogate endpoints trials, knowledge users, representatives from funding bodies, journal editors, and patient and public involvement representatives. We will identify individuals from relevant publications and through our extensive research networks. The final phase of the study involves writing and disseminating SPIRIT and CONSORT extension guidance and checklists, and an 'Explanation and Elaboration' document that provides a more detailed guide of how to use the checklists, and examples of protocol and trial reporting good practice. One of the study group who has extensive experience in acting as lay contributor to trial methodological research has been involved in writing of this application and will help us ensure public involvement in our study, if funded. BENEFITS OF THE STUDY: CONSORT and SPIRIT extensions for surrogate primary endpoints will aid in critical appraisal and interpretation for grant reviewers, funding bodies, trial methodologists, journal editors, reviewers, and readers (including patients and members of the public). The outputs of this research are expected to reduce incomplete, unclear, or inaccurate reporting of protocols and trials assessing surrogate endpoints thus limiting erroneous conclusions about the long-term safety and efficacy of treatments.