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

我们的目的：通过对当前报告清单的扩展，提高随机试验替代结果报告的准确性和准确性。重要意义：理想情况下，治疗有效性的证据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，直接测量患者的感觉、功能或生存情况。SPIRIT（标准方案项目：干预性试验建议）和CONSORT（综合试验报告标准）声明被广泛采用并以证据为基础，为随机试验的报告方案和结果提供了最低限度的建议。为了使患者更快地获得治疗，替代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，针对特定类型的限制生命的癌症的新药试验最终寻求提高患者的存活率，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）。基于替代终点的试验的优点是它们更短、更小、更便宜。然而，这种试验的一个重要的潜在缺点是，这种疗法可能没有替代疗法所预测的好处，例如，根据肿瘤大小减少的证据（与安慰剂相比），该药物获得许可并提供给患者，但结果却没有改善（甚至恶化）患者的死亡率。因此，建议使用替代终点的试验仅使用已被证明（“验证”）的终点来预测以患者为中心的结果。然而，这种情况在实践中似乎很少发生，从而导致从已发表的研究中得出潜在的误导性结论。因此，需要更好的报告。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：我们将采用与以前开发SPIRIT和CONSORT主语句和扩展类似的方法。我们已经对文献进行了范围综述，我们将用它来起草一长串我们认为可能对报告替代终点试验有用的项目。然后，我们将进行德尔菲，一种旨在产生共识的定量方法，包括(1)在线调查，(2)虚拟共识会议。对于在线调查，我们将联系利益相关者，包括具有替代终点试验设计/实施/分析/报告经验的临床试验研究人员、知识使用者、资助机构代表、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。研究的最后阶段包括编写和传播SPIRIT和CONSORT扩展指南和检查清单，以及一个“解释和细化”文档，该文档提供了如何使用检查清单的更详细的指南，以及协议和试验报告良好实践的示例。研究小组中有一位在试验方法学研究方面有丰富经验的外行贡献者参与了本申请的撰写，如果得到资助，他将帮助我们确保公众参与我们的研究。研究的好处：替代主要终点的CONSORT和SPIRIT扩展将有助于对拨款审稿人、资助机构、试验方法学家、期刊编辑、审稿人和读者（包括患者和公众成员）进行批判性评估和解释。本研究的结果有望减少评估替代终点的方案和试验的不完整、不明确或不准确的报告，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.