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

我们的目标：为了提高准确性和报告的替代结果在随机试验通过扩展到当前的报告checklists.Why这项研究是重要的：治疗的有效性的证据理想地来自设计良好的随机对照试验，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。SPIRIT（标准方案项目：干预性试验的建议）和CONSORT（报告试验的统一标准）声明被广泛采用并以证据为基础，为报告随机试验的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用作随机试验的主要结局。替代终点成为以患者为中心的结局的“替代品”，例如，针对特定类型的生命限制性癌症的新药试验最终寻求改善患者生存率，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，此类试验的一个重要的潜在缺点是，该疗法可能没有替代品预测的益处，例如，该药物是基于肿瘤大小减小的证据（与安慰剂相比）获得许可并提供给患者，但结果并没有改善（甚至恶化）患者死亡率。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局。然而，这种情况在实践中似乎很少发生，导致从已发表的研究中得出潜在的误导性结论。因此，需要更好的报告。改进以替代终点作为其结果的试验报告将增加SPIRIT和CONSORT标准现有扩展的价值。我们要做的：我们将采用与以前类似的方法来开发SPIRIT和CONSORT主语句和扩展。我们已经对文献进行了范围审查，我们将使用这些文献来制定一个长长的项目列表，我们认为这些项目可能有助于报告替代终点试验。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，知识用户，资助机构代表，期刊编辑以及患者和公众参与代表。我们将通过相关出版物和我们广泛的研究网络确定个人。研究的最后阶段包括编写和分发SPIRIT和CONSORT扩展指南和检查表，以及一份“解释和评估”文件，该文件提供了如何使用检查表的更详细指南，以及方案和试验报告良好实践的示例。其中一个研究小组在作为试验方法学研究的非专业贡献者方面具有丰富的经验，他参与了本申请的撰写，如果获得资助，他将帮助我们确保公众参与我们的研究。本研究的获益：替代主要终点的CONSORT和SPIRIT扩展将有助于资助评审员、资助机构、试验方法学家、期刊编辑、评审员和读者（包括患者和公众）的关键评估和解释。预计本研究的结果将减少评估替代终点的方案和试验的不完整、不明确或不准确报告，从而限制有关治疗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.