留在黑暗中：公开临床试验方案的重要性

Left in the dark: the importance of publicly available clinical trial protocols

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Full disclosure of research plans and their subsequent modifications facilitates transparency in medical research

Prospective registration of a randomised controlled trial (RCT) based on a protocol with formal ethics approval is a benchmark for transparent medical research. The reporting of the primary results of the study should correspond to the design, analysis, and reporting specified in the protocol and trial registration. However, modifications to various aspects of the trial are often made after registration, ranging from administrative updates to substantial protocol amendments. To track the history of revisions, the protocol and registry entry should be updated, and the documentation trail should support an independent appraisal of whether any biases have been introduced that could affect interpretation of trial results.

In this issue of the MJA, Coskinas and colleagues report their investigation of changes to 181 phase 3 RCTs registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) during 1 September 2007 – 31 December 2013.1 The authors compared protocol documents (including ANZCTR registration information) with subsequent journal publications for any changes to the primary outcome, treatment comparisons, analysis set definition, eligibility criteria, sample size, or primary analysis method. They found that protocols were available for only 124 trials (69%); it could be determined that no major changes had been made to eleven of these trials (9%), while 78 had definitely been modified (63%). By comparing publications with trial registration information, it was found that no changes were made to five of the 57 trials without available protocols (9%), and it could not be determined whether changes had been made to a further ten (18%).

The protocol is an essential document required by ethics committees before the trial commences, but, in contrast to trial registration, making the protocol publicly available is not mandatory.2 It is disappointing that protocols were not available for almost one-third of the clinical trials reviewed by Coskinas and her colleagues. This situation may have since been improved by incentives and requirements to increase accountability and transparency, including some journals accepting study protocols as stand-alone publications or requesting that protocols accompany submitted research manuscripts.

The SPIRIT 2013 statement recommends documenting protocol changes, and that major changes, including to the primary outcome or sample size, be reported in formal protocol amendments.2, 3 It is notable that Coskinas and colleagues identified differences between the primary outcome in the protocol and in the subsequent publication for 52 of 118 trials with available protocols (44%). Other investigations of such modifications have found proportions ranging between 31% (46 of 147) and 62% (51 of 82).4-6 Unfortunately, Coskinas and her co-authors did not provide details about whether these changes were acknowledged or justified by trial investigators, or whether the changes were foreseen by the protocols. Of particular concern were changes informed by unplanned assessment of interim data; that is, with knowledge of trial group allocation. Although Coskinas and colleagues reported that the changes were usually made with appropriate blinding, establishing this on the basis of the available documentation was difficult for most trials.1

Not all changes to trial protocols are inappropriate. For example, it is increasingly common to specify potential adjustments in the protocol, such as changes to the sample size or the removal of treatment arms after an interim analysis as part of an adaptive study design. Although not ideal, some unplanned changes may also be acceptable, including changes made blinded to treatment assignment and fully documented and justified in the protocol or study report. Despite careful planning, events outside the control of the investigators may necessitate unforeseen protocol modifications, including changes to the standard of care or COVID-19-related modifications of practice. In such cases, it is important to acknowledge and justify the changes to the protocol, statistical analysis plan, and study report.7, 8

We wholeheartedly agree with the recommendations by Coskinas and colleagues1 that investigators adhere to the principles of the CONSERVE statement for implementing and documenting modifications, include contingency plans in the protocol for dealing with challenges, and make all versions of the protocol and the analysis plan publicly available.7 We would add that it should also be clear whether modifications were made blinded to treatment assignment and that they be fully justified, in line with the global move toward open access for publishing medical research, strongly supported by the Australian Chief Scientist.9 Although some journals now encourage transparency by publishing study protocols, this is not a complete solution, as these publications are often condensed versions of the full protocol and not updated when modifications are made.10 Ideally, journal editors and referees would review a manuscript together with its registration and protocol documents to determine whether the reported investigation was consistent with the planned study.

The importance of detailed tracking of protocol modifications is growing, given the increasing complexity and flexibility of trial designs that anticipate potential adjustments that can lead to multiple protocol amendments.

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充分披露研究计划及其随后的修改有助于提高医学研究的透明度

随机对照试验的前瞻性注册（RCT）基于有正式伦理批准的方案是透明医学研究的基准，研究的初步结果报告应与方案和试验注册中规定的设计、分析和报告相对应，但注册后往往会对试验的各个方面进行修改，从行政更新到实质性方案修订。为了跟踪修订历史，应更新方案和登记条目，文件记录应支持独立评估是否引入了可能影响试验结果解释的偏倚。

在本期的MJA，Coskinas及其同事报告了他们对2007年9月1日至2013年12月31日期间在澳大利亚新西兰临床试验登记处（ANZCTR）登记的181项III期RCT变更的调查。1 作者比较了方案文件（包括ANZCTR注册信息）和随后的期刊出版物，以确定主要结局、治疗比较、分析集定义、合格性标准、样本量或主要分析方法的任何变化，他们发现只有124项试验（69%）的方案可用;可以确定这些试验中的11项（9%）没有重大变化，而78项（63%）明确进行了修改。通过比较出版物和试验注册信息，发现57项试验中没有可用方案的5项（9%）没有变化，并且不能确定是否对另外10项（18%）进行了修改。

试验方案是伦理委员会在试验开始前要求的基本文件，但与试验注册相反，公开试验方案不是强制性的。2 令人失望的是，科斯金纳斯和她的同事审查的近三分之一的临床试验没有方案，这种情况可能已经得到改善，因为激励和要求增加问责制和透明度，包括一些期刊接受研究方案作为独立出版物或要求方案与提交的研究手稿。

SPIRIT 2013声明建议记录方案变更，并在正式方案修订案中报告重大变更，包括主要结局或样本量。2，3 值得注意的是，Coskinas及其同事在118项试验方案中发现了52项（44%）方案中的主要结局与随后发表的文献中的主要结局之间存在差异，其他对此类修改的研究发现比例介于31%（46/147）和62%（51/82）之间。4-6 遗憾的是，Coskinas和她的合著者没有提供试验研究者是否承认或证明这些改变是合理的，或者这些改变是否是方案所预见的，特别值得关注的是，这些改变是由中期数据的计划外评估所告知的;尽管Coskinas及其同事报道了这些改变通常是在适当的盲法下进行的，但在大多数试验中，根据现有的文献资料建立盲法是困难的。1

并非所有试验方案的变更都是不合适的，例如，在方案中规定潜在的调整，如样本量的改变或中期分析后治疗组的删除，作为适应性研究设计的一部分，这一点越来越常见，虽然不理想，但一些计划外的变更也可能是可以接受的，包括对治疗分配设盲并在方案或研究报告中充分记录和证明的改变。尽管仔细计划，研究者无法控制的事件可能需要进行不可预见的方案修改，包括护理标准的变更或与COVID-19相关的实践修改。在这种情况下，重要的是确认并证明方案、统计分析计划和研究报告的变更。7，8

我们完全同意Coskinas及其同事的建议1 研究者遵守CONSERVE声明中关于实施和记录修改的原则，包括方案中应对挑战的应急计划，并公开提供所有版本的方案和分析计划。7 我们要补充的是，还应明确是否对治疗分配设盲进行了修改，并根据澳大利亚首席科学家强烈支持的全球开放获取发表医学研究的趋势，进行修改是完全合理的。9 尽管一些期刊现在通过发表研究方案来鼓励透明度，但这并不是一个完整的解决方案，因为这些出版物通常是完整方案的浓缩版本，在进行修改时不会更新。10 理想情况下，期刊编辑和审稿人将审查手稿及其注册和方案文件，以确定报告的研究是否与计划的研究一致。

考虑到试验设计的复杂性和灵活性不断增加，预期可能导致多次方案修订的潜在调整，详细跟踪方案修订的重要性正在增加。

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