Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
MRC Clinical Trials Unit at UCL, University College London , London, UK.
Cochrane Database Syst Rev. 2021 Dec 8;12(12):MR000051. doi: 10.1002/14651858.MR000051.pub2.
Trial monitoring is an important component of good clinical practice to ensure the safety and rights of study participants, confidentiality of personal information, and quality of data. However, the effectiveness of various existing monitoring approaches is unclear. Information to guide the choice of monitoring methods in clinical intervention studies may help trialists, support units, and monitors to effectively adjust their approaches to current knowledge and evidence.
To evaluate the advantages and disadvantages of different monitoring strategies (including risk-based strategies and others) for clinical intervention studies examined in prospective comparative studies of monitoring interventions.
We systematically searched CENTRAL, PubMed, and Embase via Ovid for relevant published literature up to March 2021. We searched the online 'Studies within A Trial' (SWAT) repository, grey literature, and trial registries for ongoing or unpublished studies.
We included randomized or non-randomized prospective, empirical evaluation studies of different monitoring strategies in one or more clinical intervention studies. We applied no restrictions for language or date of publication.
We extracted data on the evaluated monitoring methods, countries involved, study population, study setting, randomization method, and numbers and proportions in each intervention group. Our primary outcome was critical and major monitoring findings in prospective intervention studies. Monitoring findings were classified according to different error domains (e.g. major eligibility violations) and the primary outcome measure was a composite of these domains. Secondary outcomes were individual error domains, participant recruitment and follow-up, and resource use. If we identified more than one study for a comparison and outcome definitions were similar across identified studies, we quantitatively summarized effects in a meta-analysis using a random-effects model. Otherwise, we qualitatively summarized the results of eligible studies stratified by different comparisons of monitoring strategies. We used the GRADE approach to assess the certainty of the evidence for different groups of comparisons.
We identified eight eligible studies, which we grouped into five comparisons. 1. Risk-based versus extensive on-site monitoring: based on two large studies, we found moderate certainty of evidence for the combined primary outcome of major or critical findings that risk-based monitoring is not inferior to extensive on-site monitoring. Although the risk ratio was close to 'no difference' (1.03 with a 95% confidence interval [CI] of 0.81 to 1.33, below 1.0 in favor of the risk-based strategy), the high imprecision in one study and the small number of eligible studies resulted in a wide CI of the summary estimate. Low certainty of evidence suggested that monitoring strategies with extensive on-site monitoring were associated with considerably higher resource use and costs (up to a factor of 3.4). Data on recruitment or retention of trial participants were not available. 2. Central monitoring with triggered on-site visits versus regular on-site visits: combining the results of two eligible studies yielded low certainty of evidence with a risk ratio of 1.83 (95% CI 0.51 to 6.55) in favor of triggered monitoring intervention. Data on recruitment, retention, and resource use were not available. 3. Central statistical monitoring and local monitoring performed by site staff with annual on-site visits versus central statistical monitoring and local monitoring only: based on one study, there was moderate certainty of evidence that a small number of major and critical findings were missed with the central monitoring approach without on-site visits: 3.8% of participants in the group without on-site visits and 6.4% in the group with on-site visits had a major or critical monitoring finding (odds ratio 1.7, 95% CI 1.1 to 2.7; P = 0.03). The absolute number of monitoring findings was very low, probably because defined major and critical findings were very study specific and central monitoring was present in both intervention groups. Very low certainty of evidence did not suggest a relevant effect on participant retention, and very low certainty evidence indicated an extra cost for on-site visits of USD 2,035,392. There were no data on recruitment. 4. Traditional 100% source data verification (SDV) versus targeted or remote SDV: the two studies assessing targeted and remote SDV reported findings only related to source documents. Compared to the final database obtained using the full SDV monitoring process, only a small proportion of remaining errors on overall data were identified using the targeted SDV process in the MONITORING study (absolute difference 1.47%, 95% CI 1.41% to 1.53%). Targeted SDV was effective in the verification of source documents, but increased the workload on data management. The other included study was a pilot study, which compared traditional on-site SDV versus remote SDV and found little difference in monitoring findings and the ability to locate data values despite marked differences in remote access in two clinical trial networks. There were no data on recruitment or retention. 5. Systematic on-site initiation visit versus on-site initiation visit upon request: very low certainty of evidence suggested no difference in retention and recruitment between the two approaches. There were no data on critical and major findings or on resource use.
AUTHORS' CONCLUSIONS: The evidence base is limited in terms of quantity and quality. Ideally, for each of the five identified comparisons, more prospective, comparative monitoring studies nested in clinical trials and measuring effects on all outcomes specified in this review are necessary to draw more reliable conclusions. However, the results suggesting risk-based, targeted, and mainly central monitoring as an efficient strategy are promising. The development of reliable triggers for on-site visits is ongoing; different triggers might be used in different settings. More evidence on risk indicators that identify sites with problems or the prognostic value of triggers is needed to further optimize central monitoring strategies. In particular, approaches with an initial assessment of trial-specific risks that need to be closely monitored centrally during trial conduct with triggered on-site visits should be evaluated in future research.
试验监测是确保研究参与者的安全和权利、个人信息的保密性以及数据质量的良好临床实践的重要组成部分。然而，各种现有监测方法的效果尚不清楚。指导临床干预研究中监测方法选择的信息可能有助于试验人员、支持单位和监测人员根据当前知识和证据有效地调整他们的方法。
评估不同监测策略（包括基于风险的策略和其他策略）在前瞻性比较监测干预研究中对临床干预研究的优缺点。
我们通过 Ovid 系统地检索了 CENTRAL、PubMed 和 Embase 中的相关已发表文献，检索时间截至 2021 年 3 月。我们还检索了在线“研究内试验”（SWAT）存储库、灰色文献和试验注册处的正在进行或未发表的研究。
我们纳入了一项或多项临床干预研究中不同监测策略的随机或非随机前瞻性、经验评估研究。我们对语言或发表日期没有任何限制。
我们提取了评估的监测方法、涉及的国家、研究人群、研究环境、随机分组方法以及每个干预组的人数和比例等数据。我们的主要结局是前瞻性干预研究中的关键和主要监测结果。监测结果根据不同的错误域进行分类（例如主要资格违规），主要结局指标是这些域的综合。次要结局是个别错误域、参与者招募和随访以及资源使用。如果我们为一个比较识别了多个研究，并且定义的结果相似，我们将使用随机效应模型对类似的比较进行定量汇总。否则，我们将根据不同的监测策略比较对合格研究进行定性总结。我们使用 GRADE 方法评估不同比较组的证据确定性。
我们确定了八项合格的研究，将其分为五个比较。1. 基于风险的监测与广泛的现场监测：基于两项大型研究，我们发现基于风险的监测并不逊于广泛的现场监测的主要或关键发现的综合结局具有中等确定性的证据。尽管风险比接近“无差异”（风险比为 1.03，95%置信区间为 0.81 至 1.33，低于 1.0 有利于基于风险的策略），但一项研究中的高不精确性和合格研究数量较少导致汇总估计的置信区间较宽。低确定性的证据表明，具有广泛现场监测的监测策略与相当高的资源使用和成本（高达 3.4 倍）相关。没有关于试验参与者招募或保留的数据。2. 中央监测与触发现场访问与常规现场访问：合并两项合格研究的结果得出，风险比为 1.83（95%置信区间为 0.51 至 6.55），有利于触发监测干预。没有关于招募、保留和资源使用的数据。3. 中央统计监测和由现场工作人员进行的年度现场监测与仅中央统计监测和监测：基于一项研究，发现没有现场访问的中央监测方法可能会错过少数主要和关键发现：在没有现场访问的组中有 3.8%的参与者和在有现场访问的组中有 6.4%的参与者有主要或关键监测发现（比值比为 1.7，95%置信区间为 1.1 至 2.7；P = 0.03）。监测结果的绝对数量非常低，可能是因为定义的主要和关键发现非常特定于研究，并且两种干预组都存在中央监测。非常低的确定性证据表明对参与者保留没有相关影响，并且现场访问的额外成本为 2035392 美元。没有关于招募的数据。4. 传统的 100%原始数据验证（SDV）与有针对性或远程 SDV：评估有针对性和远程 SDV 的两项研究仅报告了与原始文件相关的发现。与使用完整 SDV 监测过程获得的最终数据库相比，在 MONITORING 研究中，靶向 SDV 过程仅在总体数据中识别出一小部分剩余错误（绝对差异 1.47%，95%置信区间为 1.41%至 1.53%）。靶向 SDV 对源文件的验证有效，但增加了数据管理的工作量。另一项纳入的研究是一项试点研究，比较了传统的现场 SDV 与远程 SDV，尽管两个临床试验网络的远程访问存在明显差异，但在监测结果和定位数据值的能力方面差异不大。没有关于招募或保留的数据。5. 系统的现场启动访问与按需现场启动访问：非常低的确定性证据表明两种方法在保留和招募方面没有差异。没有关于关键和主要发现或资源使用的数据。
证据的数量和质量都有限。理想情况下，对于五个已确定的比较中的每一个，都需要更多前瞻性、比较性的监测研究嵌套在临床试验中，并衡量本综述中指定的所有结局的效果，以得出更可靠的结论。然而，基于风险、有针对性的、主要是中央监测的策略作为一种有效的策略的结果是有希望的。正在为现场访问开发可靠的触发因素；不同的触发因素可能在不同的环境中使用。需要更多关于可以识别存在问题的站点的风险指标或触发因素的预后价值的证据，以进一步优化中央监测策略。特别是，应该在未来的研究中评估具有在试验进行期间需要密切监测的特定试验风险的初始评估并伴有触发现场访问的方法。
