Monitoring strategies for clinical intervention studies

Background 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 eJectiveness 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 eJectively adjust their approaches to current knowledge and evidence. Objectives To evaluate the advantages and disadvantages of diJerent monitoring strategies (including risk-based strategies and others) for clinical intervention studies examined in prospective comparative studies of monitoring interventions. Search methods 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We searched the online 'Studies within A Trial' (SWAT) repository, grey literature, and trial registries for ongoing or unpublished studies. Selection criteria We included randomized or non-randomized prospective, empirical evaluation studies of diJerent monitoring strategies in one or more clinical intervention studies. We applied no restrictions for language or date of publication. Data collection and analysis 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 diJerent 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 eJects in a meta-analysis using a random-eJects model. Otherwise, we qualitatively summarized the results of eligible studies stratified by diJerent comparisons of monitoring strategies. We used the GRADE approach to assess the certainty of the evidence for diJerent groups of comparisons. Main results 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 diJerence' (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 sta1 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 eJect 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 diJerence 1.47%, 95% CI 1.41% to 1.53%). Targeted SDV was eJective 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 diJerence in monitoring findings and the ability to locate data values despite marked diJerences 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 diJerence 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 eJects 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 eJicient strategy are promising. The development of reliable triggers for on-site visits is ongoing; diJerent triggers might be used in diJerent 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.