Trial monitoring

Example

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“As part of a risk-based monitoring strategy, all centres will be visited on-site or virtually after enrolment of the first 10–15 patients. Key data will be verified for 100% of patients. Trial sites will then be assessed as being either with or without noticeable findings with respect to the trial protocol, data quality and good clinical practice (GCP). Monitoring will be performed by the study centre at the site of the coordinating investigator at LMU Munich. The monitor (affiliated to the sponsor of the trial) reviews the eCRF [electronic case report form] for completeness and accuracy and instructs site personnel to make any required corrections. During monitoring visits, the monitor will ensure that data documented in the eCRF are in line with underlying source data. Sites without noticeable problems will receive no further on-site monitoring visits. Centres assessed as having noticeable problems will be visited again within 4 months. If problems persist, visits will be repeated three times per year, and key data will be verified for at least 50% of patients at the respective site. If no more findings occur, monitoring visits will no longer be required ”[463].

“Central monitoring

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A detailed monitoring plan will be developed. In summary, the CTU [Clinical Trials Unit] will closely monitor the trial to ensure the rights, safety, and wellbeing of the trial participants and to ensure the accuracy of the data. All coordinating centres and site trial teams will be trained in the trial procedures and provide extensive guidance. Central monitoring methods will be used by the CTU. A sample of consent forms from all sites will be monitored at the CTU to make sure they are properly completed. In addition, data management and statistical checks of data (central statistical monitoring) will be done to ensure that trial participants meet the inclusion criteria and trial treatment is administered in line with the protocol. Event rates for primary and secondary outcomes will be monitored. Sites with higher or lower than expected event rates will be selected for further monitoring. Quantitative variables (systolic blood pressure (SBP), heart rate (HR), respiratory rate and blood loss) will be monitored to check the accuracy of the data. For example, the coefficient of variation for the data at each site will be examined and those where there is any reason for concern will be selected for further monitoring.

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Monitoring at local site

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Onsite monitoring will be carried out at any site flagged as high risk on central statistical monitoring and other central monitoring procedures. Source data verification will be done on at least 10% of the trial data. Additionally, site self-monitoring will be carried out where needed. This will involve the PI [Principal investigator]/delegate at a site monitoring themselves against a standardised checklist. The LSHTM [London School of Hygiene and Tropical Medicine] CTU will require investigators and their institutions to provide access to source data and all trial-related documents for monitoring, audits, Ethics Committee review and regulatory inspection. All trial-related and source documents including medical records, original consent forms and original CRFs [case report forms] must be kept safely. Investigators must plan in advance of the trial start where the trial-related documents will be stored and how they will be accessed. All documents must be made available when required for monitoring/audit/inspection during the course of the trial and for up for 5 years after the end of the overall trial ” [464].

Explanation

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Clinical trial monitoring involves periodic review of core study processes, data, and documents by individuals not otherwise involved in site activities [465, 466]. It is distinct from routine day-to-day measures to promote data quality (Items 25a and 26). The purposes of trial monitoring are to support the well-being of participants, improve data quality, ensure the trial is conducted as planned, and stimulate corrective action to prevent problems [467]. The processes reviewed can relate to participant enrolment, consent, eligibility, and allocation to study groups; adherence to trial interventions and procedures to protect participants, including reporting of harms (Item 17); and completeness, accuracy, and timeliness of data collection.

Trial monitoring was addressed in 13% to 76% of protocols approved in 2016 or published in 2019–2020 [9-11, 468].

Some types of monitoring have stronger evidence for their benefits and efficiency than others. For example, central statistical monitoring has been shown to improve multiple indicators of data quality [469, 470]. New, decentralized monitoring options are also becoming more widely available [469].

In multicentre trials, monitoring can be performed using a variety of approaches applied centrally across all sites as well as to each site individually [471]. Trial data and processes can be reviewed remotely or by performing on-site visits. Rather than reviewing 100% of accumulating data and processes, it is widely recommended that trials adopt a risk-based approach to monitoring that focuses on the trial data and processes that are critical to study integrity, data validity, and participant well-being [46, 468]. Risk-based monitoring can also focus on sites that have, for example, the highest enrolment rates, large numbers of withdrawals, or atypical (low or high) numbers of adverse events.

The approaches (e.g., central, remote, on-site), scope of procedures, and anticipated frequency of monitoring should be outlined in the protocol, including a description of the personnel involved. If procedures are further detailed elsewhere (e.g., a monitoring plan), then the protocol should reference where the full details can be accessed. An explanation should be provided if no monitoring is planned. 

Summary of key elements to address

• Approach for monitoring (e.g., central, remote, on-site, risk-based)

• Scope of monitoring activities (e.g., type and amount of data at each site)

• Anticipated frequency of monitoring activities

• Who will be involved in monitoring

• Reference to where further details can be found (e.g., a monitoring plan)

If no monitoring is planned, this should be stated with reasons​​​