GCP states that ‘monitoring’ is the act of overseeing the progress of a clinical trial and of ensuring that it is conducted, recorded and reported in accordance with the protocol, with GCP and with the applicable regulatory requirements.
Within the monitoring of academic clinical trials, a risk proportionate model to monitoring is recommended. This is already well defined and adapted for clinical trials of investigational medicinal products (see here).
The risk adapted approach has been adopted as many academic clinical trials pose only a minimal additional risk to patient safety as compared to normal clinical practice. This risk-adapted approach to the design and conduct of clinical trials includes monitoring. The type of monitoring to be utilised in a trial depends upon the risks in the particular trial. There are two main approaches to monitoring:
- On-site monitoring
- Central or remote monitoring
A Risk Assessment should be completed at the start of a clinical trial to identify the risks associated with the trial. For each risk identified, mitigation strategies should be implemented to mitigate or manage that risk.
The Risk Assessment will:
- Determine the monitoring strategy for the trial
- Determine a monitoring approach which is proportionate
- Formalise the approach in a monitoring plan
The associated monitoring plan will:
- Be specific to the risks of the trial
- Describe the monitoring strategy
- Detail the monitoring methods to be used and the rationale for them
Who will perform the monitoring?
- On-site monitoring of international sites can be expensive both in terms of financial cost and staff resources.
- At trial set-up when the monitoring plan is being written, consider whether or not it is feasible for a UK-based coordinating centre to visit all international sites in person to perform on-site monitoring.
- Is there a possibility for local institutions to perform monitoring?
- Could the monitoring responsibilities be delegated to an independent team at site or local R&D or CRO if resources are available?
Language
- If English is not the first language of the international site, how will the site be monitored?
- How will monitoring occur at sites where the staff does not speak English?
- Or if the patient notes are not written in English??
Access to patient records and notes
- How will patient records and CRFs be accessed at the time of the monitoring visit?
- Who will organise this access? Can access be limited to just trial patients?
- If there are multiple systems in place for recording of patient data, will monitors have access to all systems?
Access to hospitals
- If the site to be monitored is in a remote area, how will transport to the site be organised?
- UK university staff travelling on university business must register travel plans with the university and must obtain university insurance. Universities may not provide insurance for staff to travel to some collaborating countries. How will monitoring be conducted at these sites?
Pre-monitoring preparation
- Consider the experience of the site to be monitored. Prepare the site in advance for the monitoring visit by explaining the purpose of the visit, the monitoring plan for the visit, discuss the practicalities of the visit.
Timing of un-triggered monitoring visits and costs.
- As the monitoring of international sites may be expensive, consider if the CAPA for any findings could be implemented on-site at the time of the visit.
- Is it possible to combine multiple monitoring visits into a single trip? For example, does the site run more than one trial which requires on-site monitoring?
- Could the monitoring visit be used to provide additional site training? Or conduct a site visit at another hospital?
The coordinating centre for the trial should routinely perform central monitoring. Central monitoring is a widely adopted strategy in academic led trials and is especially useful in large international trials where sites may be spread across the world. The processes for central monitoring are well documented, this section will provide some considerations for international surgery trials.
Considerations for central monitoring:
Communication
Central monitoring depends on excellent communication between the coordinating centre and the sites. Good working relationships must be established between the coordinating centre and the site. The best method for communication should be found, and consider additional options of WhatsApp, Skype, for example.
A process should be in place to ensure that the coordinating centre is promptly informed of any key staff changes.
Trial documentation
Many different types of trial documentation can be used to facilitate central monitoring. Examples include consent forms, laboratory reports, delegation logs, essential document checklist for the Trial Master File (TMF) or Investigator Site File (ISF) for sites, training logs etc.
Produce templates for all of trial documents and try to encourage collaborating countries to use them. This may be more challenging in a Hub and Spoke model but will make central monitoring easier and more effective.
Legislative requirements
Central monitoring may reply on the review of documentation containing patient identifying information. In international trials, where central monitoring is conducted outside of the collaborating country, there must be processes in place to ensure that central monitoring adheres to the General Data Protection Regulations (if in UK) and any country-specific data protection laws. Patients must be asked for consent to permit their data to be monitored by the Sponsor or another institution if central monitoring of this type is to be used.
Training
In some international trials, the experience of the collaborators in participation in RCTs may vary considerably. An overview of and the requirements for central monitoring should be clearly explained; this may be part of the SIV or form standalone training.
Oversight committees are a key component of a monitoring strategy in academic clinical trials.
The funder or Sponsor may specify particular oversight arrangements. But even if they do not, some form of oversight is strongly recommended for all trials, although the appropriate structures will vary according to the size, complexity and risks associated with the trial.
The oversight committees which may be formed as part of academic clinical trials are:
- Data Monitoring Committee (DMC)
- Trial Steering Committee (TSC)
- Trial Management Group (TMG)
Data Monitoring Committee
A DMC should be ‘considered’ for all trials, although it may not always be necessary. The DMC is a group of independent experts which is established to review the accumulating data from an ongoing clinical trial. The main remit of the DMC is to provide an ongoing review of the safety aspects of the trial. The DMC will recommend to the Trial Steering Committee (and TMG) whether to continue, modify, or stop a trial and to assess whether there are any safety issues that should be brought to participants’ attention.
Trial Steering Committee
The role of a TSC is to provide overall supervision of the trial and ensure that it is being conducted in accordance with the principles of GCP and the relevant regulations.
The TSC should agree the trial’s protocol and any protocol amendments and provide advice to the participating investigators on all aspects of the trial. The TSC monitors the progress of the trial, including recruitment, data completeness and losses to follow-up and ensures that there are no major deviations from the trial protocol.
A TSC should have members who are independent of the investigators; and an independent chairperson in particular.
Considerations for Oversight Committees
- The membership of international trial oversight committees should be well considered. Members with experience in international trials would be beneficial.
- Oversight committees should be made aware that the clinical trial regulatory environment and infrastructure may differ in international collaborating sites.
- As is for UK trials, oversight committees for international trials should adhere to a trial-specific charter. For DMCs, this can be based on the DAMOCLES Charter.
- International regulatory bodies may ask for the names and/or terms of reference of the independent oversight committees. The committees, as per the UK, should be set up in at the start of the trial and well in advance of site opening and patient recruitment.
Trial Management Committee
Every trial should have a TMG. For larger studies, this normally includes individuals who are responsible for the day to day management of the trial (e.g. the Chief Investigator (CI), Trial Manager, statistician, other clinicians, trial-specific research nurse).
The role of the TMG is to monitor the conduct and progress of the trial, ensure that the protocol is adhered to and take appropriate action to safeguard participants and the quality of the data. The group should meet regularly.
Considerations for TMGs of international trials- International collaborators should be represented on the TMG.
- The Terms of Reference of the TMG should be defined and clarified at the first meeting of the TMG. This should include the roles and responsibilities of the committee.
- If the collaborative model of the trial involves a “Hub and Spoke” model, with a UK sponsor and with responsibilities delegated to Hubs from the sponsor, consider establishing country-specific TMGs.
- If country-specific TMGs are established, consider supplying the country-specific TMG with template documents such as:
- Terms of Reference which defines remit, timing and frequency of meetings, membership, meeting frequency, decision making.
- TMG progress report.
- Country-specific TMGs could be asked to provide regular updates to the International TMG. This may be in the form of a standardised progress report. Minutes from the country-specific TMG may also be requested. This provides additional oversight.