Whilst COVID-19 has affected / is still affecting all our day to day lives we need to remember the greatest impact has been and still is in hospitals and our health service. All of us have heard about the risk/benefit ratio for a trial, now we need to take that to the next level, based on the current situation.
We should not forget that even in the midst of COVID-19, many patients are seeing benefits from clinical trials and their health greatly depend on these trials continuing. On the other hand, logistics of drug supply, investigator/nurse availability and site priorities, in conjunction with country regulations, all play a key part in whether to continue with the clinical trial, suspend new recruitment or close the trial altogether.
All countries are providing individual guidance on the situation and how to proceed in terms of progressing non COVID-19 trials but there is one thing each and every country is agreed on and that is that the safety of the patient is paramount.
In line with the EMA guidance issued on 20 March 2020, 27 March 2020 and 28 April 2020 , risk assessments should be made for each ongoing clinical trial:
Initiating new trials
The feasibility of starting a new clinical trial or including new trial participants in an ongoing trial should be critically assessed by sponsors.
Changes in ongoing trials
The sponsors should consider in their risk assessment whether the following measures could be the most appropriate during COVID-19. Measures should generally be agreed with investigators and could be:
- Conversion of physical visits into phone or video visits, postponement or complete cancellation of visits to ensure that only strictly necessary visits are performed at sites;
- A temporary halt of the trial at some or all trial sites;
- Suspension or slowing down of recruitment of new trial participants;
- Extension of the duration of the trial;
- Postponement of trials or activation of sites that have not yet been initiated;
PRA Global Clinical Delivery have released internal guidance on remote monitoring and remote source data verification along side a regulatory regulations tracker ,created in conjunction with our local country teams. This allows us to closely monitor what is happening in each country that we support with the information available to all our operational teams. This information is checked in line with the protocol, ICF, clinical monitoring plan and of course sites, as what in principal may be allowed at a country level does not always translate to a site level and in turn site agreement. Any impact on studies is discussed in the study team, with the sponsor and with the sites.
Remote/Off site monitoring can be conducted to ensure that rights and well-being of subjects are protected, reported data are collected and entered in a timely manner and site confirms source documents meet ALCOA-C/CCEA requirements. In addition these visits ensure that trials are conducted in compliance with protocol, ICH GCP, SOPs and applicable regulatory requirements, and that the site continues to be acceptable to conduct the trial. Please note remote monitoring visits do not require sites to send source documents or have any component of source data verification (SDV) during the visit and although not an exclusive list, the expectation is that that following type of checks would be made in such a visit:
1. Confirm the status of patients
2. If ICF for safety update has been released since last visit, confirm that all applicable subjects have signed.
3. Any new staff that require protocol training that are responsible for evaluation of safety and endpoints.
4. IP status
5. Critical open follow up items
6. Data flow
The majority of countries will allow this with very few requiring submissions or updates to submission documentation to Ethics or Regulatory Agencies (RAs).
Remote SDV (RSDV) is classified as Highly Restricted Data (PRA Data Governance Policy) and is sensitive by nature as Special Categories of Data, under General Data Protection Regulation (GDPR) and other data privacy legislation, therefore, security measures are mandatory.
Before COVID-19, if RSDV was allowed per country regulation, there was likely an update to ICF and submission to Ethics, required, however Ethics and/or RAs are updating guidance on this daily, so documentation at site and/or in patients source notes may be sufficient in some countries during the pandemic.
In their updated guidance dated 28 April 2020, EMA highlighted that RSDV is only considered necessary for very few trials in line with national law or temporary national emergency measures and Principal Investigators should determine whether the conditions at their site allow any of the following options:
- Sharing pseudonymized copies of trial related source documents with the monitor, this may be done electronically where manageable by the site staff
- Direct, suitably controlled remote access to trial participants’ electronic medical records;
- Video review of medical records with clinical site team support, without sending any copy to the monitor and without the monitor recording images during the review.
Although the monitoring plans are usually driven by the Clinical teams, because the regulatory guidance is changing at a country level every day, we must ensure that any planned changes to monitoring are checked internally with all applicable functional leads, including global and local regulatory experts in country.
Remember every trial, protocol, sponsor and site is unique, so each trial will need to be considered independently.