How investigators and sponsors should manage clinical trials during COVID-19
This guidance advises those involved in clinical trials on specific issues which may arise as a result of COVID-19, and what they are required to do.
We have separate guidance on Clinical trials applications for Coronavirus (COVID-19).
This includes specific information on participating in clinical trials.
The MHRA will be as flexible and pragmatic as possible with regard to regulatory requirements for clinical trials during this time. We recognise that clinical trial resource may be absent or redeployed from research activities and regulatory affairs towards front-line care.
The first priority should be the safety of trial participants and this will remain our focus.
This guidance will be updated as the situation changes over time.
Submitting paperwork for trials which have been halted
If your trial has been halted due to issues related to COVID-19, you will not normally need to inform us.
The trial master file should include a note that the trial was halted and the reason.
If a halt is due to either of the below scenarios however, you do need to inform us:
- A direct participant safety issue, especially if there is the potential to impact other trials; please inform us in the normal way
- A medicines supply issue, as we can escalate this to DHSC. Inform us of this directly by phone or email rather than an amendment form
Restarting a trial after it has been halted
If the restart of the study does not involve any substantial changes to the Clinical Trial Authorisation (CTA), then a substantial amendment notification to MHRA will not be necessary. If changes do need to be made to protect participant safety moving forward, then this should be submitted as a substantial amendment in the normal way.
Providing investigational medicinal product (IMP) to trial participants
If a trial volunteer cannot attend a trial site, then delivery of IMP to a patient’s home is acceptable and no substantial amendment notification to the MHRA will be required.
Sponsors should do a risk-assessment and record this internally.
Participants must consent verbally (and this should be documented in their notes) to providing contact details for shipping purposes. If the participant does not want to sign for the delivery due to self-isolation, then a follow up phone call could be used to confirm they have received the package. The sponsor should also consider if any training is required for administration of the IMP.
The following factors need to be taken into consideration if providing an IMP to a participant at home:
- whether the medicine has any specific storage requirements, and how those are managed during posting
- What assurance can be given about the integrity of the product during transit, for example should a temperature monitoring device be used
- The stability of the product and margin of safety: for example a product with a very stable profile at temperature extremes would require less monitoring than one with a narrow stability range. The expiry of the product may need to be shortened if is delivered in ambient temperature
Delays in posting
This will depend on the trial, but it is worth considering if there is potential to affect continuity of supply. Shortage of the medicine may be crucial for some trials but not others.
- The mechanism for confirming that the subjects have received the IMP, and it has not been delivered to someone else
- Whether the medicine needs to be signed for and sent by courier or recorded delivery
- Whether there needs to be a follow-up call to the subject
The HRA has provided guidance on this topic.
Remote monitoring for trials
We support remote monitoring where appropriate but consider the following:
- Direct access to patients EHR (Electronic Health Record) away from the site creates issues around confidentiality. Consider where this access takes place, for example will CRAs (Clinical Research Associates) be accessing records in an open plan office, public space or other location where others who are not authorised could view sensitive information
- Trial participants will need to consent to any identifiers leaving the site and be assured that their confidentiality will be protected
- It is likely that there will be increased pressures on clinical staff during this period, so it is important to make sure that extra burdens are not placed on investigators around scanning and uploading many documents.
- The use of alternative means of oversight such as teleconferences/videoconferences is encouraged
Replacing in-person visits with phone calls
Using phone calls instead of protocol-directed in-person study visits is acceptable where possible. This will not constitute a serious breach of the protocol. A substantial amendment to update the protocol will not be required. We would however expect that any protocol deviations are well documented internally.
Reducing the number of participant monitoring visits
CT-1 guidance does regard a reduction in the number of monitoring visits as a substantial amendment.
If participant monitoring visits need to be reduced due to COVID-19, this will not require a substantial amendment. However, do please ensure that your risk assessment and rationale is appropriately documented.
‘Dear Investigator’ Letters
During the COVID -19 pandemic it is acknowledged that Sponsors may need to send ‘Dear Investigator’ Letters to inform investigator sites of changes to trial conduct. These do not require regulatory oversight and should not be submitted to the MHRA.
Reporting of serious adverse events (SAEs), and submission of annual safety reports (DSURs) and end of trial notifications
We appreciate that capacity issues related to COVID-19 may prevent timely reporting. If this occurs, report this as soon as possible after the capacity issue is resolved.
Deviation from protocol defined timelines in this case does not require a substantial amendment to MHRA.
Particular attention should be paid to timely reporting of suspected unexpected serious adverse reactions (SUSARs) which put participant safety at risk on a trial or have the potential to impact participants of other trials. Every effort should be made to notify MHRA in this case.
Protocol deviations and serious breaches
Patients may be advised to stay away from hospitals and GP sites due to existing health problems that may put them at risk of infection, or they may be reluctant to travel to sites where there are high densities of people.
They may also have been advised to self-isolate as a precaution or as a result of confirmed infection so are unable to undertake required clinical trial activities.
There will therefore be an increase in protocol deviations. Please ensure they are well documented, to enable appropriate evaluation for the trial.
An increase in protocol deviations in relation to coronavirus will not constitute a serious breach, therefore there is no need to report this to us (unless of course patients are being put at risk).
Prospective protocol waivers remain unacceptable. We would not expect you to bypass the eligibility process due to difficulties in assessing subjects and carrying out tests.
Safety of patients remains a priority and they should not be included into a trial unless you can confirm they meet the inclusion and exclusion criteria.
Similarly, if the safety of a trial subject is at risk because they cannot complete key evaluations or adhere to critical mitigation steps, then consideration to discontinuing that subject must be discussed.
This may also extend to the whole trial in some cases, and a Sponsor and Investigator should remember they can use Urgent Safety Measures, or even temporarily halt a trial, or halt recruitment, if this is the best way forward.
Subject safety is of course our highest priority. Sponsors should consider the risk/benefit of conducting trials in medicines that act as immunosuppressants, for example in early phase healthy volunteer trials, where there is no therapeutic benefit to the volunteer, but taking part in the trials does pose a risk of infection.
If your processes require wet-ink signatures, consider alternative methods of demonstrating approvals, such as email confirmation.
Inspectors will take a pragmatic approach to this, but you may want to consider an SOP deviation to cover this in the interim.
Help from the MHRA
If you have any questions then do contact the Clinical Trials Unit Helpline email@example.com or 020 3080 6456. The Helpline will give inquiries relating to COVID19 the highest priority, including the possibility for fast-tracking submissions.
HRA (Health Research Authority) also have guidance on research in a public health emergency.