This guidance has been developed to assist those involved in clinical trials disrupted as a result of COVID-19. It is relevant to those involved with ongoing studies, those wishing to restart trials that have been paused or temporarily halted, and those wishing to start new studies.

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.

Managing ongoing and halted trials

The National Institute for Health Research (NIHR) issued a statement on 16 March 2020 stating that they were prioritising nationally sponsored COVID-19 research.

On 21 May 2020, NIHR set out a framework to guide the restarting of NIHR research activities which have been paused due to COVID-19.

Sponsors planning to restart trials or to initiate new clinical trials should take account of the principles described in the NIHR Restart Framework Document and the considerations set out in this guidance. Following a risk assessment, any risks to trial participants should be addressed in the benefit-risk section of the protocol along with risk mitigation measures.

Ongoing Trials – Host Organisation

The safety of the participant is the primary concern, and this must be ensured in any actions taken as the clinical site has a duty of care for the trial participants. A risk/benefit assessment on a trial by trial basis taking into account participant population, IMP mode of action, trial design etc. should be performed regarding continuation of the trial for both ongoing participants and recruitment of new participants.

In addition, Host Organisations should risk assess across trials.

Consideration should be given to the following possible actions

Halting Recruitment

Halt the recruitment of new participants immediately, unless the trial can continue to run without impacting on or being impacted by the COVID-19 pandemic.

Continue the trial but with different approaches to delivery

Continue the trial but reduce the burden of the trial on the host site by adopting different approaches to trial delivery, as described in this guidance. The ability to vary the conduct of trial activities will be dictated by the trial design and sponsor agreement prior to implementation.

Stop or suspend the trial

Withdraw participants from the trial and halt the trial temporarily (ensuring appropriate care of participants– e.g. prescribing alternative treatment via the GP.) This could be prioritised based on the length of participation and meeting the endpoint of the trial. For example, if sufficient data has already been gathered, or if a participant had just started, participation could be withdrawn as opposed to those who, if they remain in the trial for a little longer, could generate data to meet the trial objectives.

Where subjects are near to completion of their participation in the trial, consideration could be given to ensuring end of trial activities are completed as much as possible so that the participant’s trial data is as useful as possible. These could include final blood tests or assessments assuming that trial team availability permits this.

Putting risk mitigation in place

Where the risk assessment has determined that trials should continue, risk mitigation must be in place to address participants’ travel to site, ensuring the minimum number of subjects at the site at any one time to ensure social distancing (taking into account that participants may need to be accompanied by carers or legal guardians) and also that vulnerable participants are not visiting at the same time as other patient populations.

Where host sites have to make decisions about adapting or stopping trials, sponsors, should assist in the decision of whether any possible actions can be taken to adapt the trial (i.e. to reduce the burden on investigator sites). This should be done alongside the Chief Investigator and local trial teams.

It is important for sponsors to realise that access to staff, facilities and participants is likely to be severely impacted during this time. As a result the investigator may have no other choice than suspending the trial until the pandemic has passed and it is expected that the sponsor agrees to this.”

Where the trial can continue, routine follow-up and monitoring activities are likely to be impacted by investigator site staff availability or social distancing rules. Care should be taken to ensure that these are minimised to essential information only (e.g. primary endpoint data and safety reporting) until normal capacity resumes.

Where trials are being adapted, consideration should be given by the sponsor to continuing support for trial critical electronic systems such as Interactive Response Systems used for code-breaking and randomisation activities or safety reporting systems. Where these cannot be supported adequately then consider whether to continue to run the trial or put in place alternative mechanisms following discussion with us.

The sponsor should also ensure support in documenting protocol deviations due to adaptations and deal with any regulatory/ethics committee notifications/submissions as part of their oversight. For example, for temporary halts and restarts as per our guidance below.

It is likely that, following the pandemic, confirmation and evaluation of the investigator sites ability to recommence the study will be required along with the provision of any necessary retraining or revalidation of staff.

Submitting paperwork for trials which have been halted or are proposed to be restarted

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

Restart of the trial may require changes to the trial conduct, for example to participant monitoring or clinic visits as described below. 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 substantial changes do need to be made, for example to protect participant safety or data integrity moving forward then this should be submitted as a substantial amendment in the normal way. If a substantial amendment has been approved to halt the trial then another to restart will always be necessary.

If the sponsor decides not to recommence a halted trial, they should notify us via an End of Trial declaration form within 15 days of the decision.

Management of COVID-19 vaccination for subjects participating in ongoing non-COVID-19 clinical trials

This includes healthy volunteer trials for future indications that include COVID-19.

Sponsors for ongoing clinical trials for indications other than treatment or prophylaxis of COVID-19 are required to evaluate the impact of the current government programme for deployment of a COVID-19 vaccine on each trial they are responsible for. Separate guidance for COVID-19 vaccine trials is being agreed with each research team.

The Sponsor should conduct a specific risk assessment for concomitant use of a COVID-19 vaccine for each investigational medicinal product (IMP) and with specific consideration for the trial population. Some trials may also need to consider risk assessment for non-IMPs and/or combinations.

If the outcome of the risk assessment is that a COVID-19 vaccine given to a trial subject is considered as a simple concomitant medication with no interaction that requires advice on timing of the vaccine or other aspects, then the Sponsor should inform the MHRA in the next substantial amendment (as a non-substantial update).
If the risk assessment highlights potential issues that need to be mitigated for (for example, trials with immunosuppressive elements or immune related mechanisms, infection aspects or in a high risk population) then a substantial amendment to the MHRA and Research Ethics Committee (REC) is required.
The trial participant must continue to receive the deployed vaccine as planned regardless of whether the Sponsor has submitted a substantial amendment for regulatory approval (it is however important that the Sponsor submits the latter as soon as possible). There must be evidence in the patient records that the patient is aware of any risks and how these will be mitigated for and if necessary the trial participant may withdraw from the trial.

Points to consider in the risk assessment

These may include some or all of the following, as well as other trial/IMP specific elements. In addition, unless the REC has explicitly agreed a rationale for not informing GPs about study participation, it is appropriate to share information about vaccine implications of studies with GPs for safety reasons.

For blinded trials:
- It is important to consider whether subjects would require unblinding to be able to receive a COVID-19 vaccine. Whilst subjects may be unblinded on an individual basis, they should be encouraged to remain in a trial to continue to be evaluated for all evaluable trial endpoints. They should ideally not be withdrawn, unless they explicitly request this.
- REC approved information should be given to participants telling them to contact the trial team when they receive an invitation to receive a deployed vaccine. Unblinding should be delayed until this time and should follow a discussion with that participant to ensure they are fully informed. For clarification, the regulators concern is that trial participants must have the ability to contact the trial team when they receive an invitation to receive a deployed vaccine. The trial participant must have a clear, accessible process available to them to be able to contact the study team and for that information to be passed on to the sponsor.
- To allow for a baseline consideration prior to receipt of a deployed vaccine, all subjects who are unblinded and wish to receive a deployed vaccine must have an “end of study/treatment” visit. This should be aligned with the protocol visit assessments done when a subject is discontinued early and is to ensure that they have a complete status before they become unevaluable for the trial arm they were in. If this is not logistically possible then the aim should be to do this for as many subjects as possible.
Details of the deployed vaccine should be recorded in the medical notes and study visits should continue as planned if possible and appropriate.
If there are potential interactions between a COVID-19 vaccine and the IMP, or other potential subject risks such as immunosuppression, the protocol must include consideration for the specific safety profile of the vaccine and whether a minimum time period between any dose of trial IMP and dosing with a deployed vaccine must be in place. An appropriate risk benefit discussion must be provided.
The protocol must also consider how safety reporting will be conducted for causality, particularly if the IMP and COVID-19 vaccine have an overlapping safety profile. The COVID vaccine will not be an IMP and therefore the MHRA Yellow Card system is appropriate for reporting any AEs or suspected ADR. However, if an AE is considered to be the result of an interaction with an IMP in the trial then the clinical trial pharmacovigilance rules should be followed. If the event is serious and considered related to both the COVID vaccine and the trial IMP(s) then it becomes a serious adverse reaction. Expectedness must be assessed and SUSAR reporting will be initiated if the serious adverse reaction is unexpected.
The statistical plan should be updated accordingly, for example by censoring subjects in the analysis at the time of their vaccination. Additional exploratory analyses could also be included.

It should be noted that there is no MHRA position that states that trial participants must receive COVID-19 vaccination as an eligibility criterion. There is also no MHRA position that if vaccination was required and had been justified as an eligibility criterion that one COVID-19 vaccine would be preferred over another in order to take part in any clinical trial. This would be a decision for the sponsor when they design the trial and any such position must be clearly justified.

For new trials, Sponsors are encouraged to address potential vaccination upfront in their protocol and build in appropriate flexibilities in order to avoid the need for substantial amendments at a later stage. Please see our Guidance on minimising disruptions to the conduct and integrity of clinical trials of medicines during COVID-19 for further details. The points above should also be considered.

Providing investigational medicinal product (IMP) to trial participants

If a trial participant cannot attend a trial site, then delivery of IMP to a participant’s home is acceptable and no substantial amendment notification to the MHRA will be required. This applies to supply from the trial site or directly from the sponsor.

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:

Storage requirements:

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 shelf life 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.

Medicine accountability

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.

Accountability of Investigational Medicinal Products (IMP)

If COVID-19 related issues affect the ability of the investigator or institution to perform IMP accountability, then a risk assessment needs to be undertaken. If accountability is not critical, then the drug can be destroyed instead of being returned to minimise exposure to the virus. The sponsor should be involved in this decision.

If accountability is important, the sponsor should consider whether there are other ways this can be achieved whilst mitigating risks to virus exposure. For example, asking the participants to make a count, or submit a photograph.

If the reconciliation is critical (eg for controlled drugs) and needs to be done by the site or sponsor staff, then this would need to be handled appropriately. A risk-based approach should be taken for example conducting in an environment specialised for this or put in quarantine for some time so that virus on packaging is no longer viable (based on research literature review).

If additional resources are required to manage potentially contaminated IMPs then this should be managed by the sponsor. For example, the sponsor may make arrangements for collection and management of returns under these circumstances.

Remote monitoring for trials

We support remote monitoring where appropriate but consider the following when undertaking remote source data review/verification.

During the pandemic, the need for remote access to the health records of trial participants is necessary for monitoring (or auditing) activities to continue for the protection of participant safety and reliability of the results. Guidance for the expectations of remote access to the medical records has been published by the MHRA. It is recognised that making changes to EHR systems may be complex and costly, and there may be a wide range of change requests that NHS organisations need to prioritise above access by Monitors (or Auditors). In all situations where the full expectations of EHRs are not yet in place and short-term mitigations have to be relied upon during the pandemic, it is important for the sponsor to recognise the legal responsibilities and liabilities that apply to them.

Short-term mitigations should focus on setting clear expectations on Monitors (or Auditors) through reliance on the contractual measures set out in the model agreements. Measures should be put in place to allow adherence to the requirements below to be verified retrospectively as part of a quality assurance system.

Where read-only user role is not a feature of the EHR system, there is a risk that Monitors (or Auditors) could enter/edit/delete data or information in the EHR system. It should be noted that this risk exists with paper medical records. A short-term mitigation would be for the site to establish a programme of checks for inappropriate amendments to the EHR system following the monitoring (or auditing) review activity.
Where two-factor remote Log-in access to the EHR system is not a feature of the system, there is a risk of inappropriate access to the EHR system. An alternative approach would be for the remote Monitor (or Auditor) to use video contact with the site to confirm identity and their intention to log into the EHR system prior to each monitoring (or auditing) review time period. Records of such contact (including evidence of date and time) should be retained and reconciled with audit trail review to confirm compliance following the monitoring (or auditing) review activity taking place.
Where functionality for an automatic time-out facility is not yet in place, there is a risk of inappropriate Log-in Access to the EHR system. The user should log out of the EHR system when access is not required and before leaving the device used for logging into the EHR system unattended. Sponsors should implement password locks with short time-outs to all devices used by Monitors (or Auditors) for remote Log-in Access to EHR system, so that unattended devices cannot be used to access EHR systems.
Where the EHR system does not have the ability to restrict printing, copying and/or downloading of information from the EHR system, there is a greater risk of confidential participant information being retained by the Monitor (or Auditor ) via remote working, as access to printers and copiers at site can be restricted. For remote Log-in Access to the EHR system by the Monitor (or Auditor) to occur, robust documented training should be provided by (or on behalf of) the sponsor to the Monitor (or Auditor) regarding the importance of this requirement. The audit trail of the EHR system must log such actions and be reviewed following the remote Log-in Access to identify inappropriate activity (printing, copying, or downloading).
Where the EHR system has not got functionality for date and time-restricted Log-in Access, there is an increased risk of inappropriate access. A short-term mitigation would be for the site to enable Log-in Access at the start of the scheduled monitoring (or auditing) review activity and revoke the Log-in Access at the end of the scheduled review time period. The ability of the system administrators to undertake this effectively should be initially assessed and subsequently monitored. Audit trails should be able to demonstrate when Log-in Access has been given and revoked and regularly reviewed.

Please refer to the MHRA blog, the HRA blog and the MHRA GCP Forum FAQs on monitoring/remote monitoring for further guidance.

Changes to the number and type of participant monitoring visits

Using phone calls instead of protocol-directed in-person study visits is acceptable where possible, on a temporary basis for as long as the outbreak renders in-person visits impossible. This will not constitute a serious breach of the protocol.

A substantial amendment to update the protocol will not be required. It is expected that appropriate simultaneous documentation of the phone call is kept to support the remote visit as this will constitute source data.

If participant monitoring visits need to be reduced due to COVID-19, measures should be put in place to manage the risks while protecting the safety of trial participants. For example, site visits can be replaced with video-calls or phone calls and laboratory tests can be performed at a local lab. These mitigations will not constitute a substantial amendment for authorisation. If it is not possible to ensure adequate monitoring of the trial participants, the benefit-risk balance of the trial should be revisited and any additional measures discussed with the MHRA prior to submission of a substantial amendment for authorisation.

‘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), suspected unexpected serious adverse reactions (SUSARs), and submission of annual safety reports (DSURs)

Timely reporting of SAEs from investigators to sponsors and of SUSARs from sponsors to the competent authority is paramount in protecting the safety of participants. It is important that sponsors continue to report via the established routes for clinical trials and not via the Yellow Card route.

We expect regulatory timelines for reporting to continue to be met. Sponsors who plan to introduce changes to safety recording and reporting procedures are invited to contact us.

They should do this by email to clintrialhelpline@mhra.gov.uk with the subject ‘Safety recording/reporting’. The email should discuss the impact of the changes on the benefit-risk balance of the trial as well as the strategies to mitigate the potential risks introduced by the changes.

Provision of the annual list of suspected serious adverse reactions and safety report (DSUR) is expected as soon as practicable after the end of the reporting year, as per current legislation. If the DSUR is to be delayed, you do not need to inform us, but please provide a rationale in the covering letter once the DSUR is submitted.. An existing flexibility on the format of the DSUR is available for Notification scheme applications and Phase 4 (UK only) trials of licensed products, where all participants have completed treatment and are in follow-up. Further information is provided in our blog.

For lower-risk trials, sponsors are encouraged to use a risk adapted approach to trial management. If your trial fits into a ‘Type A’ category trial, then you may wish to consider submitting a substantial amendment to address risk adaptions, if appropriate. Please refer to existing guidance .

Risk adaption of safety reporting is acceptable, and MHRA have produced guidance on this along with some examples of real-life risk assessments:

Risk Adapative Approach

Examples of risk assessments

Where adverse event expectedness assessments have been delegated to investigators at clinical sites, this should be reconsidered where possible to alleviate the burden on front line staff. It should be determined if this assessment can be made by the sponsor upon receipt of the SAE. Expectedness is not a medical decision and should be based on the approved Reference Safety Information (RSI) for the trial. This change would not require prior authorisation by the MHRA.

SAEs can be reported to the sponsor initially via a telephone call, followed by a written report at a later date. Therefore the sponsor may consider alternative mechanisms for investigators onwards reporting of SAEs, such as email or telephone calls in order to reduce administrative burden on sites. However, it is important that the sponsor ensures the minimum reportable information has been provided. sponsors should ensure they have processes in place to receive this information in alternative formats to those agreed for the trial (e.g. eCRF or fax) and communicate this to the investigator sites.

In order to ensure that sites are not put under undue pressure, the sponsor should consider processes to integrate data received from emails into the clinical and safety database, whilst ensuring data integrity. The sponsor should not require the site staff to perform data entry of information that has previously been reported to the sponsor in a different format.

Changes to the way SAEs are reported to the sponsor and to data entry do not require submission of a substantial amendment.

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).

Protocol waivers

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 participants 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 discontinuing that subject must be considered.

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.

Urgent Safety Measures

Urgent Safety Measures (USM) may be taken to protect the participants of a clinical trial against any immediate hazard to their health or safety. By definition, these are implemented prior to regulatory authorisation and notification of the measures taken needs to be made to the MHRA and the relevant ethics committee. Since 16 November 2021, the notification of USMs to the MHRA should be performed following the standard procedure for USMs notifications as detailed here: Urgent Safety Measures

If a substantial amendment to the trial documentation needs to be made as a result of the USM, this should be submitted within approximately two weeks of notification to the MHRA.

Pre-planned changes to the trial conduct as a result of COVID-19, such as changes to scheduling or delivery of IMPs to participants are not USMs. These may be treated as protocol deviations as described above and investigators informed via Dear Investigator Letters. If a sponsor chooses to update their protocol as a result of the COVID-19 issues outlined above, then these may be handled as non-substantial amendments if judged so by the sponsor. Any subsequent substantial amendment submitted for authorisation should include clear details of the non-substantial amendments implemented as a result of COVID-19 related issues.

Participant safety

The safety of trial participants is of course our highest priority. Sponsors should consider the risk/benefit of conducting trials with medicines that act as immunosuppressants, both in early phase healthy volunteer trials where there is no direct therapeutic benefit to the volunteer, as well as later phase trials in patients, as taking part in the trials does pose a risk of infection.

Signatures

A request for a clinical trial authorisation (“Annex 1” form) is required to be signed by or on behalf of the sponsor. This signature does not need to be wet-ink and an electronic signature is acceptable. This can be a scanned electronic signature.

Alternatively, the IRAS/MHRA Submissions User ID can be used in the ‘signature’ field of the application form if the ID is issued to an individual person and this person is authorised by the sponsor to sign the application on their behalf.

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 clintrialhelpline@mhra.gov.uk 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.

MHRA guidance on coronavirus (COVID-19)

Managing clinical trials during Coronavirus (COVID-19)