COVID-19 – regulatory guidance documents

Update as at 30 April 2020

Essential Steps for all Clinical Trial Related Decisions in the Covid-19 situation – this includes decisions to continue ongoing trials.


MHRA Blog:


This guidance was updated on 22 April and update covers:

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. There should be explicit instructions from the sponsor and the host organisation (with input from their Caldicott Guardian) as to what can be accessed where and an agreement from the CRAs that this will be complied with. Access from home can be acceptable, provided that there is somewhere private that this can be done, away from family etc. The device through which this is accessed must have adequate security, such as adequate firewalls, secure log-in and passwords etc, and must not be left unattended and accessible. The instructions should not allow printing, emailing or downloading of any records, or that this is disabled by the system.

  • 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”

The MHRA guidance is not clear on whether remote SDV constitutes a substantial amendment or not, but the EMA guidance below says it is.

Additional quote from MHRA guidance: “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.”

SAE reporting – additional guidance

“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.”


MHRA seem to be sticking with the 3 day reporting rule, but I would think in this case that UK SI 2009 No. 1164 applies and the 3 day reporting requirement should be replaced with “as soon as possible”

If a substantial amendment is needed as a result of a USM there’s a 28 day grace period for submission.

“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.”


There’s a new bit about use of electronic signatures for CTAs.

HRA Guidance:


EMA Guidance – version 3 issued 28 April 2020:

Update covers: distributor to trial participant IMP shipment, monitoring, remote source data verification and communication with authorities

Chapter 6 – Communication with Authorities

The latest changes include:

Categorisation of actions into 3 possible categories:

USM – not required to notify prior to implementations, but CA and EC to be notified ASAP, although it is recognised that this might take longer than usual

Substantial Amendment – must be notified and approved prior to implementation. Avoid overreporting.

Other changes related to Covid-19 situation (non-substantial amendments, though it doesn’t use this term) to be notified as soon as possible – submit a list of all changes with Risk assessment, justification and follow up actions. Cumulative changes must not impact subject safety or data integrity.

Mark all communication with Covid-19 clearly in subject line.

There’s also a list of examples of the 3 categories.

Chapter 9 – changes to distribution of IMP

This also includes Non-IMP

Main change in this version is with regard to sending IMP directly to participants.  If possible this should be done from the investigational sites, but in some circumstances it can be done directly from distributors. There’s quite a bit of detail about this, so I recommend reading the guidance if you plan to do this.

Chapter 11 – Monitoring

Remote SDV – this is considered suitable only for a very few trials and is considered a substantial amendment – therefore should be approved as such before implementation.

“Investigators should not be put under undue pressure to accept remote SDV and should always give priority to the care to be given to trial participants and other patients”

Annex 1 – Protection of trial participants’ rights during remote source data verification

Need to review this information if you are planning to implement remote SDV.


FDA Guidance – Updated on 16th April 2020:

Update is an addition of a Q&A appendix giving more specific advice on particular aspects of the guidance.  The Questions cover various topics including:

  • Factors to consider when making clinical trial decisions relating to Covid-19
  • IMP issues – administration and supply
  • Protocol deviations and amendments and their submission to FDA and IRBs
  • Remote patient visits
  • Changes to monitoring – delays and remote monitoring
  • Informed consent for isolated patients
  • PerfO and ClinRO assessments
  • Waiver for eCTD requiremnts if sponsor cannot comply
  • Communication with FDA


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