Following on from our COVID-19 webinar series, we've been asked lots of questions about how to interpret the latest guidance and how to deal with specific trial management issues. 


Please see the questions below, but if you have any you'd like to ask about your specific studies, please get in touch.


Per most regulatory guidance, it is critical that trial participants are kept informed of changes to the study and monitoring plans that could impact them. It is recommended that the subjects are consented by phone. Any consent obtained this way should be documented and confirmed by way of normal consent procedures at the earliest opportunity when the trial participants will be back at the regular sites.  What's your view on the guidance?

I have read the guidance and to me it does not make it clear exactly what is expected specifically for informed consent; they do talk in general regarding the general maintenance of patient safety and keeping them informed of all changes. The MHRA guidance specifically talks about obtaining consent from a patient if they agree to have their drugs delivered to them as we need personal contact information. 

For this scenario, the guidance does say that consent should be taken verbally by phone and documented in the patient notes. The FDA guidance simply says that changes may need to be made to existing processes including those relating to consent, but does not give specific guidance.


The Regulatory Guidance statements imply that it is not required to submit the consent transcripts or informed consent forms to the EC prior to consenting/informing the subjects, is that correct?

I agree, there is no need to submit these to ECs. However, the company should review their consent SOP in line with the current situation and make amendments as required / create SOP deviation, depending on internal processes. 

I would recommend that patients are contacted, informed of any immediate changes to them, obtain their consent to this verbally over the phone and document in patient notes. I feel this is all that is needed right now.  

If the changes are to address changes to the trial conduct due to the wider impact of COVID-19 then this can be treated as a non-substantial amendment and does not need to go through IEC approval.  The changes should be outlined in a separated ICF, rather than changes to the existing ICF.  

For trial conduct amendments that relate directly to COVID-19 e.g. adding tests for the virus due to safety concerns in the patient population or to implement a sub-study related to the virus epidemiology, for example, these changes should be treated as emergency safety changes and can be implemented immediately and the EC/CAs should be notified as per the usual process, of within 15 days (in EU) of the change being implemented 


Should the ECs however be notified before these calls take place? 

No, this is not required. Refer to guidance above. What is required is the continued documentation of protocol deviations for the study, making it clear what relates specifically to the impact of Covid-19. The FDA guidance stated that this should be included in the CSR.


Should the documented version (e.g. paper ICF version or paper transcript) be submitted to the EC retrospectively?  


At this point in time, the guidance is only to do so for safety related changes. General conduct changes do not need to be notified. I do not interpret the guidance as currently requiring any new ICFs to be created or amended


Once the subject returns to the site and signs the paper version of the same consent that was provided verbally, should this paper version of this consent be approved by the EC prior to subject signing it? 

No,  following the guidance from above, it would seem this would not be necessary. I did not feel from the guidance from MHRA or FDA that either of them are enforcing ICF updates or separate forms. I think consent verbally and documented via phone will be enough. Guidance of course should be created by sponsors and shared with sites to guide the conversation with the patients, and this should still be a conversation led by an investigator.


If there are only few changes due to the COVID-19 and the need is only to inform subjects about these verbally by phone (changes not impacting subject confidentiality/data privacy hence no GDPR related consent needed), is it enough that this is documented in the patient notes / patient files? Or is it required that patient signs this verbally provide information in a ICF format when back to regular visit?

The information should be documented in a separate form, if the site are able to email this to the patients, before the phone call, this would be best.  And the patient can sign the form at their next visit. I believe we can just take consent via the telephone and document in patient notes. I cannot see in either guidance that it explicitly says an updated consent form or new consent form has to be created.


Sites have notified us to not recruit until further notice due to COVID-19 (would be overreporting? To be documented clearly in the study file?)

I agree, this would be over-reporting and the regulatory authorities do not need to be made aware of each individual site decision


My Sponsor decided to halt recruitment until further notice due to COVID-19; do I need to send notification of temporary halt within 15 days? 

The MHRA states that they should be informed of the study halt if the need to halt the study meets the following:

  • 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


I have a question regarding the shipping of IMP to patient's home (with personal address) : it is in line to do this, regarding the GDPR and the collection of data?

The MHRA guidance states this is possible if the patient gives verbal consent via telephone to release their personal information for drug to be delivered - this consent should be captured in the patient notes. The guidance states: ""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:

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 expiry of the product may need to be shortened if is delivered in ambient temperature


Is there any guidance for sites to have difficult conversations with trial participants when studies are being put on hold or stopped?  For some participants this is their "treatment". 

Unfortunately after some extensive searching we have not been able to locate anything of this nature.  Each indication and event patient situation will have unique considerations.  Its important as part of the decision to suspend the trial that continuity of patient care is carefully considered by the medical/scientific lead and key opinion leaders, part of this should be what will be communicated to patients.  This should be provided to the sites to support those converstations.  Medics assigned to the study/program at the sponsor/CRO should make themselves available to speak with site staff.  And the communication to suspend the trial should come from the medical lead/chief investigator.


If the plan is to revert back to the original protocol once COVID-19 is behind us, we understand a full official amendment is not needed but rather a document clearly indicating the changes in the visit types (remote (via call, skype etc.) vs. in person would suffice. Please comment on this further

This is correct, if your protocol changes are adjusting to the COVID-19 social distancing requirements e.g. reduced visit schedule, reduced assessments, then these do not need to be documented as an amendment, these can be managed as protocol deviations and clearly identifed as being COVID-19 related.  Recommend you have a COVID-19 plan, which clearly documents the changes you are implementing and how you will capture items such as missed visits/assessment etc, and identify these as being related to COVID-19.

If you are making additional assessments e.g. screening for the virus, due to vulnerable population or you are changing treatment plans e.g. stopping immunosuppressants, these are urgent safety measures and should be handled accordingly.  


How would you determine when to stop using the Covid19 created plan? When does it end?

Great question!  I think we will have to watch and wait, and I suspect it will be dictated somewhat by sites and what they can manage, even when advice from the WHO and  country government advice relaxes social distancing measures, the healthcare system will still take some time to recover.  Really there is no definitive answer to this, but watch the global and local government advice, and continue to communicate with your sites. 


Are Meeting Minutes with Action Items enough for documentation of Risk Assessments and Decisions?

Yes, if you are documenting within these documents the risks, and the action plans/controls then yes, absolutely, the important thing is that we are having these discussions and documenting the actions.  I would recommend that a COVID plan is put in place to hold all of the activities that are going to be executed in 1 clearly identifiable document.  This will be easier for the team to follow and similarly for sites and patients, separate documents to make it clear what we are doing/expecitng now.


Those activities that can be missed - should these be protocol deviations or should they be amendments if this is across the board for all sites?

These should be handled as protocol deviations.  Make sure you document what you are allowing to be missed and managing as deviations, as well as the justification for this.  Identify your protocol deviations as being COVID-19 related, this will make it easier to look at the effect of this and where necessary pull this from your analyses at the end of the trial.  MHRA and FDA both state they want to see this called out in the CSR, so put plans in place now so you dont have to deal with it at the end for the trial!


Can electronic Signatures via Adobe (although not 21 CFR Part 11 compliant) be used by sites?

You will need to perform a risk assessment on that process internally and make a judgement call.  You should think about the purpose of the signature is it adding value, can we wait for the signatures, get these retrospectively.  I know sometimes if I am away when documents need to be signed, I have sent emails to say I am not able to sign but I have reviewed/approved the document (naming the document in my email) and that I will sign when possible.  Then we file the email approval with the signature that is added at a later date.


Alot of countries - and major cities like NYC, London etc, are understaffed with medical qualified and bringing in even retirees, are sites in these areas closing down for studies?

Some sites are, but essentially, they are also going through a similar assessment that we are on our studies, they are considering what patients have to continue, and how can these be managed, and what can we stop.  So you will need to speak with each site individually and find out how they have assessed your trial and the continuity of care for their patients.


Are you expecting that IBs wil have specific COVID-19 section for their annual updates?

Unsure at this time, I don’t know if it will be blanket across all IBs, but each company will need to evaluate that for their product.  Sorry we cant be more definitive but very thought provoking question!


What are your QA folks doing with audit plans?

For sites, we are not auditing and I suspect inspections will be postponed too.  Vendor qualifications we are still proceeding with.


Are your QA folks performing remote site audits?

No, the sites do not need this additional activity at this time.  


Do you think it would be better to document study-specific risk assessments and mitigation plans in standalone Covid-19 documents - and/or should study-specific RACTs and associated operational plans (e.g., Monitoring Plans) be revised to include Covid-19 risks and mitigation activities?  Thanks!    

On the risk assessment front, it is really just choice, it might be easier to manage in your current tool/log and just prefix the risks/IDs and controsl with COVID-19.  You absolutely want to be able to identify them as being related to COVID, if this is not easily done then I would recommend separating them.  Monitoring plans etc I would separate as they are essentially emergency measures, superceeing what we currently have in place.  


Where CRF update isn't practical, what about use of protocol deviation recording within a CTMS (eg, due to COVID19 the following was late, missed/not done).

Identify the deviations with COVID-19 prefix, see if you can add a value to the CTMS Protocol deviation type so that this can be managed.


Is it accepted that somebody of study team is delivering IMP to the patient during home visit?

Someone from the sponsor team?  No.  IP administration must be managed by the site or centrally, if appropriate data consent and protection measures can be maintained.


Is it required to update ICF specifying new rules on performing visits, monitoring and etc?

I would recommend that a patient information sheet is created that can be sent to the site, so that the sites are providing consistent information to the patients.  But this does not need to go to IEC for review/approval.


Would you suggest for instance that subjects measure their blood pressure at home?

Consider whether or not it blood pressure is a critical assessment for the study.   If not, then it would be advisable for this assessment to be suspended for patients during the pandemic and are unable to attend site, but they could continue in the study.

If it is a critical assessment and must be performed, the team will need to consider possibilities for measuring blood pressure at home.  Factors to be considered will include:

  • Are patients competent to do measure blood pressure themselves?
  • Can blood pressure monitors be provided to them to measure at home?
  • How would instructions or training be facilitated?
  • Where and how would the measurement be captured (what is the source of the information), how would this be shared with site to review?
  • Are there others ways a measurement could be taken by a health care professional, such as at a local health clinic?"


Do you have any thoughts about devices that will collect patient stats and transferring it straight into the electronic database? 

Wild example is a bluetooth blood pressure moitor that feeds directly into a system that can be viewed by investigator and sponsor. 

Wearable technology is starting to become more common in some therapy areas.   If you are able to:

  • Source and provide a reliable device;
  • Provide training to patients to correctly use the device and know how to send the data; and
  • The data transfer had been tested / validated as per your company SOPs relating to technology systems (should probably include those relating to system validation and testing)

then yes I think this could be used. 

It is not such a wild suggestion in our opinion, as we feel this is where the industry is heading.  The pandemic may just push us there quicker than we were expecting!


Do you have QMS Business Continuity Plans examples?

We have our own (TRI) Business Continuity Plan (BCP),  but this is tailored towards the needs of our organisation. 

The main aspects to consider are the critical processes/systems that need to continue in the event of a disruption and the most likely sources of business interruption, and to focus risk mitigation efforts on these areas.  Another key aspect of a BCP is communication and how this will be maintained during a disruption - again there is a need to focus on critical personnel/roles.

For example, systems that support critical processes e.g. pharmacovigilance, need to have recovery time objectives established and disaster recovery plans (DRPs) need to align to these objectives. Critical personnel may need to have alternative provisions should they be unable to go in to their normal place of work so this may include working from home or maintaining contingency business space e.g. if the disaster is site specific.

BCPs and DRPs need to be tested periodically and improvements to plans made. 

In the context of this pandemic, and if an organisation has not already established BCPs, then it is about identifying those critical processes/personnel and issue management.  However, in theory BCPs should be in place to address/mitigate risks in order to reduce the impact and reliance on issue management.


I've heard that remote monitoring/audits are seen to be mor time consuming for the sites that on-site visits, during COVID-19 any advice on postponing KRI's? 

Remote visits, if conducted correctly, should not take longer than a full-day of on-site visits.   In our experience they last a maximum of one hour depending on how much needs to be discussed with sites and how much preparation the monitor has  completed for the visit (and tailored the remote visit for the site).

During this current period when we are unable to attend sites in person, we need to explore possible ways to continue monitoring sites remotely, be that: 

  • Remote data review using systems such as EDC;
  • System reports such as central labs, CTMS reports, etc;
  • Remote monitoring visits (if site staff are able to accommodate depending on their schedule); and
  • The continued use of centralised monitoring, such as a KRI Dashboard. 

If any of these activities have not been implemented prior to the pandemic, then their implementation should be reviewed to determine if they are appropriate to implement on the study at this time.


After P1 dosing and the subjects are allowed to return home, Is there a followup needed by the CRO to check on their COVID-19 status?

That will need to be assessed for a study - if it is deemed a requirement to either test the patient for COVID-19 or check the status, and this is new data that will be collected and documented in the EDC system, this would constitute a protocol amendment and would need to be submitted for ethical / regulatory review. If this is being captured as part of adverse event information, this would not constitute a protocol amendment. 


if you dont do any SDV how do you know the data is there?

Typically during on-site visits the monitors would conduct Source Data Review (SDR), which does ensure that data is present. Source Data Verification (SDV) is just a transcription check that what is documented in the source documents are transcribed into the EDC correctly. 

During this time where we cannot attend sites in person, all teams can do is to check that data is being entered into EDC at regular intervals for those studies and patients that are continuing during this time. 

Once on-site visits are able to commence again, study teams will need to determine the best approach to monitor the backlog of data. 

Please remember that SDV does not ensure quality data, it just ensures the site was able to correctly transcribe data from source documents into the EDC system.


How do you know the data is hundred percent matching your database?

There has been a number of studies completed by industry that demonstrate that the amount of data that changes due to SDV is tiny, <2% and the amount of ciritical data that changes due to SDV is <1%.  There are more effective ways of checking the integrity of the data that SDV, just because something was entered into the medical notes does not make it accurate or correct.  Evaluating the sites processes and central review of the data are more likely to highlight risks and inconsistencies/anomalies in the data.