Skip to main content

Discover Our New CTMS

A Summary of FDA Guidance on COVID-19: Patient Safety and Adapting Processes

By William Mellinger, Communications and Product Strategist, Trial Interactive and Gillian Gittens, Director, E-Clinical Strategy and Solutions, Trial Interactive

Regulatory Documents

Tuesday, April 7, 2020 | 2:20 PM

How do we proceed in times like these? That is a question bouncing around the minds of people worldwide. For many, the answer is simply “stay at home and wait.” However, in the medical community, the show must go on. That community includes many clinical trials. Participants are actively being treated, and so it is important study teams find a way to continue. There are no elegant solutions to a pandemic, but much of what enables us to respond, both at home and in business, is our digital infrastructure. Recently, the FDA released some guidance to help study teams make decisions, as well as handle the documentation regarding related changes to their operations and protocol.

“Challenges may arise, for example, from quarantines, site closures, travel limitations, interruptions to the supply chain for the investigational product, or other considerations if site personnel or trial subjects become infected with COVID-19. These challenges may lead to difficulties in meeting protocol-specified procedures, including administering or using the investigational product or adhering to protocol-mandated visits and laboratory/diagnostic testing.” —FDA

Below is a quick, itemized rundown of their guidance for ongoing trials (focused on Discussion Section A of the guidance), each followed by some commentary to provide additional food for thought:

  1. Participant Safety – The FDA acknowledges that the circumstances are going to disrupt supply chains, ongoing treatment of participants, participant monitoring, and recruitment. Participant impact assessments are encouraged along with participant communication on how any forced changes will impact them.

    Commentary: The scale of the impact of COVID-19 is unprecedented; therefore, the full impact on clinical trials is unknown. The FDA acknowledges that whatever the impact, the safety of trial participants is paramount. It is critical that participants are informed of any changes to a trial that could impact them (e.g., delay or nondelivery of the investigational product (IP), clinics closing, or visits being canceled). Participant communication is essential and should be continued, but social distancing means looking to alternative solutions. Telemedicine and telehealth, the practice of remote care and distribution of information, will demonstrate huge value in the pandemic. Where supply chains are disrupted, delivery of IP from a site to a participant’s home can be considered. New processes will almost certainly mean extra or new documentation being created. An email detailing new decisions and approval documentation should be retained, and to demonstrate compliance these must be filed in the TMF. Consider that TMF inventories will need updating. The TMF Reference Model Team suggests trial teams maintain a centralized listing or tracker to capture the processes impacted and the resultant new or changed TMF documentation (and its management).

  2. Choosing to Continue Treating Participants – In many cases, the benefits of continuing treatment outweigh the risks presented by the current crisis. The FDA is suggesting a collaboration with IRBs to make this determination, which will be subject to many variables, such as “the nature of the investigational product, the ability to conduct appropriate safety monitoring, the potential impact on the investigational product supply chain, and the nature of the disease under study in the trial.”

    Commentary: Sponsors should conduct ongoing risk assessments when considering what measures are the most appropriate to enable the continuation of treatment. For global studies, the approach should be country- or region-specific to follow local rules and restrictions in place due to COVID-19. Assessments should consider which activities can be performed over the phone, or remotely, such as monitoring visits. Again, these risk assessments should be documented and filed in the TMF to not only demonstrate compliance through the ability to reconstruct the trial, but also show how the “story” of the clinical trial has changed trial conduct. More and more we will see pauses to new studies and patient enrollment (except for COVID-19 vaccine trials or trials where IP is a limited option). While data integrity is essential, we must remember safety for participants and personnel comes first.

  3. Safety Assessments – Again, the general advice to all of humanity is to “stay home.” Sponsors have to determine if they have alternative means to effectively conduct safety assessments. The ability to conduct these assessments plays heavily into the topic above as to whether continuing treatment is feasible. Depending on the nature of the study, options such as “phone contact, virtual visit, and alternative location for assessment, including local labs or imaging centers” may be considerations. The decision comes down to whether or not safety can be assured with a modified approach.

    Commentary: In these unprecedented times, alternative methods for conducting safety assessments should be considered, where feasible and where safety can be assured. These could be conducting phone/video visits (using HIPAA-compliant video-conferencing tools) or moving participants to less crowded family health centers and local labs for assessments like blood tests and x-rays. Assessments will help sponsors make informed decisions on recruitment, monitoring, and retention and will result in increased communication between sponsors, sites, IRBs, and participants. File them in the TMF contemporaneously.

  4. Participants Forced to Discontinue – The FDA makes it very clear that sponsors may require a safety monitoring plan for participants forced to discontinue due to a lack of access to the IP. Depending on the treatment, the risks of discontinuation need to be assessed and appropriately managed.


    Safety is especially important if a participant cannot obtain IP during the COVID-19 pandemic. This could be because of social distancing, self-isolation, or supply chain issues, among other reasons. The guidance is that there be appropriate management after discontinuation. It is important that adverse event information continues to be collected and documented as quickly as possible, so safety monitoring as defined in the trial’s safety monitoring/management plan can be continually reviewed and adapted. This should be filed in the TMF.

  5. COVID-19 Screening – Healthcare systems may require screenings. This additional testing is not required to be documented as an amendment to protocol. If a sponsor decides to include it in the study data, only then does it need to be added.

    Commentary: COVID-19 screening procedures do not need to be reported as an amendment to the protocol unless the sponsor is incorporating the data collected as part of a new research objective. However, when is screening required? For trials that are proceeding, and when paused trials resume, screening may be necessary if participants display symptoms and if in-person contact is still occurring.

  6. Protocol Changes – The FDA expects changes to protocol or informed consent to go through the proper channels of IRB/EC (and sometimes FDA) review. They provide some wiggle room if a change is implemented rapidly for the “life and well-being” of participants. In this case, the change may be submitted after the changes are implemented. Also, it’s important to note that the FDA “encourages sponsors and investigators to work with their IRBs to prospectively define procedures to prioritize reporting of deviations that may impact the safety of trial participants.”

    Commentary: There is no doubt there will be an increase in protocol deviations. As is standard, they should be documented to ensure appropriate evaluation. Sponsors are encouraged to engage with ethics committees as early as possible when urgent changes to the protocol are anticipated as a result of the impact of COVID-19. This collaboration will help define procedures to prioritize reporting of deviations that may impact the safety of trial participants. All protocol amendments and associated documentation (e.g., protocol acceptance) should be filed in the TMF as soon as they are final.

  7. Alternative Processes – Sponsors are expected to try to align any alternative processes with the existing protocol. Additionally, there should be documentation of any contingencies and how the response to COVID-19 led to changes, the duration, and which participants were affected.

    Commentary: Document, document, document! FDA guidance states that any COVID-19 contingency analyses, discussion, or measures and a listing of participants affected by COVID-19–related disruption be summarized in the clinical study report or a separate study-specific document. Sponsors can also develop templates that capture this data. It’s worth considering tagging all documentation with COVID-19 so it can be retrieved at a later date for use by sponsors, IRBs, and regulatory authorities. Most eTMF systems have the functionality to tag, note, or capture additional information.

  8. Participant Visits – Clearly, there will be changes to participant visits. Changes to schedules, missed visits, or discontinuation all impact trial data due to missing information. Case report forms (CRF) that detail this missing information are required. This will help the sponsor communicate the story to the FDA.

    Commentary: It will be important to capture changes to visits that result in missing data in the CRF. This should be specific and explain the basis of the missing data, including the relationship to COVID-19 for missing protocol-specified information (e.g., from missed monitoring visits or trial discontinuations). The TMF Reference Model Team reminds us to cross-check other applicable documents and make revisions or amendments as needed (e.g., monitoring plan).

  9. Product Administration – How the product is administered, and the monitoring of said administration, may be impacted by product availability or the ability of a participant to be treated on-site. Secure delivery for self-administration may be an option. In other cases, alternatives like “home nursing or alternative sites by trained but nonstudy personnel” could be considerations. Standard accountability and documentation are expected regardless of the change to administration.

    Commentary: Many sites are already changing how IP is dispensed and administered. They are shipping self-administered IP to participants’ homes and looking to home care and nurses for infusions and fluid collection. This does raise very practical considerations, such as stability of IP during transit (especially for cold chain product), how IP is stored at home, and how accountability is managed.

  10. Efficacy – If efficacy endpoints are impacted, the FDA advises a protocol modification consult with the relevant review division. Virtual assessment may be an option, among some other alternatives. Reasons for failure to obtain endpoints must be documented.

    Commentary: If efficacy endpoints are not collected because of the impact of COVID-19, reasons for failing to collect should be documented. If any changes to the trial protocol result in the need to amend documents like the data management plan, sponsors should then consider consulting the appropriate FDA review division.

  11. Data and Statistical Analysis – With all of the variables created by how study teams may or may not be able to interface with participants, data management and analysis plans may be impacted, which will lead to protocol amendments. The FDA requests consultation with their relevant review division. Deviations related to COVID-19 may impact the analysis plan, and sponsors should be prepared to document the impact.

    Commentary: Before database lock, sponsors should report how protocol deviations related to COVID-19 will be handled in the statistical analysis plan. Any protocol deviations must be closely monitored and tracked and correctly documented in the TMF.

  12. Site Monitoring – The FDA recommends remote monitoring if site visits are no longer feasible.

    Commentary: The regulatory authorities have been encouraging sponsors to explore more effective monitoring strategies for a while. Sites have already started to halt on-site monitoring and introduce remote, risk-based monitoring. Introducing new plans is accomplished by identifying and mitigating the risks that could affect the quality or safety of a trial by recognizing critical data and processes, performing a risk assessment, and revising monitoring plans.

    Technology plays an important part, as it can allow the access of electronic health records (EHR) for remote source document verification and virtual conferencing. Validation comes into play with new technology. Sound advice from the TMF Reference Model Team is to enable alternatives to paper wet-ink documentation of activities such as electronic completion and e-signature. The significance of inspection readiness is that the eTMF ensures all electronic records uploaded can be easily and remotely accessed and checked.

    A quick note on audits and inspections. These are expected to continue, but remote access requests are very likely to increase.

    The TMF Reference Model Team asks organizations to think about how electronic copies will be created and provided when an organization, vendor, or site is not open for an on-site review. They should consider implementing a process for the provision of remote access to the eTMF and other e-clinical repositories that track creation, checking, and which electronic copies were provided for inspection and audit.


Read the full guidance for more details on how the FDA is seeking to help sponsors navigate this difficult time. There are many opportunities for reflection as COVID-19 disrupts our daily lives. What is clear is that, across the clinical research industry, all efforts to create more alternatives for central, remote processes and procedures are critical to helping study teams adapt. We are humbled to play a role in providing this essential clinical infrastructure. As we try to find the silver linings in a serious moment in history, one positive is that we are all being challenged to explore the upper limits of collaboration and accessibility across organizations and, most importantly, how that applies to the treatment of patients.

For help centralizing your eTMF, content management, trial management, or learning management process, contact us at

Back to Blog