FDA responds to additional concerns about protocol modification due to COVID-19

COVID-19 has complicated the clinical trial landscape, in some cases requiring protocol deviations to ensure the integrity of the trial and patient safety. AgencyIQ explores three key policies advanced by FDA that can help sponsors keep clinical trials on track.


By Aaron Badida, JD

How Things Work Now

COVID-19 has disrupted hundreds of clinical trials underway before the epidemic first hit the United States earlier this year. Concerns for the health and safety of trial participants, as well as the focus of resources of drug developers, have raised questions about how companies can make changes to their trials to ensure both that trial is conducted ethically and is suitable to collect accurate, valid data on the safety or efficacy of their investigational products.


Changes to clinical trials are often done through “protocol amendments,” which are a common (if difficult) way of making adjustments to a trial that has already started. Changes could include things like adding additional screening for patients, or making use of a new facility, or leveraging a new method of data collection.


As the result of COVID-19, many companies are exploring ways to collect data remotely and make use of different methods of ensuring patient safety, such as allowing for different laboratories to monitor patient vitals. Under normal circumstances, these interactions generally occur at a clinical testing site or at specific, pre-qualified sites. Because of COVID, however, it may be difficult for patients to access trial sites or get the predicted lab testing they need.


Finally, the FDA often requires postmarketing studies for drugs, biologics and devices. These requirements help ensure that drugs—studied in only a small number of patients before obtaining approval—are safe and effective, and that any obscure or long-term effects are quantified.


What’s New

In March 2020, the FDA issued a new guidance document, “Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency.” This guidance was created to help industry, investigators and Institutional Review Boards (IRBs) balance the public health concerns with the need to continue drug development and approval.


While the guidance is extensive, the FDA has periodically been adding updates to it reflecting its latest advice based on emerging questions from industry. In its latest update, the FDA said it recognizes that COVID-19 may necessitate the use of other laboratories and testing and imaging sites. It also said it recognized that the use of telemedicine by investigators to assess trial participants can reduce the risk of COVID-19-related interference with a clinical trial. These policies are consistent with the general recommendations of federal health agencies to practice social distancing and minimize physical interaction as much as possible.


To address concerns that arise around deviating from protocol-specific testing and imaging sites, as well as modified interaction with investigators, the FDA’s guidance makes several specific recommendations:


Changing Lab or Imaging Site
Overall, the FDA is adopting a temporary policy supportive of changing lab or imaging sites as needed. If a location is not listed in the initial Form FDA 1572, sponsors can still redirect to this location if original sites are no longer accessible.


Because lab or imaging sites can vary in the technology available, precision and accuracy can be affected by diverting participants to another site. The FDA recommends that sponsors should consider whether their primary or secondary endpoint data relies substantially on the test results. If so, study integrity could be impacted, and consultation with the FDA is recommended prior to making any changes.


The agency also notes that clinical trial enrollment—specifically eligibility testing—should be discussed with an FDA review division. Even routine testing can vary in precision across labs, which could cause validity issues with future data.


While maintaining its lack of jurisdiction over the practice of medicine, the FDA recommends three core considerations for using remote conferencing as a means of facilitating participant visits:
1) Train investigators adequately.
2) Ensure the same level of privacy as an in-person visit.,
3) Mutually confirm identification of investigator and participant.


Remote visits aren’t considered electronic records under this guidance.


Postmarketing Requirements
The agency recognizes that sponsors who have cleared clinical trials, but still have to fulfill postmarketing obligations, could also be adversely affected by COVID-19. Because PMRs generally adhere to a strict, FDA-enforced timetable, the agency suggests getting in touch with proper agency division if there’s a COVID-19-related obstacle. This applies to drugs, biologics and devices. The FDA intends to continue enforcing its expectations for PMRs and postmarketing studies, including PREA, accelerated approval and annual status reports. However, it intends to take into account pandemic-related difficulties.


What’s Next

While sponsors and investigators are given considerable flexibility under this guidance, they should be mindful that deviations from standard protocol are often complex and may not be acceptable in all cases.


The overall goal is to permit changes where the negative impacts of COVID-19 may exceed the potential negative effects of a change to the protocol. It will be critical for companies to understand the potential effects of any changes, especially for remote monitoring (where it may be more difficult for a patient to be fully evaluated) or using different testing sites (where staff may not have sufficient training in how to evaluate certain results consistently).


At present, the life sciences industry is looking to navigate from a pre-COVID-19 world to a post-COVID-19 world, and this guidance is one way in which sponsors can confidently bridge the gap without falling out of regulatory compliance. For future trials, sponsors and investigators can plan for contingencies that can minimize the impact of COVID-19 in new protocols.


To contact the author of this brief, email Aaron Badida.
To contact the editor of this brief, email Alec Gaffney.


Key Documents

Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency (March 2020)

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