FDA provides further clarity on clinical trial adverse event reporting

Newly updated guidance from the FDA provides sponsors with additional details about how to report adverse events associated with COVID-19.


By Kedest Tadesse, MS, RAC 

How Things Work Now

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.


The guidance provides recommendations on how to maintain good clinical practice (GCP), assure the safety of subjects and ensure the integrity of the trial. Since publication, the guidance has been frequently updated to including additional question-and-answer format explanations of common issues identified by the FDA and industry.


What’s New

In the latest updated to the guidance document, issues this week, the Agency addresses whether companies should report adverse events to the FDA in specific circumstances involving patients with COVID-19.


Serious adverse event reporting of an already approved product currently under investigation for COVID-19

Some drugs are already approved for one use, but may be used to help treat patients with COVID-19. Ordinarily, companies are required to report serious, unexpected adverse events associated with their drug to the FDA. Companies wanted to know: How should they handle adverse event reports associated with a drug if it’s taken for COVID-19, but the drug is also in clinical testing for another condition? For example, a person might have died while taking a drug, but the death may have been attributed to COVID and not the drug itself.


The FDA’s guidance explains that sponsors should report any serious adverse events (SAEs), “regardless of whether an SAE occurs in the course of clinical practice or during a clinical trial.” Reports should be submitted to the Vaccine Adverse Events Reporting System (VAERS) for vaccines or FDA Adverse Event Reporting System (FAERS) for drugs and biologics.


Adverse events that occur during the clinical trial for the treatment of COVID-19 should be reported to the investigational new drug application (IND) if the sponsor believes there is “a reasonable possibility that the drug caused the SAE,” FDA wrote.


Whether adverse event reporting is made first to the IND or the new drug application (NDA) of the approved product, sponsors are responsible for monitoring safety and accumulating safety data. If the accumulated data from the approved product presents a new serious risk associated with the product, a safety report to the IND should be submitted. Additionally, sponsors should update the investigator’s brochure and informed consent document accordingly.


Reporting of serious adverse event experienced by a trial subject diagnosed with COVID-19 in a non-COVID-19 trial

Is COVID-19 a reportable adverse event? The FDA’s guidance document makes clear that for companies with enrolled clinical study subjects, a COVID infection is more likely than not a reportable event.


An adverse event means “any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.” For regulators, the concern is that an investigational drug might make patients more susceptible to infection or increased complications. Such events might happen if the drug causes a patient to become immunocompromised, or have decreased kidney or liver function.


In a randomized controlled trial, a comparison of the rate of observed SAEs in COVID-19 infected trial participants in the investigational drug arm to COVID-19 infected trial participants in the control arm can help determine if there is a relationship between the investigational drug and SAE. Since such analyses will require unblinding, the Agency recommends using a data monitoring committee or safety committee that is independent of those conducting the trial.


For non-randomized trials, a comparison of COVID-19 infected trial participants to external populations infected with COVID could hint if there is an excess number of SAEs in trial participants. Comparisons should consider that reporting of COVID-19 is widely varied plus comorbidities and the level of care are different.


If the comparison indicates a causal relationship between the investigational product and SAEs in subjects diagnosed with COVID-19, a safety report should be submitted to the IND. Additionally, the report should be provided to the IRB.


What’s Next


While the FDA’s existing guidance documents related to COVID-19 are primarily marked by their flexibility, the agency’s latest guidance is perhaps notable for its lack of flexibility. The FDA calls for companies to follow existing regulations and guidance, and has not changed its approach toward adverse events and what is reportable.


As COVID-19 continues to spread in the US, it is likely to be an increasing issue for clinical trial sponsors. As the FDA’s guidance notes, among the main regulatory concerns is keeping a trial blinded. The use of separate data or safety monitoring committees for non COVID-19 trials is essential to analyze data without unblinding the trial. This is also important to consider during the preparation of the study protocol such that it can be built into the design to minimize protocol deviations and assure integrity.


Key Documents and Dates


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