FDA Declines EUA for Fluvoxamine for COVID-19


FDA regulators said the data to support the EUA, which was submitted by a physician, is not sufficient to support the use of the antidepressant fluvoxamine for the treatment of patients with COVID-19.

The FDA has rejected a request for an emergency use authorization made by a physician for the use of fluvoxamine to treat adults with COVID-19 to prevent hospitalization. Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that is approved by the FDA to treat patients with obsessive-compulsive disorder and depression.

The rationale for fluvoxamine’s use in patients with COVID-19 is based on models that found the drug binds to the sigma-1 receptor on immune cells, reducing inflammatory cytokines.

The EUA request was based on the results of several studies, including one study conducted in Brazil (the TOGETHER trial) and published in The Lancet Global Health that showed a 5% risk reduction in hospitalization.

David R. Boulware, M.D.

David R. Boulware, M.D.

David R. Boulware, M.D., is an infectious disease physician with the University of Minnesota who submitted the EUA requestion, suggests in a separate article in the same publication that fluvoxamine seems an effective low-cost therapy that provides benefit.

“There are no FDA-approved or EUA authorized medicines which have shown benefit in vaccinated populations or who are not ‘high risk,' ” Boulware wrote in a letter to the FDA about the agency’s refusal to issue the EUA. “There remains a clinical need of effective medications and possible options. More horse memes by the FDA are not helpful for those of us who are serious clinical trialists,” he said, referring to a tweet the FDA issued last year about why ivermectin shouldn’t be used to treat COVID-19.

But the FDA in a memorandum explaining its decision said based on the available evidence, the data don’t support the use of fluvoxamine for treating non-hospitalized patients with COVID-19 to prevent hospitalization. The regulatory agency indicated that while the TOGETHER study met its primary endpoint, the results were primarily driven by a reduction in the emergency department visits lasting greater than six hours. Regulators indicated there are uncertainties about whether that is a meaningful threshold.

The agency pointed out that this endpoint has not be used to support regulatory decisions about other treatments for nonhospitalized patients with COVID-19. The endpoint used in other decisions about COVID-19 therapies include “proportion of subjects with COVID-19 related hospitalization or death from any cause through Day 28” and “percentage of subjects who were hospitalized or died through Day 29 due to any cause.”

The FDA wrote: "acknowledging that retention in an emergency setting for six hours or longer was intended to serve as a proxy for hospitalization in this study, it is uncertain how accurately the study captured recommended retention time for observation, who determined the length of observation, and whether the six-hour timepoint represents a clinically meaningful threshold.”

The FDA also questioned whether the results are generalizable to patients in United States.

Boulware, in a letter to the FDA about the agency’s refusal to issue the EUA, said progression to severe disease is a valid clinical trial endpoint that was used in vaccine trials. “The EUA application noted the 36% reduction in progression to severe Covid-19 as per FDA’s definition of severe Covid-19,” he wrote.

The FDA also pointed out that other studies, STOP COVID, STOP COVID 2, and COVID-OUT, did not demonstrate a benefit of fluvoxamine in adults with COVID-19. Two of those studies were stopped for futility.

“More guidance on the choice of clinical endpoints for outpatient trials in 2022 would be useful,” Boulware wrote in his letter. “As a clinical trialist, there remains a need for greater two-way communication between FDA and the research community. FDA’s current guidance for trial endpoints for outpatient early treatment of COVID-19 pretends as if it is circa 2020. A medication is beneficial for many reasons, including shortening duration of illness or preventing progression to severe Covid-19. Progression to hospitalization/death is substantially lower in vaccinated populations and/or those with prior infection. This is no longer a realistic trial primary endpoint.”

Additionally, regulators said there are limited in vitro and in vivo data to support the proposed mechanism of action of fluvoxamine for the treatment of COVID-19. “There is no evidence to date that an anti-inflammatory therapeutic would be beneficial at an early stage of infection when COVID-19 disease severity is mild and that anti-inflammatory therapies are currently recommended only for hospitalized individuals requiring supplemental oxygen,” the FDA said.

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