Unpersuaded by the data, FDA rejects cheap, generic SSRI as a Covid-19 drug
Fluvoxamine, an SSRI already FDA-approved as an OCD treatment, appeared to show some hints of efficacy in Covid-19 too, leading University of Minnesota ID doc David Boulware last December to submit an EUA for it as an outpatient treatment for those testing positive and to prevent the progression to hospitalization.
Almost 6 months later, the FDA said Monday it’s rejecting the cheap generic drug’s Covid-19 EUA as the primary RCT from Brazil, on which the majority of the app rests: “The treatment benefit of fluvoxamine was not persuasive when focusing on clinically meaningful outcomes such as proportion of patients experiencing hospitalizations or hospitalizations and deaths.”
That Brazilian trial with almost 1,500 enrollees met its primary endpoint, although the FDA took issue with the fact that the “results were primarily driven by a reduction in the emergency department visits lasting greater than 6 hours, and there are uncertainties about the assessment of this endpoint and whether the 6-hour timepoint represents a clinically meaningful threshold.”
Another, different trial and smaller sets of real-world data studies were hampered by design limitations, endpoint selection questions, and a lack of randomization, the FDA said. “Two additional trials, STOP COVID 2 (a trial that was several times larger than the STOP COVID trial) and COVID-OUT failed to demonstrate a benefit with fluvoxamine in adults with mild Covid-19 in the outpatient setting, and both were terminated early for futility.”
The FDA also sought to address the rationale by which a fluvoxamine EUA would be submitted for Covid-19, explaining how it was based on murine sepsis and lipopolysaccharide challenge models in which fluvoxamine was found to bind to the sigma-1 receptor on immune cells, reducing the production of inflammatory cytokines.
But with limited in vitro and in vivo data to support the proposed MOA of fluvoxamine in Covid-19, FDA said it would have to reject the app.
The rejection comes as the NIH had previously said there was insufficient evidence to recommend either for or against the use of fluvoxamine for the treatment of Covid.
Boulware, who submitted the app, took issue with the FDA’s decision, responding to the rejection with a letter shared with Endpoints News, which highlights the FDA’s inconsistent use of the term hospitalization.
“FDA should evaluate clinical trials using the same endpoint definitions for generic drugs as for big pharma,” the letter says. “The deliberate creation of two-tiered system is inappropriate.”
While Boulware wrote that he concurred “that fluvoxamine has a very modest efficacy which is about the same efficacy as [Merck and Ridgeback’s] molnupiravir. The molnupiravir data are similarly weak, and the UK Panoramic trial will provide more definitive evidence.”
But he also noted that 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.