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An FDA panel recommended the agency grant full approval to nirmatrelvir-ritonavir (Paxlovid) for treating high-risk COVID-19.

By a vote of 16-1 on Thursday, the Antimicrobial Drugs Advisory Committee said the totality of evidence supports the traditional approval of the oral antiviral, which has been widely used since late 2021 under an emergency use authorization to reduce the risk of hospitalization or death in outpatients at risk for severe outcomes.

"Besides oxygen, Paxlovid has probably been the single most important treatment tool in this epidemic, and it continues to be," said Richard Murphy, MD, MPH, of the White River Junction VA Medical Center in Hartford, Vermont.

"I was influenced by the benefit on the serious outcomes -- of hospitalizations and deaths -- and particularly relevant, of course, people who may not respond optimally to vaccines," said Nina Clark, MD, of Loyola University's Stritch School of Medicine in Maywood, Illinois.

"It seems that the toxicities are manageable," based on what was presented, she added.

The lone "no" vote came from Terry Gillespie, a patient representative on the committee, of Plainfield, Illinois.

"I'm overweight, and I've had COVID four to five times and never once was Paxlovid even offered to me," she explained. "I don't feel that the doctors really know how to use it."

Data supporting the use of nirmatrelvir-ritonavir came from the phase III EPIC-HR (high risk) trial, which demonstrated an 86% relative reduction in the risk for COVID-related hospitalization or death through 28 days with a 5-day course of treatment early after symptom onset. That primary composite outcome occurred at rates of 0.7% among patients assigned to the antiviral and 6.8% for those on placebo. Patients enrolled in the trial were unvaccinated, and had risk factors for severe COVID-19 such as diabetes, obesity, or heart disease.

As discussion during Thursday's meeting went round and round, many members asked: Who is actually at high risk given the now widespread uptake of vaccines, and who would benefit most from the antiviral?

Subgroup analyses of EPIC-HR and a trial in standard-risk patients (EPIC-SR) showed the largest benefit with nirmatrelvir-ritonavir in unvaccinated patients without a prior infection, though the high-risk vaccinated patients and prior infection group in EPIC-SR also experienced better outcomes with treatment, with absolute rates of hospitalization and death below 1% versus about 2% with placebo.

"I do share the concern with the absolute rate ... because there are side effects," said committee chair Lindsey Baden, MD, of Harvard Medical School in Boston. But he noted that "the strength of the protection of vaccination is not fixed in time, we have a moving parameter that we don't fully understand."

Although the evidence from trials showed that nirmatrelvir-ritonavir and placebo patients had similar rates of viral rebound, and that rebound cases were mild in nature, committee members agreed the public discourse around rebound will be difficult to shake.

"I think there is a broad lack of understanding, not only among physicians but also among patients," said Sankar Swaminathan, MD, of the University of Utah School of Medicine in Salt Lake City. "A distressingly large number of patients told me 'Oh, I was told that I shouldn't take it because of rebound.'"

Despite the near-unanimous vote endorsing a full approval, risk-versus-benefit was hotly discussed.

Stephanie Troy, MD, a clinical reviewer at the FDA, described scenarios that showed how each individual must be evaluated for benefit independently, given the risks for drug-drug interactions.

"Clearly it's important to weigh the drug-drug interactions and the risks that those pose," said Adaora Adimora, MD, MPH, of the University of North Carolina at Chapel Hill. But Adimora also gave the drug the thumbs up, because "it's also clinically meaningful for the population as a whole, given the high incidence of COVID-19 in the U.S."

"It is especially important given the limited availability of effective oral agents," she added.

While the FDA is not required to follow the advice of its advisory committees, it typically does.

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