A panel of experts convened by the Food and Drug Administration voted by a slim margin on Tuesday to recommend the agency authorize the Covid treatment developed by Merck and partner Ridgeback Biotherapeutics, after a vigorous debate about the risks and benefits of the first oral drug to combat the SARS-CoV-2 virus.
The FDA is not obligated to follow the advice of the panels it convenes, but it usually does.
The expert panel voted 13-10 that the pill, called molnupiravir, should be authorized, although members expressed concerns that, if used in pregnancy it could cause birth defects. During the panel, discussions frequently turned to whether or not panelists trusted the effectiveness data on the drug, even when they were discussing other topics.
“I think we need to stop and acknowledge that the whole reason we’re having this discussion is because the efficacy of this product is not overwhelmingly good,” said W. David Hardy of Charles Drew University School of Medicine and Science during a discussion about the drug’s use during pregnancy. “And I think that makes all of us feel a bit uncomfortable about the fact whether this is an advance therapeutically because it’s an oral medication, not an intravenous medication.”
The vote is a blow to Merck, which seemed to emerge on Oct. 1 with a pandemic game-changer: the first antiviral pill to reduce hospitalization and death in Covid-19. However, last Friday, Merck released data from the full population of that study, showing the drug’s benefit was substantially reduced. Concerns have also been raised about whether molnupiravir, which works by inhibiting the ability of the virus to replicate its genetic material, might cause birth defects or even long-term effects from damaging patients’ DNA, potentially causing long-term harms like cancer. Both Merck and FDA scientists said such outcomes were unlikely for a medicine that would only be taken for only five days, although they faced tough questions from panelists about the specific animal studies that indicated the treatment was safe.
“Obviously we are pleased with a positive vote and, you know, there was a lot of robust discussion,” Roy Baynes, Merck’s chief medical officer, told STAT. “I think, at this moment in time, based upon all the data, we do believe that overall benefit risk is positive in high risk patients.”
Since Merck’s initial announcement, Pfizer has released interim data on its own Covid pill, also a five-day treatment, which showed 89% efficacy. Full data from that study have yet to read out. Pfizer executives say the FDA has not told it to expect an outside advisory panel. That drug must be given with another medicine, ritonavir, which interacts with many drugs.
On Tuesday, throughout the hearing of the advisory committee, panelists asked pointed questions of both Merck and the FDA, whose scientists had seemed to back the approval of the medicine in briefing documents released Friday. Among them was how to interpret the change in the results around the drug’s effectiveness. The early results released Oct. 1 showed a 50% reduction in hospitalization, or an absolute decrease of 7%. In the final results, the result shrank to a 30% decrease, or a 3% absolute difference in hospitalization in the full population.
Lindsey Baden of the Brigham and Women’s Hospital, the panel chair, asked early on how this could be. “Help me understand,” he said.
Nicholas Kartsonis, a Merck researcher, explained that the interim analysis was the primary analysis, but also said, at length, that Merck’s scientists had not been able to come up with clear reasons for the result. “I don’t have a satisfying answer to your question but at least that’s the totality of the data we have.”
Panelists also worried about data showing that use of molnupiravir might, in theory, lead to new variants of the SARS-CoV-2 virus through its mechanism, which works by causing viruses to make mistakes in copying their genetic material.
“With all respect, I think it’s incumbent upon you to make some effort to make an estimate of what is the likelihood of escape mutants occurring as a result of your drug,” said James Hildreth, a panelist and the CEO of Meharry Medical College.
However, other panelists, including John Coffin, a Tufts molecular biologist, argued that the overall risk of such mutations due to the drug was small.
But the panel was also concerned about safety, both in pregnant women and in patients in general. Merck had argued that the drug should be available in pregnancy in some cases.
Panelists stopped short of saying that the drug should not ever be given during pregnancy. But they recommended it only be used in rare circumstances, such as when other treatments such as monoclonal antibodies are not available or in the event that a new strain of Covid has become resistant to those treatments and that it should be left up to the patient.
One panelist, Sankar Swaminathan of the University of Utah, even wondered aloud whether the drug could cause birth defects if it affects sperm, and if men should be told not to have children for some time after receiving the drug.
“There are definite concerns about the potential effects of this drug on the embryo and the fetus,” said Janet Cragan, a medical officer at the Centers for Disease Control and Prevention and a panelist. “I don’t think you can ethically say it’s OK to give this drug in pregnancy. [But] I’m not sure you can tell a pregnant women who has Covid-19 that she can’t have the drug if she has decided that’s what she needs.”
After the vote, Baynes, the Merck executive, argued the decision should be left with physicians. “”We would not recommend its use in pregnancy and we would also recommend contraception in women of childbearing age,” Baynes said. “But I think the idea here is that ultimately the physician is the best position to determine the relative risk benefit for their patients.”
In the end, panelists narrowly voted that the benefits of having an oral Covid treatment to keep people out of the hospital outweighed their questions and concerns. But the FDA may write a far narrower authorization for the drug than observers would previously have expected.
“This was clearly a difficult decision,” said Michael Green, an infectious disease expert at the University of Pittsburgh, in explaining his “yes” vote.
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