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FDA advisers back withdrawal of controversial drug for preterm birth

Advisers to the Food and Drug Administration on Wednesday recommended a treatment used to prevent premature birth be removed from the market, citing study results that showed it doesn’t prevent death or health problems in newborns whose mothers took the drug.

In a meeting that stretched over two and a half days, the advisory committee was swayed by arguments from FDA officials, who argued strongly in favor of withdrawing the drug’s approval. While the agency isn’t required to follow the advice of its committees, it tends to do so.

Called Makena, the drug has been available since winning an accelerated approval from the FDA in 2011. But it has been mired in years of controversy over its pricing and its effectiveness, as well as dragging delays by its former owners in completing the confirmatory testing required by the agency. One of those companies, Amag Pharmaceuticals, finally did so in 2019, reporting negative clinical trial results.

The 14-1 vote from the FDA’s advisory committee, made up of obstetricians, gynecologists and experts in fetal medicine, will lend support to the agency’s yearslong effort to pull Makena from the market. Advisers rejected a compromise offer from the drug’s current owner, Covis Pharma, to substantially limit which patients are eligible for treatment while it conducts a new trial.

“There is no longer any evidence of effectiveness,” Patrizia Cavazzoni, director of FDA’s Center for Drug Evaluation and Research, told the expert panel. “If we look at other potential investigations with Makena or other interventions, that is a separate consideration.”

Covis, meanwhile, wasn’t able to win over the committee members, despite its attempts to build support. “We believe that when a confirmatory trial fails … that is only the beginning, not the end, of the analysis,” said Raghav Chari, Covis’ chief innovation officer, during the meeting.

The advisers were asked to weigh competing interests. In addition to the failed trial, the FDA warned that keeping Makena on the market would expose pregnant women to risks like blood clots and depression. Covis executives pointed to the incidence of premature birth — particularly among Black and socioeconomically disadvantaged women — and a plan to “partially” withdraw the drug until another clinical trial could be completed.

Panelists acknowledged the urgent need for treatments to prevent high-risk preterm births, and sympathized with the hard choices that patients and their treating physicians have to make.

“It is very weighty to think about the most vulnerable populations [and] not giving them access to a treatment that might help them,” said Anjali Kaimal, a panelist from the Department of Obstetrics and Gynecology at the University of South Florida’s Morsani College of Medicine. “But in the same conversation, to think that I’m going to give a very vulnerable population an ineffective treatment also just doesn’t seem like the right thing to do.”

Other advisers were similarly reluctant to allow the drug to remain on the market. “I think to do so would introduce complete regulatory chaos and set precedents that we don’t want to have go forward for other medications,” said Mark Hudak, division chief of neonatology at the University of Florida College of Medicine.

Cassandra Henderson, a maternal fetal medicine consultant who cast the sole vote to keep the drug on the market, said she was concerned about the impact withdrawing Makena would have on further testing. The drug would be available at compounding pharmacies, hurting recruitment and potentially exposing unborn babies to an unregulated version, she argued.

“Many people would not participate because they would not want to get the placebo. They will get the [compounded version] so I’m concerned … that they may seek it another way and get something that we don’t have any control over,” she said.

Makena has a convoluted history on the market. Before the drug’s formal approval by the FDA, doctors could prescribe its active ingredient, hydroxyprogesterone caproate, through compounding pharmacies, which sold it at low cost.

A company called KV Pharmaceutical brought Makena to the FDA, which in 2011 granted accelerated approval on the basis of a trial run by the National Institutes of Health, results of which were published in 2003. The FDA required KV run a confirmatory study to test whether use of Makena reduced premature birth as well as death, respiratory disease and other health problems in infants.

Following that approval, KV proposed raising the price of a single weekly injection of the drug to $1,500, prompting outcry from patients, physicians and other health advocates. The FDA subsequently chose not to bar compounding pharmacies from selling cheaper versions of hydroxyprogesterone caproate. KV eventually cut the price of the drug to $690 a shot.

KV declared bankruptcy one year later and, after emerging from its settlement, changed its name to Lumara Health. In 2014, Amag Pharmaceuticals bought the Lumara business that sold Makena.

KV’s troubles disrupted completion of the confirmatory trial, which the FDA had asked for by the end of 2016. Such “dangling” accelerated approvals have increasingly become a thorny issue for the FDA as drugmakers make greater use of the pathway. In Makena’s case, confirmatory trial results showed the drug did not prevent premature birth or poor health outcomes for newborns.

The advisory committee previously recommended withdrawal of the drug on a 9-7 vote in late 2019. The FDA in 2020 proposed doing just that, days after Covis announced a deal to buy Amag. This week’s hearing was a continuation of that process, giving Covis scientists the opportunity to question and challenge FDA officials while presenting a case for Makena to remain on the market.

Covis executives focused on the earlier NIH trial and on smaller groups of patients who the drug appeared to help in the confirmatory study. The company proposed limiting eligibility for Makena to only those who benefited in both clinical trials. Covis presented this plan, coupled with a pledge to stop active promotion of Makena, as an option for “partial withdrawal.”

Covis also proposed a 400-patient trial that would compare Makena to a placebo and deliver results in four to six years, as well as a larger observational trial to determine whether the drug reduces the number of babies who have health problems related to premature birth.

The FDA, by contrast, supported a trial that could prove Makena does more than reduce premature birth, likely requiring the enrollment of thousands of patients. “We don’t know whether artificially prolonging pregnancy will result in improved neonatal outcomes,” Peter Stein, director of FDA’s office of new drugs said during the meeting.