Premature birth treatment may lose FDA approval due to efficacy questions

US Food and Drug Administration advisers are again recommending that a drug aimed at preventing premature births be pulled from the market due to doubts about its effectiveness.

This week, the Advisory Committee on Obstetric, Reproductive and Urological Drugs moved a nearly unanimous vote (14 to 1) against the continued availability of the drug, known as Makena, after a three-day hearing. The FDA will consider the guidance to determine the drug’s fate.

Makena, a synthetic hormone also known as hydroxyprogesterone caproate, is an injection that can be given weekly to pregnant women to prevent premature birth or birth before 37 weeks when a baby is not fully developed. It’s made by Covis Pharma and got accelerated approval from the FDA in 2011 due to the lack of other treatments to prevent premature birth.

However, the future of the drug is in question as a confirmatory study conducted in 2019 failed to prove that the treatment was effective or led to better health outcomes compared to a placebo.

FDA advisers have been raising questions about the drug since late 2019. Since then, Covis Pharma has requested and was given the opportunity to defend its drug in this week’s hearing.

“While I believe there are no significant harms that have been demonstrated with Makena, there are still costs to continue to have it in the market as we try to determine who it might work for. and I think this is a very important question for an answer and further study is needed,” said Dr. Anjali Kaimal, member of the advisory board and vice president of the Morsani’s Obstetrics and Gynecology Clinical Operations Department. College of Medicine at the University of South Florida.

“One hundred percent there has to be another try because I want to believe there is a solution for premature births and that could be part of what our instrument can be to try to help people.”

Kaimal also noted that keeping a drug on the market that hasn’t been shown to be effective could divert further investigation and funding from different ways to prevent preterm birth.

Covis said he still believes his drug is helpful for patients at high risk of preterm labor. As part of its hearing, the company called Makena the standard of care in the United States for more than a decade and said it was neither necessary nor appropriate for the FDA to withdraw approval for use of the drug. medicine at the moment.

Rather than lose its FDA approval, Covis representatives said they were open to more studies to prove the drug’s effectiveness and would work with the FDA to reduce labeling to focus on the highest risk patients while these studies are being conducted.

“Given the demonstrated clinical benefits and safety profile of Makena, there is no reason to deprive women of the only available treatment approved by the FDA to reduce the risk of preterm birth in high-risk women during that further study is being conducted,” the company wrote. in his brief to the FDA.

In 2020, preterm birth affected 1 in 10 infants in the United States. Michigan has reported between 8,500 and 8,900 such births over the past decade.

The last weeks of development before birth are important for brain, lung and liver health. Death and disability rates are higher for babies born early, especially before 32 weeks.

The cause of preterm labor is unknown in most cases. According to the US Centers for Disease Control and Prevention, some known factors associated with early labor include previous preterm birth, infection, carrying more than one baby at a time, stress, and/or consumption of tobacco or substances. Cases are also more common among teenage girls and women over 35, low-income women and black women.

In 2020, preterm births were more common among black (14.4%) mothers than white (9.1%) or Hispanic (9.8%) mothers, according to CDC data.

Makena got accelerated approval in February 2011 after a trial involving 463 women found the drug effective in reducing the risk of preterm birth, especially in high-risk women. The approval came with the requirement that a confirmatory trial be conducted.

A larger trial in 2019 recruited 1,708 women from nine countries. Weekly administration of the drug from 16 weeks of pregnancy was found to not reduce the risk or produce better health outcomes.

Members of the advisory committee reviewed the data in October 2019 and voted unanimously that the trial did not verify the clinical benefit of Makena for neonatal outcomes. Nine members recommended withdrawing approval, while seven recommended retaining approval and requiring a new confirmatory trial.

Meanwhile, the FDA’s Center for Drug Evaluation and Research has found that all of the evidence supports the removal of Makena from the market.

“We sympathize with women who are at risk of recurrent preterm birth which could lead to death or significant health effects in newborns, but the continued availability of a drug whose efficacy has not been demonstrated for this use does not protect or promote their health,” the members of the Center for Drug Evaluation and Research wrote in December 2020. “We remain committed to working with the scientific community, stakeholders, and drug developers to accelerate the marketing of effective and safe drugs for premature births.

During its hearing, Covis claimed that the 2019 study had flaws, including that it was conducted in a low-risk population and located primarily outside the United States where there were different standards of care. The Center for Drug Evaluation and Research countered by noting that there were 391 American women in the second study, which was close enough to the original study that geographic region did not explain the lack of efficacy.

Covis proposed that another confirmatory study be conducted and said it was also willing to undertake an observational study. While the company awaits action from the FDA, Makena remains available.

Video of Wednesday’s advisory panel hearing is available on the FDA’s YouTube page, here.

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About Antoine L. Cassell

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