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Speedy FDA approvals in focus as agency weighs withdrawal of preterm birth drug

The Food and Drug Administration will decide in the coming months whether to withdraw a controversial drug for preventing preterm births. The looming choice, which comes after years of regulatory back and forth, is also a larger test of the agency’s process for speeding promising medicines to market on early evidence they might work.

The drug, called Makena, won an accelerated approval from the FDA in 2011. But eight years later, the treatment failed a mandatory trial intended to confirm it could meaningfully reduce complications related to preterm birth in infants.

On Wednesday, more than three years after those trial results were made public, advisers to the FDA set the stage for a final judgment from the agency, voting 14-1 that Makena should be removed from the market.

FDA Commissioner Robert Califf and Chief Scientist Namandjé Bumpus will ultimately make the call. Their decision could still take months, allowing Makena’s owner, Covis Pharma, to continue selling it in the meantime.

Since its introduction, the accelerated approval pathway has made dozens of drugs available to patients sick with a range of diseases more quickly than they otherwise would have. But the program has also come under scrutiny and criticism for allowing treatments with unproven benefit to remain on the market, even after negative results in follow-up testing.

The long interval between Makena’s study failure and the FDA’s attempt to withdraw its approval highlights this flaw, critics say.

“The process for withdrawing approval of a drug approved under the accelerated approval process is way too cumbersome,” said Michael Carome, director of health research at Public Citizen, a vocal non-profit group.

Carome and other advocates, along with many policymakers, have also noted how drugmakers are frequently late in completing required confirmatory testing.

Scrutiny of accelerated approvals has intensified following the agency’s controversial decision last year to grant a conditional clearance to Biogen’s Alzheimer’s disease drug Aduhelm. The federal Medicare program later refused to cover it because of questions over whether it helps patients.

In documents published ahead of this week’s meeting on Makena, FDA staff made the case that leaving Covis’ drug on the market could risk compromising accelerated approvals more broadly.

“Given that Makena is no longer shown to be effective, but does carry risks, there is no public health justification for allowing Makena to remain on the market in the interim, and doing so would undermine the integrity of the accelerated approval program,” FDA staff wrote.

At the meeting, advisers acknowledged the program’s credibility is at stake in the decision on Makena.

“I think it is important that we avoid going down a pathway that will cause regulatory chaos,” said member Mark Hudak, chair of pediatrics at the University of Florida College of Medicine. “Accelerated approval has very clear expectations and these were not met [in Makena’s confirmatory study].”

This year, Congress attempted to boost the FDA’s ability to withdraw drugs that are cleared on an accelerated basis. Legislation produced by Rep. Frank Pallone, D-N.J., would have sunset accelerated approvals after five years, for example.

A bill that passed the House, meanwhile, gave the FDA more power to pull accelerated approvals and mandate the start of confirmatory trials. Ultimately, those measures were left off of a five-year FDA funding provision that passed Congress as part of a stopgap spending bill and was signed by President Joe Biden.

Congress might have another opportunity to look at accelerated approvals in legislation required to extend certain FDA programs, including pediatric drug research incentives, that will expire in December.

“I do think the fact that the FDA was willing to go through this very expensive, time-consuming process [for Makena] certainly speaks well of the agency’s increasing efforts to enforce the terms of the program,” said Rachel Sachs, a law professor at Washington University. “But it seems as if the agency is continuing to request support in their efforts here, and they’re not always getting it from Congress.”

Sachs, along with two co-authors, wrote in the The New England Journal of Medicine in July that Pallone’s proposal would avoid prescriptive requirements, and simplify cases with its plans for automatic sunsetting.

In some cases, the FDA’s discretion helps rather than hinders the process, Sachs told BioPharma Dive. The FDA has recently tightened its oversight of cancer drugs granted an accelerated approval, convincing a number of companies to voluntarily withdraw their products, or certain indications for their use.

“If every oncology drug manufacturer who currently agrees to voluntary withdrawal were to insist on the level of process guaranteed in the [FDA reauthorization], it would actually significantly increase the amount of process the agency does have to go through,” Sachs said.

In those recent cases, companies might have been more willing to bow to FDA pressure because their treatments often have other uses for which they remain approved.

The flexibility afforded under the current process is not lost on some in the industry. The non-voting industry representative on the panel, Michelle Fox of Merck Research Laboratories, said it would not be appropriate to keep a drug on the market after it was proven ineffective.

Covis could still challenge an FDA decision to withdraw Makena in court, which could further influence the agency’s thinking about accelerated approvals.

“The more Covis fights, and the harder they make it for the FDA to withdraw some of these products on the back end, it has to impact incentives to approve these products on the front end,” Sachs said.