Covis Pharma’s preterm birth drug should be removed from the market, a panel of outside advisers to the FDA said Wednesday, citing a lack of evidence defending the drug’s clinical benefit since its approval more than a decade ago.
If the agency agrees with the advisers’ recommendation, it would mark the first withdrawal of an accelerated drug approval in more than 10 years.
The Obstetrics, Reproductive and Urologic Drugs Advisory Committee voted 14-1 to back withdrawing Makena, which the Food and Drug Administration approved through its accelerated pathway in 2011 to reduce the risk of preterm birth among patients who previously had an unexplained delivery before 37 weeks.
The recommendation, which followed a two-and-a-half-day hearing, comes as lawmakers and public health leaders advocate for giving the FDA stronger tools to better enforce post-market requirements for fast-tracked drugs.
A final decision is expected in the coming months, and will be up to FDA Commissioner Robert M. Califf and FDA Chief Scientist Namandjé Bumpus.
Accelerated approval allows drugs for serious or rare disease to reach patients more quickly by using biomarkers, or a surrogate endpoint meant to indicate whether the drug will provide a clinical benefit. In exchange, drugmakers are supposed to conduct post-market studies to demonstrate whether there was a clinical benefit.
Critics have long argued that the FDA hasn’t enforced the post-market requirement strongly enough, thereby allowing drugs to remain on the market without certainty that they are effective for patients. The issue was brought to the forefront after the FDA granted accelerated approval to Biogen’s Alzheimer’s drug Aduhelm, despite recommendations against doing so from an outside scientific advisory panel.
The majority of panel members on Wednesday agreed that while there’s an unmet treatment need for patients at risk of preterm birth, there isn’t enough evidence currently available to justify keeping Makena on the market.
Panel member Margery Gass, a professor at the University of Cincinnati College of Medicine, said following the vote that Covis “has already had the benefits of an accelerated approval process” by selling the drug while it conducted additional studies to measure clinical benefit.
“Allowing it to continue on the market would reflect very poorly on the FDA and our advisory committee,” she added.
The lone vote in favor of keeping Makena’s approval came from panelist Cassandra Henderson, a New York-based maternal-fetal medicine consultant.
She argued that a trial among the highest-risk population “demonstrated that there is some signals of effectiveness,” and echoed concerns from Covis that a loss of access to the drug could be particularly harmful for Black patients who face disproportionately higher rates of preterm birth.
Covis CEO Michael Porter said in a statement later Wednesday that the company “respects the regulatory decision-making process and appreciated the opportunity to present our patient-focused study designs and data.”
The company noted Makena remains approved and its label unchanged as it awaits a final decision by the FDA.
Raghav Chari, Covis’ chief innovation officer, said the company believes “Makena is effective in a higher-risk patient population” and “will work collaboratively with the FDA to clarify the next steps in this process.”
‘Lack of Benefit’
A previous advisory committee recommended removing Makena from the market in 2019, arguing that a confirmatory trial failed to verify the anticipated clinical benefit for Makena and that there wasn’t substantial evidence showing Makena is effective at reducing the risk of recurrent preterm birth.
The FDA’s Center for Drug Evaluation and Research proposed in October 2020 that Makena be removed from the market and gave the manufacturers of both the brand-name drug and its generics an opportunity to request a hearing.
CDER Director Patrizia Cavazzoni said Monday in a presentation that allowing Makena to remain on the market while another confirmatory trial is carried out could lead to at least another decade of offering a treatment to patients without certainty of a benefit.
Peter Stein, director of CDER’s Office of New Drugs, said that while there “are not substantial, worrisome risks” associated with Makena, “it’s really about the lack of benefit here.”
Covis agreed that its confirmatory trial didn’t verify Makena’s predicted clinical benefit on neonatal morbidity and mortality from complications of preterm birth. But it requested that the FDA issue a partial, rather than complete, withdrawal of Makena so that it may be used in higher-risk target groups.
The company said it would complete within four to six years a randomized, controlled trial to measure Makena’s effect in the higher-risk target patient population.
Covis attorney Rebecca Wood, who previously served as FDA chief counsel under former commissioner Scott Gottlieb, said in remarks to the committee Tuesday that the “accelerated approval standard is designed to be flexible.” She added that when a confirmatory trial fails, the agency should first consider before deciding to withdraw the drug why the trial failed, whether any other treatment options are available for patients, and if there is a subset of patients for whom the drug is effective.
Califf has called for improvements to the accelerated approval mechanism, saying Monday at the National Organization for Rare Disorders annual rare disease summit that the pathway needs an update “as soon as possible.”
Some key lawmakers have said that accelerated approval changes are at the top of their agenda to add into a year-end government spending package.