Top CDER leaders rake Covis over the coals on its failed confirmatory trial, negative data
The FDA put all of its highest-ranking CDER officials on display Monday in the first day of a two-and-a-half-day hearing on whether to pull Covis Pharma’s pre-term birth drug Makena (hydroxyprogesterone caproate) and its generic versions from the market.
After winning an accelerated approval in 2011, Makena failed to beat placebo on neonatal morbidity and mortality from complications of preterm birth in a confirmatory trial ending in 2018, and a prior adcomm in 2019 voted to pull the drug as Covis has continued to fight back.
Patrizia CavazzoniThe Luxembourg-based company, owned by the $32 billion private equity player Apollo Global Management, purchased Makena in 2020 as part of a $647 million deal. And while that deal may have seemed shortsighted at the time, considering the failed confirmatory trial data were already public, HHS’ inspector general recently reported that Medicaid, which insures low-income Americans, spent more than $700 million on Makena from 2019 to 2021.
CDER director Patrizia Cavazzoni offered a staunchly negative perspective at the outset Monday, making clear that the evidence presented shows that Makena is not effective, and it should be withdrawn from the market.
She told the adcomm to vote ‘No’ on all the questions presented, adding this as her final slide:
Covis, meanwhile, used its cross-examination of FDA’s experts to claim issues with multiple studies cited by FDA, raising questions about how some of them didn’t necessarily adhere to the authorized label, or didn’t match patient populations in the US.
Laura Lee Johnson, director of a division of biometrics at FDA, replied that the FDA recognized the limitations in all of the studies under review, but she also noted “a lot of consistency” across the real-world evidence trials.
“Many of the elements that Covis has brought up about what could be different between the trials are not that different,” she said.
Covis attorney Becky Wood, former chief counsel at FDA, also raised concerns about the fact that even if Makena and its generics are pulled from the market, compounded versions of the drug, which may be of lower quality than the prescription version, may remain on the market.
Peter Stein“This is clearly a medication that’s a burden, there’s many injections here … But it’s really about the lack of benefit here,” Office of New Drugs director Peter Stein said. “These are not substantial, worrisome risks, but absent benefit, that’s a problem.”
While Stein noted that there’s room for further study of Makena, Cavazzoni made clear that keeping Makena on the market while another confirmatory trial is run could lead to another decade-long delay. She stressed that any future confirmatory study must be feasible, which “would be exceedingly difficult” if the drug is kept on the market.
Namandjé BumpusStein told panelists to exercise some caution with Covis’ analyses of the confirmatory trial data, while recognizing that the FDA exercised considerable flexibility in approving Makena in the first place.
“I think we really need look with some caution when we’re taking subsets of subsets or even subsets of subsets of subsets,” he said, noting that FDA cannot discount the risks considering the lack of efficacy.
The committee will vote Wednesday on questions related to whether Makena should remain on the market, following more Covis presentations tomorrow, as well as additional adcomm questioning. FDA commissioner Rob Califf and newly-minted FDA chief scientist Namandjé Bumpus will have the ultimate say on Makena.
