A Food and Drug Administration advisory committee on Wednesday recommended removing the drug Makena from the market, after years of study showed the fast-tracked drug had failed to prevent preterm births.
Makena has been in use for 11 years, and the panel’s vote was widely viewed as a test of the agency’s “accelerated approval” program, which has expedited nearly 300 promising drugs to the market in 30 years. The program has been criticized for leaving many drugs in use as follow-up studies drag on to determine whether they work. The program drew considerable fire over the approval of the Alzheimer’s drug Aduhelm last year, a costly drug that many experts viewed as unproven.
This is the first time in more than a decade that the agency, which typically follows the advice of its expert panels, appears poised to force a drugmaker to stop selling a fast-tracked product.
The move to pull Makena from the market — the only drug approved to forestall preterm birth — has been laced with emotional appeals and issues of race and health disparity. The risk of preterm birth is much higher for Black women, a point that Covis Pharma, the drug’s manufacturer, had pressed in a lengthy effort to make its case to the FDA
According to the Centers for Disease Control and Prevention, preterm birth, defined as being born before 37 weeks of pregnancy, affected one of every 10 US infants in 2020. But the agency noted racial and ethnic differences: That same year, the rate of preterm birth among African American women (14.4 percent) was about 50 percent higher than the rate of preterm birth among white or Hispanic women (9.1 percent and 9.8 percent, respectively).
If the agency follows the panel’s recommendation and orders the drug off the market, patients who had a preterm birth and faced a second one would have no approved treatment (although Covis could continue studies of the drug).
The situation is devastating, said Annie Ellis, a patient representative on the panel from White Plains, NY, who recommended removal of the drug Wednesday.
“It is brutally painful that there’s nothing available in 2022 in the United States of America,” she told the committee. “The inequities that exist and the state of neonatal morbidity — for mothers it’s just painful on so many levels.”
The advisory committee weighed in on three separate votes on Wednesday. All 15 of the voting panel members agreed that the lengthy post-market trial of the drug did not show a benefit to babies. Thirteen also agreed that the drug was not proven to be effective in reducing risk for preterm birth in women who already had one preterm birth. Fourteen agreed that the drug should be withdrawn from the market.
After voting for the drug’s removal, Dr. Anjali Kaimal, an obstetrician and administrator at the University of South Florida, conceded that it was “terrifying” to tell a patient there is no treatment for a serious condition. But “additional study is needed,” she said. “I want to believe there is a solution for preterm birth.”
Makena was approved on a conditional basis in 2011 after it appeared to help mothers carry a baby to term — a factor thought to reduce infant death and disability. The company said 350,000 US women have taken it in the past decade. After years of follow-up study, the drug failed to benefit newborns more than a placebo.
Typically, drugmakers quietly withdraw a medication after such a defeat. Yet Covis Pharma, owned by the private equity firm Apollo Global Management, appealed to the agency to allow it to keep the drug on the market for a narrowed group of high-risk women, while promising to stop promoting the drug and to conduct one more study.
“A complete withdrawal of the product would harm the patients at the highest risk for preterm birth,” Raghav Chari, the chief innovation officer for Covis, said during the company’s presentation on Tuesday. “We’re proposing a way forward that is best for women and their babies.”
He also warned that even if the FDA withdrew the drug, it might remain available from specialized compounding pharmacies, which had a track record of sterility and contamination problems.
After the vote, Francesco Tallarico, Covis chief counsel, said the company would submit additional information to the agency. He said it was too soon to say whether the company would conduct further study of the drug.
“We are disappointed with the outcome today,” Mr. Tallarico said. “Our intention was and is to do the best thing for patients.”
During a three-day hearing this week, agency officials squared off with Covis, citing their shift from hope to disappointment that the drug would help babies at risk of death or lifelong health problems.
“We once thought Makena was likely to be part of the answer to that problem,” Dr. Patrizia Cavazzoni, director of the agency’s drug division, said. “Unfortunately, we no longer do.”
In a summary prepared for the hearing, the FDA said failing to withdraw the drug “would be a disservice to patients” at risk for preterm birth “and would undermine the accelerated approval pathway.” The agency also noted that the drug carried the risks for blood clots, depression and allergic reactions.
dr Namandjé Bumpus, the FDA chief scientist, and Dr. Robert Califf, the agency commissioner, will issue a final decision in roughly 90 days.
Among those who tested in favor of Covis’s appeal was Dr. Washington Hill, a Black maternal-fetal specialist in Florida. After the vote, Dr. Hill said he had hoped for a different result but saw one positive: The panelists all endorsed the incredible need for the high-risk “Black, brown and vulnerable” patients to get an effective treatment.
“We need the companies to do that,” Dr. Hill said. “Companies may not be willing to go down this road again. They may not.”
With no approved treatment, Dr. Hill said doctors only have therapies for subgroups of women who have had a preterm birth. He said they can also prescribe bed rest, though there’s little evidence that it works.
The NAACP also weighed in before the hearing with a letter urging advisers to heed other advocacy groups that said withdrawing the drug could “deepen profound existing maternal and infant health inequities in the US”
The hearing has been widely compared to another in 2011, when advisers considered whether to keep the drug Avastin on the market to treat breast cancer. It was also approved under the accelerated pathway, and follow-up study showed the drug presented risk, but little benefit. Still, women who took the drug and survived their cancer filled a hearing room that echoed with applause as they made emotional pleas to the agency to keep it on the market.
That hearing was so contentious that advisory committee members — who voted to pull the drug — were whisked out of the hearing by security guards into a waiting fleet of black sedans. dr Margaret Hamburg, the agency commissioner at the time, ultimately decided to pull the drug’s approval for that use.
The virtual hearing for Makena that began Monday lacked the electricity of an in-person event, with a handful of women asking the agency to study the drug further via teleconference.
The FDA announced its intention to take Makena off the market in 2020, citing the failed study of more than 1,700 women. The company that owned the drug at the time, AMAG Pharmaceuticals, appealed the decision, teeing off years of wrangling over the details of the hearing that concluded Wednesday.
The delay was lucrative for the drugmaker: A recent government watchdog report estimated that Medicaid, which covers the cost of about 40 percent of births in the United States, paid nearly $700 million for courses of Makena since the study to gauge its benefits was due in 2018. The report, by the inspector general for the Department of Health and Human Services, found that government payers spent $18 billion in total on drugs that were approved based on promising findings — but stayed on the market after the date they were supposed to prove a benefit.
The accelerated-approval pathway is meant to speed drugs to market for deadly conditions and those with no other available therapy. Since the program began in 1992, the agency has revoked the approval of 35 drugs for specific uses. Most of those decisions have occurred since last year, as criticism flared about the Aduhelm approval and other drugs languished with no proof of benefit.
The FDA this year announced “Project Confirm,” which is focused on evaluating fast-tracked cancer drugs.
The decisive advisory vote on Makena underscores why Congress should follow through with giving the FDA more authority to expedite follow-up studies and remove drugs from the market if they come up short, said Dr. Aaron Kesselheim, a Harvard physician who has researched the program.
Upholding trust in the program “requires acting expeditiously in cases like this where the initial hope” falls short.