The accelerated approval process gives patients with serious conditions earlier access to potentially life-changing treatments, but it could also mean that drugs with questionable benefits and potential risks could remain available for years before regulators take action.
“This illustrates some of the ways the accelerated approval — despite the promise and acceptance of uncertainty at the time the FDA clears the drug for use — can go bad,” said Joseph Ross, a professor of medicine and public health at Yale.
The FDA asked Congress earlier this year for clearer authority to ensure that a drug approved through the accelerated track completes and reports additional required studies more quickly, and to make it easier to take the drug off the market. if those results fail.
While Congress has yet to respond to the agency’s request, the move to take Makena indicates that the FDA wants to be more aggressive in ensuring that accelerated drugs are, in fact, safe, effective and easier to remove from circulation if them not.
A recent report from the Office of Inspector General of the Department of Health and Human Services found that more than a third of drugs that get accelerated approval have incomplete confirmatory studies, and Makena’s was one of four “significantly late” were — meaning there are five or more years past their expected end date.
FDA staff told the inspector general’s office that the Makena case is “an example of how long and onerous the withdrawal process can be when a sponsor disagrees with the FDA’s decision to withdraw approval for a drug.” pull,” the report said.
The HHS Inspector General also found that Medicare and Medicaid spent more than $18 billion between 2018 and 2021 on accelerated-approved drugs whose clinical benefit has yet to be verified. Makena had the highest estimated Medicaid spending at about $700 million.
FDA’s battle to pull Makena, which is intended for people carrying a child with a history of preterm labor, from the market, even though clinical trial results in 2019 showed it was ineffective at preventing labor before age 35 . weeks of pregnancy or reducing the risk of adverse conditions in preterm newborns. Since then, the drug’s sponsor, which has changed over the years amid company takeovers, and some patient groups have argued for the continued availability of the injection, arguing that it targets a subset of pregnant people at high risk of preterm birth. such as black women, and that there are no other treatment options for those patients.
Preterm birth, which occurs before 37 weeks of pregnancy, occurs in about 10 percent of all births and affects black women more than other racial groups in the US. The causes are not well understood. According to the FDA, premature babies have an increased risk of serious consequences, including long-term physical and developmental problems or death.
The FDA granted accelerated approval to Makena after a previous trial showed a statistically significant difference between the injection and a placebo in reducing the rate of preterm birth. Regulators said the data point would “reasonably predict the reduction in neonatal morbidity and mortality associated with” preterm birth, although the drug’s manufacturer was tasked with conducting a clinical trial to confirm the drug worked, a standard requirement for the accelerated approval process.
But the results showed that the drug is not effective in improving the health of premature babies or reducing the risk of preterm birth. That spurred outside FDA advisors in a 2019 vote to recommend the agency pull the drug from the market.
The FDA’s Drug Center proposed in October 2020 to withdraw Makena’s approval, giving owners of both the brand-name and generic drugs the opportunity to request a hearing.
“It’s been an extremely long process for the FDA to take action, and it’s not because of its inability to review evidence and make judicious decisions,” said Amy Abernethy, a former chief deputy commissioner at the agency.
FDA spokesman Shannon P. Hatch said the two years that have passed between the agency’s proposal and this week’s meeting “primarily reflect the FDA’s efforts to ensure a fair and robust process for the sponsor and the public.” to give their views on the proposed withdrawal of approval to the Bureau and an advisory committee with the necessary expertise.”
The FDA has also undergone leadership changes during that time, with three people serving as acting or confirmed commissioners since the drug center proposed that Makena should withdraw.
Covis Pharma, which now owns Makena, argues that the confirmatory study was flawed because fewer high-risk patients were enrolled, including fewer black women, than the earlier study that supported the accelerated approval bid. A company spokesperson said Covis plans to work with the FDA on further study options and narrowing Makena’s label to apply to the highest-risk patients while that study is underway.
“There is no good public health reason to deny access to the only available FDA-approved treatment to reduce the risk of preterm birth in pregnant women with a history of spontaneous preterm birth – especially when there are no other approved alternatives,” says Covis spokesman Francesco. Tallarico told POLITICO.
The FDA states that the evidence does not show that any subset of the population — whether based on race or the number of previous spontaneous preterm births — “responds more favorably to Makena.” In addition, regulators said, the drug carries risks for blood clots that, combined with a lack of efficacy, make it untenable to keep it on the market.
“Failing to withdraw Makena would mean maintaining FDA approval of a drug that, based on all of the available evidence, has not been shown to be more effective than, but riskier than, no treatment,” the FDA said. . “This would be a disservice to patients at risk of relapse.” [preterm birth] and would undermine the accelerated approval process.”
Keeping the drug on the market would also make it harder to continue studying its effectiveness, the FDA said, since the best way to collect that data — and trump the negative outcome of the earlier confirmatory study — is through a randomized placebo-controlled trial.
But that would be nearly impossible in the US, the FDA said, as patients who don’t want to risk receiving the placebo can avoid it by not enrolling in the study at all, while still having access to a FDA-approved drug. It would likely take at least another 10 years to complete, the agency added, meaning a drug with unverified benefits would remain on the market for at least 20 years.
“If [FDA’s Center for Drug Evaluation and Research] Being unable to withdraw drugs approved under the accelerated approval process when multiple reasons for withdrawal exist and the prospect of demonstrating effectiveness is remote at best would frustrate Congress’ goal to provide for an accelerated withdrawal of drugs approved under this pathway,” the FDA said.
The history of the accelerated approval program dates back to 1992, when the FDA launched it largely in response to HIV/AIDS activists who claimed the agency was acting too slowly to approve potentially life-saving treatments to stem the raging epidemic. The vast majority of accelerated approvals granted in the past decade have been for cancer drugs, although the most recent to spark controversy in the medical community is Aduhelm’s 2021 approval for Alzheimer’s disease.
Drug manufacturers will often voluntarily remove their products from the market if follow-up studies fail to show clear effectiveness, sometimes re-evaluating them in different populations to see if it’s worth pursuing a different drug indication later on.
The only time the FDA has ordered that a drug’s approval be withdrawn was in 2011 for Avastin, and that decision was limited to its indication for the treatment of metastatic breast cancer. That meant it remained on the market for other uses, allowing doctors to prescribe it “off-label” to patients if they thought their patients might benefit from it.
The FDA’s Hatch said the leadership has outlined a timeline it plans to follow to make a final decision on Makena in the coming months. The agency’s presiding officer will report on the advisers’ recommendations and her own views within 45 days of the meeting transcript being made public, and then open a 45-day comment period for the drug center and for Covis.
FDA Commissioner Robert Califf and the agency’s chief scientist will review the comments and the file before making a decision “and intend to do so urgently,” Hatch said.
Approving drugs under accelerated approval that have not subsequently been shown to be effective is not an inherent failure of the program, said Steve Pearson, president of the Institute for Clinical and Economic Review, a nonprofit organization that evaluates the clinical and economic value of assesses drugs and medical equipment.
“It is a failure if the confirmatory trial is not done on time,” he added, as well as if a trial has negative results and the FDA is still deterred from taking the product off the market.