The accelerated approval pathway gives patients with serious conditions earlier access to potentially life-changing treatments, but it can also mean that drugs with questionable benefits and possible risks can remain available for years before regulators intervene.
“This illustrates a number of ways that accelerated approval — despite the promise and the acceptance of uncertainty at the time the FDA approves the drug for use — can go wrong,” said Joseph Ross, professor of medicine and public health at Yale.
The FDA earlier this year asked Congress for clearer authority to ensure that a drug approved through the accelerated pathway completes and reports on additional required trials more quickly and to make it easier to pull the drug from the market if those results are disappointing.
While Congress has yet to respond to the agency’s request, the move to accept Makena signals that the FDA wants to be more aggressive in making sure that fast track drugs are actually safe and effective and easier to remove from circulation if they aren’t.
A recent report by the Department of Health and Human Services’ office of inspector general found that more than a third of the drugs granted accelerated approval have incomplete confirmatory trials, and that Makena’s was one of four that were “significantly overdue” – meaning five or more years beyond their expected completion dates.
FDA staff told the inspector general’s office that the Makena case is “an example of how lengthy and burdensome the withdrawal process can be when a sponsor disagrees with the FDA’s decision to withdraw a drug’s approval,” according to the report.
The HHS inspector also found that Medicare and Medicaid spent more than $18 billion between 2018 and 2021 on drugs granted accelerated approval that have yet to verify clinical benefit. Makena had the highest estimated Medicaid spending at about $700 million.
The FDA’s fight to pull Makena, which is intended for people carrying a child who has a history of going into preterm labor, off the market has dragged on, even though clinical trial results in 2019 showed it was not effective for to prevent delivery before 35 weeks of pregnancy or reduce the risk of adverse conditions in premature newborns. Since then, the drug’s sponsor, which has changed over the years as a result of corporate acquisitions, and some patient groups have advocated for the injection to remain available, arguing that it may benefit a subset of pregnant people at high risk of prematurity childbirth, 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 United States. The reasons are not well understood. Babies born prematurely have an increased risk of serious consequences, including long-term physical and developmental problems or death, according to the FDA.
The FDA granted accelerated approval to Makena after an earlier trial showed a statistically significant difference between the injection and a placebo in lowering the rate of preterm birth. Regulators said the data point was “reasonably likely to predict reductions in neonatal morbidity and mortality associated with” preterm birth, although the drugmaker was tasked with conducting a clinical trial to confirm the drug worked, a standard requirement for the expedited approval process .
But the results showed that the drug is not effective in improving the health of premature babies or reducing the risk of premature birth. That spurred outside FDA advisers in a split vote in 2019 to recommend the agency continue to pull the drug from the market.
The FDA’s Center for Medicines recommended in October 2020 that Makena’s approval be withdrawn, giving the owners of both the brand-name drug and its generics the opportunity to request a hearing.
“It’s been an extremely long process for the FDA to be able to intervene, and it’s not because of an inability to review the evidence and make sound decisions,” said Amy Abernethy, a former deputy commissioner at the agency.
FDA spokesman Shannon P. Hatch said the two years between the agency’s proposal and this week’s meeting “primarily reflect FDA’s efforts to ensure a fair and robust process for the sponsor and the public to present their views on the proposed withdrawal of approval to the Agency and an advisory committee with appropriate expertise.”
The FDA has also undergone leadership changes during the time, with three people serving as acting or confirmed commissioners since the drug agency proposed pulling Makena.
Covis Pharma, which now owns Makena, claims the confirmatory study was flawed because it enrolled fewer high-risk patients, including fewer black women, than the earlier trial that supported its accelerated approval bid. A company spokesman said Covis wants to work with the FDA on further study options and to narrow Makena’s label to apply to the highest-risk patients while this research takes place.
“There is no sound public health reason to deprive 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,” Covis spokesperson Francesco Tallarico told POLITICO.
The FDA claims that the evidence does not show that any population subgroup — whether based on race or number of prior spontaneous preterm births — “responds more favorably to Makena.” Plus, regulators said, the drug poses blood-clotting risks that, when paired with a lack of efficacy, make leaving it on the market untenable.
“Failure to withdraw Makena would mean maintaining FDA approval of a drug that, based on all available evidence, has not been shown to be more effective than, but is riskier than, no treatment,” the FDA said. “This would be a disservice to patients at risk of recurrence [preterm birth] and would undermine the accelerated approval pathway.”
Leaving the drug on the market would also make it more difficult to continue studying its effectiveness, the FDA said, since the best way to collect that data — and trump the negative result seen in the previous confirmatory trial — is through a randomized, placebo-controlled attempt.
But that would be nearly impossible to do in the United States, the FDA said, since patients who don’t want to risk being assigned a placebo could avoid it by not enrolling in the study at all while still having access to an FDA-approved drug. That would likely take at least another decade to complete, the agency added, meaning a drug with unproven benefit would remain on the market for at least 20 years.
“Whose [FDA’s Center for Drug Evaluation and Research] cannot withdraw drugs approved under the accelerated approval pathway when there are multiple reasons for withdrawal and the prospect of demonstrating efficacy is at best remote, this would frustrate the congressional purpose of providing for accelerated withdrawal of approved drugs under this procedure,” 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 argued that the agency was moving too slowly to approve potentially life-saving treatments to address the raging epidemic. The vast majority of accelerated approvals granted in the past decade have been for cancer drugs, although the latest to spur controversy in the medical community is the 2021 approval of Aduhelm for Alzheimer’s disease.
Drug manufacturers will often voluntarily remove their products from the market if follow-up trials do not show clear efficacy, and sometimes reevaluate them in different populations to see if it is worth pursuing a different drug indication later.
The only time the FDA has ordered a drug’s approval to be withdrawn was in 2011 for Avastin, and that decision was limited to its indication for the treatment of metastatic breast cancer. This meant it remained on the market for other uses, allowing doctors to prescribe it to patients “off label” if they thought their patients might benefit from it.
The FDA’s Hatch said management has outlined a timeline it plans to follow to make a final decision on Makena in the coming months. The agency’s chairwoman will issue a report on the advisers’ recommendations and her own views within 45 days of the meeting’s transcript being released, 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 case record before making a decision “and plan to do so quickly,” Hatch said.
Approving drugs under accelerated approval that later turn out not 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 drugs and hospital equipment.
“It’s a failure if the confirmatory trial is not done in a timely manner,” he added, as well as if a trial has negative results and the FDA is still discouraged from removing the product from the market.