Pregnancy drug battle highlights risks of FDA rushing drugs to market

The accelerated approval pathway gives patients with serious conditions earlier access to potentially life-changing treatments, but it may also mean that drugs with questionable benefits and possible risks may remain available for years before regulators do not act.

“It illustrates a number of ways that accelerated approval — despite promising and accepting uncertainty as the FDA clears the drug for use — can go wrong,” said Joseph Ross, professor of medicine. and public health at Yale.

Earlier this year, the FDA asked Congress for clearer authority to ensure that a drug, approved through the fast track, completes and reports the additional tests required more quickly and to facilitate the removal of the drug from the market if those results are disappointing.

While Congress has yet to act on the agency’s request, the decision to take Makena signals that the FDA wants to be more aggressive in ensuring that fast-track drugs are in fact safe and effective, and easier to withdraw from circulation if they are 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 granted expedited approval have incomplete confirmatory trials, and Makena’s was one of the four that were “significantly overdue” – that is, five or more years past their scheduled completion date.

FDA staff told the Inspector General’s Office that the Makena case is “an example of how long and cumbersome the withdrawal process is when a sponsor disagrees with the decision of the FDA. FDA to withdraw drug approval,” according to the report.

The HHS inspector general also found that Medicare and Medicaid spent more than $18 billion between 2018 and 2021 on drugs that have yet to be verified for expedited approval. Makena had the highest estimated Medicaid expenditures at around $700 million.

The FDA’s fight to remove Makena, which is for people carrying a child who has a history of early labor, from the market has dragged on even though clinical trial results in 2019 showed it was not effective. to prevent childbirth before age 35. weeks of pregnancy or reduce the risk of adverse conditions in preterm infants. Since then, the drug’s sponsor, which has changed over the years through corporate acquisitions, and some patient groups have advocated for the injection to remain available, arguing that it could benefit a subset of pregnant women at high risk of preterm birth, such as black women. , and that there are no other treatment options for these patients.

Premature birth, which occurs before 37 weeks of pregnancy, occurs in about 10% of all births and affects black women more than other racial groups in the United States. Its causes are not well understood. Premature babies 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 reducing the rate of preterm labor. Regulators said the data point was “reasonably likely to predict the reduction in neonatal morbidity and mortality associated with” preterm birth, although the drugmaker was commissioned to complete a clinical trial for confirm that 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 delivery. That prompted the FDA’s external advisers in a split vote in 2019 to recommend the agency pursue removing the drug from the market.

The FDA’s Drug Center proposed in October 2020 that Makena’s approval be withdrawn, giving owners of the brand name drug and its generics the opportunity to request a hearing.

“It’s been an extremely long process for the FDA to act, and it’s not because of their inability to review the evidence and make sound decisions,” said Amy Abernethy, former senior deputy commissioner of the FDA. ‘agency.

FDA spokeswoman 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 process and a strong forum for the sponsor and the public to present their views on the proposed withdrawal of agency approval and an advisory committee with the appropriate expertise.

The FDA has also undergone leadership changes during this period, with three people serving as interim or confirmed commissioners since the drug processing center proposed removing Makena.

Covis Pharma, which now owns Makena, argues the confirmatory study was flawed because it recruited fewer high-risk patients, including fewer black women, than the earlier trial that backed its fast-track approval bid. A company spokesperson said Covis is interested in working with the FDA on other study options and on reducing Makena’s label to apply to patients most at risk while the research is taking place.

“There is no valid public health reason to deny access to the only available treatment approved by the FDA 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 spokesman Francesco Tallarico told POLITICO.

The FDA argues that the evidence does not show that any subset of the population — whether based on race or number of previous spontaneous preterm births — “responds more favorably to Makena.” Additionally, regulators said, the drug poses blood clot risks which, coupled with a lack of efficacy, make keeping it on the market untenable.

“Not removing Makena would mean maintaining FDA approval of a drug that, based on all available evidence, has not been shown to be more effective than no treatment, but is riskier than no treatment. ‘lack of treatment,’ the FDA said. “It would be a disservice to patients at risk of recurrence [preterm birth] and jeopardize the fast-track approval pathway.

Leaving the drug on the market would also make it more difficult to continue studying its effectiveness, the FDA said, because the best way to collect that data — and to outweigh the negative result seen in the trial of previous confirmation – is to use a randomized placebo. controlled trial.

But that would be nearly impossible to do in the United States, the FDA said, because patients who didn’t want to risk being assigned the placebo could avoid it by not enrolling in the study at all, while still still having access to an FDA-approved drug. medication. It would likely take at least another decade to complete, the agency added, meaning a drug with unverified benefits would stay on the market for at least 20 years.

“Whether [FDA’s Center for Drug Evaluation and Research] cannot withdraw drugs approved under the expedited approval pathway when multiple grounds for withdrawal exist and the prospect of demonstrating efficacy is remote at best, this would defeat Congress’s goal of provide for expedited withdrawal of drugs approved under this pathway,” the FDA said.

The history of the fast-track 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 for the disease. raging epidemic. The vast majority of fast-track approvals granted over the past decade have been for cancer drugs, although the most recent to spark controversy in the medical community was the 2021 approval of Aduhelm for Alzheimer’s disease.

Drugmakers often voluntarily withdraw their products from the market if follow-up trials don’t show clear efficacy, sometimes re-evaluating them in different populations to see if it’s worth pursuing another drug indication later.

The only time the FDA ordered the withdrawal of a drug’s approval 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 to “off-label” patients if they thought their patients might possibly 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 president will release a report on the counselors’ recommendations and her own opinions within 45 days of the release of the meeting transcript, then open a 45-day comment period for the drug treatment center and for Covis.

FDA Commissioner Robert Califf and the agency’s chief scientist will review the comments and the case file before making a decision “and plan to do so quickly,” Hatch said.

Approving drugs under fast-track approval that are not subsequently 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. which examines the clinical and economic value of drugs and medical 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 deterred from removing the product from the market.

Comments are closed.