FDA Accelerated Approval Program Is Under Spotlight Again with Makena

Oct. 28, 2022 – The Food and Drug Administration’s (FDA’s) accelerated approval process is being scrutinized anew following a recent FDA advisory committee recommendation to remove from the market Covis Pharma’s Makena, a drug that received an accelerated approval in 2011 to help prevent pre-term births. According to a September report from the Office of Inspector General, the drugmaker has failed to demonstrate a clinical benefit 64 months after the original planned date for completing confirmatory studies upon which the approval was conditioned.

On Oct. 19, the advisory panel members voted 14-1 that Makena should be withdrawn from the market, despite the fact that there are no other approved treatments for this condition. The FDA has 90 days to make a decision on this matter and it usually – but not always – follows advisory committee recommendations.

FDA’s accelerated approval pathway has been a source of controversy for some time. The agency was criticized most recently for its accelerated approval of Biogen’s Aduhelm to treat Alzheimer’s disease. At a Coalition for Healthcare Communication webinar in March, Prevision Policy Senior Editor Kate Rawson said that the aftereffects of this decision have called into question “the FDA’s perceived coziness with drug sponsors, its use of advisory committees and its reliance on them, whether or not it actually follows their advice, and the way that it communicates big decisions to the public,” Rawson said.

During FDA Commissioner Robert Califf’s confirmation process, Califf promised that he would prioritize improvements in the accelerated approval process, particularly to ensure that companies complete confirmatory trials after receiving product approvals, which have lagged in the past. The OIG found that “more than one-third of accelerated approval drug applications are past their trials’ original planned completion dates.”

In 2022, the FDA ‘s Oncology Center for Excellence announced “Project Confirm,” to “promote the transparency of outcomes related to Accelerated Approvals for oncology indications,” but broader programs around accelerated approval have not yet addressed the seemingly lax confirmatory trial requirement.

Part of the problem, the OIG report states, is that the process to withdraw an accelerated approval application “involves numerous steps, including FDA detailing the reasons for withdrawal, a withdrawal hearing if requested by the sponsor, presentation of evidence and questioning by FDA and the sponsor, and a decision by the FDA Commissioner. The sponsor may then petition a court to review the Commissioner’s decision and request an order to stay the action pending review.”

In  Makena’s case, even though follow-up studies failed to demonstrate its efficacy and most drugmakers typically withdraw such a product from the market, the company did not. When the FDA indicated it would withdraw the medication in 2020, the drug’s former manufacturer appealed to the agency to keep it on the market for a smaller subset of high-risk patients.

The FDA historically has been slow to take action against companies that fail to stop marketing a product or withdraw an accelerated approval product when confirmatory trials either are not conducted or fail to demonstrate they deliver for patients. “Drugs that may not be effective can remain on the market for lengthy periods,” said Coalition for Healthcare Communication Executive Director Jon Bigelow. If the FDA follows the committee’s recommendation, he noted, “it would be a rare instance of withdrawing a drug from the market.

Advocates for patients who are in need of treatment to prevent pre-term births have called for keeping Makena available. Opponents say  doing so comes at a cost, because it potentially gives patients false hope and results in healthcare payers, such as Medicaid and private insurers, paying high price points for a drug that does not result in desired health outcomes.

The high sticker prices for many drugs granted accelerated approval, such as Aduhelm, can magnify this problem. Indeed, the OIG reports that Medicare and Medicaid spent more than $18 billion from 2018 to 2021 for accelerated approval drugs that had not completed  confirmatory trials past their original planned completion date. Among this group, the OIG states, Makena had the highest estimated Medicaid spending over this period: $700 million.

Several members of Congress have shown an appetite for this issue. Since the Aduhelm decision, multiple bills have been introduced offering various changes in the accelerated approval process. There have been reports that Congress could consider this issue during the lame-duck session after the midterms.

“The accelerated approval pathway can serve an important function in giving patients access to products where there is an important unmet need and preliminary data suggesting efficacy and safety,” Bigelow stated, “but greater rigor is needed in enforcing requirements to complete confirmatory trials on a timely basis, and in removing products that fail to show efficacy.”