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Potential drug removal spotlights latest debate over the expedited pathway.
The long, convoluted FDA process to halt marketing of drugs that fail to confirm safety and efficacy in required postapproval confirmatory studies highlights the need to update and revise FDA’s now-controversial accelerated approval policy. This initiative has succeeded in speeding multiple important therapies to patients over the last 30 years. But the recent advisory committee vote to remove Makena from the market due to its failure to demonstrate benefits for patients illustrates how difficult it is for the regulators to ensure that such drugs document safety and effectiveness in a timely manner.
Makena was approved more than 10 years ago as a treatment to lower the risk of preterm birth in patients considered at-risk for miscarriage, but a confirmatory trial failed to support earlier results. Even so, Makena marketer Covis Pharma has opposed removal, asserting that the drug remains vital for certain high-risk patients. However, FDA’s independent expert panel voted 14-1 in favor of FDA’s decision to halt sales of the therapy, setting the stage for the agency to proceed with its lengthy effort to remove from the market an expedited drug that fails to confirm benefit.
The debate over accelerated approval ignited last year with FDA’s approval of Biogen’s Aduhelm to treat Alzheimer’s disease. That decision generated a range of reform proposals to ensure that sponsors conduct required confirmatory studies and release results. FDA’s Oncologic Drugs Advisory Committee (ODAC) also highlighted the issue at meetings in April 2021 and September 2022 challenging “dangling approvals” for cancer therapies, which prompted some manufacturers to withdraw certain indications and others to renew confirmatory study efforts.
A September report from the HHS Office of Inspector General (OIG) found that more than one-third of early approvals failed to meet timeframes for completing confirmatory studies, and that FDA’s difficulties in compelling withdrawals permit some therapies to stay on the market for years without verifying predicted clinical benefit, at considerable cost to insurers and Medicare and Medicaid. The OIG estimated that Medicaid spent about $700 million on Makena in recent years and said it was “crucial” to give FDA the tools to effectively administer the accelerated approval program.1
Congressional leaders responded to FDA concerns by proposing legislation that requires sponsors to have confirmatory trials underway before gaining an early approval. Additional reforms aimed to facilitate FDA withdrawal of an approval if further study results fail to confirm efficacy within a certain period of time. These and other proposals initially were included in legislation to reauthorize FDA user fees, but were dropped to meet tight deadlines for Congress to approve the funding measure. Efforts continue on Capitol Hill to include accelerated approval revisions in proposed legislation, but a tight Congressional calendar dims prospects for enacting regulatory reform measures.
Stricter oversight of the accelerated approval program appears likely, though, as drug costs and benefits remain in the spotlight. Medicare’s decision to limit coverage of Aduhelm has prompted health plans and insurers to scrutinize more closely the costs and utilization of therapies with conditional approval status. Although anxious to retain the accelerated approval program, the cancer community and numerous patient disease groups recognize that FDA should be able to remove those products where sponsors are unable or unwilling to confirm initial efficacy. The “Project Confirm” initiative at FDA’s Oncology Center of Excellence (OCE) aims to pressure sponsors to provide postapproval data in a timely manner and to withdraw products from the market when postapproval studies fail to confirm benefit or are not completed with due diligence.2
Despite the lack of alternative treatment to Makena for women at risk of miscarriage, FDA is under pressure to halt marketing of the drug to maintain confidence in the accelerated approval program, which was established 30 years ago and is credited with facilitating access to more than 300 treatments for cancer and serious conditions. More recently, FDA has taken action to revoke approvals of some 35 drugs, most for specific indications. Leaving Makena on the market, even for limited use, is opposed as likely to encourage other sponsors to delay confirmatory studies and flout agency rules to maintain profitable sales.
In a recent speech to the National Organization for Rare Disorders (NORD), FDA Commissioner Robert Califf acknowledged the wide benefits of FDA’s accelerated approval program in generating therapies to treat serious rare diseases. He also urged fast action to reduce uncertainty about the true risks and benefits of those therapies approved based on biomarkers and limited clinical trials. More collaboration is needed, Califf said, to establish a “system of evidence generation that provides the confirmation of benefits and risks over years.”3