The Food and Drug Administration's accelerated approval pathway, designed to expedite access to crucial medicines for rare and deadly diseases, is facing scrutiny after a federal watchdog report revealed significant gaps in post-approval verification of drug benefits.
According to the U.S. Department of Health and Human Services' inspector general's report released Thursday, one-third of drugs granted accelerated approval haven't completed their required confirmatory trials. More concerning, one-third of these incomplete trials have exceeded their planned completion dates, leaving critical questions about their therapeutic value unanswered.
Growing Use of Accelerated Approvals
The accelerated approval program, initially established during the HIV crisis, has experienced dramatic growth in recent years. Of the 278 total accelerated approvals granted, 70 occurred in 2020 and 2021 alone. These approvals are based on surrogate endpoints – biological markers believed to predict clinical benefits – with the understanding that manufacturers will conduct follow-up trials to confirm actual therapeutic value.
Delayed Confirmatory Trials
The report identified 104 drugs with incomplete confirmatory trials, with 35 surpassing their intended completion dates. A notable example is AMAG Pharmaceuticals' premature birth drug Makena, whose confirmatory trial was completed 64 months behind schedule. The trial's results, which failed to demonstrate clinical benefit, have led to an upcoming FDA advisory committee meeting to discuss potential market withdrawal.
Impact on Healthcare Decision-Making
The delay in completing confirmatory trials creates uncertainty for healthcare providers and patients regarding treatment efficacy. Several factors contribute to these delays, including changes in standard of care and transitions in drug ownership. The situation has already led to some consequences, with multiple immunotherapy drugs being withdrawn from market in certain indications following negative votes from expert panels.
Calls for Reform
Michael Carome, director of Public Citizen's health research group, emphasizes the need for reform: "The inspector general report confirms what has already been widely known: Pharmaceutical companies often fail to complete FDA-mandated post-market studies after a drug product is approved under the accelerated approval pathway."
Legislative Outlook
Despite mounting evidence of systemic issues, recent legislation to renew the FDA's user fee program for five years doesn't include provisions to strengthen the agency's oversight of accelerated approvals. Some lawmakers had proposed setting strict deadlines for confirmatory trials and enhancing FDA's authority to withdraw drugs, but these measures were not included in the final bill.
The scrutiny of the accelerated approval pathway intensified following the controversial approval of Biogen's Alzheimer's drug Aduhelm, which received clearance based on its ability to reduce amyloid plaques despite conflicting data and opposition from expert advisers.
