The U.S. Food and Drug Administration initiated the Accelerated Approval program in the early 1990s to speed the availability of drugs for serious illnesses with few or no treatment alternatives. Originally instituted to spur development of medications for HIV infection, Accelerated Approval has been used primarily for cancer therapeutics over the last decade and more recently, for other slowly progressive diseases, such as Duchenne’s muscular dystrophy, Alzheimer’s disease and other neurodegenerative conditions. Unlike a full FDA approval, which requires proof of clinical efficacy and safety based on agreed-upon clinical endpoints, the agency can grant Accelerated Approval based on a surrogate endpoint – a marker such as a laboratory measurement, radiographic image, physical sign or other measurement that is believed to predict clinical benefit but is not a direct measure of it. The use of a surrogate endpoint can greatly shorten the time-to-market compared to that needed to generate the data to support a full FDA approval. However, sponsors who receive Accelerated Approval for a drug are still required to conduct a confirmatory trial and face the risk of seeing the Accelerated Approval withdrawn if the product’s efficacy and safety profile is not confirmed.
Since the start of the program in 1992, about 300 drugs have been granted Accelerated Approval. The FDA has, however, drawn criticism for failing to adequately enforce sponsors’ compliance with post-Accelerated Approval requirements. In September 2022, a U.S. Health and Human Services (HHS) Office of the Inspector General report found that at least one out of every three drugs achieving Accelerated Approval status since the program’s start had incomplete confirmatory trials; of those, 34% had at least one trial delayed past the originally planned completion date. A study of drugs receiving Accelerated Approval between 1992 and 2017 found that only one in five was confirmed to provide a survival benefit to treated patients. Additional concerns about the Accelerated Approval program stemmed from controversies surrounding Sarepta’s Exondys 51 gene therapy approval for DMD in 2016 and Biogen’s Aduhelm (aducanumab) approval for Alzheimer’s disease in 2021. As a result, FDA leadership called for tighter controls on confirmatory trials and an easier process for the agency to withdraw Accelerated Approval from products that fail confirmatory trials.
The U.S. Congress included reforms to the Accelerated Approval pathway within a spending package passed at the end of 2022, one of which was the Food and Drug Omnibus Reform Act (FDORA). The Act’s objectives were to narrow the (sometimes many years long) time period between an Accelerated Approval and confirmation of benefit as much as possible and to expedite the FDA’s ability to withdraw approvals from drugs whose clinical efficacy cannot be confirmed. The legislation enables the FDA to require an ongoing confirmation study or studies, prior to granting Accelerated Approval, or to have started within a specific, relatively short, timeframe after the approval date. The bill also includes “expedited procedures” for withdrawing an Accelerated Approval, although a sponsor may request an FDA Advisory Committee review of that withdrawal. Additionally, sponsors of drugs that receive Accelerated Approval are required to submit progress reports every six months to the FDA on their confirmatory trial(s), including progress on enrollment targets, milestones, and other information as required by the agency. The legislation also requires HHS to create an FDA intra-agency coordinating council focused on Accelerated Approvals, and in the rare cases where a confirmatory study is not required, FDA must explain publicly why such a study is not appropriate or necessary. Lastly, the FDA must also issue a new guidance by mid-2024 on Accelerated Approval topics relating to surrogate or intermediate endpoints and the design of confirmatory trials.
The full effects of these reforms are unlikely to be felt for a few years, and only time will tell whether these new requirements will improve the drug approval landscape or whether concerns will linger over the validity of Accelerated Approvals. Overall, the new requirements are expected to be more burdensome and time-consuming for drug sponsors, but to greatly increase transparency and restore the viability and credibility of the Accelerated Approval program. As a result, many industry experts believe these changes are in the best interest of both the FDA and the drug sponsors and may help avoid some of the cost-benefit battles on pricing and reimbursement that have been associated with some of the more controversial Accelerated Approvals.