FDA and Congress Re-Examine Accelerated Approval Program

Congressional leaders are proposing significant changes in FDA’s accelerated approval (AA) pathway for expedited development of important new therapies to address critical health conditions. The AA program has long faced criticism due to sponsor delays in conducting required postapproval studies to confirm clinical benefit. Moreover, FDA’s surprise decision in 2021 to approve Biogen’s controversial Alzheimer’s treatment Aduhelm under the accelerated process has focused attention on the risks, benefits, and possible reforms to the program.

These issues have moved to center stage as Congress begins consideration of a host of proposals for revising and improving policies related to drug development and regulation for possible inclusion in broader legislation to reauthorize FDA user fees. The legislative process began with a hearing March 17, 2022 before the House Energy & Commerce (E&C) Health subcommittee. The panel reviewed more than 20 reform proposals that seek to expand diversity in clinical trials, to encourage domestic drug manufacturing, and to support development of generic drugs, biosimilars, antibiotics, and orphan drugs. And the Cures 2.0 Act furthers ongoing initiatives in data collection and clinical trial design to accelerate the discovery and development of new treatments.

A main focus was on measures to reform the AA process by requiring sponsors to conduct and complete confirmatory studies and to make it easier for FDA to remove those drugs from market that fail to meet postapproval commitments. E&C chairman Frank Pallone (D-NJ) led the debate by sponsoring a bill that requires postapproval studies to be underway at time of approval, not just designed and agreed-on by FDA, and for sponsors to provide frequent updates on the status of these studies. The bill also expedites procedures for withdrawing FDA approval for drugs that don’t meet agreed study timelines and, most notable, establishes a five-year timeframe for automatic expiration of an early approval for drugs that fail to confirm efficacy through post-approval studies.

Yet, the Pallone bill raises questions about whether a requirement to begin confirmatory studies prior to approval will discourage or delay accelerated approvals, particularly for small firms with limited resources to support ongoing clinical research programs without a marketed product. And patient advocates fear that such requirements would delay access to needed therapies. However, there’s broad support for policies to make it easier for FDA to remove products from the market when confirmatory studies don’t support initial indications.

FDA analysis

As the AA debate has moved to center stage, FDA officials and reviewers continue to examine the value of the program and where reform is needed. At a forum held March 11, 2022 by the Regan-Udall Foundation for the FDA, staffers at the Center for Drug Evaluation and Research (CDER) reviewed the 30-year history of the initiative, its benefits and challenges. CDER Principal Deputy Director Jacqueline Corrigan-Curay reported that there have been more than 300 accelerated approvals through the end of 2021 for conditions with no approved therapy and where a sponsor can identify a surrogate or intermediate endpoint that permits shorter, smaller clinical trials able to predict likely clinical benefit. While the program was launched in the 1990s to provide faster access to protease inhibitors to treat HIV/AIDS, the explosion in cancer research and identification of surrogate endpoints likely to predict benefit from oncology therapies has greatly increased AAs for cancer treatments—from 18 in 1992–2002 to 112 for the 2013–2022 period. Oncology AAs may be based on tumor shrinkage and studied through single-arm trials that provide earlier measurement of effect, explained Guatam Mehta, medical officer in CDER’s Division of Oncology 2.

Kevin Fain, senior policy advisor in CDER’s Office of New Drug Policy, noted that AA trials must provide substantial evidence that benefits outweigh risks, but that the program allows some “uncertainty as to the relation of surrogate to clinical benefit.” Confirmatory trials are important for addressing that uncertainty and should be underway at time of approval. Corrigan-Curay acknowledged that once a new drug is on the market, sponsors find it difficult to identify patients willing to enter confirmatory studies.

Although most sponsors confirm benefits of AA drugs in about three years, the rise in “dangling” accelerated approvals—indications where confirmatory trials were not completed or did not verify benefit—prompted FDA to address the issue of at a meeting of its Oncologic Drugs Advisory Committee in April 2021. The session led to the removal of indications for several anti-PD(L)1 antibodies and focused attention on FDA’s challenges in seeking such actions. In response, FDA’s Oncology Center of Excellence has launched the Project Confirm initiative to identify sponsors that need to verify or withdraw certain indications for cancer therapies. These agency efforts and likely legislative changes aim to address public concerns about accelerated approvals and restore confidence in the program.

About the author

Jill Wechsler is Washington editor of Pharmaceutical Technology.