New FDA Guidance: Accelerated Approval Accountability

On January 6 and 7, 2025, the FDA released approximately 30 draft or final guidance documents¹ covering diverse regulatory topics, including:

• Pulse oximeter accuracy across different skin tones
• Use of AI in medical devices and regulatory submissions
• Importance of tissue biopsies in clinical trials
• Lead levels in baby food
• Sex differences in clinical evaluations
• Clarification of accelerated approval criteria

These guidance documents reflect priorities the FDA deems urgent, especially in light of the new administration’s efforts to alter regulatory approaches. This article will focus on the draft guidance updates to the accelerated approval pathway.²

Accelerated Approval and Confirmatory Trials

The FDA’s accelerated approval program, designed to fast-track treatments for serious or life-threatening conditions, is entering a new chapter of increased accountability. As of December 2024, the FDA has approved 328 drugs or biologics via this accelerated approval pathway.³

A new draft guidance unveiled by the Agency reflects a “tightening of the reigns,” ensuring that drugs granted early market access quickly validate their clinical benefits through timely confirmatory trials. These changes follow years of scrutiny⁴ over the program’s shortcomings and signal a commitment to safeguarding patient trust while balancing the urgency of unmet medical needs.

A key feature of the draft guidance is its strict requirements for confirmatory trials, which must now be “underway” before accelerated approval is granted. The Agency generally intends to consider a confirmatory trial to be “underway” prior to accelerated approval if:

• Timing: The target completion date is consistent with diligent conduct of the trial
• Resources: Sufficient resources have been committed to ensure trial completion
• Enrollment: Confirmatory trial enrollment has been initiated

By tightening these requirements, the FDA aims to close the long-standing gap between accelerated approval and the completion of postmarketing studies. For example, a 2022 analysis⁵ revealed that 42% of confirmatory trials were delayed by more than a year, or worse, never started at all.

Balancing Speed With Evidence

The reforms also address the controversial reliance on surrogate or intermediate clinical endpoints for accelerated approval. While these endpoints enable faster market access, they also carry inherent risks of exposing patients to unverified therapies. While the definitions of these endpoints have not significantly changed from past guidance, the new guidance offers clearer distinctions and examples:

• Surrogate Endpoints must be “reasonably likely” to predict clinical benefit
  • Examples: Sputum culture in tuberculosis and liver fibrosis measures in NASH
• Intermediate Clinical Endpoints can support accelerated approval but should be thoroughly vetted to ensure they do not already justify traditional approval
  • Example: Major functional disability-free (MFD-free) survival in adrenoleukodystrophy

Stricter Oversight and Enforcement

The FDA now wields stronger enforcement tools under the Food and Drug Omnibus Reform Act (FDORA),⁶ enabling expedited withdrawal of drugs that fail to meet confirmatory trial requirements. Sponsors who lag in trial progress or fail to confirm clinical benefits may face rapid regulatory action, including market withdrawal. The new guidance also stresses transparency, requiring sponsors to:

• Clearly indicate the limitations/uncertainties of accelerated approvals in product labeling
• Submit all promotional materials for FDA review within the first 120 days after approval

While the FDA may grant flexibility in rare diseases or small patient populations, sponsors must provide compelling justifications for any deviations from the standard trial benchmarks. The new draft FDA guidance outlines the circumstances under which the Agency will withdraw accelerated approval using expedited procedures:

• The sponsor fails to conduct any required post approval study
• The study fails to verify any clinical benefit
• Other evidence demonstrates that the drug is not safe or effective
• The sponsor uses false or misleading promotional materials for the drug

A 2023 study in Lancet Oncology⁷ found that from 1992 to 2023, the FDA approved 114 cancer therapy indications under accelerated approval but withdrew 23 (20%) of those indications. Notably, 17 of those 23 indications (~75%) were withdrawn since 2020. These indications were withdrawn because the required confirmatory trials either failed to meet the protocol-specified primary endpoint or were not completed.

Implications for Stakeholders

These changes are expected to affect multiple stakeholders:

• Sponsors must now prepare robust trial timelines, justify endpoints rigorously, and maintain transparent communication with the FDA. Failure to meet these standards could jeopardize both approval and market access
• Patients and Providers stand to benefit from reduced uncertainty, as swifter trial completions will clarify the real-world efficacy and safety of new treatments
• Payers are becoming more selective, with insurers increasingly limiting coverage for drugs approved via the accelerated pathway. This trend further incentivizes sponsors to adhere to the stricter guidelines

What’s Next?

The FDA is currently soliciting public comments on the draft guidance,⁸ leaving room for refinements before finalization in 2025. These discussions may address lingering concerns, such as vague definitions of “limited circumstances” where trials need not be underway, and the need for greater public transparency around regulatory decisions.

As the accelerated approval pathway evolves, it remains a vital tool for addressing unmet medical needs. However, the FDA’s renewed focus on accountability, data integrity, and patient safety marks a critical step forward. By raising the bar for confirmatory trials and endpoint validation, the FDA aims to restore confidence in a program that has long walked the fine line between speed and scientific rigor.

What are your thoughts on the FDA’s new draft guidance for accelerated approval and confirmatory trials? Share your perspectives in the comments below.

Aaron Csicseri, PharmD
Vice President, Scientific Services

Dr. Csicseri joined the ProEd team in November 2017 as a scientific director, responsible for scientific leadership, content development, strategic input, and effective moderation of team meetings. Aaron has extensive experience guiding Sponsor teams through the AdCom preparation process. He received his PharmD at the University of Buffalo, where he studied the clinical curriculum. Aaron has 10+ years of experience as a medical director/clinical strategist in the accredited medical education field (CME), as well as in the non-accredited PromoEd sphere. Over the past 8 years, he has been supporting Sponsors in their preparations for FDA and EMA regulatory meetings in a wide variety of therapeutic areas. Aaron is based in Grand Island, NY, just outside Buffalo.

References:

1. US FDA. Considerations for the Use of Artificial Intelligence to Support Regulatory Decision-Making for Drug and Biological Products. Draft Guidance for Industry and Other Interested Parties. January 2025. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-use-artificial-intelligence-support-regulatory-decision-making-drug-and-biological
2. US FDA. Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics. Draft Guidance for Industry. December 2024. Available at: https://www.fda.gov/media/184120/download
3. US FDA. CDER Drug and Biologic Accelerated Approvals Based on a Surrogate Endpoint as of December 31, 2024. Available at: https://www.fda.gov/media/151146/download?attachment
4. Daval CJR, Kesselheim AS, Cliff ERS. Confirmatory trials of accelerated approval drugs – will imposing fines reduce delays? N Engl J Med. 2024;391(14):1273-1275.
5. Lupkin S. Drugmakers are slow to prove medicines that got a fast track to market really work. NPR. July 22, 2022. Available at: https://www.npr.org/sections/health-shots/2022/07/22/1110830985/drugmakers-are-slow-to-prove-medicines-that-got-a-fast-track-to-market-really-wo.
6. Narayan A, et al. Food and Drug Omnibus Reform Act: A Critical Course Correction. Mayo Clin Proc. 2024;99(60:869-872.
7. Cramer A, et al. Withdrawn accelerated approvals for cancer indications in the USA: what is the marketing authorisation status in the EU? Lancet Oncol. 2023;24(9):e385-e394.
8. Regulations.gov. Expedited Program for Serious Conditions–Accelerated Approval of Drugs and Biologics; Draft Guidance for Industry; Availability. December 6, 2024. Available at: https://www.regulations.gov/docket/FDA-2024-D-2033/document.