The accelerated approval pathway has been instrumental in bringing groundbreaking therapies to patients facing serious or life-threatening conditions, enabling earlier access to promising treatments by allowing reliance on data derived from surrogate or intermediate clinical endpoints reasonably likely to predict clinical benefits to support approval. However, with the privilege of expedited approval comes a responsibility to ensure that these products are safe and effective (or withdraw approval if they are not) in a timely manner.

The section of the Food, Drug, and Cosmetic Act (FD&C Act) which codifies the accelerated approval pathway was amended by the 2023 Consolidated Appropriations Act to expand FDA’s authority and obligations regarding this pathway. In a recently published draft guidance, “Accelerated Approval – Expedited Program for Serious Conditions” in addition to providing an overview of the accelerated approval pathway (covered more extensively in FDA’s May 2014 final guidance, “Expedited Programs for Serious Conditions | Drugs and Biologics”) the FDA outlines their current thinking regarding procedures for reconsideration of accelerated approval in a process of expedited withdrawal. These updates aim to balance the need for swift access to innovative therapies with the importance of maintaining robust oversight and public confidence in approved products.

When Will FDA Consider Expedited Withdrawal Procedures?

Under the newly amended Section 506(c)(3) of the FD&C Act, the FDA outlines circumstances that may precipitate expedited withdrawal of a product under accelerated approval. These include:

• Failure to Conduct Confirmatory Studies: Confirmatory trials are required to verify the anticipated clinical benefits accelerated approval therapies. If a sponsor fails to execute these trials with due diligence (that is, in a timely manner as agreed upon with FDA prior to accelerated approval), FDA may initiate withdrawal proceedings.
• Inconclusive or Negative Study Results in Confirmatory Studies: Should the confirmatory trial(s) fail to verify the predicted clinical benefit—or even contradict initial findings—the FDA can move to withdraw the product’s accelerated approval.
• Evidence of Safety or Efficacy Issues: If new evidence emerges showing that the product is not safe or effective under approved conditions, the FDA may withdraw accelerated approval.
• Dissemination of False or Misleading Promotional Materials: Promotion of a product under accelerated approval using inaccurate claims about its benefits or limitations could prompt FDA action.

A Step-by-Step Guide to Expedited Withdrawal Procedures

The expedited withdrawal process outlined in the draft guidance emphasizes a transparent and systematic approach to addressing concerns with a product under accelerated approval:

• Step 1- Sponsor Notification: The FDA issues a formal written notice to the sponsor outlining the rationale for the proposed withdrawal. In addition to highlighting the specific grounds for withdrawal, the notice highlights opportunities for the sponsor to respond.
• Step 2- Public Engagement: A Federal Register Notice invites public comments on the withdrawal proposal. The FDA reviews all feedback, compiles a summary of public input, and publishes its responses on the FDA website.
• Step 3- Sponsor’s Opportunity to Appeal: Sponsors can submit a written appeal or request a meeting with the FDA Commissioner or a designee. The appeal allows sponsors to provide additional evidence and address identified issues.
• Step 4- Advisory Committee Review: Advisory committees are panels composed of external experts who provide independent assessments of complex regulatory issues in a public forum. Sponsors can request an advisory committee meeting to review the proposed withdrawal (provided that a prior advisory committee meeting has not already addressed the issue). The advisory committee offers expert input on whether the criteria for withdrawal have been met and on the broader implications of a potential decision to withdraw approval.
• Step 5- Final Decision by the FDA: The FDA evaluates all evidence, sponsor appeals, public comments, and advisory committee recommendations. A final decision is communicated, with supporting documentation and responses to stakeholder input made publicly available.

Insights from the Guidance: Navigating the Accelerated Approval Pathway

Understanding the requirements for initiation of the expedited withdrawal process provides sponsors with a roadmap to avoid pitfalls that can affect products under accelerated approval. To avoid issues, sponsors should ensure:

• Timely and Robust Post-Approval Studies: The confirmatory trial(s) should be planned and initiated early, ideally before the marketing application is submitted; this requirement is the most common stumbling block for accelerated approval products. Involve patients, advocacy groups, and other stakeholders (as applicable) early to ensure that the designs of the confirmatory trial(s) align with real-world needs and expectations.
• Transparency in Communication with the FDA: Open dialogue with the FDA is essential, especially when issues arise with trial progress or emerging data.
• Compliance in Marketing and Promotion: Promotional materials must accurately reflect the product’s known benefits and limitations.

The FDA’s expedited withdrawal procedures for accelerated approval reflect the agency’s commitment to protecting public health. By outlining clear criteria for initiating expedited withdrawal of accelerated approval and providing details of the process, this guidance can inform development of strategies for addressing challenges that may arise post-accelerated approval. As the healthcare landscape evolves, expedited withdrawal procedures for products under accelerated approval will remain pivotal in ensuring that biotechnological innovation meets its ultimate goal—delivering safe, effective, and life-changing treatments to patients in need.

For more details on the ins and outs of the accelerated approval pathway and other expedited pathways, check out our webinar (FDA Development & Approval Programs for Serious Conditions | Rho) and white paper (Accelerating Regulatory Product Development and Approval | Rho) for more information. If you are interested in further guidance on navigating the accelerated approval pathway, be sure to contact Rho!

Grant Broussard, Ph.D., Regulatory Scientist, has over 8 years of experience in writing and editing scientific documents and publications across a variety of scientific, clinical, and regulatory fields, which includes several publications in peer‑reviewed scientific journals. He has experience leading scientific authoring projects and has participated in the preparation of modules of regulatory submissions, briefing packages to support regulatory meetings, clinical study protocols, informed consent documents, clinical study reports, and other regulatory documents. Dr. Broussard has experience across a variety of integrated product development projects in various phases of development, including early phase (pre‑INDs and INDs) and late phase submissions (NDAs and BLAs). His therapeutic area experience includes, but is not limited to, infectious disease, neurology, ophthalmology, oncology, and dermatology. He received his Ph.D. in Genetics and Molecular Biology at the University of North Carolina at Chapel Hill, where his research focused on oncogenic viral infections. He is a current member of the Regulatory Affairs Professionals Society (RAPS) and the North Carolina Regulatory Affairs Forum (NCRAF).