On December 5, 2024, the FDA’s Center for Drug Evaluation and Research (CDER), along with the Center for Biologics Evaluation and Research (CBER) and the Oncology Center of Excellence (OCE) issued draft guidance concerning expedited programs for serious conditions[1]. The guidance document outlines procedures for accelerated approval of drugs and biologics for serious conditions, as well as expedited withdrawal of such approvals. It provides information on FDA policies, threshold criteria, and statutory procedures related to accelerated approval.
The accelerated approval pathway allows approval of drugs for serious conditions based on surrogate or intermediate clinical endpoints likely to predict clinical benefit. Recent amendments expanded FDA’s authority and obligations regarding accelerated approval, including specifying conditions for confirmatory studies and revising expedited withdrawal procedures.
I. Overview of Accelerated Approval
Accelerated approval is used for drugs addressing unmet medical needs for serious conditions. It allows approval based on surrogate or intermediate endpoints reasonably likely to predict clinical benefit, often enabling earlier approval. Additional requirements include confirmatory trials, labeling descriptions of limitations, and submission of promotional materials to FDA.
The FDA’s authority emanated from regulations and later in 1997 via the Food and Drug Administration Modernization Act (FDAMA) which added section 506 to the FD&C Act[2]. Later in 2012, Food and Drug Administration Safety and Innovation Act (FDASIA) was passed mandating that FDA should consider the “severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments[3].” The FDASIA provides that the FDA may grant accelerated approval to: “…a product for a serious or life-threatening disease or condition…upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments[4].”In 2023, Section 506(c) of the FD&C Act was amended by the Consolidated Appropriations Act (“CAA”), granting FDA “additional authorities and imposed on FDA additional obligations regarding accelerated approval. Moreover, the CAA.
II. Granting of Accelerated Approval
The recent FDA guidance covers considerations for surrogate and intermediate clinical endpoints, evidentiary criteria, requirements for confirmatory studies, and other approval conditions. It emphasizes early consultation between sponsors and FDA on novel endpoints and trial designs. Confirmatory trials should generally be underway at time of approval.
The current pathway for expedited review and approval is comprised of (1) Fast track designation, (2) breakthrough therapy designation, (3) acerated approval, and (4) priority review designation. However, “accelerated approval is available only for drugs that provide a meaningful therapeutic benefit over existing treatments, and the FD&C Act was subsequently amended to require that FDA consider ‘the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments” when approving a product under accelerated approval.[5]”
The two types of endpoints which serve the basis for accelerated approval are (1) a surrogate endpoint (generally a biomarker “such as a laboratory measurement, radiographic image, physical sign, or other measure, that is thought to predict clinical benefit but is not itself a measure of clinical benefit.[6])”; Or (2) Intermediate Clinical Endpoints – a measurement of a therapeutic effect that can be measured earlier than an effect on IMM and may support accelerated approval when it is considered reasonably likely to predict the drug’s effect on IMM or other clinical benefit. An important threshold question is whether the demonstrated therapeutic effect on the intermediate clinical endpoint alone would be a basis for traditional approval[7].”
Withdrawal of Accelerated Approval
The guidance outlines statutory procedures for expedited withdrawal, including providing notice to sponsors, opportunity for public comment, written appeal process, and advisory committee consultation if requested. It describes implementation of these procedures, decision-making process, and policies for communications during withdrawal proceedings.
Conclusion
The document provides detailed guidance on FDA’s accelerated approval program, aiming to facilitate development of drugs for serious conditions while ensuring appropriate evidence of clinical benefit through confirmatory trials and maintaining FDA’s ability to withdraw approval when necessary. Sponsors should be particularly aware of the FDA’s withdrawal procedures when clinical data does not meet the surrogate or clinical intermediate endpoints.
[1] https://www.fda.gov/media/184120/download FDA Publications [December 2024]
[2] Id. Citing 21. U.S.C. 356
[3] Id. At Page 2
[4] Id. Citing FD&C Act, Section 506(c)
[5] Id. At pages 3-4
[6] Id at page 7
[7] Id. At pages 7-8
