In honor of Rare Disease Day on February 28, 2025, we will publish a series of posts throughout the month on As Prescribed and Health Law Scan, focusing on issues impacting the rare disease community.
The US Food and Drug Administration (FDA) recently published two new draft guidances to implement provisions of the Food and Drug Omnibus Reform Act (FDORA) aimed at refining the accelerated approval pathway. These guidances seek to address regulatory challenges and enhance oversight of drug products granted accelerated approval. Additionally, a recent report from the Office of the Inspector General (OIG) underscores FDA’s efforts in refining the accelerated approval pathway. These efforts raise important implications for the rare disease community.
FDA’s accelerated approval authority, described in Section 506(c) of the Federal Food, Drug and Cosmetic Act, permits FDA to grant accelerated approval for products for “serious or life-threatening” diseases or conditions when evidence establishes that a product has an effect on a “surrogate endpoint that is reasonably likely to predict clinical benefit” or on analogous intermediate “clinical endpoint.”
Because the pathway requires the approval to be based on such a surrogate or intermediate clinical endpoint, use of the pathway requires careful consideration and planning and may not be appropriate for every development program, regardless of the unmet patient needs that a particular disease or condition may present.
Overview of the New Guidance
Both guidance documents were issued following the passage of FDORA, which gave FDA new authority to withdraw products approved under the accelerated approval pathway and allowed FDA to require for confirmatory trials to be underway before a product receives accelerated approval. The first guidance, Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics, discusses evidentiary standards required for accelerated approval and describes the procedures for expedited withdrawal of approval of a product approved under accelerated approval.
The second guidance, Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway, reinforces FDA’s authority to require confirmatory trials to be initiated before granting accelerated approval. The guidance outlines criteria for assessing whether a trial is “underway” to ensure sponsors do not delay studies to verify a product’s clinical benefit.
Findings from a Recent OIG Report
A recent OIG report found that a number of drug products approved through the accelerated approval pathway have faced delays in completing confirmatory trials, which raises concerns regarding whether sponsors are meeting their post-market commitments. The report follows a 2022 report from OIG that also discussed confirmatory trials for accelerated approval drugs.
The January 2025 report recommended FDA strengthen guardrails to ensure appropriate and consistent use of the accelerated approval pathway. Specifically, the report recommends FDA define specific factors that would require FDA’s accelerated approval council—also enacted in connection with the FDORA amendments—to advise on certain drug applications and take steps to ensure that appropriate documentation of meetings with sponsors is included in drug approval administrative files.
Implications for Rare Diseases
FDA’s recent guidance has significant implications for rare diseases. Patients with rare diseases often have limited treatment options, and the accelerated approval pathway is an important mechanism for advancing patient access to new therapies.
FDA’s strengthened withdrawal procedures, as outlined in the guidance, may also ultimately serve as a win for rare disease drug development as it may encourage FDA to greater utilize the accelerated approval pathway for new products for rare diseases by providing additional safeguards that ineffective or unsafe products can be effectively removed from the market.
At the same time, the guidance acknowledges unique challenges with confirmatory trials associated with rare disease drug development. Given the small patient populations, traditional randomized controlled trials may not always be feasible, and initiation of postapproval confirmatory trials may be particularly challenging.
The guidance suggests that alternative study designs may be used for confirmatory trials in the rare disease context such as collaboration with FDA on the development of novel surrogate or intermediate clinical endpoints or nonrandomized studies supported by the clinically relevant endpoints and disease natural history.
Additionally, the guidance notes in certain instances FDA may not require that the confirmatory trial be “underway” prior to accelerated approval if adequate justification is required, although FDA takes care in its guidance to emphasize that this outcome should be the exception rather than the rule.
Conclusion
FDA’s recent guidance represents key efforts toward improving the accelerated approval pathway. For the rare disease community, these efforts present opportunities to access innovative therapies more quickly, while the strengthened withdrawal mechanisms give FDA the confidence to utilize the pathway more frequently and ensure ineffective drugs do not remain on the market indefinitely.
Drug developers in this space, however, must be prepared to navigate the complexities of the accelerated approval pathway and related confirmatory trials in this space and leverage alternative trial designs where necessary.