FDA Accelerated Approval What’s Changing and Why It Matters for Rare Diseases

The United States Food and Drug Administration’s (FDA’s) Accelerated Approval (AA) pathway, initially established in 1992 during the HIV/AIDS epidemic to provide faster access to life-saving treatments, has been instrumental in expediting access to therapies for serious and life-threatening conditions. It is particularly significant in therapeutic areas, such as rare diseases, where surrogate or intermediate clinical endpoints may be necessary due to limited patient populations or slow disease progression. While this approach has encouraged innovation, it has also raised concerns about drugs staying on the market without confirmed evidence of their effectiveness. 

Although this pathway is more common in oncology treatments where confirmatory trials are typically completed within the same timeframe, in the context of rare diseases, conducting these trials can be significantly more challenging due to a low patient pool and limited treatment availability, making regulatory decisions even more complex.

Drugs that qualify for the Accelerated Approval Program must meet specific criteria, including therapies for conditions that:

• Are life-threatening or serious (e.g., cancer, certain chronic diseases, and rare conditions)
• Address unmet medical needs, meaning no available therapies or limited effective treatments exist
• Show evidence of effectiveness through surrogate endpoints or early clinical data

The FDA's draft guidances12 address these concerns by emphasizing the importance of completing confirmatory trials on time to verify clinical benefits and outlining expectations for trial design and data requirements. The focus now shifts to holding companies accountable for providing strong evidence of the benefits of their products, ultimately leading to more informed treatment decisions. These updates reflect the FDA’s efforts to enhance transparency in regulatory decision-making and recognize that recent initiatives, including updated guidance and public discussions, demonstrate a commitment to improving clarity around AA pathways.

This article examines the core elements of the changes in the AA pathways and their implications for the pharmaceutical industry, with a particular focus on the development of drugs for rare diseases with an unmet medical need in a serious or life-threatening condition. It concludes that the revised framework enhances regulatory accountability and fosters more reliable therapeutic innovation, while posing new challenges for sponsors in trial design, execution, and compliance.

Key Guidance Details: Decoding the Updates

Confirmatory Clinical Trials as a Prerequisite: 

The draft guidance 2 highlights the FDA’s growing preference for randomized controlled clinical trials (RCTs) over single-arm studies, citing the increased reliability and interpretability of data generated by RCTs. Sponsors should anticipate that RCCTs will be considered the default standard for demonstrating efficacy in support of accelerated approval. This shift is especially apparent in the Agency’s intent to phase out single-arm trials in indications where they were previously accepted, reflecting a broader move toward more robust designs capable of verifying clinical benefit.

A key revision introduced in the draft guidance ² is the redefinition of the criteria under which a confirmatory trial is deemed to be “underway.” Under the prior framework, AA could be granted based solely on a sponsor’s post-approval commitment to initiate the confirmatory study. The revised guidance now requires tangible evidence of trial initiation, shifting the emphasis from intention to demonstrated progress. Under the new framework, a confirmatory trial must be actively progressing at the time of or shortly after approval, with a finalized protocol, activated sites, and initiated or imminent patient enrollment. Sponsors must also present a milestone-based timeline subject to FDA oversight.

This shift mitigates historical delays in post-marketing commitments, ensuring that the generation of confirmatory evidence is contemporaneous with clinical use.

Clearer Expectations for Endpoints: 

Another core element in the 2025 draft guidance ² is the clarification regarding acceptable surrogate or intermediate clinical endpoints. Sponsors are now expected to provide a robust scientific rationale for the chosen endpoint, demonstrating its predictive value for clinical benefit. This rationale should include expert opinions, relevant data, and a comprehensive understanding of the drug's mechanism of action.

The guidance 2 also clarifies the two types of endpoints that can be eligible for the AA pathway: surrogate endpoints that are reasonably likely to predict clinical benefit, and intermediate clinical endpoints measurable earlier than irreversible morbidity or mortality (IMM) with similar predictive value.

In the context of rare diseases, where establishing direct correlations can be challenging, this approach ensures that the selected endpoints are not only scientifically sound but also clinically meaningful. The Agency emphasizes the importance of these considerations to uphold the integrity of the AA pathway and to ensure that patients receive therapies with a verified clinical benefit.

Stricter Timelines and Reporting: 

To improve transparency and regulatory oversight, the guidance ² requires submission of progress reports on confirmatory trials to the FDA every 180 days after accelerated approval. These reports must include enrollment status, trial conduct, protocol deviations, obstacles encountered, and strategies for addressing them. The increased reporting frequency enables the Agency to stay informed about ongoing trial performance, ensuring the prompt resolution of any issues.

Expedited Withdrawal: Reinforcing Accountability: 

The FDA has also delineated a more efficient and structured process for withdrawal of accelerated approvals, thereby reinforcing the agency’s capacity to ensure the scientific integrity of therapies marketed under this pathway. While sponsors retain essential rights, including advance notice, appeal mechanisms, patient group input, and advisory committee involvement, the draft guidance 12 focuses on transparency and a defined withdrawal process. If confirmatory trials fail to verify clinical benefit, are not conducted in a timely manner, or if safety issues arise, the FDA will now have an expedited process to withdraw approval. This addresses longstanding concerns that ineffective drugs could remain available without adequate evidence.

Early Engagement: 

The guidance ² encourages proactive engagement with the FDA, ideally at the end of Phase 2 development. Key areas of focus for early discussion include endpoint selection, trial design, statistical considerations, and milestone planning. Early alignment with regulators is intended to reduce disruptions in later stages and support more efficient development pathways.

Labelling and Promotional Materials: 

The draft guidance ¹ further clarifies the conditions associated with AA, specifically relating to product labeling and promotional materials.

For drugs approved under this pathway, the labeling must include a clear and concise description of the drug’s limitations, particularly any uncertainties about its anticipated clinical benefit. This information should be included in the Indications and Usage section to ensure transparency and accessibility for both prescribers and patients.

The guidance ¹ also requires that product labeling explicitly state that the approval was granted under the AA program and that continued marketing authorization is contingent upon verification and confirmation of clinical benefit through ongoing or future confirmatory studies.

In addition to labeling rules, the guidance ¹ requires sponsors to submit all proposed promotional materials, including labels and advertisements, to the FDA for review during pre-approval if they are released within 120 days of market authorization. These must be submitted at least 30 days before distribution or publication.

These provisions reflect the FDA’s intent to ensure that all stakeholders, including healthcare professionals, patients, and payers, are fully informed of the conditional nature of the drug’s approval status and the associated risks. This approach reinforces the importance of transparency, particularly in instances where the therapeutic benefit remains subject to further clinical confirmation.

Risks and Mitigation Strategies for Rare Disease Sponsors Under Accelerated Approval

Conclusion

In conclusion, these draft guidances ¹² marks a significant shift in the regulator's approach to the AA pathway, emphasizing patient safety, scientific integrity, and evidence-based decision-making. It mandates ongoing confirmatory trials, clearer standards for surrogate and intermediate endpoints, and a structured withdrawal process to address delays in confirming clinical benefits. However, the AA pathway continues to be a subject of ongoing discussion and refinement as the FDA strives to balance the need for rapid access to therapies for rare diseases with the imperative to ensure their safety and effectiveness.

The FDA plans to enforce stricter standards for trial design, conduct, and timelines to ensure the timely and reliable collection of post-marketing evidence. It also increases oversight of drug labeling and promotional materials to clarify the conditional nature of approvals and potential risks, including rare adverse events. 

Sponsors may need to realign their development timelines, resources, and trial infrastructure, which can lead to increased costs and complexity. Despite operational challenges, the AA pathway remains vital for swift access to therapies in areas of high unmet need, such as rare diseases. Success depends on proactive regulation, strategic planning, and demonstrating therapeutic benefits.

References

1. U.S. Food and Drug Administration, Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway Guidance for Industry, January 2025, URL

2. U.S. Food and Drug Administration, Expedited Programs for Serious Conditions—Accelerated Approval of Drugs and Biologics, Guidance for Industry, December 2024, URL

3. U.S. Food and Drug Administration, Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics Guidance for Industry, March 2023, URL

4. Davar, Mahnu V., Abeba Habtemariam, Daniel A. Kracov, Eva Temkin, Tyler M. Scandalios, and Nataniel Tsai. 2024. "FDA Issues New Draft Guidance for Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics." Arnold & Porter, December 12, 2024. URL

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9. U.S. Food and Drug Administration. 2022. Food and Drug Omnibus Reform Act (FDORA) of 2022. December 29. URL