Accelerated approval updated guidances: Four implications for sponsors

FDA’s Accelerated Approval (AA) Program has been a cornerstone of patient-centered drug development since its inception in 1992.1?This pathway aims to expedite patient access to drugs for serious or life-threatening conditions by allowing the use of surrogate or intermediate endpoints that are reasonably likely to predict clinical benefit. For drugs granted AA, post-marketing confirmatory trials are required to verify the anticipated long-term benefits and support subsequent traditional approval.

The FDA has issued three recent draft guidances for industry detailing revised considerations for AA:

• March 2023 – Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics2
• December 2024 – Expedited Program for Serious Conditions – Accelerated Approval of Drugs and Biologics3
• January 2025 – Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway?

Parexel’s ex-regulator experts Dr. Aaron Sosa (Danish Medicines Agency, EMA), Dr. Bernardo Haddock Lobo Goulart (FDA), Dr. Steve Winitsky (FDA) and Dr. Sinan B. Sarac (Danish Medicines Agency, EMA) assess four key implications of the guidances for sponsors intending to pursue this approval pathway:

1. Surrogate and intermediate endpoints must be robustly justified

The December 2024 draft guidance emphasizes:

• Endpoint suitability depends on disease context and effect magnitude/duration
• For drugs with potential safety issues, surrogate endpoints should predict a favorable benefit-risk balance
• AA based on intermediate clinical endpoints is only considered when verifying long-term outcomes is essential
• Many serious diseases lack suitable biomarkers that might predict benefit
• All relevant evidence, including expert input, is considered for endpoint validation

The guidance upholds FDA's views on surrogate and intermediate endpoints. While acknowledging the lack of suitable biomarkers for many diseases, sponsors must present robust evidence to demonstrate endpoint predictive value.

For rare diseases, the guidance recognizes challenges in obtaining evidence from multiple trials to support surrogate-clinical endpoint correlations. In such cases, justification should be based on understanding the surrogate's role in disease pathophysiology.

In oncology, overall response rate (ORR) remains acceptable for AA, while progression-free survival (PFS) is more nuanced. PFS is typically used for traditional approvals, rarely for AA. FDA expects a large PFS benefit, no detrimental effect on overall survival, and a favorable benefit-risk profile.

Importantly, FDA does not consider PFS or other time-to-event endpoints sufficient for single-arm trial approvals in oncology, due to the inability to distinguish drug effects from natural history of disease or other patient characteristics with respect to their impact on PFS or other time-to-event endpoints.

2. Confirmatory trial designs can be innovative

The March 2023 and December 2024 guidances emphasize the use of RCTs and clearer expectations for post-approval confirmatory trials, encouraging:

• Flexible trial designs: adaptive approach, enrichment strategies, pragmatic elements, and decentralized trials
• Incorporation of patient perspectives and focus on participant retention, especially for rare diseases

These innovative approaches offer significant opportunities for sponsors to enhance efficiency, reduce costs, and potentially accelerate approval. Novel designs can improve patient recruitment and retention and generate more relevant real-world data, benefiting both sponsors and patients.

While the FDA's emphasis on randomized clinical trials (RCTs) for oncology AA has raised concerns about costs and timelines, sponsors can innovate to meet these expectations. Proactive planning and FDA communication are essential. If proposing single-arm trials, compelling justification is necessary. For required RCTs, strategies like the "one trial" approach can efficiently generate evidence for both AA and traditional approval.

These novel designs, while requiring innovation and prioritizing participant retention, offer the potential for faster, more efficient trials and quicker access to new therapies for patients.

3. Confirmatory trials must be “underway” at time of AA

Key points in the January 2025 FDA guidance:

• Confirmatory trials must be "underway" at AA grant to minimize the "vulnerability period" between approval and trial completion
• "Underway" means realistic target completion date, progress towards that date, and initiated enrollment
• Early FDA engagement, including progress on study benchmarks, is crucial for confirmatory trial plans, ideally before AA application submission
• Post-approval, sponsors must submit trial progress reports every 180 days
• For trials supporting both accelerated and traditional approval, study integrity must be maintained after AA

This requirement demonstrates commitment to timely trial completion from both FDA and sponsors. It emphasizes proactive planning and execution, requiring substantial resource allocation throughout the trial.

Sponsors should:

• Align with FDA on trial plans before AA application submission
• Provide evidence of ongoing trial at approval time
• Anticipate post-AA drug availability effects on enrollment and implement mitigation strategies
• Expect regular progress monitoring and potential modifications

The focus on accountability and timely completion is underscored by regular progress report requirements. This approach aims to ensure faster verification of clinical benefit or prompt withdrawal of indications lacking benefit.

4. Noncompliance with confirmatory trials will result in expedited withdrawal of AA

The January 2025 guidance emphasizes accountability for initiating and completing confirmatory trials for drugs granted AA. Grounds for AA withdrawal include:

• Failure to conduct confirmatory studies with due diligence
• Studies not demonstrating predicted clinical benefit
• Post-approval safety or efficacy issues
• Promotional violations

While sponsors retain rights during the withdrawal process (due notice, appeals, public comments, advisory committee meetings), the guidance stresses transparency and a defined withdrawal process. The FDA Center that initially approved the drug typically initiates withdrawal, followed by Commissioner review and public decision publication.

This increased transparency and clearly defined process incentivize sponsors to prioritize confirmatory trial completion and adhere to regulatory requirements. Consequences for non-compliance are now more explicit and subject to public scrutiny. Sponsors must meet heightened expectations regarding trial execution and data integrity to maintain AA.

FDA's recent draft guidances offer significant opportunities for sponsors

By emphasizing expectations of robust support for proposed surrogate and intermediate endpoints, and by clarifying confirmatory trial expectations, FDA is driving innovative and evidence-based approaches that bring effective treatments to patients more quickly.

For a more in-depth assessment of how to navigate FDA’s recent AA guidances and confirmatory trial considerations, please see our Regulatory Navigator blog.

Parexel’s Regulatory Consulting team is ideally positioned to partner with you in navigating these complexities. We bring a unique combination of expertise in novel trial design, patient-centric strategies, and proactive risk mitigation, all underpinned by a deep understanding of the evolving regulatory landscape.

We’re always available for a conversation.

References:

1. Food and Drug Administration, Final Rule, “New Drug, Antibiotic, and Biological Drug Product Regulations; Accelerated Approval” (57 FR 58942, December 11, 1992) (21 CFR parts 314 and 601) and Food and Drug Administration, Proposed Rule, “New Drug, Antibiotic, and Biological Drug Product Regulations; Accelerated Approval” (57 FR 13234, April 15, 1992).
2. Draft Guidance for Industry Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics.? U.S. Department of Health and Human Services. Food and Drug Administration. Oncology Center of Excellence (OCE). Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER). March 2023.
3. Draft Guidance for Industry Expedited Program for Serious Conditions – Accelerated Approval of Drugs and Biologics. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER). Oncology Center of Excellence (OCE). December 2024.
4. Draft Guidance for Industry Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway. U.S. Department of Health and Human Services. Food and Drug Administration. Oncology Center of Excellence (OCE). Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER). January 2025.