Accelerated approval: Navigating FDA’s recent guidance and confirmatory trial considerations

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

Background

The Accelerated Approval (AA) Program has been a cornerstone of patient-centered drug development since its inception in 1992.¹ This pathway aims to expedite the approval of 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 legal framework supporting AA has evolved significantly, with key amendments to the Federal Food, Drug and Cosmetics Act (FDCA) in 1997, 2012, and most recently in 2023 through the Consolidated Appropriations Act.² This evolution is reflected in recent FDA guidance documents that clarify expectations for sponsors pursuing the AA pathway for oncology drugs.

In March 2023, the FDA issued draft guidance on studies to support AA of oncology drugs,  emphasizing the preference for randomized clinical trials (RCTs) over single-arm trials.³ This guidance represented a significant policy shift for the FDA, which historically has accepted single-arm trials as support for AA. The FDA guidance explains that RCTs provide more accurate efficacy and safety profiles, enabling robust benefit-risk assessments and potentially supporting both accelerated and traditional approval through a "one trial" approach. While acknowledging that RCTs may not be feasible in certain circumstances, such as very rare tumors, the FDA still considers single-arm trials for AA if they demonstrate a significant effect on surrogate or intermediate clinical endpoints likely to predict clinical benefit. Ultimately, the FDA recommends that sponsors seek their feedback on trial designs for AA and confirmatory trials before initiating enrollment.

The March 2023 guidance was expanded upon in two subsequent documents. In December 2024, the FDA issued new draft guidance on AA,⁴ reflecting the 2023 legislative changes mandating the FDA to specify conditions for confirmatory studies at the time of AA, and updated procedures for expedited withdrawal of approval of drugs with failed confirmatory studies. The guidance reaffirmed the existing definitions of serious condition, available therapy, and unmet medical need and introduced nuanced considerations regarding surrogate/intermediate endpoints.⁵ Additional guidance was issued in January 2025 on criteria for determining when confirmatory trials are considered “underway”, including considerations related to target completion dates, sponsor progress, and enrollment initiation.⁶

Implications of these guidance for sponsors   

Surrogate and intermediate endpoints must be robustly justified 

The December 2024 draft guidance on AA emphasizes:

• Evaluation of the suitability of a proposed surrogate endpoint will depend on disease context and on the measured magnitude and duration of the effect
• If the drug has potential serious safety issues, it may be expected that the effect established by the surrogate endpoint is at least reasonably likely to predict a favorable benefit-risk balance
• AA based on intermediate clinical endpoints is only considered when it is essential to verify the drug’s impact on long-term outcomes or other patient benefits
• It is acknowledged that many serious diseases lack suitable biomarkers that might predict benefit
• To determine if a given endpoint can predict clinical benefit, all relevant evidence is considered, including input from external experts such as advisory committees

The December 2024 guidance has upheld FDA’s views and recommendations regarding the evaluation of the suitability of surrogate and intermediate endpoints. While acknowledging the lack of suitable biomarkers for many serious diseases, the FDA maintains that any surrogate endpoint must be at least reasonably likely to predict a beneficial effect and a favorable benefit-risk balance, especially when safety is a concern. Sponsors must be prepared to present robust evidence, including expert input, to demonstrate the endpoint's predictive value.   

The guidance clarifies that AA based on intermediate clinical endpoints is reserved for situations where verifying long-term outcomes or other patient benefits is essential. Sponsors must carefully consider endpoint suitability for their specific drug and disease, and early communication with the FDA is strongly recommended for novel endpoints or biomarkers intended for use throughout clinical development. 

Crucially, for rare disease indications, the December 2024 guidance acknowledges it may be challenging to obtain evidence from multiple trials of different products to support a correlation between the effects of the drug on a potential surrogate and on a clinical endpoint. In this type of situation, the guidance emphasizes that it’s even more important that the justification for the surrogate be based on a solid understanding of the role that the surrogate endpoint plays in disease pathophysiology. 

The selection of intermediate endpoints for AA of oncology drugs continues to be an active area of discussion. In general, while overall response rate (ORR) remains an acceptable intermediate endpoint for AA of oncology drugs, progression-free survival (PFS) is a more nuanced endpoint. Although some may view PFS as an intermediate endpoint, the FDA normally uses it for traditional approvals, rarely granting AA based primarily on PFS. This is because a large PFS benefit is often viewed as demonstrating clinical benefit itself.  For any approval based on PFS, the FDA typically expects a large magnitude of benefit, no detrimental effect on overall survival (OS) effect, and a favorable benefit-risk profile. Critically, the FDA does not consider PFS or other time-to-event endpoints sufficient for single-arm trial approvals. Common time-to-event efficacy endpoints in oncology in single-arm trials are generally uninterpretable due to failure to account for known and unknown confounding factors when comparing the results to an external control. FDA considers such endpoints exploratory and not adequate to be used as measures of efficacy in single-arm trials intended to support approval. 

Confirmatory trial designs can be innovative 

The March 2023 and December 2024 guidance on AA reflect clearer and renewed FDA expectations for post-approval confirmatory trials, notably:  

• Increased flexibility in trial design: novel approaches like adaptive designs, enrichment strategies, pragmatic elements, and decentralized trials are encouraged
• Encouragement to incorporate patient perspectives in trial design and focus on participant retention, especially for rare diseases

The FDA's encouragement of innovative trial designs – including adaptive, decentralized, and pragmatic approaches – offers a significant opportunity for drug developers to enhance efficiency, reduce costs, and potentially accelerate the path to approval. These novel designs can provide flexibility, improve patient recruitment and retention, and generate more real-world relevant data, ultimately benefiting both sponsors and patients in the drug development process. Adaptive designs, for example, allow for modifications to the trial protocol based on interim data, maximizing the chances of success. Decentralized trials can improve patient access and participation, particularly in rare diseases, by reducing the burden of travel and site visits. Pragmatic trial designs can reduce data collection burdens by focusing safety data on severe, expected toxicities for drugs with established safety profiles, thereby lowering RCT costs and timelines. Incorporating patient perspectives further strengthens this patient-centric approach. While these novel designs require developers to be innovative and prioritize participant retention, especially in rare diseases, the potential benefits –faster, more efficient trials, and ultimately, quicker access to new therapies for patients– make them a compelling and promising option to explore.  

While the FDA's increased emphasis on RCTs for AA of oncology drugs has understandably raised concerns among investors about cost and timelines,⁷ sponsors have opportunities to innovate and optimize trial designs to meet these evolving expectations. Proactive planning and communication with the FDA are essential for aligning on trial design. If a single-arm trial is proposed, sponsors must provide compelling justification, such as demonstrated RCT infeasibility (e.g., rare tumors, lack of equipoise concerns). If an RCT is deemed necessary, sponsors should explore strategies like the "one trial" approach, efficiently generating evidence for both AA (intermediate endpoint) and traditional approval (clinical endpoint) in the same clinical trial. 

Confirmatory trials must be “underway” at time of AA

Key points in the January 2025 guidance are: 

• FDA now generally requires confirmatory trials to be underway at the time of AA to minimize the “vulnerability period” after approval (i.e., the time interval between AA and confirmatory trial completion, during which patients may receive therapies that may ultimately be shown to lack clinical benefit or a favorable benefit-risk profile)

-Historically, confirmatory trials were not always required to be underway at the time of AA. An FDA analysis has shown that confirmatory oncology trials being "underway" at the time of AA correlates with a shorter vulnerability period and faster verification of clinical benefit (or withdrawal of the oncology indication)⁸ 

• Sponsors should engage with the FDA early to discuss confirmatory trial plans, ideally before submitting the AA application. The confirmatory trial must be "underway" by the time the FDA grants AA, meaning it has a realistic target completion date, demonstrates progress toward that date (e.g., via enrollment milestones, site activation, and projected read-out timelines), and has initiated enrollment.  These progress benchmarks should be agreed upon with the FDA before approval
• After approval, sponsors should submit reports on the progress of the confirmatory trial every 180 days
• For trials intended to support both accelerated and eventual traditional approval, sponsors must maintain study integrity after AA (i.e., when the drug becomes available outside of the clinical trial setting). Strategies to achieve this include prioritizing or completing US-based accrual pre-approval, and maintaining blinding (where applicable) to allow unbiased assessment of time-to-event endpoints

Requiring a trial to be "underway" at the time FDA grants AA provides a mechanism for both the FDA and the sponsor to demonstrate their commitment to timely completion of the confirmatory trials. It also places a greater emphasis on proactive planning and execution of the confirmatory trial. Overall, sponsors should align with the FDA on confirmatory trial plans – design, target dates and milestones– before submitting applications for AA and provide evidence that the trial is ongoing at the time of approval.  The commitment to conduct the confirmatory trial will require sponsors to allocate substantial resources upfront and throughout the trial to meet due diligence requirements, including ongoing progress monitoring and implementing necessary modifications if needed. Sponsors should also anticipate how drug availability post-AA might affect enrollment timelines and implement mitigation strategies (e.g., prioritizing early US recruitment, and potentially completing significant enrollment pre-approval). The requirement for regular trial progress reports further underscores the FDA's focus on accountability and timely completion of confirmatory trials. 

Noncompliance with confirmatory trials will result in expedited withdrawal of AA

The January 2025 guidance emphasizes FDA's increased focus on holding sponsors accountable for initiating and promptly completing required confirmatory trials for drugs granted AA. There are several grounds for withdrawal of AA outlined, including failure to conduct confirmatory studies with due diligence, studies that do not demonstrate the predicted clinical benefit, post-approval discovery of safety or efficacy issues, and promotional violations.

While sponsors retain certain rights during the withdrawal process, such as receiving due notice, appealing decisions, allowing for public comments (including those from patients' associations), and the possibility of an advisory committee meeting, the new guidance places a strong emphasis on transparency and a defined withdrawal process. Typically, the FDA Center that initially approved the drug is expected to initiate the withdrawal process. The decision-making procedure involves a review by the Commissioner or their designee, followed by the publication of the final decision on the FDA website. All substantive communications related to the matter are filed in a public docket to ensure transparency.

This increased transparency and clearly defined process serve as a strong incentive for sponsors to prioritize the completion of confirmatory trials and adhere to regulatory requirements. The consequences of failing to meet these obligations are now more explicitly outlined and subject to public scrutiny. As a result, sponsors must be prepared to meet heightened expectations regarding the execution of confirmatory trials and the integrity of their data to maintain AA. 

In conclusion, the FDA's recent draft guidances offer significant opportunities for sponsors to understand and pursue AA of their drug products. Additionally, 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. 

Parexel’s consulting team of ex-regulators 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.

Contact us to unlock the full potential of AA for your oncology or other drug product.

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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. Section 506(c)(2)(C) of the Federal Food, Drug, and Cosmetic Act, 2023 (Public Law 117-328).
3. 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.
4. 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.
5. Guidance for Industry Expedited Program for Serious Conditions – 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). May 2014.
6. 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.
7. Shannon T, Carey K. BioWorld Insider Podcast: Better times ahead for the biopharma sector? Could be, the new numbers say. April 2023. 
8. Fashoyin-Aje LA, Mehta GU, Beaver JA, Pazdur R. The On- and Off-Ramps of Oncology Accelerated Approval. N Engl J Med 2022;387:1439-1442.

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