Concerns Persist Over Reliance on Surrogate End Points in FDA Accelerated Approvals

Many confirmatory trials supporting accelerated drug approvals and subsequent conversions to regular approval still heavily rely on surrogate measures, which raises ongoing uncertainty about their true clinical benefit.¹

The authors of the JAMA research letter explained that the FDA’s accelerated approval pathway speeds up the regulatory process by allowing drugs to receive approval based on intermediate or surrogate end points that are only “reasonably likely” to predict clinical benefit. Therefore, therapies granted accelerated approval must subsequently undergo confirmatory trials to evaluate their clinical gains. About 10% of new drugs have received accelerated approval since the pathway’s inception in 1992, with 80% of these in oncology.²

Because the ability of surrogate measures to accurately reflect how patients function, feel, or survive varies, many are skeptical about their reliability in regulatory decision-making. These concerns have been particularly prominent in recent nononcology accelerated approvals, such as aducanumab for Alzheimer disease and voxelotor for sickle cell disease.^3,4 To evaluate the FDA’s use of this pathway for nononcology products, the researchers conducted a study characterizing the pivotal and confirmatory trials supporting these approvals.¹

Many FDA accelerated approvals continue to rely heavily on surrogate endpoints, raising ongoing uncertainty about the true clinical benefits of these therapies. | Image Credit: Tada Images - stock.adobe.com

They analyzed all accelerated approvals of nononcology products between 2013 and 2024 in FDA databases, identifying approved indications, additional regulatory designations, pivotal trials supporting approval, and confirmatory trials that led to either conversion to regular approval or withdrawal. The researchers extracted key trial characteristics, including their end points, which they classified as surrogate or clinical.

Of the 206 accelerated approvals identified, 50 (24.3%) were for nononcology products across 26 disease states. These approvals were supported by 82 studies that had 22 distinct surrogate or intermediate primary end points. Among the approved products, 12 (24.0%) were vaccines for infectious diseases. The remaining approvals included 11 (22.0%) drugs for neurologic diseases, 10 (20.0%) for nonmalignant hematologic diseases, and 5 (10.0%) for infectious diseases.

The researchers noted that 35 (70.0%) of these products also received at least 1 additional FDA expedited designation, and 30 (60.0%) carried a rare disease designation. The median projected time from accelerated approval to planned confirmatory trial submission was 4.64 years (IQR, 2.69-5.70).

Following accelerated approval, 19 products (38.0%) were converted to regular approval, and 3 (6.0%) were withdrawn. These outcomes were supported by 21 confirmatory trials, with a median time from accelerated approval to conversion or withdrawal of 3.26 years (IQR, 2.10-5.20). Of the 19 conversions, 9 were based on clinical outcomes and 10 on surrogate measures, with 7 products using the same end point as in the original accelerated approval. Meanwhile, 28 products (56.0%) remain under accelerated approval, with a median time since approval of 3.70 years (IQR, 1.06-6.46).

The researchers emphasized their surprise at the heavy reliance on surrogate measures when granting conversions.

“While using surrogates with unproven links to clinical benefit is an expected feature of the accelerated approval program, pivotal and confirmatory trials reported surrogate measures as primary efficacy outcomes at similar rates, and at least one-half of conversions to regular approval were granted using surrogate measures as well, leaving uncertainty as to drugs’ clinical utility despite the change in regulatory status,” they wrote.

Lastly, the researchers acknowledged the study’s limitations, including the restriction to pivotal and confirmatory trials; this excluded unpublished data and post-conversion trials from their analysis. Still, they expressed confidence in their findings and offered recommendations for improving the accelerated approval program.

“Confirmatory trials for accelerated approval drugs should more consistently address clinical benefit so patients and clinicians can have confidence in the safety and efficacy of products receiving accelerated approval,” the authors concluded.

References

1. Liu ITT, Reynolds G, Kesselheim AS, Scheffer Cliff ER. Regulatory and clinical outcomes of nononcology accelerated approvals. JAMA. Published online July 14, 2025. doi:10.1001/jama.2025.10726
2. Liu ITT, Kesselheim AS, Cliff ERS. Clinical benefit and regulatory outcomes of cancer drugs receiving accelerated approval. JAMA. 2024;331(17):1471-1479. doi:10.1001/jama.2024.2396
3. Melillo G. How Biogen's Aduhelm approval marks a precipitous turning point for the FDA. AJMC^®. July 14, 2021. Accessed July 14, 2025. https://www.ajmc.com/view/how-biogen-s-aduhelm-approval-marks-a-precipitous-turning-point-for-the-fda
4. Inserro A. FDA approves novel sickle cell disease treatment voxelotor. AJMC. November 25, 2019. Accessed July 14, 2025. https://www.ajmc.com/view/fda-approves-novel-sickle-cell-disease-treatment-voxelotor