Experts raise concerns over lower evidentiary standard for FDA’s leucovorin approval

The US Food and Drug Administration’s (FDA) approval of leucovorin as a treatment for cerebral folate deficiency could be the start of a new evidentiary standard for drug approvals that “may come to haunt the FDA,” experts argued in a recent Viewpoint article published in JAMA.

FDA approved leucovorin in September 2025 based on a systematic review of 23 studies, which included case reports and mechanistic data for about 40 patients. The approval was granted in the absence of a supplemental new drug application (sNDA) for a new indication from GSK, the manufacturer of Wellcovorin, the brand version of the drug. FDA stated that it would work with GSK to submit an application, and the company announced it would submit a labeling change for the new indication.

Leucovorin’s approval for cerebral folate deficiency is part of a broader effort by the Trump administration to address a rise in autism spectrum disorder diagnoses over the last two decades that has been largely explained by medical societies and experts as a change in the diagnostic criteria and improved screening tools. Cerebral folate deficiency can result in a variety of neurological symptoms, including seizures, a delay in cognitive and motor processing, and autistic features. (RELATED: This Week at FDA: FDA’s autism moves, Novartis gets untitled letter over TV ad, and more, Regulatory Focus 26 September 2025)

Daniel Aaron, of the SJ Quinney College of Law at the University of Utah, and colleagues
argued that the unique circumstances behind leucovorin’s approval “would further degrade the FDA’s standard,” noting the evidence base is weaker than other controversial approvals by the agency, such as in the cases of Aduhelm (aducanumab), Elevidys (delandistrogene moxeparvovec-rokl), and Exondys 51 (eteplirsen).

“In those instances, the manufacturers submitted clinical trials demonstrating some, if arguably tenuous or illusory, benefit, whereas here neither the FDA nor GSK has cited any randomized clinical trials showing any benefit at all,” they said.

There are also concerns about the drug’s approval process, Aaron and colleagues explained. It is important to note the announcement of leucovorin’s approval was made at a press conference where controversial statements about an unproven link between autism and Tylenol use during pregnancy were made, and before an sNDA for leucovorin was submitted. “If high-level officials at the FDA are interested in the new use of a drug, they should lead with evidence, not with approval, and outline a process to ensure decisional integrity,” the authors said.

Agencies like FDA “are charged with making vital decisions grounded in science and fact,” they added. “A fair process that relies upon robust data and unbiased expert deliberation is important to protect an agency’s public trust.”

Aaron and colleagues noted that neither GSK nor patient advocacy groups were seeking the approval of leucovorin for this indication.

“Rather than suffering an ‘epidemic,’ a framing at odds with the evidence attributing rising reported autism prevalence to diagnostic shifts, what many in that community most want is support services, rights protection, and policy that enhances inclusion and quality of life, not the approval of new indications without substantial evidence,” Aaron and colleagues said.

Ultimately, the decision “may come to haunt the FDA by laying out a new precedent for evidentiary standards at the agency,” the authors said, noting that manufacturers may begin sending the agency case reports or mechanistic data instead of robust clinical trials as evidence for drug products being evaluated for other indications, and may even challenge agency decisions that reject low-quality evidence by citing leucovorin’s approval as justification.

“Maintaining evidentiary standards is important both for protecting patients and ensuring that regulated industry will continue to invest in the knowledge behind new innovations. Leucovorin represents a stark departure from these standards,” they concluded.

A drug approval without precedent

Reshma Ramachandran, assistant professor at Yale School of Medicine, and co-director of the Yale Collaboration for Regulatory Rigor, Integrity, and Transparency, who was not involved with the Viewpoint article, said this is the first time she has seen FDA approve a drug based on case reports from a systematic analysis, and without an sNDA from the drug's manufacturer.

“Previously, there have been approvals where primary endpoints of a clinical trial were missed, or the trial failed, so FDA relied on other evidence to make an approval decision. But typically, a trial has been conducted,” she told Focus.

Ramachandran said it is concerning that the basis for leucovorin’s approval does not seem to meet the threshold for substantial evidence of effectiveness, which would come from conducting at least one adequate, well-controlled clinical investigation. “Instead, the approval seems to be based on a case series—effectively, a few dozen anecdotes of very different patients, including both children and adults,” with no details on how FDA analyzed the varied cases to make this decision, she said.

“[T]his sort of evidence does not provide me assurance the drug works as is claimed by the agency,” Ramachandran added.

Patients are already asking Ramachandran about leucovorin in clinical practice, and she noted there was a shortage of leucovorin calcium in December 2025 that has not yet been recognized on FDA’s website. “In the week after the FDA Commissioner went on national television to make claims about this drug, supplement companies began advertising the drug widely over social media. I had patients come to their visits with me asking about the drug as well, as they were seeing ads for this,” she said.

Leucovorin’s approval would be an “unfortunate precedent” that FDA should not repeat for future approval decisions, Ramachandran said. “This undermines the scientific integrity of the agency as a regulator—a scientific agency doesn’t make a conclusion first and then find evidence for it later, which is seemingly what happened here,” she said.

Sponsoring a trial to evaluate leucovorin for this indication “would be a true exemplar of gold standard science, rather than misleading the public and potentially offering them false hope,” Ramachandran added.

“As a clinician, when something is FDA-approved, I have trust that the treatment has been vetted appropriately to ensure that it works and is safe for me to prescribe or recommend to patients,” she said. “Approvals like these throw that into question completely and shifts uncertainty onto us and our patients to determine whether something FDA-approved is truly something beneficial.”

JAMA Aaron et al.

Experts raise concerns over lower evidentiary standard for FDA’s leucovorin approval

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