Docs call FDA approval without an RCT 'truly bananas.' What precedent does it set for evidence standards?
Industry Buzz
It was a political decision rather than a scientific one. I agree it's a low risk intervention in a population where there may be benefit. The double standard that we can't consider vaccines safe without RCTs, but this gets approval without a trial is crazy.
—Pediatric hematologist @CatShot1948, via Reddit
There are a lot of people with autism who don’t have a folate deficiency, and there are a lot of people with a folate deficiency who don’t have autism. [To] prescribe it to everyone would be misguided. And to do it with the current level of evidence we have is literally unprecedented.
—Ben Rein, PhD
The FDA doesn’t usually approve drugs without randomized clinical trial data. That’s why a new approval involving leucovorin (folinic acid) is turning heads across medicine. []
This week, the agency cleared the decades-old drug for cerebral folate deficiency (CFD) linked to variants in the FOLR1 gene, an ultrarare condition that interferes with folate transport into the brain and can lead to seizures, developmental delays, and autism-like features. []
But the bigger story for many physicians isn’t the indication itself; it’s how the drug was approved.
The FDA relied largely on case reports, mechanistic rationale, and real-world evidence—rather than a prospective clinical trial. []
For clinicians used to the traditional drug-approval pipeline, that’s unusual territory.
Related: Trump stirs autism storm, FDA backs leucovorin for kids, most docs (but not all) express outrage onlineWhy the FDA skipped a traditional trial
The rationale centers on extreme rarity. The approved indication—FOLR1-related cerebral folate transport deficiency—affects fewer than 1 in a million people. []
Running a randomized trial in such a small population would be extraordinarily difficult. Instead, regulators reviewed existing literature and case reports involving 46 patients with CFD-FOLR1 treated with leucovorin. []
Among 27 patients who received oral leucovorin only, 24 showed clinical improvement or disease stabilization, including reduced seizures and gains in motor function, communication, or behavior. []
Investigators also saw normalization of cerebrospinal fluid folate levels in many cases, strengthening the biological plausibility. []
In short, the FDA judged the mechanistic rationale and real-world data strong enough to support approval for this narrowly defined group.
The autism controversy surrounding the drug
The approval arrives amid an already heated debate. Over the past year, political figures—including Health and Human Services leadership—publicly promoted leucovorin as a potential treatment for autism. []
That messaging helped drive a 71% spike in leucovorin prescriptions for children aged 5–17 following a White House news conference during which FDA Commissioner Marty Makary announced the drug was under review for patients with autism, even though evidence for broad autism use remains limited. []
The FDA ultimately declined to approve the drug for autism spectrum disorder. [] Instead, regulators narrowed the indication to the genetic CFD subgroup with the strongest evidence base. []
Major pediatric organizations have also urged caution. The American Academy of Pediatrics does not recommend routine leucovorin use for children with autism, citing insufficient large-scale evidence. []
“To address the nation and announce a ‘new exciting therapy’ based on two reliable trials with 32 children who got this drug is truly bananas… And comparatively, if we think back a few years, people were very upset that COVID vaccines were rolled out too soon after they were tested in tens of thousands of people,” said neuroscientist Ben Rein, PhD, in an Instagram Reel.
Dr. Rein continued, “It’s important to note that there are a lot of people with autism who don’t have a folate deficiency, and there are a lot of people with a folate deficiency who don’t have autism. So, to roll out leucovorin broadly and prescribe it to everyone would be misguided. And to do it with the current level of evidence we have is literally unprecedented.”
In r/medicine, user @CatShot1948, a pediatric hematologist, had similar thoughts. "It was a political decision rather than a scientific one. I agree it's a low risk intervention in a population where there may be benefit. The double standard that we can't consider vaccines safe without RCTs, but this gets approval without a trial is crazy," they wrote.
Why this approval matters beyond this disease
The regulatory pathway may be the real precedent. Historically, randomized controlled trials have been the gold standard for FDA approval. []
But the leucovorin decision reinforces a growing willingness by regulators to use real-world evidence and literature reviews when studying ultrarare diseases.
That approach has appeared before—for example, in transplant medicine and oncology—but remains uncommon. []
For rare disease specialists, it could signal a more flexible regulatory future. For others, it raises questions about evidentiary thresholds and consistency in drug approval.
Related: Why the FDA’s new digital health guidance has physicians on edgeWhat this could mean for your clinic
For most physicians, the direct clinical impact will be limited—but not nonexistent. A few implications to keep in mind:
1. More patient questions about leucovorin: Because of the autism controversy and media attention, clinicians—especially pediatricians, neurologists, and psychiatrists—may see increased inquiries from parents.
2. Genetic testing may matter more: The approved indication is specifically tied to FOLR1 variants, meaning treatment eligibility depends on identifying this mutation.
3. Off-label prescribing will likely continue: Leucovorin has long been used off-label for autism or suspected CFD. The new approval may increase interest in testing for folate pathway abnormalities.
4. Expect more scrutiny of real-world evidence approvals: This decision could become a case study in how regulators balance evidence standards with the realities of ultrarare disease research.