The New Politics of New Drug Approval

As feared at the start of the second Trump Administration, the Food and Drug Administration (FDA) has proven a willing good soldier in fulfilling the President’s and Health and Human Services (HHS) Secretary Robert F. Kennedy Jr.’s health agenda of questionable, often unsubstantiated positions: overriding FDA career staff to restrict access for COVID-19 vaccine boosters, raising novel doubts about the utility of coadministration of vaccines, and initiating a safety review of mifepristone on the fig leaf basis of a flawed, non-peer-reviewed report. This unprecedented level and sheer volume of politically-motivated interference in FDA’s science-based regulatory actions shows little sign of abating.

In fact, Kennedy’s April pledge to identify “what has caused the autism epidemic” and “to eliminate those exposures” by September tee’d up FDA Commissioner Marty Makary’s prominent participation in a September 22, 2025, White House event where the three leaders blamed acetaminophen for causing autism spectrum disorder (ASD) – with President Trump repeatedly saying, “Don’t take Tylenol,” and adding “Fight like hell not to take it.”

Despite contradictory population-based evidence and widespread skepticism among scientists, clinicians, and autism advocates, Commissioner Makary actively abetted the White House’s promises on autism by announcing that acetaminophen labeling would be amended to reflect an association with increased pediatric risk of neurological conditions such as autism and attention deficit hyperactivity disorder (ADHD).

Unusual and Proactive FDA Action on Leucovorin

Much less attention was paid to an equally significant FDA announcement that it was effectively pre-approving an old drug, leucovorin calcium, as a treatment for the rare disease calcium folate deficiency (CFD). Because some children with CFD also have a co-occurring ASD diagnosis, President Trump and Dr. Makary broadly and misleadingly represented leucovorin as a treatment for ASD:

“The FDA is filing a Federal Register notice to change the label on an exciting treatment called prescription leucovorin so that it can be available to children with autism,” Makary claimed after the White House announcement, adding “We have thousands of kids, in my opinion, who will benefit.”

That Federal Register notice was what can only be termed a baroque and extremely rare strategy. The FDA chose to re-approve a previously withdrawn brand-name drug approval and then pre-approve its use against CFD. The brand-name manufacturer GSK discontinued its sale of Wellcovorin tablets in 1999, leaving leucovorin’s sale to generic manufacturers for decades.

It is almost inexplicable that the FDA courted a wholly distinterested GSK through an arcane regulatory maneuver, rather than exercise clear legal authority granted by Congress in 2020 to revise generic drug labels: the MODERN Labeling Act, which was enacted specifically to update labeling of off-patent, off-exclusivity drugs withdrawn not for safety or effectiveness reasons—a laudable, bipartisan solution for a longstanding issue with many cancer drugs, and one directly applicable to leucovorin.

“Very Preliminary” Evidence Lacking “High Quality Clinical Trial” Data

But even more striking than this unorthodox process was the FDA’s unusual, if not unprecedented, proactive acceptance of a highly limited evidentiary dossier apparently lacking clinical trial data to fulfill the legal requirement of “substantial evidence” of effectiveness. Under the law and FDA’s regulations, “substantial evidence” may consist of “one adequate and well-controlled clinical investigation and confirmatory evidence.”

Yet, the FDA declared that leucovorin’s use against CFD is approvable based merely upon the Agency’s “systematic analysis of literature published between 2009-2024,” “[p]ublished case reports provid[ing] patient-level data on over 40 patients,” and non-clinical “mechanistic data.”  

By conflating leucovorin’s use against CFD and ASD, and relying proactively on an apparently highly limited evidentiary base, the Agency invited immediate, widespread contradiction from leading autism patient advocacy groups, professional societies, and researchers. As Autism Speaks noted, “larger, well-controlled clinical trials are still needed to confirm its efficacy and safety as a therapeutic treatment.”

Former FDA Commissioner Robert Califf opined, “I hope NIH or PCORI will fund an adequate sized, high quality clinical trial to define the benefit-risk profile of this intervention to treat autism. Since it’s generic there are no deep pockets in industry to fund such a trial.”

Is Leucovorin an Unintended Regulatory Precedent for Rare Diseases?

Proffering a proactive guarantee of approval on the basis of a limited, non-trial-based dossier effectively broadcasts that the FDA is prepared to approve new drugs without clinical trials. In the immediate term, this extremely limited set of evidence warrants full disclosure, consistent with Secretary Kennedy’s promise of “radical transparency,” to afford the public an opportunity to assess the decision’s completeness and rigor.

But the FDA should also be prepared for the consequences of its commitment, made to satisfy the Administration’s promises on autism, with important ramifications for ongoing initiatives to identify, study, and approve older drugs for novel diseases and conditions with significant unmet medical need. The Advanced Research Projects Agency for Health (ARPA-H) has funded the nonprofit Every Cure to identify repurposed drugs against rare diseases, and the Biomedical Advanced Research and Development Authority (BARDA) funds a partnership to repurpose drugs to treat exposure to chemical agents.

The Agency will also hear from rare disease patient communities emboldened by the leucovorin initiative. Many rare disease investigators and advocacy groups already possess evidentiary dossiers comparable to the FDA’s “approvable” leucovorin dossier, but lack funding to support clinical trials or a commercial partner to manufacture and bring their investigational treatments to the FDA.

Despite these obstacles, the leucovorin initiative is an open invitation for these communities, investigators, and even companies to file citizen petitions urging the FDA to take similar proactive and positive action on their behalf—a strategy already suggested for “nontraditional sponsors” by the Duke-Margolis Institute in September.

If such petitions are filed on the basis of comparable evidentiary dossiers for the use of old drugs against new diseases, and the FDA refuses to approve them, the Agency would be at risk not only of political and public criticism for hypocrisy, but also judicial rebuke for arbitrary and capricious decision-making under the Administrative Procedures Act (APA).

Just as the FDA had no intention of provoking widespread doubts about the scientific rigor of its strikingly unconventional action, it also probably had no intention of creating a significant precedent in its evidentiary standards for new drugs or of proofing a new pathway to rely on it. What is most concerning about its leucovorin initiative is that it is policy agenda-driven, not science-based. The FDA may not intend this as a precedent for other diseases and conditions, but the question now is whether the Administration and the Agency are prepared to observe it only for diseases that align with their political priorities.

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