A few months before the end of 2025, the FDA requested that Glaxo Smith-Kline (GSK) revise its approved labeling by submitting a supplemental application to its Wellcovorin (leucovorin calcium) to include an indication for cerebral folate deficiency (CFD), a rare disorder. This came after Secretary Kennedy’s thus far unsuccessful hunt for the cause of autism. After reviewing the data submitted in the supplement and other information before the FDA, agency scientists determined that it could only support approval of the much narrower indication noted above rather than for use in the broader treatment of autism.
On September 22, 2025, GSK posed this on its website (here):
“GSK plc (LSE/NYSE: GSK) confirmed today that it will submit a supplemental New Drug Application (sNDA) for Wellcovorin (leucovorin) to update the label to include an indication for the treatment of cerebral folate deficiency (CFD), a rare disorder. The US Food and Drug Administration (FDA) requested GSK take this action as part of the agency’s initiative to investigate opportunities to repurpose older medications for the treatment of chronic diseases.
GSK is supporting this initiative as the NDA holder by adding data from case reports identified by the FDA of genetically confirmed CFD into the US prescribing information for Wellcovorin. GSK does not manufacture or market leucovorin, which is available in generic formulations in the US.
GSK is collaborating with the FDA to request a label update for this medicine as quickly as possible.”
On September 24, 2025, the FDA published a Federal Register Notice (here) ”announcing approval of the previously withdrawn new drug application (NDA) for Wellcovorin (leucovorin calcium) tablets, equivalent to (EQ) 5 milligrams (mg) base and EQ 25 mg base. FDA is initiating this action on the basis of new data and is required to publish notice of approval of an NDA for which the Agency had previously withdrawn approval.” The FDA had originally withdrawn the same NDA on September 22, 1999, saying that it was withdrawing approval of NDA 018342 after GSK notified the Agency that Wellcovorin (leucovorin calcium) tablets, EQ 5 mg base and EQ 25 mg base, were no longer marketed and requested that the approval of the application be withdrawn under 21 CFR 314.150(c). Subsequently, in the Federal Register of April 28, 2017, the FDA announced its determination that Wellcovorin (leucovorin calcium) tablets, EQ 5 mg base and EQ 25 mg base, were not withdrawn from sale for reasons of safety or effectiveness under 21 CFR 314.161.
So, the on again, off again NDA was back from the dead but apparently only for a very short time because, today, on the prepublication page of the Federal Register (here), the Agency announced that GSK had notified the FDA “in writing that the drug products were no longer marketed and requested that the approval of the applications be withdrawn.” In addition, the notice states:
“Therefore, approval of NDA 018342, and all amendments and supplements thereto, is hereby withdrawn as of [INSERT DATE OF PUBLICATION IN THE FEDERAL REGISTER]. This document is scheduled to be published in the Federal Register on 04/10/2026 and available online… Approval of the entire application is withdrawn, including any strengths and dosage forms inadvertently missing from this notice.”
Because the FDA had made a previous finding that the Wellcovorin product was not originally withdrawn for reasons of safety or efficacy, we know that ANDAs can still be submitted, and already approved ANDAs for leucovorin calcium tablets are, therefore, not impacted by this latest withdrawal of NDA 018342.
Why play the hide-the-monkey game, so to speak, by bringing the NDA back from the dead for the purposes of obtaining a label revision and then, shortly after approval of the labeling supplement, again request the application’s withdrawal? The FDA has the authority to revise the labeling of a generic application should new information become available if and when the FDA deems it necessary for the continued safe and effective use of approved ANDA products. Did the Agency think that this maneuver gave itself more cover than just asking generic-drug manufacturers to revise their labeling? Or is that just the way that the FDA demanded the issue be handled? That’s clearly a question I can’t answer, but the FDA has done several out-of-the-ordinary and unusual things since the change in administration. I guess we’ll just have to chalk it up to getting the outcome that the Agency wanted in the most efficient and expeditious manner available. What’s next on the agenda? Let’s just wait and see!
