Leucovorin Approval Shows How FDA Weighs Evidence Without a New Trial

The Food and Drug Administration approved expanded use of Wellcovorin (leucovorin calcium) tablets on March 10 to treat cerebral folate deficiency in adults and children with a confirmed variant in the folate receptor 1 gene, a condition known as CFD-FOLR1. In its announcement, FDA said the approval "was based on a systematic review of the published literature on the topic, including published case reports with patient-level information, as well as mechanistic data." No new clinical trial was run for the application.

GSK holds the new drug application for Wellcovorin, and FDA said it worked with the company on a process to update the labeling. GSK had submitted the supplemental application in September 2025 at FDA's request, as part of an agency initiative to repurpose older medicines, HCPLive reported. GSK marketed Wellcovorin from 1983 to 1997, and leucovorin is now sold in the US as a generic, the report said.

Acting drug center director Tracy Beth Hoeg said the decision shows "how observational or 'real world' evidence can lead to an FDA approval when the product is shown to provide clear clinical benefit compared with what is seen with the natural history of the disease." The approval tests the legal standard every drug effectiveness claim must meet.

What the law requires

Section 505(d) of the Federal Food, Drug, and Cosmetic Act, codified at 21 U.S.C. 355(d), tells FDA to refuse an application when there is "a lack of substantial evidence that the drug will have the effect it purports or is represented to have." The statute defines substantial evidence as evidence from adequate and well-controlled investigations, including clinical investigations, by qualified experts, on the basis of which they could fairly and responsibly conclude the drug works as labeled.

The text does not require two trials. Since a 1997 amendment it has said FDA may treat data from one adequate and well-controlled clinical investigation plus confirmatory evidence, obtained before or after that investigation, as substantial evidence when FDA determines, based on relevant science, that this is sufficient.

Where case reports fit

FDA's regulation on adequate and well-controlled studies, 21 CFR 314.126, lists the features such a study needs, including a design that permits "a valid comparison with a control," methods that minimize bias, and well-defined ways of assessing response. Among the recognized controls is a historical control, in which results with the drug are compared with the documented natural history of the disease. The regulation says these designs are "usually reserved for special circumstances," such as diseases with high and predictable mortality or cases where the drug's effect is self-evident.

The same rule sets a floor. Uncontrolled or partially controlled studies "are not acceptable as the sole basis for the approval of claims of effectiveness," and "Isolated case reports, random experience, and reports lacking the details which permit scientific evaluation will not be considered." The drug center's director may waive specific criteria for a particular investigation, either beforehand or when evaluating a completed study.

FDA's description of the leucovorin evidence, published case reports with patient-level detail compared against what is known about how the disease progresses, maps onto the historical-control route rather than a randomized trial. FDA's announcement did not say whether any of the regulation's criteria were waived.

FDA listed possible side effects of leucovorin as including itching, rash, hives, shortness of breath, rigors and impaired temperature regulation, and named anaphylaxis as a serious side effect.