Did FDA’s Reapproval of WELLCOVORIN Dot All of the PDUFA i’s and Cross All of the PDUFA t’s?

FDA’s September 22, 2025 News Release and announcement in a prepublication Federal Register notice (to be published on September 24, 2025) that GlaxoSmithKline’s (“GSK’s”) Wellcovorin (leucovorin calcium) Tablets, EQ 5 mg base and EQ 25 mg base, which was approved under NDA 018342 (initially approved on July 8, 1983), would be reapproved took the pharmaceutical industry and the food and drug law bar by surprise.  After all, it’s a pretty rare occurrence that an application for which FDA has officially withdrawn approval is brought back to life—and with the same NDA number instead of under a new NDA number.  But, it is possible.  As FDA’s regulation at 21 C.F.R. § 314.150(c) explains:

FDA will withdraw approval of an application or abbreviated application if the applicant requests its withdrawal because the drug subject to the application or abbreviated application is no longer being marketed, provided none of the conditions listed in paragraphs (a) and (b) of this section applies to the drug.  FDA will consider a written request for a withdrawal under this paragraph to be a waiver of an opportunity for hearing otherwise provided for in this section. Withdrawal of approval of an application or abbreviated application under this paragraph is without prejudice to refiling. [(emphasis added)]

And, as FDA explained in the Agency’s Federal Register notice, there is authority under 21 C.F.R. § 314.160 for reapproving a withdrawn NDA:

The most recently approved labeling for Wellcovorin (leucovorin calcium) tablets, EQ 5 mg base and EQ 25 mg base, stated that the drug products were indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists.  In the Federal Register of September 22, 1999, FDA announced 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tablets, EQ 5 mg base and EQ 25 mg base, were no longer marketed and requested that the approval of the application be withdrawn under 21 CFR 314.150(c).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, FDA announced its determination that Wellcovorin (leucovorin calcium) tablets, EQ 5 mg base and EQ 25 mg base, were not withdrawn from sale for reasons of safety or effectiveness under 21 CFR 314.161.

Under 21 CFR 314.160, FDA, on its own initiative or upon request of an applicant, may, on the basis of new data, approve an application or abbreviated application which it had previously refused, suspended, or withdrawn approval.  With respect to leucovorin calcium tablets, FDA has conducted a systematic analysis of literature published between 2009-2024 and has determined that the information supports a finding that orally administered leucovorin calcium tablets improve certain symptoms in adults and pediatric patients with cerebral folate deficiency (CFD). . . .

Subsequent to the approval of NDA 018342 for Wellcovorin (leucovorin calcium) tablets, EQ 5 mg base and EQ 25 mg base, that is being announced in this Notice, FDA intends to request that GSK submit a prior approval supplemental NDA to revise the prescribing information for Wellcovorin (leucovorin calcium) tablets, EQ 5 mg base and EQ 25 mg base, to include the essential scientific information needed for the safe and effective use of these drug products for the treatment of CFD in adults and pediatric patients.

GSK has already stated that the company “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).”

Historically—at least since about 2009 when FDA began using the record-keeping system for drug applications known as DAARTS (Document Archiving, Reporting and Regulatory Tracking System) (see our prior post here)—FDA has required the submission of a new NDA (and assigned a new NDA number) when confronted with the reapproval of a previously withdrawn NDA.  From what we understand, DARRTS has limitations that prevent reusing a previously withdrawn NDA number.  Apparently, in the pre-DARRTS system FDA used, known as COMIS (Center-wide Oracle-based Management Information System), a withdrawn NDA number could be resurrected.

How FDA avoided the DAARTS system limitation is unclear, but it is the reuse of the Wellcovorin NDA number “018342” that piqued this blogger’s interest.  Why?  Because there’s an unanswered question about the payment of the PDUFA application fee for what was presumably a resubmitted and reapproved NDA 018342.  (By the by, there’s also an unanswered question about what, if any, data—clinical, non-clinical, and manufacturing—was resubmitted and reapproved under NDA 018342, particularly given that GSK has stated that the company “does not manufacture or market leucovorin, which is available in generic formulations in the US.”  Is it the same data included in the NDA approved 42+ years ago?  And if so, then how the heck did those data meet FDA’s enhanced 2025 standards??)

Under the statute, the PDUFA application fee, which stands at $4,310,002 in Fiscal Year 2025 for an application requiring clinical data and $2,155,001 for an application not requiring clinical data, must be paid by “[e]ach person that submits, on or after September 1, 1992, a human drug application. . . .”  The statute includes an exception for a previously filed application, which states:

(C) EXCEPTION FOR PREVIOUSLY FILED APPLICATION.—If a human drug application was submitted by a person that paid the fee for such application, was accepted for filing, and was not approved or was withdrawn prior to approval (without a waiver), the submission of a human drug application for the same product by the same person (or the person’s licensee, assignee, or successor) shall not be subject to a fee under subparagraph (A). [(Emphasis added)]

That exception does not apply here.  NDA 018342 was submitted to FDA in 1979, amended in November 1980 to add an additional 25 mg strength, and approved on July 8, 1983.  That’s nearly a decade before PDUFA was enacted.  Given that fact, NDA 018342 cannot be a “human drug application [that] was submitted by a person that paid the fee for such application.”

So, did GSK pay the the Fiscal Year 2025 PDUFA application fee for Wellcovorin NDA 018342?  Maybe we will find out soon if FDA posts an Approval Package for the new approval.  If not, then how could FDA lawfully allow an exception?  Or perhaps it could be an oversight?  We’re waiting with bated breath. . . .

While we wait, perhaps ponder this: Why would FDA go through such an obtuse resurrection process—and one not requested by GSK—when the statute already provides a route to update the labeling of generic Wellcovorin without GSK having to do anything at all?

We’re talking about the “Making Objective Drug Evidence Revisions for New Labeling Act of 2020” (or “MODERN Labeling Act”), which was passed as part (Section 324) of the Consolidated Appropriations Act, 2021 (Public Law No. 116-260).

The MODERN Labeling Act amended the FDC Act to add Section 503D, titled “Process to Update Labeling for Certain Generic Drugs,” to provide a process to update the labeling for generic drugs where approval of the brand-name drug has been withdrawn for other than safety or effectiveness reasons.  (Sound familiar??)  Specifically, a “covered drug” eligible to go through the label update process outlined in the statute is one:

(A) for which there are no unexpired patents included in the [Orange Book] and no unexpired period of exclusivity;

(B) for which the approval of the application has been withdrawn for reasons other than safety or effectiveness; and

(C) for which—

(i)(I) there is new scientific evidence available pertaining to new or existing conditions of use that is not reflected in the approved labeling;

(II) the approved labeling does not reflect current legal and regulatory requirements for content or format; or

(III) there is a relevant accepted use in clinical practice that is not reflected in the approved labeling; and

(ii) updating the approved labeling would benefit the public health.

Assuming FDA considered the MODERN Labeling Act here for generic Wellcovorin, then why not take this pathway?  Is it that the process required by the statute is too long?  Or maybe there were concerns about the “Approval Standard” “Rule of Construction” added to FDC Act § 503D by the MODERN Labeling Act: “This section shall not be construed as altering the applicability of the standards for approval of an application under section 505.  No order shall be issued under this subsection unless the scientific evidence supporting the changed labeling meets the standards for approval applicable to any change to labeling under section 505.”