Old Drugs, New Tricks: FDA’s Drug Repurposing Initiative

Don’t look now, but drug repurposing is having a moment.

On May 11, 2026, FDA announced a new public docket soliciting stakeholder input on its drug repurposing initiative—specifically, which chronic disease areas should be prioritized and which approved drugs have the most potential to treat conditions outside their existing labels.  The accompanying Federal Register notice (Docket No. FDA-2026-N-4492) has a comment deadline of June 11, 2026, which means the clock is already ticking.  In parallel, FDA launched a dedicated “Drug Repurposing” webpage.

The concept is straightforward: take a drug that is already approved—meaning its basic safety profile is well-characterized—and identify new therapeutic uses for it, particularly where compelling scientific evidence exists but there is no commercial incentive for a sponsor to seek label expansion.  This is not a new idea in drug development.  Aspirin started life as a pain reliever.  .  Bimatoprost was originally used to treat intraocular pressure. What is new here is FDA putting an institutional, structured framework around the idea—and actively soliciting the public to help build it.

We note that the U.S. is not alone in pursuing this initiative as the European Medicines Agency has already reported on a similar EU Repurposing pilot and there are at least two ongoing EU-funded repurposing initiatives (RePo4EU and REMEDi4ALL).

Let’s unpack what the initiative entails, what FDA is actually asking, what regulatory tools are on the table, and what interested stakeholders should be doing right now.

What Is FDA Actually Doing Here?

This initiative is best understood as the intersection of two things: an administrative labeling-update program and a public intelligence-gathering exercise.

On the labeling side, FDA has existing statutory tools and initiatives to support labeling updates, and that allow it—under defined circumstances—to update drug labeling without a voluntary supplemental NDA filing from the sponsor.  These include:

• The Best Pharmaceuticals for Children Act (BPCA), which incentivizes sponsors to study pediatric uses by offering exclusivity extensions when they submit data in response to a written request from FDA.
• The MODERN Labeling Act (section 503D of the FD&C Act), enacted under the 2021 Consolidated Appropriations Act, which allows FDA to require labeling updates for certain generic drugs when the reference listed drug (RLD) has been withdrawn from the market for reasons other than safety or efficacy, and no unexpired Orange Book exclusivities remain.
• Project Renewal, an initiative out of FDA’s Oncology Center of Excellence (OCE) that systematically reviews the published literature for older oncology drugs and facilitates labeling updates to reflect current clinical practice. Under this initiative, labeling for three oncology drugs—capecitabine, temozolomide, and fludarabine phosphate—has been updated to add or revise indications, dosing and administration, and safety information.
• Systematic literature review followed by Federal Register notices, a pathway FDA has used historically to encourage supplemental applications. This has historically been used for products that have uses as medical countermeasures—for example, doxycycline and penicillin G procaine for inhalational anthrax exposure, and calcium and zinc DTPA for radiation exposure treatment.
• ID (not mentioned in the Federal Register notice but mentioned on FDA’s dedicated webpage), a collaborative initiative between the FDA and NCATS (NIH) providing an internet-based repository for clinicians to crowdsource real-world case reports of approved drugs used off-label for new indications, patient populations, doses, or combinations—especially for difficult-to-treat infectious diseases.  Providers submit standardized case report forms documenting clinical outcomes, and the aggregated real-world evidence is used to identify drug-repurposing candidates and inform ongoing clinical trials.

The leucovorin calcium approval for cerebral folate transport deficiency (CFTD-FOLR1) is the most recent and highest-profile example of this approach in action.  FDA collaborated with an applicant, conducted a systematic literature review, and approved a supplemental application even though the original brand manufacturer no longer markets the drug.  See our previous blog post analyzing FDA’s announcement of the application’s re-submission for re-approval.

On the intelligence-gathering side, FDA is using this request for information (RFI) to ask the research, clinical, and patient communities: Where should we be looking, and what have you already found?

The Three Scenarios FDA Is Asking About

The Federal Register notice structures its request around three distinct categories of candidates, and this categorization matters for how you frame a comment:

• Scenario 1—Sufficient Evidence Already Exists. FDA is interested in candidates for which adequate and well-controlled evidence—published or unpublished—may already support approval of a new use without the need for additional clinical trials.  For practical purposes, this is FDA asking: where can we get from here to a labeling change quickly, using what is already on the shelf?
• Scenario 2—Preliminary Clinical Signals. This covers candidates with promising preliminary data from case reports or small pilot studies—data that does not yet rise to the level required for approval, but that warrants further study.  FDA is asking: what should be on our radar for investment, prioritization, and further research?
• Scenario 3—Preliminary Preclinical Signals. This is perhaps the most forward-looking category, covering candidates identified through high-throughput screening, in vitro models, AI/machine learning tools, and other preclinical approaches. For readers familiar with the Broad Institute’s Drug Repurposing Hub, which maintains a curated collection of clinical compounds and approved drugs for repurposing research, this is the kind of resource FDA is implicitly signaling as relevant.  FDA is asking: what pre-clinical hypotheses are worth elevating?

What Disease Areas Is FDA Prioritizing?

FDA’s current list of priority areas—subject to stakeholder comment—includes:

• Metabolic diseases
• Neurodegenerative conditions
• Women’s health conditions (e.g., menopause-related conditions)
• Men’s health conditions (e.g., testosterone deficiency)
• Substance use disorders
• Rare diseases

The notice explicitly asks stakeholders whether they agree with this list, and whether other areas should be added.  This is a genuine invitation, not a rhetorical one—and it is one of the more strategically important comment opportunities in the notice for patient advocates, professional societies, and research institutions.  Mental health strikes us as a notable absence from the list of priority areas.

The Barriers and Incentives Problem

One of the most candid aspects of this initiative is FDA’s acknowledgment of the elephant in the room: in many of the most compelling repurposing scenarios, there is no commercial incentive for a sponsor to file a supplemental NDA.  If a drug is off-patent, the brand has been discontinued, and generic manufacturers would share any regulatory exclusivity benefit across multiple competitors, the standard market-driven pathway for label expansion simply is not worth it.

FDA is asking for input on the barriers to repurposing in this environment—for sponsors, for prescribers, and for patients.  The Agency is also asking a pointed question about off-label use: what barriers do patients and clinicians face when using FDA-approved drugs for unapproved indications where a prescriber has determined it is medically appropriate?  The most obvious barrier likely being the difficulty of securing insurance coverage for off-label use.

The MAHA Connection

This RFI did not emerge in a vacuum.  The September 2025 “Make Our Children Healthy Again” strategy report directed FDA to jointly “investigate opportunities [with NIH] to strengthen the use of repurposed drugs for the treatment of chronic disease”—and specifically to harmonize authorization processes through collaborative clinical trial designs to ultimately secure FDA approval.  This initiative is FDA executing and expanding on that directive (the RFI is not limited to chronic disease). Additionally, FDA’s stated interest in collaboration with NIH (specifically, the National Center for Advancing Translational Sciences, NCATS, which has its own drug repurposing portfolio) reflects a broader interagency approach.

What is notable here is that this is one of the MAHA report’s more constructive, scientifically grounded recommendations—and the implementation by FDA is relatively careful and technically sound.  It fits within existing statutory authority, builds on established pathways like Project Renewal, and invites meaningful public input rather than moving unilaterally.

Honestly, it’s been refreshing.

What Should Stakeholders Be Doing Right Now?

A few practical considerations for those planning to engage:

Frame your position within FDA’s three scenarios.  FDA has been deliberate in structuring its request around evidentiary tiers.  A comment that clearly situates a drug candidate within one of those scenarios—and describes the nature and quality of the supporting evidence—will be far more useful to FDA, and far more likely to be acted upon, than a general endorsement of the concept.

Engage with the priority disease list.  If your organization believes a disease area with significant unmet need has been omitted, say so (I’m especially looking at you, rare disease folks!)—and explain why drug repurposing is a particularly viable approach for that area (e.g., existing mechanistic or clinical signals).

Articulate the barriers specifically.  FDA is asking about barriers in a fairly granular way: barriers to submitting supplemental applications, barriers to off-label prescribing, barriers to data collection.  Generic statements that “commercialization is challenging” will prove less persuasive than specific accounts of where in the pathway the process breaks down—and what regulatory or policy interventions might address those gaps.

Consider the MODERN Act angle.  If you are aware of a situation where a brand’s NDA has been withdrawn for non-safety reasons and generic labeling has not been updated to reflect current clinical practice, that is precisely the scenario section 503D was designed to address—and FDA may not have a complete picture of where those opportunities exist.

The Bigger Picture

FDA’s drug repurposing initiative is, in principle, a sound and long-overdue structural effort to address a real market failure.  The innovation system is quite good at generating new molecular entities, but it is structurally apathetic (and maybe even adverse) to whether existing approved drugs might be doing more work than their labels reflect.  Bringing those drugs’ labeling in line with current scientific understanding—particularly for indications where no commercial sponsor is motivated to file a supplemental NDA—is a genuine public health opportunity.

Whether this initiative produces durable, clinically meaningful labeling changes at scale will depend on whether FDA can build the institutional infrastructure, interagency partnerships, and evidentiary standards to sustain it beyond the current political moment.  Project Renewal has demonstrated that the labeling-update pathway works, at least in oncology.  Extending that model to metabolic disease, neurodegenerative conditions, substance use disorders, and rare disease—across a much more complex landscape of sponsors, generics manufacturers, and evidentiary standards—is a considerably heavier lift.

The comment period is a meaningful opportunity to shape how FDA defines that lift.  We recommend that affected stakeholders engage, and we stand ready to help draft and/or refine those comments.

Comments to Docket No. FDA-2026-N-4492 are due by 11:59 p.m. on June 11, 2026.