SUPPLEMENTARY INFORMATION:

I. Background

Drug repurposing refers to the identification of potential new uses of FDA-approved drugs, for which the new uses would be supported by safety and effectiveness data. Because drug repurposing takes into account existing knowledge of approved drugs ( e.g., safety profiles) when considering the benefits and risks of potential new uses, it can be an important approach for identifying potential treatments for diseases, conditions, or populations that currently lack adequate approved therapies. Stakeholder efforts to advance drug repurposing, including workshops and white papers, have addressed topics such as challenges and opportunities for drug repurposing and mechanisms through which labeling could be updated when supported by sufficient data.^[1 2 3] Recognizing the potential public health impact of drug repurposing, the September 2025 Make Our Children Healthy Again strategy report directed FDA to jointly investigate opportunities with the National Institutes of Health (NIH) to “strengthen the use of repurposed drugs for the treatment of chronic disease, while harmonizing authorization processes through collaborative clinical trial designs to achieve FDA approval.” ^[4]

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In many cases, applicants may consider drug repurposing and submit a supplemental application under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) seeking approval of a new use. In other cases where there are compelling data but potentially no commercial interest in submitting a supplemental application under section 505(b) of the FD&C Act ( e.g., the brand drug has been discontinued from marketing and only generic drugs are on the market; the drug is marketed by the brand name applicant and/or generic drug manufacturers but there appears to be insufficient commercial incentive to pursue approval of a new use; etc.), FDA can use other complementary approaches supported by existing legislation and regulatory pathways to encourage labeling updates with new uses for drugs. Approaches such as these have been successfully used in cases ranging from oncology drugs to medical countermeasure drugs.

Existing legislation and regulatory mechanisms supporting labeling updates. The Best Pharmaceuticals for Children's Act (BPCA, codified at section 505A of the FD&C Act (21 U.S.C. 355a) and section 409I of the PHS Act (42 U.S.C. 284m)) incentivizes the study of drugs for pediatric indications when information relating to the use of those drugs in children may produce pediatric health benefits, such as new uses of drugs. Section 505A of the FD&C Act encourages the identification of clinical areas of need in pediatric patients and offers exclusivity appended to patent and exclusivity protection in certain circumstances to applicants who, in response to a written request from the Agency, submit data to the Agency to support new uses in pediatric patients. Section 409I of the Public Health Service Act is implemented by NIH to, among other things, identify and address drug products that need further study in children.^[5]

A second piece of legislation, signed into law as section 324 of the Consolidated Appropriations Act of 2021 (Public Law 116-260), “Modernizing the labeling of certain generic drugs” (commonly referred to as MODERN), added section 503D to the FD&C Act (21 U.S.C. 353d). This legislation established a process through which FDA can require certain updates to the labeling of generic drugs when, among other things, approval of the application for the generic drug's reference listed drug (RLD) has been withdrawn for reasons other than safety or effectiveness, and when there are no unexpired patents or exclusivities listed in the FDA publication “Approved Drug Products With Therapeutic Equivalence Evaluations” (commonly referred to as the Orange Book) for the RLD. Under MODERN, FDA can initiate a process for labeling changes if, among other things, updating the approved labeling would benefit the public health and: “(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.” ^[6]

Additional Approaches. FDA has worked with applicants to submit supplemental applications to add new uses to the labeling of approved drugs in a wide range of therapeutic areas. For example, Project Renewal is a public health initiative established by the FDA Oncology Center of Excellence (OCE) that aims to update the Prescribing Information ( i.e., labeling for health care providers) and labeling for patients for certain older oncology drugs to ensure that information in the product labeling is clinically meaningful and scientifically up to date. Aligned with FDA's mission to protect public health, this initiative evaluates publicly available scientific evidence to update the Prescribing Information and labeling intended for patients, so that they contain a summary of the essential scientific information necessary for safe and effective use of these drugs.^[7] Under Project Renewal, to date, the labeling for three oncology drugs has been updated to include new and revised indications, new and revised dosing and administration recommendations, and new safety information: (1) capecitabine for the treatment of colon, rectal, colorectal, breast, gastric, esophageal, gastroesophageal junction, and pancreatic cancers; ^[8] (2) temozolomide for the adjuvant treatment of newly diagnosed anaplastic astrocytoma and refractory anaplastic astrocytoma; ^[9] and (3) fludarabine phosphate for use as a component of a combination regimen for the treatment of B-cell chronic lymphocytic leukemia (CLL), and for the treatment of B-cell CLL in patients who have not responded to or whose disease has progressed during treatment with at least 1 alkylating-agent containing regimen.^[10]

Another approach has involved FDA initiating systematic analyses of publicly available scientific literature, and upon determining that the information supports findings that could result in labeling changes, subsequently publishing Federal Register Notices to facilitate these changes by encouraging the filing of supplemental applications. This approach has resulted in labeling changes for drugs such as doxycycline and penicillin G procaine for the treatment of inhalational exposure to Bacillus anthracis (the bacterium that causes anthrax) ^[11] and penetrate calcium trisodium (Ca-DTPA) and penetrate zinc trisodium (Zn-DPTA) for treatment of certain kinds of radiation exposure.^[12]

Recently, FDA approved a supplemental application for leucovorin calcium tablets for the treatment of cerebral folate transport deficiency in adult and pediatric patients who have a confirmed genetic variant in the folate receptor 1 gene (CFTD-FOLR1).^[13] 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. FDA collaborated with the applicant on a process to update the labeling to include the essential scientific information needed for the safe and effective use of the drug for adults and pediatric patients with CFTD-FOLR1.

II. Topics for Public Input

FDA seeks public input from patient, clinical, public health, and research communities on priority disease areas and potential candidates for drug repurposing. In this Federal Register Notice, we are focusing on FDA-approved drugs for which there currently appears to be no commercial interest in adding a new use through a ( printed page 25899) supplemental application. Additionally, we are focusing on such drugs that meet the following criteria for a new use: (1) There is compelling scientific evidence to support the effectiveness of the drug for the new use, (2) the dosage form(s) and route(s) of administration for the new use are the same as for an approved indication, and (3) there is a comparable safety profile for the patient populations for the new use and approved indications. FDA is also seeking input on potential candidates for drug repurposing that may not meet all of the above criteria but have preliminary promising data that might address an unmet need. In particular, FDA seeks comments, data (including real-world data), and information on the following topics:

1. Priority areas: Initially identified priority chronic disease areas include metabolic diseases, neurodegenerative conditions, women's health conditions ( e.g., conditions related to menopause), men's health conditions ( e.g., testosterone deficiency), and substance use disorders, as well as rare diseases. Based on your understanding of disease areas with significant unmet medical needs and high potential for effective treatment through drug repurposing, do you agree with these priority areas? Are there any other priority areas you would recommend for inclusion? Please explain your response.

2. Candidates for drug repurposing: What candidates for drug repurposing have the greatest potential for effective treatment of particular identified medical conditions?

a. Scenario 1: Candidates for which sufficient evidence may already exist to demonstrate their safety and effectiveness for a potential new use.

For FDA to approve a new use, there needs to be data demonstrating that the candidate is safe and effective for use under the conditions prescribed, recommended, or suggested in the drug's labeling (section 505(d) of the FD&C Act). The substantial evidence standard is defined in statute (section 505(d) of the FD&C Act) to mean evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. The statute permits an approval based on one adequate and well-controlled clinical investigation with confirmatory evidence if FDA determines that the data are sufficient based on relevant science to establish substantial evidence. The substantial evidence of effectiveness standard ensures that sponsors have demonstrated the real effect of a drug.

This scenario would be limited to candidates where no additional data would need to be generated ( e.g., from clinical trials), and it may include potential uses for candidates based on publicly available scientific evidence, such as published literature. Please submit ideas for candidates that may have substantial evidence of effectiveness for a new use of a drug for a disease or condition, as well as supporting evidence from the published literature, unpublished adequate and well-controlled investigations that have completed results and analyses, or both.

b. Scenario 2: Candidates for which there are preliminary signals from clinical data, but sufficient evidence does not yet exist to demonstrate their safety and effectiveness for a new use.

There may be other situations in which there is information that suggests the potential for a clinical benefit of a drug to treat a disease or condition based on preliminary case reports or small pilot studies, but for which larger adequate and well-controlled investigations have not yet taken place. In these situations, the data would not yet be sufficient to support a labeling change; however, they may be suggestive of promising areas that warrant further study. Please submit ideas for candidates that meet these criteria, as well as an overview of the existing data which you believe is promising enough to merit further study.

c. Scenario 3: Candidates for which there are preliminary signals from pre-clinical data, but no clinical evidence yet exists to demonstrate their safety and effectiveness for a new use.

There may also be situations in which there is information that suggests the potential for a clinical benefit of a drug to treat a disease or condition based on pre-clinical data— e.g., via high-throughput screening, in vitro models, or artificial intelligence/machine learning—but for which there is currently no clinical evidence. Please submit ideas for candidates that meet these criteria, as well as an overview of the existing data which you believe is promising enough to merit further study.

3. Approaches to identifying candidates for drug repurposing: FDA is also interested in exploring new innovative approaches to identifying candidates for drug repurposing. Please describe methods or opportunities that you believe the Agency could use to facilitate the identification of new candidates.

4. Barriers and opportunities:

• In cases where there appears to be no commercial interest in adding a new use through a supplemental application, what are the barriers to repurposing drugs to address unmet needs?
• From the perspective of patients and clinicians, what are the barriers to using FDA-approved drugs for unapproved uses when a prescriber determines a drug is medically appropriate for a patient?
• What could FDA and other federal partners do to address these barriers?
• How can FDA and other federal partners collect and use data about unapproved uses for FDA-approved drugs to better understand how they are being used in the community?

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