Preclinical Proof of Concept Studies for Rare Diseases (R21 Clinical Trial Not Allowed) | RFA TR 23 016

Opportunity Information: Apply for RFA TR 23 016

The NIH funding opportunity titled "Preclinical Proof of Concept Studies for Rare Diseases (R21 Clinical Trial Not Allowed)" (RFA-TR-23-016) is a discretionary grant program designed to push rare-disease therapeutics past an early, high-risk stage and into a more investable, development-ready position. The core purpose is to fund preclinical proof-of-concept efficacy studies in an already established rare disease model, so applicants are expected to have a credible model system in hand and a therapeutic candidate ready for rigorous testing. The program is focused on demonstrating that a proposed therapeutic agent shows enough promise to justify the next major steps in translational development, such as more comprehensive IND-enabling work or, in certain cases like repurposing or repositioning, progression toward clinical trials. As the title states, clinical trials are not allowed under this award, meaning the work must remain in the preclinical space.

The scientific scope centers on efficacy testing in rare disease preclinical models, with additional support for pharmacokinetic (PK) and pharmacodynamic (PD) studies that help explain how the candidate behaves in the body and whether it engages the intended biological pathway. In practical terms, this means projects can pair outcome-based efficacy endpoints (for example, survival, functional measures, or disease biomarkers in the model) with PK data (exposure, distribution, clearance, dosing relationships) and PD data (target engagement, pathway modulation, biomarker shifts) to build a coherent story that the therapeutic is both active and mechanistically credible. The therapeutic modalities NIH calls out as responsive include small molecules, biologics, and other biotechnology-derived products, which keeps the door open to a wide range of candidate types as long as the proposal is geared toward demonstrating preclinical efficacy in an accepted rare-disease context.

From a development and commercialization perspective, the program is explicitly meant to de-risk projects so they can attract follow-on investment and resources. That could mean positioning a project for subsequent funding aimed at full IND application development, or generating enough preclinical evidence that a repurposed or repositioned therapy can realistically move toward human testing under a later mechanism outside this NOFO. The emphasis is not just on exploratory biology, but on producing decision-quality preclinical data that supports a clear next step in the translational pipeline.

Administratively, this opportunity is a grant mechanism within the NIH portfolio, listed under CFDA numbers 93.242 and 93.350, and it uses the R21 activity code (an exploratory/developmental research grant). The posted award ceiling is $275,000, which signals a smaller, targeted package of support intended for proof-of-concept generation rather than full-scale preclinical development. The original closing date listed is 2024-03-25, and the opportunity was created on 2023-07-05.

Eligibility is broad and includes many common U.S.-based applicant types: state, county, and local governments; special district governments; independent school districts; public and state-controlled institutions of higher education; private institutions of higher education; federally recognized Native American tribal governments; tribal organizations that are not federally recognized; public housing authorities/Indian housing authorities; nonprofits both with and without 501(c)(3) status (when not an institution of higher education); for-profit organizations other than small businesses; and small businesses. The announcement also highlights additional eligible categories such as Alaska Native and Native Hawaiian Serving Institutions, Asian American Native American Pacific Islander Serving Institutions (AANAPISIs), Historically Black Colleges and Universities (HBCUs), Hispanic-serving Institutions, Tribally Controlled Colleges and Universities (TCCUs), faith-based or community-based organizations, eligible federal agencies, regional organizations, and U.S. territories or possessions. On the foreign eligibility side, the rules are specific: non-domestic (non-U.S.) entities and non-domestic components of U.S. organizations are not eligible to apply as applicants, but foreign components (as NIH defines them in the NIH Grants Policy Statement) are allowed, which typically means a U.S. applicant can include certain foreign elements in the project if they are well-justified and compliant with NIH policy.

Overall, the opportunity is best understood as a targeted translational bridge for rare disease therapeutics: it funds well-justified, model-based preclinical efficacy studies, supports the PK/PD work needed to interpret efficacy and dosing, and aims to generate the kind of evidence package that makes a therapeutic candidate compelling for the next stage of development funding or investment, while remaining firmly outside the clinical trial space.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Preclinical Proof of Concept Studies for Rare Diseases (R21 Clinical Trial Not Allowed)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.242, 93.350.
• This funding opportunity was created on 2023-07-05.
• Applicants must submit their applications by 2024-03-25. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Each selected applicant is eligible to receive up to $275,000.00 in funding.
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

Apply for RFA TR 23 016

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