Preclinical Proof of Concept Studies for Rare Diseases (R21 Clinical Trial Not Allowed)

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Description

This NIH opportunity funds preclinical proof-of-concept studies for rare diseases, aiming to bridge the gap between early discovery and clinical development. The program supports efficacy studies in established and validated rare disease models (in vivo or advanced in vitro), as well as accompanying pharmacodynamic (PD) and pharmacokinetic (PK) studies. The goal is to generate robust data that will attract further investment for full IND-enabling studies or clinical trials, including for repurposed or repositioned therapeutics.

Therapeutic agents may include small molecules, biologics, or biotechnology-derived products. The program is administered by the National Center for Advancing Translational Sciences (NCATS).

Note: This opportunity does not support clinical trials or the development of new disease models. Applications focused on rare cancers are not eligible.

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Due Dates

• Letter of Intent (strongly encouraged):

  • May 1, 2025
  • May 1, 2026

• Full Application (New, Renewal, Resubmission, Revision):

  • June 2, 2025
  • June 2, 2026

All applications are due by 5:00 PM local time of the applicant organization.

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Funding Amount

• Total Direct Costs: Up to $275,000 for the entire 2-year project period
  • No more than $200,000 in direct costs may be requested in any single year
• Project Duration: Maximum 2 years
• Anticipated Number of Awards: 3–5
• Total NIH Commitment: Up to $1,200,000 in FY26 (future years dependent on appropriations)
• No cost sharing required

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Eligibility

Eligible Applicants:

• Public/State controlled and private institutions of higher education
• Nonprofits with or without 501(c)(3) status (excluding higher education)
• For-profit organizations (including small businesses)
• State, county, city, township, and special district governments
• Independent school districts
• Public housing authorities/Indian housing authorities
• Native American tribal governments (federally recognized and other)
• Faith-based and community-based organizations
• Regional organizations
• U.S. territories and possessions
• Eligible agencies of the federal government

Not Eligible:

• Non-domestic (non-U.S.) entities (foreign organizations)
• Non-domestic components of U.S. organizations

Foreign components (as defined in the NIH Grants Policy Statement) are allowed within U.S. organizations.

Individuals: Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as PD/PI may apply.

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Application Process

1. Letter of Intent: Strongly encouraged, but not required. Should include project title, PI(s), key personnel, institutions, and the funding opportunity number/title. Email to: ncatslettersofintent@mail.nih.gov

2. Application Submission: Use NIH ASSIST, Grants.gov Workspace, or your institution’s system-to-system solution. All required registrations (SAM, eRA Commons, Grants.gov) must be completed prior to submission.

3. Required Attachments:

   • Readiness of Agent (1 page): Demonstrate the agent’s readiness for efficacy testing (e.g., prior screening data, potency, selectivity, formulation, PK).
   • Partnership Plan (1 page): Describe a plan for partnership with a rare disease steering/oversight committee (do not name individuals or organizations).
   • Evidence Supporting Rare Disease Classification: Include in the Significance section of the Research Strategy.
   • Model Access Documentation: Provide evidence of access to the disease model (e.g., letter of support or purchase quote).

4. Research Plan: Must address biological rationale, therapeutic rationale, and model validation. Include a Data Management and Sharing Plan.

5. Budget: Use the R&R Budget Form. Modular budgets are not permitted.

6. Review Criteria: Emphasis on significance, innovation, rigor, feasibility, and readiness of the therapeutic agent and model.

7. No clinical trials: Applications proposing clinical trials will not be reviewed.

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Additional Information

• Non-Responsive Applications: Will not be reviewed if they:
  • Do not clearly address a rare disease (≤200,000 affected in the U.S.)
  • Request support for model development
  • Focus on rare cancers
• Model Requirement: Must use an established and validated rare disease model; model development is not supported.
• Partnership Plan: Required for all applications; must describe the expertise and planned interactions with a rare disease steering/oversight committee.
• Multiple Applications: Allowed if each is scientifically distinct.
• Data Management and Sharing: All applications must include a plan per NIH policy.
• No cost sharing or matching required.
• Clinical trials are not allowed.

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External Links

• NIH Funding Opportunity Announcement (RFA-TR-25-002)
• Grants.gov Opportunity Listing
• NCATS (National Center for Advancing Translational Sciences)
• NIH Application Guide
• NIH Data Management and Sharing Policy

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Contact Information

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