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

The Preclinical Proof of Concept Studies for Rare Diseases program, issued by the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS), provides funding to conduct preclinical efficacy studies for proposed therapeutic agents targeting rare diseases. The goal of this program is to advance therapeutic development by generating high-quality data to demonstrate proof of concept in a validated rare disease model. Supported studies include efficacy testing, pharmacokinetic (PK), and pharmacodynamic (PD) evaluations to determine the therapeutic agent's feasibility for further development, including progression to Investigational New Drug (IND)-enabling studies or clinical trials. The program focuses on therapeutics for diseases affecting fewer than 200,000 individuals in the United States, including small molecules, biologics, and biotechnology-derived products. Efficacy studies must be conducted using an established and validated in vivo or advanced in vitro rare disease model, with evidence supporting the model’s relevance to the disease. Applications that propose model development or focus on rare cancers will not be considered responsive. The proposed therapeutic agent must be ready for rigorous efficacy testing, and applicants must include a plan for collaboration with a rare disease steering/oversight committee to ensure project relevance. Eligible applicants include public and private institutions of higher education, nonprofit organizations, small businesses, state and local governments, Native American tribal organizations, and independent school districts. Foreign institutions are not eligible, but foreign components of U.S.-based organizations are allowed. Applicants may submit multiple applications, provided each is scientifically distinct. The NIH anticipates awarding up to 1.2 million dollars in fiscal year 2026, with an expected three to five awards. The total budget for direct costs may not exceed 275,000 dollars for the two-year project period, with no more than 200,000 dollars requested in any single year. The award project period is limited to two years. Applications must include evidence supporting the disease's classification as rare, a description of the biological rationale for the therapeutic agent, and the validation of the proposed disease model. Required components include a readiness of agent attachment, a partnership plan for the oversight committee, and letters of support if applicable. Collaborative, multidisciplinary teams with expertise in therapeutic development, statistics, and disease-specific knowledge are encouraged to apply. The earliest submission date is May 2, 2025, and the application deadlines are June 2, 2025, and June 2, 2026, depending on the funding cycle. Applications must be submitted through Grants.gov or NIH’s ASSIST system and follow the guidelines in the NIH Application Guide. Awards will be based on scientific merit, relevance to program priorities, and availability of funds. For inquiries, applicants may contact the scientific program official, Steven Pittenger, at steven.pittenger@nih.gov, or other contacts listed in the funding announcement.