Reissue of RFA-FD-22-001 - Efficient and Innovative Natural History Studies Addressing Unmet Needs in Rare Diseases (R01 Clinical Trials Optional)

The U.S. Food and Drug Administration (FDA), through its Office of Orphan Products Development (OOPD), has reissued its funding opportunity titled "Efficient and Innovative Natural History Studies Addressing Unmet Needs in Rare Diseases (R01 Clinical Trials Optional)," identified by Funding Opportunity Number RFA-FD-25-017. This grant is a reissue of RFA-FD-22-001 and is designed to support natural history studies that can advance medical product development in rare diseases with significant unmet needs. The initiative falls under the R01 Research Project Grant activity code and aims to provide critical insights that can remove major obstacles to therapeutic innovation and broaden the knowledge base for rare conditions. This opportunity is explicitly intended for both retrospective and prospective observational natural history studies. The research must involve rigorous, standardized, and interpretable data collection methods to be eligible for consideration. The funding will support projects that either incorporate or facilitate collaborative efforts among academia, industry, and patient organizations. Projects may also include the development or validation of biomarkers and clinical outcome assessments (COAs), particularly if conducted in conjunction with prospective studies. Studies employing advanced methods such as machine learning and simulation to improve trial design may be eligible for increased funding, subject to strong justification. Funding amounts vary depending on the study type. Prospective studies can receive up to $400,000 annually for four years, while retrospective studies are limited to $150,000 annually for two years. Applications requesting additional funding of up to $200,000 per year for innovative trial designs may be considered. This could bring the annual total to $600,000 over four years. Applications must detail expected expenses annually and provide comprehensive justifications, especially if requesting increased funding. The number of awards is contingent upon congressional appropriations and merit-based evaluations. This funding opportunity is open to a broad range of entities, including higher education institutions (both public and private), nonprofits, for-profit organizations (including small businesses), state and local governments, federally recognized and other tribal entities, and international institutions. Foreign organizations and foreign components of U.S. organizations are eligible, and must meet the relevant registration and compliance requirements, including having a Unique Entity Identifier (UEI), registering in SAM.gov, and obtaining eRA Commons accounts. All applications must be submitted electronically via ASSIST, Grants.gov Workspace, or an institutional system-to-system solution. The application cycle includes key deadlines. The earliest date to submit applications is December 12, 2025. Letters of intent are due by January 9, 2026, and the full application must be submitted by February 10, 2026. A second cycle is planned, with a letter of intent due on January 7, 2028, and a full application due by February 8, 2028. Scientific merit reviews are scheduled for May 2026 and May 2028, respectively, with the earliest start dates being September 2026 and September 2028. The program is not subject to Executive Order 12372 review, and no AIDS application due dates apply. Applicants must adhere strictly to FDA-specific requirements, which diverge from NIH protocols, particularly in areas such as page limits and review criteria. A maximum of 12 pages is allowed for the Research Strategy section, and resubmissions must include a one-page Introduction addressing prior review critiques. Appendices must contain the study protocol, informed consent documents, and justification for additional funding if requested. Letters of support are required for study sites and patient engagement. All applicants must include a data management and sharing plan, regardless of funding levels. For scientific or programmatic inquiries, applicants should contact Katherine Needleman at OOPD_NHGrants@fda.hhs.gov or by phone at 301-796-8660. For administrative and financial questions, Kimberly Pendleton is the primary contact at Kimberly.Pendleton@fda.hhs.gov or 240-402-7610. Interested parties are encouraged to engage early with FDA program officials to resolve any uncertainties and to ensure all requirements are met well before submission deadlines.

Engage early with FDA review divisions and adhere to submission guidelines.