Efficient and Innovative Natural History Studies Addressing Unmet Needs in Rare Diseases (R01) Clinical Trials Not Required | RFA FD 22 001

Opportunity Information: Apply for RFA FD 22 001

This funding opportunity, titled "Efficient and Innovative Natural History Studies Addressing Unmet Needs in Rare Diseases (R01) Clinical Trials Not Required" (RFA-FD-22-001), is a discretionary grant program run by the U.S. Department of Health and Human Services through the Food and Drug Administration (FDA). It sits within the health funding activity category (CFDA 93.103) and is designed to fund natural history research in rare diseases and rare conditions where there are still major unmet needs. The central idea is to generate strong, well-structured natural history evidence that can be used to speed and strengthen medical product development, including drugs, biologics, and devices, without requiring the funded work to be a clinical trial.

The program focuses on supporting natural history studies that are both efficient and innovative, meaning applicants are expected to propose approaches that gather meaningful information without unnecessary cost, burden, or ambiguity. FDA is looking for studies that produce high-quality, interpretable data elements, because in rare diseases the biggest bottleneck is often not a lack of interest in developing treatments, but a lack of reliable baseline knowledge about how the disease behaves over time. Natural history data can clarify how symptoms start and progress, how variable the condition is across patients, which subgroups exist, what outcomes matter most to patients, and which measurements best reflect true clinical change. When those pieces are missing, it becomes much harder to design clinical studies, choose endpoints, estimate sample sizes, or persuade regulators that a proposed outcome measure is meaningful.

The purpose of funding these studies is explicitly tied to medical product development impact. FDA indicates it expects funded projects to address critical knowledge gaps and remove major barriers that slow progress in rare disease research. In practice, that can include establishing clearer descriptions of disease course, identifying and validating potential clinical outcome assessments or biomarkers, mapping genotype-phenotype relationships, defining clinically meaningful milestones, and improving the ability to compare patients across sites and studies. The FOA also emphasizes broad impact: projects should be positioned to make a significant difference for a specific rare disease, or potentially for multiple rare diseases that share similar underlying biology or pathophysiology. That matters because methods, endpoints, and data standards built for one condition can sometimes be adapted to a related group, multiplying the value of the investment.

The award mechanism is an R01 grant, and the FOA states that clinical trials are not required. That does not mean clinical data cannot be collected; rather, the funded work is intended to be observational natural history research rather than an interventional trial designed to test efficacy or safety of a specific treatment. Typical natural history designs can be prospective (following patients forward in time), retrospective (using existing records), or a hybrid, and may incorporate data from registries, electronic health records, wearable devices, imaging, laboratory testing, or patient-reported outcomes, as long as the resulting dataset is robust and interpretable. A strong emphasis is placed on data quality and usefulness for regulatory and development decisions, which usually implies careful attention to standardized data elements, consistent definitions, clear protocols for measurement, and plans for handling missingness and heterogeneity.

In terms of who can apply, eligibility is broad. It includes state, county, and city or township 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; other tribal organizations; public housing and Indian housing authorities; nonprofits with or without 501(c)(3) status (excluding institutions of higher education for those categories); for-profit organizations other than small businesses; and small businesses. The listing also references an "Others" category with additional eligibility clarification in the full announcement, suggesting FDA intended to allow a wide range of capable organizations to participate, including academic centers, disease foundations, research networks, and industry partners where appropriate.

Key administrative details include an award ceiling of $2,500,000 and an expectation of about five awards. The opportunity was created on February 17, 2021, and it listed two application deadlines: February 15, 2022 and February 13, 2024, both due by 11:59 PM Eastern Time. The funding instrument type is a grant, and the opportunity category is discretionary, meaning awards are competitive and based on merit review and program priorities rather than entitlement or formula distribution.

Overall, this FOA is aimed at building the kind of foundational, decision-grade natural history evidence that rare disease developers and regulators often need before treatments can be tested efficiently. By pushing for efficient study designs and high-quality, interpretable data elements, FDA is signaling that the best proposals will not only collect data, but will collect the right data in a way that can directly reduce uncertainty, improve trial readiness, and make downstream product development faster, more feasible, and more credible for rare diseases with limited existing knowledge.

• The Department of Health and Human Services, Food and Drug Administration in the health sector is offering a public funding opportunity titled "Efficient and Innovative Natural History Studies Addressing Unmet Needs in Rare Diseases (R01) Clinical Trials Not Required" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.103.
• This funding opportunity was created on Feb 17, 2021.
• Applicants must submit their applications by February 15, 2022 Two deadlines listed below February 15, 2022,by 1159 PM Eastern Time February 13, 2024 by 1159 PM Eastern Time.. (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 $2,500,000.00 in funding.
• The number of recipients for this funding is limited to 5 candidate(s).
• 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 (see text field entitled Additional Information on Eligibility for clarification).

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