Clinical Trial Readiness for Rare Diseases, Disorders, and Syndromes (R21 Clinical Trial Not Allowed) | PAR 25 450

Opportunity Information: Apply for PAR 25 450

The National Institutes of Health (NIH) is offering a discretionary grant opportunity titled "Clinical Trial Readiness for Rare Diseases, Disorders, and Syndromes (R21 Clinical Trial Not Allowed)," funding opportunity number PAR-25-450. This program supports clinical-stage projects that are meant to solve practical, high-impact gaps that commonly prevent rare disease communities from being ready to launch informative and well-designed clinical trials. The focus is not on running an actual clinical trial, but on doing the groundwork that makes a future trial feasible, efficient, and more likely to succeed. The overarching aim is to help move promising therapeutics or diagnostics toward the point where a clinical trial can be initiated with appropriate endpoints, meaningful measures of change, and a clear understanding of the disease being studied.

The core activities NIH is looking to fund center on "trial readiness" needs for rare conditions. A major emphasis is on developing and testing biomarkers and clinical outcome assessment measures that are rigorous enough to support future interventional studies. In practice, this can include identifying biomarkers that track disease activity or progression, evaluating whether a biomarker is reliable and sensitive to change, and demonstrating that it is practical to collect in the intended patient population. Similarly, applicants can focus on developing or validating clinical outcome assessments, such as performance-based measures, clinician-reported measures, observer-reported measures, or patient-reported outcome instruments, as long as the work is geared toward producing endpoints that can credibly be used in future trials. Another key pathway to readiness highlighted in the opportunity is clarifying the presentation and course of a rare disease, such as by defining the natural history, characterizing variability across patients, mapping typical progression, or identifying clinically meaningful milestones. This kind of disease characterization is often essential for designing inclusion and exclusion criteria, selecting the most appropriate endpoints and assessment timepoints, and estimating sample sizes in small populations.

Because this is an R21 mechanism, the program is generally oriented toward targeted, milestone-driven projects that can substantially de-risk and accelerate the next steps toward clinical testing, rather than broad, open-ended research programs. The "Clinical Trial Not Allowed" designation is central: applications should not propose a clinical trial, and they should be structured as preparatory clinical research that enables a future trial rather than tests an intervention for efficacy. In other words, NIH is inviting projects that build the measurement tools and disease understanding needed to make a later clinical trial interpretable, rather than projects that evaluate a treatment or diagnostic in a trial framework.

Eligibility is broad across U.S.-based organizations and includes many common applicant types such as state, county, city, township, and 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; public housing authorities and Indian housing authorities; and Native American tribal organizations other than federally recognized tribal governments. Nonprofits are eligible whether or not they have 501(c)(3) status, provided they are not foreign entities. For-profit organizations other than small businesses are eligible, and small businesses are also eligible. NIH also explicitly notes additional eligible applicant categories, including Alaska Native and Native Hawaiian Serving Institutions, Asian American Native American Pacific Islander Serving Institutions (AANAPISIs), Hispanic-serving Institutions, Historically Black Colleges and Universities (HBCUs), Tribally Controlled Colleges and Universities (TCCUs), faith-based or community-based organizations, eligible federal agencies, regional organizations, tribal governments that are not federally recognized, and U.S. territories or possessions.

Foreign involvement is explicitly restricted. Non-domestic (non-U.S.) entities are not eligible to apply, non-domestic components of U.S. organizations are not eligible, and foreign components as defined by the NIH Grants Policy Statement are not allowed. This means applicants should plan for the funded work to be conducted within allowable U.S. organizational structures and sites, without foreign components.

The opportunity falls under health-related federal assistance and lists CFDA numbers 93.350 and 93.865. The posting shows an original closing date of 2028-07-20, indicating a multi-year application window typical of many NIH program announcements with periodic receipt dates. The source information provided does not specify an award ceiling or expected number of awards, so applicants would need to consult the full NOFO text and NIH institute or center guidance for budget expectations, scope fit, review criteria, and any institute-specific priorities.

Overall, this NOFO is best viewed as support for the essential clinical research infrastructure that rare disease trials often lack: validated biomarkers, fit-for-purpose clinical outcome measures, and well-defined disease natural history and phenotype. The intent is to make subsequent trials more efficient and more informative, improving the odds that a therapeutic or diagnostic program can be tested in a way that yields clear, actionable results despite the challenges of small patient populations and heterogeneous disease presentation.

• The National Institutes of Health in the health, income security and social services sector is offering a public funding opportunity titled "Clinical Trial Readiness for Rare Diseases, Disorders, and Syndromes (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): 93.350, 93.865.
• This funding opportunity was created on 2025-09-22.
• Applicants must submit their applications by 2028-07-20.
• 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 PAR 25 450

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