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.Apply for PAR 25 450
- 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.
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Frequently Asked Questions (FAQs)
What is the name of this NIH grant opportunity?
The opportunity is titled "Clinical Trial Readiness for Rare Diseases, Disorders, and Syndromes (R21 Clinical Trial Not Allowed)."
What is the funding opportunity number?
The funding opportunity number is PAR-25-450.
What is the main purpose of this program?
This NIH program supports clinical-stage, practical projects that address high-impact gaps that commonly prevent rare disease communities from being ready to launch informative, well-designed clinical trials. The goal is to complete the groundwork that makes a future trial feasible, efficient, and more likely to succeed.
Does this grant fund actual clinical trials?
No. This opportunity is explicitly designated "Clinical Trial Not Allowed." Applications should not propose a clinical trial and should not be structured as testing an intervention for efficacy within a clinical trial framework.
If clinical trials are not allowed, what types of activities does NIH want to fund?
NIH is looking to fund trial readiness activities for rare conditions, especially work that develops the measurement tools and disease understanding needed to make a later clinical trial interpretable. The focus areas highlighted include biomarkers, clinical outcome assessment measures, and clarifying disease presentation and course (natural history and related characterization).
What does "clinical trial readiness" mean in this announcement?
In this context, clinical trial readiness means doing preparatory clinical research that removes common barriers to starting a future interventional trial. Examples include establishing credible endpoints, developing meaningful measures of change, and building a clear understanding of the disease to support sound trial design choices.
What kinds of biomarker work are considered responsive to this opportunity?
Responsive biomarker work can include identifying biomarkers that track disease activity or progression, testing whether a biomarker is reliable and sensitive to change, and showing that the biomarker is practical to collect in the intended patient population.
What kinds of clinical outcome assessment (COA) work does NIH emphasize?
Applicants may propose developing or validating clinical outcome assessments intended to serve as credible future trial endpoints. The announcement specifically mentions performance-based measures, clinician-reported measures, observer-reported measures, and patient-reported outcome instruments, as long as the work is geared toward enabling future interventional studies.
Is natural history research relevant to this program?
Yes. Clarifying the presentation and course of a rare disease is identified as a key pathway to readiness. This can include defining natural history, characterizing variability across patients, mapping typical progression, or identifying clinically meaningful milestones.
How can disease characterization help with future trial design?
Disease characterization work is often essential for designing inclusion and exclusion criteria, selecting appropriate endpoints and assessment timepoints, and estimating sample sizes in small patient populations.
What is the overarching aim of NIH for projects funded under this opportunity?
The overarching aim is to 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.
What does the R21 mechanism imply for project scope and structure?
Based on the information provided, the R21 mechanism is oriented toward targeted, milestone-driven projects that can substantially de-risk and accelerate next steps toward clinical testing, rather than broad, open-ended research programs.
Who is eligible to apply (in general terms)?
Eligibility is broad across U.S.-based organizations and includes many common applicant types across government, education, nonprofit, and for-profit sectors, as described in the opportunity.
Are U.S. state and local government entities eligible?
Yes. The eligible categories listed include state, county, city, township, and special district governments.
Are public and private colleges and universities eligible?
Yes. Eligible applicants include public and state-controlled institutions of higher education and private institutions of higher education.
Are nonprofit organizations eligible even if they do not have 501(c)(3) status?
Yes. Nonprofits are eligible whether or not they have 501(c)(3) status, provided they are not foreign entities.
Are for-profit organizations eligible?
Yes. For-profit organizations other than small businesses are eligible, and small businesses are also eligible.
Are tribal governments and tribal organizations eligible?
Yes. The eligibility list includes federally recognized Native American tribal governments and Native American tribal organizations other than federally recognized tribal governments. The list also includes tribal governments that are not federally recognized.
Are U.S. territories or possessions eligible?
Yes. U.S. territories or possessions are included among the additional eligible applicant categories explicitly noted.
Are faith-based or community-based organizations eligible?
Yes. Faith-based or community-based organizations are explicitly listed among additional eligible applicant categories.
Are serving institutions such as HBCUs, HSIs, TCCUs, and AANAPISIs eligible?
Yes. The announcement explicitly notes additional eligible applicant categories including Historically Black Colleges and Universities (HBCUs), Hispanic-serving Institutions, Tribally Controlled Colleges and Universities (TCCUs), Alaska Native and Native Hawaiian Serving Institutions, and Asian American Native American Pacific Islander Serving Institutions (AANAPISIs).
Can foreign (non-U.S.) organizations apply?
No. Non-domestic (non-U.S.) entities are not eligible to apply.
Can a U.S. organization include a non-U.S. component or site?
No. Non-domestic components of U.S. organizations are not eligible, and foreign components (as defined by the NIH Grants Policy Statement) are not allowed.
What do the foreign involvement restrictions mean in practical terms?
Based on the stated restrictions, applicants should plan for the funded work to be conducted within allowable U.S. organizational structures and sites, without foreign components.
What CFDA numbers are associated with this opportunity?
The opportunity lists CFDA numbers 93.350 and 93.865.
What is the closing date shown for this opportunity?
The posting shows an original closing date of 2028-07-20, which suggests a multi-year application window typical of NIH program announcements with periodic receipt dates.
Does the provided information include an award ceiling or the expected number of awards?
No. The provided source information does not specify an award ceiling or an expected number of awards.
Where should applicants look for budget expectations, scope fit, review criteria, and institute-specific priorities?
The provided information indicates 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.
How should applicants think about fit for this NOFO at a high level?
This NOFO is best viewed as support for essential clinical research infrastructure that rare disease trials often lack, such as validated biomarkers, fit-for-purpose clinical outcome measures, and well-defined disease natural history and phenotype, all aimed at enabling a later informative clinical trial.
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