Clinical Trial Readiness for Rare Diseases, Disorders, and Syndromes (R21 Clinical Trial Not Allowed) | PAR 22 101

Opportunity Information: Apply for PAR 22 101

The Clinical Trial Readiness for Rare Diseases, Disorders, and Syndromes (R21 Clinical Trial Not Allowed) funding opportunity (PAR 22-101) is a National Institutes of Health (NIH) discretionary grant program designed to help rare disease research teams close key gaps that commonly delay or derail later-stage clinical trials. Rather than funding an actual clinical trial, this announcement focuses on the practical, near-term clinical groundwork that makes a future trial feasible, interpretable, and more likely to succeed. The core idea is to support targeted clinical projects that move a promising therapeutic or diagnostic concept closer to a trial-ready state by strengthening the tools, data, and disease understanding needed to design a rigorous study.

Projects under this FOA are expected to address critical needs in “clinical trial readiness” for rare diseases, disorders, and syndromes. In practice, that means work such as developing, refining, and testing biomarkers that can reliably measure disease biology or response to an intervention, and creating or validating clinical outcome assessment measures that can sensitively and meaningfully capture how a patient feels, functions, or survives. Another major theme is natural history and characterization research that defines how a rare disease presents and progresses over time, including variability across patients and stages. These efforts are especially important in rare diseases where small populations, heterogeneous symptoms, and limited baseline data make it difficult to choose endpoints, determine sample sizes, set eligibility criteria, or select appropriate follow-up intervals. By supporting these enabling studies, NIH aims to make later interventional trials more efficient and scientifically defensible, reducing the risk that a trial fails because endpoints were poorly matched to the disease or because there was not enough knowledge about expected progression.

The mechanism is an R21, which is typically used for exploratory or developmental projects that can generate key proof-of-concept data or establish feasibility. Consistent with the title, “Clinical Trial Not Allowed,” the funded work should not be an interventional clinical trial testing the safety or efficacy of a therapeutic or diagnostic in humans. Instead, the emphasis is on clinical-stage preparation activities: assembling and analyzing clinical datasets, conducting prospective observational assessments, standardizing and validating measures across sites, demonstrating reliability and responsiveness of endpoints, and producing evidence that a candidate biomarker or outcome measure is fit for purpose in a future trial setting. The overall funding activity category is Health, Income Security and Social Services, and the program is associated with CFDA numbers 93.350 and 93.865.

Eligibility is broad and includes many U.S.-based organizational types. Eligible applicants listed for this FOA include state, county, city or 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; Native American tribal organizations (other than federally recognized tribal governments); public housing authorities and Indian housing authorities; nonprofits with 501(c)(3) status and nonprofits without 501(c)(3) status (in both cases, other than institutions of higher education); for-profit organizations other than small businesses; small businesses; and other organizations. The FOA also explicitly calls out additional eligible applicant categories such as 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 agencies of the federal government, regional organizations, Indian/Native American tribal governments (other than federally recognized), and U.S. territories or possessions. This wide eligibility is meant to encourage participation from diverse institutions and communities, which is often essential in rare disease research where patient populations may be geographically dispersed and where community engagement can materially improve recruitment feasibility and the relevance of outcome measures.

Restrictions related to foreign involvement are specific. Non-domestic (non-U.S.) entities, including foreign organizations and foreign institutions, are not eligible to apply as the applicant organization. In addition, non-domestic components of U.S. organizations are not eligible to apply. However, “foreign components,” as defined in the NIH Grants Policy Statement, are allowed, meaning that certain parts of the proposed research effort may be carried out internationally under NIH rules if justified and properly structured, even though the prime applicant must be eligible and U.S.-based.

From an administrative standpoint, the opportunity was created on 2022-02-03 and listed an original closing date of 2023-04-13. The announcement identifies NIH as the sponsoring agency and uses a grant funding instrument. While the source data provided does not specify an award ceiling or the expected number of awards, the intent of the program is clear: to fund focused clinical readiness projects that deliver concrete outputs needed for subsequent trial design, such as validated biomarkers, well-characterized clinical endpoints, and clearer definitions of disease presentation and course. The end result NIH is aiming for is a stronger pipeline where candidate therapeutics and diagnostics for rare diseases can advance into later clinical testing with better measurement tools, better baseline knowledge, and a higher probability that a trial will yield interpretable, decision-quality results.

• 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 2022-02-03.
• Applicants must submit their applications by 2023-04-13. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• 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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