NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33 Clinical Trial Required) | PAR 25 269

Opportunity Information: Apply for PAR 25 269

The NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33 Clinical Trial Required), PAR 25-269, is a National Institutes of Health grant opportunity that funds investigator-initiated early phase clinical trials focused on natural products. In this program, "natural products" is meant broadly and includes botanicals, probiotics, and products marketed as dietary supplements. It also includes well-defined nutritional regimens that standardize a specific naturally occurring compound, such as omega-3 fatty acids, anthocyanidins, or polyphenols, as long as there is compelling preliminary evidence and a strong scientific rationale to justify moving forward with clinical testing in humans.

A central expectation is that the proposed clinical trial is designed to be informative regardless of outcome. NCCIH is looking for studies where both positive and negative results will still be high-value and decision-enabling, meaning they clarify whether the natural product should be advanced, refined, or discontinued for the intended use. The trials should be constructed to produce clear, interpretable evidence that supports future development choices rather than ambiguous findings that cannot guide next steps.

The award uses a phased innovation structure with two linked stages. The first stage, the R61 phase, can provide up to three years of support and is milestone-driven. During R61, investigators are expected to generate key early clinical data such as pharmacokinetics and bioavailability, and to test the natural product's effect in humans on a specified target measure tied to mechanism of action. In practice, this means applicants need a credible plan to demonstrate "target engagement" or a mechanistically meaningful human response, not simply broad wellness claims, and they must define measurable milestones that determine whether the project is ready to transition to the next phase.

If the R61 milestones are met, the project may transition to the R33 phase for up to an additional three years. The R33 phase is intended to replicate and strengthen the evidence that the natural product meaningfully impacts the target engagement measure(s) in humans and to examine whether the magnitude of that target engagement is associated with clinical outcomes in the participant population. This stage supports a more mature early-phase clinical trial effort that still remains focused on mechanistic validation and decision-ready evidence, rather than a large, definitive efficacy trial.

NCCIH also encourages applicants to use the R33 phase to learn how to optimize target engagement. That can include testing different doses, delivery strategies, or formulations to improve how consistently or strongly the natural product hits the intended biological target in humans. The NOFO also allows for thoughtful designs that pair the natural product with another intervention known to affect the same target engagement measure, or that study the natural product in a participant population expected to be more responsive, as long as the rationale is clear and the design remains capable of yielding scientifically useful, interpretable results.

Eligibility is broad across many U.S.-based organization types, reflecting the NIH emphasis on enabling clinical research across sectors. Eligible applicants include state, county, and local 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; Native American tribal organizations other than federally recognized tribal governments; public housing authorities/Indian housing authorities; nonprofits with or without 501(c)(3) status (other than institutions of higher education); for-profit organizations other than small businesses; and small businesses. The NOFO also explicitly highlights other eligible applicant categories such as Alaska Native and Native Hawaiian Serving Institutions, AANAPISI institutions, faith-based or community-based organizations, Hispanic-serving institutions, HBCUs, tribally controlled colleges and universities, certain tribal governments other than federally recognized ones, regional organizations, eligible federal agencies, and U.S. territories or possessions. At the same time, foreign organizations are not eligible to apply, and non-U.S. components of U.S. organizations are also not eligible under this opportunity.

Key administrative details from the listing include that it is a discretionary grant in the health funding activity category under CFDA 93.213, administered by the NIH. The original closing date shown is 2026-11-13. The listed award ceiling is $350,000. The opportunity was created on 2024-12-02. Overall, the program is aimed at moving promising natural products through a rigorous, milestone-based early clinical testing pathway that prioritizes human pharmacology, bioavailability, mechanistic target engagement, and clinically relevant signals that can credibly guide whether and how the product should advance.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33 Clinical Trial Required)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.213.
• This funding opportunity was created on 2024-12-02.
• Applicants must submit their applications by 2026-11-13. (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 $350,000.00 in funding.
• 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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