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

FAQs: NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33 Clinical Trial Required), PAR 25-269

What is this grant opportunity?

This is a National Institutes of Health (NIH) funding opportunity administered by the National Center for Complementary and Integrative Health (NCCIH) for investigator-initiated early phase clinical trials of natural products. The mechanism is a phased innovation award with two linked stages (R61 followed by R33) and a clinical trial is required.

What kinds of studies does NCCIH want to fund under this program?

NCCIH is looking for early phase clinical trials that generate clear, interpretable, decision-enabling evidence about a natural product in humans. A central expectation is that the trial is designed to be informative regardless of outcome, meaning that positive or negative results still clearly guide whether the product should be advanced, refined, optimized, or discontinued for the intended use.

What does NCCIH mean by "natural products" in this program?

"Natural products" is defined broadly. It includes botanicals, probiotics, and products marketed as dietary supplements. It can also include well-defined nutritional regimens that standardize a specific naturally occurring compound (for example, omega-3 fatty acids, anthocyanidins, or polyphenols), as long as there is compelling preliminary evidence and a strong scientific rationale to justify clinical testing in humans.

Are general wellness trials a good fit for this funding opportunity?

The program emphasizes mechanistic and human response evidence rather than broad wellness claims. Applicants are expected to propose a credible plan to demonstrate target engagement or a mechanistically meaningful human response tied to a specified target measure.

What is the overall structure of the R61/R33 award?

The award has two linked phases. The first phase (R61) provides milestone-driven support for up to three years to generate key early clinical data. If the predefined R61 milestones are met, the project may transition to the second phase (R33) for up to an additional three years to replicate and strengthen target engagement evidence and examine links to clinical outcomes.

How long can the R61 phase last?

The R61 phase can provide up to three years of support and is milestone-driven.

What is expected during the R61 phase?

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 the mechanism of action. The application should include measurable milestones that determine whether the project is ready to transition to R33.

What is "target engagement" in the context of this opportunity?

In this program, target engagement refers to demonstrating that the natural product produces a mechanistically meaningful human response on a specified target measure tied to the proposed mechanism of action. The emphasis is on a credible, measurable indicator of biological impact in humans, not vague or non-specific outcomes.

How long can the R33 phase last?

The R33 phase can provide up to an additional three years of support following successful completion of the R61 milestones.

What is the purpose of the R33 phase?

The R33 phase is intended to replicate and strengthen evidence that the natural product meaningfully impacts the target engagement measure(s) in humans and to examine whether the magnitude of target engagement is associated with clinical outcomes in the participant population. It supports a more mature early-phase clinical trial effort, but it is not intended to be a large, definitive efficacy trial.

Does meeting R61 milestones guarantee funding for the R33 phase?

No. The project may transition to R33 if the R61 milestones are met. The opportunity describes the transition as conditional on achieving the predefined milestone criteria.

What does "milestone-driven" mean for applicants?

It means the R61 phase is expected to have defined, measurable milestones that determine readiness to move forward. The milestones are used to assess whether the project has generated the key early clinical evidence needed to justify and inform the R33 phase.

What does NCCIH mean by "informative regardless of outcome"?

NCCIH wants trials that produce high-value results even if the natural product does not perform as hoped. The design should ensure that negative results are still interpretable and decision-enabling (for example, clearly indicating that the product should be discontinued or redesigned), rather than producing ambiguous findings that cannot guide next steps.

Is optimization work allowed in the R33 phase (dose, formulation, delivery)?

Yes. NCCIH encourages applicants to use the R33 phase to learn how to optimize target engagement. This can include testing different doses, delivery strategies, or formulations to improve how consistently or strongly the natural product affects the intended biological target in humans.

Can the natural product be paired with another intervention?

The NOFO allows thoughtful designs that pair the natural product with another intervention known to affect the same target engagement measure, as long as the rationale is clear and the study design remains capable of yielding scientifically useful and interpretable results.

Can the study focus on a participant population expected to be more responsive?

Yes. The NOFO allows studies in a participant population expected to be more responsive, provided the rationale is clear and the design remains scientifically useful and interpretable.

Who is eligible to apply?

Eligibility is broad across many U.S.-based organization types. 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.

Are any additional organization types explicitly highlighted as eligible?

Yes. The NOFO explicitly highlights categories including 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.

Are foreign organizations eligible to apply?

No. Foreign organizations are not eligible to apply under this opportunity.

Are non-U.S. components of U.S. organizations eligible?

No. Non-U.S. components of U.S. organizations are also not eligible under this opportunity.

Is this opportunity a discretionary grant?

Yes. The listing describes it as a discretionary grant.

What is the funding activity category and CFDA number listed?

The listing shows a health funding activity category under CFDA 93.213.

What is the listed award ceiling?

The listed award ceiling is $350,000.

What is the closing date shown for this opportunity?

The original closing date shown is 2026-11-13.

When was this opportunity created (as listed)?

The listing indicates the opportunity was created on 2024-12-02.

What is the main goal of this program in practical terms?

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.