NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33 Clinical Trial Required) | PAR 20 218

Opportunity Information: Apply for PAR 20 218

The NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33 Clinical Trial Required) is an NIH grant opportunity designed to move promising natural product research into well-structured early-stage human testing. It specifically targets investigator-initiated clinical trials of natural products such as botanicals, dietary supplements, and probiotics, as long as there is a strong scientific rationale suggesting the product is worth further clinical development. A central expectation is that the trial will generate results with clear decision-making value: whether findings are positive or negative, they should be informative enough to guide the next steps in development, refinement, or discontinuation of the approach.

The award uses a two-phase, milestone-driven structure intended to reduce risk and speed translation. The first phase (R61) provides up to two years of support to establish foundational human evidence that the natural product behaves in the body in a measurable, interpretable way and influences a biologically meaningful target. In practice, the R61 phase emphasizes bioavailability and pharmacokinetics (how the product is absorbed, distributed, metabolized, and excreted) as well as early evidence of biological activity in humans, framed as the product’s impact on a predefined biological signature. This biological signature functions like a mechanistic readout, a measurable marker or set of markers that reflects the hypothesized mechanism of action and helps determine whether the intervention is hitting its intended target in people.

If the project meets the prespecified milestones in the R61 phase, the grant can transition to the second phase (R33), which can provide up to three additional years of support. The R33 phase focuses on replicating and strengthening the evidence that the natural product reliably affects the biological signature in humans and then testing whether the magnitude of that biological effect is associated with functional or clinical outcomes in a patient population. Importantly, the emphasis remains on early-phase, mechanistically grounded clinical research rather than definitive proof of effectiveness. The goal is to generate rigorous evidence that continued clinical research is justified and to clarify the most sensible direction for later-stage studies.

A notable feature of the R33 phase is that applicants are allowed to design studies that optimize how the natural product produces its biological effect. The FOA highlights three common optimization strategies: adjusting delivery through dose selection or formulation changes; pairing the natural product with another treatment approach already known to influence the same biological signature; or focusing on a target population that is more likely to respond, which can increase the chance of detecting a meaningful biological signal. Across both phases, studies are expected to be hypothesis-based and explicitly tied to NCCIH’s mission and research priorities, with clear go/no-go milestones that keep the work focused on generating high-utility evidence.

This opportunity is not meant to fund full-scale efficacy trials or late-stage clinical testing. Instead, it sits earlier in the translation pipeline, where the priority is establishing whether a natural product produces reproducible, mechanistically interpretable effects in humans and whether those effects track with outcomes that matter clinically. The overall intent is to accelerate movement from emerging basic or preclinical findings toward disciplined human testing, while ensuring that the results can credibly support decisions about whether larger, more definitive trials should follow.

Administratively, the funding instrument is a grant under NIH, with the opportunity number PAR-20-218 and an NIH activity focus in health (CFDA numbers 93.213 and 93.321). The listed award ceiling is $350,000. The original closing date shown is 2023-09-07, and the FOA record indicates a creation date of 2020-05-20. Eligibility is broad and includes many U.S.-based public and private entities, such as state and local governments, public and state-controlled institutions of higher education, private universities, nonprofit organizations (with or without 501(c)(3) status), for-profit organizations (other than small businesses), small businesses, and federally recognized tribal governments, among others. The FOA also calls out a range of other eligible applicants such as minority-serving institutions (including HBCUs, Hispanic-serving institutions, AANAPISISs, and Tribal colleges and universities), faith-based or community-based organizations, and U.S. territories or possessions. At the same time, it clearly excludes non-U.S. applicants and foreign components: 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 NIH policy are not allowed.

In short, this FOA supports carefully designed, early-phase, milestone-driven clinical trials of natural products where the key deliverables are human pharmacokinetic and bioavailability data, credible evidence of a mechanistic biological effect on a defined signature, and replication plus linkage of that effect to functional or clinical outcomes in patients. The structure is intentionally built to produce actionable information quickly and reliably, helping the field decide which natural products merit larger investments in later-stage clinical research.

• 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, 93.321.
• This funding opportunity was created on 2020-05-20.
• Applicants must submit their applications by 2023-09-07. (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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