NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33 Clinical Trial Required) | PAR 18 829

Opportunity Information: Apply for PAR 18 829

The NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33, Clinical Trial Required) is an NIH grant opportunity (PAR-18-829; CFDA 93.213) designed to move promising natural products into rigorous early-stage human testing. It focuses specifically on natural products such as botanicals, dietary supplements, and probiotics that already have a strong scientific rationale based on prior evidence, and it supports investigator-initiated clinical trials that can credibly inform the next go/no-go decision for product development. A central expectation is that the study is built so the results will be scientifically valuable even if they are negative, meaning the trial should still clarify whether further testing is justified and what should be changed or improved if it is not.

The award uses a two-stage phased mechanism with defined milestones. The first stage (R61) provides up to two years of support for milestone-driven work in humans that establishes key early clinical foundations, including bioavailability and pharmacokinetics, along with an assessment of the natural product's biological effect using a measurable biological signature tied to a plausible mechanism of action. In practical terms, the R61 phase is meant to show that the product reaches the body in a meaningful way (and how), and that it produces the expected measurable biological change in people, rather than simply relying on preclinical signals.

If the R61 milestones are met, the project can transition to the second stage (R33), which can provide up to three additional years of support. The R33 phase is intended to replicate and strengthen the evidence that the natural product consistently affects the same biological signature(s) in humans and to examine whether the magnitude of that biological impact is associated with functional or clinical outcomes in a patient population. While this is still early-stage clinical development, it goes beyond basic exposure and mechanism checks by asking whether the biological change relates in a meaningful way to how people feel or function clinically, without turning the project into a full-scale effectiveness trial.

Within the R33 phase, applicants are also allowed to design studies that optimize the intervention strategy to improve or clarify the biological impact. The FOA highlights three example optimization paths: adjusting delivery through dose and/or formulation, combining the natural product with another approach already known to influence the same biological signature, or selecting a target population that is more likely to respond. This flexibility is meant to help investigators refine the product-use scenario so that the biological signal is as clear and interpretable as possible, which in turn supports better decisions about whether later-phase clinical studies are warranted.

Across both phases, NCCIH emphasizes that supported trials must be hypothesis-driven, milestone-based, and aligned with NCCIH research priorities and mission. The intent of the R61/R33 structure is to accelerate translation from emerging basic and mechanistic science on natural products into well-designed early clinical trials that clarify biological effects in humans and inform next-step development. Importantly, the FOA is not intended to support definitive clinical efficacy or effectiveness testing; instead, it targets early clinical evaluation focused on human exposure, mechanism-linked biological signatures, and the relationship of those signatures to outcomes.

Eligibility is broad and includes many types of U.S.-based organizations: 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; tribal organizations other than federally recognized 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); small businesses; and other eligible entities. The announcement also explicitly notes additional eligible applicant types such as Alaska Native and Native Hawaiian Serving Institutions, AANAPISIs, Hispanic-serving Institutions, Historically Black Colleges and Universities, Tribally Controlled Colleges and Universities, faith-based or community-based organizations, regional organizations, U.S. territories or possessions, and eligible federal agencies. At the same time, non-U.S. entities and institutions are not eligible to apply, non-U.S. components of U.S. organizations are not eligible, and foreign components (as defined by NIH policy) are not allowed.

The opportunity was posted by NIH with an original closing date of November 4, 2019, and it is categorized as a discretionary grant program within the health funding activity area. The core takeaway is that this FOA funds early phase, decision-enabling clinical trials of natural products, using a structured R61-to-R33 pathway that first proves human exposure and mechanism-linked biological impact, then replicates and links that impact to functional or clinical signals while allowing thoughtful optimization before any later-stage efficacy testing is pursued.

• 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 2018-06-13.
• Applicants must submit their applications by 2019-11-04. (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.

Apply for PAR 18 829

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