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

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

What is this grant opportunity?

This is an NIH grant opportunity from NCCIH that supports investigator-initiated, early-phase clinical trials of natural products using a phased, milestone-driven R61/R33 structure. The purpose is to move promising natural product research into well-structured early-stage human testing and generate results that clearly inform next-step decisions.

What is the main goal of the R61/R33 phased structure?

The main goal is to reduce risk and speed translation by using defined, go/no-go milestones. The project starts with an R61 phase to establish foundational human evidence, and if prespecified milestones are met, it can transition to an R33 phase to replicate and strengthen mechanistic evidence and connect it to functional or clinical outcomes.

What kinds of interventions are considered "natural products" under this opportunity?

The opportunity targets natural products such as botanicals, dietary supplements, and probiotics, as long as there is a strong scientific rationale that the product is worth further clinical development.

Are clinical trials required?

Yes. The funding mechanism is explicitly described as "Clinical Trial Required" and is intended to support investigator-initiated clinical trials of natural products.

Is this opportunity intended to fund large, definitive efficacy trials?

No. This FOA is not meant to fund full-scale efficacy trials or late-stage clinical testing. It focuses on early-phase, mechanistically grounded clinical research designed to produce actionable evidence that helps determine whether larger, more definitive trials should follow.

What does NCCIH expect the results of the trial to accomplish?

NCCIH expects results with clear decision-making value. Whether results are positive or negative, they should be informative enough to guide next steps such as continued development, refinement, optimization, or discontinuation of the approach.

How long can the R61 phase last, and what is it supposed to achieve?

The R61 phase can provide up to two years of support. It is intended to establish foundational human evidence that the natural product behaves in the body in a measurable, interpretable way and influences a biologically meaningful target.

What types of data are emphasized in the R61 phase?

The R61 phase emphasizes bioavailability and pharmacokinetics (how the product is absorbed, distributed, metabolized, and excreted) and early evidence of biological activity in humans, framed as the product's impact on a predefined biological signature.

What is a "biological signature" in the context of this FOA?

A biological signature is a mechanistic readout: a measurable marker or set of markers that reflects the hypothesized mechanism of action. It is used to determine whether the intervention is hitting its intended biological target in people.

What triggers the transition from the R61 phase to the R33 phase?

Transition is milestone-driven. If the project meets the prespecified R61 milestones, the grant can transition to the R33 phase for additional support.

How long can the R33 phase last, and what is it supposed to do?

The R33 phase can provide up to three additional years of support. It focuses on replicating and strengthening evidence that the natural product reliably affects the biological signature in humans and testing whether the magnitude of that biological effect is associated with functional or clinical outcomes in a patient population.

Does the R33 phase require proof that the natural product works clinically?

No. 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 direction for later-stage studies.

Can applicants change the dose, formulation, or delivery method during the project?

Yes. 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, including adjusting delivery through dose selection or formulation changes.

What optimization strategies does the FOA specifically highlight for the R33 phase?

The FOA highlights three common strategies: (1) adjusting delivery through dose selection or formulation changes, (2) pairing the natural product with another treatment approach already known to influence the same biological signature, and (3) focusing on a target population more likely to respond to increase the chance of detecting a meaningful biological signal.

Do studies need to be hypothesis-based?

Yes. Across both phases, studies are expected to be hypothesis-based and explicitly tied to NCCIH's mission and research priorities.

What are "go/no-go" milestones in this FOA?

These are predefined milestones used to keep the work focused on generating high-utility evidence and to support clear decisions about whether the project should proceed (including whether it can transition from R61 to R33).

What types of outcomes are examined in the R33 phase?

The R33 phase examines whether the natural product reliably affects the biological signature and whether the magnitude of that biological effect is associated with functional or clinical outcomes in a patient population.

What is the opportunity number and what agency is offering it?

The opportunity number is PAR-20-218. It is an NIH grant opportunity associated with NCCIH.

What are the listed CFDA numbers for this opportunity?

The listed CFDA numbers are 93.213 and 93.321.

What is the listed award ceiling?

The listed award ceiling is $350,000.

What is the original closing date shown in the provided record?

The original closing date shown is 2023-09-07.

What is the FOA record creation date shown in the provided record?

The FOA record indicates a creation date of 2020-05-20.

Who is eligible to apply?

Eligibility is broad and includes many U.S.-based public and private entities, including 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.

Are minority-serving institutions and community-based organizations eligible?

Yes. The FOA calls out eligibility for minority-serving institutions (including HBCUs, Hispanic-serving institutions, AANAPISISs, and Tribal colleges and universities) as well as faith-based or community-based organizations.

Are U.S. territories or possessions eligible?

Yes. The FOA includes U.S. territories or possessions among eligible applicants.

Are non-U.S. (foreign) applicants allowed?

No. Non-domestic (non-U.S.) entities are not eligible to apply under this FOA.

Are foreign components allowed if the applicant is a U.S. organization?

No. The FOA states that non-domestic components of U.S. organizations are not eligible and foreign components (as defined by NIH policy) are not allowed.

What makes this FOA different from a typical clinical trial grant?

This FOA is specifically structured around early-phase, mechanistic clinical research of natural products, with explicit focus on pharmacokinetics/bioavailability, biological signature readouts, replication of mechanistic effects, and milestone-based progression to guide decisions about later-stage investments.

What is the overall intent of the program?

The intent is to accelerate movement from emerging basic or preclinical findings toward disciplined human testing while ensuring results can credibly support decisions about whether larger, more definitive trials should follow.