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

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

What is this grant opportunity?

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) that supports rigorous early-stage clinical testing of promising natural products in humans. The goal is to generate decision-enabling evidence that informs a clear next-step go/no-go decision for further product development.

Which NIH institute is associated with this program?

This opportunity is associated with the National Center for Complementary and Integrative Health (NCCIH) at NIH.

What types of interventions does the FOA focus on?

The FOA focuses specifically on natural products, including examples such as botanicals, dietary supplements, and probiotics.

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

The phased structure is designed to accelerate translation from mechanistic and basic research into well-designed early clinical trials. The first phase (R61) establishes key early human foundations and hits defined milestones; if those milestones are met, the project can transition to the second phase (R33) to replicate and extend the evidence and connect biological effects to functional or clinical signals.

Is a clinical trial required?

Yes. The funding mechanism is explicitly labeled "Clinical Trial Required," and it supports investigator-initiated clinical trials.

What makes a project a good fit for this FOA?

A strong fit is a natural product with a strong scientific rationale based on prior evidence, proposed for an early-stage human study that can credibly inform a development decision. Trials are expected to be hypothesis-driven, milestone-based, aligned with NCCIH mission and research priorities, and designed so the results are scientifically valuable even if they are negative.

What does it mean that results should be valuable even if negative?

The FOA expects trials to be designed so that, even if the natural product does not show the desired effects, the study still clarifies whether further testing is justified and what might need to be changed or improved if it is not.

What are the two phases, and how long can each phase last?

The award has two stages with defined milestones. The R61 phase can provide up to 2 years of support. If R61 milestones are met, the project may transition to the R33 phase, which can provide up to 3 additional years of support.

What is the primary focus of the R61 phase?

The R61 phase supports milestone-driven work in humans to establish early clinical foundations. This includes evaluating bioavailability and pharmacokinetics and assessing the natural product's biological effect using a measurable biological signature linked to a plausible mechanism of action. In practical terms, R61 is meant to show the product reaches the body in a meaningful way and produces the expected measurable biological change in people.

What types of measurements are emphasized in the R61 phase?

The FOA emphasizes human bioavailability and pharmacokinetics, along with a measurable biological signature tied to a plausible mechanism of action.

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

Based on the FOA description, a measurable biological signature is a quantifiable biological readout in humans that is tied to a plausible mechanism of action for the natural product and can be used to assess whether the product produces an expected biological effect.

What is the primary focus of the R33 phase?

The R33 phase is intended to replicate and strengthen evidence that the natural product consistently affects the same biological signature(s) in humans and to evaluate whether the magnitude of that biological impact is associated with functional or clinical outcomes in a patient population.

Does the R33 phase test clinical efficacy or effectiveness?

The FOA states it is not intended to support definitive clinical efficacy or effectiveness testing. The focus remains early clinical evaluation centered on exposure in humans, mechanism-linked biological signatures, and how those signatures relate to functional or clinical outcomes.

What does it mean to link biological impact to functional or clinical outcomes?

In this FOA, it means examining whether changes in the targeted biological signature(s) are associated with outcomes that reflect how people feel or function clinically in a patient population, without turning the project into a full-scale effectiveness trial.

Can the intervention strategy be optimized during the R33 phase?

Yes. The FOA allows studies in the R33 phase that optimize the intervention strategy to improve or clarify the biological impact.

What optimization approaches are specifically highlighted by the FOA?

The FOA highlights three example paths: (1) adjusting delivery through dose and/or formulation, (2) combining the natural product with another approach already known to influence the same biological signature, or (3) selecting a target population that is more likely to respond.

What triggers transition from R61 to R33?

Transition is milestone-based. If the defined R61 milestones are met, the project can transition to the R33 phase.

What general trial characteristics does NCCIH emphasize across both phases?

NCCIH emphasizes that supported trials must be hypothesis-driven, milestone-based, and aligned with NCCIH research priorities and mission.

Is this opportunity limited to certain applicant organization types?

Eligibility is broad across many U.S.-based organizations. Examples listed 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; 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.

Are any additional specific institution types explicitly called out as eligible?

Yes. The announcement explicitly notes eligibility for 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.

Who is not eligible to apply?

Non-U.S. entities and institutions are not eligible to apply. Non-U.S. components of U.S. organizations are not eligible. Foreign components (as defined by NIH policy) are not allowed.

Is this a federal grant, and how is it categorized?

Yes. It is an NIH opportunity and is categorized as a discretionary grant program within the health funding activity area.

What is the program identifier information provided for this FOA?

The FOA is identified as PAR-18-829, and the CFDA number provided is 93.213.

When was this opportunity posted, and what closing date is provided?

The information provided states the opportunity was posted by NIH and had an original closing date of November 4, 2019.

What is the core takeaway of this funding announcement?

The FOA funds early phase, decision-enabling clinical trials of natural products using a structured R61-to-R33 pathway: first demonstrating human exposure and mechanism-linked biological impact, then replicating that impact and relating it to functional or clinical signals, with room for thoughtful optimization before any later-stage efficacy testing is pursued.