NCCIH Natural Product Mid Phase Clinical Trial Cooperative Agreement (U01 Clinical Trial Required) | PAR 20 216

Opportunity Information: Apply for PAR 20 216

The NCCIH Natural Product Mid Phase Clinical Trial Cooperative Agreement (U01 Clinical Trial Required), PAR-20-216, is a National Institutes of Health (NIH) funding opportunity designed to support investigator-initiated, mid-phase clinical trials focused specifically on natural products. The central purpose is to generate the kind of practical, decision-making evidence needed to justify and properly design a later, larger multi-site trial, rather than to run a definitive efficacy or effectiveness study now. Because it uses a U01 cooperative agreement mechanism, awardees should expect substantial scientific and programmatic involvement from NCCIH staff during the life of the project, with an emphasis on clear milestones and coordinated progress toward pre-specified goals.

This FOA is aimed at mid-phase trials that answer development questions that commonly block the field from moving forward responsibly. Applications are expected to propose a hypothesis-based clinical trial that either (1) identifies the optimal dose or formulation of a natural product for use in a future multi-site clinical trial, or (2) determines which patient phenotypes are most likely to respond versus not respond, so that inclusion and exclusion criteria for a later efficacy study can be sharpened. In other words, the work should directly de-risk a future definitive trial by improving dosing, formulation choices, and/or participant selection strategies, rather than attempting to prove the intervention works in the real world at scale.

A defining requirement of this opportunity is the expectation that applicants come in with strong preliminary evidence that the natural product is behaving in a measurable, biologically meaningful way. Specifically, applications must generally include adequate preliminary data demonstrating bioavailability and showing that the product produces a replicable and measurable effect on a biological signature, meaning an objective indicator tied to the proposed mechanism of action. This requirement is meant to prevent trials from being launched on vague rationale alone and to ensure that the intervention can be linked to a plausible, testable biological pathway. NCCIH notes limited exceptions: the biological signature requirement may be waived only when measuring such a signature in the target patient population is not possible or practical, or when there is already a fundamental understanding of the product's mechanism of action that makes the additional signature evidence unnecessary.

The program places firm boundaries on what it will and will not fund. It explicitly does not support single-site or multi-site efficacy or effectiveness trials under this FOA, and it also will not support clinical trials testing natural products for the treatment or prevention of cancer. The trials are expected to be milestone-driven, meaning applicants should lay out concrete, measurable progress points (for example, recruitment and retention targets, assay performance thresholds, decision rules for dose selection, or criteria for defining responder phenotypes) that keep the study aligned with its mid-phase objectives and NCCIH priorities.

Eligibility is broad across many U.S.-based organizational types, consistent with NIH norms. 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; other Native American tribal organizations; public housing authorities/Indian housing authorities; nonprofits with or without 501(c)(3) status; for-profit organizations (other than small businesses) as well as small businesses; and other eligible entities. The announcement also highlights a range of mission-relevant and community-connected institutions and organizations as eligible, including 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, eligible federal agencies, and U.S. territories or possessions. At the same time, it draws clear limits around foreign participation: non-domestic (non-U.S.) entities and foreign institutions are not eligible to apply, and non-domestic components of U.S. organizations are not eligible to apply. However, foreign components, as defined in the NIH Grants Policy Statement, are allowed, which typically means discrete foreign elements may be included when they add unique expertise, populations, or resources, so long as the applicant organization itself is eligible.

From an administrative standpoint, this is a discretionary grant opportunity in the health category (CFDA 93.213) administered by NIH through NCCIH, with the original FOA created on May 20, 2020. The source data lists an original closing date of September 7, 2023. The award ceiling and expected number of awards are not specified in the provided text, which usually means applicants need to rely on the FOA details and current NIH budget guidance for allowable budgets, study duration, and NCCIH program expectations.

Finally, NCCIH strongly encourages prospective applicants to contact the relevant NCCIH Scientific/Research contact before submitting. In practice, that pre-application conversation is often where investigators confirm whether their proposed natural product, mechanistic rationale, trial design, endpoints, and milestone plan fit the intent of the FOA, especially given the program's emphasis on biological signatures, bioavailability evidence, and mid-phase decision-making rather than definitive efficacy testing.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "NCCIH Natural Product Mid Phase Clinical Trial Cooperative Agreement (U01 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 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.)
• 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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