The National Center for Complementary and Integrative Health (NCCIH) has issued a funding opportunity for early-phase clinical trials on natural products through the R33 Clinical Trial Award mechanism. The funding supports investigator-initiated studies evaluating botanicals, dietary supplements, probiotics, and other natural products with a strong scientific basis. These trials aim to establish measurable target engagement in humans and explore associations between the engagement and clinical outcomes. The program emphasizes rigor, reproducibility, and the optimization of natural product delivery through studies on dosing, formulations, or combinations with other interventions.

Eligible projects should focus on natural products that have demonstrated bioavailability, preliminary evidence of target engagement, and safety in human studies. Trials must prioritize target populations relevant to the product's proposed benefits, particularly for conditions like pain, gastrointestinal disorders, sleep disturbances, and mental health issues. The funding mechanism excludes studies evaluating natural products for cancer prevention or treatment and studies lacking a strong hypothesis, reproducible evidence, or a clear pathway to clinical applicability.

The funding provides up to $1,050,000 in direct costs over three years. Applicants must design randomized, controlled trials with appropriate comparator arms and include a Plan for Enhancing Diverse Perspectives (PEDP) to advance inclusivity in research. Proposals should incorporate a clear rationale for the natural product's target engagement, rigorous data collection methods, and a plan for future clinical trials. Inclusion of pharmacokinetic studies, if necessary, is encouraged, along with milestones for recruitment, data management, and adherence to FDA regulations, including Investigational New Drug (IND) applications where applicable.

Eligible applicants include higher education institutions, nonprofit and for-profit organizations, state and local governments, and tribal entities. Foreign components are allowed under certain conditions. Applications require compliance with NIH submission guidelines, and organizations must be registered in the System for Award Management (SAM), eRA Commons, and Grants.gov. Letters of intent are requested 30 days prior to application deadlines, which occur on June 23, 2025, February 23, 2026, and October 20, 2026.

Applications will undergo rigorous peer review based on scientific merit, innovation, feasibility, and alignment with NCCIH priorities. These priorities include addressing minority health disparities, optimizing interventions for specific populations, and managing symptoms like chronic pain, stress, and post-acute sequelae of SARS-CoV-2 infection. Strong letters of support from collaborators and suppliers, as well as evidence of necessary regulatory clearances, are essential for successful submissions.

This funding opportunity represents a key mechanism for advancing evidence-based research on natural products, enabling researchers to generate data essential for subsequent efficacy trials. Prospective applicants are strongly encouraged to contact NCCIH program staff for guidance before submission to ensure alignment with the program's goals and requirements.