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

The National Center for Complementary and Integrative Health (NCCIH) invites applications under the R61/R33 phased award mechanism to support early-phase clinical trials of natural products, such as botanicals, probiotics, and dietary supplements, with promising preliminary evidence of health benefits. The program provides up to five years of funding: three years for the R61 phase to investigate pharmacokinetics, bioavailability, safety, and target engagement, and up to three years in the R33 phase to replicate findings and assess associations between target engagement and clinical outcomes. These trials aim to build rigorous evidence for the development of natural products while addressing gaps in understanding their mechanisms of action. Applications focusing on efficacy or cancer-related uses are not eligible. Eligible applicants include higher education institutions, non-profits, for-profits, state and local governments, tribal organizations, and regional entities. Foreign organizations and non-U.S. components are not eligible, but foreign collaborations may be included. Applicants must meet NIH registration requirements, including maintaining active registrations in SAM.gov and eRA Commons. Application budgets are capped at $350,000 in direct costs annually for each phase, and the total project duration must not exceed five years. Applications may propose clinical trials to optimize product formulation, dosing, or population targeting for improved outcomes. The R61 phase focuses on demonstrating that a natural product affects a specified biological or clinical target through well-designed pharmacokinetic and mechanistic studies. Go/No-Go criteria must be established to determine whether to proceed to the R33 phase. Milestones for the R61 phase include defining target engagement measures, collecting safety and tolerability data, and obtaining regulatory approvals. The R33 phase builds on these findings, replicating the product’s effects and exploring its potential association with clinical outcomes. Both phases require randomized controlled trials with placebo arms to ensure rigor and reproducibility. Applicants must include a **Plan for Enhancing Diverse Perspectives (PEDP)** to promote inclusivity across research teams, study populations, and methodologies. This plan will be evaluated as part of the review process and must outline actionable strategies to incorporate diverse perspectives in the research. Additionally, a detailed **Milestones and Go/No-Go Criteria Plan** is required to demonstrate the feasibility and decision-making framework for transitioning between project phases. Key dates include a first submission deadline of June 23, 2025, with additional due dates through October 20, 2026. Letters of intent are encouraged 30 days prior to application deadlines. Applications must comply with NIH’s submission guidelines and requirements for human subject research, data management, and safety monitoring. Post-submission materials, such as updates on regulatory approvals, may be allowed. Applications will be evaluated based on scientific merit, innovation, feasibility, expertise, and relevance to NCCIH’s mission. Successful projects should contribute to NCCIH’s strategic priorities, including symptom management (e.g., pain, mental health, gastrointestinal disorders), microbiome interactions, and minority health disparities. Funded projects are expected to lead to actionable insights that inform larger-scale efficacy trials or other advanced research efforts. For questions, applicants are encouraged to contact NCCIH’s scientific and administrative staff before submission.