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

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Description

This funding opportunity from the National Center for Complementary and Integrative Health (NCCIH) at NIH supports investigator-initiated, early phase clinical trials of natural products, including botanicals, probiotics, and dietary supplements with a strong scientific rationale. The goal is to rigorously test whether these natural products engage their biological targets in humans and to optimize their use before proceeding to larger efficacy trials.

The award uses a phased R61/R33 mechanism:

• R61 Phase (up to 3 years): Milestone-driven studies to test pharmacokinetics (PK), bioavailability, safety, and target engagement of the natural product in humans. Placebo controls are required to confirm effects are due to the product. Applicants must define clear Go/No-Go criteria for progression to the R33 phase, including quantitative thresholds for target engagement and safety/tolerability metrics.

• R33 Phase (up to 3 years): Contingent on successful R61 milestones, this phase aims to replicate target engagement findings and assess associations between target engagement and clinical or functional outcomes. It may also include dose optimization, combination treatments, or studies in more responsive populations.

This mechanism is intended to accelerate translation of basic science findings into early-stage clinical testing. It does not support efficacy or effectiveness trials, nor trials for cancer treatment or prevention.

Applicants must propose a natural product with compelling preliminary evidence and a clear scientific premise. The natural product must be well-characterized, and if required, an IND or IDE must be in place before award. The trial design should be randomized and placebo-controlled; wait-list controls are not supported.

A Plan for Enhancing Diverse Perspectives (PEDP) is required and will be evaluated during peer review and programmatic review.

Key Features

• Focus on target engagement (mechanism of action) rather than clinical efficacy in the R61 phase.
• Milestone-driven with explicit Go/No-Go criteria.
• Up to 5 years total support (R61 + R33).
• Supports optimization of dose, formulation, and population responsiveness.
• Requires rigorous clinical trial design with placebo or active comparator.
• Excludes trials of synthetic derivatives, cancer treatment/prevention, or non-natural products.
• Encourages early consultation with NCCIH scientific staff.
• Requires compliance with FDA and other regulatory requirements.
• Requires inclusion of diverse populations and a PEDP.

Due Dates

• March 4, 2024
• October 21, 2024
• June 23, 2025
• February 23, 2026
• October 20, 2026

All applications are due by 5:00 PM local time of the applicant organization.

Funding Amount

• Up to $350,000 direct costs per year for each phase (R61 and R33).
• Maximum project period: 5 years (up to 3 years R61 + up to 3 years R33).

Eligibility

Eligible Applicants

• Public and private institutions of higher education (including minority-serving institutions).
• Nonprofits with or without 501(c)(3) status (excluding institutions of higher education).
• For-profit organizations including small businesses.
• State, county, city, special district, and tribal governments.
• Other eligible entities such as independent school districts, public housing authorities, and faith-based organizations.

Ineligible

• Foreign (non-U.S.) organizations and non-domestic components of U.S. organizations are not eligible.
• Foreign components are allowed.

Additional Requirements

• Applicants must have all required registrations (SAM, eRA Commons, Grants.gov).
• PD(s)/PI(s) must have eRA Commons accounts.
• Applications must include a Plan for Enhancing Diverse Perspectives (PEDP).
• Only applications proposing clinical trials are accepted.

Application Process

• Applications must be submitted electronically via Grants.gov and tracked in eRA Commons.

• A letter of intent is encouraged but not required, due 30 days before application.

• Applications must include:

  • Milestones and Go/No-Go Criteria Plan (max 3 pages).
  • Plan for Enhancing Diverse Perspectives (PEDP) (max 1 page).
  • Detailed Specific Aims with separate aims for R61 and R33 phases.
  • Research Strategy addressing significance, innovation, and approach.
  • Human Subjects and Clinical Trials Information form with study records for each clinical trial.
  • Data Management and Sharing Plan.
  • Letters of support including product supply and regulatory documentation.
  • Budget and budget justification reflecting actual needs and PEDP implementation costs.

• Applications must follow NIH SF424 (R&R) Forms Version H instructions.

• Applications missing required attachments (e.g., milestones, PEDP) will be withdrawn.

• Applicants are encouraged to contact NCCIH scientific staff prior to submission.

Review Criteria

Applications will be evaluated for scientific and technical merit by NCCIH convened review groups, considering:

• Significance: Importance of the problem, strength of scientific premise, potential to advance knowledge of natural product target engagement.
• Investigator(s): Expertise in natural products, clinical trial experience, ability to meet milestones.
• Innovation: Novelty of approach, potential to shift paradigms, contribution of diverse perspectives.
• Approach: Study design rigor, feasibility, power to detect target engagement, plans for safety, recruitment, data management, and regulatory compliance.
• Environment: Institutional support, resources, ability to recruit eligible participants, and collaborative arrangements.

Additional considerations include study timeline, human subjects protections, inclusion of diverse populations, vertebrate animal use, biohazards, and budget justification.

Award Administration

• Funding is contingent on successful completion of R61 milestones and Go/No-Go criteria.
• Transition to R33 phase requires NCCIH administrative review and available funds.
• Awards are subject to NIH Grants Policy Statement terms and conditions.
• Clinical trials must be registered and results reported on ClinicalTrials.gov.
• Regulatory approvals (IRB, FDA IND/IDE, DEA licenses if applicable) must be in place prior to award.
• Annual progress reports and financial statements are required.
• Recipients must comply with data management and sharing policies.

Contact Information

Additional Information

• This NOFO has been reissued as PAR-25-269 with a new expiration date of December 2, 2024.
• Applicants should consult the NCCIH Natural Products Clinical Trials Resource for guidance on FDA regulatory requirements: https://www.nccih.nih.gov/grants/natural-products-clinical-trials-resource
• The NIH Data Management and Sharing Policy applies.
• Applications proposing clinical trials not aligned with the NOFO’s focus (e.g., no target engagement, only R61 or R33 phase, non-natural products, waitlist controls, cancer trials) will be deemed non-responsive.
• Applicants are encouraged to review the full NOFO and NIH application instructions carefully.

External Links

• NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33 Clinical Trial Required) - NIH Guide
• NIH How to Apply - Application Guide (Forms Version H)
• NCCIH Natural Products Clinical Trials Resource
• Plan for Enhancing Diverse Perspectives (PEDP) Guidance
• NIH Data Management and Sharing Policy
• NIH Grants Policy Statement