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Grant Analysis

Purpose & Target

This grant encourages investigator-initiated, early phase clinical trials of natural products to determine if further clinical testing is warranted.
It targets research institutions, non-profits, for-profits, and government entities capable of conducting rigorous clinical trials.
SECTOR-SPECIFIC: Focuses on complementary and integrative health, specifically natural products (botanicals, dietary supplements, probiotics, nutritional regimens).
Geographic scope: Organizations in the US. Foreign components are allowed (collaborators/consultants) but foreign sites outside the US or Canada are not eligible.
Key filtering criteria: Must propose an early phase clinical trial, involve natural products, demonstrate target engagement, and explicitly exclude cancer treatment/prevention trials.
Grant frequency: Recurring, with multiple application deadlines through October 2026.
Program context: An R33 Exploratory/Developmental Grants Phase II mechanism from NCCIH, part of the National Institutes of Health (NIH).

Financial Structure

Budget may not exceed a total of $1,050,000 in direct costs over the entire duration of the award.
The project period may not exceed 3 years.
This grant does not require cost sharing as defined in the NIH Grants Policy Statement.
Pre-award costs are allowable as described in the NIH Grants Policy Statement.
Financial reporting includes annual Research Performance Progress Reports (RPPR) and financial statements.
A final RPPR, invention statement, and expenditure data are required for closeout of the award.
Standard NIH grant policies regarding cost principles and indirect costs apply.

Eligibility Requirements

Eligible Organization Types

Higher Education Institutions (Public/State Controlled, Private)
Nonprofits (with 501(c)(3) IRS Status, without 501(c)(3) IRS Status)
For-Profit Organizations (Small Businesses, Other than Small Businesses)
Local Governments (County, City or Township, Special District)
State Governments
Indian/Native American Tribal Governments (Federally Recognized, Other)
Independent School Districts
Public Housing Authorities/Indian Housing Authorities
Faith-based or Community-based Organizations
Regional Organizations

Geographic Requirements

US organizations are eligible to apply.
Foreign organizations are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply as prime applicants, but foreign components (collaborators/consultants) are allowed if part of a U.S. organization.
Foreign sites (where research is conducted) outside of the U.S. or Canada are not permitted.

Regulatory and Capacity Requirements

Applicant organizations must complete and maintain active registrations in:
- System for Award Management (SAM)
- Unique Entity Identifier (UEI)
- eRA Commons
- Grants.gov
Principal Investigator(s) (PD/PI(s)) must have an eRA Commons account.
For trials using FDA-regulated products:
- Applicant must hold or be able to reference an open Investigational New Drug (IND) or Investigational Device Exemption (IDE) application, OR obtain one with no clinical hold prior to any award.
- If an FDA waiver is granted, the waiver letter must be provided.
For trials using controlled substances:
- Applicant must describe and obtain necessary Drug Enforcement Agency (DEA) licenses and registrations prior to award.
A multidisciplinary team is required (e.g., clinician, biostatistician, data manager, study coordinator).
Strong evidence of the study team's qualifications and ability to conduct the proposed research and future research is required.
PD/PI must have documented experience in leading clinical trials and expertise in the content area.

Exclusion Criteria

Applications that propose efficacy or effectiveness trials (fully powered clinical trials) are non-responsive.
Applications to test natural products for the treatment or prevention of cancer are non-responsive.
Applications lacking published peer-reviewed preliminary data demonstrating that the specific natural product engages the proposed target when used by humans are non-responsive.
Studies proposing to analyze data from the trial to assess efficacy or estimate effect size for efficacy are non-responsive.
Applications that do not propose to replicate the impact of a natural product on a target or assess whether there is an association between target engagement and functional/clinical outcomes are non-responsive.
Animal studies are non-responsive.
Trials that do not include a natural product or standardized nutritional regimen are non-responsive.
Studies utilizing a natural compound that has been synthetically modified (e.g., conjugates, derivatives, or pro-drugs) are non-responsive.
Studies that propose a waitlist control are non-responsive.

Application Process

Application Process Steps

Strongly encouraged: Contact NCCIH Scientific/Research staff prior to developing your application.
Optional: Submit a Letter of Intent (LOI) at least 30 days prior to the application due date. The LOI should include a descriptive title, PD/PI names/contact information, key personnel, participating institutions, and the funding opportunity number and title.
Complete all necessary organizational registrations (SAM, UEI, eRA Commons, Grants.gov); note that this process can take six weeks or more, so begin early.
Prepare the application meticulously following instructions in the 'How to Apply - Application Guide' and the specific program-specific instructions outlined in this NOFO.
Submit the application electronically via ASSIST, Grants.gov Workspace, or an institutional system-to-system (S2S) solution.
All applications are due by 5:00 PM local time of the applicant organization.
Submit early to allow adequate time for corrections to any errors identified during the submission process.
Track the application's status in eRA Commons and ensure successful submission by the due date.
Requested: Notify the NCCIH Referral Office by email once the application has been submitted, including the NOFO number and title, PD/PI name, and application title.

Key Dates

Earliest Submission Date (Open Date): May 23, 2025
Latest Application Due Date: October 20, 2026 (for New, Renewal, Resubmission, and Revision applications)
Expiration Date: November 14, 2026 (This indicates when the funding opportunity itself expires, not the project end date).

Required Documentation & Materials

Standard SF424(R&R) forms and supplements as per the 'How to Apply - Application Guide'.
Biographical Sketches for all PD/PI(s), specifically highlighting their experience in leading clinical trials and expertise in the relevant content area.
A comprehensive Research Plan (PHS 398 Research Plan), including:
- A detailed Research Strategy addressing the significance, innovation, rigor, and feasibility of the proposed research.
- Supporting data, including crucial preliminary human data demonstrating the natural product's target engagement.
- Justification for the chosen study design, target population, interventions, and all assessments.
- A summary of all necessary agreements for the use of the natural product, which must be executed prior to grant award.
- A clear timeline for third-party activities related to natural product supply and regulatory approvals.
- A concise summary outlining the anticipated future clinical trial that may follow this R33 project.
- A discussion of potential implementation challenges and robust contingency plans.
Letters of Support from key collaborators such as clinicians, clinical department chairs, subcontractors, consultants, and crucially, the natural product supplier confirming availability and specifications.
A Resource Sharing Plan.
A Data Management and Sharing Plan (mandatorily required for all applications).
A limited Appendix, which may only include blank questionnaires or blank surveys (no publications or other materials).
PHS Human Subjects and Clinical Trials Information form, detailing:
- A Recruitment and Retention Plan, supported by documented evidence of eligible subject availability at all recruiting sites.
- A Data and Safety Monitoring Plan that adheres to NCCIH-specific guidelines.
- A clear description of the Investigational Product (IP) and its Investigational New Drug (IND)/Investigational Device Exemption (IDE) status, including any relevant FDA correspondence and a timeline for obtaining necessary approvals.
- A mandatory Clinical Trial Experience table for key personnel (maximum 3 pages per study record), detailing their past clinical trial involvement.

Post-Award Requirements

Recipients are required to submit annual Research Performance Progress Reports (RPPR) and financial statements.
For project closeout, a final RPPR, invention statement, and expenditure data portion of the Federal Financial Report are required.
Registration and submission of results information for applicable clinical trials on ClinicalTrials.gov is mandatory.
Recipient institutions must ensure all research protocols involving human subjects are reviewed and approved by their Institutional Review Board (IRB) or Independent Ethics Committee (IEC).
Compliance with all applicable non-discrimination laws and federal regulations (e.g., 2 CFR Part 200) throughout the award period.

Evaluation Criteria

Overall Impact

Likelihood for the project to exert a sustained, powerful influence on the research field(s).

Scored Review Criteria

Importance of the Research (Significance and Innovation):
- Significance and innovation of the proposed clinical trial and the research question.
- Provision of rigorous preclinical or clinical preliminary data to support the study rationale.
- Clear demonstration of the need for and timeliness of the study, addressing an evidence gap.
- Explanation of how results will advance knowledge to determine if the natural product can reproducibly modify target engagement.
- Discussion of how results (positive or negative) will guide decisions about subsequent studies.
- Discussion of costs and benefits of the study.
- Clarity on whether results will be informative and provide a definitive test of the hypothesis.
- Clarity on whether results will be informative about the potential role of target engagement in the clinical condition.
- Description of how the application challenges and seeks to shift current research or clinical practice paradigms.
Rigor and Feasibility (Approach):
- Description of supporting data, including strengths and weaknesses of published literature.
- Comprehensive experimental approach and a milestone plan.
- Data from preclinical and/or clinical studies demonstrating the need for and feasibility of the proposed early phase trial.
- Required preliminary human data (preferably published):
  - Demonstrated biological mechanisms via measurement of the impact of the natural product on target engagement.
  - Evidence that the specific natural product is bioavailable in humans (e.g., short-term GI retention for prebiotics/probiotics).
  - For multi-component interventions including a mind/body approach, published data demonstrating efficacy from at least one fully powered controlled trial for the mind/body intervention.
- Appropriate study design (randomized controlled trial with at least one intervention and one comparator arm) and its rationale.
- Rationale for the chosen study population.
- Description of clinical equipoise.
- Rationale for research hypothesis, randomization methods, primary/secondary outcomes, intervention, target engagement measurement, and participant follow-up procedures.
- Rationale and supporting data for the natural product and matching placebo (including name, ingredients, supplier, characterization, standardization, and marker compounds).
- Confirmation that necessary agreements for natural product use (e.g., clinical research agreements, licensing agreements) will be executed prior to grant award.
- Inclusion of a timeline showing activities with third parties (e.g., executing agreements, product provision, IND/DMC reference).
- Justification for all assessments (e.g., PK, clinical, laboratory, physiological, behavioral, patient-centered).
- Rationale for using patient-reported outcomes or non-traditional data collection approaches.
- A concise summary of the anticipated future clinical trial beyond the R33, including its design.
- Discussion of expected challenges in implementation and proposed solutions.
- Explanation of how the trial will test the proposed hypotheses.
Expertise and Resources (Investigator(s) and Environment):
- Demonstration of the PD/PI's experience in leading clinical trials and expertise in the content area.
- Evidence of a qualified multidisciplinary team involved in design and implementation.
- Documentation of sufficient institutional resources and suitable patient populations, including feasibility of recruiting eligible participants at each site.

Additional Review Criteria (not scored, but considered for overall impact score)

Protections for Human Subjects
Vertebrate Animals
Biohazards
Resubmissions, Renewals, Revisions (as applicable)

Additional Review Considerations (not scored, do not impact overall score)

Authentication of Key Biological and/or Chemical Resources
Budget and Period of Support

Program Priorities Influence

Applications proposing research topics not identified as high program priority are likely to be considered of lesser or low programmatic priority, significantly influencing programmatic relevance and reducing the likelihood of funding.
Applications proposing research studies using an intervention and patient population that are the same as or very similar to those used in studies already in progress, conducted, or published by other groups are likely to be lower programmatic priority.
Applications that do not address dietary intake and nutritional status when appropriate will also be deprioritized.

Compliance & Special Requirements

Regulatory Compliance

All research supported must adhere to relevant U.S. Food and Drug Administration (FDA) regulations.
For FDA-regulated products: An Investigational New Drug (IND) or Investigational Device Exemption (IDE) application must be open with no clinical hold, or a waiver granted by the FDA, prior to award. Applicants must contact the FDA to determine if an IND/IDE is necessary.
For products on the Drug Enforcement Agency (DEA) controlled substance list: All necessary DEA licenses and registrations must be in place prior to award.
Compliance with NIH Grants Policy Statement is required, encompassing human subjects research protections, data and safety monitoring, and public policy requirements.
Adherence to the Inclusion Across the Lifespan policy, which mandates inclusion of individuals of all ages (including children and older adults) in human subjects research unless scientifically or ethically justified.
Compliance with the Cybersecurity Act of 2015 is required; this involves developing plans modeled after the NIST Cybersecurity framework if the project involves ongoing access to HHS IT systems or handling Personally Identifiable Information (PII) or Protected Health Information (PHI) obtained from HHS.

Data and Ethical Standards

A Data Management and Sharing Plan is required for all applications, and the approved plan must be fully implemented by recipients.
Independent monitoring is required for all research involving human subjects to ensure safety and data integrity.
Strict adherence to ethical standards for human subjects research is paramount.

Unique Aspects & Strategic Considerations

Core Research Focus: This funding opportunity is specifically designed for early phase clinical trials aimed at determining a natural product's target engagement and its association with functional or clinical outcomes. It is explicitly not for conducting full efficacy or effectiveness trials.
Rigorous Preliminary Data: A critical requirement is robust empirical preliminary data, preferably published and peer-reviewed, from human studies. This data must demonstrate a clinically meaningful and replicated change in target engagement by the specific natural product, evidence of its bioavailability in humans, and that it does not produce frequent or severe adverse events in human pilot trials.
Explicit Scope Exclusions: The NOFO specifically excludes trials for cancer treatment or prevention, animal studies, and studies using natural compounds that have been synthetically modified (e.g., conjugates, derivatives, or pro-drugs).
High Programmatic Priority Areas: Applications are strongly encouraged if they align with NCCIH's high programmatic priorities. These include symptom management (especially for sleep disorder/disturbance, pain, common gastrointestinal disorders, post-acute sequelae of SARS-CoV-2 infection (PASC), or mental health conditions common in primary care like chronic stress, depression, anxiety, and PTSD). Other high priorities include studies examining the effects of prebiotics/probiotics on gut microbiome-brain interactions, the effects of cannabinoids and terpenes, and naturally occurring psychedelics and entheogens in the noted conditions. Additionally, studies addressing minority health and reducing health disparities, as well as those examining natural products for HIV comorbidities, are highly prioritized.
Dietary Context Rigor: For nutritional intervention research, applications must incorporate rigorous methods to account for participants' background nutritional status and dietary intake (e.g., assessment of nutritional status, collection of dietary intake data, data on absorption/metabolism factors, stratified randomization, statistical methods for subgroup analysis). Applications failing to address this will be deprioritized.
Pathway to Future Research: While the R33 award provides crucial knowledge to inform future research, successful completion does not guarantee that NCCIH will accept or fund a subsequent multi-site efficacy clinical trial application. The results should clearly inform decisions about whether further study is justified.

Grant Details