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

NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33 Clinical Trial Required) is sponsored by National Institutes of Health (NIH). Encourages applications for early-phase clinical trials of natural products with strong scientific premises.

PAR-25-269: NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33 Clinical Trial Required) This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Center for Complementary and Integrative Health ( NCCIH ) Funding Opportunity Title NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33 Clinical Trial Required) R61 / R33 Exploratory/Developmental Phased Award Notices of Special Interest associated with this funding opportunity January 28, 2026 - NIH Removing AIDS Application Due Dates from NOFOs.

See Notice NOT-OD-26-029 March 31, 2025 - This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025.

See Notice NOT-OD-24-084 . August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198 .

August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189 . Funding Opportunity Number (FON) Companion Funding Opportunity Phase 1 Exploratory/Developmental Cooperative Agreement/Exploratory/Developmental Cooperative Agreement Phase II Resource-Related Research Project (Cooperative Agreements) Exploratory/Developmental Grants Phase II See Section III.

3. Additional Information on Eligibility. Assistance Listing Number(s) Funding Opportunity Purpose This Notice of Funding Opportunity (NOFO) encourages applications for investigator-initiated, early phase, clinical trials of natural products (i.e., botanicals, probiotics, and products marketed as dietary supplements), which have a strong scientific premise to justify further clinical testing.

For this NOFO, natural products include promising nutritional regimens that standardize the amount of a specific naturally occurring nutritional compound (e.g., omega-3 fatty acids, anthocyanidins, or polyphenols) and have compelling preliminary evidence.

Under this NOFO, trials must be designed so that results, whether positive or negative, will provide information of high scientific utility and will support decisions about further development or testing of the natural product.

This NOFO will provide up to three years (R61 phase) of support for milestone-driven testing of pharmacokinetics, bioavailability, and assessment of the natural product’s effect (i.e., measure of mechanism of action) when used by humans on a specified target measure.

If milestones in the R61 phase are achieved, up to 3 years of additional support (R33 phase) may be awarded to replicate the impact of the natural product on target engagement(s) when used by humans and assess whether there is an association between the degree of the impact on the target engagement and clinical outcomes in a participant population.

Applications are encouraged to design R33 studies to determine how to optimize the impact of the natural product on the target engagement by optimizing the delivery of the natural product through examination of different doses or formulations.

In addition, applications can be designed to combine the natural product with another treatment approach that is known to impact the same target engagement measure; or study the impact of the natural product in a population that is more responsive. Clinical trials submitted under this NOFO are expected to be hypothesis based, milestone-driven, and directly related to the research priorities and mission of NCCIH.

This R61/R33 funding mechanism is intended to accelerate the translation of emerging basic science findings about natural products into early-stage clinical testing to determine whether continued clinical research is warranted. This NOFO will not support efficacy or effectiveness trials, nor will it support trials to test natural products for the treatment or prevention of cancer.

A maximum of 5 years will be supported by the two phases of the R61/R33 award. Applicants are encouraged to contact the appropriate NCCIH Scientific/Research contact for the area of science for which they are planning to develop an application prior to submitting to this NOFO.

Funding Opportunity Goal(s) The National Center for Complementary and Integrative Health (NCCIH) provides funding for research into complementary and integrative health approaches. Research constituting a rigorous evidence base for complementary health approaches will be developed through a range of research strategies including basic and translational research, and clinical investigation.

Open Date (Earliest Submission Date) Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed All applications are due by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced.

Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants. gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

Use the NIH ASSIST system to prepare, submit and track your application online. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants. gov and eRA Commons to track your application.

Check with your institutional officials regarding availability. Workspace to prepare and submit your application and eRA Commons to track your application. Part 1.

Overview Information Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description Section II.

Award Information Section III. Eligibility Information Section IV. Application and Submission Information Section V.

Application Review Information Section VI. Award Administration Information Section VII. Agency Contacts Section VIII.

Other Information Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description The National Center for Complementary and Integrative Health (NCCIH) is committed to the rigorous investigation of promising complementary and integrative health approaches with nutritional therapeutic inputs (often called natural products).

Promising natural products (i.e., botanicals, probiotics, and products marketed as dietary supplements) have compelling preclinical or preliminary clinical evidence for potential health benefit.

For this NOFO, natural products include promising nutritional regimens that standardize the amount of a specific naturally occurring nutritional compound (e.g., omega-3 fatty acids, anthocyanidins, or polyphenols) and have compelling preliminary evidence suggesting potential benefit in treating a condition, disorder, or disease.

Nutritional intervention research in humans is complicated by the complex and varied background nutritional status and dietary intake of participants in clinical trials.

To enhance rigor, reproducibility, and generalizability, it is important that trials of natural products that are part of the regular or occasional dietary intake include rigorous methods to account for the dietary intake and heterogeneity across participants (e.g., assessment of nutritional status; collection of data about dietary intake at baseline and throughout the trial; collection of data about factors that may impact absorption or metabolism of the natural product; rigorous study design to ensure balance across study arms with strategies such as stratified randomization; or rigorous statistical methods to examine treatment heterogeneity through prespecified subgroup analyses or analyses of effect modification by background nutritional status or other participant characteristics on target engagement or clinical outcomes).

Clinical trials of natural products are maximally informative if they incorporate well-formulated hypotheses built on a sound foundation of basic mechanistic and pharmacologic understanding. The first step in clinical trials of natural products is to demonstrate that the intervention exerts a measurable effect on a hypothesized “target” or mechanism of action rather than just focusing on demonstrating a change in clinical symptom(s).

“Target engagement” refers to verification that the intervention has had the predicted effect on the target. Targets may be molecular, cellular, circuit, biological, tissue, organ, somatic, psychological, behavioral, or interpersonal.

Following the initial demonstration of target engagement, the next step of novel intervention development involves replicating target engagement and evaluating whether intervention-induced changes in the target are associated with clinical benefit.

In some cases, a fundamental understanding of a given natural product’s biologic target or mechanism of action has been clearly established (e.g., compound’s affinity for a specific receptor is well established). It is also recognized that for certain conditions (e.g., pain), demonstrating target engagement may not be possible or practical with human participants.

When a mechanism of action has already clearly been established or when measuring target engagement is not possible, investigators should contact a member of the program staff at NCCIH to discuss what funding mechanism is appropriate. There is a need for research to evaluate natural products to determine whether they are safe and efficacious or effective for given conditions or disorders.

To accomplish this goal, early phase clinical trials conducted through the R61/R33 are important to determine the association of the natural product with target engagement, and of target engagement with clinical outcomes, prior to conducting a fully powered clinical trial. NCCIH has designed a framework for research to describe the broad spectrum of complementary and integrative health research it supports ( https://www. nccih.

nih. gov/grants/nccih-clinical-trials-funding-opportunities/research-framework ). NCCIH supports investigators working on the continuum of the research framework, from basic science and demonstrating reproducible impact on a target engagement measure through high-impact efficacy trials ( https://www.

nccih. nih. gov/grants/nccih-clinical-trials-funding-opportunities/natural-products-clinical-trials-funding-opportunities ).

We encourage investigators to examine the full suite of natural product research NOFOs to determine which one best aligns with the proposed stage of intervention development and testing. NCCIH has an oversight process to provide stewardship and maintain excellence, integrity, and rigor in our supported clinical studies ( https://www. nccih.

nih. gov/grants/toolbox ). Investigators are encouraged to review the NCCIH Clinical Terms of Award for Human Subjects Research ( https://www.

nccih. nih. gov/research/nccih-clinical-terms-of-award-for-human-subjects-research ) to learn more about NCCIH’s requirements for clinical research.

Prior to submitting an application, NCCIH strongly encourages consultation with the NCCIH Scientific/Research contacts relevant to the area of science for which they are planning to develop an application. Early contact provides an opportunity for NCCIH staff to discuss the scope and goals, and to provide information and guidance.

Purpose of the NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33) The objective of this NOFO is to support clinical trials to increase the evidence base for a natural product. An application submitted to this NOFO must propose a pharmacokinetic (PK) study of the natural product or provide data from previous PK studies (peer-reviewed and citable) of the exact product to be used in the R61/R33 trials.

PK studies are not required for natural products that do not require absorption for their intended effect (e.g., prebiotics and probiotics). The PK study should measure a marker compound, constituent, or metabolite that is scientifically justified as a chemical entity that may have an impact on target engagement based on existing literature. The goal of the PK study is to inform the frequency of daily dosing of the product.

In addition, applications submitted to this NOFO must propose a way to demonstrate and measure, in research participants, target engagement by the natural product of interest. Target engagement should be a measure of the postulated mechanism of action or process by which the natural product might ultimately modify the clinical condition or symptom(s) of interest.

Targets may be molecular, cellular, circuit, biological, tissue, organ, somatic, psychological, behavioral, and/or interpersonal. The R61 phase of the grant application must focus on testing, with research participants, whether the proposed natural product alters the putative target or mechanism of action.

Placebo controls are needed in this phase of testing to determine whether the natural product, rather than regression to the mean, is responsible for the effect. In addition, the R61 phase should also include PK testing of the product to determine the frequency of daily dosing needed in the clinical trial unless sufficient extant, citable peer-reviewed data exists for the proposed natural product.

The R61 phase could also assess product bioavailability, pharmacodynamics, safety, and/or toxicity in humans. Projects should incorporate a go/no-go decision rule for continuing to the R33 phase based on the robustness of target engagement.

For each proposed target engagement measure, projects must incorporate a priori definitions of the expected magnitude and direction of change that will be necessary and sufficient to recommend further study in the subsequent R33 phase. The specific activities and milestones appropriate for the R61 phase will depend on the proposed natural product and its stage of development.

Generally, these activities and milestones for the R61 phase include: If not known, a PK study to determine the optimal dosing needed to conduct a subsequent “target engagement” study.

Operational definition and objective target engagement(s) measure(s) that will be assessed with research participants to test the hypothesized mechanism of action, as well as defining a predetermined clinically meaningful change and direction of the change for each measure. Demonstration of impact on target engagement for subsequent studies in humans (see power recommendations below).

Collection of tolerability data to determine if dose(s) of the natural product cause frequent adverse effects, cause severe adverse effects, or result in participants discontinuing the study. While not required, investigators may also propose to evaluate how dose or formulation variations of the natural product may have differential impact on the target engagement(s).

Demonstration of the ability of the investigative team to recruit and retain participants in the R61 trial and maintain fidelity to the study protocol. Submission of a protocol and Data and Safety Monitoring Plan for the planned R33 phase project for NCCIH review and approval.

Completion of necessary regulatory approvals for the proposed R33 clinical studies (e.g., Institutional Review Board [IRB], U.S. Food and Drug Administration [FDA] Investigational New Drug [IND] application). In the R61 phase application, investigators are required to describe a set of “Go/No-Go Criteria” (for detailed instructions please see Section IV.

2 Other Attachments, “Milestones and Go/No-Go Criteria”) that will allow for a definitive assessment of whether the R61 phase provides sufficient evidence to support the subsequent replication study that would be conducted during the R33 phase of the grant application.

Key evidence in the “Go/No-Go Criteria” includes: Provide adequate PK data to inform dosing in the target engagement study in the R61 phase or provide preliminary data about the pharmacokinetics of the product to be used in the R61/R33 trials. Detect a clear impact on the primary target engagement(s) measures (mechanistic outcome measure) by the natural product.

Demonstrate the safety and tolerability of the natural product used in the trial by a set of metrics. Demonstrate the ability to recruit and retain subjects in the clinical trial with a preplanned timeline for reaching the randomization target and not exceed the estimated drop-out rate.

3 months prior to the end of the R61 award, submit R33 trial study documents (e.g., Study Accrual and Retention Plan and Data and Safety Monitoring Plan) to NCCIH for review and approval. 2 months prior to the end of the R61 award, submit to NCCIH an “R33 Transition Request Application.

” Funding for the R33 phase is contingent on successfully meeting the milestones and the Go/No-Go Criteria in the R61 phase, as well as other factors as described in Section VI. Award Administration Information, 1. Award Notices.

Milestones accomplishments under the R61 phase will be administratively reviewed by NCCIH staff to determine whether transition to and funding for the R33 will occur.

For transition to an R33, and to ensure scientific rigor and reproducibility, the R33 phase must propose the following aims: Replicate the natural product’s impact on the target engagement measure(s) demonstrated in the R61 phase, AND Assess the strength of association between the impact on target engagement and the change in functional or clinical outcomes.

A placebo arm is usually needed to confirm that the changes in target engagement measures are due to the natural product and not regression to the mean or natural history of the condition.

If multiple doses are not included in the R61 trial or dosing trials have not previously been conducted with the natural product determined in the R61 phase or the dosing is not known, investigators are strongly encouraged to use the R33 to evaluate multiple doses to inform what dose has the greatest impact on target engagement, as this is critical information needed to plan a multi-site efficacy trial.

In addition to the primary aim of assessing the association between target engagement and functional or clinical outcomes, secondary aims in the R33 phase may also include the following: Determine the optimal dose or formulation of the natural product for a subsequent trial by conducting a dose-response functional pharmacodynamic study to test the impact on target engagement Further testing of the intervention’s tolerability, safety, and acceptability Combine the natural product with another treatment approach that is known to impact the same target that may optimize the impact of a multi-component intervention Optimize the impact of the natural product by studying it in a potentially more responsive population Demonstrate the study team’s ability to recruit, randomize, and retain participants; collect all assessments and samples; adhere to the study protocol; and report adverse events Develop and determine if functional measures are associated with target engagement measures that are feasible for use in larger efficacy and effectiveness trials The specific activities appropriate for the R33 phase will depend on the natural product under study, the stage of the study proposed, and available preliminary data on the natural product.

The R33 milestones should be clearly aligned with the aims associated with the R33 phase. The milestones should be feasible, well developed, and quantifiable with regard to the specific aims.

The objective of this NCCIH R61/R33 funding opportunity is to gain additional knowledge about a natural product’s effect on a target of interest and association with functional or clinical outcome that could inform the development of a fully powered efficacy trial.

Investigators are encouraged to include relevant stakeholders (patients, providers, health care systems, etc.) in the planning and execution of exploratory and larger clinical trials.

The outcomes of an R61/R33 award could lead to several conclusions including: (1) the product does not warrant further study; (2) additional studies must be completed before proceeding to a full-scale multi-site efficacy trial; or (3) the data generated under this phased award are informative and sufficient to warrant moving ahead with a multi-site efficacy clinical trial.

If warranted by the results from studies conducted under the R61/R33, awardees may prepare and submit an application for a subsequent clinical trial. Prospective applicants should note that funding of an R61 does not guarantee transition to and support of the R33 phase of the application.

Transition to the R33 phase of the project will occur only if an NCCIH administrative review process determines that the R61 milestones and Go/No-Go Criteria have been successfully met, and if funds are available. In addition, funding and successful completion of an R61/R33 grant does not guarantee that NCCIH will accept, or support, a subsequent full-scale multi-site clinical efficacy trial application.

Investigators should propose a randomized controlled trial design with at least one intervention arm and one comparator arm. There should be a strong rationale for the comparator condition (e.g., placebo, usual care, standard of care, and/or active comparator(s)) based on the research question to be addressed in a future powered trial.

Due to lack of rigor and potential expectancy effects, NCCIH will not support studies proposing a waitlist comparator condition. Given that the purpose of the R61/R33 NOFO is to determine the impact of the natural product on the target engagement measure, the proposed study should be adequately powered to support evaluation of these effects.

In the R61 phase, power calculations should focus on assessing the impact of the natural product on target engagement. The R33 phase should be powered to replicate this effect and assess if there is an association between the target engagement and clinical outcome(s) of interest.

The sample sizes supported under the R61/R33 grant mechanism are limited; therefore, proposing to conduct fully powered tests of clinical outcomes (i.e., efficacy) or underpowered tests of outcomes (i.e., “preliminary efficacy”), or attempting to utilize the highly variable point estimate of an effect size for power calculations would not be appropriate and are noted as nonresponsive below.

Regulatory Requirements To Consider: The FDA establishes and enforces the regulatory requirements for clinical research on natural products when they may be used as drugs. Because NCCIH is a Federal agency, any research supported with NCCIH funding must adhere to relevant FDA regulations.

Prior to submitting an application, investigators must contact the FDA to determine whether an IND application is necessary for the proposed clinical research. For trials using an FDA-regulated product and requiring an IND application, the applicant must either hold or be able to reference an open IND for the trial, or the applicant must obtain an IND with no clinical hold prior to any award.

If the FDA has granted a waiver for the trial proposed in the application, the applicant can provide this letter as part of the Study Record: PHS Human Subjects and Clinical Trials Information description of the availability of the Investigational Product (IP) and IND/Investigational Device Exemption (IDE) status.

Guidance on the IND evaluation process can be found on the NCCIH Natural Products Clinical Trials Resource webpage: https://www. nccih. nih.

gov/grants/natural-products-clinical-trials-resource . For applications that propose the use of a mobile device, similar app, or clinical decision support software, applicants must consult with their IRB to determine whether the approach may qualify as a medical device. If so, applicants must contact the FDA prior to applying to determine whether an IDE application is necessary for the proposed clinical research ( https://www.

fda. gov/medical-devices/software-medical-device-samd/your-clinical-decision-support-software-it-medical-device ). Preliminary Data Requirements Applications should be based on a clear scientific premise and compelling rationale for the proposed study, which may include preliminary data from animal studies that demonstrate biological mechanisms suggesting clinical benefit.

Alternatively, the hypothesis and empirical basis for the proposed study may be based on previously published and citable human clinical studies. Regardless, there must be a strong scientific premise and rationale as to why the specific natural product proposed is likely to benefit a clinical condition, disorder, or disease.

For applications that include a mind and body approach as part of a multi-component intervention, the application must provide published data that the mind and body intervention proposed has demonstrated efficacy for the condition being studied from at least one fully powered controlled trial.

For this NOFO, investigators should design a realistic timeline for the startup and completion of the clinical trial and provide contingency plans to proactively confront potential delays or disturbances to the planned trial.

NCCIH Priorities for Developing and Pilot-Testing Natural Products Symptom management, particularly the use of natural products for sleep disorder/disturbance, management of pain conditions, common gastrointestinal disorders, post-acute sequelae of SARS-CoV-2 infection (PASC), or mental health conditions such as those commonly managed in primary care (e.g., chronic stress, depression, anxiety disorders, and post-traumatic stress).

Studies that examine the effects of prebiotics/probiotics and other natural products on gut microbiome-brain interactions. Of particular interest are studies of prebiotics/probiotics for depression, anxiety disorders, irritable bowel syndrome (IBS), or chronic pain. Studies that examine the effects of cannabinoids and terpenes in conditions noted above.

Studies that examine the effects of naturally occurring psychedelics and entheogens in conditions noted above. Studies that address minority health and reduce disparities in conditions noted above. Studies that examine the effects of natural products to address comorbidities, coinfections, and/or complications from HIV ( https://www.

oar. nih. gov/hiv-policy-and-research/strategic-plan https://abs2.

od. nih. gov/Docs/NIH_StrategicPlan_FY2021-2025.

pdf ). Trials that examine the effects of natural products across the continuum of background dietary intake. Trials that evaluate whether nutritional status moderates target engagement or clinical outcomes.

All NIH-funded research must adhere to the Code of Federal Regulations ( https://grants. nih. gov/policy/humansubjects/policies-and-regulations/vulnerable-populations.

htm ). The Inclusion Across the Lifespan policy requires that individuals of all ages, including children (i.e., individuals under the age of 18) and older adults, must be included in all human subjects research conducted or supported by NIH unless there are scientific or ethical reasons not to include them ( https://grants. nih.

gov/grants/guide/notice-files/NOT-OD-18-116. html ). Applications proposing research topics not identified above as high programmatic priority can be submitted but are likely to be considered of lesser or low programmatic priority, which will significantly influence programmatic relevance and reduce 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.

Clinical Trials Not Responsive to This NOFO The following types of clinical trials are not responsive to this NOFO, and applications proposing such activities will be deemed nonresponsive and will not be reviewed: Applications that do not propose to study target engagement measure(s) or mechanisms of action of a natural product in the R61 phase.

Studies proposing to analyze data from the trial to assess efficacy of the natural product or estimate effect size ( https://www. nccih. nih.

gov/grants/pilot-studies-common-uses-and-misuses ). Applications that do not propose in the R33 phase to replicate the impact of the natural product on the target engagement measure(s) demonstrated in the R61 phase and that do not propose to assess whether there is an association between target engagement and clinical outcomes. Applications that propose only the R61 phase or only the R33 phase.

Trials that do not include a natural product or standardized nutritional regimen. Studies utilizing a natural compound that has been synthetically modified (e.g., conjugates, derivatives, or pro-drugs). Studies that propose a waitlist control.

Trials that propose to test natural products for the treatment or prevention of cancer. (Investigators interested in cancer treatment or prevention trials should contact the National Cancer Institute.) Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

See Section VIII. Other Information for award authorities and regulations. Section II.

Award Information Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity. Application Types Allowed The OER Glossary and the How to Apply Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Required: Only accepting applications that propose clinical trial(s). Need help determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

The budget is limited to $350,000 direct costs per year in both the R61 and R33 phases. Application budgets need to reflect the actual needs of the proposed project. The scope of the project should determine the project period for each phase.

The maximum period of the combined R61 and R33 phases is 5 years, with up to 3 years for the R61 phase and up to 3 years for the R33 phase. NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO. Section III.

Eligibility Information Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education) Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education) For-Profit Organizations (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Recognized).

Eligible Agencies of the Federal Government U.S. Territory or Possession Independent School Districts Public Housing Authorities/Indian Housing Authorities Native American Tribal Organizations (other than Federally recognized tribal governments) Faith-based or Community-based Organizations Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply. Foreign components, as defined in the NIH Grants Policy Statement , are allowed. Applicant organizations must complete and maintain the following registrations as described in the How to Apply- Application Guide to be eligible to apply for or receive an award.

All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.

3. 9. 2 Electronically Submitted Applications for additional information.

System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually . The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.

NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM. Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM. gov registration process.

The same UEI must be used for all registrations, as well as on the grant application. eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants. gov registrations; all registrations must be in place by time of submission.

eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application. Grants. gov – Applicants must have an active SAM registration in order to complete the Grants.

gov registration. Program Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials