Part 1. Overview Information

Key Dates

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.

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.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. 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.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
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

Background  

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 notice of funding opportunity (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, mid-phase clinical trials conducted through the R01 are important to determine optimal dosing of and participant characteristics for the natural product’s use prior to conducting a fully powered clinical trial.

Overview of NCCIH Natural Products Clinical Trials Research Funding Opportunities 

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 Mid-Phase Clinical Trial Award (R01)

The objective of this NOFO is to support clinical trials to increase the evidence base for a natural product. The following are examples of types of mid-phase clinical trials appropriate for this NOFO.

• Dosing and formulation optimization of the natural product to evaluate the impact on the target engagement measure(s) to be used in a future multi-site, randomized clinical trial
• Determining which patient phenotypes will be likely “responders” versus “non-responders” to the natural product to inform inclusion/exclusion criteria of a future efficacy trial
• In addition, investigators can also collect additional data documenting ability to recruit, accrue, and retain participants; achieve adherence to the study protocol; and complete collection of follow-up data

Subsequent Studies 
The objective of this NCCIH R01 mid-phase clinical trial NOFO is to gain additional knowledge about a natural product in order to plan and conduct a future multi-site, randomized clinical trial. Investigators are encouraged to include relevant stakeholders (e.g., patients, providers, health care systems, etc.) in the planning and execution of exploratory and larger clinical trials. Several outcomes from a grant awarded under this NOFO are possible: (1) the product does not warrant further study for the particular target, condition, or disorder of interest; (2) additional studies must be completed before proceeding to a full-scale multi-site efficacy trial; or (3) the data generated under this award are informative and sufficient to warrant moving ahead with a well-executed multi-site efficacy clinical trial. If warranted by the results of studies conducted, awardees may prepare and submit an application for a subsequent clinical trial when the R01 trial is complete and results have been analyzed. Prospective applicants should note that funding of a trial under this NOFO does not guarantee that NCCIH will accept, or fund, a subsequent multi-site clinical efficacy trial application. 
 

Design Considerations

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., time and attention control, usual care, standard of care, placebo, and/or active comparator(s)) based on the research question you plan to address in the future powered trial. Due to lack of rigor and potential expectancy effects, NCCIH will not support studies proposing a waitlist comparator condition.

Power Recommendations:

This R01 is a mid-phase clinical trial that is meant to support research activities that will inform future large-scale efficacy or effectiveness trials. Studies supported by this NOFO should be adequately powered to test a hypothesis/hypotheses related to the natural product dose, participant phenotype, or study process metrics identified as being essential to inform a future fully powered efficacy or effectiveness trial. The sample sizes that can be supported under this NOFO 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 U.S. Food and Drug Administration (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 Investigational New Drug (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 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 Institutional Review Board (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

This NOFO is appropriate when there is a compelling rationale, a rigorous empirical basis, and scientific premise, which should include preliminary data from animal studies and previously published and citable human studies.

The following preliminary data from human studies (published and citable data from the peer-reviewed literature) on the same product and specific formulation as proposed in the current application will provide a strong justification for the proposed work:

1. Demonstration that the natural product can produce a clinically meaningful change in measurable target engagement (e.g., mechanism of action) in the human population of interest. There must also be evidence that the change in target engagement has been replicated in a separate human study with the same natural product to be used in the proposed project, unless it is impossible or impractical to do so or when a mechanism of action has been clearly established.
2. Evidence that evaluates the pilot study data for strength of correlation between the impact on target engagement and changes in the clinical outcome that will be studied in the proposed clinical trial (unless waived by condition below).
3. Evidence that the specific natural product is bioavailable in humans. Note that for prebiotics or probiotics this may be demonstrated by documenting short-term retention in the gastrointestinal tract.
4. Evidence that the natural product does not produce frequent or severe adverse events in human pilot trials.

For the purposes of this NOFO, it is preferred that there be an established, measurable, reproducible, well-characterized target engagement measure for a given natural product in human subjects. However, NCCIH acknowledges that for some conditions, it may be impossible or impractical to directly measure the target engagement of a natural product. In these circumstances the study should be justified by: (1) a clear rationale for why studying a target engagement measure in human participants is impossible or impractical; (2) potentially proposing other objective, reproducible measures that may be proxy to or indicative of target engagement for the natural product; and (3) strong compelling preliminary data to warrant further study of the natural product in clinical studies. In other 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). In these situations, investigators are encouraged to contact NCCIH Scientific/Research staff to determine whether the R01 is the appropriate NOFO for the proposed clinical trial. 

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.

Timeline

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 
As NCCIH’s clinical research portfolio matures, NCCIH has identified targeted areas of investigation to align with the NCCIH Strategic Plan (https://www.nccih.nih.gov/about/strategic-plans-and-reports). The focus is on management of conditions for which natural products are used by the public and where there is evidence of a postulated mechanism of action. For this NOFO, NCCIH considers the following topic areas to have high program priority: 

• 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). 
• 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, which outlines specific requirements to enhance protections for pregnant women, human fetuses, and neonates; children; and prisoners (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).    

served rural populations, and people with disabilities. 

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 of 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:

• Phase I/first in human trials.
• 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).
• Trials proposing to measure or replicate the effect of a natural product through target engagement. 
• Animal studies.
• 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.)

Plan for Enhancing Diverse Perspectives (PEDP)

The NIH recognizes that teams comprised of investigators with diverse perspectives working together and capitalizing on innovative ideas and distinct viewpoints outperform homogeneous teams. There are many benefits that flow from a scientific workforce rich with diverse perspectives, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved populations participate in, and benefit from research, and enhancing public trust.

To support the best science, the NIH encourages inclusivity in research guided by the consideration of diverse perspectives. Broadly, diverse perspectives can include but are not limited to the educational background and scientific expertise of the people who perform the research; the populations who participate as human subjects in research studies; and the places where research is done.

This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP), which will be assessed as part of the scientific and technical peer review evaluation.  Assessment of applications containing a PEDP are based on the scientific and technical merit of the proposed project. Consistent with federal law, the race, ethnicity, or sex of a researcher, award participant, or trainee will not be considered during the application review process or when making funding decisions.  Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review.

The PEDP will be submitted as Other Project Information as an attachment (see Section IV).  Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP Guidance materials.

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

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

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

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

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized).

Federal Governments

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• 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
• Regional 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

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 to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019 and Notice of NIH's Interest in Diversity, NOT-OD-20-031.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the How to Apply-Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Applications with Foreign components are encouraged to read NCCIH International Health Research page. Foreign components can include foreign collaborators or consultants, but should not include foreign sites outside of the U.S. or Canada, according to NCCIH’s policy.

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows Institute and Center staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Jessica McKlveen, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-8018
Email: [email protected] 

Page Limitations

All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the How to Apply- Application Guide must be followed.

Facilities and Other Resources:

Applicants must provide strong evidence of the availability of appropriate institutional resources and suitable patient populations. Documentation of availability of eligible subjects at clinic sites, presented in tabular format, must be provided. The application must include relevant information that addresses the feasibility of recruiting participants who are eligible for the clinical trial. Specifically, applicants must provide evidence that each recruiting center in the trial has access to a sufficient number of participants who meet the eligibility criteria as defined in the submitted protocol. For multi-site applications, information must be provided for each participating site.

• Discussion of engagement with different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based).
• Description of any planned partnerships that may enhance geographic and regional diversity.
• Plan to enhance recruiting of women and individuals from groups historically under-represented in the biomedical, behavioral, and clinical research workforce.
• Proposed monitoring activities to identify and measure PEDP progress benchmarks.
• Plan to utilize the project infrastructure (i.e., research and structure) to support career-enhancing research opportunities for diverse junior, early- and mid-career researchers.
• Description of any training and/or mentoring opportunities available to encourage participation of students, postdoctoral researchers and co-investigators from diverse backgrounds.
• Plan to develop transdisciplinary collaboration(s) that require unique expertise and/or solicit diverse perspectives to address research question(s).
• Publication plan that enumerates planned manuscripts and proposed lead authorship.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as research participants including those from under-represented backgrounds.

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see https://braininitiative.nih.gov/about/plan-enhancing-diverse-perspectives-pedp

Plan for Enhancing Diverse Perspectives (PEDP)

• In an "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of actionable strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity. 
• Applicants should align their proposed strategies for PEDP with the research strategy section, providing a holistic and integrated view of how enhancing diverse perspectives and inclusivity are buoyed throughout the application.
• The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured.
• The PEDP may be no more than 2 pages in length and should include:
  • Actionable strategies using defined approaches for the inclusion of diverse perspectives in the project;
  • Description of how the PEDP will advance the scientific and technical merit of the proposed project;
  • Anticipated timeline of proposed PEDP activities;
  • Evaluation methods for assessing the progress and success of PEDP activities.

Examples of items that advance inclusivity in research and may be appropriate for a PEDP can include, but are not limited to:

• Partnerships with different types of institutions and organizations (e.g., research-intensive; undergraduate-focused; HBCUs; emerging research institutions; community-based organizations).
• Project frameworks that enable communities and researchers to work collaboratively as equal partners in all phases of the research process.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as human subjects in clinical trials, including those from underrepresented backgrounds.
• Description of planned partnerships that may enhance geographic and regional diversity.
• Outreach and recruiting activities intended to diversify the pool of applicants for research training programs, such as outreach to prospective applicants from groups underrepresented in the biomedical sciences, for example, individuals from underrepresented racial and ethnic groups, those with disabilities, those from disadvantaged backgrounds, and women.
• Plans to utilize the project infrastructure (i.e., research and structure) to enhance the research environment and support career-advancing opportunities for junior, early- and mid-career researchers.
• Transdisciplinary research projects and collaborations among researchers from fields beyond the biological sciences, such as physics, engineering, mathematics, computational biology, computer and data sciences, as well as bioethics.

Examples of items that are not appropriate in a PEDP include, but are not limited to:

• Selection or hiring of personnel for a research team based on their race, ethnicity, or sex.
• A training or mentorship program limited to certain researchers based on their race, ethnicity, or sex.

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see PEDP Guidance materials.

SF424(R&R) Senior/Key Person Profile

All instructions in the How to Apply- Application Guide must be followed.

Biographical Sketches: Document the PD’s/PI’s experience in leading clinical trials and expertise in the content area of the trial. Even exploratory clinical studies will require a multidisciplinary team (clinician, biostatistician, data manager, study coordinator, etc.), and the application should reflect their hands-on involvement in the design and implementation of the study protocol. Applicants are encouraged to provide strong evidence of the study team’s qualifications and ability to conduct the proposed as well as future research, experienced investigative team members, and previous investigative experience in related clinical trials.

R&R or Modular Budget

All instructions in the How to Apply- Application Guide must be followed.

The budget for the first year of the grant should reflect the implementation timeline.

PEDP implementation costs:

Applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7): https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm.

R&R Subaward Budget

All instructions in the How to Apply-Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the How to Apply- Application Guide must be followed.

PHS 398 Research Plan

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions:

Research Strategy

Note: Discuss the overall approach but do not duplicate information collected in the PHS Human Subjects and Clinical Trials Information Form.

The Research Strategy should be organized in a manner that will facilitate peer review. The body of the application must present an overview of the state of the science, current status and relevance of the trial, a discussion of the specific protocol, and the approach to data collection, analysis, and dissemination.

The following criteria must be addressed:

Importance of Research: The significance and innovation of the proposed clinical trial and importance of the question must be clearly stated. The application should provide rigorous preclinical or clinical preliminary data to support the study rationale. The application should make clear the need for and timeliness of the study with emphasis on how the results will address an evidence gap and therefore advance our knowledge of theory and practice in this area. The application should describe how the proposed project will advance knowledge to determine if the natural product can reproducibly modify target engagement so that future clinical trials can determine if the target is a mediator of clinical benefit. It is particularly important that there be discussion of how the results of the proposed trial (positive or negative) will guide decisions about whether a subsequent study is needed or justified, and/or provide evidence that additional studies must be completed before proceeding to a full-scale multi-site efficacy trial. A discussion of the costs and benefits of the study should be included for evaluation of the trial’s significance. The applicant is expected to provide a precise response to the following two questions: 1) Will the result, whether positive or negative, be informative and provide a definitive test of the hypothesis? 2) Will the results be informative about the potential role of target engagement in the clinical condition? .

Explain how the application challenges and seeks to shift current research or clinical practice paradigms or guidelines.

Rigor and Feasibility: The research approach section should include a description of the supporting data (including strengths and weaknesses of the published literature), clinical trial experience, the experimental approach, and a timeline for completing the trial.

Supporting Data: The studies that led to the proposed clinical trial should be presented. Data from pilot studies that show the need for and the feasibility of the trial should also be presented in the application. Additional supporting data from other research should be included so that the approach chosen is clearly justified and adequately framed. Applications must include the following preliminary data from human studies (preferably published in the peer-reviewed literature):

1. Demonstration that the natural product can produce a clinically meaningful change in measurable target engagement (e.g., mechanism of action) in the human population of interest. There must also be evidence that the change in target engagement has been replicated in a separate human study with the same natural product to be used in the proposed project, unless it is impossible or impractical to do so or when a mechanism of action has been clearly established.
2. Evidence that evaluates the pilot study data for strength of correlation between the impact on target engagement and changes in the clinical outcome that will be studied in the proposed clinical trial (unless waived by condition below).
3. Evidence that the specific natural product is bioavailable in humans. Note that for prebiotics or probiotics this may be demonstrated by documenting short-term retention in the gastrointestinal tract.
4. Evidence that the natural product does not produce frequent or severe adverse events in human pilot trials or justification for why studying target engagement in human participants is impossible or impractical;

If it is impractical/impossible to measure the impact of the natural product on target engagement or when there is a fundamental understanding of the product’s mechanism of action, such that it is not possible to provide items 1 and 2, applicants must provide the following:

• Consider proposing other objective, reproducible measures that may be proxy to or indicative of target engagement for the natural product.
• Provide strong compelling preliminary data to warrant further study of the natural product in clinical studies. 

Experimental Approach: The proposed experimental approach should include an appropriate study design and the rationale for the particular design chosen. The experimental approach description should include:

• A description and rationale for the research hypothesis(es), methods of randomization if applicable, primary and secondary outcome measures, intervention(s), measurement of the replicable target engagement measure(s) of the natural product, and participant follow-up procedures.
• A rationale, including supporting data for the natural product to be tested, including: name and ingredients of the product, rationale for the supplier, proposed methods for product characterization and standardization, and rationale for selection of and specified percentages or levels of marker compounds, if applicable. See the NCCIH Policy on Natural Product Integrity for more information (https://NCCIH.nih.gov/research/policies/naturalproduct.htm).
• All necessary agreements for the use of the natural product in the study, including clinical research agreements and licensing agreements, must be executed prior to grant award. A timeline should be included in the application showing activities with third parties such as 1) executing necessary agreements, 2) providing natural product and matching placebo, and 3) permission to reference an open IND drug master file (if available).
• Engagement of the clinical community that is playing a critical role in the recruitment, retention, and overall conduct of the clinical trial including the prioritization of this clinical trial in the context of other overlapping clinical research. Description of this commitment should be provided.
• A description and justification for all assessments including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the primary and secondary research questions. Use of patient-reported outcomes as well as non-traditional data collection approaches (e.g., telephone, mobile devices, or web-based systems) needs to be described. A description of the laboratory evaluations (as appropriate) and plans to implement and monitor Good Clinical Practices (GCP), Good Laboratory Practices (GLP), and Good Manufacturing Practices (GMP), as appropriate should be provided.
• A description of the approach to obtain regulatory approvals.
• A description of the clinical equipoise. 
• A discussion of potential challenges in implementing the research protocol and how they will be addressed.

Letters of Support

Letters of support from clinicians or clinical department chairs whose support is necessary to the successful conduct of the trial should be provided. Applicants are also encouraged to include documentation of the commitment of any subcontractors and consultants, as well as service agreements for personnel or facilities. Letters of commitment must be cosigned by the business official of the collaborating center. In addition, a letter of support should document that sufficient supply of the natural product will be available for testing at the time of award, including expiration date; that the supplier will meet and provide details regarding Chemistry Manufacturing and Controls specifications; and that the supplier will provide the data necessary for the investigator to adhere to NIH and FDA policies. Documentation should include a letter of agreement from the third party supplying the natural product.

If parts of the costs of the trial are to be provided by sources other than NCCIH, provide Letter(s) of Support signed by an authorized representative.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide.

Other Plan(s): 

All instructions in the How to Apply-Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the How to Apply- Application Guide must be followed.

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan

Include the following: 1) if there are known participant or study-related barriers to accrual or participation (based on literature or prior experience), please list these barriers and describe plans to address them to optimize success; 2) contingency plans for participant accrual if enrollment significantly lags behind accrual benchmarks; 3) participant retention and adherence strategies; 4) possible competition from other trials for study participants; and 5) strategies for outreach to minorities and women. Investigators are encouraged to review the NCCIH Study Accrual and Retention Plan (https://www.nccih.nih.gov/grants/policies/nccih-policy-study-accrual-and-retention-for-human-subject-research).

Additionally, please include a description of the study population and why it is the most appropriate group to answer the question, and how or if results will generalize to a broader population.

2.7 Study Timeline

Milestone Plan: The milestone plan should describe the key milestones that need to be met throughout the lifecycle of the clinical trial to ensure its success, the processes that will be used to reach the milestones, and a timetable identifying when each of these key milestones will be met.

All applicants must use the following definition of a milestone in their application: a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, achievable, and measurable. The research plan should include anticipated challenges to meeting milestones and propose potential mitigation or corrective actions strategies. Milestones should address overall recruitment and retention goals.

Milestones of particular interest that should be described in the application may include, but are not limited to, the following:

• Complete finalized clinical protocol approved by NCCIH and Protocol Review Committee/Data and Safety Monitoring Board (DSMB) (if required)
• Final informed consent(s) and, if applicable, assent forms (if required)
• Agreements in place for product supply
• Comprehensive laboratory plan
• Pharmacy/Laboratories Identification (as applicable)
• Contracts/Third Party Agreements (if applicable)
• Training plan for clinical site(s)
• Final Data and Safety Monitoring Plan approved by NCCIH
• Submission of an approved Study Accrual and Retention Plan by the Authorized Business Official prior to the clinical trial
• Data Completeness and Quality Monitoring Reporting Plan
• Completion of regulatory approvals
• Single Institutional Reivew Board (sIRB) approval for clinical sites
• Target dates for percent enrollment of 10, 25, 50, 75, and 100 percent of the projected recruitment for all study subjects, including women, minorities, and children (as appropriate)
• Assessment of site(s) protocol implementation performance
• Collection of data related to primary and secondary endpoints and database lock
• Submission of primary manuscript to peer-reviewed scientific journal
• Submission of study results to ClinicalTrials.gov within 12 months of the primary completion date

During the award phase, achievement of each milestone will need to be communicated to the NCCIH program officer listed on the Notice of Award. Award continuation, even during the period recommended for support, is conditional upon satisfactory progress. If, at any time, recruitment, as defined in the NCCIH Accrual of Human Subjects (Milestones) Policy, falls significantly below projections, or core milestones mutually agreed upon by the PD/PI and NCCIH are not met, the NCCIH may consider ending support and negotiating an orderly phase-out of the award. NCCIH retains, as an option, periodic external peer review of progress. NCCIH staff will closely monitor progress at all trial stages including milestones, accrual, and safety.

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan

In addition to the NIH application requirements for data and safety monitoring for clinical trials, NCCIH requires independent monitoring for research involving human subjects. Applicants should refer to NIH’s policy on data and safety monitoring (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html), as well as the NCCIH guidelines for data and safety monitoring (https://nccih.nih.gov/grants/policies/data-safety-monitoring). The Independent Monitoring Committee (IMC) or DSMB will have the responsibility to review interim and final data and recommend whether the protocol should be modified, and, at each meeting, whether the study should be continued or should be terminated early. Thus, its ethical responsibilities, to the participants as well as to the integrity of the study, are of paramount importance to NCCIH. The IMC/DSMB should meet in person or by phone at least twice a year. Applicants should not appoint IMC/DSMB members in advance of the peer review, or even inquire about the interest of possible DSMB members, because anyone so contacted would not be eligible to serve as a member of the peer review committee that will evaluate the applications for scientific merit.

Section 4 - Protocol Synopsis

4.5. Will the study use an FDA-regulated intervention?

4.5.a. If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status:

The proposed clinical trial must use a natural product (such as botanicals, probiotics, and products marketed as dietary supplementl) for this NOFO. The attachment in this section should describe correspondence from the FDA indicating whether the proposed study will require an IND/IDE or not.  Investigators should describe the process that will be used for attaining all necessary FDA or other applicable regulatory agency approvals necessary to the conduct of the trial, and an associated timeline to complete these approvals. For trials using an FDA-regulated product that require an IND/IDE application, the grant application must include evidence regarding the outcome of a pre-IND meeting, or other evidence of communication with the FDA. If the protocol is conducted under a non-U.S. regulatory agency, the applicant should submit a plan for attaining those regulatory approvals. If the protocol is exempt from an IND/IDE, a copy of the exemption letter from the FDA should be provided. The FDA has provided guidance indicating that when substances that are Generally Recognized as Safe (GRAS) are used in a clinical trial to evaluate the product’s ability to diagnose, cure, mitigate, treat, or prevent disease it may require an IND under part 312 (https://www.fda.gov/media/79386/download). If an IND is required by the FDA for the proposed R01 trial(s), the IND must be submitted to the FDA with no clinical hold imposed by the FDA prior to the application being funded. .

Section 5 - Other Clinical Trial-Related Attachments

5.1 Other Clinical Trial-Related Attachments

The following attachment must be included as a part of the application. The attachment permits expansion of certain elements that cannot be appropriately described in the Research Strategy. The attachment listed below must be provided, or the application will not be peer reviewed.

1. Clinical Trial Experience

Applicants must provide a detailed table listing the characteristics of trials that demonstrate key personnel experience in trial coordination in the last 5 years. The table must be provided as an attachment called “Clinical Trial Experience.pdf” and must not exceed three pages.

The table columns should include:

• Clinical trial title
• Applicant’s role in the trial
• A brief description of the trial design
• Planned enrollment
• Actual enrollment
• Number of sites
• Whether the trial(s) were completed on schedule or not
• Publication reference(s) 

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the How to Apply- Application Guide must be followed.

PHS Assignment Request Form

All instructions in the How to Apply- Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the How to Apply-Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

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 from the FDA 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 Investigational Product (IP) and IND/IDE status. If the protocol is conducted under a non-U.S. regulatory agency, equivalent determinations and documentation must be provided to NCCIH prior to a grant award. Funding will not be made until the necessary regulatory approvals are in place for the conduct of the proposed clinical trial. If the product to be studied is on the Drug Enforcement Agency (DEA) controlled substance list, the applicant must describe the DEA license and registrations necessary to complete the proposed trial(s) in the R01 award. Again, no awards will be made until all necessary DEA licenses and registrations are in place.

Specific to this NOFO:

• Awards issued under this NOFO will be excluded from automatic carryover. All carryover actions will require NCCIH prior approval.
• Awards issued under this NOFO will not be provided the authority to automatically extend the final budget period. All extensions, including the first, will require NCCIH prior approval.
• Awards issued under this NOFO will be excluded from Streamlined Non-Competing Award Proces (SNAP).

Applications must be submitted electronically following the instructions described in the How to Apply - Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply - Application Guide.

See more tips for avoiding common errors.

Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant, and/or nonresponsive will not be reviewed.

In order to expedite review, applicants are requested to notify the NCCIH Referral Office by email at [email protected] when the application has been submitted. Please include the NOFO number and title, PD/PI name, and title of the application.

will be considered incomplete and will be withdrawn.

Requests of $500,000 or more for direct costs in any year

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide. See NCCIH’s website on this policy (https://nccih.nih.gov/grants/policies/over500k-clinical-trials).

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected].

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

In addition to the NIH policy allowed post-submission materials, the following post-submission materials are allowed:

• Revised Clinical Trial Experience Table (e.g., due to updated enrollment numbers, publication of trial results, or newly started clinical trials)
• Revised information about FDA-regulated interventions (updates to IND or IDE status or communications with the FDA) as described in Section 4.5.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following scored review criteria and additional review criteria (as applicable for the project proposed).  An application does not need to be strong in all categories to be judged likely to have a major scientific impact. As part of the overall impact score, reviewers should consider and indicate how the Plan for Enhancing Diverse Perspectives affects the scientific merit of the project.

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. 

As applicable for the project proposed, reviewers will consider the following additional items while determining scientific and technical merit, but will not give criterion scores for these items, and should consider them in providing an overall impact score.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NCCIH, in accordance with NIH peer review policies and practices, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions, consistent with applicable law.

• Scientific and technical merit of the proposed project, including the PEDP, as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

Please note that reviewers will not consider race, ethnicity, age, or gender of a researcher, award participant, or trainee, even in part, in providing critiques, scores, or funding recommendations. NIH will not consider such factors in making its funding decisions.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.
  • HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

Successful recipients under this NOFO agree that:

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by any funded entity, recipients and subrecipient(s) are required to: Use health IT that meets standards and implementation specifications adopted in 45 CFR part 170, Subpart B, if such standards and implementation specifications can support the activity.  Visit https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-D/part-170/subpart-B to learn more.

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by eligible clinicians in ambulatory settings, or hospitals, eligible under Sections 4101, 4102, and 4201 of the HITECH Act, use health IT certified under the ONC Health IT Certification Program if certified technology can support the activity. Visit https://www.healthit.gov/topic/certification-ehrs/certification-health-it to learn more.

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

1. ongoing and consistent access to HHS owned or operated information or operational technology systems; and 
2. receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information. 

Not Applicable

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

• Awardees will provide updates at least annually on implementation of the PEDP.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

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Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Sekai Chideya, M.D., MPH 
National Center for Complementary and Integrative Health (NCCIH) 
Telephone: 301-827-1916 
Email: [email protected] 

Jessica McKlveen, PhD
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-8018
Email: [email protected] 

Debbie Chen 
National Center for Complementary and Integrative Health (NCCIH) 
Telephone: 301-594-3788 
Email: [email protected] 

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.