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 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.   

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 Program Director 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.

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-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/funding/clinicaltrials). 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 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

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 is responsible for the effect and not simply regression to the mean. 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 pharmacokinetic 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 and direction of the change for each measure ;
• Demonstration of impact on target engagement for future 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, severe adverse effects, or results 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; and
• Completion of necessary regulatory approvals for the proposed R33 clinical studies (e.g., IRB, FDA IND).

Go/No-Go Criteria

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, 1. “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 pharmacokinetic 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 pre-planned timeline for reaching the randomization target and not exceed the estimated drop-out rate.
• Three 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.
• Two months prior to the end of the R61 award, submit to NCCIH a “R33 Transition Request Application”.

The R33 Phase

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:

1. Replicate the natural product’s impact on the target engagement measure(s) demonstrated in the R61 phase, AND
2. 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 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, retain, collect all assessments and samples, adhere to the study protocol, and report of adverse events; and
• 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.

Subsequent Studies

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 (e.g., patients, providers, health care systems, etc.) in the planning and execution of exploratory and larger clinical trials. The outcomes of a 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.

Design Considerations

Investigators should propose a randomized controlled trial design with at least one intervention arm and one comparator arm. There should be 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 wait-list comparator condition.

Power Recommendations:  

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 test 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 non-responsive 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 Regulatory Communication Plan. Guidance on the IND evaluation process can be found in the NCCIH Natural Products Clinical Trials Resource web page: https://www.nccih.nih.gov/grants/natural-products-clinical-trials-resource  

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.

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). 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 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://abs2.od.nih.gov/Docs/NIH_StrategicPlan_FY2021-2025.pdf) 

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). It is the policy of NIH 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 the 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).    

¹ NIH-designated health disparity populations include racial and ethnic minorities (African Americans/Blacks, Hispanics/Latinos, American Indians/Alaska Natives, Asian Americans, Native Hawaiians, and Other Pacific Islanders), sexual and gender minorities, socioeconomically disadvantaged populations, under-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 lower programmatic priority. 

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 non-responsive and will not be reviewed:

• Applications that do not propose to study target engagement measures(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
• 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)

• This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP) as described in NOT-MH-21-310, 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 material. The PEDP will be assessed as part of the scientific and technical peer review evaluation, as well as considered among programmatic matters with respect to funding decisions. 

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

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

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 SF 424 (R&R) 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 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.

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 SF424 (R&R) Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement 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).

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 IC 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, PhD
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-8018
Email: jessica.mcklveen@nih.gov  

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 SF424 (R&R) Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Other Attachments:

All attachments listed below must be provided or the application will not be peer reviewed.

1. Milestones and Go/No-Go Criteria Plan
A Milestones and Go/No-Go Criteria Plan must be provided as an attachment called "Milestones and Go_No-Go Criteria.pdf" and must not exceed 3 pages.

The milestone plan should describe the key milestones that need to be met for each phase of the application (R61 and R33) 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. The Terms and Conditions under this NOFO will include a milestone plan that is mutually agreed upon by the investigators and NCCIH.

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

• For the R61 phase obtain NCCIH approval of the operational definition and objective measure(s) of the target engagement(s) that will be measured in humans (i.e., the hypothesized mechanism of action) and definition of a clinically meaningful change for each measure that must be achieved. This will need to be agreed to before starting the R61 trial.
• Final Data and Safety Monitoring Plan approved by NCCIH prior to starting recruitment for R61 clinical trial
• Submission of an approved Study Accrual and Retention Planned by the Authorized Business Official prior to starting both the R61 and R33 phases (https://nccih.nih.gov/grants/policies/SARP).
• Agreements in place for product supply
• Comprehensive laboratory plan (if applicable)
• Pharmacy/Laboratories Identification (as applicable)
• Contracts/Third Party Agreements (if applicable)
• Training plan for clinical site(s)
• Data Completeness and Quality Monitoring Reporting Plan
• Completion of all regulatory approvals
• sIRB approval for clinical site(s)
• 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
• Registration of the trial into ClinicalTrials.gov
• Submission of study results to ClinicalTrials.gov within 12 months of the primary completion date
• Prior to submitting the transition request for the R33 phase, obtain NCCIH approval for R33 phase data and safety monitoring plan, and study accrual and retention plan
• Complete necessary regulatory approvals for proposed R33 clinical trial (e.g., IRB, FDA IND).

In addition, Go/No-Go Criteria for transition from R61 to R33 phase must be included. Applications must provide this information in a section indicated by the heading "Go/No-Go Criteria for R61":

a. A clear effect size in changes in the primary target engagement(s) (mechanistic outcome measure) by the proposed natural product. Investigators must specify the primary target engagement outcome(s) quantitatively. For each proposed primary target engagement measure, provide references to describe and justify the measure.

i) A clear, definitive, and quantitative set of rules for the primary target engagement measure(s) to determine whether the natural product has a measurable effect on target engagement and the metrics/thresholds of No-Go criteria regarding the primary target engagement measure(s) for the R33 phase.

ii) A clear and definitive decision rule should be provided to prioritize target engagement measures if more than one is proposed, specify the direction of natural product induced changes proposed, and how contradictory changes in the measures would be handled.

b. Adequate pharmacokinetic data to justify the dosing of the product for the proposed R33 phase study.  The pharmacokinetic data can come from citable literature or results from the R61 trial.  . This data should include short-term pharmacokinetic data and bioavailability (if appropriate ) of the proposed natural product.    If the pharmacokinetic data is to be collected in the R61 phase, it should be collected prior to starting the R61 target engagement trial.

c. Demonstrate the safety and tolerability of the natural product used in the study by a set of metrics.

d. Demonstrate the ability to recruit and retain subjects in the clinical trial with a pre-planned timeline for reaching the randomization target and drop-out rate.

2. Plan for Enhancing Diverse Perspectives

In an "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity.

• The PEDP should provide a holistic and integrated view of how enhancing diverse perspectives is viewed and supported throughout the application and can incorporate elements with relevance to any review criteria (significance, investigator(s), innovation, approach, and environment) as appropriate.
• Where possible, applicant(s) should align their description with these required elements within the research strategy section
• 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 1-page in length and should include a timeline and milestones for relevant components that will be considered as part of the review

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

• 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

SF424(R&R) Senior/Key Person Profile

All instructions in the SF424 (R&R) Application Guide must be followed.

Biographical Sketches: Document the Program Director’s/Principal Investigator’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, experience of the investigative team members, and previous investigative experience in related clinical trials.

R&R Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

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 SF424 (R&R) Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims: In the single Specific Aims attachment, include headers titled R61 Specific Aims and R33 Specific Aims, and state the specific objectives of the research effort in each of the two phases of this project. The primary and major secondary hypotheses to be evaluated should be clearly stated.

Research Strategy:
The Research Strategy should be organized in a manner that will facilitate peer review. The body of the application should 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 should be addressed:

Significance: The significance of the proposed clinical trial and importance of the question should 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 engagement measure 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 should 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 the target engagement measure in the clinical condition?

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

Approach: 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 brief summary of the milestone and go/no-go criteria plan referring to the required attachments as appropriate.

Supporting Data: The application should provide data from preclinical or clinical studies that led to the proposed clinical trial, which should demonstrate the need for and the feasibility of the proposed early phase trial.

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

• A summary of the Milestones and Go/No-Go Criteria Plan (see Other Attachments).
• A rationale of why the study population is the most appropriate group to answer the question, and how or if results will generalize to a broader population.
• A rationale for the research hypothesis(es), methods of randomization if applicable, primary and secondary outcome measures, intervention(s), measurement of the replicable target engagement of the natural product, and participant follow-up procedures.
• A rationale, including supporting data for the natural product and matching placebo (if applicable) 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 (http://NCCIH.nih.gov/research/policies/naturalproduct.htm).
• A summary of the necessary agreements for the use of the natural product and any matching placebo. Note that 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). This should also be referenced in the Milestones and Go/No-Go Criteria Plan (see Other Attachments).
• A justification for all assessments including PK study marker compounds (if applicable), 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) need 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 future clinical trial beyond the R61/R33: A concise summary of the subsequent anticipated future trial should be provided including the study design.
• A description of the clinical equipoise 
• Discussion of the challenges expected in implementing the research 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 co-signed 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 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 3rd 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 SF424 (R&R) Application Guide.

Other Plan(s): Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the SF424 (R&R) 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 SF424 (R&R) 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 SF424 (R&R) 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 SF424 (R&R) Application Guide must be followed.

The R61 must include at least one clinical trial and the R33 must include at least one clinical trial that is distinct from the R61 clinical trial. As stated in the instructions, investigators must submit a study record for each clinical trial proposed in the application.

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan
Describe the following: 1) the planned recruitment methods including use of contact lists, databases or other pre-screening resources, advertisements, outreach, media / social media and referral networks or groups; 2) 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; 3) contingency plans for participant accrual if enrollment significantly lags behind accrual benchmarks; 4) participant retention and adherence strategies; and 5) possible competition from other trials for study participants; Investigators are encouraged to review the NCCIH Study Accrual and Retention Plan (https://nccih.nih.gov/grants/policies/SARP).

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 study or trial. Specifically, applicants must provide evidence that each recruiting center in the study or trial has access to a sufficient number of participants who meet the eligibility criteria as defined in the submitted protocol. For multisite applications, information must be provided for each participating site.

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan
In addition to the NIH application requirements for a 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 (http://nccih.nih.gov/grants/policies/data-safety-monitoring).

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 botanical, herbal, dietary supplement, probiotic, vitamin or mineral) for this NOFO. The attachment in this section should describe correspondence from the FDA indicating whether the proposed study will require an IND/IDE. Investigators should describe the process that will be used for attaining all necessary FDA or other applicable regulatory agency approvals necessary to the conduct the trial; and 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 FDA. If the protocol is conducted under a non-US 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 R61 or R33 trials, the IND must be submitted to the FDA with no clinical-hold imposed by the FDA prior to application being funded.

 

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 SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form

All instructions in the SF424 (R&R) Application Guide must be followed.

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

See Part 1. 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. Overview Information 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. The details of the IND status of the natural product should be provided in the attachment included in the study record for section 4.6. If the FDA has granted a waiver for either trial proposed in the application (R61 or R33 phase), then the applicant can provide this letter as part of the response to item 4.6 in the study record. If the protocol is conducted under a non-US regulatory agency, then 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 trials in the R61 and R33 phases. Again, no awards will be made until all necessary DEA licenses and registrations are in place.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) 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 SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by NCCIH, 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 jessica.mcklveen@nih.gov when the application has been submitted. Please include the NOFO number and title, PD/PI name, and title of the application.

Applications must include annual milestones and Go/No-Go criteria. Applications that fail to include annual milestones and Go/No-Go criteria will be considered incomplete and will be withdrawn. 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 withdrawn before review.

Post Submission Materials

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

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

• Revised information about FDA-Regulated interventions (Updates to IND or IDE Status or communications with the FDA) as described in Section 4.6
• Revised CCC Milestone Plan (e.g., the hiring, replacement, or loss of an investigator or key personnel; change of sites participating in the trial; or change in database or IT infrastructure)
   

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.

For this particular announcement, note the following: The R61/R33 phased award supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will assign a single impact score for the entire application, which includes both the R61 and R33 phases.

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

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 review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

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

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 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 National Advisory Council for Complementary and Integrative Health
. The following will be considered in making funding decisions:

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

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

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.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this NOFO will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: Generaland Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federalwide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, 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.

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 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.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 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.

Not Applicable

3. Data Management and Sharing

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.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

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. 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.

The Federal Funding Accountability and Transparency Act of 2006 as amended (FFATA), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All recipients of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over the threshold.  See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 2 CFR Part 200.113 and Appendix XII to 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 2 CFR Part 200 – Award Term and Condition for Recipient Integrity and Performance Matters.

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: GrantsInfo@nih.gov (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: support@grants.gov

Sekai Chideya, M.D., MPH
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-827-1916
Email: sekai.chideya@nih.gov

Jessica McKlveen, PhD
National Center for Complementary & Integrative Health (NCCIH)  
Telephone: 301-594-8018
Email:  jessica.mcklveen@nih.gov 

Debbie Chen
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3788
Email: debbie.chen@nih.gov

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.