Part 1. Overview Information

Key Dates

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts ).

Conformance to all requirements (both in the Application Guide and the FOA) 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.

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

The National Center for Complementary and Integrative Health (NCCIH) is committed to the rigorous investigation of promising natural products (i.e. botanicals, probiotics, and products marketed as dietary supplements) for which there is compelling preclinical and preliminary clinical evidence for potential health benefit. NCCIH is particularly committed to identifying effective complementary health approaches for management of symptomatic conditions that are commonly treated in primary care such as sleep disturbance, pain, or mild mental health conditions (e.g., depression, anxiety disorders, and post-traumatic stress). This includes examining the effects of probiotics and other natural products on gut-microbiome interactions with the brain and/or immune system. It also includes studies exploring the effects of cannabinoids and terpenes in early phase clinical trials for the management of the symptomatic conditions noted above.

Clinical trials of natural products are maximally informative if they incorporate well-formulated biological hypotheses, are built on a sound foundation of basic mechanistic and pharmacologic understanding, and incorporate assessment of defined replicable biological effects. Biological signatures of the natural products may be biologically based mechanisms or behavioral processes such as an objective single measure, proxy, correlate or combination of molecular/cellular, psychological, neural circuit, tissue/organ, and/or somatic changes. 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), a direct biological effect or biological signature may not be measurable in human participants.

When a mechanism of action has already been clearly established or when measuring a biological signature is not possible, investigators should contact a Program Director at NCCIH to discuss whether the U01 funding mechanism (PAR-20-216) is appropriate. In all cases, data demonstrating bioavailability of the natural product in human volunteers is required before conducting efficacy trials, when absorption of the natural product is required for activity. A careful translational research process is as important for trials of natural products as it is for the study of conventional pharmaceuticals. Critical to this process is the development of measures of a biological or behavioral effect and refinement of appropriate outcome measures for a clinical condition.

A clinical trial is defined by NIH as a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. Investigators considering applying to the NCCIH for a clinical trial award should refer to the NCCIH Clinical Trials Policy web site. Information about NCCIH Policies, Guidelines and Sample Templates for Clinical Trials at: https://www.nccih.nih.gov/grants/toolbox.

Overview of NCCIH Natural Products Clinical Trials Research Funding Opportunities

NCCIH has designed its natural products clinical trials program to support investigator-initiated studies with funding mechanisms appropriate to the stage of the translational research process. This includes pre-clinical/animal studies (which may use Parent R21 or R01 FOAs), human mechanistic studies to determine and replicate the biological effect of a given natural product (phased innovation awards using R61/R33), clinical trials to determine the optimal dose and/or determine which patient phenotypes will be responders versus non-responders (this FOA using the U01 funding mechanism), and multi-site clinical trials to perform definitive efficacy studies (UG3/UH3 with companion U24 funding mechanism).

The following research funding mechanisms have been established by NCCIH to assist in supporting research and development of a natural product along a translational research continuum from early exploratory pre-clinical or first in human research through multi-site efficacy trials. Depending on the extant evidence and research for a given natural product, applicants may use the appropriate FOA to support the next step in clinical trial research.

Clinical Trial Planning Phase - Determining and Replicating Biological Signature (R61/R33, PAR-20-218)

To maximize the impact of a natural product clinical trial, it is highly desirable to establish an objective measure or validated psychological process measure of the impact of the natural product, hence forth known as a biological signature. In general, a research grant application submitted under the R61/R33 (or R33) should precede submission of multi-site efficacy trial via the UG3/UH3 and companion U24 mechanisms described below,, although this is not a requirement and such data may be available or can be obtained through other means. The biological signature may be a measure of the postulated mechanism of action by which the natural product may ultimately modify the clinical condition or symptom(s) of interest. Biological signatures may be biologically based mechanisms or behavioral processes such as an objective single measure, proxy, correlate or combination of molecular/cellular, psychological, neural circuit, tissue/organ, and/or somatic changes.

The R61/R33 should be used to measure the pharmacokinetics (if applicable) of the product and the impact of the natural product on a biological signature, replicate the impact on and determine the reproducibility of the biological signature in a separate study; and when possible determine the dose of the natural product that optimizes its impact on the biological signature. The data collection supported under the R61/R33 or R33 should be finished and the data analysis completed before the U01 or UG3/UH3 is submitted.

Natural Product Mid-Phase Clinical Trial Cooperative Agreement Award (U01, PAR-20-216)

The Mid-Phase Clinical Trial Award FOA is intended to complete collection of preliminary data needed to inform the design of a fully powered multi-site efficacy trial. The U01, therefore, supports research that builds upon work that has 1) determined the pharmacokinetics of the product and 2) identified and replicated a biological signature of the given natural product. Investigators should only apply for the U01 Natural Product Mid-Phase Clinical Trial Cooperative Agreement if there is substantial evidence that the proposed biological signature of the natural product has been detected and replicated with research participants or patients. The U01 may also be used to investigate a well-characterized natural product for a new clinical condition if the evidence of a biological signature (i.e., mechanism of action) is known through previous research and extant data.

It is recognized that for certain conditions (e.g. pain), a direct biological effect or biological signature may not be measurable in human participants for a variety of reasons. In such instances, a strong justification for why measuring the impact on a biological signature is not possible or impractical with human participants is required. In these cases, investigators should consider including other objective measures that may be a marker of the mechanism of action and provide evidence of a biological or behavioral effect of the natural product in human participants. The U01 clinical trial FOA will support natural product clinical trials (usually phase II) such as dosing and formulation optimization of the natural product when they are needed to plan for a future multi-site randomized clinical trial; or when it is necessary to determine which patient phenotypes will be likely responders versus non-responders to the natural product to inform inclusion/exclusion criteria of a future multi-site efficacy trial. Trials supported by the U01 should also collect additional data documenting ability to recruit/accrue participants, achieve adherence to the study protocol, retain participants during study, and complete collection of follow-up data.

Multi-Site Investigator-Initiated Clinical Trials Cooperative Agreement Award (UG3/UH3, PAR-20-215)

The UG3/UH3 FOA will support applications to implement a multi-site clinical trial of a natural product (Phase III and beyond). Under this phased award the UG3 phase supports the planning and development of resources necessary to the perform the efficacy trial. If the UG3 phase successfully meets all planning milestones, the UH3 phase is awarded to implement the efficacy clinical trial. The UG3/UH3 award is used to implement a Clinical Coordinating Center (CCC) for investigator-initiated multi-site clinical trials of natural products. In addition, multi-site clinical trials require a companion Data Coordinating Center (DCC) application (U24) be submitted with and linked to the CCC application. Both applications undergo peer review simultaneously. Multi-site clinical trials are defined as trials that enroll from two or more recruitment sites. Multiple sites are necessary for efficacy trials to increase generalizability of findings and enhance recruitment efficiency as well as representativeness of the participants. Multi-Site clinical trials are expected to be designed with a minimum of 90% power for the primary outcome in order to contribute to the evidence base for important health matters of relevance to the research mission of NCCIH. In addition to scientific relevance and excellence, these clinical trials are expected to be conducted with a high degree of efficiency, with streamlined administrative procedures wherever possible. The Clinical Coordinating Center for Multi-Site Trials FOA runs in parallel with a companion FOA that solicits applications for the companion DCC. Multi-site trials will be expected to achieve the required phase III trial requirements of NIH (see: https://humansubjects.nih.gov/glossary, and http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm)

Purpose of the Phase II Clinical Trial Award (U01)

The objective of this FOA is to support clinical trials to increase the evidence base for a natural product. The following are examples of types of clinical trials (phase II) appropriate for this FOA:

• Dosing and formulation optimization of the natural product's impact on the biological signature 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 study
• In addition to one of the two bullets above, investigators can also collect additional data documenting ability to recruit/accrue participants, achieve adherence to the study protocol, retain participants during study, and complete collection of follow-up data

Preliminary data requirements.

This FOA is appropriate when there is a compelling rationale, a rigorous empirical basis, and scientific premise, which should include preliminary data from animal studies and previous human studies. The following preliminary data from human studies (preferably published in 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:

• Demonstration that the natural product can produce a clinically meaningful change in a measurable biological signature (e.g. mechanism of action). There should also be evidence that the change in biological signature has been replicated in a separate human study.
• Evidence that evaluates the pilot study data for strength of correlation between the impact on the biological signature and changes in the clinical outcome that will be studied in the proposed clinical trial;
• Pharmacokinetic data on the specific natural product and formulation to be used in the proposed trial to justify the dosing frequency in the proposed trial and to demonstrate initial safety of the product. PK studies are not required for natural products that do not require absorption for their intended effect (e.g. prebiotics and probiotics); and
• Evidence that the natural product does not produce frequent or severe adverse events in human pilot trials

For the purposes of this FOA, it is preferred that there be an established, measurable, reproducible, well characterized biological signature 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 biological impact of a natural product. In these circumstances the applicant should: (1) have a clear rationale for why studying a biological signature in human participants is impossible or impractical; (2) consider proposing other objective, reproducible measures, that may be proxy to, or indicative of a biological or behavioral effect for the natural product; and (3) have strong compelling preliminary data to warrant further study of a 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 also encouraged to contact NCCIH Scientific/Research staff to determine whether the U01 is the appropriate funding opportunity for the proposed clinical trial.

Implementation Timeline. It is important that clinical trials have a realistic timeline that explicitly addresses how long it will take from time of award to first participant accrual. NCCIH has an oversight process in place for clinical trials that may require revising and submitting a detailed study protocol, data and safety monitoring plan, case report forms, and accrual plan for NCCIH and IRB approvals, a site initiation visit by NCCIH to verify that the site is ready to begin participant recruitment and any subsequent remediation efforts.

Milestones. Delineation of milestones is a key characteristic of this FOA. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. Milestones are to be performance-based to achieve completion of the trial on time and on budget. Investigators should design a series of milestones for completion of the clinical trial and provide contingency plans to proactively confront potential delays or disturbances in attaining the milestones. Investigators should design relevant milestones that reflect essential progress of the proposed clinical trial, and a timeline to meet accrual targets at predefined increments. Investigators are encouraged to review the NCCIH Study Accrual and Retention Plan (https://nccih.nih.gov/grants/policies/SARP). Continuation of the award is conditional upon satisfactory progress and subject to availability of funds. If, at any time, recruitment falls significantly below the projected milestones for recruitment, the NCCIH will consider ending support and negotiating an orderly phase-out of the award and retains, as an option, periodic external peer review of progress. NCCIH staff will closely monitor progress at all stages, milestones, accrual, and safety.

Information to guide investigators for preparation of clinical trial implementation can be obtained from the NCCIH Scientific/Research staff. NCCIH clinical research policy and guidance information as well as NCCIH templates for the manual of operating procedures, and data and safety monitoring are available at the following website: https://nccih.nih.gov/grants/toolbox. Clinical trials supported by this FOA will have to adhere to the NIH Policy on Good Clinical Practice Training (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-148.html).

Investigators are encouraged to review the NCCIH Clinical Research Toolbox (http://NCCIH.nih.gov/grants/toolbox) to learn more about NCCIH's requirements for clinical research and NCCIH’s policy on natural product integrity (http://NCCIH.nih.gov/research/policies/naturalproduct.htm).

Investigators must contact the US Food and Drug Administration (FDA) prior to submitting an application to determine whether an Investigational New Drug (IND) application is necessary for the proposed clinical research.

NCCIH Priorities for Clinical Trials of Natural Products

As NCCIH's clinical research portfolio matures, NCCIH has identified certain areas of high priority. Particular focus is management of conditions for which natural products are widely used by the public and where there is evidence of postulated mechanism of action. For this FOA, NCCIH considers the following two general topic areas to have high program priority:

• Symptom management, particularly the use of natural products for sleep disturbance, management of pain conditions, or mental health conditions such as those commonly managed in primary care (e.g. depression, anxiety disorders, and post-traumatic stress).
  • Studies to examine the effects of probiotics and other natural products on gut-microbiome interactions with the brain and/or immune system. Of particular interest are studies of probiotics for depression, anxiety disorders, or chronic pain.
  • Studies to examine the effects of cannabinoids and terpenes in conditions noted above other than the treatment or prevention of cancer.

NCCIH encourages applications to this FOA that meet the above criteria and also address health disparities, symptom management in patients with HIV/AIDS, utilize special populations such as older adults, children, underrepresented minorities, individuals in the military, or veterans.

Applications proposing research topics not identified as high programmatic priority will be considered of lesser or low programmatic priority, which will significantly influence programmatic relevance and reduce the likelihood of funding.

Clinical Trials Not Responsive to this FOA

The following types of clinical trials are not responsive to this FOA and applications proposing such activities will be deemed non-responsive and will not be reviewed:

• First in human trials (such studies should use the Natural Products R61/R33 FOA, PAR-20-218)
• Studies to determine or replicate the effect of a natural product on a biological signature (such studies should use the Natural Products R61/R33 FOA, PAR-20-218)
• Single-site or multi-site, phase III trials of efficacy (such studies should use the Natural Product UG3/UH3 FOA, PAR-20-215)
• Drug or device safety trials
• Single or multi-site observational studies that do not meet the NIH definition of a clinical trial (such studies should use the Parent R21 or R01 FOAs)
• 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).

Specific Areas of Research Interest

Applicants are strongly encouraged to consult with the NCCIH Scientific/Research contacts for the area of science for which they are planning to develop an application prior to submitting to this FOA. Early contact (12 weeks prior to submission is encouraged) provides an opportunity for NCCIH staff to discuss the scope and goals, and to provide information and guidance

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 FOA.

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)

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

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) 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. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• 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.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons.Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but 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 DUNS number and 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 his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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 FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

The NIH will not accept duplicate or highly overlapping applications under review at the same time. 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 NOT-OD-11-101)

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 FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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:

Martina Schmidt, Ph.D.
National Center for Complementary and Integrative Health
Telephone: 301-594-3456
Email: [email protected]

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

All instructions in the SF424 (R&R) 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.

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, experienced investigative team members, and previous investigative experience in related clinical trials.

R&R or Modular Budget

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

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

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

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

All instructions in the SF424 (R&R) 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:

Significance: The significance 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. It is particularly important that there be a discussion of how the trial will test the proposed hypotheses and why there is clinical equipoise. 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. A discussion of the costs and benefits of the study should be included for evaluation of the trial's significance.

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 milestone plan.

Supporting Data: The studies that led to the proposed clinical trial should be presented. Data from pilot studies, which 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 a measurable biological signature (e.g. mechanism of action) in the human population of interest. There must also be evidence that the change in biological signature has been replicated in a separate human study.
2. Evidence that evaluates the pilot study data for strength of correlation between the impact on the biological signature and changes in the clinical outcome that will be studied in the proposed clinical trial;
3. Pharmacokinetic data on the specific natural product and formulation to be used in the proposed trial to justify the dosing frequency in the proposed trial and to demonstrate initial safety of the product; and
4. Evidence that the natural product does not produce frequent or severe adverse events in human pilot trials
5. If it is impractical/impossible to measure the impact of the natural product on a biological signature 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:
   • Justification for why studying a biological signature in human participants is impossible or impractical;
   • Consider proposing other objective, reproducible measures, that may be proxy to, or indicative of a biological or behavioral effect for the natural product;
   • Provide strong compelling preliminary data to warrant further study of a 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 biological signature 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 (http://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 are 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) 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 approach to obtain regulatory approvals
• 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 are 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.

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

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.

.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 lag 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. The Terms and Conditions under this FOA 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:

• Complete finalized clinical protocol approved by NCCIH and Protocol Review Committee/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 Planned by the Authorized Business Official prior to the clinical trial
• Data Completeness and Quality Monitoring Reporting Plan
• Completion of regulatory approvals
• sIRB approval for clinical sites
• Target dates for percent enrollment of: 10, 25, 50, 75, and 100% 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
• Data sharing plan for study data and biospecimens (if applicable)

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 the NCCIH, are not met, the NCCIH may consider ending support and negotiating an orderly phase-out of the award. The 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.

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 (http://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). The 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 the NCCIH. The IMC/DSMB will 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 reviewer committee that will evaluate the applications for scientific merit.

4.6. Will the study use an FDA-Regulated intervention?

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

A Regulatory Communication Plan must be provided for each study record as an attachment ("Regulatory Communication Plan1.pdf", "Regulatory Communication Plan2.pdf", etc) and must not exceed 3 pages of a written description. Additional pages can include copies of correspondence from the FDA indicating whether the proposed study will require an IND/IDE or not. The Regulatory Communication plan 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 associated timeline. For trials using an FDA-regulated product that require an Investigational New Drug (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 U01 trial(s) , the IND must be submitted to the FDA with no clinical-hold imposed by the FDA prior to application being funded. See additional requirements regarding IND submission in Section 6

4.7 Dissemination Plan

Discuss the strategy for timely publication and dissemination of results.

Section 5 - Other Clinical Trial-Related Attachments
5.1 Other Clinical Trial-related Attachments

2. Clinical Trial Experience

Applicants must provide a detailed table listing the characteristics of trials that demonstrate 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 3 pages.

The table columns should include:

Column A: clinical trial title

Column B: applicant's role in the trial

Column C: a brief description of the trial design

Column D: planned enrollment

Column E: actual enrollment

Column F: number of sites

Column G: whether the trial(s) were completed on schedule or not

Column H: publication reference(s)

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.

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 Policy on Late Application Submission.

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 SF424 (R&R) 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.

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 prior to any award. The details of the IND status of the natural product should be provided in the attachment entitled "Regulatory Communication Plan". 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. If the protocol is conducted under a non-US 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 U01 award. Again, no awards will be made until all necessary DEA licenses and registrations are in place.

Specific to this FOA:

• Awards issued under this FOA will be excluded from automatic carryover. All carryover actions will require NCCIH prior approval.
• Awards issued under this FOA 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 FOA will be excluded from SNAP.

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 Component of the SF424(R&R) Application Package. 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 FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number 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, NIH. Applications that are incomplete or non-compliant 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 FOA number and title, PD/PI name, and title of the application.

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.

In addition to the NIH policy allowed post-submission materials in NOT-OD-19-083, the follow post-submission materials are allowed:

• Clinical Trial Experience Table (e.g. due to updated enrollment numbers, publication of trial results, or newly started clinical trials)

Section V. Application Review Information

1. Criteria

Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) as part of the Resource Sharing Plan will not be evaluated at time of review.

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.

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Specific to this FOA:

Is there a sufficient and consistent body of relevant preclinical or clinical research of high scientific rigor to support the study rationale? Have the investigators provided sufficient justification for why this clinical trial necessary to generate preliminary data to inform the design and implementation of the future efficacy trial of the natural product that could lead to a change in clinic practice, community behaviors or health care policy? Does the applicant provide a convincing justification as to why it is important to perform the future larger clinical study in the context of the present knowledge on clinical research in natural products? Is the proposed project likely to yield clear answers needed to proceed to the next step of research as proposed in this application? Will the proposed study advance knowledge of intervention or disease mechanisms, whether the results are positive or negative?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Specific to this FOA:

How well defined are their roles and responsibilities? How well does the application provide evidence of necessary expertise about the natural product and study population? How strong is theevidence provided by the investigators to ensure that they will employ the appropriate personnel to recruit subjects and design/implement the clinical protocol? How strong is the investigative team's track record of conducting, completing, and publishing the results of clinical trials? How well does the application demonstrate that the investigative team has successfully conducted clinical trials under an Investigational New Drug (IND) application or DEA regulations (if applicable)?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Specific to this FOA:

For these Phase II clinical trials, has the investigator sufficiently described how the proposed clinical trial will inform the design of the future efficacy trial so that it can change clinical practice or practice guidelines? Does the proposed research have the potential to advance the field even if the proposed study design, methods, and intervention are not innovative? Will the results of the trial indicate whether further clinical trials of the natural product are unwarranted?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Specific to this FOA:

What strengths and weaknesses are there in the study design? How appropriately is the study designed to answer the research question, test the proposed hypothesis/hypotheses, and collect the necessary data? How efficient is the trial design? How strong is the evidence for equipoise? How well does the Clinical Protocol Synopsis attachment describe the necessary elements of the clinical trial and how likely is it that the protocol can be efficiently implemented? How strong are the formative clinical studies, including any pilot studies, underpinning the trial? Is the natural product appropriately characterized? How well are the clinical outcome measures, biological signature, dose/duration of study and follow up, appropriateness of inclusion/exclusion criteria, and sample size justified and explained? What evidence is there that the study population has been appropriately defined? Are adverse events appropriately captured and monitored?

Is the planned recruitment timeline feasible? What are the strengths and weaknesses of the plan to monitor accrual? Are planned analyses appropriate for the proposed study design?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Specific to this FOA:

Does the application sufficiently document the availability of the requisite eligible subject pool in proposed clinical site(s)? Is there documentation of the commitment of any subcontractors and consultants, as well as service agreements for personnel and facilities?

Study Timeline

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Specific to this FOA:

Milestones

How strongly do the milestones address the specific aims the study? Are the listed milestones appropriate for the goals of the project? Have the investigators provided a strong justification for how the proposed milestones will ensure success of the proposed study? To what extent are the milestones relevant, measurable, achievable, result-focused and time-bound? How well does the application address contingency plans in the event the milestones are not achieved?

Data and Safety Monitoring

Is the proposed Data and Safety Monitoring Plan appropriate for the proposed clinical trial?

Protections for Human Subjects

For research that involves human subjects but does not involve one of thecategories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable.

Revisions

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

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.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

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 policy and procedures, 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:

• 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.
• Will receive a written critique.

• 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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

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 grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. 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 FOA 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: Grantee 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 awardee 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: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

HHS recognizes that 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 FOA.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

• Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

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 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 75and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Research design and protocol development, including definition of objectives and approaches, planning, implementation, participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results.
• Establishing a Steering Committee to coordinate and manage the project. The PD(s)/PI(s) will name investigators to serve as members on a Steering Committee and other subcommittees, as appropriate, meeting periodically. Study investigators will be required to accept and implement the common protocol and procedures approved by the Steering Committee.
• Implement the core data collection method and strategy collectively decided upon by the Steering Committee. It is the responsibility of each clinical site to ensure that data will be entered in a timely way to the study’s data entry system according to the study protocol.
• Establish mechanisms for quality control and monitoring. The investigators are responsible for ensuring accurate and timely assessment of the progress of the study, including development of procedures to ensure that data collection and management are: (1) adequate for quality control and analysis; (2) as simple as appropriate in order to encourage maximum participation of physicians and patients and to avoid unnecessary expense; and (3) sufficiently staffed for the trial.
• Establishing procedures to comply with FDA regulations for studies involving investigational agents or devices and to comply with the requirements of 45 CFR Part 46 for the protection of human subjects, and the NIH policy requirements for the inclusion of women, minorities and children.
• Cooperating in the reporting of the study findings. The NIH will have access to and may periodically review all data generated under an award. Where warranted by appropriate participation, plans for joint publication with NIH of pooled data and conclusions are to be developed by the Principal Investigator or Steering Committee, as applicable. NIH policies governing possible co-authorship of publications with NIH staff will apply in all cases. In general, to warrant co-authorship, NIH staff must have contributed to the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; and (c) preparation and authorship of pertinent manuscripts
• Overseeing the overall budget, activities and performance of the cooperative agreement. Accepting the participatory and cooperative nature of the collaborative research process and complying with policies and practices of NCCIH
• Sharing data, resources and software according to the approved sharing policies for the NIH.
• Cooperating with the NIH staff and contracted on-site monitors in the design and conduct of protocols, analysis of data, and reporting of results of research.
• Agreeing to accept close coordination, cooperation and management of the project with NIH, including those outlined below under "NIH Responsibilities."
• Support or other involvement of industry or any other third party in the study -- e.g., participation by the third party; involvement of study resources or citing the name of the study or NCCIH or other NIH Institute or Center support; or special access to study results, data, findings, or resources -- may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NIH.
• Any of the above function may be performed by the applicant organization or by subcontract to the applicant organization
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• The NIH will assign a Project Scientist as the point of contact to work with the PD(s)/PI(s) and participate in the Steering Committee to ensure the objectives of the program are being met. The primary responsibility for the program resides with the awardee, although specific tasks and activities will be shared among the awardee and the NIH Project Scientist. With the agreement of the Principal Investigator, the NCCIH Project Scientist or designee may assist in the design, development, and coordination of a common research or clinical protocol and statistical evaluations of data; in the preparation of questionnaires and other data recording forms; and/or in the publication of results.
• The NIH will assign a Program Officer who will be responsible for retaining overall programmatic responsibility for the award, and will clearly specify to the recipient the name(s) and role (s) of any additional individuals with substantial involvement in the project and the lines of reporting authority.
• NCCIH may designate additional staff to provide advice to the recipient on specific scientific and/or analytic issues. Such staff may include another Project Scientist or Analyst, who will provide direct technical assistance to the recipients to optimize the conduct and/or analysis of the study; or who may assist in the coordination of activities across multiple sites.
• Prior to the start of clinical activities, NIH staff will review and approve study protocols to insure they are within the scope of peer review and for safety considerations, as required by Federal regulations. NIH will monitor protocol progress, and may request that a protocol study be closed to accrual for reasons including: (a) accrual rate insufficient to complete study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) patient safety and regulatory concerns; (e) study results that are already conclusive; and (f) emergence of new information that diminishes the scientific importance of the study question. The NIH will not permit further expenditures of NIH funds for a study after requesting closure (except for patients already on-study).
• Serve as a resource with respect to other ongoing NIH activities that may be relevant to the protocol to facilitate compatibility and avoid unnecessary duplication of effort.
• NIH staff will interact with the PD(s)/PI(s) on a regular basis to monitor progress. Monitoring may include: regular communication with the PD(s)/PI(S) and his/her staff, periodic site visits for discussion with the awardees research team, observation of field data collection and management techniques, fiscal reviews, and other relevant stewardship activities. NCCIH may designate NIH staff or contractors to conduct site initiation, interim and close out site-visits
• The NIH reserves the right to terminate or curtail the award (or an individual part of the award) in the event of inadequate progress or data reporting.
• NIH staff will provide input, expert advice, and suggestions in the design, development, and coordination and implementation of the study objectives.
• NCCIH staff will make recommendations for continued funding based on: a) overall study progress, including sufficient patient and/or data accrual; b) cooperation in carrying out the research (e.g., attendance at Steering Committee meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements.

Areas of Joint Responsibility include:

• Steering Committee organized by the Principal Investigator will be the main oversight body of the study.
• The Steering Committee has primary responsibility to design research activities, establish priorities, develop common protocols and manuals, questionnaires and other data recording forms, establish and maintain quality control among recipients, review progress, monitor patient accrual, coordinate and standardize data management, and cooperate on the publication of results. Major scientific decisions regarding the core data will be determined by the Steering Committee. The Steering Committee will document progress in written reports to the NCCIH Program Officer, and will provide periodic supplementary reports upon request.
• The Steering Committee will be composed of the PI(s)/PD(s) and co-investigators as deemed necessary, such as the study biostatistician and trial manager, the NCCIH Project Scientist, and additional designees of NIH. The NCCIH Project Scientist or designee will have voting membership on the Steering Committee, and as appropriate, its subcommittees. The NCCIH Program Officer will serve as an ex officio member of the Steering Committee. The Steering Committee will typically meet in-person twice in the first year of the award and then at least yearly thereafter. More frequent phone meetings will occur as required during the award period. The first in person meeting will occur before clinical activities begin.
• Ensuring that sites and investigators as well as NIH and other research partners fully comply with federal regulatory requirements. This includes, but is not limited to those relating to human subjects protections, informed consent, and reporting of adverse events.
• Jointly developing appropriate confidentiality procedures for data collection, processing, storage and analysis to ensure the confidentiality of data on individual health.
• A Data and Safety Monitoring Plan will be required for both phases of the project. An independent Data and Safety Monitoring Board will be appointed and established by NIH for the clinical trial, in accordance with NIH and NCCIH policies for monitoring (https://nccih.nih.gov/grants/policies/data-safety-monitoring). The Data and Safety Monitoring Board will play a crucial role in ensuring safety and welfare of patients enrolled in the trial and will regularly review study progress and some interim data; and will provide recommendations to NIH. During the award the recipient will provide interim data and reporting, as requested, to the Board as outlined in NCCIH Guidelines (https://nccih.nih.gov/research/policies/datasafety

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

All costs requested and all changes in budgets after the first year should be clearly identified and justified.

Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the 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.

3. Reporting

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.

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.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreementsare required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, 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 45 CFR Part 75 Award Term and Conditions 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 threatensubmission by the due date, and post-submission issues)

Finding Help Online:http://grants.nih.gov/support/(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: 301-637-3015

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

Wendy Weber, ND. Ph.D., MPH
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-402-1272
Email: [email protected]

Martina Schmidt, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3456
Email: [email protected]

Shelley Carow
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 45 CFR Part 75.