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

Research Objectives

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 or preliminary clinical evidence of 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 possible or practical with human participants.

When a mechanism of action has already clearly been 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: http://www.NCCIH.nih.gov/Funding/Clinical_Research/NCCIH_guidelines.asp

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, 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.

Natural Product Early Phase Clinical Trial - Determining and Replicating Biological Signature (R61/R33, PAR-20-218, R33, PAR-20-217)
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 the context of the study conditions. In general, a research grant application submitted under the R61/R33 (or R33) should precede submission of a 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 (R61 phase); replicate the impact on and determine the reproducibility of the biological signature in a separate study (R33 phase); and when possible determine the dose of the natural product that optimizes its impact on the biological signature (R33 phase). The data collection supported under the R61/R33 (or R33 if pilot data is available demonstrating the pharmacokinetics and initial impact of the natural product on the biological signature) 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 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 and U24, PAR-20-219)

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 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 (UG3/UH3) runs in parallel with a companion FOA that encourages applications for the companion DCC (U24). 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 NCCIH Natural Product Early Phase Clinical Trial Phased Innovation Award (R61/R33) (This FOA)

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 early phase clinical trials appropriate for this FOA:

• Studies to measure the pharmacokinetics of the natural product
• Studies to demonstrate that when used by humans the natural product modulates a biological signature(s) or mechanism(s) or process related to a clinical condition (thus providing an initial proof of principle) in the R61 phase
• Studies to replicate the impact of the natural product on the biological signature(s) in the R33 phase
• Studies to determine how to optimize the impact of the natural product on the biological signature by (1) optimizing the delivery of the natural product by dose or formulation; (2) combining the natural product with another treatment approach that is known to impact the same biological signature; or (3) studying the impact of the natural product in a target population that is more responsive.
• In addition to the bullets above, investigators can also collect additional data documenting ability to recruit/accrue participants, achieve adherence to the study protocol, retain participants during study, demonstrate tolerability and initial safety of the natural product, and complete collection of follow-up date

An application submitted to this FOA must propose pharmacokinetic (PK) study of the natural product or provide data from previous PK studies of the exact product to be used in the R61/R33 trials. PK studies are not required for natural products that do not require absorption for their intended effect (e.g. prebiotics and probiotics). The PK study should measure a marker compound, constituent, or metabolite that is scientifically justified as the compound that may have an impact on the biological signature based on existing literature. The goal of the PK study is to inform the frequency of daily dosing of the product.

In addition, applications submitted to this FOA must propose a way to measure the effect of the natural product on a biological signature when the natural product is used by humans. This biological signature should be a measure of the postulated mechanism of action or process by which the natural product might ultimately modify the clinical condition or symptom(s) of interest. Biological signatures may be biologically-based mechanisms or behavioral processes such as objective single measure, proxy, correlate or combination of molecular/cellular, psychological, neural circuit, tissue/organ, and/or somatic changes.

The R61 Phase

The R61 phase must focus on testing whether, when used by human participants, the proposed natural product alters the presumed biological signature or mechanism of action. It may be necessary to include a placebo control in this phase of testing to determine whether the natural product is responsible for the change in the biological signature instead of regression to the mean. The R61 phase must also include PK testing of the product to determine the frequency of daily dosing needed in the biosignature trial. If previous PK studies have been conducted on the product, results of the studies provide the necessary background to inform the dosing needed in the biosignature trial. The R61 phase could also a product bioavailability, pharmacodynamics, safety, and/or toxicity in humans. Projects should incorporate a go no/go decision rule for continuing to the R33 phase based on the robustness of the measure of the biological signature. For each proposed biological signature(s), projects must incorporate a priori definitions of the magnitude and direction of change that will be sufficient to recommend further study in the subsequent R33 phase.

The specific activities and milestones appropriate for the R61 phase will depend on the specific natural product under study and its stage of development. Generally, these activities and milestones for the R61 phase include:

1) pharmacokinetic study to determine the optimal daily dosing needed for the biological signature trial. (Note that if previous pharmacokinetic studies have been conducted on the exact product, this previous data can be used to inform the dosing for the biological signature trial).

2) operational definition and objective measure(s) of the biological signature(s) that will be measured in humans (i.e., the hypothesized mechanism of action), definition of a clinically meaningful change for each measure, and direction of change anticipated;
3) demonstration of adequate impact on the biological signature to provide a basis for future subsequent studies in humans;
4) feasibility data to indicate that an adequate dose of the natural product (defined by biological signature) can be applied in the select human population with adequate safety and tolerability;
5) demonstration of the ability of the investigative team to recruit and retain participants in the R61 trial;
6) NCCIH approved protocol, and data and safety monitoring plan for the planned R33 phase project; and
7) completion of necessary regulatory approvals for proposed R33 clinical studies (e.g., IRB, FDA IND).

Go/No-Go Criteria

In the R61 phase application, investigators are required to describe a set of Go/No-Go Criteria (for detailed instructions please see: Section IV.2 Other Attachments, 1. Milestones and Go/No-Go Criteria ) that will allow for a definitive assessment of whether the R61 phase provides sufficient evidence to support the subsequent replication study that would be conducted during the R33 phase of the grant application. Key evidence in the Go/No-Go Criteria includes:

• Provide adequate pharmacokinetic data to inform dosing in the biological signature study in the R61 phase or provide preliminary data about the pharmacokinetics of the product to be used in the R61/R33 trials.
• Detect a clear effect size in the primary biological signature(s) (mechanistic outcome measure) by the natural product.
• Demonstrate the safety and tolerability of the natural product used in the trial by a set of metrics.
• Demonstrate the ability to recruit and retain subjects in the clinical trial with a pre-planned timeline for reaching the randomization target and estimated drop-out rate.
• Three months prior to the end of the R61 award, submit R33 Study Accrual and Retention Plan, and Data and Safety Monitoring Plan to NCCIH for review and approval.
• Two months prior to the end of the R61 award, submit to NCCIH a R33 Transition Request Application .

While not required, investigators may also propose to evaluate how dose or formulation variations of the natural product may have differential impact on the biological signature(s).

The R33 Phase

Funding for the R33 phase is contingent on successfully meeting the milestones and the Go/No-Go Criteria in the R61 phase, as well as other factors as described in Section VI. Award Administration Information, 1. Award Notices. Milestones accomplishments under the R61 phase will be administratively reviewed by NCCIH staff to determine whether transition to and funding for the R33 will occur.

For transition to an R33, the R33 phase must propose to replicate the impact of the natural product when used by humans on the biological signature(s) demonstrated in the R61 phase and assess whether there is an association between the degree of the impact on the biological signature and functional or clinical outcomes in a patient population. Pilot studies supported by the R33 should not be statistically powered to assess clinical efficacy, but rather should test a hypothesis, replicating the natural product’s effect on the biological signature and inform a decision about whether the natural product warrants further study. Again, a placebo is usually needed to confirm that the replicated changes measured in the biological signature are due to the natural product and not regression to the mean or natural history of the condition. If not determined in the R61 phase or not known, it is strongly encouraged that the R33 study evaluate multiple doses to inform what dose has the greatest impact on the biological signature, as this is critical information needed to plan a multi-site efficacy trial.

In addition to the primary aim of assessing the association between the biological signature and functional or clinical outcomes, secondary aims in the R33 phase may also include the following:
1) determine the optimal dose or formulation of the product for a subsequent trial by assessing dose-response with respect to a functional pharmacodynamic readout of the impact on the biological signature in response to multiple doses of the natural product;
2) further testing of the intervention’s feasibility, safety, and acceptability;
3) combine the natural product with another treatment approach that is known to impact the same biological signature to optimize its impact;
4) optimize the impact of the natural product by studying it in a potentially more responsive target population;
5) demonstrate the study team’s ability to recruit, randomize (if appropriate), retain, collect all assessments and samples, adhere to the study protocol, and report of adverse events; and
7) develop functional biological signature measures and clinical outcome measures feasible for use in larger efficacy and effectiveness trials.

The specific activities appropriate for the R33 phase will depend on the natural product under study, the stage of the study proposed, and available preliminary data on the natural product. The R33 milestones should be clearly aligned with the aims associated with the R33 phase. The milestones should be feasible, well developed, and quantifiable with regard to the specific aims.

Subsequent Studies

The objective of this NCCIH R61/R33 funding opportunity is to improve the knowledge for natural product clinical trials planning. Investigators are encouraged to include relevant stakeholders (e.g., patients, providers, health care systems, etc.) in the planning and execution of exploratory and larger clinical trials. The outcomes of a R61/R33 award could lead to the realization that the product does not warrant further study; additional studies must be completed before proceeding to a full-scale multi-site efficacy trial; or the data generated under this phased award are informative and sufficient to warrant moving ahead with a well-executed multi-site efficacy clinical trial. If warranted by the results of studies conducted, R61/R33 awardees may prepare and submit an application for a subsequent clinical trial when the R33 trial is complete and results have been analyzed.

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

This FOA encourages highly innovative projects, with the recognition that such projects may entail a greater failure rate. NCCIH values this early, efficient, and objective testing of an intervention’s proposed mechanism of action to determine which natural products should or should not be further tested. This FOA uses a phased innovation approach (R61/R33) to manage the risk by requiring a demonstration R61 phase to test a natural product’s bioavailability and pharmacodynamic effects on a biological signature in human participants before moving to the R33 phase of the award to attempt to replicate the effect and measure the association between the biological signature and the clinical outcome changes.

Preliminary Data Requirements.
Applications should be based on a clear scientific premise and compelling rationale, for the proposed study, which may include preliminary data from animal studies that demonstrate biological mechanisms suggesting clinical benefit; alternatively, the empirical basis may be based on previous human clinical studies. Regardless, there must be a strong scientific premise and rationale as to why the specific natural product proposed is likely to benefit the clinical condition or indication under study.

NCCIH Priorities for Developing and Pilot-testing Natural Products
As NCCIH’s clinical research portfolio matures, NCCIH has identified certain areas of high program priority. Particular focus is on management of conditions for which natural products are used by the public and where there is evidence of postulated mechanism of action. For this FOA, NCCIH considers the following 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-brain interactions. 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 also encourages applications to this FOA that address the above priorities as well as health disparities, symptom management in patients with HIV/AIDS, and/or utilize special populations such as older adults, underrepresented minorities, children, 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.

ODS Priorities

The Office of Dietary Supplements (ODS) is interested in supporting early phase clinical trials of the effects of dietary supplements (or their ingredients or bioactive metabolites) on objective outcomes relevant to health maintenance (e.g., measures relevant to metabolic, cognitive, immune, anti-inflammatory, and/or aging processes) or resilience (the capacity to withstand and successfully adapt to change, disturbance, stress, or other challenges) where there is rigorous evidence that a specific chemical component or components are required for the proposed bioactivity(ies). Relevant biomarkers of resilience in the context of this FOA might include (but are not limited to) well validated measures of metabolic resilience such as HbA1c or effects on specific cognitive or immune measures of sleep disruption, or other biological or psychosocial stressors. Research on effects of treatment is inconsistent with the ODS mandate and cannot be supported by ODS unless the data to be collected are demonstrably relevant to health maintenance or resilience.

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:

• Applications that do not propose in the R33 phase to replicate the impact of the natural product on the biological signature(s) demonstrated in the R61 phase and assess whether there is an association between the degree of the impact on the biological signature and functional or clinical outcomes in a patient population.
• Clinical trials designed solely to estimate intervention effect size or power calculations for a future trial.
• Applications that do not propose to give the natural product to human participants and measure the impact on a biological signature(s) or mechanisms of action.
• Trials that propose to test natural products for the treatment or prevention of cancer.

Applications that propose the following will be considered non-compliant and will not be reviewed:

• Applications that propose only the R61 phase or only the R33 phase.
• Applications that do not propose giving the natural product to human participants in both the R61 and R33 phases.
• Phase III trials of efficacy (such studies should use the Natural Product UG3/UH3 FOA, PAR-20-215 ).
• 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).

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 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 not 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.
Telephone: 301-594-34-56
Email: schmidma@mail.nih.gov

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

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.

Other Attachments:

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

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

The milestone plan should describe the key milestones that need to be met for each phase of the application (R61 and R33) to ensure its success; the processes that will be used to reach the milestones; and a timetable identifying when each of these key milestones will be met.

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

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

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

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

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

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

b. Adequate preliminary data (collected through prior studies, other concurrent studies, or prior to starting the R61 phase biological signature study) to justify the proposed replication study in the R33 phase. Preliminary data should include short-term pharmacokinetic data and bioavailability (if necessary) of the proposed natural product to determine dosing for the R61 biological signature trial. If the pharmacokinetic data is to be collected in the R61 phase, it should be collected prior to starting the R61 biological signature trial.

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

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

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 Budget

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.

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

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

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

The following criteria should be addressed:

Significance : The significance of the proposed clinical trial and importance of the question should be clearly stated. The application should provide rigorous preclinical or clinical preliminary data to support the study rationale. 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. The application should describe how the proposed project will advance knowledge to determine if the natural product can reproducibly modify a biological signature, so that future clinical trials can determine if the biological signature is a mediator of clinical benefit. It is particularly important that there be discussion of how the results of the proposed trial (positive or negative) will guide decisions about whether a subsequent study is needed or justified, and/or provide evidence that additional studies must be completed before proceeding to a full-scale multi-site efficacy trial. A discussion of the costs and benefits of the study should be included for evaluation of the trial's significance. The applicant should provide a precise response to the following two questions: 1) Will the result, whether positive or negative, be informative and provide a definitive test of the hypothesis? 2) Will the results be informative about the potential role of the biological signature in the clinical condition?

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

Approach: The research approach section should include a description of the supporting data (including strengths and weaknesses of the published literature), clinical trial experience, the experimental approach, and a brief summary of the milestone and go/no-go criteria plan referring to the required attachments as appropriate.

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

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

• A summary of the Milestones and Go/No-Go Criteria Plan (see Other Attachments).
• A rationale of why the study population is the most appropriate group to answer the question, and how or if results will generalize to a broader population.
• A rationale for the research hypothesis(es), methods of randomization if applicable, primary and secondary outcome measures, intervention(s), measurement of the replicable biological signature of the natural product, and participant follow-up procedures.
• A rationale, including supporting data for the natural product and matching placebo (if applicable) to be tested including: name and ingredients of the product, rationale for the supplier, proposed methods for product characterization and standardization, and rationale for selection of and specified percentages or levels of marker compounds, if applicable. See the NCCIH Policy on Natural Product Integrity for more information (http://NCCIH.nih.gov/research/policies/naturalproduct.htm).
• A summary of the necessary agreements for the use of the natural product and any matching placebo. Note that all necessary agreements for the use of the natural product in the study, including clinical research agreements and licensing agreements must be executed prior to grant award. A timeline should be included in the application showing activities with third parties such as 1) executing necessary agreements, 2) providing natural product and matching placebo, and 3) permission to reference an open IND drug master file (if available). This should also be referenced to the Milestones and Go/No-Go Criteria Plan (see Other Attachments).
• A justification for all assessments including PK study marker compounds (if applicable), clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the primary and secondary research questions. Use of patient reported outcomes as well as non-traditional data collection approaches (e.g., telephone, mobile devices, or web-based systems) need to be described. A description of the laboratory evaluations (as appropriate) and plans to implement and monitor Good Clinical Practices (GCP), Good Laboratory Practices (GLP) and Good Manufacturing Practices (GMP), as appropriate should be provided.
• A description of the future clinical trial beyond the R61/R33: A concise summary of the subsequent anticipated future trial should be provided including the study design.
• Discussion of the challenges expected in implementing the research and how they will be addressed.

Letters of Support:
Letters of support from clinicians or clinical department chairs whose support is necessary to the successful conduct of the trial should be provided. Applicants are also encouraged to include documentation of the commitment of any subcontractors and consultants, as well as service agreements for personnel or facilities. Letters of commitment must be co-signed by the business official of the collaborating center. In addition, a letter of support should document that sufficient supply of the natural product will be available for testing at the time of award, including expiration date; that the supplier will meet and provide details regarding Chemistry Manufacturing and Controls specifications; and the supplier will provide the data necessary for the investigator to adhere to NIH and FDA policies. Documentation should include a letter of agreement from the 3rd party supplying the natural product.

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

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

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.

When involving human subjects research, clinical research, and/or NIH-definedclinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

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

Section 2 - Study Population Characteristics

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

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

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan
In addition to the NIH application requirements for a data and safety monitoring for clinical trials, NCCIH requires independent monitoring for research involving human subjects. Applicants should refer to NIH’s policy on data and safety monitoring (https://grants.nih.gov/grants/guide/notice-files/not-od-00-038.html), as well as the NCCIH Guidelines for Data and Safety Monitoring (http://nccih.nih.gov/grants/policies/data-safety-monitoring).

Section 4 - Protocol Synopsis

4.6. 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:
The proposed clinical trial must use a natural product (such as botanical, herbal, dietary supplement, probiotic, vitamin or mineral) for this FOA. The attachment in this section should describe correspondence from the FDA indicating whether the proposed study will require an IND/IDE. Investigators should describe the process that will be used for attaining all necessary FDA or other applicable regulatory agency approvals necessary to the conduct the trial; and associated timeline to complete these approvals. For trials using an FDA regulated product that require an IND/IDE application, the grant application must include evidence regarding the outcome of a pre-IND meeting, or other evidence of communication with FDA. If the protocol is conducted under a non-US regulatory agency the applicant should submit a plan for attaining those regulatory approvals. If the protocol is exempt from an IND/IDE, a copy of the exemption letter from the FDA should be provided. The FDA has provided guidance indicating that when substances that are Generally Recognized as Safe (GRAS) are used in a clinical trial to evaluate the product's ability to diagnose, cure, mitigate, treat, or prevent disease it may require an IND under part 312 (https://www.fda.gov/media/79386/download). If an IND is required by the FDA for the proposed R61 or R33 trials, the IND must be submitted to the FDA with no clinical-hold imposed by the FDA prior to application being funded.

4.7 Dissemination Plan
Describe how the investigators will facilitate and support timely publication and dissemination of results as appropriate and consistent with achieving the goals of the program.

Section 5 - Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-related Attachments
The following attachments must be included as a part of the application. Attachments permit expansion of certain elements that cannot be appropriately described in the Research Strategy. All attachments listed below must be provided or the application will not be peer reviewed.

1. Clinical Trial Experience
Applicants must provide a detailed table listing the characteristics of trials that demonstrate Key Personnel experience in trial coordination in the last 5 years. The table must be provided as an attachment called "Clinical Trial Experience.pdf" and must not exceed 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.

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 the FDA prior to any award. The details of the IND status of the natural product should be provided in the attachment included in the study record for section 4.6. If the FDA has granted a waiver for either trial proposed in the application (R61 or R33 phase), then the applicant can provide this letter as part of the response to item 4.6 in the study record. If the protocol is conducted under a non-US regulatory agency, then equivalent determinations and documentation must be provided to NCCIH prior to a grant award. Funding will not be made until the necessary regulatory approvals are in place for the conduct of the proposed clinical trial. If the product to be studied is on the Drug Enforcement Agency (DEA) controlled substance list, the applicant must describe the DEA license and registrations necessary to complete the proposed trials in the R61 and R33 phases. Again, no awards will be made until all necessary DEA licenses and registrations are in place.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

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

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile 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 {IC} Referral Office by email at SchmidMa@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

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

• 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.

For this particular announcement, note the following:

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

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 is 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 it clear why the proposed exploratory trial is essential to inform the design and implementation of subsequent steps in the evaluation of the natural product? 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 the natural product's impact on a biological signature, 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 the PD/PI roles and responsibilities? How well does the application provide evidence of necessary expertise about the natural product and study population? How strong is the evidence provided by the investigators to ensure that the investigators will employ the appropriate personnel to recruit subjects and design/implement the clinical protocol? Does the investigative team have a track record of conducting, completing, and publishing the results of clinical trials? How strong is the evidence provided by the investigators to 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 early phase 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 exploratory trial have the potential to advance the field (e.g., by breaking ground for future trials in this area) even if (a) the proposed study design, methods, and intervention are less innovative, and/or (b) the results of the trial indicate that further clinical development of the intervention is 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?

For this specific FOA:
How strong is the application's description that the underlying hypothesized biological signature is appropriate and relevant, and will be rigorously tested by giving the product to humans and assessing the impact on the biological signature? Is the need for the R61 phase well justified?

Does the R33 phase include sound methodology for (a) replicating and extending the initial impact of giving the natural product to humans on the hypothesized biological signature from the R61 phase, and (b) evaluating associations between biological signature and subsequent clinical or functional outcomes? If needed, will the proposed PK study measure an appropriate marker compound, constituent, or metabolite that is scientifically justified as the compound that may have an impact on the biological signature and will the PK study inform the frequency of daily dosing of the product? If optimization studies are described, will the methods proposed allow investigators to design a future study with a more impactful intervention by selecting the dose, formulation, patient population, or combination treatment that has the greatest effect on the biological signature while maintaining safety?

How well does the applicant describe how the proposed study relates to a larger strategy for research of this natural product and will it provide pilot and feasibility data needed to advance that strategy? Does the application demonstrate the feasibility of methods for developing tools for data management and study oversight, finalizing protocol documents and manuals, as well as addressing appropriate regulatory requirements (FDA, IRB, and DEA)? How well justified are the outcome measures, dose/duration of study, appropriateness of inclusion/exclusion criteria, and sample size for the early phase study?

What strengths and weaknesses are there in the study design? How strong is the evidence for equipoise? How well does the study record 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?

Is there a clear strategy for tracking recruitment and facilitating retention? Will sufficient and appropriate data be collected to inform a decision whether further clinical testing is warranted? Are likely problems anticipated?

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?

For this specific FOA:
Does the information provided in the application give reasonable assurance that the target sample size can be enrolled in the timeframe proposed? Does the application document the availability of the requisite eligible subject pool in proposed clinical center(s)? Is there documentation of the commitment of any subcontractors and consultants, as well as service agreements for personnel and facilities?

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

Milestones

R61 Milestones:Are quantitative criteria pre-specified and rigorously defined to assess milestone achievement, Go/No-go criteria, and operational feasibility relevant to advancing from the R61 to the R33 phase? Are R61 milestones feasible, well developed and quantifiable and consistent with the specific aims? Specifically, will the milestones aid investigators and NCCIH Program Officials in determining whether the project succeeded in: (a) demonstrating that when used by humans the natural product alters thebiological signatureor mechanism (thus providing an initial proof of principle), (b) demonstrating human bioavailability of the natural product and/or its active metabolites, and (c) providing preliminary evidence that the intervention can be applied in a clinical population with adequate acceptability and tolerability to patients?How well developed and quantifiable are the milestones and Go/No-go criteria for continuing to the R33 phase if the measure of biological signature is sufficiently robust? Does the application provide sufficient justification for the specificconditions under which they would not proceed to the R33 phase? Have the investigators adequately described anticipated problems ?

R33 Milestones:Are appropriate, evaluative milestones clearly defined for the aims associated with the R33 phase? Are R33 milestones feasible, well developed, and quantifiable with regard to the specific aims? Are the plans for sample size and timely recruitment of subjects feasible? Is there a clear strategy for tracking recruitment and facilitating retention? Will sufficient and appropriate data be collected in the R33 phase to inform a decision whether further clinical testing is warranted?

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)?

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

Not Applicable.

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.

Not Applicable

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

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

Wendy Weber, ND. Ph.D., MPH
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-402-1272
Email: weberwj@mail.nih.gov

Barbara C. Sorkin, Ph.D.
Office of Dietary Supplements (ODS)
Telephone: 301-275-7420
Email: sorkinb@mail.nih.gov

Martina Schmidt, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3456
Email: schmidma@mail.nih.gov

Shelley Carow
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3788
Email: carows@mail.nih.gov

Section VIII. Other Information

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.