Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

Office of Dietary Supplements (ODS)

National Center for Complementary and Integrative Health (NCCIH)

National Institute on Drug Abuse (NIDA) Participation added April 3, 2024 (NOT-DA-24-020)

Funding Opportunity Title
Botanical Dietary Supplements Translational Research Teams (RM1 Clinical Trial Required)
Activity Code

RM1 Research Project with Complex Structure

Announcement Type
New
Related Notices

    See Notices of Special Interest associated with this funding opportunity

  • April 12, 2024 - Notice of Change to Foreign Component Eligibility in RFA-OD-24-014. See Notice NOT-AT-24-040.
  • April 3, 2024 - Notice of NIDA Participation in RFA-OD-24-014, "Botanical Dietary Supplements Translational Research Teams (RM1 Clinical Trial Required)". See Notice NOT-DA-24-020
  • March 26, 2024 - Notice of NCCIH Technical Assistance Webinar for RFA-OD-24-014 "Botanical Dietary Supplements Translational Research Teams (RM1 Clinical Trial Required)". See Notice NOT-AT-24-039
  • August 31, 2022- Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198.
  • August 5, 2022- Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189.
Funding Opportunity Number (FON)
RFA-OD-24-014
Companion Funding Opportunity
None
Number of Applications

See Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s)
93.321, 93.213, 93.279
Funding Opportunity Purpose

The purpose of this Notice of Funding Opportunity (NOFO) is to support trans-disciplinary, translational research on chemically complex botanical products or natural products traditionally used as dietary components, to inform future clinical trials of the efficacy of exceptionally promising dietary supplements for improving resilience. Clinical efficacy trials of such products are often challenged by gaps in understanding that critically affect the design and/or interpretation of a clinical trial. For example, the molecular mechanism(s) of action of a botanical dietary supplement might not be well established and thus the optimal product chemistry, for a given health outcome may not be known; in the absence of such information to guide product specifications, stability testing and assessments of bioavailability and absorption kinetics a clinical trial might not provide a good test of the effect of that botanical on the health outcome(s) assessed. Similarly, the best outcome measure for a trial of a product reputed to have many different health effects, or to have effects where many different quantitative outcomes might be relevant might benefit from deeper understanding of the biological structure(s) and/or system(s) affected by the product, and the health outcomes expected from modulating those targets. Interpretation of a clinical trial of an ingested product will benefit from the availability of methods to assess bioavailability of active constituents of the product or target engagement by those constituents. Clinical trial design will benefit from an understanding of the ways in which trial participant characteristics, whether genetics, background diet, epigenomics, gut microbiota, or health history, for example, may influence the effect of the intervention tested. The forgoing are examples of the types of knowledge gaps of interest for this NOFO.

The overarching goal of this NOFO is to address those knowledge gaps most critical to the optimal design or interpretation of a future randomized clinical trial (RCT). Knowledge gaps to be addressed may include, but are not limited to those cited above, and should depend on the product and outcomes to be studied and the extent and strength of prior, relevant evidence. The RM1 is intended to support research that requires the capabilities of multiple laboratories working together as equal contributors on a single over-arching set of integrated specific aims.  Projects proposed in response to this NOFO, therefore, must require dynamic, synergistic interactions among a range of experts to address the proposed specific aims while ensuring rigor in all aspects of this research. These trans-disciplinary projects must be supported by  multi-PD/PI (Program Director/Principal Investigator) teams. Plans for enhancing workforce and institutional capacity to conduct future rigorous, trans-disciplinary research on chemically complex natural products must be built into the research plans. Achievement of the RM1 specific aims is expected to provide a strong foundation for future trans-disciplinary research on botanical natural products and for a future highly informative clinical efficacy trial of the effects on resilience of a chemically complex natural product.

This NOFO is part of the Consortium Advancing Research on Botanicals and Other Natural Products (CARBON) Program. Other elements of this Consortium include RFA-AT-24-008, Leveraging Data at Scale to Understand Natural Product Impacts on Whole Person Health and RFA-AT-24-007, Limited Competition: Research Resource for Natural Product Nuclear Magnetic Resonance Data.

Key Dates

Posted Date
March 14, 2024
Open Date (Earliest Submission Date)
June 08, 2024
Letter of Intent Due Date(s)

June 7, 2024

Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed Scientific Merit Review Advisory Council Review Earliest Start Date
July 08, 2024 Not Applicable Not Applicable October 2024 January 2025 July 2025

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

Expiration Date
July 09, 2024
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

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

Conformance to all requirements (both in the How to Apply - Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

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

  1. Use the NIH ASSIST system to prepare, submit and track your application online.
  2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background
 

Plants, plant-derived products, and other dietary supplement-relevant natural products are widely consumed worldwide and in the United States for basic nutrition, to promote health and well-being, and for medicinal purposes. The use of combination therapies, usually in the form of chemically complex natural product mixtures, is a mainstay of traditional healing practices. More recently, combination therapies have become the standard of care in 21st century biomedical treatments for cancer, malaria, HIV, and COVID-19, among others. A growing number of rigorous reports document the contributions of multiple chemical constituents via multiple molecular mechanisms to the in vivo effects of botanical products. Despite this evidence and their prevalent use, many of these products have not been rigorously evaluated. Replicable clinical translation of such chemically complex botanical dietary supplements remains challenging and has not been a major focus of NIH-supported research.
Since 1999 the National Institutes of Health (NIH) Office of Dietary Supplements (ODS) and National Center for Complementary and Integrative Health (NCCIH) along with other NIH components have supported the Consortium Advancing Research on Botanicals and Other Natural Products (CARBON). The Centers and pilot projects of the current CARBON have addressed gaps in knowledge of the products studied and their causal, molecular mechanisms of action to support the conduct and design of future highly informative clinical trials. The current CARBON has also developed a methodological pipeline using untargeted methods to generate testable hypotheses on the molecular mechanisms underlying biological effects of chemically complex natural products. Finally, the program has generated methods and resources to support utilization of and sustainable access to relevant structural and biological activity data from natural products.

The NIH CARBON Program is one of the few to focus on the effects of chemically complex natural products on human resilience. Resilience, despite being a critical focus for individual and population health and health economics, and a research priority for both NCCIH and ODS, has also not been a major focus of NIH-supported research. An NIH Expert Panel, in 2022 noted that the CARBON Program, of which awards from this notice of funding opportunity (NOFO) will be a part, fills a critical research gap.

This NOFO is being released in conjunction with NOFOs for two additional elements of the CARBON Program, RFA-AT-24-008, Leveraging Data at Scale to Understand Natural Product Impacts on Whole Person Health (R01), and RFA-AT-24-007, Limited Competition: Research Resource for Natural Product Nuclear Magnetic Resonance Data (R24).

Objectives

Projects supported through this NOFO will require trans-disciplinary teams to conduct translational research on chemically complex natural products. The proposed project objective must be to fill in the most critical knowledge gaps for the optimal design and interpretation of a future clinical trial assessing the efficacy of the product(s) to improve resilience to any of a range of stressors, as assessed using experimentally optimized, objective, quantitative outcome measures. The applicant must justify the specific aims based on the existing rigorous and convergent evidence for the proposed product(s)-outcome(s) pairing from at least two methodologically distinct lines of experimentation, based on different scientific principles (e.g.,epidemiology or a microphysiological system and an early phase clinical trial), and the importance of the knowledge to be generated for the design and interpretation of a future clinical trial.

  Eligible applications for RM1 multi-PD/PI team projects must include the following information:

  • Rigorous evidence, whether published in the peer-reviewed literature or provided in preliminary data, of a statistically and potentially clinically significant and reproducible effect on quantitative, objective outcomes relevant to human biological or cognitive/behavioral resilience,
  • Rigorous evidence that the presence of one or more specific components (or precursors thereof) in the intervention is necessary for a relevant proximate biological effect, health outcome, or both. This evidence should be for a product that is substantially similar to the intervention and for outcomes that assess the same biological processes as those described in the supporting data. Supporting data must include at least two distinct, rigorous lines of evidence both pointing to similar benefits, e.g., from both mechanistic animal data and prior clinical trials.
  • Each application must include Information supporting the applicants’ ability to meaningfully screen for additional chemical components of the product(s) that may contribute to or otherwise modulate the effect(s) of the known biologically active constituent(s) to be studied, or include data showing the results of such a screening.
  • Each application must include an approach to screen for additional targets of the known bioactive constituents of the products, especially any targets that might affect safety or other health outcomes proposed for study.

To support the achievement of the NOFO objectives:

  • Collaborative program teams of three to six (multiple) PD/PIs must propose to accomplish goals that require considerable synergy and managed team interactions. Project goals must demonstrably benefit from real time, trans-disciplinary exchange and collaboration. They must require a team approach involving interactive contributions from distinct disciplines and/or theoretical points of view. Specific aims achievable with a collection of individual efforts or parallel projects, as opposed to true, dynamically interactive collaborations, will not be accepted for this NOFO. The participating research teams may all be within a single institution or at multiple institutions. 
  • Each PD/PI team must include the requisite phytochemical or other chemical expertise and facilities to ensure product quality control, support product optimization, and develop new analytical methods as needed for both quality control and for assessment of bioavailability, including in different tissues. Project teams must also include expertise in other specialties critical to the proposed research, e.g., in the biological or behavioral effects of interest, human and or other animal nutrition, natural product clinical trials and clinical use of the proposed product(s).
  • Each project should provide an environment in which the career development of a diverse group of investigators, including students, post-doctoral researchers and non-tenured faculty (or equivalents) are supported, including through mentorship in the rigorous and ethical conduct of trans-disciplinary research on health effects of chemically complex natural products.
  • Each application must include an NIH-defined clinical trial, but applications proposing clinical efficacy or effectiveness trials will be considered ineligible and returned without review. Outcomes proposed as the focus for a future clinical trial or included as supporting evidence for the proposal must be objective, quantitative, and relevant to resilience, defined by the Trans-NIH Resilience Working Group as the ability to resist, adapt to, recover, or grow from a challenge or stressor. Outcomes included in the required, NIH-defined clinical trial must be critical to inform a future resilience efficacy trial. These might include, but are not limited to bioavailability or pharmacokinetics of biologically active compounds from different formulations or doses of a product, palatability of different product formulations, development and validation of assays of target engagement, outcomes designed to refine understanding of the causal, molecular mechanism(s) of action, etc. 
  • Applications where either the supporting evidence or the proposed research (or both) use patient-reported outcomes as the or a primary outcome will not be accepted for this NOFO.

Products of interest:

For the purposes of this NOFO, products of interest are limited to terrestrial plants, algae or macroscopic fungi (and products derived from them). Applications that include experiments using purified entities found in, or synthetic compounds derived from natural product sources (other than as experimental controls) will be considered only where such research is necessary to elucidate the mechanisms of action or activities of the chemically complex product. This NOFO supports research on traditional herbal medicines as well as on foods of plant origin that are proposed to contain bioactive components beyond basic nutrients. While optimization of product formulation is appropriate for this NOFO, 1) to justify the level of focus implied by the team research approach there must be rigorous data from at least two distinct scientific approaches (e.g., in vitro and in vivo) identifying at least one constituent of the proposed product as required for the proposed outcome(s), and 2) applications focused on methods to improve large-scale production of individual natural products or their derivatives, or on tools to synthetically modify natural products to improve bioavailability or potency, will be considered nonresponsive and will not be reviewed. Projects with a primary focus on highly purified individual compounds, or on natural products that have been developed as drugs will be considered ineligible and returned without review.

Product doses or concentrations proposed for testing must be justified in the context of the documented range(s) of traditional or commercially recommended levels to the extent this information is available and the concentrations/doses are compatible with vertebrate animal well-being and/or clinical trial participant safety.

Applications must demonstrate the ability to obtain or generate the proposed products, to ensure that they comply with NCCIH’s Natural Product Integrity Policy, and to detect compounds necessary for the biological activity(ies) of interest (or the metabolites of such compounds) in dosage forms and relevant body fluids and tissues.

Application required elements

The focus of these awards is on addressing the most critical gaps in the evidence and methodological base for future efficacy RCT of botanical or other natural products relevant to dietary supplements. Dietary supplements are, by definition, ingested. Therefore, applications in which the focus is not on effects of oral intake on resilience will be considered nonresponsive to the NOFO and withdrawn without review.

The Research Strategy section of each application, as described in Section IV.?, must include two tables:

1) A table identifying the contributions expected from each PD/PI toward accomplishing each specific aim. For a truly integrated collaborative project, it is expected that most or all of the scientific aims will require substantial contributions from more than one PD/PI. This table will aid reviewers in assessing the degree of integration and collaboration, and the availability of appropriate intellectual and technical expertise for each aim.

2) A table that identifies critical milestones and performance criteria, a timeline for completion, and whether critical milestones depend on the completion of antecedent milestones.

Applicants must plan, and applications must allocate part of their budget for attending virtual and in-person meetings associated with activities of the CARBON Program, including annual meetings of the full consortium. Participation of early career investigators, including post-doctoral fellows and students in the annual CARBON meetings is strongly encouraged.

Features of successful RM1 applications include:

  • Each PD/PI is committed to team science and willing to devote a major part of their research effort to the team project.
  • Achieving the goal(s) requires a team approach.
  • Each biological question posed requires a cohesive team with an integrated approach.
  • A team management structure is developed for achieving program goals.

Examples of areas of research interest

With the provision that all proposed RM1 activities must contribute to providing critical information for the design of a future highly informative clinical trial, the proposed activities might include among the specific aims, but are not restricted to:

  • For a highly promising botanical for immune system resilience to age-related senescence, a mechanistic clinical trial or other animal model study to test the association of engagement of a proposed intervention target with biological or behavioral outcomes,
  • Each application must include a proposed method for the identification of components (in addition to those previously known) in the intervention that significantly modify the activity profile of the product(s). This may be omitted if such studies have been previously conducted. In the latter case the resulting data should be provided in the Research Strategy section of the application, or the relevant peer-reviewed publication summarized and referenced.
  • Investigation of how inter-component interactions between bioactive compounds, or bioactive and other compounds within a product, and/or between a product and other environmental exposures including diet modulate molecular and cellular mechanism(s) required to generate clinically relevant biological effects, including pharmacokinetics and pharmacodynamics.
  • Elucidation of the role in modulating natural product effects of individual differences in genetics, epigenetics (including microbiota), and/or of historical and environmental contexts, including timing of exposures and behaviors such as sleep and physical activity.
  • Development and validation of methods to elucidate dynamic, reciprocal interactions between the gut microbiota and metabolism of chemically complex ingested plant natural products and their implications for modulating or mediating health effects of the products.
  • Development of in situ detection approaches for product active constituents or their active metabolites following ingestion, and/or of target engagement, and assessment of correlation of these measures with the biological and/or cognitive/behavioral outcomes of interest or relevant upstream pathways for these outcomes.
  • Adaptive clinical trials to optimize product formulation and/or mode/timing of administration for bioavailability of the active constituents or production of the active metabolite(s), or for optimal target engagement or optimal consumer acceptability.

The following examples, or others like them, would be considered non-responsive and will be administratively withdrawn without review.  

  • Projects lacking evidence for a reproducible effect(s) relevant to human resilience, with the effect(s) consistent across at least two separate and scientifically distinct lines of evidence, e.g., from epidemiology, cell-based or preclinical in vivo models and prior clinical research.
  • Research where the focus is solely on treatment rather than on outcomes relevant to risk reduction, health maintenance or resilience. Some examples of responsive measures include bone density or bone structural integrity, cortisol levels and their variation over the circadian cycle, HbA1c, aspects of immune function, or actigraphic measurements.
  • Applications in which the Specific Aims do not focus on quantitative, objective outcomes relevant to human resilience.
  • Projects without a proposed, NIH-defined clinical trial.
  • Projects proposing clinical trials of efficacy or effectiveness.This includes trials aimed at estimating an effect size. Please see https://www.nccih.nih.gov/grants/pilot-studies-common-uses-and-misuses for further information on appropriate aims for pilot clinical trials.
  • Applications proposing to conduct clinical research at a non-domestic component of a US institution will be considered non-responsive. Clinical research responsive to this NOFO must be conducted at domestic components of domestic institutions.
  • Applications proposing to focus on parenteral or topical administration of interventions are generally beyond the scope of this NOFO, as dietary supplements are intended to be orally ingested and swallowed. Applications proposing parenteral or topical administration may be considered responsive only where the outcome is demonstrably applicable to understanding the mechanism of action of orally ingested product.
  • Projects lacking rigorous data identifying one or more components of the botanical product or their metabolites as bioavailable and required for an in vivo bioactivity. Rigorous data would include, for example data from appropriately powered, blinded experiments showing that the same extract that shows activity when the proposed active components are present loses activity when only those components are removed, while a similar process (e.g., solvent exposure and incubation temperatures) leaves activity of the control (more complete) extract essentially unaffected. Similarly, data for bioavailability should show clearly that the compound detected in vivo originates in the ingested test product and is detected at levels in vivo that correspond to those at which activity is reported in model systems or prior clinical research.
  • Projects lacking a proposed unbiased (i.e., non-targeted) approach to assess the potential presence of additional bioactives or in vivo targets beyond those previously described, except where data from such an approach are previously reported and/or included as preliminary data.
  • Projects where the focus is a small number of largely purified phytochemicals. Minimally processed botanicals are within scope.
  • Projects focused on classical drug development.
  • Research on bacterial or yeast fermentation products as the delivered intervention. Aims focused on bioactives generated within a human or other animal by its microbiota would be in scope.
  • Research focused on the development of methods to improve large scale production of individual botanicals or their derivatives, or on synthetic approaches to modify botanicals or their components to improve bioavailability or potency.

Each application must include:

  • A multi-PD/PI leadership (MPI) plan as an attachment
  • A detailed Team Management Plan must be included in the Research Strategy section. In addition to the required MPI plan, applications must develop and include a comprehensive team management plan that addresses the following:
    • Planned team composition and organizational structure
    • Plans for leadership sharing, expected contributions, and how decision-making responsibility will be distributed.Plans for ongoing resource allocation
    • Plans for support of professional development
    • Plans for conflict resolution 

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

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

Section II. Award Information

Funding Instrument

Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed
New

The OER Glossary and the How to Apply - Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Clinical Trial?

Required: Only accepting applications that propose clinical trial(s).

Funds Available and Anticipated Number of Awards

ODS and partner components intend to commit $3 million total costs per fiscal year to fund two awards.

Award Budget

Application budgets are limited to up to $1.5 million in Total Costs per year, including consortium F&A, but need to reflect the actual needs of the proposed project.

Award Project Period

The scope of the proposed project should determine the project period.  The maximum project period is 5 years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

  • Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
  • Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

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

Local Governments

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

Federal Governments

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

Other

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

Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed. 

Required Registrations

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply - Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information

  • System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
    • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
    • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
  • eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
  • Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

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

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. 

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

The application is required to be submitted as a multiple PD/PI application, with three to six PDs/PIs. All PDs/PIs must have an appointment at a domestic institution. Scientists employed solely by foreign institutions may not serve as one of the PDs/PIs of the multiple PD/PI team, although they may be included in the application as collaborators/co-investigators, consultants, or other significant contributors. See the multiple PD/PI Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide, and the Grant Policy Statement on Multiple Principal Investigators. Any eligible scientists with the interest and ability to develop a team science program to address an important research question are welcome to apply. Participation of early career investigators as part of the multiple PD/PI team as appropriate is encouraged. Note that early-stage investigators (ESIs) and new investigators who participate as a PD/PI will lose their ESI or new investigator status for future NIH applications. 

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

Letter of Intent

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

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

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

The letter of intent should be sent to:

Barbara C. Sorkin, Ph.D. Co-Director NIH CARBON Program
Email: sorkinb@mail.nih.gov

Page Limitations

All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed, along with the following page limitations for the two required components of the Research Strategy:

SectionPage limit
Research Program30
Team Management Plan3
Instructions for Application Submission

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R Budget

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

CARBON Annual Meeting Costs:

  • Applications must allocate part of their budget for attending virtual and in-person meetings associated with activities of the CARBON Program, including annual meetings of the full consortium.

Scientific Project Manager:

  • Inclusion of a scientific project manager or coordinator as a Senior/Key Person with adequate authority is recommended.

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific Aims 

Explain why achievement of the Specific Aims would be expected to be critical for the optimal design or interpretation of a future clinical trial of the effect(s) of oral administration of the natural product(s) proposed for study. It will usually be helpful to describe, in general terms, the future clinical trial the design and/or interpretation of which this application is intended to inform. Provide the rationale for prioritizing the knowledge gaps selected as foci for the application. Explain how achievement of the Specific Aims is expected to influence specific parameters in the design of a future clinical trial protocol, and the rationale for prioritizing the proposed research objectives over other potentially influential variables. Explain how the new knowledge generated by achievement of the proposed Specific Aims is expected to contribute to learning important new information from the envisioned clinical trial, regardless whether the trial rejects the null hypothesis, and discuss strategies to address or mitigate remaining knowledge gaps that may pose challenges to the design and/or interpretation of a future clinical trial. Describe the importance of the target clinical trial for public health and/or for providing new insights into human biology.

Research Strategy:

The Research Strategy must consist of the following two subsections, uploaded as a single pdf attachment with two major section headings:

A. Research Program

B. Team Management Plan

A. Research Program:

The Research Program section should thoroughly describe the underlying premise and scientific foundation of the project, experimental rationale, approaches, and steps taken to assure scientific rigor, with attention to the reasons a team-science approach is required.

This must include the rationale for the choice of natural product(s) and outcome(s) proposed. The rationale may be based on prevalence of use and strong evidence for human benefits or adverse effects (including food or drug interactions), or other issues that justify prioritizing the selected product(s)-outcome pair for substantial investment towards the future clinical trial envisioned. The proposed product-effect pairing should make sense in the biological, ecological and evolutionary contexts.

The applicant must explain how achieving the proposed Specific Aims will significantly and critically enhance design of a future, highly informative clinical trial of the product (or an optimized form of it), i.e., a trial expected to rigorously inform decisions about further research on, or use of the product, whether or not the trial outcome rejects the null hypothesis.

In describing the strengths and weaknesses of prior data cited in support of the application, applicants must consider and describe similarities and differences between the products and outcomes studied in the cited data and those proposed in the current application, the extent to which product characterization was reported for supporting data, sample sizes, extent to which blinding/masking or other approaches to limit placebo or nocebo effects or the effects of bias were described in prior reports, relevance of model systems used in those studies to the human outcome of interest, and the extent to which data are consistent between different publications, and between different models or research approaches. Applicants must indicate whether they or others have analyzed the supporting data for evidence of publication bias; if such analyses have been performed, the results should be described.

Applications must describe plans and capacity for thorough characterization of products to be used and for ensuring throughout the course of the project that there are sufficient supplies of product(s) meeting study specifications for the clinical trial and for all other research aims.

Plans for assessing the presence of additional product constituents that may modulate biological activity must be included in the Research Strategy unless such studies have been previously published and are cited in the application, or are shown in supporting data. As appropriate based on available data, plans for optimizing the products for clinical testing (including chemistry and product formulation) or for advancing understanding of molecular level mechanism(s) of action should be included in the Research Strategy. Plans for ensuring compliance of all natural products and other key biological and chemical reagents with both the NIH’s policy on Rigor and Reproducibility (https://grants.nih.gov/policy/reproducibility/guidance.htm) and with the Natural Product Integrity Policy of the NIH National Center for Complementary and Integrative Health (https://www.nccih.nih.gov/research/nccih-policy-natural-product-integrity) must be included in the section on Authentication of Key Biological and/or Chemical Resources (see below).

Model systems proposed, whether in silico, in vitro or in vivo, should be  well-justified as appropriate for the research question addressed. Known and likely disparities between the model system(s) and human biology must be described, as well as any aims intended to compensate for or otherwise address those differences in order to enhance translational relevance of the results.

Applications must describe the rationales for the choice of the product dose/concentration(s) to be studied, as well as timing of exposures and preparations or formulations. Relationship between dose/concentration to be studied and traditional usage should be described where applicable. Product doses/concentrations to be studied should include this range unless a strong justification for not doing so is provided.

.Applications must describe critical research milestones and any innovative aspects of the approach, including those arising from collaborative interactions.

Two tables are required and must be included within the page limit for the Research Program:

1) A table, organized by specific aims, that identifies the contributions expected from each PD/PI toward accomplishing that aim. For a truly integrated collaborative project, it is expected that most or all of the scientific aims will require substantial contributions from more than one PD/PI. This table will aid reviewers in assessing the degree of integration and collaboration, and the availability of appropriate intellectual and technical expertise for each aim.

2) A table that identifies critical milestones and performance criteria, a timeline for completion, and whether critical milestones depend on the completion of antecedent milestones. Metrics for identifying successful completion of program aims and goals, and criteria for acceptable outcomes, should be defined. It is useful to identify interdependent steps with critical risks. Risk management and alternative approaches can be addressed elsewhere in the Research Strategy and can reference the table. This table will aid reviewers in assessing the feasibility and likelihood that the work plan is adequate for achieving project objectives within the funding period.

Multiple PD/PI Leadership Plan

All RM1 applications must include multiple PD/PIs, therefore all RM1 applications must include a Multiple PD/PI (MPI) Leadership Plan. The MPI Leadership Plan should be included as Section I of the Research Program section. The MPI Leadership Plan must describe the governance and organizational structure of the research project, including  plans for sharing leadership and decision-making, for allocating resources, the process for making decisions on publications and intellectual property issues to ensure that credit is fairly shared, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the program for the PD/PIs must be described, including responsibilities for human subjects or animal studies as appropriate. 

B. Team Management Plan (TMP): A "Multiple PD/PI Leadership Plan" is required separately in Part A, the Research Program section, and the information in that plan should not be duplicated here. Rather, this section must contain an overall team management plan that addresses how the team as a whole will function to accomplish program objectives. Inclusion of a scientific project manager or coordinator as a Senior/Key Person with adequate authority is recommended. A key characteristic that distinguishes productive teams is the degree to which all member contributions are valued. Many resources exist to aid in developing effective team-based programs (see e.g., the NCI Team Science Toolkit; https://cancercontrol.cancer.gov/brp/research/team-science-toolkit).

The comprehensive team management plan should address in detail the following points:

  • The proposed organizational structure and team composition, including plans for managing interactions between separate departments or institutions. Include all key personnel, consultants, and other significant contributors regardless of effort level.
  • Plans for sharing responsibility for project management, including required administrative functions. Describe strategies that will be used for building and maintaining group participation, for management and decision-making processes that promote collective input for the overall project objectives and for oversight and reallocation of program resources, recognizing that resources may need to be dynamically reallocated to achieve programmatic goals. Describe plans for real time communication, intra-team data sharing, and data archiving for team use as well as for future data sharing.
  • It is recommended that the TMP include procedures for evaluating scientific progress and overall support for program objectives of each of the PDs/PIs and key personnel, the changing need for PD/PI expertise to achieve program objectives, and the replacement of key personnel and PD(s)/PI(s) as needed, with the required prior approval for PD/PI changes. Describe methods for attributing contributions to publications.
  • The TMP should include a description of how the PD/PIs will establish and sustain a diverse and interdisciplinary team of researchers with an optimal range of backgrounds, expertise, skills and levels of experience to successfully accomplish the goals of the program,  through appropriate mentoring of students, post-doctoral fellows and other early stage investigators participating in the RM1 project. Obtaining or leveraging separate sources of support for mentoring obtained through fellowship or career development awards or training grants is encouraged. There is evidence that teams employing complementary approaches and having diverse areas of intellectual and technical expertise are more productive if the process for making decisions incorporates different points of view.
  • Programs may wish to appoint an external advisory committee (EAC) to provide advice and perspectives on progress and any major changes in project direction. If an EAC is to be appointed, its areas of expertise, functions and operation should be described in this section. However, applicants should not identify any members in the application or contact potential candidates before the application has been reviewed. EACs are optional.
  • Describe the plan for conflict resolution.

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

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

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

  • All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.
  •  CARBON awardees are required to deposit data in one of the NCCIH preferred repositories (https://www.nccih.nih.gov/grants/policies/data-management-and-sharing-policy/preferred-repositories) unless there is a more appropriate domain-specific repository for sharing the data type. 

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

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

PHS Human Subjects and Clinical Trials Information

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

PHS Assignment Request Form

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

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

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

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

Post Submission Materials

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.

Section V. Application Review Information

1. Criteria

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

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.

Overall Impact

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).

Scored Review Criteria

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.

 

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 NOFO:

How convincing is the evidence that the envisioned, future clinical efficacy trial could significantly alter practice or affect public health? How prevalent and/or urgent is the public health need that the envisioned trial would address? 

Why are the knowledge gaps to be addressed by the current specific aims especially critical to the design and interpretation of a future clinical trial? What are the important ways in which achievement of the RM1 specific aims would contribute to the design and interpretation of a future clinical trial?

To what extent does rigorous evidence drawn from distinct methodological approaches support the proposed specific aims AND the longer term objectives?

How strong are the data supporting a clinically relevant effect on resilience of the proposed product(s) and how strong are the data supporting the necessity of one or more specific, identified product components for the effect of interest? In other words, how strong is the evidence that the compound to be used for product standardization, assessment of bioavailability or dose, etc, is required for the resilience effect to be studied? To what extent do these data come from distinct research approaches? To what extent do the reported effects make biological, ecological and evolutionary sense?

 

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 NOFO:

To what extent does the PD/PI team have the complementary expertise and skills to be able to effectively combine concepts, approaches, and good practices for rigor and transparency from all the sub-disciplines required to achieve the specific aims, including phytochemistry, pharmacology, nutrition, clinical research and practice, and other areas as appropriate? 

In what ways and to what extent has the PD/PI team demonstrated the ability to collaborate effectively? 

In what ways and to what extent has the PD/PI team demonstrated the ability to effectively mentor newer researchers and support team members of diverse backgrounds?

 

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?

 

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

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

Does the application adequately address the following, if applicable

Study Design

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

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

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

Data Management and Statistical Analysis

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

Specific to this NOFO:

Research Program:

How appropriate for the product(s) studied and how feasible and rigorous are the plans to ensure product supplies and compliance with the NCCIH Natural Product Integrity Policy?

How feasible, appropriate and rigorous are the plans to assess the product(s) for additional chemical constituents modulating the effect of interest, and for additional potential clinically relevant targets (e.g., cytochrome P450’s). If such studies are reported in supporting data, how well do they justify the proposed specific aims in the current application?

How strong are the data supporting the range of concentrations or doses of the product and its chemical constituents or metabolites to be studied? To what extent are these ranges scientifically well justified and consistent with subject health and safety and with traditional or current prevalent usage?

To what extent is the program presented as a coherent and fully integrated set of specific aims or objectives?

Are the timeline and milestones proposed appropriate for accomplishing the specific aims? Does the work plan make adequate use of existing institutional and/or regional resources?

Team Management Plan:

What are the arguments that the specific aims of the application are best addressed with a trans-disciplinary team approach? What aspects of these arguments are most and least convincing?

To what extent does the team management plan give confidence that fair and adequate governance processes will be used for decision-making?

To what extent does the plan:

  • Describe feasible and adequate plans for ensuring needed communication and data sharing among the research team?
  • Provide for effective team leadership and management with distributed responsibility and decision-making processes, ensuring that all investigators are encouraged to have a voice in decision-making so that no single PD/PI will become overly dominant?
  • Convincingly describe processes to create a sustainable environment for a team of researchers with an optimal range of backgrounds, expertise and skills, maintaining trust and shared input, credit and vision?
  • Describe feasible and adequate plans for allocating shared professional credit? Is there evidence of institutional buy-in for shared professional credit for team activities that is sufficient for professional advancement?
  • Describe adequate plans for ensuring that all team members will have the access they require to shared resources and to project-generated data?
  • Describe adequate plans for shared decision-making and flexibility when changes to plans or reallocation of resources are required, for allocating credit and publications, and for resolving disagreements or conflicts?

If an external advisory committee is proposed, to what extent does the plan for this suggest the committee will be utilized in ways that will contribute to success of the project and the research team? To what extent are the areas of expertise and plans for interactions with the committee likely to foster success of the project and the research team?

If a scientific program manager or coordinator is proposed, how likely are the qualifications and role described for this individual to contribute to the success of the project? 

 

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

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

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

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

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

Specific to this NOFO:

What are the strengths and weaknesses of the resources and capacity available to the team for natural product characterization and standardization?

What are the strengths and weaknesses of the environment for including students, post-doctoral fellows and other early stage investigators as full participants in the research team? What institutional resources or senior team member track records are available that are likely to support early career investigators in their career development and ability to participate fully in the research team?

Additional Review Criteria

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.

 

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)?

 

For research that involves human subjects but does not involve one of the categories 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.

 

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.

 

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

 

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.

 

Not applicable.

 

Not applicable.

 

 Not applicable.

Additional Review Considerations

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.

 

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Not applicable.

 

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).

 

Reviewers will comment on whether the Resource Sharing Plan(s) (e.g., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

 

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.

 

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 policies and practices, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

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

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

Appeals of initial peer review will not be accepted for applications submitted in response to this NOFO.

Applications will be assigned  to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by NCCIH. The following will be considered in making funding decisions:

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

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

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

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

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

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

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

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

2. Administrative and National Policy Requirements

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

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

If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.

HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

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 System for Award Management (SAM.gov) requirements. SAM.gov requires Federal agencies to review and consider information about an applicant in the designated integrity and performance system (currently SAM.gov) prior to making an award. An applicant can review and comment on any information in the responsibility/qualification records available in SAM.gov. NIH will consider any comments by the applicant, in addition to the information available in the responsibility/qualification records in SAM.gov, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

3. Data Management and Sharing

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

CARBON awardees are required to deposit data in one of the NCCIH preferred repositories (https://www.nccih.nih.gov/grants/policies/data-management-and-sharing-policy/preferred-repositories) unless there is a more appropriate domain-specific repository for sharing the data type. 

4. Reporting

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

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

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

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

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

Section VII. Agency Contacts

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

Application Submission Contacts

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

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

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-637-3015

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Scientific/Research Contact(s)

Barbara C. Sorkin, Ph.D.
Co-Director, NIH CARBON Program
Office of Dietary Supplements (ODS)
Email: sorkinb@mail.nih.gov

D. Craig Hopp, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-496-5302
Email: hoppdc@mail.nih.gov

Jia Bei Wang, MD, Ph.D.
National Institute on Drug Abuse
Phone: 240-974-4703
Email: jiabei.wang@nih.gov

Peer Review Contact(s)

Jessica McKlveen, Ph.D.  
National Center for Complementary and Integrative Health (NCCIH)
Email: jessica.mcklveen@nih.gov

Financial/Grants Management Contact(s)

Amy Connolly
National Institute On Drug Abuse (NIDA)
Phone: 301-827-4457
E-mail: amy.connolly@nih.gov

Debbie Chen
National Center for Complementary and Integrative Health (NCCIH)
Email: debbie.chen@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.

Authority and Regulations

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

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