It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the 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 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Plants and plant-derived products are widely consumed for basic nutrition, and to promote health and well-being, worldwide and in the U.S. Nevertheless, there is only a partial understanding of what effects (beneficial or adverse) many of these products have on human health and well-being. To the extent that these products may have clinical efficacy, the underlying mechanisms of action are rarely fully understood. The challenges of doing research on these complex and inherently variable materials contribute to slow progress towards a definitive understanding of these issues.

Randomized, controlled clinical trials (RCTs) are the most widely accepted standard for assessing the efficacy of an intervention, but the majority of RCTs (whether of botanicals or of pharmaceuticals) fail to reject the null hypothesis (i.e., they fail to provide evidence supporting the tested hypothesis). Given the substantial cost of Phase III RCT, they should be undertaken selectively, with their initiation generally limited to situations where there is a body of rigorous and compelling evidence, consistent over a range of research approaches and/or distinct preclinical and/or clinical models, that:

a) supports the likelihood of seeing the hypothesized effect in humans,

b) indicates the proposed intervention(s) are unlikely to expose trial participants to inappropriate risks, and

c) is sufficient to inform and justify design of the trial protocol, such that if the completed trial fails to provide evidence of the hypothesized effect, it is difficult to blame that failure on those design decisions.

In addition, it is preferable to conduct large RCTs only when the level of preliminary data is sufficient to support design of a trial where, regardless of the results of the completed trial, they are expected to be useful to rigorously inform decisions about further research on, or use of the product. In general, such preliminary data will include compelling evidence on the bioactive components of the product, their bioavailability, mechanism(s) of action, etc.

Achievement of the Specific Aims of the transdisciplinary research centers responsive to this FOA must address the most critical gaps in information needed for future design (by the applicant or others) of optimally informative clinical trials. Taking into consideration that each clinical trial entails myriad design decisions, some of which will likely have stronger effects on trial outcomes than others, applicants must set forth an evidence-based case that achieving the proposed Specific Aims will provide key information towards design decisions for the anticipated, future RCT, and that the future RCT is likely to rigorously inform practice or other health-critical next steps.

Past clinical trials of botanicals have been criticized for real or imagined design flaws. The objective of these BDSRC is to obtain evidence to inform critical clinical trial design decisions, presumably enhancing the chances that a future RCT rejects the null hypothesis, but also making it more difficult to discount the result in the event of a failure to do so. Objectives of the BDSRC might therefore include, but are not limited to, optimizing the composition or formulation of the botanical intervention, optimizing dose or dose timing, assessing bioavailability and pharmacokinetics of bioactive components, elucidating proximate biological effects underlying the health outcome of interest, elucidating individual determinants of response, or optimizing outcome measures. BDSRC researchers must monitor, and may focus on, evidence relevant to safety of human use. In addition, BDSRC Specific Aims should generate information that will allow confirmation or falsification of a detailed mechanism of action hypothesis during a future RCT. The BDSRC might, for example, aim to obtain information necessary to allow monitoring the concentration of a bioactive component at its target(s), or the extent to which the proximate biological effect is generated and correlated with the outcome.

The two research projects and the Botanical Core are expected to apply - and, where appropriate, develop - rigorous, state-of-the-science approaches to understanding the potential to affect human biological or cognitive/behavioral resilience of the complex botanical product(s) studied.

The BDSRC may include certain clinical trials (as defined by NIH; https://grants.nih.gov/policy/clinical-trials.htm), including, but not limited to, assessments of bioavailability, pharmacokinetics of a product component, or approaches to predict responsive individuals (where there is evidence that response is heterogeneous).

The BDSRC may NOT include applications proposing clinical trials of efficacy and/or effectiveness. Such applications will be considered nonresponsive and withdrawn without review. Future RCTs building on the BDSRC findings may be supported in a variety of ways, including, but not limited to, FOAs such as NCCIH’s PAR 17-172 and 17-174.

Clinical research may be included in the Research Projects or the Botanical Core, but may not be included in an Administrative Core.

BDSRC Structure

Each BDSRC will be required to include a Botanical Research Core and two research projects that all synergize with each other, and will, separately and together, provide information that will fill in the most critical gaps in the existing body of data relevant to the optimal design of a future clinical trial of the effects on human resilience of orally consumed, complex botanical products. We define synergy, in this context, as collaboration of the various projects and Cores, such that data or methods from each component inform the others, and the scientific contributions of the Center as a whole are greater than the sum of outcomes of the individual projects and Cores in the absence of intensive collaboration.

The Botanical Core of each proposed BDSRC must be responsible for ensuring product integrity and providing in sufficient amounts materials used by both research projects and any collaborating projects within the CARBON Program, and for advancing understanding of the chemistry of the product(s). If a broad, non-targeted approach has not previously been applied to the product(s) to be studied, then the Botanical Core must include one or more Specific Aims to rigorously assess the potential presence in the product of additional bioactive components which may synergize with or add to the proposed (known) bioactives, counteract them, or have quite different bioactivities, including in vivo targets not previously noted for the product studied. Such aims may include the use of untargeted screening platforms or other approaches, as appropriate.

BDSRC must have clearly delineated plans for a governance and organizational structure. An Internal Steering Committee (ISC) and an External Advisory Committee (EAC) are required (please see Section VI. of this FOA). An Administrative Core is allowed, but is not required. The planned governance and organizational structure must encompass processes for making decisions on scientific direction in conjunction with the EAC, and procedures for resolving conflicts.

BDSRC must develop and regularly update a BDSRC website providing information on (at least) the U19 supported research, research publications and research presentations.

BDSRC should be strong environments for research career development and must have plans for obtaining funds (or utilizing existing resources) to provide graduate students and post-doctoral fellows with training and career development opportunities in transdisciplinary approaches to understand the biological and/or cognitive/behavioral effects of complex botanicals.

Collaboration beyond, as well as within each BDSRC is expected to be a critical contributor to the Program's success. Therefore BDSRC are expected to interacti with other components of the CARBON, including through a pilot project component, to be described later. Such collaborations are expected to include, where appropriate and productive, collaborative demonstration projects with the concurrently awarded Centers for Natural Product Technology, Methodology and Productivity Optimization and must include participation of key personnel in meetings, including, but not limited, to the annual meetings of the CARBON.

Participation of younger investigators, including post-doctoral fellows and students in the annual CARBON meetings is also strongly encouraged.

Specific Areas of Research Interest

The purpose of this BDSRC FOA is to support research to develop additional information most critical to the optimal design of, and decision-making for clinical trials of the effects of ingested, complex botanical products on quantitative, objective, well-validated indicators relevant to biological or cognitive/behavioral resilience. Responsive applications must provide rigorous evidence supporting a biologically and mechanistically plausible, reproducible effect, the magnitude of which is sufficient to justify a human intervention trial. The evidence provided, whether newly developed or in peer-reviewed research publications, must be consistent across at least two independent and scientifically distinct (e.g., orthogonal) lines of evidence, and must include data that address causality (e.g., results of knock-out and/or over-expression designs). For example, data from an in vitro model (using a physiologically relevant product and concentration) supporting a mechanism of action, and data from an early-phase clinical trial, consistent with the in vitro results, as well as with a correlation between the mechanism of action and the physiological or cognitive/behavioral outcome of interest, would be responsive. Data from two different product doses, both in the same pre-clinical model, would not be sufficient support for a responsive application.

Responsive BDSRC applications must include rigorous evidence that the presence of one or more proposed bioactive components (or precursors thereof) in the intervention is necessary for a relevant proximate biological effect, health outcome, or both, and of the applicants' ability to meaningfully monitor product quality, bioavailability, and pharmacokinetics based on one or more of these proposed bioactives. In addition, responsive applications must include rigorous evidence of bioactive bioavailability, i.e., that, following product ingestion, the bioactive components (which may be metabolites of the product) can reach a concentration in vivo, preferably at the presumed proximate target, that is sufficient for the activity of interest.

Successful BDSRC applications must have made a compelling case that achieving the proposed Specific Aims will significantly enhance the design of a future clinical trial of the product (or an optimized form of it), such that that future RCT is expected to be highly informative whether or not it rejects the null hypothesis, as described in Section II.1 (Research Objectives) above.

Products appropriate for applications responsive to this FOA will be limited to complex botanical products for which there is rigorous, but not definitive, evidence supporting a clinically or public health significant and reproducible effect (as described above) on quantitative, objective outcomes relevant to human biological or cognitive/behavioral resilience. Applications in which a purified phytochemical is the main focus, or in which the focus is not on effects of oral intake, will be considered nonresponsive to the FOA and withdrawn without review.

Research objectives supported by this FOA may include, but are not limited to:

• Obtaining additional data on the causal, molecular mechanism through which the bioactive component(s) of the product act(s) on the proximate in vivo target(s). Model systems used, whether in silico, in vitro or in vivo, must be well-validated and well-justified as appropriate for the research question posed.
• Obtaining data on genetic or epigenetic sources of diversity in human responses to the intervention, and their underlying causal, molecular mechanisms. The contributions of age, sex, diet, and/or differences in gut microbiota to such differences are of particular interest.
• Further elucidation of the mechanisms through which the proximate biological activity(ies) of the product are effected, or through which they generate the hypothesized health outcome.
• Generation of data on dose-response, optimal product composition, pharmacokinetics/pharmacodynamics (PK/PD) and optimal dose regimen, and/or optimization of circadian timing of intervention.
• Generation of data on the time course of a health effect.

Resilience

For the purposes of the BDSRC FOA, resilience is defined as capacity to withstand and successfully adapt to change, disturbance, stress, etc., or to recover efficiently from disturbance, challenge, illness, etc. Applicants must use models in which resilience can be measured quantitatively and objectively over relatively short time frames appropriate for a 5-year award. Examples of such outcomes include, but are not limited to, restoration, in initially healthy individuals, of baseline microbiome ecology after disturbance, HbA1c levels, response to vaccine or viral challenge, time to return to initial or normal/healthy levels of inflammatory cytokines or blood glucose after a perturbation, or measures of fatigability.

Botanicals of interest

Terrestrial plants, algae or macroscopic fungi (and products derived from them) are included within the purview of this FOA. Applications that include experiments using purified entities found in, or synthetic compounds derived from, botanical sources will be considered only where such research is necessary to elucidate the mechanisms of action or activities of the complex botanical. This FOA 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 based on the results of the proposed research are appropriate for this FOA, 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.

Investigators wishing to propose research that doesn t meet the strict eligibility criteria for this FOA may wish to consider submitting applications to NCCIH's R61/R33, PAR 18-828, and PAR 18 -829 instead.

Each BDSRC Botanical Core will be responsible to:

• ensure product integrity and consistent availability in sufficient quantity, of materials used by both research projects and any collaborating projects within the CARBON,
• implement, and where necessary, develop rigorous, cutting-edge methods for assessing composition, stability, bioavailability, pharmacokinetics, etc., of the products used in the BDSRC,
• advance understanding of the chemistry of the product(s). If a broad, non-targeted approach has not previously been applied to the product(s) to be studied, then the Botanical Core must include Specific Aims to rigorously assess the potential presence in the product of additional bioactives, which may synergize with or add to the proposed (known) bioactives, counteract them, or have quite different bioactivities, including in vivo (animal) targets not previously noted for the product studied. Such aims may include unbiased screening platforms, as well as other approaches, as appropriate. High-throughput, high-content approaches including but not limited to in vitro as well as in vivo (e.g., Drosophila, Caenorhabditis, or Danio) are encouraged.

In addition, Botanical Core Specific Aims may include:

• Generation of modified versions of the products, based on data produced through the research projects (e.g., enriched or depleted in putative bioactives),
• Rigorous and specific quantitation of the (known) bioactives or relevant metabolites thereof in vivo or in relevant biological specimens.
• Clinical assessment of pharmacokinetics and pharmacodynamics.

Projects proposing any of the following research will be considered nonresponsive and will not be reviewed:

• Projects lacking evidence for a biologically and mechanistically plausible, reproducible effect(s) relevant to human resilience, with the effect(s) consistent across at least two independent and scientifically distinct lines of evidence.
• Projects lacking justification for the importance of achieving the Specific Aims to the future design of a follow-on clinical trial.
• Research involving models of chronic diseases or conditions where the focus is solely on treatment rather than on outcomes relevant to risk reduction, health maintenance or resilience.
• Applications in which the Specific Aims do not focus on quantitative, objective outcomes relevant to human resilience.
• Projects proposing clinical trials of efficacy or effectiveness.
• Applications proposing to focus on parenteral or topical administration of interventions are generally beyond the scope of this FOA, 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.
• Projects lacking a proposed unbiased and rigorous 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.

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

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

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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• o 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.

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

Only one application per institution (normally identified by having a unique DUNS number or NIH IPF number) is allowed.

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).

The application forms package specific to this opportunity must be accessed through ASSIST or an institutional system-to-system solution. A button to apply using ASSIST is available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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

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

The letter of intent should be sent to:

Martina Schmidt, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3456
Fax: 301-480- 2419
Email: [email protected]

Available Component Types	Research Strategy/Program Plan Page Limits
Overall	12
Admin Core	6
Botanical Core	12
Project	12

Additional page limits 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 a multi-component application.

The application should consist of the following components:

• Overall: 1 required
• Administrative Core/Structure: 1 Required
• Botanical Core: 1 Required
• Research Projects: 2 Required

When preparing your application, use Component Type Overall .

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

Complete entire form.

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Follow standard instructions.

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

Specific Aims: Describe the Specific Aims of the Center as a whole, the knowledge gaps to be addressed by the Center, how achievement of the Center Specific Aims is expected to contribute to the optimal design of a future clinical trial of the effect(s) of oral administration of the botanical product to be studied by the Center. It will usually be helpful to describe, in general terms, the future clinical trial the design and/or interpretation of which the BDSRC 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 BDSRC 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

Research Strategy: Applicants must provide a rationale for the choice of botanical product(s) and outcome(s) proposed. The rationale may be based on prevalence of use, and/or strong evidence for human benefits or adverse effects (including food or drug interactions), or other issues that justify prioritizing work towards the future clinical trial the BDSRC Specific Aims envision.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 rejects the null hypothesis.

• Applicants are required to describe the strengths and weaknesses of prior data cited in support of the BDSRC application, including similarities and differences between the products and outcomes studied in the cited data and those proposed in the current application, extent to which product characterization was reported for supporting data, sample sizes, extent to which blinding/masking or other approaches to limit the effects of bias were described in prior reports, relevance of model systems used in those studies to the human outcome of interest, 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, their results should be described
• Model systems used, whether in silico, in vitro or in vivo, must be well-validated and well-justified as appropriate for the research question addressed. Known and likely disparities between the model systems used and human biology should be described, as well as any aims intended to compensate for or otherwise address those differences to enhance translational relevance of the results.
• Applicants must clearly and specifically delineate and describe their planned governance and organizational structure. An Internal Steering Committee (ISC) and an External Advisory Committee (EAC) are required (please see Section VI. of this FOA). Applicants must clearly describe in the Administrative Core/Structure component of the application processes for making decisions on scientific direction in conjunction with the EAC, and procedures for resolving conflicts.
• Names of potential EAC members should not be included in the application, except where those individuals would be continued from a currently active CARBON Center.
• An Administrative Core is allowed, but is not required. The roles and administrative, technical, and scientific responsibilities for the BDSRC PI(s), and Project and Core Leaders must be clearly delineated.
• Each application must describe in the Administrative Core/Structure component plans for development and regular updating of a BDSRC website providing information on (at least) the U19 supported research, research publications and research presentations.

Timeline: Describe the timeline for research milestones to be achieved by each BDSRC component and by the BDSRC as a whole.

Career Development: BDSRC are expected to provide an environment suitable for the training of investigators able to design, conduct and participate in transdisciplinary botanical research. The application must describe in the Administrative Core/Structure component plans to obtain or leverage other sources of funding to support training and career development opportunities for graduate students and postdoctoral fellows in transdisciplinary approaches to understand the biological and/or cognitive/behavioral effects of complex botanicals. These activities should be integrated into the research of the BDSRC and described in the Administrative Core/structure component of the application.

Collaborations: Describe aspects of the research projects or the Core(s) that might participate in mutually beneficial collaborations with a project developing novel natural products methods (as in the concurrently issued RFA AT 19-002), or with a pilot project.

Names of potential future collaborators should not be included in the application.

It must be clear from the description of the approaches for the Research Projects and Cores how specific data or materials from each Project or Core will feed into the other BDSRC components to support synergy by mutually and iteratively enhancing research design, conduct, or implementation. Applicants must explain how funding this research as a Center is expected to support research advances that would be unlikely to be achieved through separate support of the individual research projects.

Letters of Support: Attach letters of support relevant to the center as a whole (e.g., letters of institutional support). Letters of support relevant to specific projects or cores should be attached in the relevant Project or Core research plans. A letter of institutional commitment from the Dean or another official of similar rank must be included. If the application includes multiple institutions, similar letters of support from each of the participating institution must be included.

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, with the following modification:

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

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Overall)

When involving NIH-defined human subjects research, clinical research, and/or clinical trials 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, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

Study Record: PHS Human Subjects and Clinical Trials Information

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

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

When preparing your application, use Component Type Admin Core.

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

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Administrative Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• An Administrative Core is NOT required.
• If an Administrative Core is not proposed, the investigators must describe in this Administrative Core/Structure component how all the functions otherwise required of an Administrative Core will be structured and performed in the proposed BDSRC.
• The Admin Lead must be a Center PD/PI.

Budget forms appropriate for the specific component will be included in the application package.

Limited funds may be allocated for program enrichment activities such as seminars and research workshops. Funds from the award cannot be allocated for website development or maintenance, nor for newsletters, consumer information or outreach activities.

Funds must be allocated for travel of the PD/PI(s) and other key personnel to the CARBON annual meeting.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Specific Aims: Describe the Specific Aims for the Administrative Core or for Administrative Structure of the BDSRC. Clinical research may not be included in this component of the application.

Research Strategy: Center administration: A PD/PI must be named as the Administrative Lead. The following aspects of BDSRC management must be addressed in this application component whether or not an Administrative Core is proposed. Clinical research may not be included in this component of the application.

A) Clearly delineate the proposed governance and organizational structure for the BDSRC, describing how research, communications, administrative, and other activities within the Center will be managed and coordinated, both within the Center, and with external collaborators, including other components of the CARBON. Describe the plan for regular evaluation of scientific progress and approach, including appropriate research prioritization, problem and/or conflict resolution, and effective coordination and sharing of relevant BDSRC resources including data. Clearly describe the allocation of responsibilities among the key personnel.

An Internal Steering Committee (ISC) and an External Advisory Committee (EAC) are required (please see Section VI. of this FOA). Applicants must clearly describe in this Administrative Core/Structure component of the application processes for making decisions on scientific direction in conjunction with the EAC, and procedures for resolving conflicts.

B) Describe the External Advisory Committee (EAC; please see Section VI.2, Cooperative Agreement Terms and Conditions of Award), which will provide oversight and assist the Center PD(s)/PI(s) in making scientific and administrative decisions. In addition to evaluating scientific progress of the Center, the EAC must periodically comment and report on Center operations to ensure that resources, especially Core resources, are devoted to the most scientifically meritorious, critical, and significant projects, and that maximal synergy is being achieved.

EAC members and the committee chair will be appointed by the Center PD(s)/PI(s) in consultation with NIH Program Staff; members may serve on a rotating basis. It is strongly recommended that EAC members be senior scientists with relevant expertise who are not current or recent faculty at the awardee institution or other participating institutions and are not recent trainees of the PD(s)/PI(s) or Project or Research Core leaders. The PD(s)/PI(s) will serve on the EAC in an ex-officio capacity only. The EAC should consist of three to five members in addition to the Center PD/PI(s). EAC members cannot participate directly in the research of the Center. If an EAC member becomes directly involved in the research of the Center, the resulting committee vacancy must be reported to NIH program staff and a replacement sought in a timely manner. Applicants should not identify potential EAC members in their applications. While description of EAC activities should be included in the application, potential members of the committee should not be contacted, named, or selected until an award has been made. This will allow a wider pool of potential reviewers of the applications. In addition to specifying the type of expertise needed, the applicant should also describe the process by which EAC members will be selected. The first EAC must be convened within three months of the start of the first budget period. Thereafter, the EAC shall meet at least once a year. Minutes of all (i.e., scheduled and ad hoc) EAC meetings must be kept. Minutes of all EAC meetings shall be sent to NIH staff within 30 days and also be included in the annual progress report.

C) Describe the constitution, roles and processes of an Internal Steering Committee (ISC) composed of the Research Project and Core Leads, which will meet regularly with the Center PD(s)/PI(s) to assess research progress and determine whether research goals are being met. A plan for regular ISC meetings should be described.

While the final administrative structure of the Center will be left to the discretion of the Center PD(s)/PI(s), experience demonstrates that effective development of a Center program requires interaction among the Center PD(s)/PI(s), Research Project and Core leads, advisory groups, appropriate institutional administrative personnel, and NIH program staff.

D) BDSRC are expected to provide an environment suitable for the training of investigators able to design, conduct and participate in transdisciplinary botanical research. The application must include plans to obtain or leverage other sources of funding to support training and career development opportunities for graduate students and postdoctoral fellows. Supplemental funding for training and career development could be sought from NIH institutional training grants (T32), individual fellowships (F31, F32), mentored career development awards (K01, K08) and other sources including, but not limited to, the parent institution and private foundations. Explain how efforts to support research training and career development will be managed and coordinated. Clearly describe in this component of the application the allocation of responsibilities for these efforts.

E) Each application must describe in the Administrative Core/Structure component plans for development and regular updating of a BDSRC website providing information on (at least) the U19 supported research, research publications and research presentations.

Letters of Support: Attach only letters of support relevant only to the Administrative Core/structure in this section

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, with the following modification:

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

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

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

When preparing your application, use Component Type 'Core.

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

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Application guide states that Project Narrative is required. However it is only required for the Overall component.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Specific Aims: Specific Aims for each Botanical Research Core should address the following:

• Obtaining and/or preparing, in sufficient quantity and quality, botanical materials, associated controls, and optimized preparations, as appropriate for the research aims, for all components of the BDSRC and BDSRC collaborators within the CARBON,
• Ensuring accurate identification and consistent quality (bioactivity and chemistry) of the botanical materials over the course of the projects, including during storage and transfer to end users,
• Assessing the potential presence in the product of additional bio actives, which may synergize with or otherwise modulate the bioactivity(ies) of the proposed (known) bioactive components. The presence in a product of such additional bioactive components (or their precursors) or of additional bioactivities may generate apparently anomalous and variable outcomes in in vivo studies. If their presence is detected, appropriate controls can be incorporated in future studies.

Research Strategy:

• Applicants must describe how the Specific Aims will be achieved, including clearly describing technologies or approaches that will be newly developed or newly adapted to botanical research.
• Applicants are strongly encouraged to consult NCCIH’s Natural Product Integrity Policy (https://nccih.nih.gov/research/policies/naturalproduct.htm). Satisfactory Just-in-Time information on product integrity must be submitted before an application can be funded. Where research to optimize or otherwise further develop the botanical product is a component of the BDSRC, information on plans to obtain, identify, characterize and optimize product may satisfy this requirement.
• Model systems used, whether in silico, in vitro or in vivo, must be well-validated and well-justified as appropriate for the research question posed. Known and likely disparities between the model systems used and human biology should be described, as well as any aims intended to compensate for or otherwise address those differences to enhance translational relevance of the results.
• Applicants should describe possible future areas for collaboration with related botanical or natural products research efforts, including the associated NMR Open Access Data Exchange (RFA AT-19-002, and the Center(s) for Natural Products Technology, Methodology and Productivity Optimization (RFA AT-19-003), and what advances might be generated from such potential collaborations, but should NOT cite specific collaborators in the application.
• Core resources should not duplicate resources already available to Center investigators. Where fee-for-service arrangements (i.e., Center use of existing facilities) satisfy analytical or other needs of the BDSRC, use of these is acceptable, but should not be considered as constituting, in and of itself, a separate Research Core.
• Where applicable, validated methods and reference materials, such as those available via ODS' Analytical Methods and Reference Materials Program, should be used.

Letters of Support: Attach only letters of support relevant only to the Botanical Core in this section

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, with the following modification:

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

Appendix:

Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Botanical Core)

When involving NIH-defined human subjects research, clinical research, and/or clinical trials 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 a 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

Full study records include a number of fields and attachments related to human subjects and clinical trials.

Delayed Onset Study

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

When preparing your application, use Component Type Project

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

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Application guide states that Project Narrative is required. However it is only required for the Overall component.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

ASSIST will default to Project Lead".

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Specific Aims: Describe the Specific Aims for this Research Project. Explain how achievement of these Specific Aims is expected to inform the design and/or interpretation of a future clinical trial.

Research Strategy:

Given the importance of understanding how information to be used in support of a clinical trial design is likely to translate to a relevant human population, applicants must describe approaches that will be used to rigorously test the reproducibility, preferably across distinct experimental approaches, and assess the translational validity, of their results. Examples of possible approaches include, but are not limited to, orthogonal approaches, alternate models, over-expression or knockout models.

The following include some of the issues applicants should carefully consider. Rationales must be clearly explained for the choices described in in the Research Plan:

• Choice of models or model systems. Explain the rationale for selecting the specific models proposed, known differences between the models and humans, and how those differences would be accounted for in using the Project's results to inform the design of a clinical trial.
• For in vivo models or clinical research, the choice of control or baseline diets or chow.
• The selection of the specific preparation(s) of the botanical to be used in a given research project and/or model system must be justified. Relevance of the delivered form of the botanical to a future clinical trial should be carefully considered in terms of bioavailability, metabolites generated after ingestion, relevance of concentrations used, and various aspects of intervention timing.
• Data to be collected, including the rationale and supporting data for mediators or markers of proximate bioactivity, as well as for end points.

Applicants must indicate which, if any, preclinical experiments will be pre-registered.

Letters of Support: Attach only letters of support relevant only to this Research Project in this section

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, with the following modification:

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

Appendix:

Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials 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 a 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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed

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.

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) using ASSIST or other electronic submission systems. 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.

This initiative is not subject to intergovernmental review.

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.

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

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

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) and component Project Leads 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.

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 (SAM). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

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.

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.

In assigning the impact score for the application as a whole, although primary emphasis will be placed on scientific merit of the Research Projects and Cores, the assessment of scientific synergy (i.e., the extent to which the potential for scientific impact of the proposed Center as a whole is deemed likely to be greater than the sum of its component Research Projects and Cores) and the extent to which the proposed Center is deemed likely to make important contributions to future clinical research on the efficacy of botanicals, should contribute significantly to the overall score.

In addition, for applications involving clinical trials:

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

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the Center 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 Center 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 Centert that by its nature is not innovative may be essential to advance a field.

Does the Center 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 Center 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?

Do the data provided support the likelihood that the future clinical trial towards which the current Center Specific Aims are directed could, through enhanced understanding of the effects of the product(s) studied, meaningfully and significantly affect a prevalent health issue?

Do they support the likelihood that achievement of the Specific Aims of the current application will provide information that will significantly inform and enhance the design and/or interpretation of such a trial? (i.e., is the information obtained through achievement of the Specific Aims likely to de-risk the envisioned trial, by providing clear guidance with respect to optimal product dose, formulation, treatment timing, outcomes, markers of bioavailability and/or proximate biological activity?)

Has the applicant compellingly explained why the knowledge gaps addressed by this proposed Center are priorities for the rigorous evidence-based design and/or better-informed interpretation of a future clinical trial?

Is achievement of the Specific Aims proposed for this Center likely to fill critical gaps that currently hinder evidence-based design of this future trial?

In addition, for applications involving clinical trials:

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?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the Center? 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?

In addition, for applications involving clinical trials:

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?

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?

In addition, for applications involving clinical trials:

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 Center? Have 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 Center 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 applicants' assessment of the strengths and weaknesses of the supporting data, including the potential for publication or other bias, support the rationale for the future trial and for the Specific Aims of the current Center application?
• Are the rationales for the proposed intervention and outcomes, and proposed mechanisms of action physiologically, chemically, biologically and mechanistically plausible?
• Are the Specific Aims for the overall BDSRC feasible?
• Do the data provided in support of this application make a compelling case that achieving the Specific Aims will significantly and critically enhance the design and/or interpretation of the envisioned future trial?
• Are data provided that rigorously demonstrate the presence of one or more bioactive components (or their precursors) in the product, that orally consumed product can generate a concentration in vivo, preferably at the presumed proximate target, sufficient for activity, and that the presence in the intervention of the proposed bioactive(s) or precursor(s) is necessary for a project-relevant proximate biological effect or health outcome, or both?
• Are choices evidenced in the application (intervention, population, outcomes) well-justified, based on the evidence provided or cited?
• How rigorous and robust, mutually consistent, and relevant to the future clinical trial, are the data cited or provided in support of the current application?
• Is the timeline provided for the Center feasible, appropriate, and likely to support achievement of the Specific Aims?

Are areas of the Center research described that support the potential for productive and mutually beneficial collaborations with researchers and research groups outside the proposed Center?

In addition, for applications involving clinical trials

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?

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?

Is there evidence of substantial institutional commitment on the part of each participating institution?

Is there evidence of prior productive collaboration of the research team (including in the U19 application)?

Are the application and investigator track records indicative of the establishment of a strong collaborative environment?

In addition, for applications involving clinical trials

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?

As applicable for the Center 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.

Each application will receive a merit descriptor (highly synergistic, synergistic, not synergistic) that reflects the degree of synergy of the proposed BDSRC.

Program synergy will be evaluated on the extent to which the combined approaches to the research question(s) proposed for the BDSRC are synergistic, and the integration and parallel pursuit of the projects and cores are likely to advance this research area to a greater extent than could be achieved without Center support. The presence of Administrative and Research Cores does not, in and of itself, constitute or guarantee synergy.

Assessment of synergy will include the following:

Are the scientific contributions of the proposed Center highly likely to be greater than those of the sum of its component Research Projects and Cores?

Is there evidence of a collaborative integrated transdisciplinary research approach?

Are plans to integrate data from phytochemistry with outcomes relevant to human resilience (including outcomes from in silico, in vitro, preclinical or human subjects research) to enhance understanding of botanical mechanism(s) of action clearly described and likely to be productive?

Are plans for use of the Core(s) by the Research Projects appropriate, including criteria for prioritization?

Are the ways in which results from the Research Projects to inform each other's design, and interpretation of projects convincingly described? Are these interactions likely to enhance the impact of the BDSRC as a whole?

Are the Research Projects likely to benefit from Core resources or services?

Are there appropriate plans for information from the Research Projects to influence the research of the Botanical Core, and vice versa?

Is clear evidence of collaborative relationships among participating departments and institutions provided?

Does each collaborating entity bring critical functions, commitments and contributions to the BDSRC?

Study Timeline

Specific to applications involving clinical trials

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)?

The Administrative Core or proposed Administrative structure, if no Administrative Core is proposed, will receive a merit descriptor (outstanding, acceptable, unacceptable) that reflects:

• Are the Core personnel, or individuals designated to administer the BDSRC qualified and have they demonstrated the ability to administer a large, multi-component research program?
• Are innovative approaches proposed which are likely to enhance the coordination of personnel, materials, other resources, or data management?
• Is there a clear, detailed plan for managing the Center's research, communications and administration, ensuring appropriate prioritization of research, needed course corrections, problem identification and resolution, and effective sharing of resources, that conveys a high likelihood of effective, productive management of the Center as whole?
• Is an organizational structure described that is likely to facilitate coordination, integration, collaboration, efficient research progress, and timely evaluation of Center activities and progress?
• Are the plans for communication, coordination, and collaboration among Research Project and Core investigators likely to support strong research collaborations? If there are long-distance collaborations, are the plans for investigator interactions and for transfer of materials well-described and likely to support strong research collaboration?
• Is a feasible plan proposed for obtaining support for research training and career development for graduate students and postdoctoral fellows in transdisciplinary research on botanicals as they relate to human health?
• Do proposed areas for collaboration with other CARBON components and additional relevant researchers appear feasible?
• Are there appropriate and feasible plans for use of an External Advisory Committee and an Internal Steering Committee to provide scientific and managerial oversight?
• Is an organizational structure described that is likely to facilitate coordination, integration, collaboration, efficient research progress, and timely evaluation of Center activities and progress?
• Are the plans for communication, coordination, and collaboration among Research Project and Core investigators likely to support strong research collaborations? If there are long-distance collaborations, is the plan for investigator interactions and plans for transfer of materials well-described and likely to support strong research collaboration?

If vertebrate animals, or biohazards research is to be supported in the Administrative Core, the adequacy of these sections must be assessed and will be considered in determining the merit descriptor of the individual core.

Each Botanical Research Core will receive a merit descriptor (outstanding, acceptable, unacceptable) that reflects:

• Are the proposed Core Specific Aims likely to contribute to the development or adaptation of techniques or approaches that will significantly enhance the progress of research on complex botanicals as they relate to human health?
• Are the Botanical Core Lead, collaborators, and other researchers well qualified to achieve the Specific Aims of the Core?
• Do they have the requisite, complementary expertise?
• Are their track records indicative of the ability to achieve the Botanical Core Specific Aims?
• Are the institutional support, equipment and other physical resources available to the Botanical Core adequate for the Specific Aims proposed?
• Will the project benefit from unique features of the scientific environment?
• Does the approach proposed for the Botanical Core show technical merit appropriate to the proposed Specific Aims?
• Are the approaches to sourcing and quality control of botanical products and assays to be performed well justified?
• If such studies are not reported in preliminary data, are strong plans described in the application to evaluate the presence of additional (beyond those described in the application) bioactive compounds (or their precursors) in the botanical products used in the project, as well as to evaluate the possibility that the bioactives to be studied act on additional in vivo targets (beyond those already described)? The presence in a product of such additional bioactives (or bioactive precursors) or of additional bioactivities may generate apparently anomalous and variable outcomes in in vivo studies. If their presence is detected, appropriate controls can be incorporated in future studies.
• Is the proposed timetable appropriate in relation to the scope of the proposed research and research support?
• 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?

In addition, for applications involving clinical trials:

Significance

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?

Investigator(s)

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?

Innovation

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?

Approach

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?

Environment

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?

Study Timeline

In addition, for applications involving clinical trials:

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)?

Reviewers will consider each of the review criteria below in the determination of scientific merit of each proposed Research Project, and give a separate numerical (1 to 9) score for each criterion, as well as an overall impact score for the project. A project 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?

If the specific aims of the Project are achieved, is the resulting information likely to inform the design or interpretation of a future clinical trial of the effect of the product on human biological or cognitive/behavioral resilience??

Does the Project address an important problem or a critical barrier to progress in the field, particularly to design and/or interpretation of a clinical trial of the product studied?

In addition, for applications involving clinical trials:

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?

Are the Project Lead, collaborators, and other researchers well suited to the Research 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?

In addition, for applications involving clinical trials

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?

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?

In addition, for applications involving clinical trials

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?

Is there a strong scientific premise for the project, based on the strengths and weaknesses of the supporting data?

Does the evidence cited in support of the choices of bioactives to be used in assessing product stability, bioavailability, metabolism, derive from more than one experimental approach, and is it consistent across these approaches?

Has at least one bioactive compound, or precursor of a bioactive metabolite, been rigorously shown to be bioavailable and required for the bioactivity of interest?

Are choices made in the Project (e.g., product formulation and dose range or concentration) well-justified? Is appropriate evidence provided or cited in these justifications?

Is the choice of any model system to be used well justified based on appropriateness for the research question, and clinical or translational relevance or validity?

Have the investigators presented adequate plans to address relevant biological variables, such as sex, age, and background diet for studies in human subjects or other animals?

Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed?

Are potential problems adequately addressed, and are alternative strategies, and benchmarks for success compellingly presented?

In addition, for applications involving clinical trials

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?

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?

In addition, for applications involving clinical trials

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 for applications involving clinical trials:

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 Center 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 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.

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

As applicable for the Overall Center, Cores and Research Projects 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.

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 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 .

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.

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.

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council for Complementary and Integrative Health. The following will be considered in making funding decisions:

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

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.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

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

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 law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. 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. HHS provides general 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/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/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. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. 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 http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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.

Cooperative Agreement Terms and Conditions of Award

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

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

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

• Determining experimental approaches, designing protocols, and conducting the work.
• Coordination and maintenance of the center activities within his or her institution, with collaborating scientists, and with the NIH Project Scientist and Program Official
• Coordinating activities including the External Advisory Committee (EAC) meetings (see below).
• Incorporating relevant improvements and developments in technology over time, as appropriate.
• Establishing and chairing an Internal Steering Committee (ISC) to coordinate and manage the Center activities. The ISC will include all Research Project and Core Leads. The PD/PI(s) may name additional investigators to serve as members of the ISC and subcommittees, as appropriate, and must coordinate regular meetings.
• Cooperating in the reporting of study findings. The recipient will retain custody of and have primary rights to the data and software developed under these awards, subject to the Government rights of access consistent with current HHS, PHS and NIH policies. The NIH will have access to and may periodically review all data generated under an award. Where warranted by appropriate participation, plans for joint publication with NIH of pooled data and conclusions are to be developed by the PD/PI(s) or ISC, as applicable. NIH policies governing possible co-authorship of publications with NIH staff will apply in all cases. In general, to warrant co-authorship, NIH staff must have contributed to the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; and (c) preparation and authorship of pertinent manuscripts.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

• Acting as the contact point for all facets of the scientific interaction with the recipient. As required for the coordination of activities and to expedite progress, NIH may designate additional NIH staff to provide advice to the recipient on specific scientific and/or analytic issues. Such staff may include another Project Scientist or Analyst, who will provide direct technical assistance to the recipients to optimize the conduct and/or analysis of the study, or who may assist in the coordination of activities across multiple sites.
• Retaining overall programmatic responsibility for the award including normal program stewardship and review of the scientific progress of each of the center projects and cores.
• Interacting with the PD/PI(s) on a regular basis to monitor study progress. Monitoring may include: regular communication with the PD/PI(s) and staff, periodic site visits for discussions with recipient research teams, observation of management techniques, quality control, fiscal review, and other relevant matters; as well as attending ISC, EAC and related meetings. The NIH retains, as an option, the right to conduct periodic external review of progress.
• Providing advice on the management and technical performance of the projects and cores.
• Assisting in promoting the availability data or resources developed during the course of this project to the scientific community at large.
• Helping to coordinate the work on this project with related projects.
• Convening the first meeting of and subsequently participating in the ISC that oversees study conduct. The NIH Project Scientist or designee will be a full participant and voting member of the ISC and, if applicable, subcommittees.
• Will be responsible for establishing an External Advisory Committee (EAC), in consultation with the PD/PI(s), and working with the PD/PI(s) to coordinate regular EAC meetings. The EAC will be composed of the Project Scientist, who will serve as a voting member, and up to five external advisors with appropriate expertise to provide advice relative to the BDSRC as well as make recommendations to NIH regarding progress, priorities, and modifications for the research projects and cores. The EAC will serve as the primary advisory body of the BDSRC, and the Project Scientist will rely on the EAC for objective evaluation of the Program.
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

The EAC will:

• Monitor progress of the Research Projects and Core(s).
• Evaluate the effectiveness of the BDSRC PD/PI(s), and of the Center as a whole.
• Identify problems and suggest possible solutions, especially with respect to effective focus on scientifically meritorious, critical and significant research, optimal allocation of resources, and synergy within the Center, and between the Center and extra-Center collaborators.
• Make recommendations to NIH staff about priorities and directions for the Center.
• The EAC’s evaluations and recommendations, in the form of a written annual report, are to be submitted to the Project Scientist and the BDSRC PD/PI(s), and will be used by the Project Scientist and the BDSRC PD/PI(s) to guide and direct the program. Subcommittees with additional ad hoc advisors may be established by the EAC as necessary in order to meet its planning, priority setting and evaluation responsibilities. Awardees generally will be expected to accept and implement the recommendations of the EAC; in those situations where implementation of the recommendations is not feasible, the BDSRC PD/PI(s) must provide a thorough explanation and rationale to relevant NIH staff.
• The first EAC meeting will be convened by the Awardee within three months of the award date. The EAC will then meet annually three months before the anniversary of the BDSRC award date.
• The EAC will take minutes of all EAC meetings, which will be sent to NIH staff within 30 days of the meeting, and also included in the annual progress report of the BDSRC.

Areas of joint responsibility include:

• Evaluating the Center's progress in meeting its goals, and the continued significance of those goals for the design of a future clinical trial.
• Ensuring appropriate and necessary coordination with related projects.
• Assessing progress in meeting the goals of the BDSRC Research Projects and Botanical Core.
• Establishing an ISC. The ISC Chair will not be an NIH staff member. The ISC may add additional members. Other government staff may attend the ISC meetings if their expertise is required for specific discussions.
• The ISC will be composed of the PD/PI(s) and other key personnel as deemed necessary, including the study biostatistician and Project and Core Leads, and the NIH Project Scientist or designee. An initial meeting of the ISC will be convened early after award by the NIH Project Scientist or designee. The final structure of the ISC will be established at the first meeting. The NIH Project Scientist or designee will have voting membership on the ISC, and as appropriate, its subcommittees. The NIH Project Scientist will serve as an ex officio member of ISC, which will meet at least twice yearly.
• The ISC has primary responsibility to design research activities, establish priorities, establish and maintain quality control, review progress, coordinate and standardize data and resource management, and cooperate on the publication of results. Major scientific decisions regarding the core data will be determined by the ISC. The ISC will document progress in written reports to the IC Program Officer, and will provide periodic supplementary reports upon request.

Dispute resolution:

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

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

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are 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.

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

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

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

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

Barbara C. Sorkin
Office of Dietary Supplements (ODS)
Telephone: 301-435-3605
Email: [email protected]

D. Craig Hopp
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-496-5825
Email: [email protected]

Giovanna Zappal , Ph.D., M.P.H.
National Institute on Aging (NIA)
Telephone: 301-827-6240
Email: [email protected]

Martina Schmidt, Ph.D.
Telephone: 301-594-3456
Fax: 301-480-2419
Email: [email protected]

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

Mahasin Ingram
National Institute on Aging (NIA)
Telephone: 301-402-7736
Email: [email protected]

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.