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

Americans consume natural products (NP) every day either through their diet or via dietary supplements. The 2012 National Health Interview Study estimates that 18% of adults in the U.S. use non-vitamin, non-mineral natural products as supplements. An estimated 20-30% of patients on prescription medication indicate they are also taking dietary supplements concomitantly. In the late 1990s reports emerged regarding severe and life-threatening interactions involving both St. John’s Wort and grapefruit juice and a variety of medications (Rx). This led to widespread concerns about potential interactions with other natural products. Subsequently, numerous reports emerged describing possible interactions between large numbers of NP/Rx pairings. However, the evidence for many of these purported interactions came from preclinical models, case studies, or was based on purely theoretical arguments, leading to questions about their clinical relevance.

Despite the lack of human subjects studies to establish the clinical relevance of many hypothesized interactions, multiple public resources continue to warn against the use of NP in combination with various Rx as a precautionary measure. This has resulted in much confusion on the part of consumers and health care providers. Furthermore, due to the highly variable approaches employed in the research field, it is very difficult to clearly answer questions about clinical significance and relevance regarding many purported interactions involving natural products.

To address this knowledge gap, in 2015 NCCIH created a Center of Excellence for Natural Product Drug Interaction Research to establish definitive approaches for assessing the potential of natural products to produce clinically meaningful pharmacokinetic interactions with commonly consumed medications. The Center of Excellence for Natural Product Drug Interaction Research focuses on pharmacokinetic interactions involving various Phase I and Phase II metabolizing enzymes and small molecule transporters as these pathways represent the most common mechanisms of known drug interactions. This initiative will renew and continue that investment in natural products drug interaction research.

Our expectation is that the work supported through this Center will ultimately lead to better health care decisions either through mitigation of risk or through exploitation of the interaction for patient benefit as has been shown for grapefruit juice. However, the primary goal of this initiative is to continue building the knowledgebase around pharmacokinetic interactions involving complex natural products. Identification of natural products to be used under this program will involve a joint effort between the Center and the NIH. Natural products will be selected for further study based on the body of existing literature and their potential to produce clinically relevant pharmacokinetic interactions with one or more pharmaceutical agents. Once the natural products are identified and prioritized, the Center and the NIH will work collaboratively to design a research plan which will establish the mechanism(s) and magnitude of the interaction in vitro. This will then shape decisions about any future clinical research that might be needed. The resulting data will be collected, organized, analyzed and made available through an open access repository maintained by the Center to facilitate additional research hypotheses and improved research designs.

Primary objectives for the Center are to:

• Identify, prioritize, source and characterize a discrete (3-5) number of complex natural products that have evidence of potential interactions with commonly used medications but for which there is not enough human subjects data to establish the clinical relevance.
• Perform necessary preclinical research for each of the selected natural products which will address existing gaps in the scientific literature and allow for an informed decision regarding the need for additional human subjects research to establish the clinical relevance of any NP-Rx interaction
• If warranted, conduct a clinical trial on the prioritized natural products that will establish the clinical relevance of any identified drug interaction
• Archive, organize, analyze, and publicize the Center’s research results through an open access data repository to allow for better design of future research
• Coordinate with the grantees supported through the companion R21 RFA to import data generated through their research into the data repository; data generated by the R21 projects may influence the choice of natural products to be studied in the Center
• Provide broad leadership to the relevant research communities through promotion of the resources generated by the Center and through guidance in how best to carry out research on natural product drug interactions

Criteria to be considered when identifying natural products should include, but are not limited to, overall prevalence of use, high use in specific vulnerable populations (based on possible combination of age, ethnicity, health status, genotype, etc.), severity of potential interactions, quantity and quality of existing data, etc. Natural products proposed may include a combination of those with a mild to moderate interaction potential in a wide population or more significant interaction potential in a more narrow population. Importantly, the products to be studied are all expected to be complex mixtures.

Once the set of natural products is identified and approved by the Steering Committee, the Center will develop and execute a research plan for each natural product which will address any gaps in the preclinical data as well as describe plans for a clinical study (assuming the preclinical data support advancing to human subjects). The Center is expected to generate any necessary in vitro data to establish mechanism of the interaction, potency, critical metabolites, bioavailability, etc. Research plans should take into consideration the recommendations contained within the FDA guidance for industry regarding the design of drug interaction studies (https://www.fda.gov/media/108130/download and https://www.fda.gov/media/82734/download). These research plans will be developed in consultation with the NIH.

The Center also will continue to develop and maintain the existing repository for the deposition and permanent archiving of the resulting data. This repository has been established during the current cycle of funding and will be transferred, if necessary, to the successful applicant. The repository must continue to be structured and maintained such that it can be transferred at the end of the funding period, if necessary, to another entity. Additionally, the Center is expected to develop a publicly accessible, user friendly portal to allow for access to data and methodology in a rapid fashion. Importantly, the repository will need to accommodate the data generated by outside researchers, especially the companion R21 projects that will be engaged in medium to high throughput screening efforts to assay a larger number of plants and compounds for their ability to interact with various drug metabolizing enzymes and transporters.

The Center Director is expected to have broad experience in the field of pharmacology with a demonstrated track record of managing projects and data comparable to the scale and scope required for this initiative. Key personnel within the Center should include individuals with significant experience or knowledge in the following areas; the application should highlight the depth of experience and how it will be provided by the proposed team.

• Preclinical assessment of natural product drug interactions across a wide spectrum of targets, but primarily involving Phase I and Phase II metabolizing enzymes and small molecule transporters
• Evaluation of case reports, adverse event alert systems, primary literature and other toxicology evidence associated with natural product drug interactions
• Human subjects studies involving investigation of pharmacokinetic based drug interactions
• Sensitive quantitation of small molecules and their metabolites in biological fluids
• Sophisticated analytical methodology for performing quality control of complex natural products
• Management, organization, and integration of data from multiple sources including establishing databases and online portals for public access
• The Center will establish Cores to facilitate the execution of various aspects of the project. Cores are expected in the following areas: Administrative, Pharmacology, Analytical, and Informatics. The application should identify a leader for each of these Cores. The leader of each Core is also expected to serve on the Steering Committee.

The Center will be awarded as a cooperative agreement. As such, close interaction between the grantee and the NIH will be required to meet the objectives of this program.

A Steering Committee will be established by the Center to address issues that span all components and projects. This includes approval of high priority natural products and associated research plans. At a minimum, the Steering Committee will include the Center PD/PI, the Core leaders, the NIH Program Scientist, and additional NIH representatives as needed. NIH representation on the Steering Committee must be below 50% throughout the duration of the project. All members are expected to actively participate in all Steering Committee activities.

An External Advisory Panel (EAP) will be established to review the progress of all components of the program and provide recommendations to the NIH. The members with relevant expertise will be selected and invited by the NIH. The EAP is expected to have 4-6 permanent members; however, the membership may be changed as needed. The EAP will make recommendations in writing (made individually by each member and not by consensus) regarding progress of the program to NIH, and regarding including changes, if any, that would benefit the program. Applicants should not identify potential EAP candidates in their applications or contact potential EAP candidates prior to review.

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:

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

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 not allowed.

Applicant Organizations

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

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

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

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

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

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

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time. 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
Telephone: 301-594-3456
Email: [email protected]

Available Component Types	Research Strategy/Program Plan Page Limits
Overall	6
Admin Core	6
Core (Use for Pharmacology, Analytical, and Informatics Cores)	6 per Core

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: Required
• Administrative Core: Required
• Pharmacology Core: Required
• Analytical Core: Required
• Informatics Core: 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:

Research Strategy: This Center will provide broad leadership in the study of natural product drug interactions. Emphasize how the assembled team will work together to address the stated objectives of this initiative. This section should reveal a deep knowledge of the challenges associated with this type of research.

Describe overarching approach for identifying and prioritizing natural products with the potential for clinically significant interactions with medications. Explain the strategy for assessing the impact of potential interactions including identification of specific vulnerable populations where appropriate. Describe broadly plans for organizing and analyzing the resulting data and how they will be made available to the scientific community.

Describe how the structure and resources of the Center will allow for more productivity than could be achieved otherwise. The application should describe how the Center structure will maximally leverage expertise and resources to achieve synergy between the various components. Include a timeline that indicates how resources will be allocated throughout the lifespan of the project.

Describe how the Center would facilitate the transition of resources generated during this award to a potential successor at the end of the project period. This should include ongoing documentation of required software, hardware, and licenses, as well as ongoing maintenance of standard operating procedures, best practices, and other documentation for management of the Center. Inclusion of approaches and activities that will facilitate the transition of the activities and infrastructure of the Center, including content of the permanent repository and public website, at the end of the award period is expected.

Letters of Support: The applicant should include a detailed statement from the applicant's institution describing institutional commitment to this proposed Center. Letters should also be provided here for any collaborating institutions.

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.

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 human subjects research, clinical research, and/or NIH-defined 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

This Center will potentially perform a clinical trial for each proposed natural product. However, applicants should include just one Study Record for the first clinical trial to be conducted. Other clinical trials will be considered delayed onset. Reviewers will be asked to assess the rationale, design, timeline, and rigor of the proposed study.

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.

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.

The applicant should explicitly allocate resources so that Core Leaders and other Key Personnel are able to attend the Center's Annual Meeting. This meeting will alternate between the Bethesda area and the grantee institution or another location that is mutually agreed upon.

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 overall objectives of this Core.

Research Strategy: The Administrative Core will be responsible for all day to day operations of the Center. Applicants must describe how the Administrative Core will manage, coordinate and supervise the entire range of proposed Center activities. The application should describe the organizational structure and staff responsibilities of the Center participants. Describe how the PD/PI and the proposed Center staff will be organized in order to meet the specified objectives. Describe the scientific and managerial skills and expertise of the staff that will perform the various duties.

Importantly, the Administrative Core will be responsible for coordinating guidance and leadership to relevant research communities regarding how best to conduct research on pharmacokinetic natural product drug interactions. These outreach efforts should highlight areas where the methodology in existing literature has generated inconclusive or misleading evidence of clinically relevant interactions in humans. Examples include, but are not limited to, choice of preclinical models including guidance on when animal models are useful and when they are not, proper decisions regarding dosages relevant to human exposure, consideration of human pharmacokinetics when designing preclinical studies, distinction between statistical significance and clinical significance, and importance of measuring and reporting key variables regarding the product composition and formulation when publishing results. The application should include a detailed plan for communicating the clinical data, research methodologies, and resources developed by the Center. Furthermore, the application should include a model for how the Center will coordinate with the associated R21 grantees to import their results into the Center's data repository.

This section should also describe plans for how the Center will establish metrics of success for their outreach activities. There are a variety of ways this could be accomplished. These include, but are not limited to:

• Tracking visits to the Center website in terms of total views as well as unique visitors on a monthly or yearly basis
• Monitoring usage of the data repository including views of the data as well as uploads or downloads of the data
• Tracking citations of publications emerging directly from Center activities
• Invitations to present at national meetings directly related to the Center's research
• Attendance at any workshops organized by the Center on natural product drug interaction research
• Analysis of new publications by other research groups to gauge how effectively recommendations and guidance from the Center are being incorporated into new research efforts

The Administrative Core will also be responsible, in collaboration with the NIH, for establishing and coordinating activities of the Steering Committee. The Steering Committee should include the PD/PI as well as the leaders of the various Cores. Additional NIH membership will be identified post award. The applicant should describe plans for various Committee and Center management activities including regular meetings with Center staff and Steering Committee, attendance at annual meetings, collaboration with Interaction Project Teams, etc.

Milestones: The Administrative Plan should describe a set of milestones or defined objectives that the PD/PI and NIH staff can use for annual assessments of whether the proposed research and other activities of the Center are progressing appropriately toward the goals of the Center. Clearly describe (1) an overall detailed process and outcome evaluation plan for coordinating center activities, including milestones for each Core activity, and milestones for the overall coordination; (2) a clear description of interim objectives to be achieved for each activity during the course of the project; (3) potential impediments that could require a revision of the milestones with a discussion of possible solutions; (4) detailed quantitative and/or concrete criteria by which milestone achievement will be assessed; and (5) detailed schedules or timelines for the anticipated attainment of each milestone in each Core component and overall goals with alternatives should milestones not be reached. The proposed milestones or objectives for the out-years may be less detailed than those for the first year of the project.

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.

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 human subjects research, clinical research, and/or NIH-defined 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.

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.

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: Describe the overall objectives for this Core.

Research Strategy: The Pharmacology Core will be responsible for 1) the selection and prioritization of natural products to study and 2) development and execution of a subsequent research plan to study their potential drug interactions. Selection and prioritization should be based on a combination of criteria including, but not limited to, prevalence of use, evidence of emerging use, usage in specific vulnerable populations (based on possible combination of age, ethnicity, health status, genotype, etc.), severity of possible interactions, quantity and quality of existing data, etc. Natural products proposed may include a combination of those with a mild to moderate interaction potential in a very wide population or more significant interaction potential in a more narrow population. They may also include natural products which are thought to target a variety of CYP enzymes and transporters. Importantly, the natural products should all be complex products.

The applicants should describe in detail the criteria to be used for natural product selection. Applicants should describe the methodology by which they will prioritize among natural products of interest. Applicants should include a proposed list of 3-5 natural products which meet their criteria. Applicants should provide detailed research plans for specific natural products in their applications. However, it should be understood that there may be changes to the proposed list and/or the design of the research plan after consultation with the Steering Committee post-award. The research plans should address any gaps in the preclinical data as well as describe plans for a potential clinical study.

Preclinical work will likely be necessary to establish mechanism(s) of the interaction, potency, critical metabolites, bioavailability, etc. The research plans should take into consideration the recommendations contained within the FDA guidance for industry regarding the design of drug interaction studies (https://www.fda.gov/media/82734/download). The research plan should include a description of in vitro assay format, cell types to be used, target population, probe drugs, etc. to be used for each natural product.

The application should provide the criteria that will be used in evaluation of preclinical data to justify the need for further human subjects research. In anticipation of clinical trials run by the Center, the application should include estimations of potential number of participants needed, possible study design, samples to be collected, outcomes to be measured, etc. Applicants should assume that clinical trials will be conducted for all chosen natural products and budget accordingly. However, it should be understood that decisions regarding a clinical trial for each natural product will be made based on the strength of the preclinical data.

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.

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 human subjects research, clinical research, and/or NIH-defined 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.

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.

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: Describe the overall objectives of this Core.

Research Strategy: The Analytical Core will establish specifications for the selected natural products. These specifications should include quantification of specific constituents thought to be responsible for observed interactions as well as other major and minor components that allow for confident assessment of product integrity. The analysis plan should also include more untargeted measurements of the totality of compounds present as well as their relative abundance such that a chemical fingerprint can be established for each product. Subsequently, the Analytical Core will be tasked with securing a suitable source for that product that meets the established specifications. The Analytical Core will also have responsibility for conducting necessary analyses to verify the chosen product meets the established specifications. This work may include isolating constituents from complex mixtures to help identify key mediators of any observed interactions.

Importantly, these analyses should also include dosage performance tests in addition to verifying content. This work will be particularly important in planning for any clinical studies. The applicant should describe the approach to be used for setting specifications, sourcing, and testing of the chosen products. This may require a combination of analytical techniques based on the natural product. Describe the facilities available to conduct the necessary analyses.

The Analytical Core may also need to perform analyses of biological fluids to assess pharmacokinetic parameters associated with any clinical studies involving the natural product. Describe the procedures, methodology, and instrumentation that will be used or will be available for analysis of clinical research samples.

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.

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 human subjects research, clinical research, and/or NIH-defined 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.

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.

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: Describe the overall objectives of this Core.

Research Strategy: The Informatics Core will be responsible for maintenance and further development of the existing data repository. The applicant should describe the informatics infrastructure to be used and plans for long term sustainability and transferability of the repository. The application should describe possible models for sustaining the data repository in the absence of future NIH support. Furthermore, the Informatics Core should describe a plan for managing data submission including establishing a common format for data submission to the repository from outside researchers. Describe how the submitted data will be analyzed and made publicly available as appropriate and consistent with achieving the goals of the program. Applicants should also describe how they plan to manage concerns from outside researchers about public availability of deposited data that is not yet published. Applications should include a description of how will comply with FAIR data principles such that the data the repository

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.

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 human subjects research, clinical research, and/or NIH-defined 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 NCCIH, 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.

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

For this particular announcement, note the following: In their evaluation reviewers will weigh the relative strengths and weaknesses of each proposed Core by assessing how individually and collectively they will impact the Center overall in its ability to meet the stated objectives.

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 Core 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?

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

Specific to this FOA:

Considering the strategy proposed, will the center be able to establish the clinical relevance of pharmacokinetic interactions from a select number of natural products? Will the center be able to provide guidance and leadership to the broader research community on how best to research metabolism mediated drug interactions involving complex natural products? Does the proposed list of natural products adequately take into consideration the breadth of natural products in common use and the range of subpopulations that use them? How well do the described research plans allow for definitive assessment of potential interactions? Will the strategy for sourcing and analysis allow for generalizable statements regarding potential interactions involving that product considering the wide variability of product composition? Does the Center create synergy by effective interactions among the components and maximally leveraging resources? How will the center as designed be able to provide leadership in the study of NP drug interactions?

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?

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

Specific to this FOA:

Is there relevant and appropriate expertise across the Cores in natural products, pharmacology, toxicology and clinical research? Is there leverage of the expertise of the personnel across the Center? Does the PD/PI have necessary skills to effectively lead the 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?

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 application adequately address the following, if applicable:

Study Design

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

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

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

Data Management and Statistical Analysis

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

Specific to this FOA:

Are the plans describing overall management of the Center appropriate? Is the timeline realistic? Is the strategy for selection of natural products reasonable? Is the strategy for sourcing and methods of analysis of the high priority natural product rigorous enough to allow for definitive interpretation of any potential interactions? Are the described research plans reasonable? Does the proposed research have the potential to advance the field even if the proposed study design, methods, and intervention are not innovative?

Has the long term sustainability of the permanent data repository been sufficiently described? Are plans for management of data submission adequately described and appropriate? Will the plan for data analysis and public access result in distribution of readily available, easily understood information to the research community, consistent with achieving the goals of the program?

Are the plans for disseminating information about the processes, protocols, methods, and results of the Center appropriately targeted? Does the communications plan include a comprehensive set of activities and methods to inform the appropriate research communities of the Center’s work? Is the communications plan reasonable and likely to succeed?

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

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

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

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

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

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

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)?

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.

For Renewals, the committee will consider the progress made in the last funding period.

Not Applicable.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

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.

Review Criteria - Pharmacology Core

The Pharmacology Core will receive a merit descriptor (outstanding, acceptable, unacceptable) that reflects:

• Do the Pharmacology Core personnel have appropriate expertise in natural products to allow for critical analysis of the primary literature in choosing natural products for further study?
• How well does the application describe the strategy for selection and prioritization of the 3-5 natural products to be studied?
• Are the natural products proposed all complex mixtures?
• To what extent does the application provide justification for the public health impact of any potential interactions associated with the chosen natural products?
• How well does the research plan for this Core utilize existing guidance for drug interaction research? If there are deviations from this guidance are they well justified?
• Will the proposed preclinical research in this core provide sufficient data to make an informed decision about the need for future clinical studies?
• Are proposed study designs to assess potential drug interactions reasonable?

Review Criteria - Analytical Core

The Analytical Core will receive a merit descriptor (outstanding, acceptable, unacceptable) that reflects:

• Is the approach to be used for setting specifications, sourcing, and testing appropriate for the chosen products?
• Does the application provide a comprehensive plan for the analysis of each selected natural product including assessment of the content and dissolution profiles of the final formulation?
• How well does this plan describe how the products will be chosen such that they are representative of those used by consumers?
• Do the personnel in the Analytical Core have appropriate expertise in analysis of complex mixtures? Do they have necessary skills and experience in isolation and identification of known and unknown constituents?
• To what extent is the Analytical Core prepared for analysis of biological specimens collected in the clinical studies?

Review Criteria - Informatics Core

The Informatics Core will receive a merit descriptor (outstanding, acceptable, unacceptable) that reflects:

• Do the Informatics Core personnel have appropriate expertise in management of data repositories?
• How appropriate are the plans for the maintenance and further development of the already existing data repository?
• How reasonable are plans for establishing future sustainability and transferability of the data repository?
• How well does the application describe plans to accommodate data from external sources?
• How well developed are the plans for analyzing submitted data and incorporating it into the repository?
• To what extent does the repository comply with FAIR principles?

Review Criteria - Administrative Core

The Administrative Core will receive a merit descriptor (outstanding, acceptable, unacceptable) that reflects:

• Does the Administrative Core have personnel experienced in the dissemination of research methods and results?
• Does the application include a detailed plan for day to day operations of the Center including how the Administrative Core will manage, coordinate and supervise the entire range of proposed Center activities?
• Does the Core staff have the scientific and managerial skills and expertise to perform the outlined duties in an effective manner?
• How well does the application describe the organizational structure and staff responsibilities of the Center participants? Are the PD/PI and the proposed Center staff well organized in order to meet the specified objectives?
• Is there a reasonable plan for coordinating guidance and leadership to relevant research communities regarding how best to conduct research on pharmacokinetic natural product drug interactions?
• How will the proposed milestones ensure that the proposed center is progressing appropriately to its proposed goals?
• Are there clear metrics of success for their outreach activities?

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 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.

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that 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.

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

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

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

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

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

Awardee-selected projects that involve {clinical trials or studies involving greater than minimal risk to human subjects} require prior approval by NIH prior to initiation.

The awardee institution will provide NIH with written study protocols that address risks and protections for human subjects in accordance with NIH s Instructions for Preparing the Human Subjects Section of the Research Plan.

The awardee institution will provide NIH with specific plans for data and safety monitoring, and will notify the IRB and NIH of serious adverse events and unanticipated problems, consistent with NIH DSMP policies.

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.

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

• Overseeing day to day operations and overall budget, activities and performance of the Center as described above
• Establishing a Steering Committee whose role will be to review specific recommendations from the Center; representation on the Steering Committee will be allocated as described above
• Presenting recommendations for high priority natural products and detailed research plans to the Steering Committee and collaborating with the Steering Committee on revision of those plans as needed
• Organizing symposia, workshops, seminars, etc. to publicize and disseminate results
• Coordinating regular communication with project teams to facilitate execution of work plans for each natural product to be studied
• Collaborating across project teams to share experiences and issues related to execution of work plans
• Collaborating across project teams to increase harmonization of data and sharing of tools, methods, and approaches
• Establishing common data format to be used for deposition of data into repository
• Ensuring public access to the data resulting from this award and associated activities through maintenance of an online resource
• Planning face to face meetings of the Steering Committee and External Advisory Panel

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

The NCCIH Program Coordinator will have the following responsibilities:

• General oversight of project to monitor progress and achievement of objectives; this will include regular communication with the grantee, periodic site visits, and review of documents, plans and reports
• Providing input, advice, and suggestions to the Center based on NIH priorities and recommendations from prior workshops and expert panel discussions
• Establishing an External Advisory Panel whose role will be to review overall progress and provide broad input on an annual basis
• Serving as a point of contact to facilitate interactions across and between the grantee and other project team members and with the Steering Committee and External Advisory Panel
• Attending Steering Committee and External Advisory Panel meetings
• Additionally, an NCCIH Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of joint responsibility include:

• Coordinating workflow to maintain adequate progress across multiple projects simultaneously
• Participating in regularly scheduled meetings to monitor progress
• Participation in, and governance by, the Steering Committee; Steering Committee will be composed of Center PI, Core Leaders, the NCCIH Program Coordinator, representatives from the participating ICs

Dispute Resolution:

Any disagreement that may arise in scientific/programmatic matters (within the scope of the award) between award recipients and the NCCIH may be brought to dispute resolution. A dispute resolution panel will be composed of three members: one selected by the Steering Committee (with the NCCIH member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NCCIH, and the third member selected by the two prior members. This special arbitration procedure does not alter the awardee's right to appeal an adverse action in accordance with the PHS regulations at 42 CFR part 50, Subpart D and HHS regulation at 45 CFR part 16, or the rights of NCCIH under applicable statutes, regulations and terms of the award

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]

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

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

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

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.