NIH’s new Application Submission System & Interface for Submission Tracking (ASSIST) is available for the electronic preparation and submission of multi-project applications through Grants.gov to NIH. Applications to this FOA must be submitted electronically; paper applications will not be accepted. ASSIST replaces the Grants.gov downloadable forms currently used with most NIH opportunities and provides many features to enable electronic multi-project application submission and improve data quality, including: pre-population of organization and PD/PI data, pre-submission validation of many agency business rules and the generation of data summaries in the application image used for review.

Required Application Instructions

It is critical that applicants follow the 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) and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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 2007 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 pairs. 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. At present, there is insufficient ability to distinguish or discriminate between the numerous signals of mild to moderate interactions. Furthermore, due to the highly variable, and occasionally inappropriate, 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, NIH is creating a program to establish definitive approaches for assessing the potential of natural products to produce clinically meaningful pharmacokinetic interactions with commonly consumed medications.

Spearheading this effort will be a Center of Excellence for Natural Product Drug Interaction Research (hereafter referred to as the Center). The initial focus of this program will be on pharmacokinetic interactions involving cytochrome P450 (CYP) metabolizing enzymes and small molecule transporters as these pathways represent the most common mechanisms of known drug interactions. A better approach to the study of such interactions may 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 create a roadmap for researchers rather than directly change clinical practice. 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 interactions with one or more pharmaceutical agents. Examples of possible natural products of interest to NIH include, but are not limited to, cannabinoids and green tea. Once the natural products are identified and prioritized, the Center and the NIH will work collaboratively to develop a statement of work (SOW) for the rigorous assessment of their potential for drug interactions using state of the science in vitro and clinical research methodology. The selection of medications to be studied will be driven by the FDA guidance for industry on drug interaction studies (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm292362.pdf) which has identified a suite of probe drugs for the most common CYP enzymes and transporters based on their safety and selectivity. Execution of the preclinical and clinical research will be funded separately through a series of Interaction Projects which will leverage, to the extent possible, significant capacity within federal labs and existing contracts. NIH expects to fund 1-2 such Interaction Projects annually. The resulting best practices and data will then be collected, organized, analyzed and made available through an open access repository by the Center to facilitate additional research hypotheses, improved research designs, and ultimately better informed health care decisions.

The Center will be expected to survey the available information on natural product drug interactions, including existing literature, public databases, adverse event reports, etc., to identify and prioritize candidate natural products for further study. The Center also will have primary responsibility for sourcing the natural products selected for Interaction Projects, performing necessary quality control, and subsequently drafting a detailed statement of work (SOW) for the ensuing Interaction Project. Through the course of this project, the Center will build a set of best practices establishing optimal approaches for assessing the clinical significance and relevance of interactions between natural products and various medications. Furthermore, the Center will be charged with organizing, analyzing, and archiving the results of that work through an open access repository. Lastly, the data and methodology generated should be actively pushed out to the research community to improve future research hypotheses and quality.

Primary objectives for the Center are to:

• Identify, prioritize and source a discrete (4-6) number of natural products that may exhibit clinically significant interactions with commonly used medications
• Work collaboratively with the Steering Committee, NIH appointed Advisory Panel and associated Interaction Project team members to develop and execute a SOW for each of the selected natural products which will address existing gaps in the scientific literature and result in a definitive assessment regarding the clinical relevance of any NP-Rx interaction
• Establish a set of best practices to address the unique challenges related to the study of drug interactions involving natural products which are often consumed as complex mixtures
• Archive, organize, analyze, and publicize the results of the program to allow for better design of future research and ultimately better decisions regarding health care management

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. Also, the list of natural products may include isolated constituents, partially purified mixtures containing a small number of compounds, as well as more complex products. NIH has particular interest in studying pharmacokinetic interactions involving cannabinoids and green tea.

Once the set of natural products is identified and approved by the Steering Committee, the Center will develop a detailed SOW 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). Preclinical work may be necessary to establish mechanism of the interaction, potency, critical metabolites, bioavailability, etc. NIH will use that SOW to execute the work through a series of separately funded Interaction Projects most likely through existing federal labs and contracts. SOWs should take into consideration the recommendations contained within the FDA guidance for industry regarding the design of drug interaction studies (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm292362.pdf).

The Center will continue to collaborate throughout the duration of the Interaction Project through participation in various project teams involved in project oversight. The Center is expected to establish uniform data format requirements that will be adopted across all Interaction Projects. The Center will also establish a repository for the deposition and permanent archiving of the resulting data. The repository should be designed 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 publically accessible, user friendly portal to allow for access to data and methodology in a rapid fashion.

The Center, in collaboration with NIH, will be responsible for identifying 4-6 natural products with potential to have clinically meaningful interactions with medications. Based on the existing literature, the research questions will be different for each of the selected natural products. Therefore, the Center will also be charged with developing a detailed SOW for each natural product to answer specific scientific questions. This may include a need for additional in vitro and in vivo studies to establish the mechanism of possible interactions, potency of inhibition or induction, and early stage clinical work to establish critical pharmacokinetic properties before possibly proceeding to a definitive clinical drug interaction study if warranted. Design of the studies through each step should be guided by the FDA guidance for industry regarding drug interaction studies (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm292362.pdf). However, that guidance was written specifically to address drug-drug interactions and may need modification for studies involving complex mixtures of phytochemicals. Importantly, it is assumed that the necessary clinical studies will maximize safety through use of probe drugs as a proxy for any narrow therapeutic index drugs. The Center will present recommendations for high priority natural products along with an accompanying detailed SOW to the Steering Committee. The Steering Committee will review the recommendations, suggest revisions as appropriate, and make final decisions about which products are selected for Interaction Projects. The NIH will then determine the most cost effective approach for executing the necessary work. This may include, but is not limited to, leveraging existing federal resources, Administrative Supplements to existing NIH grants, new research initiatives (RFA), or by establishing new contracts (RFP). Typically, strong preference will be to leverage existing federal investments. There is substantial capacity either through internal governmental facilities or through existing contracts to carry out a wide range of preclinical and clinical studies of the type and scope expected through this program.

For each Interaction Project, a project team will be established. This team will include representation from the Center, the Steering Committee, the NIH and other membership as needed. Close communication of team members is expected during the duration of the individual Interaction Projects. The Center, with input from the Interaction Project Team, will be responsible for establishing specifications for the natural product. Subsequently, the Center will handle sourcing the natural product and ensuring the sourced product meets established specifications by conducting independent analyses as needed. Once properly vetted, the natural product will be provided to NIH to execute the SOW. The Center will take the lead in organizing regular meetings of the Interaction Project Team to assess progress. If changes to the SOW become necessary, these should be approved by the Steering Committee before implementation.

The Center will organize and coordinate data for all Interaction Projects. This will entail managing workflow across multiple Interaction Project Teams and harmonizing the reporting of data across projects into a consistent format. Critically, the Center will be tasked with establishing both a user friendly public access portal and a permanent repository for the data. The permanent repository should be designed to be transferrable to a potential successor if needed.

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 CYP 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 SOW. 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 regarding progress of the program to NIH including changes, if any, which would benefit the program. Applicants should not identify potential EAP candidates in their applications or contact potential EAP candidates prior to review.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to 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) (formerly CCR) 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 and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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.

The Center Director must also be a Leader of at least one of the Cores and must commit a minimum of 3.6 person months to the project.

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).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants can access the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

Most applicants will use NIH’s ASSIST system to prepare and submit applications through Grants.gov to NIH. Applications prepared and submitted using applicant systems capable of submitting electronic multi-project applications to Grants.gov will also be accepted.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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:

D. Craig Hopp, Ph.D.
Telephone: 301-496-5825
Email: hoppdc@mail.nih.gov

Component Types Available in ASSIST	Research Strategy/Program Plan Page Limits
Overall	6
Admin Core	6
Core (use for Pharmacology Core, Analytical Core, Informatics Core)	6

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 in ASSIST, use Component Type Overall .

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

SF424 (R&R) Cover (Overall)

Complete entire form.

PHS 398 Cover Page Supplement (Overall)

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

Research & Related Other Project Information (Overall)

Follow standard instructions.

Project/Performance Site Location(s) (Overall)

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.

Research & Related Senior/Key Person Profile (Overall)

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.

Budget (Overall)

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.

PHS 398 Research Plan (Overall)

Specific Aims: Describe the long range objectives for the Center.

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. Provide an outline for developing best practices to guide future research. 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 proposed plan for each specific objective and administrative support of the Center would facilitate the transition of those activities to a potential successor at the end of the five-year 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 (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When preparing your application in ASSIST, use Component Type Admin Core.

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

SF424 (R&R) Cover (Administrative Core)

Complete only the following fields:

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

PHS 398 Cover Page Supplement (Administrative Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Administrative Core

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.

Project /Performance Site Location(s) (Administrative Core)

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.

Research & Related Senior/Key Person Profile (Administrative Core)

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

Budget (Administrative Core)

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.

PHS 398 Research Plan (Administrative Core)

Specific Aims: Describe the overall objectives of this Core.

Research Strategy: The Administrative Core will be responsible for all the 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 developing and disseminating best practices for future research on natural product drug interactions based on the data collected and generated throughout the course of this project. Best practices 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 describe a strategy for development and dissemination of best practices. The application should include a detailed plan for communicating the clinical data, research methodologies, and resources developed by the Center. Furthermore, the application should describe specific expertise of Center personnel in the communication of research methods and results that extends beyond publication of research papers.

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.

Milestones for the Proposed Administrative Core: The applicants must address the Milestones listed below and provide realistic plans substantiating their capabilities to meet these Milestones.

• By the end of 3 months of the project period The Administrative Core must establish the membership of the Steering Committee and hold an initial teleconference meeting.
• By the end of the first year of the project period - The Administrative Core must establish a list of best practices to be developed.
• By the end of the second year of the project period - The Administrative Core must have completed development of at least one fourth of the proposed best practices.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Administrative Core)

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report (Administrative Core)

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

When preparing your application in ASSIST, use Component Type Core.

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

SF424 (R&R) Cover (Pharmacology Core)

Complete only the following fields:

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

PHS 398 Cover Page Supplement (Pharmacology Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Pharmacology Core)

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.

Project /Performance Site Location(s) (Pharmacology Core)

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.

Research & Related Senior/Key Person Profile (Pharmacology Core)

In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.

• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Pharmacology Core)

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.

PHS 398 Research Plan (Pharmacology Core)

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 of a subsequent SOW to study its 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. Also, the list of natural products may include isolated constituents, partially purified mixtures containing a small number of compounds, as well as more 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 4-6 natural products which meet their criteria. NIH has particular interest in exploring pharmacokinetic interactions involving cannabinoids and green tea. Once the set of natural products are identified and approved by the Steering Committee, the Pharmacology Core will also have primary responsibility to develop a detailed SOW for each natural product which will address any gaps in the preclinical data as well as describe plans for a clinical study. Preclinical work may be necessary to establish mechanism of the interaction, potency, critical metabolites, bioavailability, etc. NIH will use that SOW to execute the work through a series of separately funded Interaction Projects. Importantly, there is significant capacity through existing federal labs and contracts to carry out much of the anticipated research. SOWs should take into consideration the recommendations contained within the FDA guidance for industry regarding the design of drug interaction studies (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm292362.pdf). Applicants should NOT provide detailed SOW for specific natural products in their applications. Rather, the application should describe a strategy that will be followed in developing the SOW. This should include a description of in vitro assay format, cell types to be used, target population, etc. to be used in different scenarios.

Milestones for the Proposed Pharmacology Core: The applicants must address the Milestones listed below and provide realistic plans substantiating their capabilities to meet these Milestones.

• By the end of 6 months of the project period - The Pharmacology Core must have in place an approved list of 4-6 natural products proposed for further study.
• By the end the first year of the project period The Pharmacology Core must present a detailed SOW describing further preclinical and clinical research on 1-2 of the approved natural products.
• By the end of the second year of the project period The Pharmacology Core must have developed detailed approved SOW for the remaining natural products.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Pharmacology Core)

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report (Pharmacology Core)

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

When preparing your application in ASSIST, use Component Type Core.

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

SF424 (R&R) Cover (Analytical Core)

Complete only the following fields:

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

PHS 398 Cover Page Supplement (Analytical Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Analytical Core)

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.

Project /Performance Site Location(s) (Analytical Core)

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.

Research & Related Senior/Key Person Profile (Analytical Core)

In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.

• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Analytical Core)

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.

PHS 398 Research Plan (Analytical Core)

Specific Aims: Describe the overall objectives of this Core.

Research Strategy: The Analytical Core will establish specifications for the selected natural products. 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. Importantly, these analyses should also include dosage performance tests in addition to verifying content. 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.

Milestones for the Proposed Analytical Core: The applicants must address the Milestones listed below and provide realistic plans substantiating their capabilities to meet these Milestones.

• By the end of 6 months of the project period The Analytical Core must identify appropriate quality specifications for the first 1-2 approved natural products.
• By the end of 9 months of the project period The Analytical Core must have identified suitable sources of the first 1-2 natural products and obtained sufficient material for subsequent experimentation.
• By the end of the first year of the project period - The Analytical Core must have completed QC analysis of the sourced 1-2 natural products.
• By the end of the second of the project period - The Analytical Core must have established specifications, sourced, and verified specifications for the remaining natural products to be studied.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Analytical Core)

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report (Analytical Core)

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

When preparing your application in ASSIST, use Component Type Core.

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

SF424 (R&R) Cover (Informatics Core)

Complete only the following fields:

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

PHS 398 Cover Page Supplement (Informatics Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Informatics Core)

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.

Project /Performance Site Location(s) (Informatics Core)

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.

Research & Related Senior/Key Person Profile (Informatics Core)

In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.

• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Informatics Core)

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.

PHS 398 Research Plan (Informatics Core)

Specific Aims: Describe the overall objectives of this Core.

Research Strategy: The Informatics Core will be responsible for establishing a permanent, publicly accessible, repository for the resulting data as well as creating a user friendly public portal for dissemination of the findings. The applicant should describe the informatics infrastructure to be used and plans for long term sustainability and transferability of the repository. The applicant should use existing infrastructure where possible. If using existing infrastructure, the applicant should describe how they plan to utilize or adapt that resource. Furthermore, the Informatics Core should describe a plan for managing data submission including establishing a common format for data submission to the repository across all Interaction Projects. Describe how the submitted data will be analyzed and made publicly available as appropriate and consistent with achieving the goals of the program.

Milestones for the Proposed Informatics Core: The applicants must address the Milestones listed below and provide realistic plans substantiating their capabilities to meet these Milestones.

• By the end of 6 months of the project period The Informatics Core must identify the infrastructure for the permanent repository as well as the public portal.
• By the end of the first year of the project period - The Informatics Core must have an operational data interface for deposition of Interaction Project data.
• By the end of the second of the project period - The Informatics Core must have established a uniform data format for deposition into the repository.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Informatics Core)

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report (Informatics Core)

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. 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.

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.

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 Applying Electronically.

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 by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

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 method that by its nature is not innovative may be essential to advance a field.

Significance

Does the Center address an important problem or a critical barrier to progress in the field? 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?

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? Will the strategy for developing SOWs 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?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the Center? If Early Stage Investigators or New Investigators, or 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?

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? Is there relevant and appropriate expertise in toxicology and clinical research? Do the Analytical Core personnel have appropriate expertise in the chemical characterization of natural product mixtures? Do the Informatics Core personnel have appropriate expertise in management of large data sets? Is there leverage of the expertise of the personnel across the Center? Does the Administrative Core have personnel experienced in the dissemination of research methods and results?

Innovation

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

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Center? 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?

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 children, justified in terms of the scientific goals and research strategy proposed?

Are the plans describing overall management of the Center appropriate? Is the timeline realistic? Have plans to develop and disseminate best practices been adequately described? 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 strategies for development of statements of work reasonable? Has the long term sustainability of the permanent data repository been sufficiently described? If using an existing resource, are plans for using and adapting that resource adequately described? Are plans for management of data submission adequately described and appropriate? Will the public portal allow for interaction with interested groups (e.g. researchers, practitioners, consumers)? Will the plan for data analysis and public access result in distribution of readily available, easily understood information to the general public, 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?

Environment

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

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

Transition Plan

Do the specific objectives and administrative support of the Center facilitate transition to a potential successor? Are there plans for ongoing documentation of required software, hardware, and licenses, and maintenance of standard operating procedures, best practices, and other documentation for management of the Center?

Milestones

Does the proposed plan detail the strategies to be used in order to reach all the milestones specified for each core? Is the plan to reach the milestones in the prescribed time clear and feasible? How well does the management structure support achievement of the proposed goals and milestones?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six 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 six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children

When the proposed activity 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 children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by NCCAM 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 NCCAM Advisory Council. 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.
• A set of Center milestones or objectives will be negotiated with program staff prior to the award.

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.

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.

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.

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 Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), 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
• Organizing Working Groups as described above to facilitate flow of information and speed progress of Interaction Projects from conceptualization to execution
• 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 SOW 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 across project teams 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 which will allow access to raw data as well as summaries and interpretations of results
• Planning face to face meetings of the Steering Committee and External Advisory Panel
• The awardee will retain custody of and primary rights to any software developed under these awards

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

The NCCAM 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
• NIH will maintain ownership of all data generated through the course of this award
• Additionally, an NCCAM 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:

• Establishment of and participation in Interaction Project teams to execute work plan for individual natural products projects; project teams will be composed of one representative from the Center, the NCCAM Program Coordinator, one representative from the Steering Committee, and additional representatives as needed
• Coordinating workflow to maintain adequate progress across multiple Interaction 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 NCCAM 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 NCCAM may be brought to dispute resolution. A dispute resolution panel will be composed of three members: one selected by the Steering Committee (with the NCCAM member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NCCAM, 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 NCCAM under applicable statutes, regulations and terms of the award.

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590 or RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

Progress toward the milestones or objectives should be reported annually, and the milestones will be reconsidered, and renegotiated if necessary, as part of the annual non-competing continuation application process.

A final progress report, 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.

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
Email: GrantsInfo@nih.gov

D. Craig Hopp, Ph.D.
National Center for Complementary and Alternative Medicine (NCCAM)
Telephone: 301-496-5825
Email: hoppdc@mail.nih.gov

Dale L. Birkle Dreer, Ph.D.
National Center for Complementary and Alternative Medicine (NCCAM)
Telephone: 301-451-6570
Email: birkled@mail.nih.gov

George Tucker, MBA
National Center for Complementary and Alternative Medicine (NCCAM)
Telephone: 301-594-9102
Email: gt35v@nih.gov

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 Parts 74 and 92.