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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Governments

• Eligible Agencies of the Federal Government, including the NIH Intramural Program
• U.S. Territory or Possession

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

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

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

Applicant organizations

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

• System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. SAM registrations prior to fall 2021 were updated to include a UEI. For applications due on or after January 25, 2022, the UEI must be provided on the application forms (e.g., FORMS-G); the same UEI must be used for all registrations, as well as on the grant application.
  • Dun and Bradstreet Universal Numbering System (DUNS) – Organization registrations prior to April 2022 require applicants to obtain a DUNS prior to registering in SAM. By April 2022, the federal government will stop using the DUNS number as an entity identifier and will transition to the Unique Entity Identifier (UEI) issued by SAM. Prior to April 2022, 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.

• eRA Commons - Once the unique organization identifier (DUNS prior to April 2022; UEI after April 2022) is established, organizations can register with eRA Commons in tandem with completing their full SAM and Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.

• Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

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

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

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

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST 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.

2. Content and Form of Application Submission

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.

Letter of Intent

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

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

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

The letter of intent should be sent to:

Wen Chen
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-451-3989
Email: [email protected]

Page Limitations

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

Instructions for the Submission of Multi-Component Applications

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
• Administration Core: required
• Clinical Core: required
• Data and Analysis Core: required
• Ancillary Project: optional

Overall Component

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.

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 Locations (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 and 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 goals for the proposed VESPA Center. Include a succinct summary of the Center and its relevant experience to the stated objectives of this solicitation. State the proposed Center's objective and significance to the field of vagal neuromodulation.

Research Strategy: Centers are expected be national leaders in facilitating the acquisition and analysis of clinical data. Applicants are encouraged to use this section to demonstrate that the Center’s activities are integrated into a cohesive and coherent unit.

• Describe how the Center will be structured and governed, having well-delineated roles and responsibilities. Clearly indicate the roles of participating institutions and key individuals, as well as plans for conflict resolution.
• Describe how the center will operate. Provide a narrative description of how the Cores and Project(s) will work together to support the objectives of SPARC VESPA.
• Applicants should provide examples of past successes relevant to the objectives of this FOA without duplicating information in biosketches.

Applications must include milestones for success that describe anticipated performance of the Center. Milestones proposed should be quantitative (e.g., "Data collected from 40 Participants by 18 months") rather than quantifiable (e.g., "we will report on the number of participant data collected ") or qualitative (e.g., "we will report on the data collected from participants").

Example Center Milestones and Timeline:

• Milestone 1 - By 6 months, data/knowledge management agreement completed among the VESPA Cores and Projects, and SPARC DRC establishing data workflow

• Success criterion: Data workflow plan finalized and approved by the NIH

• Milestone 2 – By 10 months, IRB approval for the common study protocol and all Ancillary Projects

• Success criterion: Documentation of IRB approval submitted to the NIH

• Milestone 3 – By 12 months, begin study participant enrollment

• Success criterion: First study participant enrolled

• Milestone 4 – By 18 months, at least 40 study participants enrolled in the common study protocol

• Success criterion: 40 study participants enrolled

• Milestone 5– By 24 months, at least 100 study participants enrolled common study protocol

• Success criterion: 100 study participants enrolled.

• Milestone 6– By 24 months, data from first 40 study participants is uploaded into the SPARC DRC (non-public facing) and summarized for NIH to demonstrate the fidelity and consistency of the stimulation parameters and outcome measures.

• Success criterion: data from 40 study participants uploaded to the SPARC DRC.

• Milestone 7 – By 30 months, data collected from all study participants

• Success criterion: Data uploaded to the SPARC DRC

• Milestone 8 – By 30 months, demonstration of at least one difference in outcome modulation observed across populations or parameters.

• Success criterion: Difference demonstrated statistically in report to NIH.

• Milestone 9 – By month 36, study manuscript, with links to associated datasets on the SPARC Portal, published to preprint server.
• Success criterion: Publication with scientific results.

Letters of Support: Applicants must provide letters from the appropriate senior institutional officials from the lead institution and partner institutions that:

• Commit the institution(s) to the Center goals, indicating that the program will be integral to their broad vision of informing clinical interventions.
• Define the institutional officials' positions and authority to commit the institutions.
• Provide evidence and/or assurances that adequate cooperative arrangements are in place between participating 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.

The following modifications also apply:

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

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.

PHS Assignment Request Form (Overall)

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

Administration Core

When preparing your application, use Component Type ‘Admin Core.’

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

SF424 (R&R) Cover (Admin 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 (Admin Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Admin 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) (Admin 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 (Admin 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 (Admin Core)

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

The Administration Core budget should include funds to perform all the required activities as specified by the RFA, including planning, coordinating, and implementing an annual VESPA Center meeting, supporting attendance and participation by all Core and Project PIs, NIH SPARC program representatives, and NIH-appointed Steering Committee members. The budget should include travel support for 4-6 NIH-appointed steering committee members for their participation in the annual VESPA meeting.

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

PHS 398 Research Plan (Admin Core)

Specific Aims: State concisely the goals of the Administration Core. Include a succinct summary of the core and its relevant experience to the stated objectives of this solicitation.
 

Research Strategy: This section should provide a clear description of the plan, timeline, and milestones to implement the proposed Administration Core activities, including but not limited to:

• Administrative responsibilities not covered by other VESPA components
• Planning, coordinating, implementing an annual VESPA Center meeting of all Core and Project PIs to support the objectives of the Center, and organizing and supporting other meetings (including but not limited to steering committee meetings, core meetings, and external advisory board/panel meetings at defined frequencies)
• Providing a meeting agenda and meeting materials in advance to participants of the VESPA Center annual meeting, including NIH and an NIH-appointed steering committee
• Developing and maintaining resources to facilitate communication and collaboration across VESPA components as well as dissemination of the study results both internally and to the external research community and general public.
• Engaging one or more patient advocates to participate in VESPA Center activities, including but not limited to, participation in annual meetings as well as review and selection of additional clinical sites and additional Ancillary Projects.
   

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

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

Appendix:

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

PHS Human Subjects and Clinical Trials Information (Admin Core)

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.

Clinical Core

When preparing your application, use Component Type ‘Clinical Core.’

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

SF424 (R&R) Cover (Clinical 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 (Clinical Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Clinical 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) (Clinical 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 (Clinical 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 (Clinical 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.

The applicant's budget should include travel funds for the PI(s) to attend the annual VESPA Center meeting. The applicant’s budget should include participant incentive costs for the common study protocol and any Ancillary Projects for all clinical sites for distribution to those sites upon successful enrollment of participants, instead of including those costs in partnering site(s) subaward budgets.

PHS 398 Research Plan (Clinical Core)

Specific Aims: The overall goal of the VESPA Center is to execute a common study protocol using standardized stimulation parameters and outcomes across a large number of individuals implanted with vagal nerve stimulators, to enable the optimization of VNS treatment by providing a multi-system view of the nerve’s functional connectivity in humans. In this section, describe the objectives and goals of the common study protocol, how the proposed project contributes to the overall goal of the VESPA Center, and how the clinical core will oversee and coordinate the implementation of the common study protocol and Ancillary Projects at all clinical sites.

Research Strategy: This section of the application should address the background and salient approaches and methods in the common study protocol with enough detail for critical evaluation of both the quality of the proposed research activities and how they contribute to the goals and objectives of the VESPA Center.

Address the following aspects of the proposed common study protocol:

• Significance of the proposed common study, the innovation of the science, and the details of the experimental approach (including a rationale for the methodology)

• Statistical and scientific rationale for the proposed number of participants

• Participant stratification that is scientifically and statistically justified to determine the intra- and inter-subject variability of the physiological responses across age, sex, VNS indication and treatment plan, comorbidities, and the VNS device type and manufacturer

• Scientific and/or clinical rationale for the proposed stimulation parameter(s) and protocol

• Scientific rationale for the physiological/clinical outcome measures to be acquired from each participant from at least three peripheral systems (e.g., gastrointestinal and digestive, cardiovascular, pulmonary, endocrine, immune and inflammatory, excretory, sympathetic nervous activity), with rationale for the temporal resolution of the measurements at acute, chronic, and/or remote assessments

• Data on the patient population available to recruit from for each clinical site

• Technology readiness of the tools/devices to stimulate the vagus and measure the proposed outcomes

• Regulatory status and/or requirements of the device(s) proposed for stimulation and measurement of the proposed outcomes

• Timeline and milestones for the common study protocol, broken down by enrollment prospects per site, and including any preparatory and/or start-up activities. Milestones should align with the overall milestones and goals of the Center.

• Potential strategies and solutions to enrollment challenges, in the event of enrollment shortfalls

• Use of novel study/trial designs, such as Adaptive Clinical Trials and Design of Experiments methodology

Address the following aspects of the Clinical Core functions related to oversight, support, and coordination across all study sites for the common study protocol and/or Ancillary Projects (if any):

• Overall design and structure of the Core, including its governance and management structure, integration of components, and any possible subcontracts

• Ensuring staff at all sites are trained and able to implement the stimulation and outcome measurement protocol, in coordination with the Clinical Core

• Plan for obtaining and maintaining compliance with all regulatory approvals

• The Data and Safety Monitoring Plan (DSMP) and selecting and managing the Data and Safety Monitoring Board (DSMB) and DSMB meetings

• Monitoring adherence and fidelity of the study protocols

• Plans for managing and distributing participant incentive funding to clinical sites upon successful enrollment of participants

• Communicating with the DSMB, Administration Core, and the NIH regarding protocol deviations and modifications as specified or required

• Developing, implementing, and monitoring study recruitment plans

• Ensuring proper transmission of data from all the clinical sites to the Data & Analysis Core

Collaboration across VESPA Center Components

Describe the willingness to coordinate and collaborate with other Center components, including via participation at an annual VESPA Center meeting, which will be facilitated by the Administration Core. Describe coordination with other VESPA components before study initiation to establish a workflow and data standards/structure for sharing data from the sites implementing the common study protocol and Ancillary Projects to the Data & Analysis Core.

Expertise, Experience, and Environment

Describe the relevance of the expertise of the research team at each clinical study site; how the clinical expertise of the proposed teams aligns with the outcome measures proposed; prior experience of key personnel with neuromodulation studies and large, multi-site clinical trials without duplicating information in biosketches; the strengths of the research environment, and ability to access to the proposed study population at each clinical study site.

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

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

Appendix:

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

PHS Human Subjects and Clinical Trials Information (Clinical Core)

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

Data and Analysis Core

When preparing your application, use Component Type ‘Data and Analysis’

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

SF424 (R&R) Cover (Data and Analysis)

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 (Data and Analysis)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Data and Analysis)

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) (Data and Analysis)

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 (Data and Analysis 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 (Data and Analysis)

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.

The applicant's budget should include travel funds for the PI(s) to attend the annual VESPA Center meeting.

PHS 398 Research Plan (Data and Analysis)

Specific Aims: The Data & Analysis Core is responsible for gathering and analyzing data acquired from the clinical sites and interfacing with the SPARC DRC to make data and resulting analyses available on the SPARC Portal, in a format that can be leveraged for designing and optimizing VNS treatments. This includes working with the Clinical Core to develop the common clinical protocol, modeling and analyzing the collected data, and collaborating with the SPARC DRC to establish processes for making data, knowledge, analyses, models, simulations, and/or visualizations available through the DRC. The applicant should describe the objectives and goals of the Data & Analysis Core, and how the proposed core will achieve these goals.

Research Strategy: This section of the application should address the background and salient approaches and methods in the Data & Analysis Core with enough detail for critical evaluation of both the quality of the proposed research activities and how they contribute to the VESPA Center.

Applicants should highlight the significance of the research project, the innovation of the science, and the details of the experimental approach (including a rationale for the methodology). Applicants should address the following aspects of the proposed study:

Ahead of study implementation:

• Describe plans to work with Clinical Core on developing the common study protocol, with a focus on what data are needed to achieve the necessary statistical power for modeling and analysis.

• Establish methods to collect and analyze physiological/clinical data from the clinical sites, including guidelines for capturing data in consistent formats, with sufficient metadata describing linkage between input variables (e.g., stimulation parameters, participant phenotypes, electrode placement, etc.) and specific physiological outcomes.

• Assist the Clinical Core with establishing details of data collection at the clinical sites and at-home/remote monitoring if applicable, as well as data processing at the sites and at the Data & Analysis Core, initial minimum set of data types, data/metadata standards, and any filtering/compression of the data performed prior to submission to the Data & Analysis Core. Work with the SPARC DRC to establish processes for leveraging SPARC data standards.

• Develop plans for analyzing the data to generate models, simulations, visualizations, and/or knowledge that will assist therapeutic developers in designing and optimizing VNS treatments. This should include plans for an interactive simulator to predict physiological outcomes based on a set of input variables, or to predict sets of input variables for achieving desired therapeutic outcomes.

• Develop data QA/QC processes between clinical sites and the Data & Analysis Core, including plans for data harmonization across sites.

• Describe plans to transfer data, analyses, etc. to the SPARC DRC for downstream consumption by the public.

While the study is ongoing:

• Monitor and assist sites with adherence to data/metadata collection and sharing workflows.

• Collect data and metadata from individual clinical projects and perform QA/QC.

• Provide interim analyses of the collected data and metadata to the other U54 Cores.

• Develop visualization, modeling, and simulation tools as necessary to provide insights into functional connectivity of vagal nerve as probed by established VNS. Identify possible system level effects and confounders. Monitor use of SPARC data standards by clinical sites, and work with the SPARC DRC to update these standards when necessary.

• Work with the SPARC DRC to ensure that the outputs of the Data & Analysis Core are made available on the SPARC Portal in a user-friendly manner. Models, simulations, and visualizations should be transferred to SPARC’s o2S2PARC platform (https://docs.osparc.io) as appropriate.

• Timeline and milestones for the Data & Analysis Core. Milestones should align with the overall milestones and goals of the Center.

• Willingness to coordinate and collaborate with the Center components, including via participation at an annual VESPA Center meeting, coordinated by the Administration Core

Describe the relevance of the expertise of the research team and environment; how the expertise of the proposed team aligns with goals of the Data & Analysis Core; prior experience of key personnel with analyzing data from large, multi-site clinical trials (without duplicating information in biosketches); and the strengths of the research environment.

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

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. The plan should include a description of interfacing with the SPARC Data and Resource Center for sharing data via the SPARC Portal.

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 (Data and Analysis Core)

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

Ancillary Project

When preparing your application, use Component Type ‘Ancillary Project.’

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

SF424 (R&R) Cover (Ancillary Project)

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 (Ancillary Project)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Ancillary Project)

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) (Ancillary Project)

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 (Ancillary Project)

• 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 (Ancillary Project)

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.

The applicant's budget should include travel funds for the PI(s) to attend the annual VESPA Center meeting. Budgets should not include participant incentives (participant incentives will be provided via capitation from the Clinical Core).

PHS 398 Research Plan (Ancillary Project)

Specific Aims: Describe the specific aims of additional vagal nerve stimulus targets and/or outcome measurements with the greatest chance of success.

Research Strategy:

• Describe how and why any additional vagal nerve stimulation target(s) or modality(ies) will add to the understanding of vagal regulation of multisystem organ function, and how direct comparisons will be made to the stimulus parameters in the common study protocol.

• Describe how and why any additional outcome measure(s) will add to the understanding of vagal regulation of multisystem organ function, and how direct comparisons will be made to the outcome measures in the common study protocol.

• If more than one site will be involved, provide a clear governance strategy

• Demonstrate willingness to coordinate and collaborate with the Center Cores, including via participation at an annual VESPA Center meeting, coordinated by the Administration Core.

• Provide a timeline with quantitative milestones and completion criteria for the Ancillary Project(s). Milestones should align with the overall milestones and goals of the Center

Letters of Support: Applicants may provide letters of support from institutions not previously included in the ‘Overall’ section of the application only if those letters of support are specific to work performed at sites under the scope of the proposed ancillary 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, with the following modification:

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

Appendix:

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

PHS Human Subjects and Clinical Trials Information (Ancillary Project)

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.

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

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

4. Submission Dates and Times

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

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies) 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.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

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

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 fieldof the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the unique entity identifier (DUNS number or UEI as required) provided on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

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

Applications Involving the NIH Intramural Research Program

Should intramural scientists submit an application through this FOA, or should an extramural application include a collaboration with NIH intramural scientists, the requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

If selected, appropriate funding will be provided by the Common Fund through the NIH Intramural Program. NIH intramural scientists will participate in this program as PD/PIs in accord with the Terms and Conditions provided in this FOA. Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above in the NIH Intramural Source Book.

Post Submission Materials

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

Section V. Application Review Information

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.

An overall score will be given to the entire U54. Additionally, each core and project will be reviewed and scored separately.

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

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

Significance

Does the VESPA 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 VESPA Center rigorous? If the aims of the VESPA 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 Center address the needs of the vagal neuromodulation community that it will serve? Is the scope of activities proposed for the Center appropriate to meet those needs? Will successful completion of the aims bring unique advantages or capabilities to the research consortium?

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

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the VEPSA 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 Center 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 investigators have appropriate expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Have they demonstrated experience in managing multi-site clinical trials, multi-organ physiology research, and data analysis and modeling? Are the plans for governance, conflict resolution, and organizational structure appropriate for the VESPA Center? Does the applicant have experience overseeing selection and management of subawards, if needed?]

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

Innovation

Does the 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 VESPA Center include innovative elements, as appropriate, that enhance the potential to inform the optimization of vagal neuromodulation? Does the approach involve novel strategies for implementing the common study protocol, such as adaptive clinical trials and design of experiments methodology?

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the VESPA Center? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed Center? 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 Center 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 VESPA 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?

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?

Does the environment enable the proposed participant recruitment plans?

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?

Review Criteria for the Administration Core

Reviewers will provide only one score/adjectival rating for the Administration Core (criterion scoring is not used for this component). Reviewers will consider the following criteria to determine an impact score:

• Are administrative responsibilities not covered by other VESPA components adequately described?
• Do the investigators have demonstrated experience supporting the implementation and providing logistics for multi-component research consortia?
• Is the plan to engage one or more patient advocates to participate in VESPA Center activities feasible and appropriate?
• Are plans clear and appropriate for coordinating with other VESPA components?

Review Criteria for the Clinical Core

Reviewers will provide only one score/adjectival rating for the Clinical Core (criterion scoring is not used for this component). Reviewers will consider the following criteria to determine an impact score:

Will the proposed stimulation parameter(s), protocol, and physiological/clinical outcome measures provide valuable and new information to inform the optimization, development, and/or specificity of vagal nerve stimulation as a therapy?

• Is the proposed study population appropriately scientifically justified? Is the target enrollment feasible and statistically justified to enable determination of variability of physiological responses to VNS parameters across the proposed study population and subgroups, including age, sex, VNS indication and treatment plan, comorbidities, and the VNS device type and manufacturer?
• Does the technology readiness and regulatory status of the stimulation and outcome measurement devices support the feasibility of the approach, milestone plan, and timeline?
• Does the research team include neuromodulation, clinical expertise, and experience that is relevant to the proposed common study protocol?
• Does the milestone plan include important benchmarks in the development and implementation of the common study protocol? Do milestones align well with the overall milestones and goal of the Center?
• Is the study timeline feasible, well justified, and sufficiently described to take into account any necessary preparatory activities and the anticipated rate of enrollment per clinical site?
• Does the data on the patient population at each proposed clinical site support the proposed target enrollment?
• Are potential strategies and solutions to enrollment challenges feasible and appropriate, in the event of enrollment shortfalls?
• Are plans clear and appropriate for coordinating with other VESPA components?
• Are the Clinical Core structure and governance adequate to oversee and support the implementation of the proposed common study protocol and/or Ancillary Project(s)?
• Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Review Criteria for the Data & Analysis Core

Reviewers will provide only one score/adjectival rating for the Data & Analysis Core (criterion scoring is not used for this component). Reviewers will consider the following criteria to determine an impact score:

• Will the proposed Research Plan result in efficient data/metadata collection at the individual clinical sites and subsequent transfer to the SPARC DRC for consumption by the scientific community?
• Will the proposed analysis, visualization, modeling, and/or simulation tools enhance data collection and enable more efficient therapeutic development by end users?
• Does the team include adequate expertise in data standards, statistics, data curation, annotation, and analysis? Have they successfully served in a role similar to the VESPA Data & Analysis Core?
• Has the team previously built visualization, modeling, and/or simulation tools that were adopted by the scientific community?
• Are plans clear and appropriate for coordinating with other VESPA components?

Review Criteria for Ancillary Project(s)

Reviewers will provide only one score/adjectival rating for each Ancillary Project (criterion scoring is not used for this component). Reviewers will consider the following criteria to determine an impact score:

• Does the additional vagal nerve stimulation target(s) or modality(ies) add actionable understanding of vagal regulation of multisystem organ function?
• Does the additional outcome measure(s) add actionable understanding of vagal regulation of multisystem organ function?
• Are the methods to compare with the stimulus and/or measurement protocol(s) used in the common study protocol appropriate and justified?
• Do the personnel and site(s) of the Ancillary Project(s) have the appropriate expertise and capability to perform the project?
• Do the milestones have appropriate completion criteria, and is the timeline aligned appropriately with the overall project?
• Are plans clear and appropriate for coordinating with other VESPA components?

As applicable for the VESPA 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.

Study Timeline

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Protections for Human Subjects

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed VESPA 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.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

As applicable for the VESPA 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) Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by convened by the Center for Scientific Review, 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 will receive a written critique.

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

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

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

3. Anticipated Announcement and Award Dates

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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in theNIH 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 recipient's business official.

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

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

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

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

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

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

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

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: Generaland Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federalwide Research Terms and Conditions
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

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

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex (including gender identity, sexual orientation, and pregnancy). This includes ensuring programs are accessible to persons with limited English proficiency and persons with disabilities. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

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

Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.

• For information on an institution's specific legal obligations for serving qualified individuals with disabilities, including reasonable accommodations and making services accessible to them, see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• For guidance on administering programs in compliance with applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 and 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of the 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 75, 2 CFR Part 200, 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 recipient is anticipated during the performance of the activities. Under the cooperative agreement, the NIH's 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 reside with the recipient for the project as a whole, although specific tasks and activities may be shared among the recipient and the NIH as defined below.

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

• Defining objectives and approaches, and for planning, conducting, analyzing, interpreting, drawing conclusions on their studies, publishing and sharing the results
• Developing and proposing rigorous milestones that will be achieved during the project period
• Retaining custody of and have all rights to the data and technology developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies
• Working closely with his/her institution's technology transfer officials to ensure that royalty agreements, license selection and application, patent filings, and all other necessary intellectual property arrangements are completed in a timely manner
• Providing complete progress reports that include experimental design with rigor, including assumptions for the design of the experiments, the results of the investigations, interpretations of the results, and for concluding whether milestones have been met or not. In cases when NIH program staff request raw data, recipient agrees to provide the data
• Communicating any regulatory meeting dates and agenda to the NIH program staff and inviting their participation
• Providing to the NIH letters and other forms of communications with FDA, and other authorities, and to provide IDE and registration numbers in clinicaltrials.gov, if applicable
• Providing regulatory and clinical documents that are required for administrative review
• Registering clinical trials and report results in ClinicalTrials.gov or Regulations.gov
• Uploading an IRB-approved informed consent form to ClinicalTrials.gov or Regulations.gov within 60 days of enrolling the last participant in the trial
• Providing names and a description of the relevant expertise of DSMB members to the NIH
• Providing reports from or summaries of DSMB meetings (inclusive of a listing of DSMB members participating in the meetings)
• Inviting NIH participation in open DSMB meetings
• Participating in NIH site visits as needed to ensure compliance with study administration procedures
• Ensuring all study staff involved in the clinical trial completes Good Clinical Practice (GCP) training
• Notifying NIH of major changes related to human subjects research, including: amendments to the protocol, termination of the protocol, temporary suspension of the protocol, changes in informed consent or IRB approval status, temporary suspension or permanent termination of participant accrual, other problems or issues that could affect the safety of participants in the study
• Presenting project updates (including raw data, when requested) in conference calls and/or, and/or SPARC Consortium meetings
• Providing approval of the protocol and written reports from meetings with the DSMB to the NIH
• Coordinating VESPA annual meetings and inviting NIH and the NIH-appointed steering committee
• Collaborating and communicating effectively with NIH and across the VESPA Center to achieve project goals.

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

• NIH Program staff will have substantial programmatic involvement during conduct of this activity, through technical assistance, advice, and coordination above and beyond the levels required normally for program stewardship of grants.
• Each project may have the support of one or more Subject Matter Expert(s) who are consulted based on their expertise in the areas relevant to the project. The responsibility of the SME(s) is to advise the Program Official on project approvals.
• NIH may appoint a VESPA steering committee to review the progress of the VESPA Center, assess the ability of the Center and its objectives to inform the optimization of vagal neuromodulation, and provide individual advice to the NIH regarding the VESPA Center’s objectives and milestone progress.
• NIH program staff provide input on the milestones and make recommendations regarding their finalization.
• NIH program staff will be responsible for assessing the progress of the project towards the specified milestones, and for recommending if further funds should be released to the project.
• NIH program staff, in consultation with the PIs, may in rare occasions add critical experiments or tests that need to be conducted prior to or during the award as an additional milestone(s). In some cases, these studies will be supported by additional funds from NIH.
• NIH program staff participate in meetings together with PIs with regulatory agencies related to the funded project.
• NIH program staff may consult as necessary with independent consultants or specialists with relevant expertise, assuming confidentiality agreements are in place to mitigate conflicts and protect intellectual property.
• A SPARC Program Director may be assigned with the primary responsibility for the overall coordination of research efforts across different funding mechanisms and research activities.
• In rare, well-justified occasions, future-year milestones may be renegotiated based on data and information obtained during the previous year.
• If, based on the progress report, a funded project does not meet the milestones, funding for the project may be discontinued, restricted, or reduced.
• The NCCIH Program Director will be responsible for normal programmatic stewardship as the Program Official.
• NIH will make decisions on project continuation based on:

• Successful achievement of milestones
• The overall feasibility of project advancement, considering data that may not have been captured in milestones
• Program priorities
• Availability of resources
• Availability of funds

Collaborative Responsibilities:

Clarifying and negotiating the milestones and timelines.

Coordination of site visits, if needed, at critical milestones or transition points of the award

The members of this collaborative effort should be made aware of the requirement for confidentiality due to any intent of the recipient to pursue commercialization of any qualified outcomes. Contractors and consultants of NIH will be made aware of the confidential nature of work done under this collaborative effort. The handling and disposition of this confidential data and business privileged information may be covered by the Trade Secrets Act, 18 U.S.C. Section 1905.

Dispute Resolution:

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

When multiple years are involved, recipients 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. NIH FOAs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

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

In accordance with the regulatory requirements provided at 45 CFR 75.113 and 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM)about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (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 75and 2 CFR Part 200 – Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

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]

Wen Chen, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-451-3989
Email: [email protected]

Center for Scientific Review (CSR)

Email: [email protected]

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

Section VIII. Other Information

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 and 2 CFR Part 200.