Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

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

In May of 2013 the National Institute of Neurological Disorders and Stroke (NINDS), with input from the National Institute on Aging (NIA), held an Alzheimer's Disease-Related Dementias Conference in response to the National Plan to Address Alzheimer's Disease. The Conference brought together national and international experts and members of the public to develop research priorities for accelerating the development of therapies for the Alzheimer's disease-related dementias (ADRDs). The ADRD 2013 research recommendations that resulted are part of the National Plan to Address Alzheimer's Disease. This FOA addresses the National Plan's highest priority for human-based research on vascular contributions to cognitive impairment and dementia (VCID): to develop noninvasive markers of key vascular processes related to VCID in Alzheimer's and related dementias. The research program initiated here underscores the need to facilitate the development of biomarkers to improve the efficiency and outcome of Phase II and III clinical trials and advance therapeutic development. These companion FOAs (RFA-NS-16-019, i.e. this FOA; and RFA-NS-16-020 for the Biomarkers Development Projects) establish the Small Vessel VCID Biomarkers Consortium, and are focused on small vessel (i.e. arterioles, capillaries, and venules) VCID in vascular cognitive impairment (VCI), vascular dementia, and all mixed and pure cognitive impairment and dementias with contributing small vessel vascular disease, including such as commonly occurs in sporadic Alzheimer's disease. Awards funded under these two FOAs create a consortium and infrastructure to complete development projects as well as planning that will enable follow-up activities (to be carried out under future separate funding; for example large scale multi-site validation studies and other activities, for future FDA qualification of small vessel VCID biomarkers and use in clinical trials).

Applicants are strongly encouraged to consult with NINDS Scientific/Research Staff early on during the planning stage of their application (see Agency contacts, Section VIII). See also Applicant Webinar information under Section IV.7 below ("Other Submission Requirements and Information").

The Small Vessel VCID Biomarkers Consortium Coordinating Center will provide a common support infrastructure that is essential to the goals of this program. The timing of Coordinating Center activities will be in parallel with the timing of Development Projects which will: study promising biomarkers as individual projects and concurrently work with the Coordinating Center to establish the interactive consortium (UH2, years 1-2); and then work together within the consortium to perform collaborative cross-project multi-disciplinary studies to further evaluate and develop the most promising biomarker candidates (UH3, years 3-5) to the point of being fully ready for large scale multi-site clinical validation studies including toward FDA qualification of small vessel VCID biomarkers for phase II clinical trials (to be carried out under future separate funding).

The Coordinating Center will establish and maintain an Administrative Core and a Data Core. All NIH/NINDS sharing policies are expected to be followed throughout the project. For data sharing, during years 1-2, the Coordinating Center will drive preparation for data submission to and sharing by the Data Core that will occur during years 3-5. While the Coordinating Center will not bank and share biospecimens, it will be responsible for coordinating biospecimen (e.g. whole blood, plasma, serum, or cerebrospinal fluid) banking and sharing by Consortium members: during years 1-2 the Coordinating Center will drive Consortium preparation for sharing biospecimens via NINDS repositories that will occur during years 3-5.

The Coordinating Center will be expected to maintain the necessary infrastructure and service-oriented staff with top level expertise in all necessary information technology and clinical database development and implementation. Ideally, the Coordinating Center will also include staff with high competency and understanding of other aspects of the Small Vessel VCID Biomarkers Consortium needed to be a valuable and active collaborator, for example: human subjects considerations, clinical data relevant to small vessel vascular contributions to cognitive impairment and dementia, biological samples and imaging for biomarker discovery, control data, standardization, and implementation including for electronic submission of data, webcatalog development for distribution of data, and relevant best practices.

Administrative Core

The Administrative Core will organize, coordinate and administratively drive Consortium-specific activities including: establishing all committees (except the Advisory Committee, which will be established by the NINDS); driving the logistics of committee activities including, for example, scheduling, soliciting agenda items, finalizing and distributing agendas, arranging calls including conference calls, minutes (drafting, editing based on Consortium input, and finalizing), and conflict resolution; establishing a core set of clinical data elements (all submitted clinical data will be de-identified), including for cognitive outcomes and assessments that are sensitive to change, or predictive of functional cognitive impairment; all logistic and financial requirements for in person Consortium meetings including meeting space, accommodation, travel, per diem reimbursement, etc.; required sharing activities including providing support and advice to Development Projects on informed consent and for coordinating NINDS repositories as needed.

Data Core

The Data Core will establish infrastructure, including for real time data entry, to collect, curate for quality (e.g. accuracy, completeness, and internal consistency), display, house, and distribute (within the consortium and with external scientists after appropriate publication) data, including de-identified clinical data and imaging data. Once established, the Data Core will build into its infrastructure the core set of de-identified clinical data elements agreed upon by the Consortium. The Data Core will provide full instructions and support for submitting data, and for obtaining data from the Core.

Small Vessel VCID Biomarkers Consortium Committees and Meetings

The Small Vessel VCID Biomarkers Coordinating Center Administrative Core will serve as the consortium's information, data, and administrative hub, will organize meetings, and will work closely with the Scientific Project Officer as well as the VCID Biomarkers Development Projects within the Consortium.

Considerations for sharing and informed consent

It is required that all biospecimens and data collected and/or used for research under funding from this FOA (including extant samples) have appropriate informed consent per NIH policy and as mandated by law.

When new biospecimens and clinical data are collected during year 3 to year 5, consent must allow all enrolled individuals the opportunity to consent to share, via NINDS repositories, their de-identified samples and data to researchers in academics, not for profits, and industry (for internal research only, for profit use is not allowed). Considerations that Consortium investigators should include in consent forms for samples and data collected during year 3 to year 5 are as follows:

• That the sample and de-identified clinical data may be submitted to an NINDS repository or database, research resources supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke
• The de-identified samples and clinical data will be securely stored at the repository or database
• No personal identifiers will be sent with samples and data
• Blood samples may be used for preparation of DNA, plasma, serum, and cells that may be used for cell culture, including stem cells, from which DNA can be prepared; other biological samples may be collected as applicable, for example cerebrospinal fluid
• The de-identified samples (and their derivatives) and clinical data can be distributed to scientists for use in research and teaching only, and as such the Repository does not return results to donors
• The de-identified samples and clinical data could be used for research in any type of disease or genetic factors, not just vascular contributions to cognitive impairment and dementia
• The de-identified samples and clinical data will be available for research and teaching purposes to hospitals, universities, not for profit research organizations, and commercial organizations
• The de-identified samples and clinical data will be used for research only, and will never be distributed for profit
• There is a risk that someone could use information from the sample submitted, via DNA, to identify the person from which it came if it were matched with another DNA sample provided by that person. However, any user of this sample must agree not to use it for that purpose, and the risk, while real, is small.
• Individuals have the right to withdraw from this research project at any time. If possible, any samples contributed will be discarded if requested; however, because of the sample masking, NINDS may not always be able to identify which samples were donated by a specific person. Withdrawal from the study will in no way affect access to medical care for which the subject is eligible.

It is expected that any embargo time will follow NINDS guidance (2 years maximum for biospecimens; release at time of relevant publication for data). Following submission to NINDS repositories, samples are subject to NINDS policy and oversight.

When submitting to relevant NINDS database and/or repositories, investigators must provide up to date and officially IRB-approved and NINDS-approved (template) consent forms; these forms are the NINDS record of appropriate handling of consent. A copy of the consent form for each subject should be kept on file by the project investigator but does not need to (and should not be) sent with samples and data submitted.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

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

Applicant Organizations

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

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

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

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

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

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

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

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

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

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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

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

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

The letter of intent should be sent to:

Roderick A. Corriveau, Ph.D.
Telephone: 301-496-5680
Fax: 301-480-1080
Email: roderick.corriveau@nih.gov

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

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

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

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

The PDs/PIs should have experience and demonstrated excellence technically, in communication, in large scale geographically dispersed consortia in neurological and/or biomarkers research, in neurological clinical data, in sharing data (collecting, banking, receiving, curating, distributing de-identified clinical data), and in informed consent that will ensure successful leadership of the Coordinating Center. Ideally, leadership for the Consortium will have proven success and a strong plan for facilitating interactions, e.g. data requests, harmonization, transfer, sharing, etc., with other databases such as dbGAP, PDBP, LONI, NACC, NINDS Repositories, and NCRAD.

It is also critical to the success of the Small Vessel VCID Biomarkers Consortium that the two Cores (Administrative and Data) interact effectively with the Biomarkers Development Projects, the NINDS, as well as with each other. Therefore, in addition to strong leadership and staff with highly specialized expertise needed for each Core, both the Administrative Core and the Data Core must include a 6.6 person months per year, or more if justified dedicated staff member as Key Personnel who: (i) will be the point of contact for their respective Core; and (ii) is highly motivated, has excellent communications skills, and has significant training and/or experience with BOTH the IT and the biological/clinical data/scientific subject matters that are essential to the success of this Consortium.

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

The budget must reflect the actual needs of the proposed project. The Coordinating Center will budget all funds for all activities associated with and for all participants (travel, lodging, food) in the Kickoff and Annual meetings.

Applications must budget funds for banking biospecimens in NINDS repositories planned for years 3-5; no biomarkers specimens from the Consortium will be banked in NINDS repositories during years 1-2. These funds for banking biospecimens should be budgeted at $250,000 total costs per year during each of years 3-5; these funds are dedicated to cover costs of banking biospecimens at NINDS repositories and as reported by NINDS Repositories (e.g. the NINDS Biomarkers Repository currently housed at Indiana University) and are not available for any other use at or by the Coordinating Center.

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

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

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

Specific Aims: State the specific aims to convey understanding of and a clear strategy for implementing the goals of the FOA. Indicate how the Small Vessel VICD Biomarkers Consortium Coordinating Center will, via an Administrative Core and a Data Core, provide a common support infrastructure that is essential to the goals of the Small Vessels VCID Biomarkers Consortium.

Research Strategy: Organize the Research Strategy by Significance, Innovation, and Approach. A milestone plan, under separate heading, must be included in the approach.

Significance: The Significance section should provide justification and rationale indicating that the proposed team and plan can fulfill the Coordinating Center's role as the Consortium's information, data, and administrative hub, and in doing so will work closely, expertly, collegially and effectively with the Development Projects, the NINDS/NIH, and relevant members of the biomarkers scientific community.

Innovation: Describe the leading edge and innovative attributes that the proposed Coordinating Center offers the Consortium, for example in IT, data management, communication strategies, approaches to organization of meetings and conference calls, and other activities that are the responsibility of the Coordinating Center. The application should provide evidence of harmonization of data across platforms for metanalyses.

Approach: The approach should address administrative commitment and ability, and technical ability, to carry out the functions of the Coordinating Center. The Approach section should be organized by Administrative Core, Meetings and Committees, Data Core, and Milestone Plan.

Administrative Core: Describe the overall management plan, organizational hierarchy of the Coordinating Center, its administrative structure, the communication plan, and the conflict resolution plan. Describe how the Administrative Core will organize, coordinate and administratively drive Consortium-specific activities including: establishing all committees (except the Advisory Committee, which will be established by the NINDS); logistical components of committee activities including, for example, scheduling, soliciting agenda items, finalizing and distributing agendas, arranging calls including conference calls, minutes (drafting, editing based on Consortium input, and finalizing); establishing a core set of standardized VCID clinical data elements to be used for harmonized and sharing, including for cognitive outcomes and assessments that are sensitive to change, or predictive of functional cognitive impairment; all logistic and financial requirements for in person Consortium meetings including meeting space, accommodation, travel, per diem reimbursement, etc.; required sharing activities including providing support and advice to Development Projects on informed consent and for coordinating with NINDS repositories. The application should describe how the Administrative Core will work with multiple and de-centralized investigators and end users, schedule large (dozens of participants) interactive and possibly international conference calls including with visual support.

Meetings and Committees: Describe how the Administrative Core will establish and drive all meetings and Committees, in consultation with the Scientific Project Officer. Note that the External Advisory will be appointed by the NINDS. Indicate how Consortium members (from both the Development Projects and the Coordinating Center) will be selected for Committees by nomination and vote (NINDS/NIH will be represented on Committees as well).

• Consortium Kickoff and Annual Meeting Committee
• Core Standardized Clinical Data Elements Committee, including subcommittees on:
  A. Clinical Data, Physiological Data, and Cognitive Assessments
  B. Imaging Biomarkers Data
  C. Fluid-Based Biomarkers Data

• Protocol Standardization and Biospecimen Best Practices Committee
• Sharing Committee
  A. Access to Data (within the Consortium and with others in the field)
  B. Access to Samples (within the Consortium and with others in the field)
  C. Publication Policies (within the Consortium and with others in the field)
• Consortium Steering Committee
  A. Assessment of strengths and weaknesses of candidate biomarkers for the UH3 phase
  B. Planning next steps beyond activities covered under this FOA, including for large scale multiple site biomarkers validation toward FDA qualification and use in clinical trials
  C. Liaison with related relevant efforts

Data Core: Describe how the Data Core will establish infrastructure, including for real time data entry, to collect, curate for quality (e.g. accuracy, completeness, and internal consistency), display, house, and distribute (within the consortium and with external scientists after appropriate publication) data, including de-identified clinical data, imaging data, longitudinal data, and all relevant control data. Indicate how the Data core will facilitate efficient and accurate incorporation of new and/or extant clinical data via electronic data entry from remote locations. Indicate how the Data Core will build into its infrastructure the core set of de-identified clinical data elements agreed upon by the Consortium. Detail how the Data Core will provide full instructions and support for submitting data, and for obtaining data from the Core. Indicate how the Data Core capacity will meet needs starting in year 3 for banking data from up to 3000 individuals, on the order of 250 data elements per individual record, up to 3 data collections (records) per individual per year, plus imaging data (e.g. MRI, DTI) up to twice per year. Indicate how the Data Core will receive in real time, and by remote electronic submission, data from up to 20 sites per year, and distribute data to approximately the same number. Detail how the data core will harmonize compatible but not identically coded extant data across platforms for sharing and metanalyses. The application should explain the Data Core's statistical expertise to help inform study design and analyses. Applications must detail how standardization of imaging will be harmonized to be compatible with the Medical Image Processing, Analysis, and Visualization tool (MIPAV: http://mipav.cit.nih.gov/).

Milestone Plan: The application must include a Milestone Plan in the approach section with a timeline for establishing the Administrative Core to full functionality as indicated below (minimally). The timeline and milestones will be used to evaluate applications both in peer review and also in consideration of the awarded Coordinating Center for funding of non-competing award years. See the section below on Cooperative Agreement Terms and Conditions of Award for specific guidance on content and timing of Milestones. The final Milestone plan is subject to concurrence by the Project Officer.

The Administrative Core will initiate call to organize committees by 1 month after Notice of Grant Award.

The Administrative Core will establish Consortium Committees (except the Advisory Committee, which will be established by the NINDS) by nomination and vote, which will be formed by 4 months after Notice of Grant Award. Consortium Committees will include members from both the Development Projects and the Coordinating Center, as well as representation from the NINDS/NIH.

The Administrative Core will organize the Consortium Kickoff Meeting to be held within 4 month of receiving a Notice of Grant Award.

The Administrative Core will organize Annual meetings (1 per year within a month of annual date of original Notice of Grant Award) to enable exchange of data and synergy across the consortium.

The Administrative Core will administratively drive establishment of a core set of de-identified small vessel VCID clinical data elements (to be complete by 1 year after notice of grant award) including for cognitive outcomes.

The Administrative Core will develop, coordinate and implement process and solutions surrounding informed consent (by 1 year after notice of grant award).

The Administrative Core will develop a system to track and document Consortium activities that require appropriate informed consent (the tracking system should be in place by 1 year after notice of grant award). This of not negate the responsibility of individual Development Projects to ensure appropriate informed consent at all stages of the project.

The Administrative Core will facilitate communication and interaction with other relevant biomarkers activities including such as PDBP, ADNI, dbGAP, LONI, NACC other resources such as the NINDS Repositories and NCRAD, as well as related activities that can inform success approaches to biomarker development such as at CAMD and other organizations (by 6 months after notice of grant award).

The Data Core's IT infrastructure for receiving real time data entry from multiple remote locations (including de-identified clinical data of the core set of de-identified small vessel VCID core clinical data) will be fully functional and successfully beta-tested by the end of year 2.

The Data Core's IT infrastructure and SOPs for sharing (via webcatalog) all submitted data from the Biomarkers Development Projects will be fully functional by the end of year 3. The sharing infrastructure and protocols must be able to facilitate sharing within the Consortium and also with scientists outside of the Consortium.

Applicants also applying to RFA-NS-16-020 must include discussion of how any perceived or real conflicts of interest will be managed.

Letters of Support: If an application plans to utilize the infrastructure or resources of existing activities, letters of support from the project leadership and co-signed by appropriate official signing authority, as appropriate, detailing approval, feasibility, terms of collaboration and data sharing must be included. If applicable, informed consent forms for the parent clinical study and any ancillary studies should be included as part of the appendix.

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 Data Core must allow for data be submitted on a real time basis; if real time submission is not possible, then all data must be submitted at least on a quarterly basis.

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

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

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

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

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

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

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

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

An Applicant Webinar will be scheduled to provide an overview of the FOA and answer questions. The webinar is open to all prospective applicants. Participation in the teleconference is not a prerequisite for applying, and is not required for a successful application. Information about how to participate in the webinar will be posted at http://www.ninds.nih.gov. Potential applicants are encouraged to submit their questions or comments to roderick.corriveau@nih.gov prior to the meeting. Afterwards, the webinar slides and a summary of the questions and answers will be posted on the same site. NIH will also post a list of Frequently Asked Questions (FAQs) and answers; this information may be updated without additional notice.

In order to expedite review, applicants are requested to notify the NINDS Program Officer by email at roderick.corriveau@nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

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

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

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Do the PDs/PIs have proven success and a strong plan for facilitating interactions, e.g. data requests, harmonization, transfer, sharing, etc., with other NIH-funded and other databases that support reach in neurological disorders?

Do the Administrative Core and the Data Core each include highly competent and motivated personnel with excellent communications skills? Do the proposed point of contact key personnel for each Core (one each for the Administrative and Data Cores, respectively) have appropriate training and/or experience with both the IT and the biological/clinical data/scientific subject matters that are essential to the success of this Consortium?

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 application include leading edge and innovative attributes that the proposed Coordinating Center offers the Consortium, for example in IT, data management, communication strategies, approaches to organization of meetings and conference calls, and other activities that are the responsibility of the Coordinating Center? Does the application demonstrate expertise in harmonization of data across platforms for metanalyses?

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

Does the application provide justification and rationale indicating that the proposed plan can fulfill the Coordinating Center's role as the Consortium's information, data, and administrative hub, and in doing so will work closely, expertly, collegially and effectively with the Development Projects, the NINDS/NIH, and relevant members of the biomarkers scientific community?

Does the application describe how the administrative Core will organize, coordinate and administratively drive Consortium-specific activities including committee-related activities; Consortium meeting related activities; establishment of a core set of standardized VCID clinical data elements to be used for harmonized and sharing; sharing-related activities (including support and advice to projects on informed consent)?

Does the application describe how the Data Core will establish infrastructure supporting the required capacity for receiving and distributing data, a web catalogue and necessary quality control procedures? Does the application indicate how the Data Core will provide full instructions and support for submitting data in real time, and for obtaining data from the Core? Is it clear how the Data Core will facilitate efficient and accurate incorporation of new and/or extant clinical data via electronic data entry from remote locations? Is it clear how the Data Core will build into its infrastructure the core set of de-identified clinical data elements agreed upon by the Consortium? Does the application detail how the data core will harmonize compatible but not identically coded extant data across platforms for sharing and metanalyses? Is it clear how standardization of imaging will be harmonized to be compatible with the Medical Image Processing, Analysis, and Visualization tool? Does the Data Core include statistical expertise to help inform study design and analyses? Does the application demonstrate ability to use a global unique identifier (GUID) system for sample coordination and to prevent duplication? Does the application demonstrate a sound plan for quality control and curation of submitted clinical data, and receiving longitundal data?

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

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?

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

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

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

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

Not Applicable

Not Applicable

Not Applicable

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

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

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

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

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

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NINDS, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

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

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

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

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

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

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

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

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

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

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

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

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

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

The Small Vessel VCID Biomarkers Consortium Coordinating Center PD/PI(s) will have the primary responsibility for:

• Designing, leading and implementing all aspects of the Small Vessel VCID Biomarkers Data Coordinating Center as described in this FOA
• Setting all milestones, subject to concurrence of the Coordinating Center Program Director
• Adherence to all applicable NIH/NINDS policies including for data sharing and human subjects
• Adherence to the law
• Reports to Project Officer regarding timeline and milestone achievement
• Annual progress reports in a format as agreed upon by NINDS program staff
• Coordinate with all projects in and relevant to, as applicable, the Small Vessel VCID Biomarkers Consortium, e.g. the NINDS Biomarkers Repository;
• Attending and providing Coordinating Center leadership input at Kickoff and Annual in-person Small Vessel VCID Biomarkers Consortium meetings
• Coordinating and facilitating development and implementation of Consortium-specific protocols (e.g. core common clinical data elements for small vessel VCID) and policies (e.g. regarding publication, sharing, etc., as applicable)
• Providing appropriate guidance to Consortium members regarding sharing and informed consent.

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

NINDS program staff will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination. However, the role of NINDS Project Scientists will be to facilitate and not to direct or drive the activities.

The NINDS Project Scientist will:

• Contribute to the adjustment of Consortium research protocols, best practices, project milestones or approaches as warranted;
• Serve as a liaison among Consortium awardees, the NINDS Advisory Council and the larger scientific community;
• Coordinate the efforts of the Consortium with others engaged in VCID biomarkers and other biomarkers research;
• Assist in promoting the availability of data and resources developed in the course of this project to the scientific community at large;
• Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action;

Areas of Joint Responsibility include:
None

Other Components

External Advisory Committee

The NINDS will establish an independent External Advisory Committee to assist in determining the broad direction of the Consortium.

Milestone Plan

The Milestone Plan should include, at a minimum, and adhere to, the following:

Milestone Plan: The application must include a Milestone Plan in the approach section with a timeline for establishing the Administrative Core to full functionality as indicated below (minimally). The final Milestone plan is subject to concurrence by the Project Officer.

The Administrative Core will initiate call to organize committees by 1 month after Notice of Grant Award.

The Administrative Core will establish Consortium Committees (except the Advisory Committee, which will be established by the NINDS), which will be formed by 4 months after notice of grant award.

The Administrative Core will organize the Consortium Kickoff Meeting to be held within 4 month of receiving a Notice of Grant Award.

The Administrative Core will organize Annual meetings (1 per year within a month of annual date of original Notice of Grant Award) to enable exchange of data and synergy across the consortium.

The Administrative Core will administratively drive establishment of a core set of de-identified small vessel VCID clinical data elements (to be complete by 1 year after notice of grant award) including for cognitive outcomes.

The Administrative Core will develop, coordinating and implement process and solutions surrounding informed consent (by 1 year after notice of grant award).

The Administrative Core will track and document that Consortium activities that require appropriate informed consent (tracking system in place by 1 year after notice of grant award). This of course does not negate the responsibility of individual Development Projects to ensure appropriate informed consent at all stages of the project.

The Administrative Core will facilitate communication and interaction with other relevant biomarkers activities including such as PDBP, ADNI, dbGAP, LONI, NACC other resources such as the NINDS Repositories and NCRAD, as well as related activities that can inform success approaches to biomarker development such as at CAMD and other organizations (by 6 months after notice of grant award).

The Data Core's IT infrastructure for receiving real time data entry from multiple remote locations (including de-identified clinical data of the core set of de-identified small vessel VCID core clinical data) will be fully functional and successfully beta-tested by the end of year 2.

The Data Core's IT infrastructure and SOPs for sharing (via webcatalog) all submitted data from the Biomarkers Development Projects (infrastructure and protocols must be able to facilitate sharing within the Consortium and also with scientists outside the Consortium) will be fully functional by the end of year 3).

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: (1) a designee of the Advisory Committee chosen without NIH staff voting, (2) one NIH designee, and (3) a third designee with expertise in the relevant area who is chosen by the first two members; in the case of disagreement between the first two members, the third member will be chosen by the Consortium-elected Chair of the Steering Committee. This dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16

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

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

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, 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)

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

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

Roderick A. Corriveau, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5680
Email: roderick.corriveau@nih.gov

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email: nindsreview.nih.gov@mail.nih.gov

Tijuanna Decoster, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: tijuanna.decoster@nih.gov

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

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