Part 1. Overview Information

Key Dates

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from 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 2. Full Text of Announcement

Section I. Funding Opportunity Description

• In 2013, 2016, and 2019 the National Institute of Neurological Disorders and Stroke (NINDS), with input from the National Institute on Aging (NIA), held Alzheimer’s Disease-Related Dementias Summits in response to the National Plan to Address Alzheimer's Disease. The Summits brought together national and international experts and members of the public to set research priorities for accelerating the development of therapies for the Alzheimer's disease-related dementias (ADRDs), including vascular contributions to cognitive impairment and dementia (VCID). The ADRD Summit 2019 research recommendations that resulted are now implementation milestones in the National Plan to Address Alzheimer's Disease, updating the ADRD implementation milestones from the 2016 and 2013 ADRD Summits. This FOA addresses the National Plan's highest priority for human-based research on VCID: to develop biomarkers of key vascular processes related to VCID. The research program supported by this initiative underscores the need to develop biomarkers that will facilitate therapeutic development by improving the efficiency, design and outcome of clinical trials, including large-scale phase III trials.

This FOA (RFA-NS-21-005, for the sites) and its companion FOA (RFA-NS-21-004, for the Coordinating Center) together continue the VCID biomarkers consortium established under RFA-NS-16-019 and RFA-NS-16-020. The sites will drive the consortium scientifically and will be responsible for implementation of multi-site testing over the next five years to complete longitudinal clinical validation of NINDS-selected small vessel VCID biomarkers, initially developed during the first five years of this program, for use in clinical trials (all phases), including in diverse populations. The FDA defines clinical validation as establishing that the biomarker acceptably identifies, measures, or predicts the concept of interest. With respect to regulatory considerations, the concept of interest is the aspect of an individual’s experience or clinical, biological, physical, or functional state that the biomarker is intended to capture or reflect.

Awards funded under these companion FOAs will provide expertise and infrastructure to complete rigorous clinical validation for up to 6 of 11 candidate VCID susceptibility/risk and diagnostic biomarkers initially developed by the consortium during the previous 5 years (see https://markvcid.partners.org/). The NINDS will, in a separate process, select and rank-order prioritize the most promising of these candidate biomarkers by the end of FY 2021. At the time of award under this FOA the NINDS will work with grantees to determine the number of prioritized biomarkers that will move forward into multi-site clinical validation based on resources, expertise, and power analyses. While applicants are to plan for up to 6 biomarkers to move forward, at the time of award and implementation the actual number may be lower or higher depending on protocols, resources, and scientific justification. Each selected VCID biomarker will undergo comprehensive multi-site clinical validation and will have, at the conclusion of the next five years: no or minimal legal (e.g. IP, licensing) or logistic (e.g. cost, invasiveness) barriers to widespread use; a designated category and context of use as defined by the FDA; and a finalized public protocol that describes all details needed to utilize the biomarker independently including but not limited to a biomarker measure, specified cognitive data, and specified other clinical data. This program is intended to fully prepare small vessel VCID biomarkers for integration into and widespread use in clinical trials (all phases) including in large-scale late phase clinical trials in general and diverse populations in the United States. Applicants are strongly encouraged to consult with NINDS Scientific/Research Staff early on during the planning stage of their application (see Agency contacts, Section VII).

Site Objectives

This program is centered on small vessel VCID biomarkers for individuals with cognitive complaints and/or early symptomatic stages of cognitive impairment and dementia diagnoses potentially associated with cerebrovascular small vessel (i.e. arterioles, capillaries, and venules) disease. Sites will provide the scientific expertise and infrastructure to perform comprehensive multi-site clinical validation of up to 6 small vessel VCID biomarkers developed by the NINDS small vessel VCID biomarkers consortium during the previous 5 years and selected by the NINDS in a separate process. The focus of the next 5 years will be clinical validation in longitudinal studies in general and diverse populations that are typical in clinical settings in the United States. The NINDS expects that this objective will be reflected across the consortium during the coming five years in terms of human subjects engagement, recruitment, enrollment and longitudinal retention needed for appropriately powered clinical validation studies that will result in clinical trial ready biomarkers for, at a minimum, Hispanic, African American and Caucasian populations. When beneficial to the goals of the consortium, further protocol refinement, instrumental validation, biological validation and cross-sectional analyses will be in scope. Each site will have: the capacity to enroll at least 200 human subjects for this research during the first 2 years of funding that will allow longitudinal clinical validation studies over the following 3 years; equipment, expertise and infrastructure for both fluid- and imaging-based small vessel VCID biomarker validation; statistical expertise for VCID biomarker validation in human subjects; expertise in obtaining and managing clinical data; a strong track record in sharing clinical data and biological samples in the neuroscience research community; and proven ability to meet or exceed timed milestones with deliverables, both for reporting and scientific outcomes.

Standard NIH sharing policies apply to the full scope of activities supported under this program. In addition, all funded studies will be required to share experimental data and to facilitate sharing of de-identified clinical data and images generated and/or used, including via appropriate informed consent, via the Coordinating Center database. Sharing of original experimental data will be within consortium; sharing of de-identified clinical data and images will be with other members of the consortium (as the data are generated) as well as with researchers that are not part of the consortium (2 years maximum embargo for biospecimens with diagnosis and demographic data; release at time of relevant publication for clinical data). For newly generated clinical data an appropriate consent option to facilitate this sharing must be provided to study participants. See further consent guidance below.

For participation in consortium, it is required that investigators will facilitate sharing of biospecimens and will budget accordingly, including for banking of biospecimens. For biospecimens generated with funding due to this FOA, an appropriate consent option to facilitate this sharing is expected to be provided to study participants, including the possibility that biospecimens will be banked in the NINDS biomarkers repository.

Characteristics of Responsive Applications

Specific and detailed plan with experienced personnel and established or feasible cohorts to meet or exceed enrollment and longitudinal retention of U.S. populations, including at a minimum African American, Hispanic, and Caucasian populations, found in typical clinical settings and that will be required to meet the goals of the consortium for powered VCID biomarker clinical validation studies.

Team with expertise in the science of VCID, or related topics in stroke or AD/ADRD imaging-based and fluid-based brain biomarkers, statistical analyses and evaluation of biomarkers. Documented ability to meaningfully contribute to refinement, design and interpretation of final appropriately powered multi-site clinical validation studies with specified biomarker category and context of use.

Applications can propose to move forward with new or existing cohorts. It may be advantageous in terms of the scope of longitudinal data and the power and flexibility of clinical validation under this consortium to leverage existing relevant cohorts.

Commitment, including with innovation when possible, to strategic planning efforts to use the resulting biomarker protocols widely in future clinical trials.

Ability to rigorously and efficiently implement existing NINDS small vessel VCID biomarker consortium imaging-based (at least 4) and fluid-based (at least 2) protocols, including as documented in the application with relevant preliminary data.

Human subject recruitment plan that focuses on individuals with cognitive complaints and/or early symptomatic signs of cognitive impairment and dementia diagnoses potentially associated with small vessel disease.

Documented track record of sharing de-identified clinical data both within consortia and more broadly with the neuroscience research community.

Documented ability to harmonize protocols and data with collaborators VCID and related research.

Characteristics of Non-Responsive Applications

Applications that do not document the ability to recruit diverse human subjects including, at a minimum, African American, Hispanic, and Caucasian populations that are seen in typical clinical settings in the United States.

Applications that propose biomarker discovery or specific biomarkers for validation are non-responsive. The NINDS will, in a separate process, select candidate biomarkers developed during the first five years of this program (see https://markvcid.partners.org/) for comprehensive multi-site longitudinal clinical validation during the next five years of this program.

Applications that include vertebrate animal research are not responsive to this FOA.

Opportunities for Partnership

Projects involving partnerships with industry, small businesses or non-government organizations are encouraged under this FOA. The policy of the NIH is to make available to the public the results and accomplishments of the activities that it funds.

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 and DHHS policy and as mandated by law.

The informed consent process 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). Successful applicants are to work with the Coordinating Center on developing a consortium wide policy on consent forms for samples and data collected that includes the following considerations:

• That the sample and de-identified clinical data may be submitted to an NINDS repository or database, research resources supported by the NINDS.
• 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 research results will not be returned to the participants.
• 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.

The informed consent process for the subject, as well as next of kin, when applicable, must include plans and consideration to implement or facilitate, in the event that a subject passes away during the course of the study, autopsy and pathological analyses to increase understanding of the relationships between imaging results during life and postmortem pathological findings

It is expected that any embargo time will follow NINDS guidance (2 years maximum for biospecimens with diagnosis and demographic data; release at time of relevant publication for other clinical data). Samples and clinical data collected in this program are subject to NINDS policy and oversight.

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

Section II. Award Information

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
• U.S. Territory or Possession

Other

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

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

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

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed. 

Applicant organizations

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

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

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

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

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

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

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.  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).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are 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

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:

Roderick A. Corriveau, Ph.D.
Telephone: 301-496-5680
Email: [email protected]v

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.

R&R or Modular Budget

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

For purposes of application preparation develop a budget to move forward up to 4 imaging-based biomarkers and up to 2 fluid-based biomarkers that were developed by projects funded under RFA-NS-16-019 and RFA-NS-16-020 (see https://markvcid.partners.org/). To meet this objective with adequate numbers of subjects and power each site must propose to recruit within the first 2 years and retain at least 200 subjects.

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:

 Investigators: Without duplicating information in the biosketches, applications are to document that the PI/PD and team have extensive expertise in the science of VCID, imaging-based and fluid-based biomarkers for brain disorders, VCID biomarkers, statistical analyses and evaluation of biomarkers, and recruitment and retention for longitudinal clinical research in diverse populations in the United States. The PI/PD and any MPIs should have an established track record of sharing, including with collaborators and more broadly in the neuroscience research community.

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

Significance: Describe how the proposed site is poised to make a significant contribution to the next phase of the NINDS small vessel VCID biomarkers program based on previous work on VCID biomarkers or related brain biomarker studies, including by effective leadership, meeting milestones and other deadlines, and meaningful contributions to development, refinement, design and interpretation of appropriately powered multi-site biomarker studies.

Innovation: Indicate how the proposed site will use cutting edge innovative strategies to move forward to goals of the consortium, including by contributing to planning efforts that will maximize the likelihood that the resulting biomarker protocols will be widely utilized in future clinical trials in academic, biotech, and industry settings.

Approach: Demonstrate, including with interpreted preliminary data, readiness to implement with rigor and efficiency, at least 4 imaging-based and at least 2 fluid-based NINDS small vessel VCID biomarker consortium protocols that are published here: https://markvcid.partners.org/ (Applicants should not include this link in their application).

Describe ability to harmonize effectively protocols and data with collaborators in VCID and related research, including with examples.

Describe a specific and detailed plan to meet or exceed enrollment during the first two years with subsequent additional longitudinal assessments and retention of at least 200 human subjects including U.S. populations (at a minimum African American, Hispanic, and Caucasian populations) seen in typical clinical settings. Detail how the proposed enrollment and retention are suitable for assessing small vessel VCID biomarkers in individuals with cognitive complaints and/or early symptomatic signs of cognitive impairment and dementia diagnoses potentially associated with cerebrovascular small vessel (i.e. arterioles, capillaries, and venules) disease. Provide quantitative preliminary or other supporting data indicating feasibility.

 For the proposed cohort, if individuals pass away during the course of this research, please describe plans, including for informed consent of the subject, as well as, next of kin when applicable, to implement or facilitate autopsy and pathological analyses to increase understanding of the relationships between imaging results during life and postmortem pathological findings.

Detail an approach to sharing biospecimens and clinical data with the Coordinating Center (see RFA-NS-21-004), the other sites within the consortium, and more widely in the field with other investigators. Provide preliminary or other supporting data indicating feasibility of this approach for VCID or other dementia disorders.

Milestone Plan: The application must include a Milestone Plan in the approach section with a timeline for human subject recruitment and enrollment to be complete by the end of year 2, and milestones for retention of at least 200 subjects for the remaining years of this program. Separate milestones must be included for each group (at a minimum, African-American, Hispanic, and Caucasian populations) that will be recruited. Note that while the number of human subjects is not expected to change, specific details of cooperative agreement milestones proposed including but not limited to timelines and diversity are subject to negotiation and adjustment at the time of award based on the needs of the consortium.

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.

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.

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

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

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

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). 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.

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) 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.

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

1. Criteria

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.

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.

Significance

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

To what degree does the application demonstrate that the proposed site is poised to make a significant contribution to the next phase of the NINDS small vessel VCID biomarkers program based on previous work on VCID biomarkers or related brain biomarker studies, including by effective leadership, meeting milestones and other deadlines, and meaningful contributions to development, refinement, design and interpretation of appropriately powered multi-site biomarker studies?

Investigator(s)

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

To what extent do the PD/PI and team have extensive expertise in the science of VCID, imaging-based and fluid-based biomarkers for brain disorders, VCID biomarkers, statistical analyses and evaluation of biomarkers, and recruitment and retention for longitudinal clinical research in diverse populations in the United States? To what degree do the PD/PI and any MPIs have an established track record of sharing, including with collaborators and more broadly in the neuroscience research community?

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 proposed site use cutting edge innovative strategies that will move forward the goals of the consortium?

Approach

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

How well does the application demonstrate, including with interpreted preliminary data, readiness to implement with rigor and efficiency, at least 4 imaging-based and at least 2 fluid-based NINDS small vessel VCID biomarker consortium protocols that are published here: https://markvcid.partners.org/?

How well does the application indicate ability to harmonize effectively protocols and data with collaborators in VCID and related research, including with examples?

To what degree does the application describe a sound, specific and detailed plan to meet or exceed enrollment during the first two years with subsequent additional longitudinal assessments and retention of at least 200 human subjects?How well does the application detail how the proposed enrollment and retention are suitable for assessing small vessel VCID biomarkers in individuals with cognitive complaints and/or early symptomatic signs of cognitive impairment and dementia diagnoses potentially associated with cerebrovascular small vessel (i.e. arterioles, capillaries, and venules) disease? How convincingly does the application provide quantitative preliminary or other supporting data indicating feasibility?

To what extent does the application detail an effective approach to sharing biospecimens and clinical data with the Coordinating Center (see RFA-NS-21-004), the other sites within the consortium, and more widely in the field with other investigators? To what degree does the provided preliminary or other supporting data indicate feasibility of this approach for VCID or other dementia disorders?

 To what degree is there a sound plan, including for appropriate informed consent, to implement or facilitate autopsy and pathological analyses, in the event that one or more individuals from the cohort pass away during the study, to increase understanding of the relationships between imaging results during life and post mortem pathological findings?

Milestone Plan: Are there separate milestones must for each group (at a minimum, African American, Hispanic, and Caucasian populations) that will be recruited?

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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

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?

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.

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 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 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

Not Applicable

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

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

Revisions

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.

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 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 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.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Neurological Disorders and Stroke (NANDSC) 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.

3. Anticipated Announcement and Award Dates

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

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

2. Administrative and National Policy Requirements

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 laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. 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 and http://www.hhs.gov/ocr/civilrights/understanding/section1557/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. HHS provides guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov. 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 https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

• 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.

• HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. 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.

• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please 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 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

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

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

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

Determining experimental approaches, designing protocols, and conducting experiments;

• Submitting annual progress reports during the funding period, in a format as agreed upon by NINDS program staff;
• Accepting and implementing any other common guidelines and procedures developed for the Small Vessel VCID Biomarkers consortium initiative and approved by NINDS program staff;
• Attending consortium calls and participating actively in small vessel VCID biomarkers consortium activities;
• Being willing to serve as a chair or member of the small vessel VCID biomarkers consortium Steering Committee and other consortium committees if elected;
• Attending in-person small vessel VCID biomarkers consortium meetings (including the initial Kickoff Meeting) once per year organized by the Coordinating Center with input from the NINDS, the Steering Committee, and the Advisory Committee, and present up to date findings (including unpublished results) on ongoing projects.
• Awardees are expected to make new information and materials known to the research community not only in the annual consortium meeting but also in a timely manner through publications, web announcements, reports to NINDS program staff, and other mechanisms.
• Timely submission of all abstracts, manuscripts and reviews (co)authored by project investigators and supported in whole or in part under this Cooperative Agreement. The PD(s)/PI(s) and Project Leaders are requested to submit manuscripts to the NIH Project Scientist within two weeks of acceptance for publication so that an up-to-date summary of program accomplishments can be maintained. Publications and oral presentations of work conducted under this Cooperative Agreement are the responsibility of the PD(s)/PI(s) and appropriate Project Leaders and will require appropriate acknowledgement of NINDS support. Timely publication of major findings is required.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in 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. The NINDS Administrative Project Officer is responsible for evaluating standard budgetary, milestones, and grants and other official reporting to the NINDS. 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 research protocols or approaches as warranted;
• Serve as a liaison between the awardees, the NINDS Advisory Council and the larger scientific community;
• Serve on committees of the small vssel VCID biomarkers consortium as appropriate;
• 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;
• Retain the option to recommend the withholding or reduction of support from any cooperative agreement that either substantially fails to achieve its goals agreed to at the time of award, fails to maintain state-of-the-art capabilities, or fails to comply with the Terms and Conditions of the award including biospecimen and data sharing requirements.

Additionally, an NINDS Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Other Components

External Advisory Committee

The NINDS will establish an independent External Advisory Committee to assist in determining the broad direction of the NINDS small vessel VCID biomarkers consortium.

Milestone Plan

The Milestone Plan, agreed upon by applicant and the NINDS Administrative Project Officer, will be included in the cooperative agreement terms and conditions.

Areas of Joint Responsibility include:

None

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 awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. Reporting

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

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

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.

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]

Roderick A. Corriveau, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5680
Email: [email protected]

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email: [email protected]

Anna Taylor, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301.827.3565
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.