Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the How to Apply - Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of 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

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background:

Under the 2011 National Alzheimer’s Projects Act (NAPA), the first goal of the National Plan to Address Alzheimer’s Disease is to prevent and effectively treat Alzheimer’s Disease (AD) and Alzheimer’s Disease-Related Dementias (ADRD). Starting in 2012, the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS) have held research summits triennially to assess research priorities and set research implementation milestones for the ADRDs, which include frontotemporal dementia (FTD), Lewy body dementia (LBD), multiple etiology dementias (MED), and vascular contributions to cognitive impairment and dementia (VCID). The NINDS ADRD Summits in 2019 and 2022 resulted in the current ADRD research priorities for advancing the state-of-the-science toward meeting Goal 1 of the National Plan. In line with these research priorities, the NINDS has sought to solicit diverse community input on AD/ADRD research priorities, identify imaging biomarkers to monitor disease and treatment progression in AD/ADRD patients, and to conduct trials on promising interventions.

Since 2021, two anti-Aβ monoclonal antibodies (mAbs) have received approval by the FDA for use in patients with mild cognitive impairment (MCI) or mild dementia due to AD, with Aducanemab receiving accelerated approval and Lecanemab receiving full approval. While Aducanemab and Lecanemab have been reported to delay symptom progression, the removal of Aβ plaques through the use of anti-Aβ mAb therapies has been associated with the presence of magnetic resonance imaging (MRI) signal abnormalities, termed Amyloid Related Imaging Abnormalities (ARIA). ARIA include signal abnormalities related to vasogenic edema/extravasation (ARIA-E) and hemosiderosis/microhemorrhages (ARIA-H).

Depending on anti-Aβ mAb dosage and targets, ARIA have been observed in up to approximately 40% of patients receiving mAbs. While most clinical trial reported cases identified during appear to be mild and asymptomatic, data have shown that up to approximately 33% of ARIA-related events may be classified as moderate to severe, and up to approximately 25% of patients with ARIA report symptoms. Furthermore, subgroup analyses across several trials have also shown that positive ApoE-4 carrier status appears to be associated with a higher incidence of ARIA. Moreover, potential long-term effects of ARIA in patients receiving anti-Aβ mAbs are not clear. Therefore, an improved understanding of the vascular pathophysiology and mechanisms underpinning ARIA is needed, along with identification of additional biomarkers. beyond ApoE-4 genotype, indicative of risk for ARIA-related serious adverse events and symptoms.

To consider these needs, NINDS and NIA held a joint workshop in September 2023 titled “Anti-Beta-Amyloid Passive Immunotherapy for Alzheimer’s Dementia and Amyloid Related Imaging Abnormalities (ARIA): What’s Next?”. The workshop yielded numerous insights and highlighted several topics ripe for investigation, including the need for in-depth neuropathological study of patients who developed ARIA while receiving anti-Aβ mAbs and linkage of neuropathological findings to signs and symptoms of ARIA observed during life. To address this need it will be necessary, for example, to include autopsy endpoints in observational studies and clinical trials, perform timely in vivo and/or ex vivo MR data acquisition to identify pathological tissue before blocking, and develop standardized in vivo and/or ex vivo MRI atlases at various resolutions to facilitate co-registration between MRI and neuropathology blocks.

Please note that this Notice of Funding Opportunity (NOFO) builds upon work currently being funded under RFA-NS-23-002 (Tools and resources to understand the vascular pathophysiology of in vivo neuroimaging findings in TBI-related dementia and/or VCID) and expands the scope to focus on ARIA. RFA-NS-23-002 was motivated by an NINDS workshop held in July of 2022 titled “Imaging the Future of In vivo Neuropathological Diagnosis through Postmortem Analyses”, which sought input from the scientific community on how to bridge the gaps between in vivo imaging, ex vivo imaging, and neuropathology work, with the explicit end goal of improving in vivo diagnosis of the ADRDs. There, several methodological issues hindering the neuropathological study of dementia cases were identified, including long postmortem intervals that lead to artifactual changes, fixation mediums and processes that distort ex vivo MR imaging, inappropriate block sampling due to irregular disease distribution patterns, and non-standard coordinate systems across institutes or studies.

Specific Research Objectives:

The overarching purpose of this funding opportunity is to develop and share resources that advance and expand community-wide research capacity for performing joint neuropathological and neuroimaging analysis. Resources developed under this NOFO include tools and techniques, such as innovative technologies, methods, protocols, and biomedical materials, and it is expected that they demonstrate reproducibility and feasibility of use by the broader research community. Resource development topics of interest include, but are not limited to:

• Streamlined approaches that reduce postmortem intervals.
• Methods or techniques for MR data acquisition of fresh tissue.
• Innovative fixation techniques that reduce MR signal loss.
• Techniques that enable improved neuropathological analysis of regions demonstrating vascular neuropathology / MR signal abnormalities.
• Development of analytical MR models to better understand disease processes and neuropathology findings.
• The development of common coordinate systems, or improved co-registration techniques, for co-registration of MR and neuropathology images.
• Development of standardized procedures and/or acquisition techniques to facilitate co-registration across sites. This includes practices that would facilitate the use of machine learning for co-registration.
• Comparisons of various types of techniques, such as fixation techniques or solutions, methods to avoid fixation before MR, blocking/sectioning techniques, 3D mold types, etc., to demonstrate which lead to the best preservation of the tissue, MR signal, and genetic material.
• Development of atlases to be used in co-registering MRI and neuropathology images.
• Development and discovery of biomedical materials such as new antibodies for staining and processing brain tissue.
• Development of novel MR sequences suitable to detecting neuropathology in postmortem or ex vivo tissue.
• Development of novel in-vivo MR sequences with increased sensitivity to vascular pathophysiology, based on ex vivo MR and post-mortem neuropathology findings.

Resources developed under this NOFO are ultimately intended to improve stratification and prognosis of patients receiving anti-Aβ mAbs and must therefore also yield novel discoveries or insights into a least two of the following:

• Pathogenesis and pathophysiology of ARIA-E and ARIA-H in anti-Aβ mAbs induced cases
• Pathogenesis and pathophysiology of spontaneous ARIA-H and ARIA-E triggered by cerebral amyloid angiopathy (CAA) and/or CAA-related inflammation (CAA-ri), respectively
• Asymptomatic vs symptomatic ARIA
• Factors affecting ARIA symptom severity
• Potential differential treatment effects of anti-Aβ mAbs in APOE ε4 carriers
• Biomarkers and/or risk factors for ARIA (e.g., pre-existing blood brain barrier (BBB) damage, overactive immune response, APOE ε4)
• Biomarkers and/or mechanisms of increased susceptibility to BBB disruption/leakage related to Aβ accumulation or clearance
• Biomarkers and/or mechanisms of inflammation related to amyloid presence or clearance
• Potential interactions between BBB leakage and inflammation
• Cerebral vascular dysfunction and ischemia including, but not limited to, impaired cerebrovascular reactivity, chronic hypoperfusion, perivascular hemorrhage, vessel wall abnormalities, and cerebral small vessel disease
• Impaired neurovascular coupling
• Tau-related effects
• Other novel topics not listed that directly relate to the pathogenesis and pathophysiology of ARIA

Plan for Enhancing Diverse Perspectives (PEDP)

• This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP) as described in NOT-MH-21-310,submitted as Other Project Information as an attachment (see Section IV).
• Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance material. The PEDP will be assessed as part of the scientific and technical peer review evaluation, as well as considered among programmatic matters with respect to funding decisions.

Non-responsive applications under this NOFO include:

• Applications proposing to use non-human animal models, data, or tissue.
• Applications that do not explicitly propose the development and distribution of innovative technologies, methods, protocols, or biomedical materials that would enhance the joint analysis of human MR and neuropathology data, particularly as it relates to understanding the underlying pathophysiology of ARIA seen during in vivo imaging.
• Applications that do not include milestones.
• Applications that do not propose analysis of postmortem/ex vivo MR and postmortem neuropathology data.
• Applications that are not focused on resource development related to ARIA in patients treated with anti-Aβ mAbs.
• Applications proposing any type of NIH defined clinical trial (i.e., BESH, mechanistic, exploratory, efficacy, etc. clinical trials).

Applications deemed not responsive to the NOFO will be withdrawn without review.

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 NOFO.

Section III. Eligibility Information

1. Eligible Applicants

All organizations administering an eligible parent award may apply for a supplement under this NOFO.

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 Government

• 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 Organizations) are not eligible to apply.

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

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply - 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information. 

• System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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 How to Apply - Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, 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 NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

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

Carlos C. Faraco, Ph.D., M.S.
National Institute of Neurological Disorders and Stroke (NINDS)
Division of Clinical Research
Telephone: 301-496-9135
Email: carlos.faraco@nih.gov

All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply – Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

Other Attachments:

Milestones (Required; 2 page maximum)

A detailed set of milestones covering all aspects of the proposed project must be presented. This includes annual milestones with metrics that will document progress towards the achievement of the ultimate goals. Applicants must include plans for critically evaluating and revising milestones on a regular basis. Applicants must describe how they will prioritize their activities to ensure that the main goals of the project will be achieved. Milestones are required to provide clear indicators of a project's continued success or emergent difficulties and will be used to evaluate the application during both peer review and non-competing award years.

Proposed milestones, at a minimum, must include timelines and steps for:

• Arriving at collaborative solutions between award recipients under this NOFO. This will be based on the Administrative and Data Coordination Plans and must be completed within a maximum of six months after funding has begun.
• Modifying proposed plans or approaches to align with the arrived at collaborative solutions.
• The development and testing of the proposed innovative technologies, methods, protocols, or biomedical materials proposed in the project.
• The dissemination of said innovative technologies, methods, protocols, or biomedical materials.

Milestones will be used to evaluate the application during both peer review and non-competing award years. It is expected that proposed timelines for achieving milestones be realistic, efficient, and include necessary steps. Milestones should be clear, quantitative, and actionable, and establish feasibility, as applicable. Since these awards will be managed as cooperative agreements, projects that do not comply with terms, conditions, and established milestones of the award and of this program may be terminated prior to the project end-date.

The NIH Program Official will contact the applicant(s) to discuss the proposed milestones before the award. The NINDS may require revisions to the study protocol and execution prior to the award. This includes modifications that may be needed after bringing applicants together to discuss proposed projects and associated milestones.

Administrative Plan (Required; 2 pages maximum):

All U24 recipients under this NOFO will be required to collaborate with each other in order to ensure consistency in data standards, method, and/or resource development between the cooperative agreements.

The Administrative Plan will serve to coordinate the integration and management of activities within each award, including reporting and establishing milestones, for example, and coordinating activities with the project teams of the other award(s) funded under this NOFO. Doing so will help to accelerate project-startup; facilitate communication amongst and across sites; work to ensure that multi-disciplinary, collaborative approaches are implemented once projects commence; discuss common approaches that can be taken between projects (e.g., agree on data, methods, and tissue processing and storage standards, where possible); and resolve any potential disagreements.

It is suggested that, if possible, applicants contact recipients funded under RFA-NS-23-002 to develop these plans in coordination with their related efforts.

This plan must describe how the study team will:

• Facilitate collaborative interactions (e.g., reporting of data and integrated review across teams with various disciplines, decision-making, etc.) over the course of the project. This description should include an outline of roles and responsibilities for each team member responsible for working on the plan.
• Execute the research strategy for developing resources as indicated in this NOFO.
• Collaborate with other recipients funded under this NOFO and address potential roadblocks that might be encountered.
• Organize any virtual or, if necessary, in-person meetings across awards.
• Follow or improve upon community standards for MRI and neuropathological nomenclature related to anatomical areas, disease diagnosis, and pathological features.
• Either identify, use, and support standard practices and pipelines and/or develop innovative strategies to collect and coordinate datasets generated between U24 awards, as appropriate.
• Attempt to resolve differences in the approach to the Administrative Plan across U24 awards for the portions that require collaboration between recipients.

Plan for Enhancing Diverse Perspectives (PEDP) (Required; 1 page maximum): 

• In an "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity.
• The PEDP should provide a holistic and integrated view of how enhancing diverse perspectives is viewed and supported throughout the application and can incorporate elements with relevance to any review criteria (significance, investigator(s), innovation, approach, and environment) as appropriate.
• Where possible, applicant(s) should align their description with these required elements within the research strategy section.
• The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured.
• The PEDP may be no more than 1-page in length and should include a timeline and milestones for relevant components that will be considered as part of the review.

Examples of items that advance inclusivity in research and may be part of the PEDP can include, but are not limited to:

• Discussion of engagement with different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based).
• Description of any planned partnerships that may enhance geographic and regional diversity.
• Plan to enhance recruiting of women and individuals from groups historically under-represented in the biomedical, behavioral, and clinical research workforce.
• Proposed monitoring activities to identify and measure PEDP progress benchmarks.
• Plan to utilize the project infrastructure (i.e., research and structure) to support career-enhancing research opportunities for diverse junior, early- and mid-career researchers.
• Description of any training and/or mentoring opportunities available to encourage participation of students, postdoctoral researchers and co-investigators from diverse backgrounds.
• Plan to develop transdisciplinary collaboration(s) that require unique expertise and/or solicit diverse perspectives to address research question(s).
• Publication plan that enumerates planned manuscripts and proposed lead authorship.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as research participants including those from under-represented backgrounds. 

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see https://braininitiative.nih.gov/about/plan-enhancing-diverse-perspectives-pedp

All instructions in the How to Apply - Application Guide must be followed.

R&R Budget

All instructions in the How to Apply - Application Guide must be followed.

PEDP implementation costs

• Applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7:https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm).

R&R Subaward Budget

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Provide the overall goals of the entire project and list separate Specific Aims to be accomplished, outline the methods proposed, and summarize the expected outcomes.

Projects must utilize methodological, procedural, or technological developments that advance and expand community-wide research capacity for performing joint neuropathological and neuroimaging analysis, particularly toward implementation on a large scale. Applications must describe projects that address at least two of the following goals (or other goals not listed, but in the spirit of the award):

• Streamlined approaches that reduce postmortem intervals.
• Methods or techniques for MR imaging of fresh tissue.
• Innovative fixation techniques that reduce MR signal loss.
• Techniques that enable improved neuropathological analysis of regions demonstrating vascular neuropathology / MR signal abnormalities.
• Development of analytical MR models to better understand disease processes and neuropathology findings.
• The development of common coordinate systems, or improved co-registration techniques, for co-registration of MR and neuropathology images.
• Development of standardized procedures and/or acquisition techniques to facilitate co-registration across sites. This includes practices that would facilitate the use of machine learning for co-registration.
• Comparisons of various types of techniques, such as fixation techniques or solutions, methods to avoid fixation before MR, blocking/sectioning techniques, 3D mold types, etc., to demonstrate which lead to the best preservation of the tissue, MR signal, and genetic material.
• Development of atlases to be used in co-registering MR and neuropathology images.
• Development and discovery of biomedical materials such as new antibodies for staining and processing brain tissue.
• Development of novel MR sequences suitable to detecting neuropathology in postmortem or ex vivo tissue.
• Development of in-vivo MR sequences with increased sensitivity to vascular pathophysiology, based on ex vivo MR and post-mortem neuropathology findings.

Also note that proposals must include a multidisciplinary team with expertise in data science/data standards, in vivo and postmortem (or ex vivo) human MR neuroimaging, human MR neuroimaging methods and data analysis, human neuropathology methods and data analysis, and vascular neurology and/or neuroradiology. Such a multidisciplinary, team-science strategy should encourage cross fertilization of knowledge and utilize appropriate subject matter expertise for interrogating data. Further, NINDS encourages applications from diverse teams of investigators, including team members that are from groups that are underrepresented in the biomedical, behavioral, or clinical research workforce.

The Research Strategy must clearly describe the following within the appropriate section (i.e., Significance, Investigators, Innovation, Approach, Environment). Information to be included in each grant application, but not limited to bulleted items, are listed below:

Significance

• Discuss how the proposed methods, practices, techniques, technologies, or tools developed will help improve understanding of the vascular pathogenesis and pathophysiology of ARIA.
• Discuss the uniqueness of the proposed integrative approach and methodology to address the unmet clinical need specifically referenced in the application.
• Describe how the product(s) and their sharing will enable and facilitate future MRI work in vivo and postmortem, or ex vivo neuropathology work.
• Describe how the proposed product(s) will enhance the joint analysis of human neuropathology and neuroimaging findings.
• Describe how the proposed project will ultimately help to improve stratification and prognosis of patients receiving anti-Aβ mAbs and must therefore also yield novel discoveries or insights into at least two of the following:
  • Pathogenesis and pathophysiology of ARIA-E and ARIA-H in anti-Aβ mAbs induced cases
  • Pathogenesis and pathophysiology of spontaneous ARIA-H and ARIA-E triggered by cerebral amyloid angiopathy (CAA) and/or CAA-related inflammation (CAA-ri), respectively
  • Asymptomatic vs symptomatic ARIA
  • Factors affecting ARIA symptom severity
  • Potential differential treatment effects of anti-Aβ mAbs in APOE ε4 carriers
  • Biomarkers and/or risk factors for ARIA (e.g., pre-existing blood brain barrier (BBB) damage, overactive immune response, APOE ε4)
  • Biomarkers and/or mechanisms of increased susceptibility to BBB disruption/leakage related to Aβ accumulation or clearance
  • Biomarkers and/or mechanisms of inflammation related to amyloid presence or clearance
  • Potential interactions between BBB leakage and inflammation
  • Cerebral vascular dysfunction and ischemia including, but not limited to, impaired cerebrovascular reactivity, chronic hypoperfusion, perivascular hemorrhage, vessel wall abnormalities, and cerebral small vessel disease
  • Impaired neurovascular coupling
  • Tau-related effects

Other novel topics not listed that directly relate to the pathogenesis and pathophysiology of ARIA

Investigators

• Discuss and describe the collaborative expertise, nature, and interactions of the clinical and basic scientists, as well as that of other team members that makes them suited to this project.
• Describe the multidisciplinary expertise in data science/data standards, in vivo and postmortem (or ex vivo) human MR neuroimaging, human MR neuroimaging methods and data analysis, human neuropathology methods and data analysis, and vascular neurology and/or neuroradiology needed to accomplish the specific aims.

Innovation

• Describe the unique methods, practices, strategies, techniques, and/or technologies that will be used and studied as part of the proposed project.
• If the project is proposing the development and discovery of biomedical materials, such as new antibodies for staining and processing brain tissue, describe how likely it is that the new materials will advance the field. Additionally, describe how difficult it may or may not be to produce these materials or to replicate the methods/techniques necessary to do so.

Approach

• Discuss how the proposed approach and methodology will address the unmet clinical need specifically referenced in the application.
• Describe how the proposed approaches will enhance the rigor and reproducibility of the work being performed.
• Describe how reproducible the product(s) will be.
• If applicable, describe extent the various types of techniques (e.g., fixation techniques or solutions), methods to avoid fixation before MRI, blocking/sectioning techniques, 3D mold types, etc., that will be compared to demonstrate which technique leads to the best preservation of the tissue, MR signal, and/or genetic material.
• If applicable, describe any premortem data that will be utilized. This includes any premortem MR or clinical data.
• If applicable, describe any new machine-readable solutions.

Environment

• Describe how the institutional environment in which the study takes place will contribute to the probability of success in facilitating the research.

Rigor and Transparency:

NINDS, as part of NIH, strives for rigor and transparency in all research it funds. For this reason, NINDS explicitly emphasizes the NIH application instructions related to rigor and transparency and provides additional guidance to the scientific community. For example, the biological rationale for the proposed experiments must be based on rigorous and robust supporting data, which means that data should be collected via methods that minimize the risk of bias and be reported in a transparent manner. If previously published or preliminary studies do not meet these standards, applicants should address how the current study design addresses the deficiencies in rigor and transparency. Proposed experiments should likewise be designed in a manner that minimizes the risk of bias and ensures validity of experimental results. Investigators are urged to discuss these issues with Scientific/Research staff prior to submission of applications.

Resource Sharing Plan:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide. 

Other Plan(s):

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

All applications need to meet the data sharing requirements set forth in the NIH’s Policy for Data Management and Sharing (DMS Policy; NOT-OD-21-013) for applications due on or after January 25, 2023 and must therefore provide a DMS Plan. For additional information on the DMS Policy, please also refer to the Data Management and Sharing Policy webpage, the NIH guidance on writing a DMS plan, as well as the supplemental notices for the DMS Policy.

Applicants who plan to utilize data not currently in their possession (originated from another party) must confirm availability of the data and demonstrate (at a minimum via a letter of support) the willingness and permissibility of the original investigators to share the data for the purposes of the harmonization, curation, secondary analyses, in accordance with all applicable rules for the protection of human subjects.

Any resources developed under this NOFO must follow the goal of strengthening FAIR (Findable, Accessible, Interoperable, and Re-usable) principles in data sharing. Investigators will be expected to share code/scripts, analytic tools/statistical models, protocols/processes, and metadata -- used or developed for harmonization, curation, and analysis -- through open-access repositories, as applicable. Therefore, investigators are strongly encouraged to use open-source software, analytic tools, and programming languages to promote interoperability as well as reproducibility. In this way, the FAIR principles for data sharing and the rigor and reproducibility of research will be enhanced. Applicants who plan to utilize data not currently in their possession (originated from another party) must confirm availability of the data and demonstrate (at a minimum via a letter of support) the willingness and permissibility of the original investigators to share the data for the purposes of the harmonization, curation, secondary analyses, in accordance with all applicable rules for the protection of human subjects.

Additionally, applicants should describe any training that will be made available (e.g., seminars or webinars) in order to facilitate the use of shared resources/tools, as applicable.

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

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 How to Apply - 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 How to Apply - Application Guide must be followed.

Delayed Onset Study

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

All instructions in the How to Apply - Application Guide must be followed.

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

See Part 2. 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. 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply – Application Guide.

5. Intergovernmental Review (E.O. 12372)

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 Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply - 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 form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply - Application Guide.

See more tips for avoiding common errors.

Applications must include annual milestones. Applications that fail to include annual milestones will be considered incomplete and will be withdrawn. Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be withdrawn before review.

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

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 must evaluate and score the “Scored Review Criteria” keeping the below resource development goals of the NOFO in mind. Reviewers should also keep in mind that proposed projects are required to address at least two of these goals, or other goals that are not listed but in the spirit of the award.

• Streamlined approaches that reduce postmortem intervals.
• Methods or techniques for MR imaging of fresh tissue.
• Innovative fixation techniques that reduce MR signal loss.
• Techniques that enable improved neuropathological analysis of regions demonstrating vascular neuropathology / MR signal abnormalities.
• Development of analytical MR models to better understand disease processes and neuropathology findings.
• The development of common coordinate systems, or improved co-registration techniques, for co-registration of MR and neuropathology images.
• Development of standardized procedures and/or acquisition techniques to facilitate co-registration across sites. This includes practices that would facilitate the use of machine learning for co-registration.
• Comparisons of various types of techniques, such as fixation techniques or solutions, methods to avoid fixation before MR, blocking/sectioning techniques, 3D mold types, etc., to demonstrate which lead to the best preservation of the tissue, MR signal, and genetic material.
• Development of atlases to be used in co-registering MR and neuropathology images.
• Development and discovery of biomedical materials such as new antibodies for staining and processing brain tissue.
• Development of novel MR sequences suitable to detecting neuropathology in postmortem or ex vivo tissue.
• Development of in-vivo MR sequences with increased sensitivity to vascular pathophysiology, based on ex vivo MR and post-mortem neuropathology findings.

Overall Impact

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).

Scored Review Criteria

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 proposed Center address the needs of the research projects and resources that it will coordinate? Is the scope of activities proposed for the Center appropriate to meet those needs? Will successful completion of the aims bring unique advantages or capabilities to the research projects and resources?

Specific to this NOFO:

• How significant will the product(s) produced/provided by the study be in helping to improve the understanding of the vascular pathogenesis and underlying biology of ARIA?
• How likely is it that the product(s) developed from this study will be adopted by the broader scientific community?
• How likely is it that the product(s) developed from this study will help to improve in vivo stratification and prognosis?
• How well does the application explain how the proposed product(s) will enable or enhance the joint analysis of human neuropathology and neuroimaging findings?
• Does the application yield any novel discoveries or insights into at least two of the following as they relate to ARIA?
  • Pathogenesis and pathophysiology of ARIA-E and ARIA-H in anti-Aβ mAbs induced cases
  • Pathogenesis and pathophysiology of spontaneous ARIA-H and ARIA-E triggered by cerebral amyloid angiopathy (CAA) and/or CAA-related inflammation (CAA-ri), respectively
  • Asymptomatic vs symptomatic ARIA
  • Factors affecting ARIA symptom severity
  • Potential differential treatment effects of anti-Aβ mAbs in APOE ε4 carriers
  • Biomarkers and/or risk factors for ARIA (e.g., pre-existing blood brain barrier (BBB) damage, overactive immune response, APOE ε4)
  • Biomarkers and/or mechanisms of increased susceptibility to BBB disruption/leakage related to Aβ accumulation or clearance
  • Biomarkers and/or mechanisms of inflammation related to amyloid presence or clearance
  • Potential interactions between BBB leakage and inflammation
  • Cerebral vascular dysfunction and ischemia including, but not limited to, impaired cerebrovascular reactivity, chronic hypoperfusion, perivascular hemorrhage, vessel wall abnormalities, and cerebral small vessel disease
  • Impaired neurovascular coupling
  • Tau-related effects
  • Other novel topics not listed that directly relate to the pathogenesis and pathophysiology of ARIA
• To what extent do the efforts described in the Plan for Enhancing Diverse Perspectives further the significance of the project?

Investigator(s)

Are the PD(s)/PI(s) and other personnel well suited to their roles in the Center? Do they have appropriate experience and training, and have they demonstrated experience and an ongoing record of accomplishments in managing biomedical research? Do the investigators demonstrate significant experience with coordinating collaborative basic and/or clinical research? If the Center is multi-PD/PI, do the investigators have complementary and integrated expertise and skills; are their leadership approach, governance, plans for conflict resolution, and organizational structure appropriate for the Center? Does the applicant have experience overseeing selection and management of subawards, if needed?

Specific to this NOFO:

• Does the applicant(s) propose a collaborative, multidisciplinary team with expertise in data science/data standards, in vivo and postmortem (or ex vivo) human MR neuroimaging, human MR neuroimaging methods and data analysis, human neuropathology methods and data analysis, and vascular neurology and/or neuroradiology? 
• To what extent will the efforts described in the Plan for Enhancing Diverse Perspectives strengthen and enhance the expertise required for the project?

Innovation

Does the application propose novel organizational concepts, management strategies, or instrumentation in coordinating the research projects and resources the Center will serve? Are the concepts, strategies, or instrumentation novel to one type of research program or applicable in a broad sense? Is a refinement, improvement, or new application of organizational concepts, management strategies or instrumentation proposed?

Specific to this NOFO:

• To what extent does the project bring technical and/or conceptual innovation, such as novel concepts, models, research approaches, techniques, and/or technologies that might contribute to enhanced understanding of the pathogenesis and pathophysiology underlying ARIA?
• If the project is proposing the development and discovery of biomedical materials, such as new antibodies for staining and processing brain tissue, how likely are the new materials to advance the field? How difficult will it be to produce these materials or to replicate the methods/techniques necessary to do so?
• To what extent will the efforts described in the Plan for Enhancing Diverse Perspectives meaningfully contribute to innovation?

Approach

Are the overall strategy, operational plan, and organizational structure well-reasoned and appropriate to accomplish the goals of the research projects and resources the Center will serve? Will the investigators promote strategies to ensure a robust and unbiased scientific approach across the projects and resources, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the projects and resources are in the early stages of operation, does the proposed strategy adequately establish feasibility and manage the risks associated with the activities of the projects and resources? Are an appropriate plan for work-flow and a well-established timeline proposed? Have the investigators presented adequate plans to ensure consideration of relevant biological variables, such as sex, for studies of vertebrate animals or human subjects?

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?

Specific to this NOFO:

• How reproducible is the resource?
• For software development:
  • Is there a detailed description for the timing and processes involved in software testing? Are those testing procedures sufficiently rigorous to ensure that the software being developed is robust?
  • How scalable is the software solution? Are the plans to make the software readily available for distribution to the scientific community or public feasible?
• How rigorous is the proposed approach to analyze and correlate ex vivo/postmortem MR data with neuropathological data?
• If applicable, to what extent does the approach compare various types of techniques (e.g., fixation techniques or solutions), methods to avoid fixation before MR data acquisition, blocking/sectioning techniques, 3D mold types, etc., to demonstrate which technique leads to the best preservation of the tissue, MR signal, and genetic material?
• If applicable, does the application propose analyses of pre-mortem imaging data from the same cohort? Will existing cohorts be utilized to link prospectively collected premortem and postmortem data or focus solely on the collection of postmortem data (employing retrospective chart review or other means to assess premortem health)?
• If applicable, does the proposed approach allow for or develop new machine-readable solutions?
• Are the timeline and milestones associated with the Plan for Enhancing Diverse Perspectives well-developed and feasible?

Environment

Will the institutional environment in which the Center will operate contribute to the probability of success in facilitating the research projects and resources it serves? Are the institutional support, equipment and other physical resources available to the investigators adequate for the Center proposed? Will the Center benefit from unique features of the institutional environment, infrastructure, or personnel? Are resources available within the scientific environment to support electronic information handling?

• To what extent will features of the environment described in the Plan for Enhancing Diverse Perspectives (e.g., collaborative arrangements, geographic diversity, institutional support) contribute to the success of the project?

Additional Review Criteria

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.

Specific to this NOFO:

Milestones and Timelines

• How detailed are the milestones covering all aspects of the proposed project?
• Are milestones clear, quantitative, actionable, and establish feasibility for all aspects of the proposed research?
• Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps?
• Do the applicants propose a reasonable plan to arrive at collaborative agreements with other recipients within six months of the award?

Review Criteria for Administrative Plan

• How clear and effective is the plan to coordinate the integration and management of activities within each award and with the project teams of the other funded award(s) under this NOFO?
• Are plans for reporting, establishing milestones, and coordinating activities appropriate and well-designed?
• How well suited are the personnel to accomplishing the goals of the administrative plan?
• Is there an organizational structure that will facilitate communication, collaboration, coordination, integration, and timely evaluation of activities and progress?
• How well designed are the plans for integrating data/tools/resources?

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

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

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

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

As applicable for the 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 Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

For [programs/projects/networks/consortia/resources] 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.

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

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 NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. 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

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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

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

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

Any application awarded in response to this NOFO 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: Recipient 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 recipient 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, Recipients, and Activities, including of note, but not limited to:

• Federal-wide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

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

If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website. 

HHS recognizes that NIH 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 NOFO.

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 System for Award Management (SAM.gov) requirements. SAM.gov requires Federal agencies to review and consider information about an applicant in the designated integrity and performance system (currently SAM.gov) prior to making an award. An applicant can review and comment on any information in the responsibility/qualification records available in SAM.gov. NIH will consider any comments by the applicant, in addition to the information available in the responsibility/qualification records in SAM.gov, 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 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of 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 (HHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients 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 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

Definitions:

NIH Program Official

A NIH Program Official (PO) will provide the standard programmatic oversight and stewardship of the projects, including review of pre-award and award documents/requirements; review of progress reports, budgets, and milestones; approval of changes in scope, budget allocation, or aims; and any other programmatic issues that may arise. The PO will serve as an ex officio member of the External Advisory Committee.

NIH Project Coordinator

One or more NIH Program Staff will serve as Project Coordinator (PC), will provide technical assistance, advice, coordination, and other program actions to support the recipients of the cooperative agreements during the conduct of an activity. Specifically, the Project Coordinator will contribute to developing final milestones for the study, serve as a liaison between the recipients, the NINDS Advisory Council and the larger scientific community, serve on committees, assist in promoting the availability of data and resources developed during this project to the situations that require coordinated action. The Project Coordinator will refrain from activities that rise to a level of involvement that results in conflicts of interest, and will be recused from all funding decisions, RPPR and milestone reviews, and go/no?go project decisions. The PC will work closely with the PD/PI to maximize progress towards the goals of the project and the program and will serve as a voting member of the External Advisory Committee.

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

• Organizing and hosting necessary annual scientific or programmatic meetings.
• Advertising the resources available to the community through outreach activities.
• Assembling the External Advisory Committee and participating in EAC activities.
• Managing and coordinating project activities scientifically and administratively at the recipient institution and with any collaborating institutions.
• Ensuring that all data and information are disseminated according to the FAIR principles; that is data and information should be identifiable and annotated with metadata including data quality and assurances.
• Ensuring that all data and information involving human subjects has the appropriate security and clearances.
• Wherever possible, adhering to the Open Science Initiative, to guarantee the right of others to read, redistribute, modify, and freely use any software.
• Updating goals and milestones at the time of award and providing summaries of progress toward those goals, including the Project Management Plan, at least yearly, as requested by NIH. The milestones will be reviewed annually (and at other times, if necessary), and new milestones will be negotiated, as needed by working with the Project Coordinator as appropriate.
• Participating in regular discussions with the NIH staff.

Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

Program Official:

• Responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.
• Review the progress of the project and monitor for compliance with NIH Grants Policy.
• Make recommendations to the NIH for continued funding based on performance and compliance with the Terms and Conditions of the award.
• Conduct more frequent progress reviews, with the possibility that the recipient submit quarterly progress reports should problems arise in the conduct of the study.
• Serve as an ex officio member of any External Advisory Committee.

Project Coordinator:

• Participate in the process of coordinating collaborative project efforts and setting priorities.
• In consultation with the program officer, provide advice in the development of operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action.
• Serve as a voting member of any External Advisory Committee or Steering Committee as a representative of the NIH extramural staff.
• Serve as a liaison to the NIH, and as an information resource for the recipients about related research activities.

Areas of Joint Responsibility include:

• PD(s)/PI(s) will constitute the External Advisory Committee (EAC) and this committee is expected to consist of individuals who are not key personnel or collaborators of the key personnel of the award. The EAC meetings will include NIH staff and may include the PD(s)/PI(s) and other members of the funded project. The EAC will select one member to act as the Chair of the committee and the Chair may not be an NIH employee. The EAC will meet at least once a year.

Dispute Resolution:

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

3. Data Management and Sharing

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

Applicants who plan to utilize data not currently in their possession (originated from another party) must confirm availability of the data and demonstrate (at a minimum via a letter of support) the willingness and permissibility of the original investigators to share the data for the purposes of the harmonization, curation, secondary analyses, in accordance with all applicable rules for the protection of human subjects.

4. Reporting

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

• Recipients will provide updates at least annually on implementation of the PEDP.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

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

In accordance with the regulatory requirements provided at 2 CFR Part 200.113 and Appendix XII to 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (Responsibility/Qualification in SAM.gov, formerly 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 2 CFR Part 200 – 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: https://www.era.nih.gov/need-help (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: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Carlos C. Faraco, Ph.D., M.S.

Health Science Administrator
Division of Clinical Research
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9135
Email: carlos.faraco@nih.gov

Alessandra Rovescalli, Ph.D.
National Institute on Aging (NIA)
Phone: 301-555-1212
E-mail: rovescaa@nih.gov

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Email: nindsreview@nih.gov

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: ChiefGrantsManagementOfficer@ninds.nih.gov

Philip E. Smith
National Institute on Aging (NIA)
Phone: 301-555-1212
E-mail: philip.smith2@nih.gov

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 2 CFR Part 200.