Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Neurological Disorders and Stroke (NINDS)

National Institute on Aging (NIA)

Funding Opportunity Title
Development and Validation of Models for Alzheimer’s Disease-Related Dementias (ADRD) (R61/R33 - Clinical Trial Not Allowed)
Activity Code

R61/R33 Exploratory/Developmental Phased Award

Announcement Type
New
Related Notices
  • August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189.
  • August 8, 2022 - New NIH "FORMS-H" Grant Application Forms and Instructions Coming for Due Dates on or after January 25, 2023. See Notice NOT-OD-22-195.
  • August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198.
  • October 26, 2022 - Reminder: FORMS-H Grant Application Forms & Instructions Must be Used for Due Dates On or After January 25, 2023 - New Grant Application Instructions Now Available. See Notice NOT-OD-23-012.
Notice of Funding Opportunity (NOFO) Number
PAR-23-154
Companion Funding Opportunity
None
Assistance Listing Number(s)
93.853, 93.866
Funding Opportunity Purpose

This funding opportunity announcement (NOFO) supports the development and validation of clinically- and pathophysiologically-relevant models of ADRD. These models need to be innovative and address a gap in the currently available models. Models could include in vivo models (e.g., invertebrate, small and large vertebrate), ex vivo models, human induced Pluripotent Stem Cells (iPSCs), organoids, tissue-on-chip, or other in vitro models. Rigorous validation is required. This includes internal, face, construct, and predictive (to the extent possible) validation. Such validation could include looking at underlying mechanism/pathways, functional imaging, behavior, and other cognitive readouts. Independent replication is also encouraged.

It is essential that models reflect multiple aspects of the human condition as much as possible. Novel models of multiple pathologies or comorbid conditions are encouraged. Such models could include multiple manipulations (e.g., genetics, environment, metabolic, age) to better reflect the complex aspects and interactions of disease and risk factors. The R61 phase will support initial development, internal validation and optimization of the model. The R33 phase will support external validation studies. The outcome should be a fully validated model.

Key Dates

Posted Date
April 11, 2023
Open Date (Earliest Submission Date)
May 20, 2023
Letter of Intent Due Date(s)

30 days prior to application due date

Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS Scientific Merit Review Advisory Council Review Earliest Start Date
June 20, 2023 June 20, 2023 Not Applicable November 2023 January 2024 April 2024
October 20, 2023 October 20, 2023 Not Applicable February 2024 May 2024 July 2024

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.

Expiration Date
October 21, 2023
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

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 NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) 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.

Table of Contents

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background

Goal 1 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) by 2025. ADRD are defined as Frontotemporal dementia (FTD), Vascular Contributions to Cognitive Impairment and Dementia (VCID), Lewy Body Dementias (LBD) and Multiple Etiology Dementias (MED). Starting in 2012, the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS) have held research summits to assess the needs and set AD/ADRD research implementation milestones. The NINDS ADRD Summit in 2022 resulted in ADRD research priorities for advancing the state-of-the-science toward meeting Goal 1 of the National Plan. This initiative is responsive to several high priority milestones established at the 2022 ADRD Summit (https://www.ninds.nih.gov/news-events/events/adrd-summit-2022).

While there are multiple models of ADRDs that capture some aspects of disease, more work needs to be done to fully model all aspects of these complex diseases, advance knowledge of newer or multiple pathologies, integrate vascular elements, and incorporate relevant clinical, pathologic, and molecular phenotypes. Novel cellular and animal models of multiple interacting pathologies, that mimic the multiple interacting risk factors and comorbidities seen in patients, and that advance knowledge of key molecular pathways in a pathophysiologically-relevant context are particularly needed.

This NOFO is intended to support the development of validated, clinically- and/or pathophysiologically-relevant models (this could include small animals, larger animals, ex vivo models, human iPSCs, organoids, tissue-on-chip, or other in vitro models). All models must have translatability to human studies. For the purposes of this NOFO, small animal models are defined as invertebrates and smaller vertebrates such as zebrafish and rodents. Large animal models would include, for example, dogs, pigs, and rabbits.

Development of models that translate to a human disorder or disease requires rigorous internal and external validation.To demonstrate internal validation, it is important to evaluate and understand the precision, reliability, sensitivity, accuracy, and dynamic range characteristics of the endpoints used to assess the effect of therapeutic or physiological intervention in the animal model or model system. In addition, it is essential that the experimental design procedures utilized in characterizing the model are conducted in a rigorous manner, utilizing randomization, blinding and the appropriate power analysis.

It is also important to address external validation, showing that the model can recapitulate aspects of the disease phenotype and etiology, where endpoints or biomarkers of disease are similar and measurable in both the model system and in human disease. One component of external validity is face validity-the similarity between the model and the clinical manifestation of the disease (as measured by overt clinical symptoms, patterns of activation using functional Magnetic Resonance Imaging (fMRI) or electroencephalography (EEG), functional or behavioral read-outs, disease progression, etc.). Another component of external validity is construct validity--the similarity between the physiological or biological basis of the model and the actual human disorder (e.g., genetic, proteomic, metabolomic markers). Although components of both face and construct external validity are certainly desirable in a model, predictive validity provides the most confidence in the ability of the model to translate to human disease. Predictive validity refers to the probability that a clinically validated therapeutic (biologic, small molecule, device, surgical procedure, etc.) will have the same effects in the model as it will in the intended clinical population. By definition, the evaluation of predictive validity requires a validated tool/therapeutic that has a known effect in humans. Note that experimental therapeutics cannot be used to validate an experimental model. Since these tools do not necessarily exist for many ADRDs, it is not always possible to obtain true evidence of predictive validity until the candidate therapeutic is actually tested in humans. Therefore, it may not always be possible to evaluate the predictive validity of a new model system. However, it is important to include evaluations of internal validity, and face, construct, and predictive validity (to the extent possible), to provide evidence that the proposed model represents a significant advance over existing models.

NOFO Scope
This NOFO will utilize a phased approach to support the development and validation of novel models of the multifaceted aspects of ADRDs such as the complex pathology, neurorcircuitry changes, or comorbid conditions and risk factors in ADRD. Such models could include multiple manipulations (genetics, epigenetic, environment, metabolic, age, etc.) to better reflect the complex aspects and interactions of disease and risk factors in patients. Other factors to consider include but are not limited to use of appropriate cell types, time of life, disease stage, vascular contributions, interactions between multiple pathologies, inflammatory contributions, and anatomical progression. Models need to address a gap in what is currently available in the field.

This NOFO will support applications to develop and validate animal models of ADRD that recapitulate multiple aspects of the disease pathophysiology as well as its etiology, where endpoints or markers of disease are similar and measurable in the model and human disease (i.e., neurological deficits, patterns of activation using fMRI or EEG, measurable genetic markers, functional or behavioral read-out, disease progression, etc.). In addition, it will support the development and validation of in vitro or ex vivo testing systems that utilize existing human or animal cell systems (e.g., iPSC). Applicants proposing iPSC studies must follow NINDS Requirements for iPSC Development and Resource Sharing NOT-NS-14-032.

Applications that propose to validate existing models are also appropriate for this NOFO. However, development of de novo models without validation is not appropriate for this NOFO.

Phased Award Mechanism and Transition to R33
The identification and characterization of clinically- and/or pathophysiologically-relevant preclinical models typically require a multi-step process that includes initial feasibility testing of the model system followed by internal and external validation. Therefore, this funding opportunity will use a phased R61/R33 mechanism. The R61 phase will support initial development, internal validation and optimization of the model. The R33 phase will support external validation studies. The final outcome should be a fully validated model that can be utilized for either basic disease mechanism research or for future testing of the biological effects of candidate therapeutics designed to treat ADRDs. Transition from the R61 to the R33 phase is contingent upon the successful completion of proposed milestones. Milestones are goals that are quantifiable for measuring success that can be used for go/no-go decision-making at the R61/R33 transition point and should have timelines and quantitative criteria associated with them. All milestones should be useful as a measure of progress toward the overall goal of the project (see Section IV). NINDS emphasizes the importance of the robustness and reproducibility of experimental results in evaluating progress. Specific Aims or a list of activities planned for each year are not considered milestones because they do not provide decision-making goals. For frequently asked questions and milestone examples, please see https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Translational-Research/Funding-Programs-Researchers/IGNITE.

Examples of activities in the R61 Phase include, but are not limited to:

  • Initial development of the model
  • Any optimization of the above related to feasibility, endpoint range and sensitivity, potential to scale up for validation studies (breeding, aging, etc.), specificity of the model system as it relates to the disease or endpoint measures, identification of confounding variables, etc.
  • Complete internal validation for endpoints used in the model

Examples of activities in the R33 Phase include, but are not limited to:

  • All external validation studies, including comparisons of phenotypes and endotypes to human disease, comparisons of disease etiology in preclinical systems to what is known about the human disease and efficacy of clinically validated therapeutic agents (if available) in the new model system

Collaborations:

Demonstration of collaborative relationships between applicants with preclinical and clinical expertise (such as biostatisticians and clinicians) is highly encouraged. It is preferred that the collaborating clinician is listed as a co-investigator or a formal member of the investigative team. Alternatively, a letter of support from the collaborating clinician can be used to demonstrate involvement in the project but should include a plan for collaboration with the principal investigator.

In addition, applicants should strive to increase the diversity of their teams. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogenous teams. Scientists from diverse backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. There are many benefits that flow from a diverse NIH-supported scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved or health disparity populations participate in, and benefit from health research, and enhancing public trust. Please see NIH NOT-OD-20-031 for details.


Applications Not Responsive to this NOFO:

Non-responsive studies include those that involve any of the following activities:

  • Projects that are not primarily focused on AD/ADRD
  • Development of de novo models without validation
  • Development and/or validation of models that are purely computational
  • Discovery of disease initiation, pharmacodynamic or progression biomarkers (covered by PAR-22-089)
  • Assay development, test agent screening or test agent optimization (covered by PAR-21-124)
  • Studies aimed at evaluating a potential therapeutic agent for efficacy or safety (covered by PAR-21-122) except as part of predictive validation of the model
  • Pharmacokinetic studies of a potential therapeutic agent (covered by PAR-21-122)
  • Discovery or development of therapeutic devices, device/drug combinations, therapeutic surgical procedures, diagnostics, or rehabilitation strategies
  • Human subjects research, unless it meets the E4 exemption (e.g. entirely deidentified human samples, cells and clinical data). Please note that use of human biospecimens MIGHT be considered human subjects research, depending on the collection and the provider. For help determining if your research is considered human subjects research, please see here: https://grants.nih.gov/grants/policy/hs/private-information-biospecimens-flowchart.pdf. For help determining if your human subjects research meets the E4 exemption, please see here: https://grants.nih.gov/sites/default/files/exemption_infographic_v8_508c_1-15-2020.pdf

Studies that fail to include quantitative, go/no-go milestones as well as a clear demarcation of which activities are in the R61 phase and which are in the R33 phase are also considered non-responsive. The R61 and R33 must not overlap in time. Non-responsive applications will be administratively withdrawn without review.


Additional Considerations

Applicants are strongly encouraged to contact NIH Program staff to discuss potential applications prior to submission.

When appropriate, Small Business applicants who are eligible for the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs are strongly encouraged to submit through either the SBIR or STTR Omnibus Solicitations (https://seed.nih.gov/small-business-funding/find-funding) or other appropriate SBIR or STTR funding opportunity to take advantage of the congressionally mandated set-aside specifically for small businesses. Please see https://www.ninds.nih.gov/Funding/Small-Business-Grants for more information about the programs.

Prior to award, NINDS Program staff may contact the applicant to discuss the proposed milestones and any changes suggested by the NINDS review panel or Program staff. A final set of approved milestones will be specified in the Notice of Award.

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

Section II. Award Information

Funding Instrument

Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed
New
Resubmission

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Clinical Trial?

Not Allowed: Only accepting applications that do not propose clinical trials.

Funds Available and Anticipated Number of Awards

NIH intends to commit the following amounts in FY24: $5,000,000 total budget to fund up to eight awards contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget

Direct Costs cannot exceed $360,000 per year for small animal models (e.g., rodents, zebrafish). It is anticipated that in vitro models will request a lower budget, however, funds requested should reflect the actual needs of the project. Large animal models may request up to $600,000 direct costs per year.

Award Project Period

The total project period for a combined R61/R33 application submitted in response to this NOFO may not exceed five years, with no more than three years for the R61 phase and no more than four years for the R33 phase. Conversion to the R33 phase is contingent on completion of milestones in the R61 award period.

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

Eligible Organizations

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
Foreign Institutions

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

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

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

Required Registrations

Applicant Organizations

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

  • System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
    • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
    • Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. 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.

Eligible Individuals (Program Director/Principal Investigator)

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 SF424 (R&R) Application Guide.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, 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 SF424 (R&R) Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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) 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:

Rebecca Roof rebecca.roof@nih.gov

Page Limitations

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

Instructions for Application Submission

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific Aims: Within the Specific Aims section, include headers titled R61 Phase Specific Aims and R33 Phase Specific Aims. Under each header, state the specific objectives of the efforts including the technical questions to be answered to determine the feasibility and the validity of the proposed model systems relative to the end goal. Briefly provide the context and overall rationale for the proposed studies, with an emphasis on how the proposed model will significantly improve the field.

As this is an R61/R33 mechanism, clear demarcation of which activities are in the R61 and which are in the R33 is required (the two phases must not overlap in time). Applications that do not propose both an R61 and R33 phase will be administratively withdrawn without review.

Research Strategy: The Research Strategy section must include the following sections:

  • Rationale and Unmet Need
    • Rationale for the proposed model, which includes any existing clinical or pathophysiological evidence that the model could be relevant to complex ADRDs. Rationale should address unmet need and provide details for how well the model recapitulates multifaceted aspects of ADRD in humans such as complex pathology, comorbid conditions, risk factors, disease progression, neurological deficits, neurocircuitry changes, etc. Applicants should describe the benefits of the model and what role it will play in advancing the field.
    • Discuss the strengths and weaknesses of the prior research used to support the application and describe how the proposed research will address weaknesses or gaps identified by the applicant. This may include the applicant’s own preliminary data, data published by the applicant, or data published by others.
    • Novelty of the model, along with the potential advantages of the proposed model over alternatives available in the neurological disease of interest. A table outlining the landscape and what the new model adds could be included.
  • Approach
    • Description of how the model will be produced, including a plan to confirm the feasibility and applicability of the model system or testing paradigm.
      1) Will it be feasible to implement and meaningfully translate to human biology? For applicable models, is there evidence that the endpoints would be feasible in a clinical setting?
      2) If the model requires breeding or aging, will sufficient animals be available to conduct validation studies within the 5-year limit of the full project period?
      3) What are the plans to optimize (if necessary) the model system in order to conduct the studies required to provide external validation of the model system?
    • Applications should have a strong biological rationale for the intended approach and proposed studies that exhibit methodological rigor. NINDS urges investigators to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm) and additionally recommends the research practices described at https://www.ninds.nih.gov/Funding/grant_policy. This will ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include, where applicable, expressing clear rationale for the chosen model(s) and endpoint(s), describing parameters clearly, blinding, randomizing, ensuring adequate sample size, pre-specifying inclusion/exclusion criteria, appropriately handling missing data and outliers, implementing appropriate controls, preplanning analyses, and using appropriate quantitative techniques. Consider study limitations, and plan for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications. Investigators should indicate whether data presented or cited in the application as key support for the proposed work were collected, analyzed, and reported in a rigorous and transparent manner as indicated above. A plan to address any ambiguities, weaknesses, or limitations in the prior research should be included in the application. Proposed experiments should similarly adhere to these high standards of rigor and transparency.
    • Include a detailed plan for internal and external validation of the model.
      • Provide a clear outline of the studies designed to evaluate internal and external validity.
      • Examples of points to address for the evaluation of internal and external validity in the development of model systems are provided in Part 2, Section I of this announcement.

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.

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 SF424 (R&R) 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.
Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

  • No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.
PHS Human Subjects and Clinical Trials Information

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.

Delayed Onset Study

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

PHS Assignment Request Form

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 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 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 NINDS, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Post Submission Materials

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.

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 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?

Specific to this NOFO:

How well will the model translate to human ADRD, taking into consideration disease complexity and/or comorbidities? How well have the investigators considered the phenotype, physiology, and feasibility of measurement of the clinical population in the design and validation of their preclinical model system? How appropriate is the utility of the model from both preclinical and clinical perspectives? How strong is the rationale of unmet need for the model in the defined ADRD? How well have investigators defined the patient population that the model best reflects (i.e., pathology, stage of disease, comorbidities, etc.)? How well does the model address gaps and advance the field?

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?

Specific to this NOFO:

How knowledgeable and experienced are the investigators about the biological target and/or disease biology? How appropriate is the expertise in the areas of in vitro, in vivo or ex vivo model validation, experimental design, statistical analysis, systems analysis, etc. (as appropriate) for the project? Have they formed collaborations with clinicians and others as appropriate; is there evidence that the clinical collaborator will play an active role in the design and validation plans of the models to ensure models are clinically relevant?

Innovation

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

Approach

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

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 good are the plans to optimize the model (if necessary)? How well do the plans estimate the feasibility of the model for validity?
How thorough and detailed are the plans for model validation (internal and external)? In the case of endpoint measures, how adequate are the methods for addressing internal validity characteristics such as dynamic range, precision, accuracy, etc.? How appropriate is the proposed statistical analysis for the experimental design and the quantitative characteristics of the endpoints? How well have methods for evaluating external validity characteristics (how well the model system recapitulates human clinical symptoms, pathology, physiology and genetic basis for disease) been systematically outlined in the application for model characterization?
How feasible will the model be to implement and how well will it translate to human biology? For applicable models, how good is the evidence that the endpoints for the model system would be feasible in a clinical setting? How well does the application show an understanding of the state of the field and where the proposed model contributes to the field?
If the model requires breeding or aging, will sufficient animals be available to conduct validation studies within the 5-year limit of the full project period? How well does the proposed research incorporate adequate methodological rigor where applicable, including, but not limited to, clear rationale for the chosen model(s) endpoint(s), clear descriptions of parameters, blinding, randomization, adequate sample size, pre-specified inclusion/exclusion criteria, appropriate handling of missing data and outliers, appropriate controls, pre-planned analyses, and appropriate quantitative techniques? How well do the applicants consider study limitations, and plan for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications?

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?

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.

Milestones and Timelines

How appropriate are milestones and are they associated with clear, quantitative criteria for success that allow go/no-go decisions at the R61/R33 transition point? If criterion is not to be used for go/no-go decisions, is it justifiable?

How well do the milestones allow the evaluation of progress in the R61 phase and how well will successful completion of these milestones provide confidence that the investigator will be able to successfully implement the R33 phase? How appropraite are the timelines proposed for achieving the milestones? Are they realistic and inclusive of necessary steps, but also efficient without unnecessary steps?

How well-justified are the milestones and approach to address the questions and objectives of the application?

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

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations

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 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), in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group convened by the NINDS 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.

All applications under this announcement are to be assigned to the NINDS as the administrative institute. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the NINDS National Advisory Council. The following will be considered in making funding decisions:

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

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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

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

Recipients 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 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:

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

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a condition of receiving the grant, to administer programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity, The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. See https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

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

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

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

Cooperative Agreement Terms and Conditions of Award

Not Applicable

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the 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.

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.

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 45 CFR Part 75.301 and 2 CFR Part 200.301.

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

5. Evaluation

Enter text here.

Section VII. Agency Contacts

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

Application Submission Contacts

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: 301-637-3015

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

Scientific/Research Contact(s)

Larry Refolo, Ph.D.
NATIONAL INSTITUTE ON AGING (NIA)
Division of Neuroscience (DN)
Phone: 301-594-7576
E-mail: refolol@mail.nih.gov

Becky Roof, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Email: rebecca.roof@nih.gov

Linda McGavern, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Email: mcgavernlm@ninds.nih.gov

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

Jeni SMITS
National Institute on Aging (NIA)
E-mail: jeni.smits@nih.gov

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

Authority and Regulations

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

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