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.

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 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.

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. One priority is to develop, validate, and refine therapeutic targets through the creation, validation, and use of pre-clinical and translational tools and resources.

The majority of efforts to develop disease modifying therapies for ADRD have been focused on single drugs developed against a single target. However, an individual with an ADRD can have multiple pathologies that involve multiple pathways, which may change depending on comorbidities and over time. These complexities are likely contributing to the low success rate for disease-modifying therapies. There is a need to support the development of therapeutics that tackle ADRDs from multiple fronts at the same time in affected individuals -- this could mean targeting multiple pathways, cellular functions, circuits, systems or pathologies, for example. This could also mean a therapeutic that targets a ‘node’ or point where multiple pathways, circuits or systems converge. The first step toward developing such a therapy is the validation of multiple targets working in synergy. For this NOFO, a ‘target’ is defined as an endogenous molecule (such as a protein), circuit or system that is associated with a disease that, if modulated, would have a benefit. Validated targets could be used for future therapy development, beyond the scope of this NOFO. For this NOFO, ‘synergy’ is defined as a phenomenon where modulating two or more targets results in an outcome that is greater than the sum of the outcomes of the individual targets. While synergy is a goal, even if a second target enhanced the first in a way that is beneficial to patients, that could be of value.

Future development of disease-modifying therapies that take into consideration this complexity will require a strong foundation built on well-validated targets. For targets to be validated, there must be strong evidence supporting a causative link between the modulation (i.e. activation or inhibition) of the targets and the functional physiological consequences associated with treating or preventing a clearly defined disease state while maintaining safety. There must be a good understanding of how the target needs to be modulated (positively or negatively) and to what extent. Timelines also need to be understood; when in the disease progression should the targets be modulated and for how long? There needs to be an understanding of potential safety and translatability. Are there related variants or anti-targets and is target engagement selectivity of a future therapeutic likely or possible? Are there species differences that will need to be considered in future therapy development efforts? What is the impact of relevant environmental factors, comorbidities or ageing?  And lastly, since multiple targets are being investigated at the same time, how do they directly or indirectly interact? What is the mechanism of synergy? Does one impact the levels, desired degree of modulation, time course or safety profile of the other? This NOFO provides the opportunity to address these knowledge gaps. The end goal of this effort is to have a well-validated set of novel synergistic therapy-modulating targets for future therapy development for ADRD through the  NINDS IGNITE Program or other similar funding mechanisms. 

R61/R33 Phased Mechanism and Transition to R33

This NOFO uses the R61/R33 Phased Innovation Award mechanism. The R61 will support the demonstration that two or more targets are in fact synergistic (ideally), or at least show substantial advantage over modulation of just one target. This will be done using multiple methods of modulation (genetic, antibodies, chemical tools, etc.), and looking at multiple levels: 1) molecular and pathological outcomes in cellular and animal models, 2) physiological and anatomical outcomes and 3) behavioral, cognitive and dementia outcomes. Where possible, validation will be done in patient-derived samples as well as rodent or other models. The R33 will support evaluation of the degrees of modulation that are required, the timelines, possible safety concerns, the mechanisms, and any other factors important for future therapy development. It will also support independent replication. 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. 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. Section IV includes additional information regarding project milestones. 

Entry Criteria

• A strong rationale, based on either the literature or investigator-generated data, that two or more novel targets would be synergistic/advantageous for a particular ADRD patient population. This population needs to be defined in terms of the complex pathology, comorbidities, and stage of disease. 
• Tools (reagents, cell lines, models, etc.) needed to feasibly complete the validation of multiple targets by the end of the grant period (although limited optimization of the tools within the project period is supported).

Example activities

This NOFO supports these R61 and R33 activities with the goal of rigorously validating that two or more novel targets are synergistic or have an advantage over a single target to create a foundation for future therapy development. Based on what's already known about individual novel targets and the patient population, some of the below R61 and R33 activities may be higher or lower priority. 

Examples of activities for R61 phase include, but are not limited to:

• Limited studies demonstrating that the required tools, assays and read-outs are rigorous, reproducible, and fit for use (day to day, batch to batch, etc.), if this isn't already provided in the grant application preliminary data. (If extensive validation of an animal model is needed, please consider PAR-23-154.) Performing power analyses to support future R33 work
• Demonstrating synergy/advantage for two or more targets at multiple levels (molecular, metabolic, cellular, tissue, neuronal network, behavior, cognition etc.) using both human (for example iPSCs) and non-human model platforms

Milestones at the end of the R61 must reflect that all tools, assays and models are in place and rigorously validated to support R33 work. Milestones must also reflect that the two or more targets are indeed synergistic/adventagous and safe to support future development. 

Examples of activities for the R33 phase include, but are not limited to:

• Evaluating the effects (beneficial and toxic) of different degrees of modulation of each target separately and together to understand the desired window of activity
• Evaluating the timelines including age of animal, stage of disease, and length of target modulation for each target separately and together to understand the desired timelines
• Evaluating the impact of relevant environmental factors (such as diet) and comorbidities
• Limited studies evaluating the mechanism of synergy/advantage of combining two or more targets
• Blinded, rigorous replication of key experiments by an outside and independent laboratory

Applications Not Responsive to this NOFO include those that involve any of the following activities:

• Applications not focused on ADRD
• Applications focused on a single target unless it's a ‘node’ modulating multiple pathways, cellular functions, circuits, systems, or pathologies
• Activities focused on the development of a therapeutic small molecule, device or biologic. Use of existing small molecule, device, or biologic probes are appropriate
• Target identification studies
• Human subject research unless it meets the E4 exemption. Please note that use of human biospecimens MIGHT be considered human subject research, depending on the collection and the provider. For help determining if research is considered human subject research, please see here: https://grants.nih.gov/grants/policy/hs/private-information-biospecimens-flowchart.pdf. For help determining if human subject research meets the E4 exemption, please see here: https://grants.nih.gov/sites/default/files/exemption_infographic_v8_508c_1-15-2020.pdf

Applications that fail to include quantitative, go/no-go milestones between the R61 and R33 are non-responsive. Applications that do not contain a clear demarcation of which activities are in each phase (R61 versus R33) are also non-responsive. Phases must not overlap in time. Non-responsive applications will be administratively withdrawn without review.

Collaborations

NINDS encourages building multidisciplinary teams including those with the technical expertise to do the proposed work, biostatisticians, and clinicians with an understanding of the patient population. 

In addition, NINDS encourages applicants to assemble diverse 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.

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

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 Institutions) are not eligible to apply.

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

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted 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.

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 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 Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

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

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

• Descriptive title of proposed activity
• Name(s), 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

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

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

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

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

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

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

R&R 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.

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

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

Specific Aims: Within the Specific Aims section, include headers titled R61 Phase Specific Aims and R33 Phase Specific Aims. 

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 should include the following sections:

Rationale and Unmet Need (all of the following are required):

• Describe the basis for the hypothesis that two or more novel targets are synergistic or advantageous (genomic, proteomic, other -omic, big data, patient data, etc.)
• Describe the patient population that this target would address. Include a consideration for the complex disease state, the multiple pathologies, the interacting risk factors, comorbidities, disease stage, etc. 
• Describe the therapeutic landscape for this indication. If there are already therapeutics under development for the same indication, describe what advantage the new synergistic targets provide
• Describe any other knowledge gaps that are preventing future therapy development and how they are being addressed in this application

Approach:

Based on what's already known about the novel targets and the intended patient population, applicants must  describe how R61 and R33 phase activities will be prioritized to reach the end goal of validating that two or more novel, disease modifying targets are synergistic or have an advantage over a single target to create a foundation for future therapy development. This NOFO supports validation on many levels and in multiple models. Applicants must describe their choice of models, assays, and endpoints and how this will support a complete and rigorous validation. Applicants must describe which models, assays and endpoints are necessary for validation, and which are just ‘nice-to-have’ and how results will be interpreted if different models, assays or endpoints don't all point to the same result. Applicants must describe what will be done to evaluate the desired timings for modulating the two targets (pre-disease onset, early onset, late onset) and if the ideal target modulation windows overlap in time.

This could include but is not limited to:

• (R61)  Describe limited studies demonstrating that the required tools, assays and read-outs are rigorous, reproducible, and fit for use (day to day, batch to batch, etc.), if this isn't already provided in the grant application preliminary data. Describe the biological rationale justifying the ADRD relevance of the tools and assays. Tools and assays could include, for example, gene editing tools, ASOs, viral infection agents, antibodies, small molecule probes, isolated cells, ex vivo slices, human iPSCs or animal models of disease. (Note that if extensive model development and validation is needed, PAR-23-154 should be considered). Since use of multiple tools will provide added confidence in the targets, describe the complementarity and limit of each methodology. Describe the criteria for determining if a tool is fully rigorously tested and ready for use. This should include measures of batch-to-batch, day-to-day, sample-to-sample variability, reliability over time, dynamic range, power analyses, sex differences, and other measures of rigor and reproducibility.
• (R61) If in vitro assays are based on the generation of patient-derived human iPSCs, discuss plans to identify functional phenotypic difference(s) between control and disease states, and address how genetic mosaicism and other potential pitfalls from expanding cell lines in vitro can be avoided. Include feasible alternatives (such as multiple lines, or isogenic cell lines from genetic isoforms of the target).
• (R61) Describe the experiments and combinatorial design that will be performed to test the hypothesis that two or more targets are synergistic/adventageous at multiple levels (molecular, metabolic, cellular, tissue, network, circuit, behavioral, multiple species, etc.) and using multiple readouts.
• (R33) Describe the single and combinatorial design used for experiments that will be done to better understand the effects (desired effects and side effects) of various degrees of modulation of each target separately and together. Describe how the desired optimal window of modulation will be determined based on efficacy and safety. 
• (R33) Describe what will be done to better understand the desired time course of target modulation for each target separately and together. Do the two overlap in time? Consider both the stage of disease, the impact of ageing and how long the targets need to be modulated to have efficacy and safety. 
• (R33) Describe what will be done to understand the impact of relevant environmental and comorbid conditions. These variables should depend on the patient population of interest but could include factors like diet, exercise levels, or vascular disease.
• (R33) Describe what experiments with combinatorial design will be done to understand the mechanism behind the synergy/advantage
• (R33) Independent replication is encouraged. If included, describe how this will be done and address the level of independence of the outside laboratory.
• (R61 and R33) Applicants must address 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.

Milestones:

Applications that fail to include quantitative, go/no-go milestones for the transition from the R61 to R33 are non-responsive. Applications that do not contain a clear demarcation of which activities are in each phase (R61 versus R33) are also non-responsive. Phases must not overlap in time. Non-responsive applications will be administratively withdrawn without review.

Each R61 activity must include a go/no-go milestone reflecting that the activity supports further work in the R33. Milestones should be project-specific based on what's already known about the targets and the intended patient population, but must include:

• Clear go/no-go criteria reflecting that tools, assays, models, readouts, etc. are rigorously tested and optimized to support the proposed experiments, if not presented in preliminary data. That could include measures of reproducibility (such as r²), dynamic range and error (such as z'), power analyses, quality control (purity, activity), or other relevant measures.
• A clear definition of what endpoints would need to be seen from modulating two or more targets simultaneously to reflect a clinically meaningful benefit to warrant further development in the R33. This definition may vary depending on the level (molecular, metabolic, cellular, tissue, neuronal network, behavior, etc.), assay, or readout. Address how a decision about progressing to the R33 would be made if synergy/advantage is only found in some assays but not others.

While statistical significance is quantitative, applicants are encouraged to instead consider what's biologically meaningful and supported by literature when choosing milestone criteria. (For example, a readout in an animal model could be statistically significant but still too small to reflect a difference that would be meaningful to a patient.)

Timeline: 

Provide a timeline with specific milestones for progression from the R61 phase to the R33 phase. The timeline, specific goals and feasibility milestones should be clear and complete. Indicate when it is anticipated that essential components of the project will be completed. The proposed timeline with specific milestones should be clearly delineated and should appear as the last element of the Research Strategy section.

Collaborations:

Applicants should build multidisciplinary teams including those with the technical expertise to do the proposed work, biostatisticians, and clinicians with an understanding of the patient population. 

In addition, applicants are encouraged to diversify 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.

Resource Sharing Plan:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide. 

The following modifications also apply:

• Generally, Resource Sharing Plans are expected, but they are not applicable for this FOA

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.

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

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

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 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 SF424 (R&R) 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.

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.

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 is the hypothesis that two or more targets are likely to be synergistic/advantagous and improve patient outcomes supported by strong literature or investigator-initiated data? How novel are the targets? How well-defined is the patient population that would stand to benefit from these therapeutic targets, if successful? How well have the applicants considered the complexity of disease, including multiple interacting pathologies, risk factors, comorbidities, stages of disease ect. of the patient population when choosing targets to validate? How well have applicants considered the therapeutic landscape? If there are already therapeutics under development for the same indication, how convincing is the argument for an advantage that the new combination of targets would provide?

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 appropriate is the multidisciplinary team including those with the technical expertise to do the proposed work, biostatisticians, and clinicians with an understanding of the patient population?

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:

While tool optimization is supported, do applicants have in hand the tools necessary to feasibly achieve the project goals within the 5-year grant period? How appropriate and rigorous are the plans for testing and optimization of all tools, assays, models, and readouts that are not already optimized in the preliminary data? How strong is the biological rationale for the ADRD relevance of the models/assays proposed to demonstrate the advantage of the combinations? Are alternative approaches provided and how appropriate are they? This NOFO supports validation on many levels and in multiple models; how appropriate are the choice of models, assays, and endpoints for a complete validation of the targets? How appropriate is the prioritization of activities to include necessary and ‘nice-to-have’ activities? How well have the applicants considered how to interpret results if different models, assays or endpoints don't all point to the same result?

How appropriate are the planned experiments and do they appropriately include combinatorial design that will test the hypothesis that two or more disease modifying targets are synergistic/advantagous at multiple levels: 1) molecular and pathological outcomes in cellular and animal models, 2) physiological and anatomical outcomes and 3) behavioral, cognitive and dementia outcomes? What, if any experiments are missing that are essential to this goal? How appropriate are planned experiments to allow for a better understanding of the effects (positive and negative) of various degrees of modulation of each target separately and together? How well will the proposed experiments allow the applicants to define the desired window of modulation of all targets (separately and together) based on efficacy and safety? How appropriate are the experiments to determine the time course of modulation for each target separately and together? 

How appropriate are considerations for the stage of disease, the impact of ageing and how long the targets need to be modulated to have efficacy and safety? As appropriate, how well do applicants propose to look at the impact of external environmental and comorbid conditions? How relevant are the choice of models, assays and endpoints to the patient population of interest? How appropriate are the proposed experiments and combinatorial design for allowing them to gain some understanding of the mechanistic basis for synergy/advantage of the targets? If independent replication is planned, how independent is the outside laboratory? Most importantly, how well will the proposed experiments set the foundation for a strong future therapy development project?

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?

Milestones and Timelines:

How robust are the milestones and are they associated with clear, quantitative criteria for success that allow go/no-go decisions at the R61/R33 transition point? To what extent do these milestones reflect clinically-meaningful endpoints? How well do the milestones allow for the evaluation of progress in the R61 phase and will successful completion of these milestones provide confidence that the investigator will be able to successfully implement the R33 phase? How appropriate are the milestone criteria for measuring the reproducibility, dynamic range and error, power analyses, quality control (purity, activity), or other relevant measures for tools, assays, models, endpoints, etc. that are necessary for the success of the project?

How appropriate are the milestones around the synergy/advantage of the targets? Are they appropriately inclusive of measures at multiple levels (molecular, metabolic, cellular, tissue, neuronal network, behavior, cognition etc.)?

How realistic is the timeline and is it inclusive of necessary steps, but also efficient without unnecessary steps? What, if any, additional key experiments need to have milestones designated?

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.

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

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

Budget and Period of Support

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

2. Review and Selection Process

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

As part of the scientific peer review, all applications will receive a written critique.

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

Responsive applications will be assigned to NINDS. 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 National Advisory Neurological Disorders and Stroke Council. The following will be considered in making funding decisions:

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

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.

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.

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 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.

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

• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and to provide effective communication, see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html.

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

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

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

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

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 and 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

Rebecca Roof, PhD
National Institute of Neurological Disorders and Stroke
Email: rebecca.roof@ninds.gov

Nandini Arunkumar, Ph.D.
NATIONAL INSTITUTE ON AGING (NIA)
E-mail: arunkumarn2@mail.nih.gov

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

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

Jeni Smits
NATIONAL INSTITUTE ON AGING (NIA)
E-mail: jeni.smits@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 45 CFR Part 75 and 2 CFR Part 200.