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 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.

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.

This NOFO supports early development of novel small molecule, or biologic therapeutics to targets that are novel, but validated for ADRDs. It is anticipated that successful applicants will be able to meet the entry criteria for the Blueprint Neurotherapeutics Network for Small Molecules, Blueprint for Biologics or other similar later-stage translational programs at the end of the R61/R33 grant period.

R61/R33 Phased Mechanism and Transition to R33

This Notice of Funding Opportunity (NOFO) uses the R61/R33 Phased Innovation Award mechanism. The R61 phase supports progression through the following research stages: Stage 1) development of in vitro and/or ex vivo assays that can support therapeutic screening efforts, Stage 2) screening efforts to identify and characterize potential therapeutic agents, and Stage 3) therapeutic optimization, pharmacodynamic and pharmacokinetic studies. The R33 phase Stage 4 supports in vivo efficacy studies in an animal model of disease. Each stage of research is delineated by milestones that represent go/no-go decision points from one stage of research to the next and applicants must include milestones gating each stage of research proposed. Additionally, applicants must include milestones for the R61/R33 transition. For example, an application that includes all 4 stages of research must propose 2 sets of milestones within the R61 phase and one for the R61/R33 transition. Applicants may start later than stage 1 if those activities have already been completed or are not necessary (i.e., the starting point is a small molecule or biologic that is ready for stage 3 and 4 work, so assay optimization and screening isn t required). This means that applicants can propose projects that start at stage 1, 2 or 3 depending on what is scientifically needed to advance the project to BPN, BPN-Bio or other later stage programs. Applicants cannot skip the entire R61 or the entire R33 phase; such projects are encouraged to consider other funding opportunities. This means that stages 1 and 2 are optional, but applications must include stages 3 and 4. It is expected that applicants proposing fewer than 4 stages of work will request proportionally less time and budget.

Milestones are goals that are quantifiable for measuring success that can be used for go/no-go decision-making between stages within the R61 and the R61/R33 transition point and should have timelines and quantitative criteria associated with them. Because each stage of work depends on the success of the prior stage of work, milestones should measurably demonstrate that a stage of work was successful and that the project is ready for the next stage of work. Milestones should also 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. For milestone examples, please see https://www.ninds.nih.gov/Funding/Apply-Funding/Application-Support-Library/IGNITE-Milestone-Examples

Entry Criteria

• Novelty: This NOFO seeks to apply new knowledge around targets, mechanisms, pathways or therapeutic indications. Projects should aim to develop or repurpose novel small molecule or biologic therapeutics for NINDS mission-relevant, FTD, LBD, VCID, MED. Here, novel is defined as a target that has not yet been tested in interventional clinical trials for the proposed indication.
• Biological rationale and preliminary data: Projects funded through this opportunity must have a strong biological rationale for the intended approach and intended target. The target should be novel but validated. For this NOFO, a validated target is defined as a target that has strong evidence for being relevant for the disease. This supporting data could be based on a mechanistic understanding of the disease supported by preclinical or clinical based science. Preliminary data should reflect rigorous, well-designed experiments (either from the literature, data from other sources, or, when available, from investigator-generated data). Examples of the most critical elements for a well-designed study are summarized on the NINDS website (https://www.ninds.nih.gov/Funding/grant_policy).
• Relevance for therapy development: Projects should aim to develop novel therapeutic agents that can be advanced towards development for ADRD. Applications should illustrate how the candidate therapeutic(s) will be optimized and advanced toward later stages of discovery once the R33 phase is complete. Projects should take into account that ADRDs are heterogeneous and the same therapeutic might not be appropriate for all patients with a common diagnosis or appropriate for all stages of disease. Projects should describe which patient population would benefit from the therapy, if successful.

Examples of activities

R61 Stage 1: development of in vitro and/or ex vivo assays that can support therapeutic screening efforts

This Stage is intended to support development of new in vitro and/or ex vivo assays, in support of Stage 2. These activities include (but are not limited to) set up and optimization, standardization, and validation of measures of fundamental cellular/molecular events such as binding, bioactivity at the target, and activity downstream of the target relevant to neurological function. The proposed assays must have sufficient throughput for iterative screening of potential therapeutic agents such as small molecules and biologics, if high-throughput screening is proposed in Stage 2.

Examples of activities for this Stage include but are not limited to:

• Development and validation of assay(s) (including phenotypic assays) to support a succinct testing funnel.
• Development of in vitro or ex vivo potency/efficacy assays designed to indicate the specific ability of an agent to achieve a desired biological effect, for example: structural changes that may impact product quality, stability and efficacy. For use and development of induced Pluripotent Stem Cell (iPSC) lines, please see NOT-NS-14-032.
• Development of assays to evaluate cellular uptake, engagement, infection, aggregation, downstream functional measures in vitro or ex vivo, purity and specificity. Assays to measure DNA, RNA, and protein levels of either endogenous genes or delivered products, downstream in vitro or ex vivo functional read-outs, viral titer, viral particle load stability and specificity.
• Assay development and/or optimization for High-Throughput Screening (HTS).
• A combination of assays may be developed to demonstrate relevant biological activity when a single assay may not provide adequate measurement of overall potency due to a complex mechanism of action or multiple activities of a preliminary therapeutic agent.

R61 Stage 2: screening efforts to identify and characterize potential therapeutic agents

This Stage is intended to support screening efforts to identify and characterize novel therapeutic agents for ADRD. This Stage also includes design and preparation of a focused set of therapeutic agents, and characterization thereof.

Examples of activities for this Stage include but are not limited to:

• HTS, comprising screening of large libraries for activity against biological targets via the use of automation, miniaturized assays and large-scale data analysis.
• Preparation and screening of select series of therapeutic agents using for example medicinal chemistry or biological processes.
• Preparation of therapeutic agent(s) and confirmation of structure, sequence or biological characteristics.
• Development and selection of cell lines/vectors to produce bioactive agents with acceptable potency and stability, cellular uptake/engagement, or secondary in vitro functional assays.
• Assessment of therapeutic agent’s properties using computational analysis and early physicochemical measurements, polar surface area, solubility, cell permeability and efflux.
• Assessment of initial in vitro parameters such as absorption, distribution, metabolism, and excretion (ADME).
• Assessment of potential off-target activities.
• Optimization of therapeutic agent(s) for future in vivo testing.

R61 Stage 3: therapeutic optimization, pharmacodynamic and pharmacokinetic studies.

Prior to preclinical efficacy studies, a combination of in vivo efficacy, pharmacodynamic (PD) and pharmacokinetic (PK) measures are warranted to determine the feasibility of candidate therapeutic agent(s) to serve as a starting point for further therapy development. Combined measures of PK and PD greatly increase the understanding of the in vivo efficacy of the therapeutic agent(s) by exploring the relationship between the concentration of the agent(s) at the site of action and the resulting efficacy measures. PK measurements reflect the body’s effect on the absorption, metabolism, distribution and excretion of the therapeutic agent. For some biologic modalities, traditional PK might not apply; such applicants should still aim to measure the kinetics and distribution as needed for therapeutic development. For the purposes of this NOFO, in vivo efficacy measures reflect the effects of the therapeutic agent on endpoints that are closely tied to the desired clinical endpoints, but do not necessarily reflect target engagement. While PD measures may also reflect the effects of the therapeutic agent on endpoints closely tied to the desired clinical endpoint, they must also reflect target engagement

Pharmacodynamic studies may include but are not limited to determination of 1) target occupancy (e.g., binding) and 2) proximal target activation (i.e., signal transduction, neurotransmission, protein synthesis, and gene regulation and transcription).

Examples of activities for this Stage include but are not limited to:

• Preparation of the therapeutic agent(s) to support proposed activities. For use and development of iPSC line therapeutics, please see NOT-NS-14-032.
• Characterization of therapeutic agent(s). This could include for example, confirmation of purity, stability, in vitro absorption, distribution, metabolism, and excretion, in vitro potency and selectivity.
• Studies to develop dosage form(s) to support proposed PD measures and/or in vivo studies.
• Pharmacokinetics studies to determine direct or indirect therapeutic agent levels. For gene and cell therapy, these include characterization of gene copy numbers or tropism in tissues or cell engraftment.
• Studies to confirm that therapeutic agent(s) reach and engage the target site (directly or indirectly) at a concentration that exceeds in vitro pharmacological potency over the desired period.
• Studies to confirm selectivity of the therapeutic agent(s).
• Limited studies to identify potential pharmacodynamic biomarkers specific for the purposes of developing the therapeutic agent(s) to be tested in the application.
• Studies to inform design and refinement of the PD measure and/or in vivo efficacy models and testing procedures, including examination of model variability to estimate sample size, calibration of the model according to positive and negative controls, along with the age, time course and window of disease that are relevant for therapeutic testing.

R33 Stage 4: in vivo efficacy studies

This stage supports in vivo efficacy studies to demonstrate that proposed therapeutic agent(s) have sufficient biological activity to warrant further development to treat ADRD.

Examples of activities for this Stage include but are not limited to:

• Rigorously conducted pharmacodynamic and/or in vivo efficacy studies with chemically and biologically characterized therapeutic agent(s) including positive and negative controls, as appropriate.
• Dose (exposure)-response activity with a route of administration relevant to future clinical studies.
• Studies correlating pharmacokinetic and pharmacodynamics measures (PK/PD).
• Preliminary studies to assess early safety (not including IND-enabling toxicity).
• Validation and replication studies to confirm observed results.

Applications Not Responsive to this NOFO

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

• Applicants not focused on ADRD.
• Discovery and development of risk, detection, diagnostic, prognostic, predictive, or prevention biomarkers, although use of existing biomarkers is appropriate.
• GLP toxicology studies/Investigational New Drug (IND) enabling studies with optimized therapeutic agents. (Covered by Blueprint Neurotherapeutics Network for Small Molecules and Blueprint for Biologics)
• Discovery or development of devices device/drug combinations, surgical procedures, diagnostics, or rehabilitation strategies.
• Studies with the goal of understanding basic mechanisms of disease.
• Study or use of therapeutic agents to identify new targets relevant to a disease.
• Manufacture of therapeutic agents for clinical trials.
• 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 your 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 your 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 each stage and phase (R61 to R33) are non-responsive. Applications that do not contain a clear demarcation of which activities are in each stage and phase (R61 versus R33) are also considered non-responsive. Stages and phases must not overlap in time. Non-responsive applications will be administratively withdrawn without review.

Collaborations:

Developing therapeutics requires a multidisciplinary approach. Investigators should form collaborations with those familiar with successful drug/biologic development (such as those from industry) as well as those familiar with what the desired end-product should look like (such as biostatisticians, technical experts and clinicians). Applicants should consider how they will identify and foster relationships with potential licensing and commercialization partners early in the therapy development process once an award is made. PDs/PIs are expected to work closely with their institutional technology transfer officials to ensure that royalty agreements, patent filings, and all other necessary IP arrangements are completed in a timely manner and that commercialization plans are developed and updated over the course of the project.

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 NOT-OD-20-031 for details.

Additional Considerations

Applicants are strongly encouraged to contact Scientific/Research Staff to discuss potential research projects prior to submitting an application.

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 specific SBIR/STTR ADRD NOFOs such as PAS-22-196 and PAS-22-197. Please see https://www.ninds.nih.gov/Funding/Small-Business-Grants for more information about the programs.

Prior to funding an application, 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

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 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.

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.

Letter of Intent

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

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

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

The letter of intent should be sent to:

Rebecca Roof, Ph.D.
National Institute of Neurological Disorders (NINDS)
Email: [email protected]

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.

Other Attachments:

Applicants must include an Intellectual Property (IP) strategy. Applicants are encouraged to prepare this section of the application in consultation with their institutions's technology transfer officials. Applicants should describe the IP landscape surrounding their therapeutic agent(s). Applicants should describe any known constraints that could impede their therapeutic discovery and development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar therapies that are under patent protection and/or on the market, etc.) and how these issues could be addressed with achieving the goals of this program. If the applicant proposes using an agent(s) whose IP is not owned by the applicant's institution, either an investigational therapeutic, FDA-approved therapeutic, or other licensed product, the applicant should include a letter (see letter of support) from any entities owning the IP indicating there will not be any limitations imposed on the studies or the product which would impede achieving the goals of the funding program. If patents pertinent to the therapeutic agent(s) being developed under this application have been filed, the applicant should indicate the details of filing dates, what type of patents are filed, and application status, and associated USPTO links, if applicable.

Applicants should discuss future IP filing plans. For a multiple-PD/PI, multiple-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing IP) among the institutions. Applicants should clarify how IP will be shared or otherwise managed if multiple PD/PIs and institutions are involved, consistent with achieving the goals of the program.

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 Aim section, include headers for each stage (1-4) and phase (R61 and R33). Clearly delineate each stage and phase. Under each header, state the specific objectives of the efforts, including the technical questions you will try to answer. Since the goal is therapy development, hypothesis testing, per se, may not be the driving force in developing such an application.

Research Strategy: Within the Research Strategy, applicants must describe all categories including transitional milestones and timeline. If stage 1 and/or 2 are not included, justification must be provided. A background and significance section should outline the biological and therapeutic rationale for the application, including: 1) a description of the biological rationale linking the proposed therapeutic target and the disease of interest, including a description of which patient population would benefit from the therapeutic, if successful, 2) a brief description of any pertinent history for therapeutic development in the disease area, 3) evidence supporting the novelty of the therapeutic approach, and, 4) a summary of the project status, including information regarding therapeutic agents to be tested in the current application (for applications coming in at stage 3). The applicant should 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. The NIH expects this consideration to include attention to the rigor of the previous experimental designs, as well as relevant biological variables and authentication of key resources.

Stage 1: if included, applications should address the methods and rationale for an assay validation plan in a thorough and carefully thought-out manner. Assay validation is a process that determines the fitness of an assay, which has been properly developed, optimized and standardized, for an intended purpose. Assay validation should be clearly outlined to cover critical topics such as but not limited to i) definition of the intended purpose(s), ii) optimization, iii) standardization, iv) reproducibility, v) sensitivity, vi) specificity, and vii) thresholds (cut-offs). In order to assess the predictive value of preclinical research, sufficient information should be available about study design, execution, analysis, and interpretation.

Stage 2: if included, applicants should address the plans for compound/biological agent screening. Plans for hit prioritization and validation should be included.

Stage 3: applicants should include a carefully designed plan for characterizing the proposed preliminary therapeutic agents from a physicochemical, biophysical, and biological perspective, as appropriate. Since the goal of the R61 phase is to ensure that the candidate therapeutic is optimized for in vivo efficacy or pharmacodynamic studies, the research strategy for the R61 phase should also address plans for optimization of formulation or pharmacokinetic characteristics, as necessary to provide useful in vivo or pharmacodynamic data. Characterization of selectivity and early safety are also appropriate at this stage.

Stage 4: applicants should include a description of the rigorous testing of the new small molecule or biological therapeutics in clinically relevant animal model(s) of disease. Careful attention should be paid to NIH rigor guidelines and standards of the field. An important component of the R33 phase strategy should be a carefully developed rationale for the experimental design and a description of the data analysis strategy. Applicants are encouraged to consider that ADRDs are complex and heterogeneous; thus,a therapeutic might not be appropriate for all patients with a common diagnosis or appropriate for all stages of disease. Careful thought should be given to which patient population is likely to benefit from the therapeutic, if successful, and models should be chosen that reflect this population to the extent possible. Finally, an outline of how data obtained in the R33 phase will provide a path for optimization of the preliminary therapeutic agent should be included.

Clear demarcation of which activities are in each Stage (1, 2, 3, and 4) and phase (R61 and R33) is required. The Stages and phases must not overlap in time.

Innovation: Include headers and address the innovation for each stage and phase (R61 and R33). Novelty of therapeutic strategy/target over what is currently available in the clinic or under therapeutic development by the field should be emphasized. A description of the therapeutic agent proposed in relation to the state of the field should be included.

Milestones: Transition from one stage to the next and from the R61 to the R33 phase is contingent upon the successful completion of proposed milestones. Projects spanning all 4 stages should propose 2 sets of milestones within the R61 phase and one for the R61/R33 transition. These milestones, with timelines (described below), are to be included as the last element of the Research Strategy section of the application and will be evaluated as part of the scientific and technical merit of the R61/R33 application. The milestones proposed in the application must be well-described, quantifiable, and scientifically justified to allow program staff to assess progress in the R61 phase. In addition, milestones should reflect the objectives of the application and be appropriate for the therapeutic approach and indication. Rationale should be provided for the choice of measures and values proposed for the milestones. Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. A discussion of the milestones relative to the progress of the Stages within the R61 phase and the implications of successful completion of the milestones for the R33 phase should be included. The clarity and completeness of the R61/R33 application with regard to specific goals and feasibility milestones are critical. Milestones should provide clear indicators of a project's continued success or emergent difficulties and will be used to evaluate the application as part of the consideration of the awarded project for further funding of non-competing award years by the Program Director(s)/Principal Investigator(s), and Program Official(s). The existence of clear, quantitative, go/no-go milestones for transition from one stage to the next and from the R61 to the R33 phase is a requirement for this NOFO. Applications lacking milestones will be administratively withdrawn without review. Potential applicants with questions about suitable milestones are encouraged to contact NINDS program staff prior to application. Example milestones can be found at https://www.ninds.nih.gov/Funding/Apply-Funding/Application-Support-Library/IGNITE-Milestone-Examples.

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 (e.g. validation of assays, identification of screening hits, generation and characterization of therapeutic agents, pharmacokinetics studies, in vivo animal model adaptation and validation with positive and negative controls) 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.

Rigorous Study Design and Supporting Data: An R61/R33 Phased Innovation Award application in translational research should have a strong biological rationale for the intended approach, supporting data from rigorously designed experiments, 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 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 primary/secondary endpoint(s), describing tools and 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. It is also strongly recommended to indicate clearly the exploratory vs. confirmatory components of the study, 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.Please see https://grants.nih.gov/policy/reproducibility/guidance.htm for more information on these requirements. Applicants should consider the rationale for the chosen model systems(s) and endpoints, adequacy of controls, route and timing of therapeutic dosing, justification of sample size, statistical methods, blinding methods, strategies for randomization, and robustness and reproducibility of results.

Therapeutic Development Plan: At the completion of this project, it is expected that applicants have a promising small molecule or biologic starting point for the BPN, BPN-Bio, or other later-stage NIH program or private investment. Applicants are encouraged to review the BPN or BPN-Bio entry criteria and associated funding opportunities, as projects should include all steps necessary to get to this point. More details can be found at BPN (https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-small-molecules) and BPN-Biologics (https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics). It is essential for applicants to include, within the Research Strategy, a description of how knowledge gained from this work will support future therapeutic discovery efforts beyond the project period through to early clinical trials. As part of this consideration, attention should be paid to the intended patient population such that appropriate experiments (animal models, endpoint measures, routes of administration, etc.) are used in the current application.

Collaboration: NINDS strongly encourages applicants to form multidisciplinary teams that consist of academic/industry experts relevant to the research plan (i.e., biostatisticians, clinicians, drug development experts, technical experts). This multidisciplinary team should be able to define the goals of the research, outline specific gaps that need to be addressed during this funding period, outline detailed plans and experiments, and execute the research strategy.

NINDS strongly encourages applications from diverse teams of investigators, including PI/PDs and team members that are underrepresented in the biomedical workforce (defined in NOT-OD-20-031).

Letters of Support: Applicants should include letters of support from consultants, contractors, and collaborators.

If applying from an academic institution, include a letter of support from the technology transfer official who will be managing intellectual property associated with this project.

If research will be performed at more than one institution, include a letter of support from each institution clarifying how intellectual property will be shared or otherwise managed across the institutions.

If collaborating with a private entity, include a letter of support that addresses any agreement to provide agent(s), any limits on the studies that can be performed with said agent(s), any limitations on sharing of data (including negative results), and whether a licensing agreement(s) is in place. This letter should come from a high official within the private entity who has authority to speak on these issues.

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.

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.

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.

Please notice that use of human samples MIGHT be considered human subject research. For help determining if a proposal is Human Subject research, please see https://grants.nih.gov/policy/humansubjects/research.htm.

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 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.

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:

Is there a strong biological rationale based on well-designed rigorous experimental data?

Is the project relevant for therapeutic development? Have applicants considered which patient population is likely to benefit from the therapeutic, if successful, considering the complexity and heterogeneity of disease?

Will the project, if successful, bring the investigators closer to a therapeutic that will be a substantial improvement over existing therapeutics to treat ADRDs?

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:

Is the investigator team knowledgeable and experienced with the proposed biological target?

Do the researchers have sufficient preclinical and therapeutic discovery expertise?

Do the researchers have relevant therapy development experience that includes design and implementation of the preclinical studies?

Have the researchers formed multi-disciplinary collaborations?

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?

Specific to this NOFO:

Does the project pursue novel but validated targets, mechanisms and pathways, and treatment approaches?

Does the application show an understanding of the state of the field and where the proposed therapeutic approach fits within the therapeutic landscape?

Does the application make a compelling case that the strategy proposed is distinct from other therapeutic approaches and has a reasonable chance of success considering the landscape?

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:

Stages 1 and 2: If proposed, will stage 1 produce a well-validated assay that can support future therapeutic development for ADRD? If stage 2 is proposed, is the process for selecting compounds/biologics at each iteration clear and appropriate? Is the plan for therapeutic candidate discovery reasonable? If one or both stages are not included, is there adequate justification?

Stages 3 and 4: Is there a sufficiently developed plan for the assessment of therapeutic agent chemical, biophysical, and biological characterization within the proposed grant period? Are the proposed in vivo efficacy study and/or pharmacodynamic measures relevant to the proposed clinical indication? Are the proposed experiments part of a well-thought-out and clearly defined therapeutic discovery plan? Are the in vivo models and preclinical outcome measures to assess efficacy and/or PD optimal for the proposed clinical indication? Will the project, if successful, produce robust pharmacodynamic and in vivo efficacy results that can support future therapeutic development?

Whole project:

For key experiments, does the application explain assumptions for power analysis, describe statistical analysis methods and criteria for data inclusion or exclusion, and detail the procedures of how blinding and randomization will be conducted? Are controls appropriate, and have efforts been made to demonstrate and acceptable level of variability, so that the feasibility of the proposed studies can be adequately assessed? Is the overall plan rigorously designed?

Is the timeline reasonable for the work proposed? Is the plan for stage transitions reasonable?

Does the team have sufficient expertise to not only perform the experiments purposed, but anticipate and mitigate issues that might arise in Therapy Development Plan and set the project up for success beyond this application?

Will it produce therapeutic agent(s) that meet the entry criteria for BPN for Small Molecules, BPN-Biologics or other future development mechanisms at the completion of the project? Key entry criteria for BPN include:

1. Rigorous data supporting the hypothesis that modulating the putative target/affected pathway will produce a desirable outcome for the intended disease indication.
2. One or more characterized bioactive therapeutic leads from which a candidate can potentially be derived.
3. Suitable and available in vitro and in vivo assays proposed to optimize the leads.

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?

Specific to this NOFO:

Are collaborations in place to support the application?

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:

Are milestones robust and associated with clear, quantitative criteria for success that allow go/no-go decisions at the stage and R61/R33 transition points? Are mliestones included for each stage and phase transition?

Do milestones measurably demonstrate that a stage of work was successful and that the project is ready for the next stage? Do the milestones allow the evaluation of progress in each stage and will successful completion of these milestones provide confidence that the investigator will be able to successfully implement the next stage/phase?

Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without unnecessary steps? Are there additional key experiments that need to have milestones designated?

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.

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.

Intellectual Property (IP) Strategy:

Are the following addressed as appropriate and consistent with achieving the goals of the program: Does the application outline any known constraints that could impede the therapeutic from being developed (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar therapies that are under patent protection and/or on the market, etc.) and how these issues could be addressed while achieving the goals of the program?

If applicable, how strong is the applicant's IP portfolio/position (pertinent to the proposed project), and to what extent does the applicant have a reasonable strategy to protect its IP going forward?

If IP will be shared among co-investigators, is a clear plan in place for sharing of the IP that will set the project up for success beyond this grant?

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.

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

3. Anticipated Announcement and Award Dates

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

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

Section 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:

• Federal wide Research Terms and Conditions
• 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 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.htmlandhttps://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: [email protected] (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: [email protected]

Larry Refolo, Ph.D.
NATIONAL INSTITUTE ON AGING (NIA)
Division of Neuroscience (DN)
Phone: 301-594-7576
E-mail: [email protected]

Rebecca Roof, Ph.D.
National Institute of Neurological Disorders (NINDS)
Telephone: 301-496-1779
Email: [email protected]

Shardell Spriggs, Ph.D.
National Institute of Neurological Disorders (NINDS)
Telephone: 301-443-8189
Email: [email protected]

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

Jeni SMITS
National Institute on Aging (NIA)
E-mail: [email protected]

Shellie Wilburn, M.B.A
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: [email protected]

Section VIII. Other Information

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

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