Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Neurological Disorders and Stroke (NINDS)

National Institute on Aging (NIA)

Funding Opportunity Title
Functional Target Validation for Alzheimer's Disease-Related Dementias (ADRDs) (R61/R33 Clinical Trial Not Allowed)
Activity Code

R61/R33 Exploratory/Developmental  Phased Award

Announcement Type
Reissue of RFA-NS-19-015
Related Notices

None

Funding Opportunity Announcement (FOA) Number
RFA-NS-22-055
Companion Funding Opportunity
None
Assistance Listing Number(s)
93.853, 93.866
Funding Opportunity Purpose

This FOA invites applications that propose the comprehensive functional validation of newly identified therapeutic target candidates for Alzheimer's Disease-Related Dementias (ADRD). This FOA seeks to promote critical target validation approaches to help de-risk subsequent translational research and accelerate the advancement of novel therapies for ADRD. Target(s) or molecular pathway(s) to be considered for validation must have been already identified using tissue expression or genetic data generated in human samples. In its initial phase, this FOA provides support for up to two years (R61 stage) for the development of customized technologies, models, and protocols to modulate the expression or activity of target candidate(s) in cells and/or tissues and monitor their functional biological consequences in in vitro or in vivo disease models. Upon demonstration of technical feasibilities, a second phase (R33 stage) will carefully and reproducibly measure and cross-validate the impact of the target modulation in different modalities across collaborating laboratories using the NIH rigor and reproducibility guidelines. Applicants responding to this FOA must address objectives for both the R61 and R33 phases and are expected to have a substantial collaborative effort between independent laboratories.

This FOA is not specific for any one or group within the ADRD spectrum of disorders. Disorders covered in these applications are frontotemporal degeneration (FTD), Lewy body dementias (LBD) (including dementia with Lewy bodies (DLB)), Parkinson disease dementia (PDD), vascular contributions to cognitive impairment and dementia (VCID), and mixed dementias including the multiple etiology dementias (MED).

Key Dates

Posted Date
July 22, 2022
Open Date (Earliest Submission Date)
October 07, 2022
Letter of Intent Due Date(s)

30 days prior to the application due date

Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS Scientific Merit Review Advisory Council Review Earliest Start Date
November 08, 2022 Not Applicable Not Applicable March 2023 May 2023 July 2023

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

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

No late applications will be accepted for this Funding Opportunity Announcement.

Expiration Date
November 09, 2022
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts).

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

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

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

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

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

Alzheimer's Disease and Alzheimer's Disease Related Dementias (AD/ADRD) refers to the most common forms of dementia. Dementia affects more than 5 million people in the U.S. and more than 47 million people worldwide. At this time, there are no known treatments to prevent or stop the progression of dementia. The toll on individuals, caregivers and society is enormous and will only increase as the population ages unless effective interventions are developed. The National Institute of Neurological Disorders and Stroke (NINDS) collaborates with the NIH’s National Institute on Aging (NIA), the lead NIH Institute for Alzheimer’s disease (AD) research, to establish research priorities and fund biomedical research in AD as well as several ADRDs.

Starting in 2012, the NIA and the NINDS have held research summits to assess the needs and set AD/ADRD research implementation milestones (https://www.nia.nih.gov/research/milestones).This FOA is responsive to those resulting recommendations to fully characterize and validate therapeutic targets for ADRD.

A major obstacle in the development of promising treatments for ADRD and also other CNS disorders is the need for well-validated targets linked to the disease process. Translating these discoveries to the clinic will depend on the quality of the target validation process plus confidence in a causative link between the modulation of a target(s) and its functional physiological consequence(s) associated with treating or preventing a disease state. In addition, partial and incomplete knowledge about the biology of the selected molecular target(s) often limit their chance to translate into successful future drug screening campaigns and drug discovery projects. This FOA provides the opportunity to address these knowledge gaps.

NIH expects that the end goals of this FOA will provide the translational research community with increased confidence in the efficacy and safety of the novel emerging target(s) to trigger the development of customized therapeutic strategies in ADRD. NIH expects the application to be composed of multi-components and multidisciplinary collaborative teams that have scientific expertise in a specific disorder within the ADRD spectrum, technical proficiency in running CNS functional assays/models plus support in statistical design and analysis. Development of the technological tools to modulate the target expression can be executed within the collaborative team or by a contract research organization.

Research Objectives and Scope

The R61 phase (year 1- year 2) will support activities for the development of customized technology to specifically modulate the expression or activity of target candidate(s) in cells and/or tissue. Preference will be given to applications that propose target validation strategies using both in vitro human cellular model(s) and in vivo animal models. During this time, applicants will develop, in parallel, protocols to monitor the functional consequences of the target modulation in diseased-relevant in vitro (e.g., electrophysiology in differentiated human iPSC) or in vivo (e.g., behavior, EEG in knock out/transgenic) models. Target-centric as well as phenotypic target-based validation approaches will be considered. The end of this first R61phase will be completed by a proof of concept study showing the feasibility of the chosen technological approach. Progress toward R33 phase and subsequent year award(s) will be milestone-based.

The R33 phase (up to two additional years) will carefully and reproducibly measure the positive and negative functional impacts of the target modulation in different proposed modalities across collaborating laboratories. Modalities can include, but not limited to, testing additional time points (e.g., prodromal vs. acute phase), uncharacterized isoforms or genetic variants of the target, fine tuning to reach target-related maximal therapeutic effect(s) while minimizing negative safety side-effect(s), or co-influence of environmental insults or aging process. This validation phase will follow the NIH rigor and reproducibility guidelines.

Applications should include the following key components.

Selection of the target candidate, potential druggability and knowledge gaps

Comprehensive applications will initially include a target identification rational, druggability and knowledge gaps(s) section that will cover the rationale and supporting experimental data in human for the target selection and its association to the ADRD disease state. Such target identification approaches include, but are not limited to, genetics, genomic, proteomic, metabolomics or other omics-based approaches, system biology, analysis of public literature-big data mining and the bioinformatic tools used to analyze large data sets. A summary of the results should include a description of the experimental protocols and statistical analyses used to assess the rigor and quality of the data linking the target candidate to the pathology of ADRD. Supportive data could be included in the Appendix (see section IV) with 6 pages limitation.

Disease relevance alone is insufficient for a protein to become a drug target, it must be druggable. Drug screening and discovery efforts are out of scope for this application. Nevertheless, applicatons should address the current knowledge about the biology and potential “druggability” of the selected target. Druggability refers to the ability of a target to have its function directly modulated by the binding of a therapeutic agent. Such ability relates to the known molecular activity of the target, or can be predicted based on its structure, other properties or belonging to a protein family with known developed therapeutics. The hypothesized nature of the modulatory interaction that would either mimic or restore to normalcy the physiological abnormality observed in a disease state must be discussed. Such therapeutic agent with modulatory interaction(s) could include small molecules, biologics or natural products.

Novel target candidates include, but are not limited to, proteins, lipids, sugar, nucleic acids or epigenetic modification. Those targets can commonly be used for a target-centric drug discovery approach but could also be proposed to develop future phenotypic assay(s) and drug discovery strategies. Target(s) for future phenotypic assay(s) and drug screening could include, but are not limited to, indirect read out of the target activity via an engineered reporting system, molecular and metabolic pathways, or cellular and physiological tissue functions. The validation strategy of the “phenotypic target(s)” should demonstrate that its modulation leads to the normalization or impairment of the functional read outs selected to represent respectively the disease or control states in in vitro or in vivo models.

The expected direction and efficacy of the target modulation leading to a therapeutic effect or mimicking a disease state should be discussed to justify the choice of the target validation approaches. In the absence of a strong hypothesis, the application could propose a comprehensive and un-biased target validation strategy that would test both the inhibition and activation of the target in a dose dependent manner.

The application should address and discuss the knowledge gap(s) about the biological function of the target(s) related to the pathophysiology of the ADRD disease state and its therapeutic application. The following describes some examples of questions related to the expected effectiveness of the translational ability of the validation approach. Are the target’s mechanism of action and physiological consequences well understood at different system organizational levels (molecular, metabolic, cellular, tissue, neuronal network and behavior)? How is the target selected and expressed when multiple uncharacterized isoforms or genetic variants are present? Which degree of modulation is expected to reach target-related maximal therapeutic effect(s) while minimizing negative safety side-effect(s)? Does the prevention or mimicking of a disease state require the co-influence of environmental insults and aging process?

Target validation approaches

Comprehensive target validation is a low-throughput process that involves more than a single method or assay. It depends on convergent evidence collected from a variety of studies. Therefore, preference will be given to applications proposing a comprehensive target validation strategy with different but complementary tools and multi-disciplinary in vitro assays and in vivo models. The functional validation strategy should include the technical approaches to be used to modulate the target expression or activity under different modalities and the functional assays/models to monitor their physiological impacts.

First, the selection and description of the target validation tool(s) should be outlined. Examples of tools to modulate the expression of the target or pathway include, but are not limited to, the state-of-the-art gene manipulation methods for genome editing, silencing, knocking out, or knocking in. Examples of tools used to modulate the activity of the target or pathway are antibodies, chemical genomics or pharmacology if specific small molecules or peptides have been previously identified and characterized.

Second, the application should include a description of the models and functional read out(s) selected to monitor the physiological consequences of the modulation of the target expression or activity on cellular, ex vivo or in vivo systems. For in vitro, proposed cellular models should include highly differentiated and organized CNS 2D or 3D cultures in order to replicate some of the relevant disease physiological processes. The use of transformed, immature, immortalized or cancerous cell lines is out of scope. Examples of acceptable cellular models with relevance to the disease mechanism(s) are highly differentiated CNS cultures derived from human induced pluripotent stem cells (iPSCs) or from animals generated with engineered genetic modifications (transgenic, knockout/in, viral infection…). This later example could also represent the main sources for the in vivo animal models. Other animal models using pharmacological and surgical modifications can be also proposed as long as a solid case can be made for their relevance to certain aspects of the disease mechanism(s) or phenotypic exhibition. Examples of physiological read outs include, but are not limited to, measurements of activity of molecular pathway(s), organelle and cellular functions, synaptic and channel electrophysiology, structural and functional imaging, neuronal network activity and animal behaviors, anatomy and safety profiles.

Third, the application should include a description of the different experimental modalities that should be tested in the R33 phase. Those should include parameters that can achieve comprehensive validation and inform future therapeutic approaches on the optimal level of target tuning or engagement to obtain maximal therapeutic efficacy and minimal adverse effects. Examples of modalities include, but are not limited to, testing a different range of expression levels of the target, time window of modulation, age of onset, various isoforms or genetic variants, or environmental conditions.

R61/R33 Phased Mechanism and Transition to R33

All projects will be milestone-driven with clear go/no-go criteria that are quantifiable. Prior to funding an application, the Program Official will contact the applicant to discuss the proposed R61 and R33 milestones and any changes suggested by NIH staff or the NIH review panel. The Program Official and the applicant will negotiate and agree on a set of approved R61milestones which will be specified in the Notice of Award. These milestones will be the basis for judging the successful completion of the work proposed in the R61 stage and progress towards interim milestones in the R33 stage. An administrative review will be conducted by NIH program staff to decide which projects will advance from the R61 phase to the R33 phase. Only R61 projects that meet their milestones will have an opportunity to move to the R33 phase.

R61 milestones guidelines:

  1. Demonstrate that the team members work and communicate cohesively and collaboratively to respect the timelines and deliveries of the R61 phase. PD(s)/PI(s) will organize a kick off meeting at the beginning of the project to facilitate and coordinate the collaboration. This event will be followed with emails communications and bi-annual virtual conferences to monitor progress toward the milestones.    
  2. Demonstrate that the technical approaches and tools selected to modulate the expression or activity of the target(s) are set up and ready for the next R33 steps.
  3. Demonstrate that the in vitro and/or in vivo models are set up and ready for the next R33 phase.
  4. Demonstrate that the functional read out methods are set up and ready to measure the physiological consequences of the target modulations in different models.
  5. For each technical approach, demonstrate feasibility and the integration of each component (# 1-4) in a proof-of-concept experiment:

    a. The implementation of the modulatory tools in the in vitro and/or in vivo models should show that the expression or activity levels of the target(s) are measurable and significantly different between the “control” and the “disease” biological samples. The degree and the direction of the target modulation should be consistent with the proposed validation and disease hypothesis. Power analysis should address reproducibility and significance of the results.

    b. Modulation of the target(s) expression or activity in in vitro and/or in vivo models should translate into measurable functional or physiological differences between the “control” and the “disease” biological samples. The degree and the direction of the functional read out modulations should be consistent with the proposed validation and disease hypothesis. Power analysis should address reproducibility and significance of the results.

Before moving to the next R33 phase, the Program Official and the applicant will negotiate and agree on a final set of R33 specific milestones which will be specified in the Notice of Award. R33 milestones will be the basis for judging progress towards and completion of interim milestones in the R33 stage.

R33 milestones guidelines:

  • For each technical proposed modality to be tested, provide the expected measurable outcomes on the target expression or activity levels and their functional or physiological consequences in the in vitro or in vivo models between the “control” and the “disease” biological samples. Power analysis should address reproducibility and significance of the results.

Collaborations

Collaborative interactions between interdisciplinary teams are a critical aspect of this FOA. Successful target validation applications will require extensive collaboration among experts. The later would include, but are not limited to, specialists in assay biology and development, CNS cellular models, tissue engineering, ADRD pathophysiology, animal models and behaviors, histopathology, electrophysiology, drug discovery and translational research, bioinformatics and biostatistics. Development of the technological tools to modulate the target expression can be executed within the collaborative team or via a contract research organization. The application should describe how the collaboration between this interdisciplinary team would work in the R61 and R33 phases of the grant.

Resources Available

Applicants are encouraged to leverage existing NINDS resources for disorders within the ADRD spectrum. Such resources may include cellular or DNA samples from NINDS BioSEND or other existing biospecimen and data repositories. Human ADRD iPSC resources targeting Frontotemporal Degeneration and Lewy Body Dementia are available through the NINDS Human and Cell Repository (NHCDR). Based on NOT-NS-14-032 and the availability of these resources, NINDS will no longer support the development of iPSC lines (e.g. control lines and/or lines with specific mutations) that are already represented in the NHCDR or in similar resources such as the NIMH or NIGMS Repositories. Studies are also encouraged that leverage the resources of cell banks supported through other Federal or private funds.

The following types of studies are non-responsive and will not be reviewed:

  • Clinical trials or basic experimental studies in humans
  • Target identification, genome-wide ‘omics profiling studies
  • Validation of biomarkers
  • Assay development for high-throughput drug screening.
  • Development or use of transformed, immature, immortalized or cancerous cell lines as physiological cellular CNS disease models.

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

Section II. Award Information

Funding Instrument

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

Application Types Allowed
New

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

Clinical Trial?

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

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

NIH intends to commit up to $2,700,000 to fund up to 3 awards for the R61 phase. For the R33 phase, the NIH intends to commit up to $4,500,000.

Award Budget

For the R61 phase, applications budgets are limited to $600,000 DC per year. For R33 phase, budgets are limited to $1,000,000 DC per year.

Award Project Period

The R61 phase is limited to up to two years. The R33 phase is limited to two years. The combined phases are limited to 4 years

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

  • Public/State Controlled Institutions of Higher Education
  • Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

  • Hispanic-serving Institutions
  • Historically Black Colleges and Universities (HBCUs)
  • Tribally Controlled Colleges and Universities (TCCUs)
  • Alaska Native and Native Hawaiian Serving Institutions
  • Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

  • Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
  • Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

  • Small Businesses
  • For-Profit Organizations (Other than Small Businesses)

Local Governments

  • State Governments
  • County Governments
  • City or Township Governments
  • Special District Governments
  • Indian/Native American Tribal Governments (Federally Recognized)
  • Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Government

  • Eligible Agencies of the Federal Government
  • U.S. Territory or Possession

Other

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

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

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

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

Required Registrations

Applicant Organizations

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

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

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

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

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her 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.

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time, 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 FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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 funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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

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

Pascal Laeng, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-7416
Email: pascal.laeng@nih.gov

Page Limitations

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

Instructions for Application Submission

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R Budget

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

PDs/PIs are required to organize an initial face-to-face kick-off meeting at the PI/PD's host institution. Additional virtual project meetings should be scheduled via conference calls to report and discuss the overall progress and challenges of the target validation project. Funds to support travel of the PD(s)/PI(s) and key collaborating team members to attend the kick-off meeting and organize the administrative logistics of the virtual project meetings should be included in the budget.

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific Aims:

Define the type of disease within the ADRD spectrum that is considered for this target validation application. Describe a brief history of the target identification main result, the hypothesized biological function of the target in the pathophysiology of the ADRD disease, and the target validation approach. Provide a description of the overall goals or hypotheses for the entire project. Identify the Specific Aims to be accomplished in the R61 phase and R33 phase.

Target Selection Rational, Druggability and Knowledge Gap(s)

  • Provide a clear description of the target identification process that will cover the rationale and a comprehensive summary of the supporting experimental data in human and/or animal models for the target selection and its causal link to the ADRD disease state. The target selection rational should describe a summary of the overall experimental approach, source of tissue, data mining and the rigor and reproducibility (see https://grants.nih.gov/policy/reproducibility/guidance.htm and research practices described at https://www.ninds.nih.gov/Funding/grant_policy) process used for this effort. Discuss the statistical analyses used to identify the target along with the overall strength and potential shortcoming of the result. Additional supporting data can be included in the Appendix (see section IV) and should be entitled “Supportive Data for Target Identification Selection” and must not be longer than 6 pages.
  • Describe the current knowledge about the biology and potential “druggability” of the selected target and the hypothesized nature of the modulatory interaction that needs validation.
  • Address and discuss the knowledge gap(s) about the known biological function of the target(s) related to the pathophysiology of the ADRD disease state and its translational application toward a successful therapeutic application.

Research Strategy:

Under this FOA, the research strategy should include the following components relevant to the technical tools and protocols to modulate the expression/activity of the target and to monitor their physiological consequences in in vitro assays and/or in vivo models.

  • Provide separate sections that describe both the R61 and R33phases.
  • Describe the “tool(s)” and protocols selected to modulate specifically the target in cells and/or in tissue. Discuss the strength and weakness of the technological approach. If more than one approach is considered, describe the complementarity and limit of each methodology.
  • Describe the technical tools and protocols that will be developed and used to monitor the physiological consequences of the target modulation.
  • Describe the in vitro assays and/or in vivo models that will be developed and used to modulate the target and monitor its physiological consequences.
  • Define the plan to ensure appropriate standardization of the samples and data that are used for each critical component of the target validation approach.
  • If in vitro assays are based on the generation of patient-derived human iPSC to identify functional phenotypic difference(s) between control and disease states, please address how genetic mosaicism and other potential pitfalls from expanding cell lines in vitro can be avoided? Add feasible alternatives (e.g. multiple lines, isogenic cell lines from genetic isoforms of the target…).
  • Outline the innovative aspects of each experimental approach including the generation of novel technology, protocol, assay, model and data set.
  • NINDS urges investigators to follow the NIH guidance for rigor and transparency including design of experiments that minimize bias including 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.
  • Outline the timeline and collaborative organization of the activities for each R61/R33 phases.
  • Propose a plan with clear go/no go criteria to obtain a proof of concept for the target validation approach at the end of the R61 phase. This should include a power analysis and the determination of suitable sample size.
  • Define the variables or the different modalities of the target validation that should be tested in the R33 phase. Describe the analytical process that will be used to determine the positive (therapeutic or disease modeling) as well as the potential negative (side effects) physiological consequences of the target modulation under different experimental conditions.
  • Discuss the possibility of cross-validating some key results between two independent sites.
  • Describe the workflow and data sharing plan between the collaborating teams and the final delivery of the results to the ADRD scientific community.

Milestones Plan and Progression Metrics

  • A milestone plan specific for each phase (R61 and R33) should include an outline of the timeline (simplified Gantt Chart) and description of the acceptance criteria to successfully implement and complete each key deliverable including the development of the experimental “tools”, protocols, assays, models, proof of concept experiment(s) and testing of the different experimental modalities.
  • Go/No Go milestones for the transition of the R61 phase to the R33 phase
  • Propose measurable criteria to demonstrate that all components are in place and implemented to conduct future research on the different experimental paradigms in the R33 phase:
    • a collaboration plan to facilitate the communication and logistics between team members.
    • the set-up of the different technical approaches and tools to modulate the expression or activity of the target(s)
    • the set-up of in vitro and/or in vivo models
    • the set-up of the functional read out methods.
    • For each target validation approach, a proof-of-concept experiment proving technical feasibility by integrating each component:
      • Modulation of the target(s) expression or activity in in vitro and/or in vivo models should translate into measurable functional or physiological differences between the “control” and the “disease” biological samples. The degree and the direction of the functional read out modulations should be consistent with the proposed validation and disease hypothesis. Power analysis should address reproducibility and significance of the results.
      • The implementation of the modulatory tools in the in vitro and/or in vivo models should show that the expression or activity levels of the target(s) are measurable and significantly different between the “control” and the “disease” biological samples. The degree and the direction of the target modulation should be consistent with the proposed validation and disease hypothesis. Power analysis should address reproducibility and significance of the results.

Letters of support

  • Applicants should include letters of support from consultants, contractors, and collaborators.
  • 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 reagent(s), any limits on the studies that can be performed with said reagent(s), any limitations on sharing of data (including negative results), and whether a licensing agreement(s) will be needed and in place once the project is funded. 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.

  • Description of what specific data (e.g. initial target identification rational, functional validation read outs like synaptic activity, cell survival, electrophysiology immunohistochemistry, behavioral read outs...) and resources (modulatory tools, in vitro and in vivo models, protocols...) will be shared.
  • Timeline for availability of data and resources to other users.
Appendix:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
  • A supportive data package to the target identification rational section could be included. It should provide supportive evidences for the experimental approach including literature search, big data mining, source of biological resources, design and statistical analyses used. It must be 6 pages maximum and entitled “Supportive Data for Target Identification Selection”.
PHS Human Subjects and Clinical Trials Information

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

PHS Assignment Request Form

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

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

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.  Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential fieldof 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 FOA 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 components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or non-responsive will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.  Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

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?

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 announcement:

Does the application include a sufficient number of external collaborators with complementary expertise to address the scope and objectives of the research? If this is not the case, do the internal resources (team or institution) of the applicant provide sufficient multi-disciplinary expertise to fulfil all the components (modulatory tools, models, functional read outs) of the research objectives without limiting the overall scope and mission of this FOA?

Are the roles of each investigator clearly defined in the research plan?

Does the project management plan communicate and coordinate the logistics effectively between each collaborating members of the team, address progress toward the milestones and potential issues, and incorporate regular meetings (one kick off on site meeting and bi-annual virtual conferences)?

Is the PI proposing to cross-validate some of the key results with a collaborating team in the R33 phase?

Are the investigators knowledgeable and experienced about the biological target and the ADRD disease biology?

Are any key letters of support missing?

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 announcement:

Does the application describe convincing supporting data and evidence for the novelty of the target and its preliminary association to the pathophysiology of ADRD? How innovative are the proposed target and the validation approach?

What is the likelihood that the completion of the target validation research objectives will provide the field with sufficient new technologies (methods, assays, models, functional read outs), knowledge (e.g., optimal degree of target modulation) and confidence to prime the target for translational screening research projects and the discovery of novel therapeutics in ADRD?

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 announcement:

In the target indentification rational section, how strong are the evidences linking the target to potential causality in the pathophysiology or symptoms of the disease within the ADRD spectrum? Are the quality and number of human samples, big data search, methods and statistical analysis supportive of the applicant’s conclusions?

Is the proposed target validation approach answering the knowledge gap(s) about the biological function of the target(s) in relation to the pathophysiology of the ADRD disease state and its translational applicability toward a successful therapeutic application?

Is each component of the target validation approach (selection of the modulatory tools, physiological read outs, protocols, in vitro and in vivo models, testing of different experimental modalities) well discussed and does each component fit the hypothesized druggability of the target and the proposed mechanisms for the disease and therapeutic intervention? Will the proposed proof of concept experiment (end of R61 phase) and the key final target validation results (R33 phase) be generated with a sufficient number of independent replicates and statistical power? Do the proposed experimental modalities to be tested in the R33 phase, i) complement the knowledge gap(s) about the target and ii) aim to find optimal conditions for the target modulation to optimize therapeutic and limit negative effects? Is the monitoring of potential negative functional (side effects) read outs included in the application? In case the modulation of the target expression or activity shows positive and potential negative effects on the functional read outs is there a plan to propose an acceptable therapeutic index and path forward toward the development of novel therapeutics?

Is there a plan to address minimizing bias including blinding of the samples, randomization and statisitical analysis with scientific rigor to provide high quality data? Are the functional or physiological read outs in the different models fitting the known or hypothesized biological role of the target(s)? Is the approach addressing the target validation in more than one biological system level (molecular and metabolic pathways, cellular, tissue, neuronal circuitry, behavior…)? 

For in vitro assay(s) and in vivo model(s):

If models are used for exhibiting mechanistic or phenotypic aspects of the ADRD disease, does the application describe the expected benchmark criteria for the disease and reference control states? If human iPSC lines are generated in the application, are the sources of the biosamples and engineered methods well identified and described? Does the approach to identify functional phenotypic difference(s) between control and disease states address genetic mosaicism and other potential pitfalls from expanding cell lines in vitro? Are feasible alternatives included (e.g. multiple lines, isogenic cell lines from genetic isoforms of the target…)?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment, and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Specific to this announcement:

Milestones

Are the measurable criteria proposed as Go/No Go milestones based on the design of the proof-of-concept experiment(s) for the R61 phase and the final project deliverables for the R33 phase clearly outlined, customized and well-timed to the technical challenges of the research approach?

R61 milestones guidelines:

  1. Demonstrate that the team members work and communicate cohesively and collaboratively to respect the timelines and deliveries of the R61 phase. PD(s)/PI(s) will organize a kickoff meeting at the beginning of the project to facilitate and coordinate the collaboration. This event will be followed with emails communications and bi-annual virtual conferences to monitor progress toward the milestones.
  2. Demonstrate that the technical approaches and tools selected to modulate the expression or activity of the target(s) are set up and ready for the next R33 steps.
  3. Demonstrate that the in vitro and/or in vivo models are set up and ready for the next R33 phase.
  4. Demonstrate that the functional read out methods are set up and ready to measure the physiological consequences of the target modulations in different models.
  5. For each technical approach, demonstrate feasibility and the integration of each component (# 1-4) in a proof-of-concept experiment:

a. The implementation of the modulatory tools in the in vitro and/or in vivo models should show that the expression or activity levels of the target(s) are measurable and significantly different between the “control” and the “disease” biological samples. The degree and the direction of the target modulation should be consistent with the proposed validation and disease hypothesis. Power analysis should address reproducibility and significance of the results.

b. Modulation of the target(s) expression or activity in in vitro and/or in vivo models should translate into measurable functional or physiological differences between the “control” and the “disease” biological samples. The degree and the direction of the functional read out modulations should be consistent with the proposed validation and disease hypothesis. Power analysis should address reproducibility and significance of the results.

R33 milestones guidelines:

  • For each technical proposed modality to be tested, provide the expected measurable outcomes on the target expression or activity levels and their functional or physiological consequences in the in vitro or in vivo models between the “control” and the “disease” biological samples. Power analysis should address reproducibility and significance of the results.

Intellectual Property

If multiple institutions are proposed, is it clear how intellectual property will be shared or otherwise managed to avoid encumbering the IP, consistent with achieving the goals of the program?

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 Animal 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.

Additional Review Considerations

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), 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 FOA.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Neurological Disorders and Stroke Council. The following will be considered in making funding decisions:
  • Scientific and technical merit of the proposed project as determined by scientific peer review.
  • Availability of funds.
  • Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

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

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

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

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

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex (including gender identify, sexual orientation, and pregnancy). This includes ensuring programs are accessible to persons with limited English proficiency and persons with disabilities. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and 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 FOA.

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

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

Cooperative Agreement Terms and Conditions of Award

Not applicable.

3. 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 FOAs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

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

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

Section VII. Agency Contacts

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

Application Submission Contacts

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

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

Scientific/Research Contact(s)

Pascal Laeng, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-7416
Email: pascal.laeng@nih.gov

Peer Review Contact(s)

Natalia Strunnikova, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: (301) 496-9223
Email:nindsreview.nih.gov@mail.nih.gov

Financial/Grants Management Contact(s)

Shellie Wilburn, M.B.A
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: ChiefGrantsManagementOfficer@ninds.nih.gov

Section VIII. Other Information

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

Authority and Regulations

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

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