Part 1. Overview Information

Key Dates

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

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

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

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

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

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

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

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



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background 

Novel opportunities for T1 translational research (i.e., bench to bedside) on a spectrum of aging-related conditions are increasingly emerging from basic, clinical, and applied research. Despite the emergence of these exciting new research directions, very few of the initial discoveries reach the stage of FIH studies. This underscores the critical need for the introduction of newly developed methodologies to the current translational aging research paradigm which has mostly relied on traditional drug discovery and development approaches.  In this regard, the integration of computational approaches or tools into the traditional drug discovery and development pipeline (for both de novo drug development and drug repurposing) could streamline the process for identifying more high-quality hits and leads with optimal pharmacokinetic (PK) and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and facilitate subsequent preclinical and clinical development. For the purposes of this NOFO, drug repurposing (also known as drug repositioning, reprofiling or re-tasking) refers to approaches for identifying alternative uses for FDA-approved drugs or investigational therapeutics which are beyond the scope of the original intended clinical indication.

Discoveries of genes/variants, cellular processes, molecular pathways, endocrine and other circulating factors associated with protective or adverse aging outcomes avail potential new therapeutic targets to improve the health of older adults. Moreover, data from model organisms suggest the involvement of fundamental aging mechanisms (e.g., macromolecular damage, impairments in proteostasis and autophagy, inflammation, and increased burden of cell senescence) across several aging-related conditions.  Geroscience-based translational research posits that targeting aging mechanisms could lead to the development of therapeutics to halt or delay multiple age-related conditions. The translation of potential targets to new therapies, however, requires timely studies of their assayability, drugability, validation, and target-related safety issues.  Greater attention to these types of studies in the future, earlier validation of possible targets, and the application of computational drug repurposing strategies could improve the overall efficiency of therapeutics development for aging-related conditions. 

Research Objectives

This NOFO invites applications on T1 translational aging research with the overall goal of advancing new therapeutics from preclinical stages to FIH trials. 

This NOFO supports the following two categories of projects:

1. De novo drug development (i.e., new chemical/molecular entities) with one of the following entry points to the translational pipeline
   • Screening through preclinical validation, or
   • Hit to lead through IND, or
   • Late-stage preclinical development through FIH trials

2. Data-driven computational drug repurposing strategies with subsequent experimental validation of predictions and generation of proof-of-concept data in pertinent animal models and/or in human in vitro studies.

Possible topics for T1 translational studies include, but are not limited to, the following:

• De novo development of novel agents to treat age-related conditions or deficits such as sarcopenia, physical functional impairments, immunosenescence, and fibrotic conditions. Biologics or stem/progenitor cell therapies for improving injury repair in older adults (e.g., fractures, wound healing) may be proposed. This may include treatments with cytokines, trophic factors, etc., to improve stem/progenitor cell function to promote more efficient repair of injuries or wounds, as well as homeostasis of the damaged tissues. Proposed studies are encouraged to incorporate computational approaches to complement traditional methods. The relationship between the condition and/or deficit targeted by the drug and the clinical outcome(s) of interest must be clearly stated.
• Data-driven computational drug repurposing for the treatment and prevention of aging-related conditions using heterogenous data resources such as target protein structural databases, chemical structure databases, biological pathway databases, protein-protein interactions, drug-target interactions, omics data, clinical trials databases and electronic health records (EHRs). Approaches used could be disease-, target- or drug-centric.
• Geroscience-based translation approaches.  This could include either computational drug repurposing studies or de novo development of drugs to target fundamental mechanisms of aging for a specific clinical indication. The application should describe the current state of knowledge about the intended clinical application, age-related condition(s) of interest, and the underlying role of the aging mechanism being targeted for preclinical drug development.

The types and scale of proposed translational research activities in the projects are anticipated to vary and will depend on whether the project focuses on de novo drug development or involves computational drug repurposing strategies. The incorporation of computational approaches at any step of de novo drug development process is encouraged.
UG3/UH3 Exploratory/Developmental Phased Award Activities

This NOFO utilizes the UG3/UH3 activity code, a milestone-driven, phased innovation funding mechanism. The application must be submitted as a single application for both the UG3 and UH3 phases. Awards made under this NOFO will initially support the UG3 phase. Attainment of recipient-specified milestones in the UG3 phase will be required to proceed to the UH3 phase of the award. Each phase is structured as follows: 

The UG3 Exploratory/Developmental Phase (Phase 1)

The UG3 phase is the first phase. This phase provides up to two years of support for planning and preliminary study activities, including pilot activities.  Depending on the entry point of the proposed projects, pilot activities may include:

• Development and testing of new computational approaches
• Screening of candidate compounds (including virtual methods)
• Identification of a lead compound
• Studies of structure activity relationship (SAR)
• Characterizing and optimizing promising hit compounds
• Assay development
• Target identification and engagement studies (characterization of on-target and off-target effects)
• Exploration of different formulations
• Generation of preliminary efficacy data using animal models (e.g., in vivo and in vitro) and/or human in vitro studies including investigation of potential differences due to age and sex
• Identification of possible pharmacodynamic biomarkers
• Pilot ADMET studies, including in silico prediction
• For candidate therapeutics at more advanced stages of preclinical development, the UG3 phase may be used for pre-Investigational New Drug Application (pre-IND) protocol development.

Milestones, Go/No-Go Criteria, and the UG3/UH3 Transition: The application must include go/no go criteria, associated milestones, and a timeline for the UG3 phase. At the completion of the UG3 phase, the awardee will be required to submit a detailed request to transition to the UH3 phase. It is crucial that the UG3 milestones are objectively defined and quantifiable to ensure clear demonstration that the proposed milestones were met at the time of the transition request. The transition request will be administratively reviewed for successful completion of the go/no-go criteria and milestones within the specified timeline. 

NOTE: Prospective applicants should note that the funding of a grant application for the UG3 phase does not guarantee support of the UH3 phase. Transition to the UH3 phase of the project will occur only if the administrative review process recommends that the UG3 planning activities have been successful and the implementation phase of the project can proceed with confidence of success, and if funds are available.

The UH3 Implementation Phase (Phase 2)

The UH3 phase is the second phase. This phase provides up to three years of support for implementation activities. The UH3 phase will enable more comprehensive pharmacology and/or toxicology evaluations (including experimental validation of in silico predictions) of the proposed therapeutics, as well as replication studies to confirm preliminary findings. Possible activities to be conducted during the UH3 phase include:

• Testing of analogs in ADMET assays
• Scale-up synthesis
• Compound stability studies
• Efficacy and/or target engagement studies
• Multiple dose PK testing with pharmacodynamic (PD) correlations, if possible
• Dose-ranging finding toxicology studies
• Initial IND-enabling toxicology/toxicokinetics
• Early phase FIH trials of safety/tolerability, dose-ranging, and PK/PD

Both Phases

Assay and methodological development, including new computational approaches or tools, may be included in both the UG3 and UH3 phases, depending on the needs of the project. 

Investigators must propose annual milestones with timelines for the UG3 and UH3 phases. A milestone is defined as a scheduled event in the project timeline signifying the completion of a major project stage or activity. The specified milestones should be quantifiable goals (or deliverables) which can be used to monitor progress at each phase, and for go/no-go decision-making at the UG3/UH3 transition point.

Evaluation of the Overall Research Program 

Achievement of annual milestones and adherence to timelines established by the investigators will be used to assess translational research progress of the individual UG3 and UH3 projects awarded under this NOFO. These metrics, along with additional input from the UG3/UH3 awardees will be used by the NIA staff to develop an independent evaluation of the overall research program during the last quarter of the -02 budget year of the UH3 phase.  

Quality and Compliance Requirements

Since one of the goals of this program is to generate drug candidates which will be eligible for FDA approval, adherence to compliance and quality criteria is required.

• It is expected that all IND enabling nonclinical studies will be performed in a manner consistent with Good Laboratory Practices (GLP) and current FDA guidance.
• All clinical trials must be performed following Good Clinical Practices (GCP) and in accord with the NIH Policy for Data and Safety Monitoring.

Intellectual Property

The ultimate goal of this program is to bring new therapies to the market. Therefore, the creation and protection of intellectual property (IP) that will make drug candidates attractive to potential licensing and commercialization partners is an important activity to be undertaken by the PD/PI in consultation with their institutions' technology transfer officials. This program is structured so that the awardee institution retains their assignment of IP and thereby controls the patent prosecution and licensing negotiations for drug candidates developed in this program. It is expected that the awardee institution will take responsibility for patent filings, maintenance, and licensing efforts toward eventual commercialization.

Expertise of Research Teams

Investigative teams of the UG3/UH3 projects must be multidisciplinary and include expertise pertinent to the proposed translational research project.  At a minimum, the investigative teams should include basic, clinical, translational/Pharma expertise, biostatistics, and a multi-PI arrangement to ensure necessary leadership as the project progresses through translational pipeline stages.  Projects involving data-driven computational approaches for drug development should include additional expertise in data science, bioinformatics, computational chemists, and computational biologists, as needed. Teams may collaborate with academic, nonprofit, or commercial entities to achieve the requisite expertise, experience, and research resources.

Pre-Application Webinar

A webinar is planned to provide prospective applicants the opportunity to receive information and ask questions about the scientific scope of this NOFO and technical details for applying. The webinar will be open to all prospective applicants. Participation in the webinar is not a prerequisite to applying to this NOFO, but prospective applicants will need to register in order to participate in the webinar. Prospective applicants are also encouraged to submit their questions regarding the NOFO in advance of the webinar; further details on where to submit the questions will be provided once the webinar has been scheduled. Please refer to NIA's web page regarding this NOFO  for further details on the pre-application webinar, including the time and date, and registration information.

Non-Responsive Applications

The following types of applications are outside the scope of this NOFO. Such applications will be considered non-responsive to this NOFO and will be administratively withdrawn prior to scientific peer review:  

• Applications that focus on neurodegenerative diseases and Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD).
• Applications lacking specified aims and milestones for both the UG3 and UH3 phases.  

Clinical Research Operations Management System

NIA uses a central resource to NIA staff and extramural investigators to facilitate/support the conduct and management of clinical research. NIA Clinical Research Operations & Management System (CROMS) is a comprehensive data management system to support the business functions, management, and oversight responsibilities of NIA grants that support the conduct of clinical research with human subjects. NIA investigators of grants, contracts, and cooperative agreements that are active as of July 1, 2021, including clinical trials funded as pilots, exploratory studies, or other projects through this Consortium, and support human subjects research as defined by the DHS HHS OHRP regulations at 45 CFR 46 will be required to interact with and use existing and future components of CROMS as required by NIA throughout the lifecycle of the grant, as described in NOT-AG-23-017. Data to be submitted to NIA CROMS includes those elements reported in the standard NIH requirement annual progress report (GPS 4.1.15.7). Details regarding the standard operating procedures for CROMS can be found on the NIA CROMS website.

When applicable, all NIA grantees must ensure:

1. The study’s Informed Consent Document (ICD) lists “The National Institutes of Health (NIH) and its authorized representatives” as one of the organizations that may look at or receive copies of information in participants’ study records. According to DHS HHS OHRP 45 CFR 46 §46.116, all ICDs must contain “A statement describing the extent, if any, to which confidentiality of records identifying the participant will be maintained.” If using the NIA informed consent template, please see Section 6: Statement of Confidentiality.

2. An assigned NIH ClinicalTrials.gov identifier (NCT number) is reported in its respective CROMS study record within three months after assignment, and the reporting of final enrollment data to CROMS is consistent with final enrollment data reported in ClinicalTrials.gov.

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

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

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 Governments

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

Other

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

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

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

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply - Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information

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

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

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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

Letter of Intent

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

Chhanda Dutta, Ph.D.
Telephone: 301-496-4161
Email: DuttaC@mail.nih.gov

Page Limitations

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

,with the following exceptions or additional requirements: 

For this specific NOFO, the Research Strategy section is limited to 30 pages. 

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

Investigative teams of the UG3/UH3 projects must be multidisciplinary and include expertise pertinent to the proposed translational research project.  At a minimum, the investigative teams should include basic, clinical, translational/Pharma expertise, biostatistics, and a multi-PI arrangement to ensure necessary leadership as the project progresses through translational pipeline stages.  Projects involving data-driven computational approaches for drug development should include additional expertise in data science, bioinformatics, computational chemists, and computational biologists, as needed. Teams may collaborate with academic, nonprofit, or commercial entities to achieve the requisite expertise, experience, and research resources. 

R&R Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

The Research Strategy section must include the following subsections:

• Significance
• Approach
• Milestones and Timelines
• Intellectual Property
• Letters of Support

Note: Applicants proposing human subjects and/or FIH trials must use the PHS Human Subjects and Clinical Trials Information Form to capture detailed study information. You may use the research strategy to discuss the overall approach but do not duplicate information collected in the PHS Human Subjects and Clinical Trials Information Form.

A. Significance

Clinical Impact and Feasibility:

• Describe the current state of knowledge about the relationship between the candidate compound or therapeutic target of interest for preclinical development and the proposed clinical indication/age-related condition(s) of interest.
• If different treatment modalities are currently available for the selected age-related condition(s), provide a brief discussion of their limitations and how the proposed drug/therapy would provide a therapeutic advantage. The discussion should address all available classes of current treatments and whether the proposed therapy represents a new class of drugs, etc.
• Discuss how the proposed project relates to known therapy development efforts underway in academia and industry, regardless of therapeutic class.
• Provide a Target Product Profile (TPP) which states the ultimate goals of the proposed therapy development effort such as stages of the age-related condition proposed for the project, patient population, mode of administration, dosing regimen, duration of treatment, biomarkers and/or outcome measures, and criteria for determining clinical efficacy.  Information regarding developing a TPP can be found at: Example Target Product Profile
• For projects proposing early phase FIH trials, briefly discuss the rationale behind the selected clinical population and provide evidence in support of feasibility for evaluation of clinical efficacy should the proposed therapy be tested (for example, describe strategies for gaining access to appropriate patient population, the selection of clinical endpoints).  Describe the group clinical expertise used to determine the goals of the therapeutics development program and the proposed FIH trial.

B.  Approach

Proposed de novo therapeutic:

• Provide a description of the structure/identity, selectivity, bioactivity, potency, stability, production, etc. of the candidate therapeutic.
• Define the anticipated characteristics of the optimized lead, if applicable. Include quantitative characteristics for structure/identity, in vitro activities and in vivo pharmacology, specificity, selectivity, stability, etc.

Computational drug repurposing:

• Describe the data resources (e.g., omics data, biomedical literature, pharmacological data) and computational tools that will be used to identify new uses for existing or abandoned drugs for the treatment of aging conditions. 
• Provide details of the in vivo and/or in vitro studies which will be conducted for experimental validation of the predictive models.

Testing Strategy:

• Discuss the evidence base that modulation of target(s) of interest will result in a therapeutic effect and its relationship to the proposed clinical application.
• Provide high-quality proof-of-concept data obtained in aging-relevant experimental models and/or from human in vitro systems (if available) which demonstrate that the candidate therapeutic influences the relevant biological pathway and/or age-related clinical outcomes and condition(s) of interest. Efficacy must be measured in appropriate animal models and models of appropriate age and sex, using clinically relevant outcome measures and in vivo target engagement, with sufficient detail to allow reviewers to critically evaluate the findings. Include quantitative information on purity and selectivity of the proposed therapeutic.
• Include a justification for the choice of animal model(s) or assay(s), primary, secondary and/or composite, exploratory endpoints, and explain the basis for their clinical relevance.
• Any data figures included in the application should be accompanied by a brief description of the study design (e.g., age and sex of animals, number of animals/group).

Methodologies and Assays:

• If the development of new computational approaches/tools, methodologies or assays is proposed in the research plan, describe how these methodologies are critical to advancing the preclinical development of the proposed therapeutic.
• Provide details on how the new methodologies, including computational approaches and predictive models, will be validated and the feasibility of applying them to the preclinical development process within the project period.

Additional Information Regarding FIH Trials:

• Applicants are strongly advised to discuss plans for FIH trials with NIH program staff prior to submitting their application.
• Applicants must submit supporting trial and regulatory documents to NIH for administrative review prior to the commencement of any FIH trial.

C.  Milestones and Timelines

Investigators must propose annual milestones with timelines for the UG3 and UH3 phases. 

The application must include go/no go criteria, associated milestones, and a timeline for the UG3 phase. At the completion of the UG3 phase, the awardee will be required to submit a detailed request to transition to the UH3 phase. It is crucial that the UG3 milestones are objectively defined and quantifiable to ensure clear demonstration that the proposed milestones were met at the time of the transition request. The transition request will be administratively reviewed for successful completion of the go/no-go criteria and milestones within the specified timeline. 

In this section applicants must provide a Gantt chart for the entire project period (both UG3 and UH3 phases) with proposed milestones and points for go/no-go decisions that will be used to assess research progress for each of the key objectives in the research plan. One or more milestone(s) should be used for each key objective. Details should be provided on the methods, assumptions, experimental design, and data analysis plans for each of the proposed milestones. The quantitative criteria for measuring success and related rationale must be specified. Quantitative criteria should be robust and be consistent with the state-of-the-art in the field. The quantitative criteria for success in the milestones will also be used for making go/no-go decisions, and this should be specified.

D. Intellectual Property (IP)

Applicants are encouraged to prepare this section in consultation with their institutions' technology transfer officials.

• Applicants must describe any constraints of which they are aware that could impede their use of compounds, assays, or models for research purposes and/or commercial development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present intellectual property filings and publications, compounds with similar structures that are under patent and/or on the market, etc.) and how these issues would be addressed. If the applicant's institution has filed pertinent patents, the applicant should indicate filing dates, the type of patent, and application status.
• 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 intellectual property) among the institutions consistent with achieving the goals of the program. Applicants should clarify how IP will be shared or otherwise managed if there are multiple PDs/PIs and institutions involved.

E. Letters of Support

• Applicants should include letters of support from consultants, contractors, and collaborators.
• If collaborating with a private entity, include a letter of support that addresses any agreement to provide agent(s), access to proprietary research resources including databases, any limits on the studies that can be performed with said agent(s), any limitations on sharing of data (including negative results). This letter should come from a senior 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 How to Apply - Application Guide.

Other Plan(s): 

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

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan. If collaborating with a private entity, the plan should address any limitations on sharing of data (including negative results).

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

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

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

If you answered #147;Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

PHS Assignment Request Form

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

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

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

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

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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

Information on the submission process and a definition of on-time submission are provided in the How to Apply – Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

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 Section 7.9.1 Selected Items of Cost.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the How to Apply - Application Guide. Paper applications will not be accepted.

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

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by NIA, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

In order to expedite review, applicants are requested to notify the NIA Referral Office by email at Ramesh.Vemuri@mail.nih.gov  when the application has been submitted. Please include the FON and title, PD/PI name, and title of the application.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at grantdisclosures@oig.hhs.gov. 

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

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

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

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).

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.

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.

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National Institute on Aging, in accordance with NIH peer review policies and practices, 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 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 National Advisory Council on Aging (NACA). 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.

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov.  NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 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.

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

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.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all 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.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website. 
  • HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (HHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

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

• All aspects of the study, including any modification of study design; conduct of the study; quality control; data analysis and interpretation; preparation of publications; dissemination of data, tools, and technologies; and collaboration with other investigators. The awardee agrees to accept close coordination, cooperation, and participation of NIA staff in those aspects of scientific and technical management of the study as stated in these terms and conditions.
• Proposing a feasible timeline with rigorous milestones to monitor translational research progress.
• Pursuing patent protection. Patents should include a reference to NIH funding support by including the grant/cooperative agreement number in the patent.
• Support or other involvement of industry or any other third party in the study--e.g., participation by the third party; involvement of project resources or citing the name of the project or the NIA support; or special access to project results, data, findings, or resources--may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NIA.
• Obtaining prior written approval from NIA for changes in any of the key personnel identified in the Notice of Grant Award.
• Convening regularly scheduled virtual meetings to review research progress and status of any interactions with FDA staff and to discuss with NIA any anticipated need for modifications to the preclinical development strategy or planned FIH trials (as applicable).
• Notifying NIA of planned meetings with the FDA and communicating the meeting date and agenda. Awardees agree to NIA staff participation in any meetings with the FDA.
• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

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

• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.
• Have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. NIA staff may use information obtained from the data for the preparation of internal reports on the activities of the study. However, awardees will retain custody of and have primary rights to all data developed under these awards, subject to Government rights of access consistent with DHHS, PHS, and NIH policies.
• Provide input on project milestones and guidance when modifications to established milestones are needed.
• Provide guidance and support in the development, assembly, and submission of all required regulatory documents, e.g., those regarding the use of investigational drugs/therapeutics, to the FDA.
• Serve as a resource to provide scientific/programmatic support during the accomplishment of the research by participating in the design of the activities and advising in the selection of sources or resources (e.g., availability of aged animals), provision of research resources, and management and technical performance through participation in study meetings.
• Monitor progress of study milestones; as with any award, continuation, even during the period recommended for support, is contingent upon satisfactory progress. As relevant, transition of a project from UG3 to UH3 will be based on research achieved milestones and assessed by an internal NIA panel. In general, continuation of funding will be dependent upon the awardee's ability to show adequate progress towards milestone accomplishment.
• Funding for the project may be restricted or discontinued if there are delays in meeting milestones or if milestones are not met. Continuation of funding will also be based on the overall robustness of the data generated and their interpretation, overall progress, competitive landscape, and availability of funds.
• If a study is finally determined to lack feasibility, recipients are required to submit a close-out plan to NIA staff within two (2) months of the decision either by NIA staff or the grantee that an awarded study is no longer feasible. The plan must be approved and signed by the Institutional Official and the PD(s)/PI(s) listed on the award prior to submission.
• Additionally, an NIA program official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

The PD(s)/PI(s) will form a Steering Committee (SC), which will serve as the main decision-making body for the project. The SC will have an important role in clarifying and finalizing the project milestones and timelines. The SC will be composed of the PD(s)/PI(s), specialized core facilities (if any), and one NIA representative (the Project Scientist). The NIA Project Scientist will have voting membership on the SC and, as appropriate, its subcommittees. The SC will have primary responsibility for facilitating the conduct and monitoring of studies and reporting study results. As the components of the SC may be geographically dispersed, the SC should convene regularly scheduled virtual meetings and, supplemented as deemed necessary by face-to-face meetings.

Each full member will have one vote. Awardee members of the SC will be required to accept and implement policies approved by the SC.

Dispute Resolution:

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

3. Data Management and Sharing

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

If collaborating with a private entity, the plan should address any limitations on sharing of data (including negative results).

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 Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

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 Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

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

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

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

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

Chhanda Dutta, Ph.D.
Division of Geriatrics and Clinical Gerontology
National Institute on Aging (NIA)
Telephone: 301-496-4161
Email: Duttac@mail.nih.gov

Jennifer Fox, Ph.D.
Division of Aging Biology
National Institute on Aging (NIA)
Telephone: 202-510-4801
Email: Jennifer.Fox@nih.gov

Lorenzo M. Refolo, Ph.D.
Division of Neuroscience
National Institute on Aging (NIA)
Telephone: 301-594-7576
Email: refolol@nia.nih.gov

Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-402-7700
Email: ramesh.vemuri@nih.gov

Laura Pone
National Institute on Aging (NIA)
Telephone: 301-451-9956
Email: laura.pone@nih.gov

Section VIII. Other Information

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

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