Part 1. Overview Information

Key Dates

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

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

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

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

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

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

Overview

AD is the most common cause of dementia in older persons and is among the greatest healthcare challenges of the 21st century. The disease currently affects an estimated 6.7 million in the United States; by 2050, this number could rise as high as 14 million. To avert this public health crisis, effective therapies that prevent AD, slow its progression, or treat its cognitive and behavioral symptoms are urgently needed. To catalyze drug development for AD, NIA is reissuing, with this NOFO, the Alzheimer's Drug Development Program (ADDP). The ADDP offers researchers funding for drug development activities that can be conducted in their own laboratories, in collaboration with contract research organizations (CROs) that specialize in various drug development activities including the following:

• Medicinal chemistry
• PK
• ADMET  
• Formulations development
• Efficacy in animal models
• Development of biomarkers for target engagement
• Chemical synthesis under GMP
• IND enabling safety-toxicology
• Initial Phase I clinical testing

Scope

The overarching goal of the ADDP is the development of a broad range of novel drug candidates for AD, including small molecules, natural products, and biologics which will be eligible for Food and Drug Administration (FDA) approval. 

Projects can enter the ADDP at one of the following stages: 

1. Early Stage - To optimize the agent's potency, drug-like properties, specificity, pharmacological properties, and/or ADMET properties and undergo dose-range finding toxicology and initial IND-enabling safety toxicology, or 
2. Late Stage - To advance development of candidates through all required IND-enabling toxicology studies, IND document preparation, and initial single dose, single ascending dose, or multiple ascending dose Phase I clinical testing

Applicants are encouraged to contact the NIA Scientific/Research contact listed in Section VII. Agency Contacts of this NOFO regarding the suitability of their projects for the ADDP and to clarify which entry stage is most appropriate for their project.

Stage Specific Entry Criteria

Early Stage Entry Criteria for Small Molecule Projects

Small molecule projects must meet the following requirements prior to entering the Early Stage:

1. Rigorous data supporting the hypothesis that modulating the putative drug target/affected pathway will produce a desirable outcome for the intended AD indication (i.e., pre-clinical, prodromal/Mild Cognitive Impairment (MCI), early, mid and late stage).
2. A bioactive compound, in hand, that will serve as a starting point for optimization with proof of identity and purity (typically greater than 95%, as determined by, e.g., Nuclear Magnetic Resonance (NMR), melting point, or Liquid Chromatography/Mass Spectrometry (LC/MS), with no single impurity greater than 0.5%).
3. In vitro biological activity (typically less than 1 micromolar (μM) in biochemical assays and less than 10 μM in cell-based assays relevant to the drug target), confirmed by repeat dose-response testing, with more than one batch of compound.
4. Selectivity for the intended target over closely related targets, if desired (and when the target is known).
5. Availability of primary and secondary in vitro bioactivity assays that can be used or optimized for driving Structure-Activity Relationship (SAR) studies.
6. Availability of preclinical animal model(s) that can be used to assess in vivo efficacy or target engagement (i.e., measurement of target binding or proximal downstream effects).
7. Studies using animal models presented to justify the choice of therapeutic target, drug candidate or, to determine efficacy, must be in compliance with NIH guidance on rigor and reproducibility. In particular, investigators proposing animal model studies are expected to follow the general ARRIVE guidelines for rigorous animal research and the best practices guidelines for AD preclinical efficacy studies. These studies should include a power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were balanced for sex and were replicated.
8. Availability of selectivity and counter-screening assays to address potential activity at related targets and other undesirable activities or artifacts.
9. Demonstration that the proposed secondary bioactivity assays and counter-screening and selectivity assays have sufficient reliability and throughput for their proposed use in the project.
10. Demonstration of a clear correlation between activity in the primary assay and activity in confirmatory assays and models, sufficient to justify advancement criteria in a testing funnel.
11. No obvious legal (e.g., intellectual property) constraints to pursuing the proposed chemical scaffold(s) and using the proposed assays and models for research purposes and/or commercial development.

Early Stage Entry Criteria for Biologics Projects

Biologics projects should meet the following qualifications prior to entering the Early Stage:

1. Applicants should have one or more drug lead(s) from which a candidate can be derived.
2. The drug lead(s) should be sufficiently characterized so that the parameters to be optimized can be quantitatively specified.
3. Established preliminary in-vivo efficacy and target engagement data using agent(s) in relevant animal model(s). The agent(s) should show in-vivo efficacy using clinically relevant outcome measures (e.g., biochemical, neuropathological, behavioral, and/or functional, when possible) and in-vivo target engagement (e.g., measurement of target binding or proximal downstream effects) at the clinically intended site of action using sufficient experimental and statistical rigor in a relevant animal in-vivo proof-of-concept model.
4. Applicants should have pre-existing data demonstrating that the key in vitro and in vivo assays proposed to optimize the leads are suitable for the proposed purpose and available in either the applicant's or collaborator's laboratories.
5. Availability of animal and/or cell-based model(s) that can be used to assess in vivo efficacy or target engagement (i.e., measurement of target binding or proximal downstream effects).
6. Studies using animal models presented to justify the choice of therapeutic target, drug candidate or to determine efficacy must be in compliance with NIH guidance on rigor and reproducibility. In particular, investigators proposing animal model studies are expected to follow the general ARRIVE guidelines for rigorous animal research and the best practices guidelines for AD preclinical efficacy studies. These studies should include a power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were balanced for sex and were replicated.
7. No obvious legal (e.g., intellectual property) constraints to pursuing the proposed biologic agent(s) using the proposed assays and models for research purposes and/or commercial development.

Late Stage Entry Criteria for Small Molecule Projects

Small molecule projects should meet the following qualifications prior to entering the Late Stage:

1. A strong data package linking the putative drug target/affected pathway to the proposed disease indication and supporting the hypothesis that altering the target activity as proposed will produce desirable outcomes for the disease.
2. Proposed compounds should have in vitro and in vivo biological activity and ADMET properties appropriate for the intended clinical use (i.e., the disease indication, patient population, delivery mode, treatment duration, and treatment regimen) and outcomes.
3. In vivo study results that include assessments of PK, bioavailability at the relevant site of action, and the pharmacokinetics-pharmacodynamics (PK/PD) relationship.
4. Rigorous evidence that the agent is a blood-brain-barrier penetrant (unless the agent is proposed to be delivered directly to the Central Nervous System (CNS)).
5. A data package showing a clear and convincing demonstration of preclinical efficacy. The data package can include in vivo efficacy in an established AD animal model and/or in vivo target engagement.
6. Studies using animal models presented to justify the choice of therapeutic target, drug candidate or, efficacy must be in compliance with NIH guidance on rigor and reproducibility. In particular, investigators proposing animal model studies are expected to follow the general ARRIVE guidelines for rigorous animal research and the best practices guidelines for AD preclinical efficacy studies. These studies should include a power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were balanced for sex and were replicated.
7. A data package that includes Ames mutagenicity, hERG activity, microsome stability, cytochrome P450 (CYP) inhibition, plasma protein binding, and aqueous solubility.
8. A data package that includes counter-screening aimed at determining selectivity across a broad panel of closely related and unrelated pharmacological targets (e.g., G protein-coupled receptors, kinases, etc.).
9. No obvious legal (e.g., intellectual property) constraints to pursuing the proposed small molecule(s) using the proposed assays and models for research purposes and/or commercial development.

Late Stage Entry Criteria for Biologics Projects

Biologics projects should meet the following qualifications prior to entering the Late Stage:

1. A data package demonstrating completed optimization and final characterization of the candidate, such as structure/identity, selectivity, bioavailability stability, formulation, manufacturability, sufficient purity, clinically intended route of administration, minimal effective dose, optimal effective dose, time and duration of treatment as determined in relevant in vivo assays using clinically relevant functional and/or pathological outcome measures, and/or in vivo target engagement assays.
2. Proposed compounds should have in vitro and in vivo biological activity and ADMET properties appropriate for the intended clinical use (i.e., the disease indication, patient population, delivery mode, treatment duration, and treatment regimen) and outcomes.
3. In vivo study results that include assessments of PK, bioavailability at the relevant site of action, and the PK/PD relationship.
4. Details concerning special formulations, if proposed (i.e., slow release, liposomes, nanoparticles, etc.).
5. Rigorous evidence that the agent is a blood-brain-barrier penetrant (unless the agent is proposed to be delivered directly to the CNS).
6. A data package showing a clear and convincing demonstration of efficacy. The data package can include in vivo efficacy in an established AD animal model and/or in vivo target engagement at the clinically intended site of action.
7. Studies using animal models presented to justify the choice of therapeutic target, drug candidate or, efficacy must be in compliance with NIH guidance on rigor and reproducibility. In particular, investigators proposing animal model studies are expected to follow the general ARRIVE guidelines for rigorous animal research and the best practices guidelines for AD preclinical efficacy studies. These studies should include a power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were balanced for sex and were replicated.
8. A data package that includes Ames mutagenicity, hERG activity, microsome stability, CYP inhibition, plasma protein binding, and aqueous solubility.
9. No obvious legal (e.g., intellectual property) constraints to pursuing the proposed biologic agent(s) using the proposed assays and models for research purposes and/or commercial development.

Drug Development Activities Supported Through this NOFO

Supported Early Stage Activities for Small Molecule Projects

Examples of Early Stage activities for small molecule projects include, but are not limited to, the following:

• Establishment of the SAR
• Testing of analogs in bioactivity assays and animal models
• Testing of analogs in selectivity and counter-screening assays
• Assessment of efficacy and/or target engagement. Studies using animal models to measure target engagement and/or efficacy must be in compliance with NIH guidance on rigor and reproducibility. In particular, investigators proposing animal model studies are expected to follow the general ARRIVE guidelines for rigorous animal research and the best practices guidelines for AD preclinical efficacy studies. These studies should include a power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were balanced for sex and were replicated
• Identification of biomarkers for target engagement
• Testing of analogs in ADMET assays (e.g., microsome stability, CYP induction and inhibition, solubility, permeability in Madin-Darby Canine Kidney (MDCK) or Caco-2 cells, plasma protein binding, brain/plasma ratio, PK in multiple species)
• Scale-up synthesis
• Compound stability studies
• Pre-formulation studies
• Multiple dose rodent PK testing with PD correlations, if possible
• Dose-range finding toxicology studies
• Initial IND-enabling toxicology

Supported Early Stage Activities for Biologics Projects

Examples of Early Stage activities for biologics projects include, but are not limited to, the following:

• Optimization of leads for improvement in potency, specificity, bioavailability, and suitability for human testing
• Selection of the best promoter or viral serotype for a gene therapy product
• Humanization of a mouse monoclonal antibody
• Characterization of identity and properties (e.g., cell phenotype, aggregation, epitope mapping, post-translational modifications, sequences, viscosity, stability)
• Assessment of in vitro activities (e.g., affinity, specificity, activity in cells, cellular uptake)
• Assessment of efficacy and/or target engagement. Studies using animal models to measure target engagement and/or efficacy must be in compliance with NIH guidance on rigor and reproducibility. In particular, investigators proposing animal model studies are expected to follow the general ARRIVE guidelines for rigorous animal research and the best practices guidelines for AD preclinical efficacy studies. These studies should include a power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were balanced for sex and were replicated
• Identification of biomarkers for target engagement
• Assessment of in vivo pharmacology such as determination of dose range, dosing regimen, duration of treatment
• Assessment of PK/PD properties
• Evaluation of metabolism
• Minimizing a predicted or previously encountered toxicity
• Optimization of delivery systems and special formulations (i.e., slow release, liposomes, etc.)
• Optimization to have better suitability for the route of administration
• Developing a production plan
• Dose-range finding toxicology studies
• Initial IND-enabling toxicology

Supported Late Stage Activities for Small Molecule Projects

Examples of Late Stage activities for small molecule projects include, but are not limited to, the following:

• Chemistry, Manufacturing, and Control (CMC) activities (e.g., purification development, CMC analytical development, formulation development, salt and polymorph screening, scale-up manufacturing, compound stability studies, and GMP manufacturing) for IND-enabling pharmacology/toxicology testing
• Multiple dose rodent PK testing with PD correlations, if possible
• Dose-range finding toxicology studies
• Metabolite identification
• IND-enabling toxicology, with toxicokinetics, if applicable
• Pre-IND meeting
• IND document preparation (the PD/PI will be responsible for the submission of the IND application and scheduling meetings with the Food and Drug Administration (FDA))
• GMP manufacturing of material for Phase I clinical testing
• First-in-human Phase I clinical trial (i.e., single dose, single ascending, or multiple ascending study. Clinical trial outcomes may include safety, tolerability, PK and PD, target engagement, and target modulation endpoints)

Supported Late Stage Activities for Biologics Projects

Examples of Late Stage activities for biologics projects include but are not limited to the following:

• CMC activities (e.g., master and working cell banks development, purification development, CMC analytical development, formulation development, scale-up manufacturing, compound stability studies, and cGMP manufacturing) for IND-enabling pharmacology/toxicology testing
• PK evaluations in species relevant for toxicology or human dose-prediction
• Preliminary safety such as safety pharmacology and/or dose-range finding toxicology
• IND-enabling toxicology, with toxicokinetics, if applicable
• Tumorigenicity evaluations particularly for gene therapies and cell therapies
• Immunogenicity evaluations
• Biodistribution studies
• Pre-IND meetings
• IND document preparation
• GMP manufacturing of material for Phase I clinical testing
• First in-human Phase I clinical trial (i.e., single dose, single ascending or multiple ascending dose study. Clinical trial outcomes may include safety, tolerability, PK and PD, target engagement, and target modulation endpoints)

Non-Responsiveness Criteria:

The following types of applications will be considered non-responsive to this NOFO and will be administratively withdrawn prior to scientific peer review:

• Basic research and studies of disease mechanism
• Studies aimed at mechanisms of drug action
• Animal model development studies 
• Stand-alone preclinical efficacy studies in animal models
• Screening studies to identify hit compounds
• Projects aimed at anti-amyloid therapies (e.g., beta- and gamma-secretase inhibitors, amyloid aggregation inhibitors, and anti-amyloid immunotherapies)
• Projects aimed at developing anti-tau immunotherapies
• Projects that propose to develop generic or off-patent compounds for AD
• Projects that propose to repurpose or develop new formulations or drug delivery systems for compounds that have previously been approved for another indication by FDA or any other worldwide regulatory agency
• Projects that propose to develop and/or test combination therapies
• Development of risk, detection, diagnostic, prognostic, predictive, and prevention biomarkers projects
• Development of diagnostics and diagnostic devices projects
• Stand-alone clinical trials
• Studies directed beyond Phase I clinical testing 

Milestones

Milestone-driven research is used to ensure research is focused on a well-defined goal and achieving that goal with the greatest efficiency. As drug development research is inherently high risk, the use of milestones provides clear indicators of a project's continued success or emergent difficulties. The milestones must provide objective and quantitative success criteria which are recognizable as appropriate endpoints for a specific scientific goal and can be used to monitor the progress made by a research project. The milestones will serve as a basis for go/no-go decision making between NIA program staff and the project research team. Therefore, the application must include a table or list of go/no-go milestones with quantitative success criteria for each year of funding. Prior to funding of an application, NIA program staff will contact the applicant to discuss the proposed milestones and any modifications to the milestones recommended by the review committee or NIA Program staff. A final set of approved milestones will be specified in the Notice of Award. Progress towards achievement of the established milestones will be evaluated by a committee composed of NIA program staff. If warranted, the milestones for future years may be revised based on data and research progress during the preceding year.

Note: If a funded project does not make satisfactory progress toward the agreed upon milestones at any stage during the funding period, future year grant funding may be discontinued. 

Quality and Compliance Requirements

Since one of the goals of the ADDP 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 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.

Evaluation of this Program

In carrying out its stewardship of this NOFO, NIA may request information essential to an assessment of the effectiveness of this program from the participants. Participants may be contacted during and after the completion of this award for periodic updates on information helpful in evaluating the impact of the program. In carrying out its stewardship of this NOFO, NIA may request information essential to an assessment of the effectiveness of this program from the participants. Participants may be contacted during and after the completion of this award for periodic updates on information helpful in evaluating the impact of the program. NIA will use this information to determine overall success of the program in developing drugs for AD. 
OutreachPro

NIA is committed to ensuring that clinical research studies have diverse and inclusive representation, particularly of those communities understudied in research. NIA’s National Strategy for Recruitment and Participation in Alzheimer’s and Related Dementias Clinical Research provides an emphasis on the urgent need for more research volunteers and from various populations and it encourages examining research study populations across multiple factors such as age, race, ethnicity, sex, education, socioeconomic status, geographic location, comorbidities, and cognitive status. To increase participation in AD/ADRD clinical trials, NIA developed a public facing tool, OutreachPro. OutreachPro is an online recruitment materials generator that enables grantees to develop customizable and culturally appropriate materials in multiple languages to raise awareness of, and interest in, AD/ADRD clinical trials. Grantees and research teams are encouraged but not required to use this free online resource to enhance their recruitment and retention plans and related activities for their NIA-funded clinical studies.

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. 

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

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal 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 eligible to apply.

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the 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 the 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 and Notice of NIH's Interest in Diversity, NOT-OD-20-031.

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 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 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:

Lorenzo M. Refolo, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-594-7576
Email: [email protected]

Page Limitations

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

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.

R&R or Modular 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:

Specific Aims: The Specific Aims section should include aims delineated either for the Early or Late Stages of the project. For proposed Phase I clinical trials, define the aims of the study (e.g., safety, tolerability, PK/PD, target engagement and target modulation, dose-range).

Research Strategy:

Note: Applicants proposing human subjects and/or clinical 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.

The Research Strategy section must include the following six sections. The sub-bullets provide details regarding what should be addressed in each section.  

1. Clinical Impact (Significance):
   • Applicants should include a brief statement of the therapeutic hypothesis that includes: the projected patient reduction of symptoms, slowing disease progression, side effects, dose administration and regimen, and sustainability of effect.
   • Provide a Target Product Profile (TPP) in a table based on an FDA template that summarizes the minimal/ideal profile of the final marketed product and shows the ultimate goals of the proposed drug development effort, such as disease indication, patient population, delivery mode, treatment duration, treatment regimen, and standards for clinical efficacy.
   • Applicants requesting funding for a clinical trial should include a clinical protocol and management plan.
   • Indicate the target clinical population and specific stage of disease in which the treatment would be most efficacious.
   • Describe possible clinical trial endpoints. Indicate if biomarkers are available in animal models and humans to detect if the drug engages the target.
   • Describe the group clinical expertise used to determine the goals of the drug development program and the clinical trial.
   • Discuss how the proposed project relates to therapeutic development efforts underway in academia and industry.
      
2. Biological Rationale and Profile of the Drug Candidate (Significance):
   • Applicants should summarize the evidence that validates the drug target from cellular or animal models and clinical studies, provide a brief summary of the rationale for the selection of the target, the level of agreement in the field regarding the target's role in disease pathogenesis and clinical relevance of the target, including the optimal disease stage (e.g., asymptomatic, MCI, mild, moderate, or severe AD) to pharmacologically engage the target.
   • Provide the evidence that altering target activity as proposed will give desirable outcomes for the proposed stage of AD.
   • Applicants should discuss the disease-relevance of in vitro or in vivo models that are proposed or that have been used and whether the endpoints measured, and levels of activity observed are likely to be clinically relevant.
   • Applicants should discuss plans to incorporate any translatable, clinically relevant biomarkers into their preclinical development program.
   • Applicants should discuss how target engagement and/or pharmacodynamic markers will be used to detect activity at the putative target in preclinical models and in patients, if available or proposed for development.
   • All studies using animal models presented to justify the choice of therapeutic target, drug candidate or, to measure efficacy must be in compliance with NIH guidance on rigor and reproducibility. In particular, investigators proposing animal model studies are expected to follow the general ARRIVE guidelines for rigorous animal research and the best practices guidelines for AD preclinical efficacy studies.These studies should include a power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were balanced for sex and were replicated.
   • Provide a Drug Candidate Profile Table that summarizes the drug-like properties, pharmacological and ADMET activities of the drug candidate proposed for optimization or as the development candidate. Note any potential liabilities.
   • For Early Stage projects, show that the drug candidate proposed as the starting point for optimization alters the activity of the putative target as intended and/or produces desired outcomes in disease models, with sufficient detail to allow reviewers to evaluate the rigor of the experimental design. Explain the choice of models, assays, and endpoints for these studies.
   • For Late Stage projects, show that the proposed development candidate has clinically relevant in vivo activity, when delivered by the clinically intended route of administration, at exposure levels that can likely be achieved clinically with the proposed human dosing regimen.
   • For Late Stage projects, show the data that demonstrate the relationship between drug candidate exposure and activity and explain how these data support the clinical dosing regimen proposed in the TPP.
      
3. Testing Strategy (Approach):
   • Specify whether the project is proposed for entry at the Early or Late Stage.
   • For small molecule projects, present evidence that the drug candidate(s) meet the stage specific entry criteria outlined in Section I. Notice of Funding Opportunity Description of this NOFO for the proposed project stage (Early or Late).
   • For biologics projects, present evidence that the drug candidate(s) meet the stage specific entry criteria outlined in Section I. Notice of Funding Opportunity Description of this NOFO for the proposed project stage (Early or Late).
   • Explain the rationale for the choice of assays, assay design, and advancement criteria, and clarify how these relate to the desired drug properties presented in the TPP.
   • Show assay validation data or present plans to optimize and validate assays.
   • Include a figure showing the Testing Funnel that shows how proposed assays will be ordered and grouped into testing tiers.
   • Include a table of proposed activities that provides the following information: activity (e.g., medicinal chemistry, optimization of biologic candidate, assays, PK, etc.), throughput for testing chemical analogs or biologic derivatives, and advancement criteria through the testing funnel.
   • Clearly indicate which activities will be conducted by the PD/PI and associated personnel and which activities will be conducted by contractors. Include experimental designs and justification for all studies that will be conducted by the PD/PI and associated personnel. Activities that will be conducted by CROs should be specifically described in terms that will include expected deliverables. Use of foreign CROs must be justified.
   • Include a Gantt chart that lays out each step in the critical path of the project (e.g., optimization of drug-like properties, optimization of bioactivity, pharmacology profiling, toxicology profiling, efficacy in animal models, GMP synthesis, formulations development, and IND-enabling studies, Phase I clinical trial).
      
4. Milestones:
   • Because drug discovery and development are inherently high risk, it is expected that there may be significant attrition as projects progress. Therefore, the application must include a Table of go/no-go milestones with quantitative success criteria for each year of funding.
      
5. Innovation
   • If the drug candidate targets the same molecule, pathway, or cellular process that has previously been tested in clinical trials for AD, explain why the proposed approach would be expected to provide a benefit over previously tested approaches.
   • If similar drugs have been tested in clinical trials for AD, explain why the proposed drug candidate would be expected to give significantly better clinical outcomes.
   • If the drug candidate is an improvement over an earlier generation of drug(s) that has not been marketed, discuss the advantages of the proposed new drug candidate over those previously tested. Include results from previous clinical trials with related agents.
   • Comment on the novelty of proposed approach, target, pathway, assays, or models.
      
6. 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 must indicate filing dates, the type of patent, and application status.
   • For a multiple-PD/PI, multiple-institution application, applicants must 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 must clarify how IP will be shared or otherwise managed if there are multiple PDs/PIs and institutions involved.

Information Regarding Clinical Trials

• Applicants are strongly advised to discuss plans with NIH program staff prior to submitting their application to determine whether a clinical trial is feasible within the proposed funding timeframe.
• Applicants must submit supporting trial and regulatory documents to NIH for administrative review prior to the commencement of the trial.

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 patent protection is being sought, investigators should explain how data will be shared after filing for patent protection to allow for both further research and the development of commercial products to advance forward, consistent with achieving the goals of the program.

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 “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.

Section 2 - Study Population Characteristics

2.2 Eligibility Criteria 

The Human Subjects and Clinical Trials Information form includes the following attachments in Section 2: Study Population Characteristics: Inclusion of Individuals Across the Lifespan and Inclusion of Women and Minorities. Without duplicating information in those attachments of the Human Subjects and Clinical Trials Information form, applications in response to this funding opportunity must provide further rationale supporting eligibility criteria and study population characteristics (see section 2.5  Recruitment and Retention Plan). 

2.5 Recruitment and Retention Plan 

The Human Subjects and Clinical Trials Information form includes the following attachments in Section 2: Study Population Characteristics: Inclusion of Individuals Across the Lifespan and Inclusion of Women and Minorities. Without duplicating information in those attachments of the Human Subjects and Clinical Trials Information form, applications in response to this funding opportunity should propose innovative and proactive recruitment strategies including, as applicable and justified by the scientific goals, strategies to involve understudied populations as research study participants. Applicants should ensure that they address the populations outlined in the NIH-designated Populations with Health Disparities as well as other populations that experience health disparities as appropriate and relevant to the proposed research and scientific goals. Recruitment and retention plans should demonstrate an understanding of the participant burden involved in research participation and strategies for minimizing this burden, as well as leveraging community partners and outreach efforts. The recruitment and retention plan must:

• Describe potential barriers to participation and plans to minimize these barriers.
• Describe a plan to leverage existing relationships with and/or conduct outreach to a broad range of community groups.
• Describe staff training to address cultural and linguistic competence.

In addition, without duplicating information in the Inclusion of Individuals Across the Lifespan and Inclusion of Women and Minorities attachments of the Human Subjects and Clinical Trials Information form, applications in response to this funding opportunity must provide further rationale supporting eligibility criteria and study population characteristics that are 1) representative of the population affected by the disease/condition, and 2) address the populations outlined in the NIH-designated Populations with Health Disparities as well as other populations that experience health disparities as appropriate and relevant to the proposed research and scientific goals.

Where applicable, study teams should also demonstrate that they have critically evaluated whether eligibility criteria from an earlier phase trial should be carried forward into a later phase trial. Further rationale supporting eligibility criteria and study population must:

• Describe how the study results generalize to the wider patient population with this disease/condition.
• Explain how the rationale for selected eligibility criteria justifies the level of restriction in the study compared to clinical practice.
• Provide evidence that the eligibility criteria support the proposed research and encourage inclusion of NIH-designated Populations with Health Disparities.

Section 4 - Protocol Synopsis

4.1. Study Design

4.1a. Detailed Description

Include determination of dose levels.

4.1c. Interventions

For "Intervention Description", include route of administration.

4.2. Outcome Measures

At least one outcome measure should include PK assessments, with attention to demonstration of CNS penetration (if appropriate) and target engagement or modulation.

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.

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.

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 [email protected].

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.

For this particular NOFO, note the following:

• Projects should not be penalized if the mechanism of action of the compound is unknown. While this may add to the risk, the increased risk may be counterbalanced by increased novelty.
• Evaluation of the approach should focus on the biological rationale, the rigor and transparency of supporting preclinical data, the potential for identifying a compound/biologic with drug-like properties, potential patient benefit, competitive landscape (novelty), and strengths/weaknesses of studies to be conducted by the PD/PI.
• Work to be conducted by CROs, specifically expected deliverables for each type of CRO, is subject to review.
• Applications that propose entry at the Late Stage, but that reviewers consider better suited for the Early Stage or vice versa should nevertheless be evaluated and scored based on the entry criteria and expectations for the proposed entry stage. Reviewers can note in their comments that the project may be more appropriate for entry at a different stage.
• All studies using animal models presented to justify the choice of therapeutic target or drug candidate must be in compliance with NIH guidance on rigor and reproducibility. In particular, investigators proposing animal model studies are expected to follow the general ARRIVE guidelines for rigorous animal research and the best practices guidelines for AD preclinical efficacy studies. These studies should include a power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were balanced for sex and were replicated.

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 scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. 

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

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 National Institute on Aging (NIA), 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.

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. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

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 #147;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. 

Successful recipients under this NOFO agree that:

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by any funded entity, recipients and subrecipient(s) are required to: Use health IT that meets standards and implementation specifications adopted in 45 CFR part 170, Subpart B, if such standards and implementation specifications can support the activity.  Visit https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-D/part-170/subpart-B to learn more.

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by eligible clinicians in ambulatory settings, or hospitals, eligible under Sections 4101, 4102, and 4201 of the HITECH Act, use health IT certified under the ONC Health IT Certification Program if certified technology can support the activity. Visit https://www.healthit.gov/topic/certification-ehrs/certification-health-it to learn more.

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

1. ongoing and consistent access to HHS owned or operated information or operational technology systems; and 
2. receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information. 

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:

• Determining experimental approaches, designing protocols, conducting experiments, and analyzing and interpreting research data for studies funded through this NOFO. The PD/PI is ultimately responsible for the project and will make the final decisions regarding all project plans, provided that they can be executed within NIH-approved budgets and according to NIA/NIH grant and contract policies.
• Collaborating with NIA Program Staff in establishing a Go/No-Go milestone plan (typically a minimum of one milestone per funding year) at the start of the project and updated as needed.
• Submitting mid-year and annual milestone progress reports in a standard format for evaluation by NIA Program Staff.
• Adhering to NIA/NIH policies, including those regarding data release, intellectual property, and publications.
• Implementing all scientific and policy decisions approved by the NIA/NIH.
• Working closely with the PDs/PIs' institution's technology transfer officials to ensure that royalty agreements, patent filings, and all other necessary intellectual property arrangements are completed in a timely manner.
•  Submitting an IND with documentation for one of the following: 1) acceptance of clinical protocol by FDA; 2) elapse of the 30-day post filing waiting period without comment from the FDA; 3) completion of protocol changes or amendments requested by FDA.
• Submitting a data and safety monitoring plan (DSMP) in accordance with the NIA policies to NIA for review and notification of NIA approval.
• Registering Phase I trial on clinical trials.gov.

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:

• An NIA Program Officer will be assigned to the project and will be responsible for the normal scientific and programmatic stewardship of the award. The NIA Program Officer will be named in the award notice and will be the primary contact with the PI/PD. The Program Officer will be responsible for assessing the progress of the project towards accomplishment of milestones, and for recommending the level of continued funding.
• An NIA Project Scientist will be assigned to the project with substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice and coordination that is above and beyond the normal stewardship role in awards. The NIA Project Scientist will provide additional expertise that is needed for proper scientific management of the award. This includes assisting the PI/PD in the development of a project milestone plan at the outset of the project, approving the final milestone language for incorporation into the award notice, enhancing the project's progress by providing access to various NIH resources, when appropriate, providing technical assistance, advice, and coordination to the project, although the dominant role and responsibilities for the activities funded by this NOFO reside with the PI/PD.
• PLEASE NOTE: If a funded project does not make sufficient progress toward the agreed upon milestones at any stage, funding for the project may be discontinued.

Areas of Joint Responsibility include:

• None; all responsibilities are divided between recipients and NIH staff as described above.

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.

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 patent protection is being sought, investigators should explain how data will be shared after filing for patent protection to allow for both further research and the development of commercial products to advance forward, consistent with achieving the goals of the program.

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: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Lorenzo M. Refolo, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-594-7576
Email: [email protected]

Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-402-7700
Email: [email protected]

Jeni Smits
National Institute on Aging (NIA)
Telephone: 301-496-1472
Email: [email protected]

Section VIII. Other Information

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

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