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

Background

Alzheimer’s disease (AD) and AD-related dementias (ADRD) are complex brain disorders that affect millions of Americans and are among the greatest healthcare challenges of the 21^st century. NIA , as the primary federal agency for AD research, supports research spanning from basic understanding of disease pathology to clinical intervention, to public health outcomes. Despite the discovery of many candidate biomarkers for AD/ADRD, few of them progress to validation, and their clinical and scientific utility remain indeterminate. A particularly pressing issue is the co-occurrence of AD and ADRD pathologies, since autopsies show that neuropathological comorbidities are common in the brains of people who lived with dementia. Studies are needed to characterize longitudinal trajectories of biomarkers during the course of disease or treatments. The performance of given biomarkers/biomarker signatures in populations that have been understudied/underrepresented in research and their generalizability to heterogenous real world communities are also crucial.

A biomarker is defined as any measurable characteristic that can serve as an indicator of normal or pathogenic biological processes, or responses to exposures or interventions. Biomarkers are used in basic, translational, and clinical research, and in clinical settings to inform patient care (i.e., disease-related biomarkers) and/or facilitate medical product development decisions (i.e., product-related biomarkers). Types of biomarkers are molecular, -omics, histologic, radiographic, or physiologic and behavioral characteristics. Biomarkers can be collected from body fluid chemistry, imaging, behavioral and/or digital phenotyping, and physiologic endpoints. The Biomarkers, EndpointS, and other Tools ( BEST) resource developed by the FDA-NIH Joint Biomarkers Working Group, provides a glossary of terms to be used in translational science and medical product development, with a focus on study endpoints and biomarkers. According to BEST, biomarkers are defined by their specific Context of Use (COU) . The COU is the specific manner and purpose of use for a biomarker and includes two components: (1) the BEST biomarker category (diagnostic, prognostic, predictive, pharmacodynamic/response, monitoring, safety, or susceptibility/risk) and (2) the biomarker’s intended use. The Biomarker Qualification Program (BQP) is the FDA's process that establishes the evidentiary framework for use of a biomarker in a medical product development program, and provides guidance for rigorous analytical and clinical validation, and, ultimately, determination of the clinical utility of a biomarker or biomarker signatures.

Purpose

This NOFO invites applications to accelerate the establishment of effective and reliable biomarkers of AD/ADRD for use in therapy/medical product discovery and development, clinical trials, and/or clinical practice. Specifically, this NOFO will support analytical and/or clinical validation of a biomarker, composite biomarker, or biomarker signature, with rigor comparable to the expectations described in the FDA's BQP or recommended by other FDA regulatory pathways.

This NOFO utilizes the U01 Research Project Cooperative Agreements activity code. This milestone-driven funding mechanism enables significant input from NIH staff in assisting investigators with preparing and evaluating their validation strategy. As part of the agreement, NIA will discuss with the Principal Investigator(s) any recommended changes to the research plan or suggestions from peer reviewers, and the plan will be revised, as appropriate, prior to the award.

Research Objectives

This NOFO seeks to address a critical gap in AD/ADRD biomarkers development pipelines by enabling rigorous validation of already discovered candidate biomarkers or biomarker signatures. This NOFO encourages analytical and/or clinical validation within a specified COU in clinical research, practice, or intervention trials, with criteria for rigor and clinical utility that are comparable with the expectations described in the BQP or those recommended by other FDA regulatory pathways. Projects must focus on validation of a candidate biomarker, biomarker signature, or biomarker composite to be used in translational and clinical research in AD/ADRD, to inform disease pathophysiology and/or facilitate medical product development decisions, or in clinical settings, to inform diagnosis, prognosis, patient care, treatment, or prevention, including in understudied and/or heterogenous populations. All types of fluid and imaging biomarkers (including markers measured with digital technology), individually or in combination, as well as biomarkers that can be used to strengthen or complement the Amyloid-Tau-Neurodegeneration (A-T-N) framework may be included. Proposed research may encompass biomarkers for AD, ADRD, as well as mixed AD pathologies, including, but not limited to AD/Lewy body dementia (LBD), AD/frontotemporal disorders (FTD), AD/limbic-predominant age-related TDP-43 encephalopathy (LATE), and AD/vascular etiologies.

Research topics suitable for this NOFO include, but are not limited to, the following:

• Determine the predictive biomarker, and its suitability for use, to enrich enrollment of a subgroup of AD/ADRD patients who are more likely to respond to a novel therapeutic in Phase 2/3 clinical trials
• Investigate the longitudinal trajectory of a biomarker to determine its clinical value for predicting conversion from clinically unimpaired to mild cognitive impairment to AD/ADRD, as well as responses to treatment/prevention during the timeframe of a clinical trial
• Establish reliable safety biomarkers for the detection of adverse effects on exposure/intervention
• Validate reliable prognostic biomarkers for the determination of risk, and/or monitoring biomarkers for response to intervention, in heterogenous populations
• Evaluate the diagnostic biomarkers for differentiating AD/ADRDs (e.g., LBD, FTD, LATE)

Proposed projects may be for analytical validation, clinical validation, or both, depending on the current stage of development of the specific biomarker, biomarker signature, or composite

Functions and Activities

The research strategy must clearly describe how the investigators will utilize rigorous design, execution, and analysis of the data for the purpose of validation. For Analytical Validation, the status of the existing detection methods must be stated and the plan for optimization in clinical laboratories or point of care settings should be described. Criteria for validation should be clearly described; specific metrics should be identified as appropriate for the biomarker category, modality and, COU. In general, Analytical Validation may include, but is not limited to, assessment of the following:

1. Accuracy
2. Precision
3. Analytical sensitivity
4. Analytical specificity, including interfering substances or signals
5. Reportable range of test results for the test system
6. Reference intervals (normal values) with controls and calibrators
7. Establishment of appropriate quality control and improvement procedures
8. Any other performance characteristics necessary for establishing calibration and control procedures of the method, detecting device and/or technology.

Clinical validation should definitively test the ability of the biomarker to identify, measure, or predict a meaningful clinical, biological, physical, or functional state. The outcome(s) used to validate the biomarker/biomarker signature must be clearly stated and justified acceptably and safely. The clinical utility of the biomarker and risk/benefits to the patient should be discussed. Specific metrics for clinical validation should be identified as appropriate for the biomarker category, modality, and COU. Examples of metrics that could be used for clinical validation include, but are not limited to, the following

1. Sensitivity and specificity of the biomarker within the COU, including methods for binary and/or continuous analysis
2. Area Under the Curve (AUC) as determined by Receiver Operator Characteristic (ROC) Analysis
3. Estimation of the prevalence of the marker within subjects or patients for the intended clinical context.
4. Establishing the appropriate cut-off or threshold for the biomarker for decision-making within the COU
5. Positive Predictive Value
6. Negative Predictive Value
7. Any other performance characteristics necessary to definitively establish that the biomarker identifies, measures, or predicts a meaningful clinical, biological, physical, or functional state, efficiently and safely

Resources for Applicants

Applicants may leverage existing NIA research resources and supported initiatives , as appropriate for their studies. Such resources may include available data and/or samples from clinical trials, and other existing bio-specimen. The following is a list of relevant NIA resources.

• Alzheimer's Disease Neuroimaging Initiative (ADNI)
• Alzheimer's Clinical Trials Consortium (ACTC)
• NIA-funded Alzheimer's Disease Research Centers (ADRC)
• National Alzheimer's Coordinating Center (NACC)
• National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)
• Alzheimer’s Biomarkers Consortium-Down Syndrome (ABC-DS)
• Accelerating Medicines Partnership Alzheimer’s Disease Target Discovery and Preclinical Validation (AMP-AD)
• The Dominantly Inherited Alzheimer Network (DIAN)
• The Longitudinal Early-onset Alzheimer’s Disease Study (LEADS)
• Health and Aging Brain study Health Disparities (HABS-HD)

Clinical Research Operations Management System

NIA utilizes 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 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.

Non-Responsiveness Criteria

The following research activities will be considered non-responsive to this NOFO, and such applications will be administratively withdrawn prior to scientific peer review:

• Applications that propose studies of basic mechanisms of disease or medical product action
• Applications that propose the discovery/ or early development of novel biomarkers
• Applications that propose non-human research studies
• Applications that propose studies focused on behavioral biomarkers

Investigators seeking support for studies described as above, may consider other funding opportunities such as the following:

• PAR-22-094 Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21)
• PAR-22-093 Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01)
• PAR-22-089 Development of Biomarkers or Biomarker Signatures for Neurological and Neuromuscular Disorders (R61/R33)

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 Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are 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 SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov 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 SF424 (R&R) Application Guide.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

Letter of Intent

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

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

• Title and specific aims 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:

Yuan Luo, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: [email protected]

Page Limitations

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

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R or Modular Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific aims

The application must include specific aims summarizing the proposed project. Proposed projects may be for analytical validation, clinical validation, or both, depending on the current stage of development of the specific biomarker, biomarker signature, or composite, and must meet the following criteria:

• The project must focus on a biomarker for AD, ADRD, or both
• The intended COU and targeted population must be identified
• For clinical validation, the candidate biomarker(s) must have already been analytically validated. Evidence supporting analytical validation should be provided, and consistent with FDA standards

The applicants must clearly describe:

• The candidate biomarker, modality, and method of detection
• The COUs of the biomarker(s), study population(s) targeted level of analytical and/or clinical validation, and the objectives of the proposed studies
• Significance and anticipated impact of the use of the candidate biomarker in AD/ADRD clinical research or practice.

Research strategy

The research strategy must clearly describe how the investigators will utilize rigorous design, execution, and analysis of the data for the purpose of validation.

For analytical validation, the status of the existing detection methods must be stated and the plan for optimization in clinical laboratories or point of care settings should be described. Criteria for validation should be clearly described; specific metrics should be identified as appropriate for the biomarker category, modality, and COU.

Clinical validation should definitively test the ability of the biomarker to identify, measure, or predict a meaningful clinical, biological, physical, or functional state. The outcome(s) used to validate the biomarker/biomarker signature must be clearly stated and justified acceptably and safely. The clinical utility of the biomarker and risk/benefits to the patient should be addressed. Specific metrics for clinical validation should be identified as appropriate for the biomarker category, modality, and COU.

The applicants must clearly describe:

• The scientific rationale for the candidate biomarker and the unmet need
• The biomarker methods for detection, pre-analytic procedures, key reagents and technology, reference standards/datasets used for validation and/or standardization
• The proposed COU for the biomarker and targeted clinical population, including any relevant demographic variables such as race, gender, age etc.
• For Clinical Validation entry point, the evidence that the candidate biomarker and detection method(s) have been analytically validated consistently with FDA standards, including the selection of controls, consideration of pre-analytic variables, quality control and standardization.
• Any existing evidence that the biomarker has undergone initial testing for the intended COU
• Power analysis/justifications for sample sizes, analytical approaches to determine analytical and/or clinical sensitivity and specificity, metrics and methods to determine clinical performance, variables used in the statistical analysis, and assumptions used in statistical models.
• The plan to recruit the patient population of interest and/or obtain appropriately standardized samples/data
• The sites for validation and their justification, including plans for harmonization of protocols and data.
• Threats to internal and external validity of the data, plans for mitigation, and generalizability of the biomarker(s).
• Alternative plan(s) if the proposed method/technology fail to provide expected or satisfactory results

The biomarker or biomarker signature must be described using the BEST glossary. Biomarker categories include

• Monitoring biomarkers to track the success of a therapeutic intervention or disease progression
• Diagnostic biomarkers for detecting clinical manifestation of disease
• Prognostic biomarkers for predicting outcomes
• Predictive biomarkers for determining responders and non-responders to a therapeutic intervention
• Pharmacodynamic/response biomarkers for demonstrating therapeutic target engagement
• Safety biomarkers to indicate the likelihood, presence, or extent of an adverse effect, and susceptibility/risk biomarkers that indicate the potential for developing a disease or medical condition in an individual who does not currently have a clinically apparent disease.

The COU must be identified, and applications must include a statement with the heading "Context of Use" that fully and clearly describes the specific manner and purpose for use of the biomarker. The COU is critical for determining the experimental design and level of analytical and clinical validation required.

Preliminary data is required by illustrating the detection method and that the biomarker reflects the intended pathophysiology and/or clinical endpoint appropriate for the COU.

For clinical validation, evidence of rigorous validation of the biomarker must be provided and COU in human studies or clinical use must be specified. Metrics should be determined to establish the Sensitivity and Specificity of the biomarker within the defined COU(s) and population of interest, including heterogenous and/or understudied populations, as appropriate, as well as appropriate cut-offs or thresholds and predictive values.

While the activities supported through this NOFO are independent of the regulatory approval of the biomarker/biomarker composite, criteria for rigorous analytical and clinical validation should be comparable to those expected by the FDA. Though not required, applicants are encouraged to create a path toward approval from the FDA, such as the Biomarker Qualification Program or other regulatory pathways.

Timeline and Proposed Milestones

Applications must provide milestones and timelines under a separate, specific heading at the end of the Research Strategy Section. Milestones must describe project decision points with quantitative metrics for go/no-go decision-making throughout the funding period.

The milestones will serve as a basis for go/no-go decision-making between NIA program staff and the project research team. 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. A timeline for the anticipated attainment of each milestone must be included.

Quantitative milestones should include items such as:

• Progress metrics (i.e., enrollment goals, sample and data collection goals, key experiments conducted)
• Performance metrics (i.e., data quality, positive predictive value and negative predictive value, demonstration of standardization across sites)
• Qualification metrics (letter of intent submission for FDA qualification and/or consultations)
• Discuss potential pitfalls and provide alternative plans

Letter of Support

• Applicants should include letters of support from consultants, subcontractors, and collaborators.
• If applying from an academic institution, include a letter of support from the technology transfer official who will be managing intellectual property associated with this project.
• If collaborating with a private entity, include a letter of support that addresses any agreement to provide agent(s).

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

Other Plan(s): Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

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

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

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

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

• Guidance documents provided by the FDA regarding qualification of the proposed biomarker(s)
• Standardized protocols for measuring the biomarkers proposed

PHS Human Subjects and Clinical Trials Information

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

PHS Assignment Request Form

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

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

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

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

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

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

Important reminders:

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

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by National Institute on Aging, 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 [email protected] when the application has been submitted. Please include the NOFO number and title, PD/PI name, and title of the application.

Requests of $500,000 or more for direct costs in any year

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

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 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.

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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

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

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

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

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

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

• Federal-wide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

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

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a term and condition of receiving the grant, to administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

• For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.
• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and to provide effective communication, see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html.
• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.
• For guidance on administering programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

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

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

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 45 CFR Part 75 and 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 U01. 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/U01 grant and contract policies.
• Collaborating with NIA Program Staff assisting in the development of a project milestone plan at the outset of the project.
• Submitting periodic milestone progress reports in a standard format.
• 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
• Providing protocol, supporting clinical documents and regulatory documents required for administrative review prior to clinical trial.
• Providing milestones and timelines. Milestones must describe project decision points with quantitative metrics for go/no-go decision making throughout the funding period

All data or materials generated under this U01 award and through efforts of the PD/PI will be owned by the respective recipient and the data will be considered to be confidential and business privileged information of the recipient , which nevertheless does not affect its obligations to share or deliver the material or data with the government as set forth elsewhere in the grant agreement or regulations.

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 Science Officer 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 the U01 reside with the PI/PD.

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.

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.

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

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

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

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

In accordance with the regulatory requirements provided at 45 CFR 75.113 and 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 and 2 CFR Part 200 Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

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

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

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

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

Yuan Luo, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: [email protected]

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

Philip Smith
National Institute on Aging (NIA)
Telephone: 301-402-3465
Email: [email protected]

Section VIII. Other Information

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

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