PAR-25-209: Analytical and Clinical Validation of Biomarkers for Alzheimer's Disease (AD) and AD-Related Dementias (ADRDs)

PAR-25-209: Analytical and Clinical Validation of Biomarkers for Alzheimer's Disease and AD-Related Dementias (U01 Clinical Trial Optional) is a grant from the National Institute on Aging (NIA) at NIH that funds research to accelerate validation of biomarkers for Alzheimer's disease and related dementias.

The program supports analytical and clinical validation of candidate biomarkers, composite biomarkers, and biomarker signatures with rigor comparable to FDA Biomarker Qualification Program standards. Projects address critical gaps including longitudinal biomarker trajectories, performance in underrepresented populations, and co-occurring neuropathological conditions. Eligible applicants include universities and research institutions.

The U01 cooperative agreement mechanism enables significant NIH staff input in shaping the validation strategy. Deadlines follow NIH standard submission cycles.

Expired PAR-25-209: Analytical and Clinical Validation of Biomarkers for Alzheimers Disease (AD) and AD-Related Dementias (ADRD) (U01 Clinical Trial Optional) This notice has expired. For NIH, in limited situations, applications may be accepted on a case-by-case basis for a short period after expiration to accommodate NIH late or continuous submission policies . Contact the eRA Service Desk for any submission issues.

Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations Funding Opportunity Title Analytical and Clinical Validation of Biomarkers for Alzheimers Disease (AD) and AD-Related Dementias (ADRD) (U01 Clinical Trial Optional) U01 Research Project – Cooperative Agreements March 31, 2025 - This funding opportunity was updated to align with agency priorities.

Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084 .

August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy.

See Notice NOT-OD-22-189 . Funding Opportunity Number (FON) Companion Funding Opportunity See Section III. 3.

Additional Information on Eligibility . Assistance Listing Number(s) Funding Opportunity Purpose This notice of funding opportunity (NOFO) invites applications to accelerate the establishment of effective and reliable biomarkers of Alzheimer’s disease (AD) and AD-related dementias (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 Food and Drug Administration (FDA's) Biomarker Qualification Program (BQP) or recommended by other FDA regulatory pathways.

Funding Opportunity Goal(s) To encourage biomedical, social, and behavioral research and research training directed toward greater understanding of the aging process and the diseases, special problems, and needs of people as they age. Open Date (Earliest Submission Date) The following table includes NIH standard due dates marked with an asterisk.

Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed 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.

Required Application Instructions 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.

Part 1. Overview Information 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 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.

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.

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 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: Analytical specificity, including interfering substances or signals Reportable range of test results for the test system Reference intervals (normal values) with controls and calibrators Establishment of appropriate quality control and improvement procedures 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 Sensitivity and specificity of the biomarker within the COU, including methods for binary and/or continuous analysis Area Under the Curve (AUC) as determined by Receiver Operator Characteristic (ROC) Analysis Estimation of the prevalence of the marker within subjects or patients for the intended clinical context.

Establishing the appropriate cut-off or threshold for the biomarker for decision-making within the COU Positive Predictive Value Negative Predictive Value 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 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 recipients 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 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) 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 Cooperative Agreement: A financial assistance mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.

2 for additional information about the substantial involvement for this NOFO. Application Types Allowed The OER Glossary and the How to Apply Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Optional: Accepting applications that either propose or do not propose clinical trial(s). Need help determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Application budgets are not limited but need to reflect the actual needs of the proposed project. For projects proposing research on both analytical and clinical validations, or clinical validation only, the maximum project period is 5 years.

For projects proposing research onanalytical validation only, the project period is limited to 4 years NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO. Section III.

Eligibility Information Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education 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 (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Recognized).

Eligible Agencies of the Federal Government U.S. Territory or Possession 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 Non-domestic (non-U.S.) Entities (Foreign Organizations) Non-domestic (non-U.S.) Entities (Foreign Organizations) 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 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.

Eligible Individuals (Program Director/Principal Investigator) Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the How to Apply-Application Guide. 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 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. All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed. Instructions for Application Submission 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.

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

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. 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.

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 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.

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.

Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement , and procedures for foreign organizations described throughout the How to Apply- Application Guide. 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