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.

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background

The biggest risk factor for Alzheimer's disease (AD) is age. AD is the most common cause of dementia in those aged 65 and older. As populations age worldwide, this disorder, as well as AD-related dementias (ADRD), will reach epidemic proportions even in best-case scenarios, with an enormous human and economic burden. Dementia is one of the most persistent and devastating neurodegenerative diseases because it eventually leads to widespread brain and neuropsychological dysfunction, and the loss of the ability to interact with others and to function independently. It is estimated that over 6 million Americans aged 65 and older are living with AD today. This number could grow to 12.7 million by 2050. From an economic perspective, estimates suggest AD/ADRD cost society over $355 billion in 2021. These human and economic costs are untenable, and it is critical to accelerate the development of interventions to prevent, slow, or cure AD.

Recent biomedical advances inspire optimism for the path ahead. In 2022, the Food and Drug Administration (FDA) approved the disease modifying anti-amyloid agent, Aduhelm, for the treatment of AD via the accelerated approval pathway. Subsequently, and also via the accelerated approval pathway, the FDA approved the disease modifying anti-amyloid agent, Leqembi, in early 2023. Leqembi is the first medicine to demonstrate a modest yet significant slowing of cognitive decline. Together, these medications represent important advancements in the ongoing fight to effectively treat AD. Nevertheless, additional efforts remain necessary to tackle the devastating effects of AD/ADRD.

On January 4, 2011, President Obama signed into law the National Alzheimer's Project Act (NAPA) that established a national plan to address the looming public health crisis. The first goal of the plan is to prevent and effectively treat AD/ADRD by 2025. As part of the strategic planning process for the implementation of the plan's goals, NIA organized and hosted four AD Research Summits in 2012, 2015, 2018, and 2021. The gaps and opportunities identified during the summits formed the basis for the AD/ADRD research implementation milestones which outline a research framework detailing specific steps and success criteria towards achieving the goals of the plan.

To meet the congressionally mandated goal of preventing and treating AD/ADRD, it is critical that we have efficient mechanisms to fund clinical trials pursuing a myriad of therapeutic targets and approaches to prevent, delay, and treat AD/ADRD. This NOFO directly addresses a gap noted in the 2021 NIH AD Summit and the corresponding new AD/ADRD Milestone 4.Y by accelerating the early clinical development of novel (non-amyloid/non-tau) candidate therapeutic agents (small molecules/biologics).

Purpose

The purpose of this NOFO is to invite applications that bundle independent protocols for phase 1 clinical trials with phase 1b/phase 2a clinical trials to streamline the early-stage evaluation of promising pharmacological interventions for AD/ADRD. Candidate interventions evaluated through this program, which can include small molecules or biologics for example, must engage non-amyloid/non-tau mechanisms and aim to address cognitive and/or neuropsychiatric symptoms in individuals across the spectrum, from pre-symptomatic to more severe stages of disease.

Research Objectives

This NOFO supports the evaluation of promising novel pharmacological interventions for AD/ADRD by facilitating the timely, successive progression of candidates from phase 1 clinical trials to phase 1b/2a trials based on prespecified, go/no-go safety and tolerability criteria. Candidates, including small molecules and biologics evaluated through this program, must engage non-amyloid/non-tau mechanisms and aim to address cognitive and/or neuropsychiatric symptoms in individuals across the spectrum from pre-symptomatic to more severe stages of disease. The UG3 mechanism will be used to plan and execute phase 1 studies. The UH3 mechanism can support additional Phase 1-level studies but is primarily intended to support the execution of the phase 2a clinical trial. Transition to the UH3 will depend on successfully reaching agreed-upon milestones and go/no-go criteria.

This NOFO invites clinical trial applications that propose activities including, but not limited to, the following focus areas:

• Evaluation of safety and pharmacokinetics of novel therapeutics in healthy volunteers or the target population, as appropriate
• Projects directed at a phase I trial that will be able to reference prior Good Laboratory Practice (GLP) toxicology studies (e.g., repeat dose toxicology in rodent and large animal, genotoxicology, human Ether- -go-go-Related Gene (hERG) and safety pharmacology)
• Good manufacturing practice (GMP) of drug substance/product needed for the proposed clinical trials
• Preparation of protocols, and acquisition of regulatory approvals
• Food effect studies
• Evaluation and optimization of dose, formulation, safety, tolerability, or pharmacokinetics of an intervention to enable FDA required (cite guidance or provide documentation from FDA with their specific request) activities for start of phase 2a in healthy volunteers, or the target population
• Aims focused on the acquisition and analysis of biomarkers
• Evaluation of whether an intervention produces sufficient evidence of short-term activity (e.g., biomarker activity, target engagement, dose-response trends, pharmacodynamic response) in a human proof of concept trial

Examples of interventions for evaluation that are appropriate for this NOFO include, but are not limited to, the following:

• Pharmacological interventions, including small molecules and biologics that target eradication or progression of disease
• Pharmacological interventions, including small molecules and biologics that target disease symptomatology including neuropsychiatric symptoms
• Repurposed drugs that have promise for AD/ADRD treatment, such as chemotherapeutic agents or drugs for insulin dysregulation/diabetes

In addition, applicants are encouraged to promote diversity in the biomedical research workforce. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogenous teams. Scientists from diverse backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. There are many benefits that flow from a diverse NIH-supported scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved or health disparity populations participate in, and benefit from health research, and enhancing public trust. Please see NIH NOT-OD-20-031 for details.

This NOFO supports phase 1, phase 1a, phase 1b, food effect studies, and phase 2a clinical trials. Applications should aim to generate data that informs further clinical development of the proposed intervention. The earliest studies should be designed to provide important initial information regarding the intervention (e.g., safety, tolerability, dosing). Phase 1 studies may include randomization and blinding and must yield data that allows for a clear go/no-go decision (typically based on safety/tolerability data) regarding whether the intervention should proceed to latter stages of evaluation. Participants within trial cohorts must be heterogeneous. Timely access to trial data and associated biosamples to the broader research community is required.

This NOFO is not intended to support the conduct of a clinical trial where the primary aim is to establish or confirm definitive efficacy; although, where appropriate, exploratory studies of preliminary efficacy can be a secondary aim. Applications to implement definitive efficacy trials (e.g., Phase 3 trials of drugs/biologics or pivotal trials) will be considered nonresponsive to this NOFO. Such applications may be more appropriate for PAR-23-081.

Applicants are strongly encouraged to consult with NIA Program staff as plans for an application are being developed (see Section VII, Agency Contacts) no later than 12 weeks prior to the anticipated application submission date. This early contact will provide an opportunity to clarify NIA policies and guidelines, as well as to discuss how to develop an appropriate project timeline and milestone plan, which is subject to peer review. NIA Program staff are also available to discuss strategies for recruitment and inclusion, including the recruitment and inclusion of women and minorities.

UG3/UH3 Exploratory/Developmental Phased Award

This NOFO uses the UG3/UH3 phased award activity code. The UG3/UH3 application must be submitted as a single application at the time of the initial application. Applications must include prespecified, go/no-go safety and tolerability milestones that must be met to advance from phase 1 (UG3) to latter stages of clinical development (UH3).

During the UG3 phase, researchers will plan and execute phase 1 studies. The UG3 phase will permit both scientific and operational planning activities.

During the UH3 phase, additional phase 1-level studies maybe supported, but this phase is primarily intended to support the execution of the phase 2a clinical trial. The UH3 phase of the award will support the clinical trial of the small molecules and biologics.

Transition to the UH3 will depend on successfully reaching agreed-upon milestones and go/no-go criteria. Only UG3 projects that have met scientific milestones and feasibility requirements will be approved to transition to the UH3 phase.

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 (Applications Not Responsive to this NOFO)

The following types of applications will be considered non-responsive and will be withdrawn prior to review

• Applications to implement definitive efficacy trials (e.g., Phase 3 trials of drugs/biologics or pivotal trials)
• Applications that only propose UG3 or UH3 activities

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:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Akanni Clarke, Ph.D.
Telephone: 301-496-9350
Fax: 301-496-1494
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 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:

This NOFO encourages the submission of applications for the clinical testing of novel candidate therapeutics engaging non-amyloid/non-tau mechanisms (small molecule and biologics), as well as for repurposed drugs. Candidate interventions evaluated through this program, which can include small molecules or biologics for example, must engage non-amyloid/non-tau mechanisms and aim to address cognitive and/or neuropsychiatric symptoms in individuals across the spectrum, from pre-symptomatic to more severe stages of disease. Investigators are strongly encouraged to incorporate pharmacodynamic biomarkers in the design. Investigators are also expected to collect and store blood and other biosamples for future genomic and other 'omic' analyses aimed at interrogating treatment responsiveness and examining predictors of decline and progression. Additional guidance for this section is provided below, based on the clinical trial phase.

Specific Aims
The application must describe the specific aims for each of the two phases (UG3 and UH3) on the single Specific Aims attachment. Include headers indicating the UG3 specific aims and the UH3 specific aims.

Research Strategy

UG3 Phase (Phase 1/1a Studies)
Applications for therapeutic agents against known target(s) are expected to include information on the mechanism of action for the therapeutic agent, information regarding the target's role in disease pathogenesis and clinical relevance of the target, and information on the predicted optimal disease stage (e.g. pre-symptomatic, Mild Cognitive Impairment, mild, moderate or severe AD) to engage the target from preclinical development studies. Applicants proposing a multi-target therapeutic should summarize the available information on the pathogenic pathways that the agent engages and provide a strong clinically-relevant rationale for this approach.

If the specific molecular target of the therapeutic agent is not known, applications should summarize what is known about the agent's mechanism of action and whether the agent engages a disease-relevant pathophysiological process.

The application must include prespecified, go/no-go safety and tolerability milestones that must be met to advance from phase 1 (UG3) to latter stages of clinical development (UH3). Transition to the UH3 will depend on successfully reaching agreed-upon milestones and go/no-go criteria. Only UG3 projects that have met scientific milestones and feasibility requirements will be approved to transition to the UH3 phase.

UH3 Phase (Phase 1b/2a Studies)
If available, applicants must provide evidence of safety from earlier phase clinical trials and must include further evaluation of safety in the proposed trial design. Applications containing phase 2a clinical trials must be designed as proof of mechanism/target engagement/proof of concept studies. For applications proposing phase 1b or food effects studies in the UG3 phase, applicants should also provide evidence of safety from earlier phase clinical trials and should include further evaluation of safety in the trial design.

Significance and Biological Relevance

Applications should describe the significance of the proposed Phase 1 and Phase 2 clinical trials in the context of the status of therapeutics for the disease and the costs and benefits of the proposed study intervention. The application must state how the trial will test the hypotheses proposed and how the results of the trial (positive or negative) will advance the field. The application must summarize plans for future clinical development of the intervention in the event the exploratory trial yields promising results and explain why the proposed exploratory trial is necessary to inform the design of a subsequent clinical trial for efficacy. This should include details about the clinical indication (e.g., disease stage, target population), the plan for use of biomarkers in the course of further clinical development (i.e., biomarkers for target engagement, responsiveness to treatment, and/or tracking of disease progression), and a clinical development timeline. The application must describe how the proposed intervention will likely be an improvement over existing therapies.

Preliminary Studies
The application must detail the major findings of the preclinical and clinical studies that led to the proposed exploratory trial. Applicants must ensure that the data supporting the proposed trial meets the NIH scientific rigor guidelines. If the proposed trial plans to study the intervention(s) are based on preclinical mechanism studies, the application should summarize and reference the results from these studies. Applicants must describe the rigor, robustness, and transparency of supporting data that are being used to justify the proposed trial and address any gaps identified.

Approach
The proposed research plan should include a detailed description of the proposed UG3 and UH3 activities as described above. The application must describe the rationale for the trial design, population(s) and hypotheses being tested, and control groups. Potential biases and/or challenges in the study design and protocol should be identified and addressed. The proposed study design should enable the rigorous assessment of outcomes focused on safety, tolerability, dosing, target engagement, or other appropriate measures. Participants within trial cohorts must be heterogeneous. Timely access to trial data and associated biosamples to the broader research community is required.

NIA urges investigators to follow the NIH's guidance for rigor and transparency in grant applications. This will ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include, where applicable, expressing clear rationale for the chosen primary/secondary endpoint(s), describing tools and parameters clearly, blinding, randomizing, ensuring adequate sample size, pre-specifying inclusion/exclusion criteria, appropriately handling missing data and outliers, implementing appropriate controls, preplanning analyses, and using appropriate quantitative techniques. It is also strongly recommended to indicate clearly the exploratory vs. confirmatory components of the study, consider study limitations, and plan for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications.

All trials, regardless of stage, must have clear go/no-go criteria for proceeding with a subsequent clinical trial(s).

Letters of Support
The application should include a page listing the names and institutions of all providers of letters of support.

If some trial costs are to be borne by sources other than NIH, include documentation of this support, signed by individuals who have the authority to make a commitment on behalf of the organization they represent, if it is available at the time of submission. This may include, for instance, an agreement by a pharmaceutical company to donate study drug and placebo.

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.

The Resource Sharing Plan must address which biosamples will be shared, where biosamples will be stored, and how approved parties will access these resources. Biosamples must be available for sharing at the time of publication of the primary results or within 9 months of database lock, whichever comes first.

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.
  • Applicants should describe the proposed methods and systems for data collection and quality control, and for ensuring data confidentiality and privacy, and the process for locking the final dataset and providing for data sharing. Applicants should also describe the plans, if any, to use non-traditional data collection approaches (e.g., digital/mobile/sensor technologies and web-based systems) and why these are appropriate.
• Sharing of clinical trial data (participant level and summary level data, raw and processed) is expected at the time of publication of the primary results or within 9 months of database lock, whichever comes first. The Data Management and Sharing Plan must address which data will be shared, where data will be stored, and how approved parties will access the data. NOT-OD-21-015 provides guidance regarding allowable costs associated with data management and sharing. The Data Management and Sharing Plan must also specify where the data will be stored. Appropriate data repositories can be publicly supported or can be hosted by the home institution. Examples of NIA-supported public repositories include the Alzheimer's Clinical Trials Consortium (ACTC) and the National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD).

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.

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.

Section 2 Study Population Characteristics

2.4 Inclusion of Women and Minorities

Applicants must include a plan to enroll women and racial and ethnic minorities. The plan must also consider translation of all the study-related documents to enroll participants from communities that do not speak English. Considerations that may contribute to successful inclusion are appropriate site selection, patient- or community-engagement for the major elements of the project, use of focus groups that include racial and ethnic minorities to address barriers to inclusion, etc.

2.7 Study Timeline

Applicants must provide detailed study performance and timeline objectives. The proposed milestones must include achievable goals for each stage of the study timeline within the UG3/UH3 project.

Proposed milestones should be clear and quantitative and need to be included for the entire UG3/UH3 proposal. Regulatory milestones (e.g., related to FDA) also may need to be included. Milestones and timelines will be refined and finalized in consultation with Program staff at the time of award.

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan

Applicants should refer to the NIA's Guidelines for Data and Safety Monitoring in Clinical Trials when developing their Data and Safety Monitoring Plan.

3.5 Overall Structure of the Study Team

Describe the composition and role of any advisory committees.

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 NIA, NIH. Applications that are incomplete, non-compliant, and/or nonresponsive will not be reviewed.

In order to expedite review, applicants are requested to notify the NIA Scientific Review 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 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 submitted in response to this FOA. 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 (DHHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award 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 the NIH as defined below.

The Principal Investigator(s) (PI/PIs) will have the primary responsibility for:

• Defining objectives and approaches, and planning, conducting, analyzing, and publishing results, interpretations, and conclusions of the studies.
• Recipients have the additional responsibility to engage in broad sharing of the data collected through the supported program. All applications for early-stage clinical trials, regardless of the amount of direct costs requested for any one year, must address a Resource Sharing Plan. Sharing of biosamples is expected at the time of publication of the primary results or within 9 months of database lock, whichever comes first. The Resource Sharing Plan must address which biosamples will be shared, where biosamples will be stored, and how approved parties will access these resources.
• Recipients agree to accept the following involvement from the NIA Project Scientist: 1. Participate in the monitoring of issues relating to recruitment, follow-up, quality assurance /quality control, and adherence to protocols; and 2. assist in the development and/or adjustment of study protocols.
• 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 has substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• The NIA Project Scientist will have substantial scientific-programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination that is above and beyond the normal program stewardship role in awards.
• The NIA Project Scientist will participate in the monitoring of issues relating to recruitment, follow-up, quality assurance /quality control, and adherence to protocols; and assist in the development and/or adjustment of study protocols.
• The NIA program official will be responsible for assessing the progress of the projects and for recommending the level of continued funding.
  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.

Sharing of clinical trial data (participant level and summary level data, raw and processed) is expected at the time of publication of the primary results or within 9 months of database lock, whichever comes first. The Data Management and Sharing Plan must address which data will be shared, where data will be stored, and how approved parties will access the data. NOT-OD-21-015 provides guidance regarding allowable costs associated with data management and sharing. The Data Management and Sharing Plan must also specify where the data will be stored. Appropriate data repositories can be publicly supported or can be hosted by the home institution. Examples of NIA-supported public repositories include the Alzheimer's Clinical Trials Consortium (ACTC) and the National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD).

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]

Akanni Clarke
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: [email protected]

Laurie Ryan
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: [email protected]

Ramesh Vemuri
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.