Part 1. Overview Information

Key Dates

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

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

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

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

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

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

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



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

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background

Currently, roughly 53%of American adults living with HIV are over the age of 50. By 2030, that number is projected to rise to over 70%. The portion of older adults with HIV is expected to rise primarily because of the successes of modern antiretroviral therapy (ART), which has allowed individuals infected at a younger age to survive into older age. Additionally, the prevalence of HIV infection in older age is attributable to new infections in later life, with approximately 16% of new diagnoses in Americans occurring in adults age 50 and older.

In contrast to the pre-modern era of HIV treatment, where AIDS-related opportunistic infections and cancers were common, the most frequent morbidities and causes of death for individuals undergoing treatment for HIV infection are similar to those seen in older non-infected adults. These conditions include cardiovascular disease, lung disease, infection-related and non-infection-related cancers, neurocognitive and neuropsychiatric disorders, osteopenia/osteoporosis, liver cirrhosis, and renal disease. In addition, individuals living with HIV infection may exhibit many of the clinical and socio-behavioral characteristics commonly observed in aging, such as multiple morbidities, polypharmacy, declining physical and cognitive function, alterations in body composition, social isolation, and increasing caregiver burden. People living with HIV (PLWH) also exhibit molecular changes associated with aging, such as epigenetic alterations, mitochondrial impairment, and telomere shortening. Thus, accumulating evidence suggests that HIV and/or its treatment may lead, at least in part, to an accelerated aging phenotype. In addition, recent advances have led to greater adoption of pre-and post-exposure prophylaxis, but the impact of these measures on aging is unclear.

Purpose

This NOFO invites applications at the intersection of HIV and aging by proposing research that aims to meet the following objectives:

1) Improve the understanding of biological, clinical, and socio-behavioral aspects of aging through the lens of HIV infection and its treatment; and

2) Improve approaches for testing, preventing, and treating HIV infection, and managing HIV-related comorbidities, co-infections, and complications in different populations and cultural settings by applying current aging science approaches.

Scope

Proposed research must be consistent with the HIV/AIDS Research Priorities outlined by NIH’s Office of AIDS Research (OAR) as described in NOT-OD-20-018. This NOFO encourages applications with the following characteristics:

• Clinical orientation: HIV in aging involves complex interactions among multiple physiologic systems and a variety of human-level factors such as functional status, quality of life, health behaviors, and psychosocial issues; therefore, studying individual factors in isolation may be counter-productive. This NOFO encourages animal models and in vitro studies where appropriate; however, inclusion of such approaches should be integrated with human studies or demonstrate direct relevance to clinical features of HIV/AIDS.
• Focus on aging or the aged: Applicants are strongly encouraged to enroll individuals across the range of older ages, especially individuals at the upper end of the age range (i.e., 70 years or older). Comparisons between younger and older HIV-infected populations or comparisons between older HIV-infected individuals and their age-matched non-HIV-infected counterparts are appropriate.
• Attention to geriatric outcomes: In addition to traditional important outcomes of HIV/AIDS research (e.g., viral load, survival), studies are encouraged to also include outcomes considered important in geriatric medicine and gerontology, such as physical and cognitive function, quality of life measures, and social support.
• Leveraging existing resources where possible: A variety of NIH-funded resources are available to study HIV in aging, such as longitudinal studies of HIV-infected individuals and/or their non-infected counterparts (observational or interventional), clinical networks, and research centers. Leveraging such resources through secondary analyses of available data, ancillary studies, or utilization of existing infrastructure are cost-effective approaches to testing hypotheses or generating relevant data for further studies. Please see OAR's quick reference guide on HIV and Aging Efforts Across NIH for a detailed list of relevant resources and cohort studies.
• Selection of appropriate controls: Aging individuals living with HIV have varied and complex clinical pictures. Biological and psychological co-morbidities, treatment regimens, lifestyle and behavioral factors, socioeconomic factors, and social support may all impact disease development, coping, and progression. This complexity presents a significant challenge to identifying appropriate control populations in observational studies of aging individuals with HIV. Such studies should include adequate justification for selection of the proposed control group(s).
• Characterization of phenotypes: Several biological or behavioral phenotypes of HIV in aging that have been elucidated may have markedly different disease courses, biological underpinnings, and treatment responses. Such phenotypes may be described by characteristics like frailty/disability, accelerated aging, successful aging, or other descriptors. Investigators are encouraged to maximize the homogeneity of subgroups by defining specific phenotypes in analyses.
• Exploratory/Developmental nature: New directions that expand or shift existing paradigms are needed to advance the science of HIV and aging. Studies that move the science into new directions with little or no preliminary data are appropriate for this mechanism.

Interests of Specific Institutes/Centers/Offices

Supporting multidisciplinary studies of HIV/AIDS and aging is consistent with the mission of multiple NIH Institutes, Centers, and Offices (ICOs). Below are the specific research interests of the majority of ICOs participating in this NOFO.

Applicants are strongly encouraged to contact the ICO’s Scientific/Research contact listed in Section VII. Agency Contacts of this NOFO prior to submission of an application to discuss the research interest of a specific ICO,

National Institute on Aging (NIA)

NIA is interested in understanding how biological, clinical, and socio-behavioral processes affect older individuals with HIV and their caregivers, and the social, economic, and health consequences of HIV. Example topics include the following:

• Interactions among aging-related genetic, molecular, cellular, and physiological changes with HIV risk, infection, and pathogenesis.
• Interactions among individual-level factors and interpersonal, social, and structural factors, and their contributions to the physical, psychological, and economic well-being of individuals; and interactions among HIV/AIDS, other disease, and population aging, particularly in low-income areas such as low-income areas of sub-Saharan Africa.
• Interactions among HIV infection, treatment, and development or progression of cognitive decline (HIV-associated neurocognitive decline (HAND), dementia, and other disabilities in older adults.
• Interactions of HIV infection and treatment with other aging-related diseases, conditions, and syndromes and geriatrics-informed approaches to assessment and management of older adults with HIV.

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Alcohol use disorders (AUD) are prevalent among PLWH. Consequently, PLWH and AUD are known to experience the common adverse health effects of alcohol use (organ and tissue injury and accidents such as falls) and comorbid psychological conditions (e.g., depression, anxiety, post-traumatic stress, and pain). How these alcohol-related health problems and comorbidities, individually or in combination, progress as individuals age is complex and still poorly understood. In addition, alcohol use and viral expression and associated immunological responses, including progressive dysregulation of the immune system, may have additive or synergistic effects on the progression of aging. Among individuals who drink, even treated HIV can be associated with accelerated aging, possibly from treatment sequelae or legacy effects, and notably from AUD comorbidity. Improved biomarker measurement may facilitate a more complete understanding of the mechanisms underlying accelerated aging in the context of alcohol-related comorbid conditions. In general, alcohol exposure, hazardous (and harmful) patterns of use, and AUD diagnosis are associated with different types of functional impairment (e.g., frailty). Improved management of alcohol use could lead to improved fulfillment of social roles, as well as improved HIV-related health outcomes over the lifespan. Further research is needed to take into account the important relationships between patterns of alcohol use and HIV treatment and care outcomes among PLWH as they age. Supported studies may include, but are not limited to:

• Addressing the important relationships between patterns of alcohol use and HIV treatment and care outcomes among PLWH as they age, including the development and application of innovative adaptive intervention strategies and implementation research to inform efforts to bring evidence-based interventions to population scale.

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

NIAMS encourages studies focused on the following:

• Observational, biopsychosocial/behavioral, translational, basic/pre-clinical/clinical research, and mechanistic clinical trials focused on how the process of aging in the presence or treatment of HIV/AIDS impacts diseases within the NIAMS core mission, which are more common among the aging population (e.g., rheumatologic disorders, bone fractures, osteoporosis, osteoarthritis).
• Interdisciplinary research aimed at elucidating factors that may drive the aging population living with HIV/AIDS to develop NIAMS mission-related diseases and understanding how the interplay between aging and HIV/AIDS may promote the acceleration or worsening of these diseases.

NIAMS will not support applications proposing clinical trials submitted in response to this NOFO. Clinical trials instead should be submitted to a NIAMS clinical trial-specific funding opportunity (see NIAMS' Investigator-Initiated Clinical Research web page). Consultation with NIAMS staff is strongly recommended for investigators planning a clinical trial with a mechanistic outcome. If NIAMS determines after submission that a clinical outcome is a primary objective of the study, NIAMS will not accept the application.

National Institute of Dental and Craniofacial Research (NIDCR)
NIDCR is interested in soliciting innovative and multi-disciplinary basic, translational, and clinical research on the intersection of HIV/AIDS and aging that is relevant to dental, oral, and craniofacial (DOC) health. Specifically, NIDCR encourages research investigating how the process of aging impacts the presence or treatment of HIV-associated oral comorbidities, co-infections, and complications (CCCs) in the context of PLWH. NIDCR will not support applications proposing clinical trials submitted in response to this NOFO. Supported studies may include, but are not limited to:

• Periodontal disease progression in the context of HIV infection and highly active antiretroviral therapy (HAART).
• Mechanisms of dental caries development and progression in PLWH.
• Effects of HIV/AIDS and HAART on salivary gland infiltrates, fibrosis, and xerostomia.
• Oral mucosal pathologies and composition changes in the context of HIV/AIDS.
• HIV infection, HAART, and their influence on developing osteonecrosis of the jaw.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIDDK supports biomedical research on diabetes and other endocrine and metabolic diseases; digestive diseases, nutritional disorders, and obesity; and kidney, urologic, and hematologic diseases, to improve people’s health and quality of life. NIDDK encourages projects that seek to elucidate how aging-related mechanisms and pathways contribute to comorbidities, co-infections, complications, and tissue reservoirs located in anatomical sites relevant to its mission. Topics of interest at the intersection of HIV and aging include, but are not limited to, the following:

• Pathophysiological processes underlying NIDDK-related comorbidities or complications.
• Impact of HIV or its treatment with physiological processes within its mission, such as metabolism, normal blood development, or gastrointestinal immune homeostasis.
• Viral reservoir dynamics in anatomic sites relevant to NIDDK’s mission, such as the gastrointestinal mucosa, adipose tissue, liver, kidney, and male genital tract.
• Social determinants of health that impact co-occurring conditions with NIDDK’s mission.
• Effectiveness research on programs aimed at social determinants of health impacting co-occurring conditions within NIDDK’s mission.

National Institute on Drug Abuse (NIDA)

NIDA is interested in research to explore the impact of substance use and substance use disorders (SUD) on HIV acquisition, prevention, care and clinical course in relation to aging, including changes across the adult life span and research questions of particular application to people age 50 and older. Substances of interest include: cannabinoids, nicotine, cocaine, stimulants, opioids, prescription drugs, or combinations of these drugs.

The research areas of interest include, but are not limited to:

• Leveraging existing epidemiological data (e.g., MWCCS: MACS/WIHS Combined Cohort Study) to evaluate the effects of aging on substance use patterns and their associations with viral suppression, mortality and HIV-related comorbidities among PLWH.
• Examining long-term patterns of HIV and substance use on service utilization, substance use outcomes, and medical consequences among aging PLWH.
• Optimizing, Integrating and/or scaling up of evidence-based HIV and SUD prevention and/or care interventions for older people who use or misuse addictive substances.
• Examining the intersection of social determinants of health, aging and substance use on HIV clinical and service utilization outcomes.
• Addressing HIV and substance use stigmas and how they affect substance use and HIV services among aging populations.
• Genomic, epigenomic, or single cell studies at the intersection of aging, neuroHIV, and SUD.
• Impact of chronic substance use on the emergence of age-related cognitive and behavioral deficits (e.g., memory, attention, self-regulatory processes, social behavior, decision making, compulsivity, balance, mobility) in PLWH.
• Metabolomics of the aging brain in the context of ART, HIV and SUD and the impact of waste clearance on healthy aging in these populations.
• Aging-related changes that impact drug metabolism and their impact on HIV and currently available antiretrovirals and pharmacological treatments for substance use. Of particular interest are studies examining patterns of use and effects of cannabis products in aging PLWH, including interactions with alcohol and medications commonly prescribed to people over 65 (or NIA’s threshold age).
• Patterns of polysubstance use and its physiological effects in PLWH who are over age 65.
• Non-pharmacologic and non-invasive interventions to prevent or reduce substance use and misuse in aging adults living with HIV.

National Institute of Mental Health (NIMH)

NIMH is keenly interested in interdisciplinary research studies that are conceptually grounded and employ basic, translational, and clinical approaches to better comprehend outcomes at the intersection of aging and HIV.

NIMH and its Division of AIDS Research (DAR) research program areas of interest in HIV and Aging include, but are not limited to:

• Evaluate Impact and Identify Targets: Investigate HIV's impact on cognition, motor function, and mental health in aging adults to comprehend mechanistic pathways and identify potential intervention targets.
• Mechanisms and Aging-Related Traits: Study physiological and biobehavioral etiopathogenesis relevant to cognitive, motor, and mental health outcomes in aging individuals with HIV. Explore how HIV status and viral load affect accelerated aging, neurocognitive aging, and successful aging traits.
• Neurotherapeutic Approaches: Identify neurotherapeutic approaches addressing interactions between HIV and aging processes.
• Behavioral Factors and Comorbidities: Investigate the effects of social and behavioral factors on mental health and HIV outcomes in aging populations, while also assessing the impact of neurological and psychiatric comorbidities on health outcomes to enable the development of targeted interventions.
• Interventions and Continuum Optimization: Research interventions for preventing HIV acquisition in aging populations and explore adaptations to the HIV care continuum to enhance outcomes in aging individuals living with HIV.

National Institute of Neurological Disorders and Stroke (NINDS)

NINDS supports basic, translational, and clinical research on the brain and nervous system and uses this knowledge to reduce the burden of neurological disease. In the context of HIV disease, NINDS is particularly interested in the neurological complications of HIV infection that affect the brain, spinal cord, and peripheral nervous system. For the purposes of this NOFO, specific topics of interest might include (but would not be limited to):

• The long-term consequences of latent HIV in the CNS as it pertains to the modulation of chronic neuroinflammation and cognitive impairment in aging; the mechanisms by which chronic HIV exacerbates long-term blood-brain barrier damage and cerebrovascular dysfunction.
• Studies of the mechanisms by which chronic HIV primes the CNS for neurodegeneration, including in the context of AD/ADRD and other age-associated neurodegenerative disorders.
• The long-term effect of chronic antiretroviral therapy (ART) exposure throughout the lifespan on the central and peripheral nervous systems.
• Mechanisms of HIV-associated peripheral neuropathy and chronic pain in aged individuals; and studies that address the question of whether chronic HIV infection and exposure to ART cause accelerated aging of the CNS.

While NINDS will support studies focused on the effect of chronic HIV on cognitive outcomes in the setting of neurological disease, applications that are solely interested in mental health and psychiatric outcomes will not be supported by NINDS. This includes applications that solely rely upon RDoC-based constructs for neurobehavioral analyses. Rather, NINDS strongly prefers the incorporation of additional multidimensional measures of neurological function, such as NIH Toolbox and Neuro-QOL -based assessments of cognitive, motor, and sensory function. In addition, only mechanistic clinical trials and Basic Experimental Studies with Humans (BESH) will be supported by NINDS under this funding opportunity. Clinical trials that seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, clinical management, and/or implementation of pharmacologic, behavioral, biologic, surgical, or device (invasive or non-invasive) interventions will not be supported under this NOFO Rather, such projects should be submitted to one of NINDS clinical trial-specific funding announcements (such as PAR-22-142 or PAR-21-237 ).

NINDS urges investigators to follow the NIH guidance for rigor and transparency in grant applications and additionally recommends the research practices described on NINDS' resource web page on preparing applications to 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: rationale for the chosen model(s) and primary/secondary endpoints, clear descriptions of tools and parameters, blinding, randomization, ensuring adequate sample size, pre-specified inclusion/exclusion criteria, handling of missing data and outliers, appropriate controls, preplanned analyses, appropriate quantitative techniques, clear indication of exploratory vs. confirmatory components of the study, consideration of limitations, and plans for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications.

National Cancer Institute (NCI)

Recent data indicates an increase in a variety of cancer types (e.g., anus, liver, oral cavity/pharynx, lung, and Hodgkin lymphoma), which is driven primarily by the growth and aging of PLWH who are on highly effective antiretroviral therapy. Aging is, by itself, a key factor promoting the development of many cancers, and HIV infection can itself cause certain manifestations of premature aging. There is a lack of data on the interplay between aging, HIV, long-term exposure to antiretroviral drugs, and other factors promoting cancer development in PLWH who are aging. In addition, there is little understanding of the interplay between host factors and immune perturbations that occur in aging and how these interactions affect cancers that are mostly seen in older people (e.g., clonal hematopoiesis and biological aging). Therefore, NCI is interested in applications proposing studies on the following:

• Research studies to help understand how aging in the presence of chronic HIV infection affects the risk, spectrum, and biology of cancer in PLWH.
• Cancer treatment outcomes and survivorship in PLWH.

Office of Research on Women's Health (ORWH)

ORWH is part of NIH's Office of the Director. ORWH works with NIH's 27 Institutes and Centers to advance rigorous research of relevance to the health of women. ORWH does not award grants but co-funds women’s health-related applications and research projects that have received an award from one of the participating NIH Institutes and Centers (ICs) listed in this NOFO. Applications seeking ORWH co-funding, in response to this NOFO, should ensure that the proposed work is aligned with at least one goal and objective outlined in the Trans-NIH Strategic Plan for Women’s Health Research.

ORWH supports research projects that address topics of relevance to aging, HIV, and women including cisgender, transgender, and gender diverse women and individuals assigned female at birth. Intersectional approaches to women, aging, and HIV are encouraged. For this NOFO, areas of particular interest include:

• HIV and menopause
• Projects to understand and address weathering, social isolation, stigma, and loneliness in the context of HIV and aging.
• Community-led interventions to improve testing, prevention, and treatment among older populations of women.
• Comorbidity and multi-morbidity among older populations of women living with HIV.
• Understanding the influence of sex on HIV infection and pathogenesis in the context of aging.
• Understanding the role of HIV in violence, trauma and mental health in aging women living with HIV.
• Community-centered interventions to engage older women in HIV research, including HIV cure-related research.

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 and 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 that are not aligned with OAR's priority areas, as described in NOT-OD-20-018, will be considered non-responsive to this NOFO. Non-responsive applications will not be reviewed. Examples of research not aligned with OAR's priority areas include:

• Research on natural history and epidemiology that is entirely focu?sed on a co-morbidity and does not have any focus on or inclusion of HIV.
• Research on co-infecting pathogens, but not in the context of HIV infection; basic immunology studies of general relevance, but not specific to HIV; basic cancer-related immunology studies not in the context of HIV infection; or studies on co-morbidities of general relevance, but not in the context of HIV.
• Data analysis and systems tools that are not HIV related (e.g., genomics and other omics studies with little or no relevance to HIV).
• Studies of behaviors (e.g., sexual activities, drug use activities) or social conditions where HIV/AIDS is only one of many outcomes without a focus on how HIV/AIDS is unique in that context.

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

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Organizations)

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

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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information

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

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

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

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

Page Limitations

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

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R or Modular Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

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

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

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

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

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

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

PHS Human Subjects and Clinical Trials Information

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

PHS Assignment Request Form

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

Foreign Organizations

Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the SF424 (R&R) 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 the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the 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 components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Post Submission Materials

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

Section V. Application Review Information

1. Criteria

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

For this particular NOFO, note the following:

The R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.

In addition, for applications involving clinical trials:

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

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

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

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the Center for Scientific Review, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

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

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

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

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

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

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

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: Generaland 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:

• Federalwide 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.

If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the HHS Office for Civil Rights website.

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

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 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.

Not Applicable

3. Data Management and Sharing

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

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 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 as amended (FFATA), 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 2 CFR Part 200.113 and Appendix XII to 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 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: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

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

Ann Namkung, MPH
National Institute on Aging (NIA)
Telephone: 301-496-6838
Email: ann.namkung@nih.gov

Peter J Perrin, Ph.D.
NIDDK - NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Phone: 301 451-3759
E-mail: peter.perrin@nih.hhs.gov

William Daley, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1431
Email: william.daley@nih.gov

Geraldina Dominguez, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-781-3420
Email: domingug@mail.nih.gov

Richard A Jenkins
NIDA - NATIONAL INSTITUTE ON DRUG ABUSE
Phone: 301-443-6504
E-mail: jenkinsri@mail.nih.gov

Elizabeth Anne Barr
ORWH - Office of Research on Women's Health
Phone: 301-402-7895
E-mail: elizabeth.barr@nih.gov

Kendall J. Bryant, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-402-0332
Email: kbryant@mail.nih.gov

Vasudev Rao
NIMH - NATIONAL INSTITUTE OF MENTAL HEALTH
Phone: 301-825-3259
E-mail: vasudev.rao@nih.gov

Hongen Yin, MD, PhD
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: (301) 496-0525
E-mail: yinho@nidcr.nih.gov

Heiyoung Park, PhD
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: 301-594-5032
E-mail: parkh1@mail.nih.gov

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

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

Sunshine Wilson
NIDDK - NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Phone: (301) 827-4670
E-mail: sunshine.wilson@nih.gov

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: ChiefGrantsManagementOfficer@ninds.nih.gov

Dawn Mitchum
National Cancer Institute (NCI)
Telephone: 240-276-5699
Email: dawn.mitchum@nih.gov

Pamela G Fleming
NIDA - NATIONAL INSTITUTE ON DRUG ABUSE
Phone: 301-480-1159
E-mail: pfleming@mail.nih.gov

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-4704
Email: judy.fox@nih.gov

Rita Sisco
NIMH - NATIONAL INSTITUTE OF MENTAL HEALTH
Phone: (301) 443-2805
E-mail: rr46w@nih.gov

Gabriel Hidalgo, MBA
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: 301-827-4630
E-mail: hidalgoge@mail.nih.gov

Erik Edgerton
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: 301-594-7760
E-mail: erik.edgerton@nih.gov

Section VIII. Other Information

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

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