Part 1. Overview Information

Key Dates

Conformance to all requirements (both in the Application Guide and the FOA) 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. Funding Opportunity Description

Background:

Central Nervous System (CNS) disease associated with HIV continues to persist in people living with HIV (PLHIV) despite effective antiretroviral therapy (ART). Although excellent virologic control in the periphery and brain has been achieved, CNS disease including neurologic, neurocognitive and mental health problems are observed. Considerable gaps exist in our understanding of pathogenesis of CNS disease associated with HIV. The current understanding of HIVassociated CNS disease pathogenesis is largely based on clinical phenotypes that were predominantly observed prior to the ART era or from the time where patients were transitioning to using ART. The role of associated co-morbidities, long term ART treatment and chronic inflammation in HIVassociated CNS disease pathogenesis have not been fully delineated.

A majority of the basic research in the NeuroHIV field has modeled neuronal damage in the context of active viral replication or the impact of HIV proteins like Tat/gp120 with focus on endpoints such as encephalitis and neuronal death. CNS disease outcomes such as atrophy and encephalitis seen in the pre-ART era are not evident in the current era. There is a possibility that other mechanisms such as neuroimmune dysfunction and chronic inflammation in the setting of co-morbidities may play a role in causation of observed HIVassociated CNS disease outcomes. There could be several other potential unexplored mechanisms and pathways that are driving the development of CNS disease such as subtler neuro-metabolic changes, alterations in neuronal circuitry or altered? signal transmission. New research directions could include studies of factors related to neural membrane channel function, neurotransmitter trafficking, synaptic plasticity and neural activity anomalies. The role of extracellular vesicles (EVs) and microRNAs in modulating the micro-environment around the synapse are also of interest.

Although the prevalence of mental health problems such as depression and anxiety disorders are high in PLHIV, CNS disease research has been traditionally focused on cognitive impairment and there is a lack of understanding of the biological mechanisms underlying mental health disorders. People at risk for HIV often experience life stressors that could lead to neuroinflammation as well as depression and anxiety disorders. Among PLHIV, both HIV and ART cause inflammatory/ immune related changes in the CNS and the periphery. In addition, social and environmental factors such as violence, stigma, and stress, which are common among people at risk for or living with HIV, also contribute to disruption of the neurotransmitter/ neuroinflammatory homeostasis in the brain. To-date there is a paucity of studies that examine the impact of somatic and non-somatic causes of mental health disorders in people living with HIV. A better understanding of the unique mechanisms underlying these mental health disorders in PLHIV is an area of interest of this Funding Opportunity Announcement (FOA). Such studies may potentially lead to novel mental health interventions in HIVinfected populations.

Development of biological measures to assess CNS disease associated with HIV is another area of high research priority for the field. Recent technological advances in mass spectrometry, proteomics and systems biology may be harnessed to enable discovery of disease progression tracking biomarkers. To better understand the neuropathogenesis and the etiology of clinical outcomes observed in people living with HIV on modern ART regimens, studies examining neuronal networks, neural circuits and pathways have the potential to provide a framework to develop quantitative biomedical diagnostic tools that reflect the true nature and extent of CNS impairment, thereby diminishing the reliance on complicated subjective neuropsychiatric batteries. This FOA encourages neuroimaging studies and discovery of mechanistic biomarkers both to understand the mechanisms of HIVassociated CNS disease and to identify diagnostic signatures.

Definitional criteria and diagnosis of HIVassociated CNS disease have largely relied on outcomes inferred from neuropsychological test performance. Several recent reports have highlighted the heterogeneity of HIV-associated CNS disease outcomes, but the existing diagnostic methods discount the heterogeneity and classify disease according to the degree of impairment. To understand the heterogeneity of CNS disease observed in the current era, there is a need to explore other diagnostic modalities such as domain-based approaches. Using a domain-based framework such as Research Domain Criteria (RDoC) can assist the field in understanding the varying degrees of disease and heterogeneity seen in patients in the context of ART and co-morbidities. RDoC is a research framework that integrates many levels of information (from genomics and circuits to behavior and self-reports) in order to explore basic dimensions of functioning that span the full range of human behavior from normal to abnormal (https://www.nimh.nih.gov/research/research-funded-by-nimh/rdoc/index.shtml). Development of novel assessment tools using RDoC parameters is an area of interest of this FOA.

Viral and host genetic factors contribute to pathophysiology of HIV-1associated CNS disease. New genetic technologies may complement the effort to provide unique perspectives on the neuropathology and aid in the identification of innovative strategies for the discovery of therapeutic drug targets. GWAS data available from a reasonably large number of HIV-infected patients from several large cohorts (CHARTER, MACS and WIHS) can be utilized to understand how host genetics impacts the development/progression of cognitive impairment associated by HIV. The use of state-of-the-art genetic approaches (including transcriptomics, phenomics, epigenomics, single cell genomics, whole genome association studies, ultra-deep sequencing, exome sequencing, and systems biology) as well as the use of human sample resources and animal model systems are encouraged to study, and validate, viral and host genetic contributions to HIV neuropathogenesis.

Another key focus area of this initiative is to support research to aid the identification/ validation of biomarkers and pre-clinical targets with quantifiable neurophysiological/ neuroimaging readouts implicated in the pathogenesis of HIVassociated CNS co-morbidities. Discovery of novel pre-clinical therapeutic agents with the ability to cross the blood-brain barrier and understanding the consequences of increased/decreased uptake of ART into the brain tissue is of interest alongside research on mechanisms of neuro-adverse consequences oflong term ART.

The number of older individuals living with HIV/AIDS has risen dramatically over the past decade. In 2015, an estimated 47% of Americans with diagnosed HIV were aged 50 and older. People aged 50 and older accounted for 17% of the new HIV diagnoses in 2016 in the United States. An emerging area of research interest is the interaction of chronic HIV infection, people living with HIV on ART long term, and aging associated neurodegenerative processes. As a result of a major demographic shift in the HIV-1 infected population in the US, there is a need to better define the underlying pathophysiology of neurological complications decline in the aging HIVinfected populations.

There are several in vitro and in vivo models being used to investigate the pathogenesis of HIVassociated CNS disease, but these models have limitations in their ability to mimic current clinical phenotypes. Additional research is needed to develop better models that consider the effect of chronicity of viral infection, ART toxicity and co-morbidities. There is also a need for appropriate models to validate potential therapeutics for HIV-1associated CNS disease.

In summary, the goals of this FOA are to stimulate further research on delineating the pathophysiology of HIV-1associated CNS disease in the setting of chronic viral suppression and ART. In addition, this FOA also encourages research studies to aid in the identification/ validation of biomarkers and pre-clinical targets with quantifiable readouts in domestic and international settings. Multidisciplinary research teams and collaborative alliances are encouraged, but not required.

NOTE: Studies utilizing in vitro, in vivo and ex vivo models that can mimic the current clinical outcomes in the context of viral suppression and ART are highly encouraged under this FOA.

Areas of Research Interest:

The research areas that are pertinent to this FOA include, but are not limited to:

Pathogenesis of HIV-1 associated CNS disease in the context of ART

• Basic research on neuronal disease focusing on neuronal receptors, neurotransmitters, neural activity, neural circuits and synapto-dendritic damage;
• Understand and decipher at a molecular level, how neuroimmune dysregulation caused by HIV impacts neuronal receptors, neurotransmitters and synaptic plasticity;
• Undertake studies to adapt existing diagnostic neuroimaging and electrophysiology-based methods to measure and monitor activity of neuron ensembles and pathways in patients living with HIV that can augment our understanding of the disease etiology;
• Develop and utilize tailored cognitive assessments using the RDoC framework in conjunction with other biological measures such as neuroimaging and immune profiles to identify pathways and mechanisms associated with CNS disease outcomes;
• Identify novel molecular biomarkers in cerebrospinal fluid (CSF) and blood linked with milder and chronic forms of HIV-associated CNS disease using state-of-the art techniques including genomics, proteomics, metabolomics, systems biology and neuroimaging;
• Assess the role of extracellular vesicles and micro-RNAs in context of neuroimmune dysfunction caused by HIV as well as evaluate the potential role of exosomes as biomarkers for HIV-1 associated CNS disease
• Identify molecular and cellular mechanisms underlying neurological impairment in acute and early infection in addition to assessing the impact on early initiation of treatment on immune recovery and resulting long term neurological outcomes;
• Studies to better understand the neurobehavioral sequelae and developmental consequences of perinatal and in-utero exposure to HIV and related treatments.
• Assess the impact of metabolic disturbances related to long term ART on CNS outcomes among HIV-1 infected patients including but not limited to studies on the effect of insulin resistance, lipid abnormalities and mitochondrial disease on HIV-associated CNS disease;
• Assess the contributions of non-infectious co-morbidities (vascular, stroke, epilepsy) to HIV-1 associated CNS disease and reciprocal interactions of HIV-1 associated CNS disease with other neurodegenerative diseases;
• Studies to understand the neuropsychiatric adverse events and potential CNS toxicities associated with ART and other emergent treatments;
• Research on pharmacologic interactions of therapeutic drugs including ART and other relevant medications on CNS co-morbidities in people living with HIV.

Pathogenesis Studies using model systems primarily focused on single viral gene products (such as HIV-1 Tat/gp120) in isolation and those that do not represent the current clinical phenotypes of HIV-1 associated CNS disease will NOT be supported under this FOA.

Mechanisms underlying Mental Health disorders in people living with HIV

• Epidemiology studies to understand the phenotype and heterogeneity of mental health outcomes in people living with HIV in the context of ART and co-morbidities;
• Studies of the biological, behavioral and psychosocial mechanisms of mood disorders in people at risk for or living with HIV;
• Studies of functional changes in brain neurochemistry and neuroendocrine milieu that lead to mood disorders in the context of HIV and ART;
• Studies that model the impact of HIV and associated inflammation on brain circuits and networks regulating mood, cognition and behavior;
• Studies that integrate genetic, neurobiological, imaging, behavioral, psychosocial and clinical data to characterize the nature and mechanisms of mood disorders in people at risk for or living with HIV

Neuroimaging Studies

This FOA encourages neuroimaging studies using magnetic resonance spectroscopy (MRS), positron emission tomography (PET), magnetic resonance imaging (MRI), functional MRI (fMRI), resting state functional MRI (rsfMRI), Magnetoencephalography (MEG), blood oxygenation level dependent functional magnetic resonance imaging (BOLD fMRI), diffusion tensor imaging (DTI), and arterial spin-labeling MRI (ASL-MRI), chemical shift imaging and other novel imaging technologies in the context of ART suppressed individuals exhibiting mild to moderate forms of CNS disease to

• Better understand the pathogenesis and the circuits involved in HIV-1 associated CNS disease across the lifespan;
• Conduct neuroimaging studies involving HIV-1 infected patients and utilize systems biology/machine learning approaches to identify the pathognomonic signatures with the ability to diagnose HIV-1 associated CNS disease;
• Delineate key biological neuroimaging markers that correlate with disease symptoms, progression, and clinically relevant information regarding cognitive, emotional, neurological, and behavioral performance in patients exhibiting HIV-1 associated CNS disease across the lifespan.

Viral Genetics

• Study the role of HIV-1 sequence diversity in understanding neurovirulence, neurotropism, discordant and compartmentalized viral evolution, CNS cell type-specific infection, regional genetic heterogeneity, and associated functional effects;
• Identify mechanistic viral genetic signatures associated with HIV associated CNS disease;
• Study the role of viral epigenetic factors in the pathophysiology of HIV associated CNS disease;
• Understand the role of viral and host transcriptional regulation (including viral protein modifications, histone modifications, changes in chromatin structure, and non-coding RNA) in HIV neuropathogenesis.

Host Genetics

• Study the role of host genetic factors, including epigenetic mechanisms in regulating susceptibility to HIV-1 associated CNS disease;
• Assess epigenetic host response to viral infection mediated through chromatin modification, non-coding RNAs, and DNA methylation in CNS resident cells;
• Study host genetic factors involved in regulating responsiveness to antiretroviral therapy and neuroprotective adjuvant therapies (pharmacogenomics);
• Delineate the genetic basis of host restriction factors in CNS cell types that impact HIV replication.

Pre-clinical research

• Pre-clinical research to target neuroimmune dysregulation and altered neuronal circuitry in individuals living with HIV on suppressive ART;
• Identify mechanistic pre-clinical targets for interventions of mental health disorders in people living with HIV on ART;
• Pre-clinical research to prevent blood brain barrier dysfunction and discovery of therapeutics with the ability to cross the blood-brain barrier to alleviate CNS comorbidities in HIV-infected individuals on ART

NINDS Research Focus

NINDS supports basic, translational and clinical research on the effects of HIV infection and co-morbidities on the CNS. NINDS is interested in the majority the research areas as identified above. Applications focused on Mental health disorders associated HIV will not be supported by NINDS. NINDS is also interested in HIV-associated neurological disorders, such as neurodegenerative diseases, Alzheimer’s disease (AD) and Alzheimer's Disease Related Dementias (ADRD).

NIA Research Focus

NIA is particularly interested in projects in the area of aging, co‐morbidities, co‐infections and HIV-induced CNS dysfunction in Alzheimer’s disease (AD) and Alzheimer's Disease-Related Dementias (ADRD). This includes but is not limited to studies on: (1) neuropathological indices of AD/ADRD in HIV; (2) fluid biomarkers of AD/ADRD associated with HIV infection; (3) neuronal circuits that are compromised in HIV‐induced CNS dysfunction, including similarities and differences in circuits compromised in AD/ADRD; (4) whether deficits in molecular and cellular mechanisms observed in AD/ADRD such as autophagy or mitochondrial dysfunction is impaired in HIV and (5) whether the treatment of HIV increases the risk of AD/ADRD, and the molecular and cellular mechanisms that may underlie this risk.

NIDA Research Focus

NIDA is particularly interested in projects in this area which have one or more aims or sub-aims investigating 1. opioid, cannabinoid, nicotinic, dopaminergic, or other signaling pathways relevant to addictive substance use, or 2. exposure to addictive substances, or 3. analysis of samples from patients that have used addictive substances or have SUDs. Addictive substances of interest include: nicotine, cocaine, methamphetamine, stimulants, opioids, prescription drugs, cannabinoids, combinations of these drugs, or combinations of these drugs with alcohol.

NIAAA Research Focus:

NIAAA seeks to expand research on the additive and interactive effects of alcohol and HIV in ART compliant and non-compliant patients aging with HIV to assess cognitive decline in multiple domains including executive functioning, learning and memory, and speed of information processing.

Data Sharing

Applications supported by this FOA are expected to include data sharing plans, incorporating data dictionaries, current definitions, and careful documentation. As such, it is expected that applications will include information on the type and descriptors of data that will be generated and shared, as well as a plan for data coordination, standardization, access privileges, timeline for release of data, and location of data to be shared post-award, consistent with achieving the goals of the program.

Animal Models and Specimen Resource

The use of animal models is encouraged for the development of novel in vitro, ex vivo or in vivo models for research on HIV-1 associated CNS disease that reflect current clinical phenotypes in the context of chronic viral suppression and ART . The use of human specimen resources from the below mentioned NIH-funded HIV related studies are also encouraged. These include, but not limited to

• Multi-center AIDS Cohort Study (MACS);
• Women’s Interagency HIV Study (WIHS);
• CNS HIV Antiretroviral Therapy Effects Research (CHARTER);
• AIDS Clinical Trials Group (ACTG); and the
• National NeuroAIDS Tissue Consortium (NNTC).

Note: Applications for basic experimental studies with humans (BESH) in which participants are prospectively assigned to experimental conditions and receive an intervention or experimental manipulation for the purpose of understanding basic mechanisms can apply to the NIH Parent PA (PA-19-091)

Section II. Award Information

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)

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)
• U.S. Territory or Possession

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• 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 Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• 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.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons.Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but 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 DUNS number and 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.

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 FOA 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. 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 NOT-OD-11-101)

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 FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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

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

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

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.

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.

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

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 Policy on Late Application Submission.

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 Component of the SF424(R&R) Application Package. 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 FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number 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, NIH. Applications that are incomplete or non-compliant will not be reviewed.

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.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information

1. Criteria

Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) as part of the Resource Sharing Plan will not be evaluated at time of review.

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.

Significance  

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator(s)  

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation  

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach  

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Environment  

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Protections for Human Subjects  

For research that involves human subjects but does not involve one of thecategories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan  

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals  

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards  

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions  

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals  

For Renewals, the committee will consider the progress made in the last funding period.

Revisions  

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

Applications from Foreign Organizations  

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research  

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans  

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:  

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support  

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by 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.

• 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.
• Will receive a written critique.

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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

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 grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. 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 FOA 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.

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

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, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. 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 http://www.hhs.gov/ocr/civilrights/understanding/section1557/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 FOA.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please 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 further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

• Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. 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.

• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please 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 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

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.

3. Reporting

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreementsare required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. 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 Appendix XII to 45 CFR Part 75, 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 – Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

Finding Help Online:http://grants.nih.gov/support/(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: 301-637-3015

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

Jeymohan Joseph, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 240-627-3869
Email: jjeymoha@mail.nih.gov

John A. Matochik, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-451-7319
Email: jmatochi@mail.nih.gov

Miroslaw (Mack) Mackiewicz, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-594-7636
Email: mirsoslaw.mackiewicz@nih.gov

Shang-Yi Anne Tsai, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-827-5842
Email: stsai@nih.gov

May Wong, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1431
Email: wongm@ninds.nih.gov

Rita Sisco
National Institute of Mental Health (NIMH)
Telephone: 301-443-2805
Email: siscor@mail.nih.gov

Judy S. Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-4705
Email: jfox@mail.nih.gov

Traci Lafferty
National Institute on Aging (NIA)
Telephone: 301-402-7700
Email: laffertt@nia.nih.gov

Pam Fleming
National Institute on Drug Abuse (NIDA)
Telephone: 301-827-6698
Email: pfleming@mail.nih.gov

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9531
Email: chiefgrantsmanagementofficer@ninds.nih.gov

Section VIII. Other Information