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

All applications submitted to this Funding Opportunity Announcement must propose basic science experimental studies involving humans, otherwise referred to in NOT-OD-18-212 as prospective basic science studies involving human participants, that fall within the NIH definition of a clinical trial and also meet the definition of basic research.

NIH defines basic research consistent with the definition of basic research in federal code, the systematic study directed toward greater knowledge or understanding of the fundamental aspects of phenomena and of observable facts without specific applications towards processes or products in mind. (32 CFR 272.3 ).

NIH defines a clinical trial as "A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes." (NOT-OD-15-015 ).

Types of studies that should submit under this FOA include studies that prospectively assign human participants to conditions (i.e., experimentally manipulate independent variables) and that assess biomedical or behavioral outcomes in humans for the purpose of understanding the fundamental aspects of phenomena without specific application towards processes or products in mind.

For the purposes of this FOA, specific application towards processes or products refers to the application of biomedical or behavioral products, procedures, or services intended to affect a health-related outcome of the individual or a group of individuals either by better understanding the mechanism of action of an intervention or a measurable improvement in health .

Basic experimental studies in which participants are prospectively assigned to experimental conditions and receive an intervention or experimental manipulation where the effect will be assessed for the purpose of understanding fundamental aspects of phenomena may submit under this FOA.

Please refer to the table comparing Funding Opportunity Types by Clinical Trial Allowability for additional guidance on the most appropriate FOA for the type of study.

Purpose

This funding opportunity announcement (FOA) solicits research projects that seek to explain the underlying mechanisms, processes, and trajectories of social relationships and how these factors affect outcomes in human health, illness, recovery, and overall wellbeing.

Research areas of interest include understanding differences and similarities between objective social isolatedness and loneliness, how complex biopsychosocial processes are regulated in the body, what occurs in response to dysregulation, and antecedent processes that influence responses to the trajectories of social relationships. Studies that involve neurobiological approaches for example, how social or isolated settings influence neurobiological systems, brain function, and/or behavior are welcome. Projects designed to study how changes in the quantity and/or quality of social connections influence health behaviors and outcomes are encouraged. This FOA also encourages projects that incorporate aims to promote methods and measures needed to support a cumulative and integrated approach to the study of social connectedness and isolation.

The terms "social connection" and "social isolation" often are used interchangeably in research. For the purposes of this FOA, "social connectedness" encompasses both perceived and actual connections to others, as well as an individual's perception of belongingness to the social environment. Researchers with questions regarding these terms should inquire with IC scientific contacts.

All applications submitted through this FOA must propose basic science experimental studies with humans, also referred to in NOT-OD-18-212 as prospective basic science studies involving human participants. These studies meet the NIH definition of basic research and also fall within the NIH definition of a clinical trial. Observational studies involving humans should submit under the companion Clinical Trials Not Allowed version of this FOA.

Background

It is well-established that social ties can facilitate overall wellbeing, recovery from acute illness, and self-management of chronic conditions. Less well understood are the processes by which connection and isolation lead to positive or negative impacts on health, wellbeing, illness, or recovery. A more comprehensive understanding of the mechanisms, processes, and trajectories involved in social connectedness and isolation may identify novel targets to inform future intervention developments and to strengthen individual and group functions.

For example, the prefrontal cortex can handle multiple, yet not infinite, concurrent processes. Changes in prefrontal processing may lead individuals to adaptively self-isolate as a way to reduce external social stimulation, to protect or avoid stress, or to focus on specific cognitive tasks Yet extended isolation can lead to negative changes in neuronal size, activity patterns, and intracellular processes that can reduce cognitive and sensory capacities and subsequent behavior.

Social media usage, such as sharing photos and videos with family members and friends, can facilitate connections and have salutary effects. Social media also can be used to publicly bully or shame others, often youth. Targets of social media abuse subsequently may engage in maladaptive behaviors including aggression, delinquency, substance use and misuse, self-harm, social withdrawal, or suicidal ideation. We currently lack an understanding of the biopsychosocial processes that facilitate wellbeing among some youth who use social media but not others.

This FOA solicits research to better understand the basic individual, social, and biobehavioral processes by which social connectedness and isolation have positive or negative impacts across the lifespan. It encourages projects that explore the relationships between various factors, including those that can be objectively measured (e.g., biomeasures or data from health records, occurrence or length of relationship disruption) and those that require self-report.

The arena of social connectedness, connection, and isolation health research is relatively new, and therefore ripe for construct, theory, and measurement mapping and measurement harmonization efforts. Therefore, in addition to understanding the mechanistic relationships between aspects of social connection and isolation in health contexts, research projects in the areas such as knowledge representation and behavioral ontology development are welcomed. If appropriate, projects may use NIH-supported common data elements (CDEs), electronic health record data, and/or propose sophisticated statistical analyses of existing and/or synthesized datasets hat lead to hypotheses for testing in humans or animals.

Research projects focused on either animals or human subjects are encouraged. Also encouraged are projects that strive to determine optimal measurement approaches across species, that validate and utilize measures across the lifespan, and that test measures in a range of clinical contexts.

This FOA solicits R01 applications that may range between 2-5 years. The R01 mechanism, common to all NIH ICOs participating in this FOA, was chosen expressly to empower investigators to propose innovative scopes of work with correspondingly appropriate budgets. Regardless of the number of project-years proposed, investigators should budget each year for travel to an annual meeting of grantees on or near the NIH Campus in Bethesda, MD, to share research methods and findings. Awardees will be encouraged to work together on some shared scientific opportunities at the annual meeting and across the award period.

Three areas of focus especially of interest to OppNet and participating NIH ICOs include, but are not limited to, those below:

1. Effects of social connectedness, connection, and isolation across the lifespan

• Affective and cognitive function during the aging process
• Contextual factors that increase or mitigate impact of disruption or isolation at different developmental time points, e.g.,
  • Caregivers of people with dementia, severe illness, end-of-life
  • Chronic illness or limited mobility
  • Perceived strength or quality of extant social connections
  • Recent diagnosis with a serious medical illness
  • Sleep changes across the lifespan (e.g. during adolescence, early parenthood, menopause)
  • Impact f transitions across the lifespan (e.g., transitioning from the family home to college or another home; transitioning from full-time work to retirement)
• Molecular markers and mechanisms (e.g., epigenetic modifications, gene expression, microbiome alterations, telomere attrition) associated with changes in social connectedness
• Neurobiological developmental trajectories
• Protective and/or risk factors associated with isolation or connection disruption at different times in development and over the lifespan
  • (e.g., adolescence, middle-age men, people who receive a serious medical diagnosis, retirement, death of spouse/parent)
• Risky sexual activity and/or aggressive behaviors associated with connection trajectories

2. Mechanisms of connectedness, connection, and isolation

• Neurobiological factors
  • Impact on structure and function of the nervous system (central, peripheral, autonomic)
  • Impact of neuroimmune and neuroendocrine systems
  • Impact on neural systems associated with basic affective, cognitive, and social processes
  • Importance of inter-individual neural synchrony in mediating or moderating effects in relationship trajectories
  • Neurobiological biosignatures that predict sensitivity to connection disruption or isolation
  • Neurobiological processes that could be targets to ameliorate negative effects of disruption or isolation
  • Neuro-physiological consequences of disruption or isolation on substance use disorders (SUDs) and mental illness

• Behavioral and environmental factors
  • The consequences of perceived isolation (e.g., loneliness) and/or objective/observed isolation on behavioral and clinical outcomes in adolescence and adulthood
  • Connections between intersectional stigma and social disruption/isolation among specific populations or health/illness contexts, e.g.,
    • Sex/gender differences; sexual and gender minorities
    • Racial/ethnic differences, acculturation/bicultural adaptations and contributions to social integration versus isolation
    • Autism, HIV, mental illness, recovery status, substance use disorder
  • Whether the source of connection disruption leads to different processes or outcomes
    • E.g., Self-induced isolation versus isolation by others, or sense of undesired loneliness vs. enjoyed solitude

3. Knowledge representation and behavioral ontology development

• Development of clearly defined vocabularies and taxonomies
• Elucidating relationships across constructs and between constructs and measures,
• Integration of knowledge related to social connectedness, connection, and isolation into existing interoperable and shareable measures or ontology frameworks

About OppNet

OppNet is a trans-NIH initiative that funds research activities that build the collective body of knowledge on the nature of behaviors and social systems and deepen our understanding of basic social-behavioral mechanisms and processes. All OppNet initiatives invite investigators to propose research projects that will advance basic social and behavioral sciences and produce knowledge and/or tools of potential relevance to multiple domains of health research. All NIH Institutes and Centers that fund research and Program Coordination Offices within the NIH Office of the Director (ICOs) collectively manage OppNet's scientific direction yet may not participate in every OppNet FOA. Consequently, applicants should review the list of ICOs in this FOA's Components of Participating Organizations. For more information about OppNet, visit https://oppnet.nih.gov.

OppNet strives to ensure that proposed projects focus primarily on basic socio-behavioral and biopsychosocial sciences. Though OppNet defers from imposing a definition on the field, OppNet uses the following statement to guide the concepts it develops toward funding opportunity announcements: basic behavioral and social sciences research (b-BSSR) furthers our understanding of fundamental mechanisms and patterns of behavioral and social functioning, relevant to the Nation's health and wellbeing, and as they interact with each other, with biology, and with the environment. OppNet acknowledges that disease-, risk-, and wellness-contexts can provide opportunities to study basic behavioral or social processes, basic biobehavioral or biosocial interrelationships, or methodology and measurement relevant to b-BSSR.

Research Objectives

OppNet recognizes that basic research in the behavioral and social sciences can be conducted in a broad variety of settings, including general population and clinical samples. It can also be embedded within studies that include disease (or risk-factor) outcomes, as long as the focus of the study is on basic behavioral or social processes, basic biobehavioral or biosocial interrelationships, or methodology and measurement relevant to BSSR research. Applications submitted cannot include any specific aims that propose to measure clinical efficacy or effectiveness of any intervention. Investigators who wish to conduct studies with clinical endpoints as the primary outcomes should consider other NIH FOAs . The ICs participating in this FOA have specific interests and priorities listed below. OppNet strongly encourages researchers to contact Scientific/Research contacts well in advance of submitting applications.

National Center for Complementary and Integrative Health (NCCIH)

Understanding mechanisms of action through which complementary and integrative health approaches affect social connection and isolation on health, resiliency, and well-being across the lifespan. Examples of complementary and integrative health approaches relevant to this FOA include, but are not restricted to,

• Mind and body approaches such as meditation
• Hypnosis
• Acupuncture
• Massage
• Spinal manipulation/mobilization
• Yoga
• Tai-chi
• Qigong
• Music and art therapy
• Natural products such as botanicals, probiotics, dietary supplements, and special diets

National Eye Institute (NEI)

Social connection and isolation across the lifespan in people with visual impairment (i.e., living with blindness or low vision), including but not limited to:

• Basic and/or translational research that examines social connection and/or isolation in individuals with visual impairment
• Effects of social connection and/or isolation on adapting to progressive vision loss
• Impact of social connection and/or isolation on vision rehabilitation or assistive device use in individuals with visual impairment

National Institute on Aging (NIA)

Causal pathways through which social connectedness and social isolation are associated with health and well-being, e.g.,

• Identify intervention targets for modifying social isolation and/or loneliness and optimal time points for interventions to support healthy aging.
  • The role of long-term, cumulative psychosocial factors associated with perceived or objective social isolation; the availability, absence, or loss of social connections; and social engagement on aging health and well-being.
  • Relationship between genetic variation, individual differences in gene expression, and social connectedness and isolation.
  • The unique challenges that social disconnectedness, social disengagement, and social isolation poses in midlife and older age, and resources that promote resilience; especially for caregivers of people with Alzheimer’s disease and related dementias.
  • Identification of intervention targets for modifying social connectedness, isolation and/or loneliness and optimal time points for interventions to support healthy aging. NIA encourages a mechanisms-focused approach to behavior change intervention development as promoted by the NIH Science of Behavior Change (https://commonfund.nih.gov/behaviorchange) and the NIH Stage Model (https://www.nia.nih.gv/research/dbsr/stage-model-behavioral-intervention-development).

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Impact of social connection and/or isolation across the lifespan, e.g.,

• Underlying behavioral, cultural, neurobiological mechanisms of social connection and isolation leading to alcohol use, addiction, or cessation of consumption
• Effects of social connection and isolation on alcohol withdrawal and relapse
• Social media use settings, including use of non-English language social media, that facilitate social connection or isolation and subsequent impact on other behavioral and affective disorders associated with alcohol use disorder (AUD)

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

Basic and/or translational research that examines behavioral or biopsychosocial mechanisms of connection or isolation in patients with NIAMS core mission diseases:

• Arthritis
• Musculoskeletal
• Skin disorders

Note that the effect of social isolation on disease outcomes is not the focus of this PAR.

Eunice Kennedy Shriver National Institute on Child Health and Human Development (NICHD)

Typical and atypical social development in childhood and adolescence

• Impact of social isolation on social, affective, and cognitive development; health-related outcomes; risky and healthy behaviors in children, adolescents and individuals with intellectual and developmental disabilities (IDD)
• Individual, family-level risk and protective factors
• Relation between social isolation and other social experiences such as peer victimization
• Research to identify targets for behavioral intervention
• Understanding mechanisms by which social isolation negatively impacts health and psychosocial development
• Understanding social isolation across development and levels of development (i.e. levels of cognition)
• Social isolation and its relation to obesity in childhood and adolescence
• Understanding virtual social isolation via social media exclusion and cyberbullying
• Role of pets in promoting social capital and reducing social isolation
• Understanding social isolation among trauma-exposed youth
• Examining the effects of social isolation on recovery from injury or critical illness
• Impact of social isolation on recovery of function after illness or injury; determinants of the impact of social media or internet engagement on functional recovery
• Research to understand the interaction of social isolation with rehabilitation engagement especially through the use of novel technologies or methods
• Relationship among determinants of social connection and enhancement of rehabilitation outcomes to include improved functional status, performance, and health-related quality of life
• Examining the effects of social isolation on the development of co-occurring mental health conditions such as depression and anxiety in individuals with autism and other IDD conditions
• Examining levels of cognitive function and language abilities as predictors of social isolation
• Secondary analyses of population representative datasets to explore: community, family, and/or individual-level risk and protective factors; and the relationship between population processes, such as migration or housing change, and social isolation

National Institute on Deafness and Other Communication Disorders (NIDCD)

Social connection and isolation across the lifespan in people with communication disorders

• NIDCD will accept applications when/if including human participants living with disorders of hearing, balance/vestibular, voice, speech, language, taste and smell.

National Institute on Drug Abuse (NIDA)

Contextual factors, behavioral/neurobiological mechanisms associated with social isolation in substance use disorders (SUDs) e.g.,

• Determine if youth connections through social media platforms may protect against drug use initiation
• Characterize the effects of social media on social connection, disruption, or isolation to exacerbate substance use disorders or to facilitate treatment and recovery
• Delineate the neurobiological, psychological, and emotional contributions of social connection trajectories to SUDs
• Identify genetic associations among social isolation and SUD
• Determine predictive biomarkers associated with social isolation and SUD

National Institute of Mental Health (NIMH)

Mechanistic studies of the biopsychosocial causes and effects of social connection and isolation across the lifespan, including but not limited to:

• Neurobiological mechanisms associated with disruption of social connectedness, isolation, or perceived loneliness
• Effects of social connection and/or isolation on affective, social, and cognitive outcomes across levels of analysis
• Biopsychosocial mechanisms which increase social connectedness or mitigate loneliness
• Computational neuroscience approaches to characterize social group dynamics and/or individual experience of social interactions and their impacts on emotional or cognitive systems and abilities
• Research that utilizes remote biosensors and/or ecological momentary assessments to investigate positive and negative changes in social connectedness in natural environments
• Interactive ways in which social isolation impacts patients with psychiatric and co-morbid conditions including but not limited to SUDs and HIV.
• Mechanism-based research to identify potential intervention targets for modifying social connectedness, isolation and/or loneliness via social media to prevent the development of clinically significant mental health symptoms.
• Mechanism-based intervention research, consistent with the NIMH experimental therapeutics approach, that investigates social isolation as a target/moderator related to mental health treatment engagement, adherence, and/or continuation. Areas of particular interest include, but are not limited to:
  • Suicide prevention interventions (e.g., in the context of the Interpersonal Theory of Suicide)
  • Functional disability among individuals with Serious Mental Illness
  • HIV/AIDS treatment engagement, adherence, and/or continuation
  • Sexual and gender minorities, rural residents, people with autism, and their demographic groups shown to experience higher levels of social isolation

National Institute on Minority Health and Health Disparities (NIMHD)

The mission of NIMHD is to lead scientific research to improve minority health and reduce health disparities. NIMHD supports the study of many aspects of minority health and health disparities from biological and population sciences to clinical, behavioral, and translational research, as well as research on health care services, health systems and workforce development. NIMHD focuses on the full continuum of causes of health disparities and the interrelation of these causes. Projects must include a focus on one or more NIH-designated health disparity populations in the United States, which include African Americans, Latinos/Hispanics, American Indians/Alaska Natives, Asians, Native Hawaiians and other Pacific Islanders, less privileged socioeconomic groups, underserved rural residents, and sexual and gender minorities (SGMs). Comparison groups/populations may also be included as appropriate for the research questions posed. NIMHD encourages projects that use approaches encompassing multiple domains of influence (e.g., biological, behavioral, sociocultural, environmental, physical environment, health system) and multiple levels of influence (e.g., individual, interpersonal, family, peer group, community, societal) to understand and address health disparities (see the NIMHD Research Framework, https://www.nimhd.nih.gov/about/overview/research-framework.html, for more information).

For the purposes of this funding opportunity announcement, we seek to understand the interrelation between social connectedness and social isolation and minority health and health disparities.

• Impact of social connectedness and social isolation on health disparity populations and health disparities
• Positive and negative impacts of social connectedness and social isolation
• Unique challenges for health disparity populations
• Identify intervention targets for health disparity population
• Impact of interpersonal and systemic discrimination and microaggressions on social connectedness and social isolation
• Impact of neighborhood/place, poverty, stigma, on social connectedness and social isolation
• Impact of diverse cultures on social connectedness and social isolation

National Institute of Neurological Disorders and Stroke (NINDS)

Neurobiological processes underlying the influence of social connection and isolation on the development, progression and recovery of neurological disease and disorders, e.g.,

Mechanistic studies of the effects of social isolation on neuro-repair and recovery after stroke, progression of neuro-degenerative conditions, or on level of disability in neuro-developmental disorders.

Impact of social isolation and connection on neuroimmune and neuroendocrine systems as they impact brain disorders.

National Institute of Nursing Research (NINR)

Disease-agnostic, holistic approach to address social isolation in diverse populations and across the lifespan

• Further elucidate the biobehavioral factors that contribute to social isolation and associated health outcomes
• Characterize mechanisms underlying social isolation-related outcomes to:
  • Identify prognostic markers of poor health outcomes
  • Inform the future development of personalized, biobehavioral interventions to improve health and quality of life

National Institute of Dental and Craniofacial Research (NIDCR)

Mechanistic research on the processes underlying social connection or isolation as they relate to dental, oral, or craniofacial health. Specific topics may include:

• Characterizing process by which social connection or isolation influence dental care utilization
• Understanding mechanisms by which dental, oral, or craniofacial conditions impact social processes (e.g., communication, identity, relationships, etc.)
• Illuminating processes that may inform strategies for reaching and providing dental care to individuals who are otherwise socially isolated

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

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

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

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 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, with the following additional instructions:

1.4 Clinical Trial Questionnaire

Applications to this FOA must propose a study that falls within the NIH definition of a clinical trial and also meets the definition of basic research. Consequently, applicants must answer "yes" to the four questions on 1.4 Clinical Trial Questionnaire and complete the subsequent form fields accordingly.

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.

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.

Section V. Application Review Information

1. Criteria

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

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

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?

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

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?

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

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?

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

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?

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

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?

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Study Timeline

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories 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

Not applicable.

Renewals

Not applicable.

Revisions

Not applicable.

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 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.

• 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.

• 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.

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.

Institutional Review Board or Independent Ethics Committee Approval: Grantee 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 awardee 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).

2. Administrative and National Policy Requirements

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. 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.

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.

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. HHS provides general 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/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.htmlhttps://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/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. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. 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 http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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 agreements are 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: [email protected] (preferred method of contact)
Telephone: 301-945-7573

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

The Office of Behavioral and Social Sciences Research (OBSSR) facilitates OppNet on behalf of NIH but cannot accept assignment of applications or manage awards that are funded. Please contact one of the IC-based contacts below for inquiries regarding the suitability of the proposed project for this FOA and the IC's research portfolio.

William Elwood, PhD
Office of Behavioral and Social Sciences Research (OBSSR)
Telephone: 301-402-0116
Email: [email protected]

Rebecca Ferrer, PhD
National Cancer Institute (NCI)
Telephone: 240-678-5075
Email: [email protected]

Merav Sabri, PhD
National Center for Complementary and Integrative Health (NCCIH)
National Institutes of Health (NIH)
Telephone: 301-496-2583
Email: [email protected]

Cheri Wiggs, PhD
National Eye Institute (NEI)
Telephone: 301-451-2020
Email: [email protected]

Melissa Gerald, PhD
National Institute on Aging (NIA)
Individual Behavioral Processes Branch
Telephone: 301-496-3136
Email: [email protected]

Amelia Karraker, PhD
National Institute on Aging (NIA)
Population and Social Processes Branch
Telephone: 301-496-3131
Email: [email protected]

Ivana Grakalic, PhD
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Division of Neuroscience and Behavior
Telephone: 301-496-3136
Email: [email protected]

Benjamin Xu, PhD
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Division of Neuroscience and Behavior
Telephone: 301-443-6545
Email: [email protected]

Ricardo Cibotti, PhD
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: (301) 451-5888
Email: [email protected]

Layla Esposito, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6888
Email: [email protected]

Amy Lossie, PhD
National Institute on Drug Abuse (NIDA)
Genetics, Epigenetics, and Development Neuroscience Branch
Telephone: 301-827-6092
Email: [email protected]

Shelley Su, PhD
National Institute on Drug Abuse (NIDA)
Services Research Branch
Telephone: 301-402-3869
Email: [email protected]

Lana Shekim, PhD
National Institute on Deafness and Communication Disorders (NIDCD)
Telephone: 301-496-5061
Email: [email protected]

Jovier D. Evans, PhD
National Institute of Mental Health (NIMH)
Neuroscience of Mental Disorders and Aging Program
Telephone: 301- 443-1369
Email: [email protected]

Janine Simmons, MD, PhD
National Institute of Mental Health (NIMH)
Social and Affective Neuroscience Program
Telephone: 301-443-6652
Email: [email protected]

Nadra C. Tyus, DrPH, MPH
National Institute on Minority Health and Health Disparities (NIMHD)
Telephone: 301-594-8758
Email: [email protected]

David A. Jett, PhD
National Institute on Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: [email protected]

Lois Tully, PhD
National Institute of Nursing Research (NINR)
Telephone: 301-594-5968
Email: [email protected]

Elise Rice, Ph.D.
National Institute of Dental and Craniofacial Research
Telephone: 301-594-4814
Email: [email protected]

Maribeth Champoux, PhD
Center for Scientific Review (CSR)
?Telephone: 301-594-3163
?Email: [email protected]

Karen Robinson-Smith
National Eye Institute (NEI)
Phone: (301) 451-2020
Email: [email protected]

Priscilla Grant, J.D.
National Institute on Minority Health and Health Disparities (NIMHD)
Telephone: 301-594-8412
Email: [email protected]

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]

Dede Rutberg, MBA
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: [email protected]

Section VIII. Other Information