Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). 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 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The purpose of this Funding Opportunity Announcement (FOA) is to inform the scientific community of the pain research interests of the various Institutes and Centers (ICs) at the National Institutes of Health (NIH) and to stimulate and foster a wide range of basic, clinical, and translational studies on pain as they relate to the missions of these ICs.

Background

Pain is a critical national health problem; it affects millions of Americans and incurs significant economic costs to society. Pain often results in disability and, even when not disabling, it has a profound effect on the quality of life. Its deleterious effects have been demonstrated in morbidity, immune function, sleep, cognition, eating, mobility, affective state, psychosocial behaviors, and overall functional status. In the hospitalized patient, pain may be associated with increased length of stay, longer recovery time, and poorer patient outcomes, which in turn have health care quality and cost implications.

The NIH Pain Consortium was established in 1996 to enhance pain research and promote collaboration among researchers across the many NIH ICs that have programs and activities addressing pain. Currently, the research interests of twenty-one NIH Institutes, Centers, and Offices are represented in the Consortium. Although these combined efforts have resulted in great scientific progress, the understanding and treatment of pain remains incomplete. In 2011, the Institute of Medicine (IOM) released its report, "Relieving Pain in America", which outlined the state of pain prevention, care, and research, and provided a blueprint to guide efforts to transform pain care in the United States. The core recommendations of the IOM report led to development of the National Pain Strategy (NPS), which was released by HHS in 2016. The NPS outlines the federal government’s first coordinated plan for reducing the burden of chronic pain that affects millions of Americans. NIH is responsive to and in alignment with the NPS and the IOM report, and continues to be committed to supporting research to advance the scientific understanding of pain and the treatments available to those suffering in pain.

The NIH Pain Consortium supports research on all conditions in which pain is a prominent feature. Of interest are diseases, such as cancer, that of themselves or their treatment may result in pain. Many primary conditions, whether acute (such as injury), recurring (such as migraine), or chronic (such as arthritis) are significantly complicated by co-morbid pain disorders. Some pain conditions are unassociated with other primary diagnoses. Chronic pain is widely believed to represent a disease itself, causing long-term detrimental physiologic changes and requiring unique assessments and treatments. The areas of research detailed below and the following acute and chronic pain conditions are of special interest but do not comprise a comprehensive or complete listing of research areas relevant to this FOA.

• Inflammatory Pain
• Visceral pain
• Chronic urologic pelvic pain syndromes
• Neuropathic pain
• Spinal cord injury pain
• Headache
• Musculoskeletal pain, including back pain
• Cancer related pain (e.g. pain due to metastasis or primary disease)
• Cardiovascular pain disorders
• Chemotherapy-induced neuropathies and other related toxicities (e.g. aromatase inhibitor-induced arthralgias).
• Fibromyalgia
• Temporomandibular joint and muscle disorders
• Pain associated with HIV/AIDS
• Pain associated with osteoporosis
• Pain associated with communication disorders (e.g., otitis media, tinnitus, burning mouth syndrome, dysphagia)
• Pain at the end of life
• Pain in older persons with multiple chronic conditions
• Pain in people with drug and alcohol addictions
• Pain in persons with neuromuscular conditions
• Pain in preterm neonates exposed to multiple medical interventions and/or procedures
• Skin disorders and pain
• Orofacial pain

Research Objectives

The R21 mechanism is intended to encourage new exploratory and developmental research projects. For example, such projects could assess the feasibility of a novel area of investigation or a new experimental system that has the potential to enhance health-related research. Another example could include the unique and innovative use of an existing methodology to explore a new scientific area. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models, or applications that could have a major impact on a field of biomedical, behavioral, or clinical research.

Applications for R21 awards should describe projects distinct from those supported through the traditional R01 mechanism. For example, long-term projects, or projects designed to increase knowledge in a well-established area, will not be considered for R21 awards. Applications submitted under this mechanism should be exploratory and novel. These studies should break new ground or extend previous discoveries toward new directions or applications.

New and innovative advances are needed in every area of pain research, from the microperspective of molecular sciences to the macro perspective of behavioral/social sciences. Although great strides have been made in some areas, such as the neural pathways of pain, chronic pain and the challenge of its treatment have remained uniquely individual and largely unsolved. Applications that seek to improve the understanding of the causes, costs, and societal effects of both acute and chronic pain and the relationships between the two are highly encouraged. Studies on the mechanisms underlying the transition from acute to chronic pain are also needed. Additionally, applications that link such understandings to the development of better approaches to therapeutic interventions, including complementary and alternative medicine (CAM) interventions, and self-management of acute and chronic pain are in keeping with the current translational focus of NIH and are encouraged.

The following topic areas are not intended to be comprehensive or exhaustive. Synergistic studies that reach across two or more of these areas are encouraged. Interdisciplinary and multidisciplinary research is especially encouraged, as is research that involves specific cooperation between basic and clinical scientists, incorporates longitudinal and innovative clinical trial designs, and uses comparative effectiveness research techniques. These pain research areas also cut across ICs and programs and should not be viewed as restricted to only one specific IC.

Molecular and Cellular Mechanisms of Pain

Improved treatments of acute and chronic pain conditions require a thorough understanding of the processes underlying the transmission and perception of painful stimuli. Discovery of the molecules, cells, and neuronal pathways involved in nociception/pain perception and affective aspects of pain are critical. Molecular and cellular studies, when coupled with studies in animal models and clinical research, will provide a comprehensive basis for the development of new pharmacological, behavioral, and technology-based treatments for chronic pain disorders, and/or research on the mechanisms of action of therapies effective for chronic pain. Hormones, neurotransmitters and their receptors, ion channels, G-protein coupled receptors, neuropeptides, and neurotrophic factors are just a few of the molecules of interest in pain studies. Molecular mechanisms and nervous system circuitry involved in facilitation and inhibition of pain signaling and in the development of hypersensitive pain states are important targets of pain research. Neurons, glial cells, and keratinocytes all play important roles in pain sensation and approaches examining their individual functions and their interactions are vital for understanding pain processes. Research is encouraged but not limited to science in the following areas:

• Mechanisms that underlie sex differences in the pain experience.
• Cellular and molecular mechanisms involved in pain processing, modulation, and perception.
• Molecules and processes that target cellular mechanisms involved in signaling, modulation, and perception of pain, as well as changes in these processes over the developmental life-course, to enhance innovative therapeutic development.
• Ontogeny and neuropharmacology of the pain system.
• Endogenous and environmental factors that alter pain during the course of development, in response to injury, and related to disease processes.
• Mechanisms of hypersensitivity including both central and peripheral mechanisms of hyperalgesia and allodynia.
• Endogenous molecules that modify pain perception and analgesic treatments.

Genetics of Pain

Clinical studies have identified polymorphisms at several gene loci that are associated with differential sensitivity to experimental pain. Inbred strains of mice also show differential pain responses in models of neuropathic and inflammatory pain. These studies strongly suggest that genetics plays an important role in pain mechanisms. Chronic pain conditions are complex disorders where environmental and genetic influences interact to affect sensitivity to noxious stimuli and relief from pain. Polymorphisms and mutations in mitochondrial DNA may also play a role in modulating pain, especially in muscles and peripheral nerves. Elucidating the genetic contributions to the individual variability in pain sensitivity and perception is of much interest. Research is encouraged but not limited to science in the following areas:

• Genes and gene variants involved in the complex processes of pain perception.
• Genome-wide screens for polymorphisms associated with increased risk for onset, development and persistence of pain disorders.
• Utilization of pharmacogenetics to identify gene variants with potential to inform treatment providers which pain medications may be most effective for the individual needing therapy, with the fewest side effects.
• Use of gene therapy to ameliorate chronic pain.
• Gene polymorphisms and gene-environment interactions that predict pain development or treatment response.
• Epigenetic mechanisms underlying chronic pain conditions.

Biobehavioral Pain

The experience of pain is a complex interaction of biological, cognitive, behavioral, sociocultural, spiritual, and environmental factors. Pain etiology, severity, tolerance, exacerbation, maintenance, and treatment are all significantly influenced by this complex of acknowledged but poorly understood interactions. Comorbid conditions that alter affect, such as mood disorders, can induce or exacerbate pain. Although it is recognized that psychological factors, such as expectation or stress, significantly contribute to pain tolerance and treatment efficacy, the physiological mechanisms of these effects are poorly understood. Physiologic responses such as autonomic arousal, muscle tone and activity, skin thermal receptor activation, and cardiopulmonary reactivity, are perceived as painful in some behavioral and sociocultural environments, but not in others. The elucidation of these complex interactions will enable better assessment of pain in clinical settings, more effective therapeutic approaches, greater ability to prevent pain onset, and potentially will increase the individual's ability to self-manage pain.

Research is encouraged but not limited to science in the following areas:

• Adaptation to pain and ways to incorporate this adaptation into treatments.
• Mechanisms and process variables that are responsible for the efficacy of behavioral and CAM interventions for pain. This research includes studies to better understand the effect of patients' expectations and beliefs, psychophysiological states (e.g., anxiety, relaxation, stress), adherence, and specific cognitive (e.g., imagery) and sociocultural (e.g., support systems) components in behavioral and CAM interventions to treat pain.
• Biobehavioral techniques for optimizing adherence to pain management. Identify and reduce barriers to adherence to pain management strategies.
• Sensory, cognitive, and affective aspects of acute and chronic pain in individuals across the lifespan.
• Development of methods for assessing relative contributions of biological, psychological, behavioral, and environmental predictors of the course of pain, pain dysfunction, and response to treatment for pain.
• Interactions of pain and sleep, their combined impact on function and illness recovery, and interventions that target these interactions.
• Relationships among a variety of emotional states (e.g., anger, fear, anxiety and depression), which are associated with acute and chronic pain conditions, and how these affective states modify the experience of pain and treatment outcomes.
• Interaction of biological markers, central nervous system mechanisms, and drug, behavioral, and CAM interventions.
• Mechanisms that underlie gender and cultural differences in the pain experience.

Models of Pain

There are many factors responsible for pain experienced by patients. Current animal models of pain have been useful in understanding the mechanisms of pain and developing interventions that target these particular mechanisms. However, many of the existing animal models do not adequately reflect clinical pain conditions and, in particular, chronic pain disorders. The development of new animal models is necessary in order to discover the underlying mechanisms of pain perception as well as the mechanisms of analgesia that will prove useful in treating patients. Innovative clinical modeling studies are also needed to advance our understanding of these underlying mechanisms. Research is encouraged but not limited to science in the following areas:

• New animal models and refinement of existing animal models.
• New measures of pain in animals that are non-invasive and objective, and that permit a behavioral or functional assessment of pain and pain treatment outcomes.
• Use of transgenic animals in the study of pain mechanisms.
• Studies in patients with chronic pain conditions that develop, test, and validate new models of these chronic disorders.
• Computational models that predict development of pain and/or treatment responses.
• Computer simulations of pain that overcome ethical concerns and expand the range of studies possible.
• System models to improve understanding of pain and treatment integrating multiple layers of biological and behavioral sciences (e.g. across domains of genes, neuron, brain, behavior, family/social/work/environment and culture).
• Objective Measures of spontaneous pain in validated animal models of chronic pain conditions.

Diagnosis and Assessment of Pain

Most healthcare system interactions are initiated by persons with complaints of pain. To date, direct patient report is the basis of most pain assessments. Yet many patients, including the very young, persons with cognitive, sensory, psychiatric, or physical disabilities, those rendered unresponsive by their physiologic state (e.g., drug intoxication, severe brain injury), and those persons who by culture, education, language, or communication skills may be unable to effectively respond using currently validated assessment tools. To study, model, predict, prevent, diagnose, treat, or manage pain effectively, sensitive multimodal measurement tools are needed. Pain assessment techniques must be valid and reliable and provide sensitivity, both with single and repeated measurements, and allow for the assessment of acute, chronic, persistent, and breakthrough pain. Severity/intensity, type/location/source (i.e., somatic, visceral, neuropathic), and duration (acute, chronic, persistent, breakthrough) are key components to assess. Assessment should include diagnostic as well as outcomes measures. Research is encouraged but not limited to science in the following areas:

• Refinement of existing physiologic techniques for measuring pain for greater sensitivity and specificity.
• New, outcome-specific techniques for different populations.
• Sensitive assessment tools that are not language (neither receptive nor production) dependent.
• Refinement of pain measurements that can account for or predict the trajectory or course of pain, as well as the changes in pain over time.
• Predictive biomarkers and biosignatures of pain that are sensitive to rapid changes in pain.
• Develop pain assessments that are sensitive across both developmental and cognitive spectrums, especially assessments of pain in children and in older adults with declining cognitive function.
• New technologies to improve pain assessment in all populations, but especially in those persons with limited language abilities or those unable to verbalize their pain.
• Use of Patient Reported Outcomes Measurement Information System (PROMIS) measures for quantifying pain interference, behavior and severity

Pain Management

The prevalence of pain and inadequate pain management in patients is well documented. It is estimated that 75% of patients with advanced cancer experience moderate to severe pain; an IOM report states that 40% of people at the end of life have severe, unrelieved pain. A number of advances have been made in the treatment of chronic pain, most notably the neuroactive medications, counter-stimulation methods, and cognitive-behavioral therapies. However, adoption of these advances remains modest. Many patients report that they are reluctant or afraid to report their pain, are unaware of available pain management modalities, or do not adhere to pain treatment when available. Healthcare providers undertreat pain, fearing patient addiction, drug interactions, or adverse events. In addition, research findings consistently show the heterogeneity of response to treatment, even for pain of the same type and etiology.

Due to the biobehavioral nature of pain, pain management should engage interdisciplinary teams and involve both pharmacologic and non-pharmacologic approaches and self-management strategies. Longitudinal research in pain to include comparative effectiveness research and novel randomized controlled trials will ensure patients receive pain care that works best in the short and long term. Research is encouraged but not limited to science in the following areas:

• Interventions involving combinations and sequencing of pharmacological, non-pharmacological, self-management and behavioral interventions to manage pain in progressive, incurable diseases.
• Interventions to reduce pain that are customized to the group (i.e., targeted), as well as to the individual (i.e., tailored).
• New methods to manage pain in cognitively impaired individuals or those unable to verbalize their pain.
• Interventions to manage co-occurring symptoms related to pain such as depression and fatigue.
• Role of pain and pain management approaches in improving rehabilitation outcomes and preventing functional decline.
• Role of pain and pain management approaches on population health outcomes, utilization and cost
• Methods for optimizing maintenance and stability of treatment in patients with advancing disease or with pain from multiple contributing disease processes.
• Novel interventions to manage pain in progressive, incurable, nonmalignant conditions.
• Novel interventions to manage metastatic cancer pain which is progressive and incurable.
• Interventions to improve management of side-effects related to pharmacological pain therapy or to address interactions between therapeutics for pain and other diseases of their treatments.
• New techniques for managing pediatric pain.
• Models of therapy in those with uncontrolled pain and/or breakthrough pain.
• Pain management strategies at the end of life.
• Long-term (i.e., physiologic, behavioral, or developmental) effects of pharmacologic treatment during the neonatal period and childhood.
• Long term efficacy of existing pain therapies (e.g. chronic opiod therapy).
• Clinical trials to establish best pain management practices.
• Evaluation of pain management for acute trauma prior to transport to hospital or clinic.
• Pain management in individuals with multiple chronic conditions.

Epidemiology of Pain

One goal of this FOA is to stimulate innovative investigations that enhance our understanding of the incidence, prevalence, and correlates of pain within and across populations. Epidemiology is one of the fields of science recognized for its contribution to understanding of physical and mental disorders. However, epidemiologic information concerning pain disorders is not well developed. Research is encouraged but not limited to science in the following areas:

• Incidence and natural history of pain disorders and their correlates over time.
• Interplay of environmental (e.g., familial and/or neighborhood quality and resources), physical (e.g., co-morbid medical disorders that are a result of, or a cause of pain), behavioral (e.g., co-morbid mental and substance use disorders), and social or socio-economic (e.g., loss of employment-including issues of secondary or tertiary gain, social isolation, lack of mobility, dependence on others for basic caretaking) factors.
• Risk factors; including age, ethnicity, family history, gender, genetic predisposition, lifestyle, occupation, pre- or co-existing mental and physical disorders, and socio-economic status (SES); and the mechanisms that are associated with the occurrence, maintenance, and remission of pain conditions.
• Impact of pain on an individuals SES and the resulting health consequences (e.g., obesity, deconditioning, mental disorders, substance abuse) controlling for the effect of the cultural and socio-economic influence of the community.
• Prevalence of and methods for self-management of pain within and across cultural, racial, ethnic populations, and populations of special interest such as persons with disabilities, across age groups.
• The effect changes in practice or policy have on the measures of pain, e.g., effect of the increase in the amount of opioid prescriptions on the natural course of pain using aggregate population measures.
• Creation and adoption of innovative epidemiologic and statistical methodologies and study designs to further the understanding of pain disorders. Also use these techniques to maximize the analytic yield from new and existing data sets.
• Interrelationship of psychiatric disorders (e.g., borderline personality, histrionic, antisocial) and chronic pain, and relate these findings to pharmacological and behavioral therapies.
• Co-morbid disorders and pain, including descriptive studies of risk and protective processes, and interventions aimed at relieving adverse consequences associated with co-morbid disorders and pain.

Health Disparities

The Institute of Medicine reported significant racial and ethnic disparities with regard to the socioeconomic, health, and quality-of-life impacts of pain. Racial and ethnic minorities tend to be under treated for pain when compared with non-Hispanic Whites. There is also evidence for racial/ethnic differences in pain care for various types of pain. Persons with disabilities report greater levels of pain and less benefit from treatment than do those without disabilities. Little other data exists as to pain disparities in persons with disabilities, the homeless, or persons living in frontier/extremely rural areas. It is clear that many factors contribute to these health disparities, including patient preferences, differences in attitudes toward and response to treatments, access to and accessibility of health care providers, and health care system factors. This program announcement invites research applications that seek to address the underlying causes of these disparities and suggest ways to address and remedy them. In particular, clinical investigations and appropriate clinical trials relevant to health disparity issues are of interest. Research is encouraged but not limited to science in the following areas:

• Differences in care for various types of pain, acute postoperative pain, treatment-related pain, cancer pain, or chronic non-malignant pain, in various settings (i.e., health clinics, physician and dental offices, institutional settings including long-term care facilities, assisted living facilities, or emergency departments), and management of pain at the end of life.
• Differences in the factors contributing to pain disparities including patient-related (e.g., communication, attitudes), health care provider-related (e.g., decision making), and health care system-related (e.g., access to pain medication) factors.
• Differences in perceptions of pain and responses to pain and how these differences impact appropriate treatment management of pain.
• The nature and extent of disparities in the delivery of pain treatment in diverse populations.
• Existing and potential barriers to quality pain care and management including patient-related barriers, health care provider-related barriers, health care system-related barriers, and sociocultural barriers.
• Novel, evidence-based interventions to improve training for health care providers and educational interventions for minority patients.
• Measures of pain perception for those with cognitive impairment, or limited health literacy and from varied cultures.
• Assessment of the global impact, including societal and medical consequences, of pain related disparities on both individuals and society, and the potential impact of pain-related disability.
• Diverse cultural beliefs about and actions taken for pain and its management including self-care and that of lay caregivers.
• Treatment and management strategies for chronic pain in diverse populations.
• Means to identify population differences in pain perception and processing by addressing the incidence, severity, and consequences of pain in these and the general populations, and in specific disease states.
• New diagnostic tools for different pain mechanisms, and objective measures of treatment response that have validity in diverse populations.
• The prevalence and effectiveness of the use of non-pharmacological and novel (e.g. virtual reality) therapies for pain treatment in diverse populations such as ethnic minority groups and persons with disabilities.
• Pain management for special populations including infants, children, elderly, cognitively impaired, disabled, chronically and/or terminally ill, and patients with psychiatric diagnoses.

Translational Pain Research

The translation of laboratory-based, scientific discoveries into practical, clinical applications is a current priority for NIH. Such translational research has a reasonable probability of leading to practical outcomes within the foreseeable future and likewise resultant clinical findings should stimulate new areas of basic research. Inherent in translational research is the recognition of both efficacy (i.e., does the intervention work in a controlled setting) and effectiveness (i.e., does the intervention work in the natural environment) research. Effective translational research is extremely important in pain research and is needed to bridge the inherent differences in approach between basic studies of pain and the clinical study of pain conditions. Accordingly, applications directed toward translational pain research are of particular interest. Research is encouraged but not limited to science in the following areas:

• Novel pharmacological and non-pharmacological pain treatments and self-management pain strategies.
• Improved treatment protocols and adjunctive therapies that promote greater effectiveness, self-management, patient adherence or tolerance.
• Characteristics (e.g., gender, race, age, type of pain) that predict which patient populations will benefit most or least from various pain treatments.
• Barriers to effective pain treatment.
• New technologies for use in the study and treatment of pain in the natural environment of the patient’s daily living.
• Clinical studies to inform, develop, and validate new animal models of chronic pain conditions; i.e. a bedside to bench approach.
• Design and development of small molecule mimics and other advanced pharmacological approaches.

Specific to NIAMS: Applicants who wish to submit clinical trial applications for consideration by NIAMS should not submit the application to this FOA. Instead, applicants are encouraged to submit clinical trial applications to one of the FOAs listed at http://www.niams.nih.gov/Funding/Clinical_Research/clinical_main.asp.

Specific to NINDS: NINDS will not accept clinical trials under this FOA. Applicants submitting applications to NINDS which contain a clinical trial must submit to one of the NINDS FOAs specifically designed for clinical trials (see: http://www.ninds.nih.gov/research/clinical_research/index.htm ).

Specific to NCCIH: For this FOA, NCCIH will only support the following types of research: 1) basic and mechanistic studies to examine the impact of complementary health approaches on pain in cellular systems or model organisms; 2) mechanistic studies in humans to investigate the processes by which complementary health approaches exert their effects on pain and clinical conditions that often co-occur with pain; or 3) basic, mechanistic, or translational studies of phytocannabinoids and their derivatives for pain. NCCIH is not interested in applications of human clinical studies or trials that propose primary aims to evaluate efficacy or effectiveness. Investigators are encouraged to consult NCCIH Scientific/Research staff to identify NCCIH-specific FOAs to support clinical studies or trials that propose to measure the clinical impact of complementary or integrative health approaches.

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

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

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH 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) (formerly CCR) 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 and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

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).

Applicants must obtain the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

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

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

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

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

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

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

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

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

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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.

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

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.

This initiative is not subject to intergovernmental review.

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.

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 Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. 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 are required to follow our Post Submission Application Materials policy.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

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

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

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

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? 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 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?

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?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the 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 children, justified in terms of the scientific goals and research strategy proposed?

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?

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

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

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 children 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.

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.

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.

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.

Not Applicable

Not Applicable

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

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.

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).

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).

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.

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

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

As part of the scientific peer review, all applications:

• 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.

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

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

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

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

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 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.

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 http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. 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. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.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.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: https://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Ann O'Mara, Ph.D., R.N.
National Cancer Institute (NCI)
Telephone: 240-276-7050
Email: omaraa@mail.nih.gov

Martha Matocha, PhD
National Institute of Nursing Research (NINR)
Telephone: 301-594-2775
Email: matocham@mail.nih.gov

Yolanda F. Vallejo-Estrada, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-8926
Email: yolanda.vallejo-estrada@nih.gov

Wen G. Chen, PhD
National Center for Complimentary and Integrative Health (NCCIH)
Telephone: 301-451-3989
Email: chenw@mail.nih.gov

Jennifer Alvidrez, PhD
National Institute on Minority Health and Health Disparities (NIMHD)
Telephone: (301) 594-9567
Email: jennifer.alvidrez@nih.gov

Molly V. Wagster, PhD
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: wagsterm@nia.nih.gov

Michael Oshinsky, PhD
National Institute of Neurological Disorders & Stroke (NINDS)
Telephone: 301-496-9964
Email: michael.oshinsky@nih.gov

James Witter, MD, PhD, FACR
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-1963
Email: witterj@mail.nih.gov

David Thomas
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-1313
Email: dthomas1@nida.nih.gov

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

Sean Hine
National Cancer Institute (NCI)
Telephone: 240-276-6291
Email: hines@mail.nih.gov

Ron Wertz
National Institute of Nursing Research (NINR)
Telephone: 301-594-2870
Email: wertzr@mail.nih.gov

Diana Rutberg, MBA
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: rutbergd@mail.nih.gov

Shelley Carow
National Center for Complimentary and Integrative Health (NCCIH)
Telephone: 301-594-3788
Email: carows@mail.nih.gov

Priscilla Grant
National Institute on Minority Health and Health Disparities (NIMHD)
Telephone: 301-594-8412
Email: priscilla.grant@nih.gov

Jessi Perez
National Institute on Aging (NIA)
Telephone: 301-402-7739
Email: perezj@mail.nih.gov

Tijuana Decoster, PhD
National Institute of Neurological Disorders & Stroke (NINDS)
Telephone: 301-496-9531
Email: decostert@mail.nih.gov

Andrew Jones
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-451-0610
Email: jonesan@mail.nih.gov

Christine Kidd
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-1372
Email: ckidd@nida.nih.gov

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.