It is critical that applicants follow the Research (R) 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

As the population of older adults continues to increase, the prevalence of diseases and conditions common in aging is expected to rise. Cardiovascular diseases, cancer, chronic lung diseases, dementia, and chronic kidney disease will likely continue to be the greatest sources of morbidity and mortality, as well as the costliest conditions to healthcare systems. However, older Americans infrequently have just one chronic health condition. In 2010, over two-thirds of Medicare beneficiaries had more than one chronic condition, and 14% had 6 or more chronic conditions. Disability and greater care needs associated with these conditions is leading to an increase in residence in nursing homes and other long-term care facilities. Healthcare costs will continue to grow, with health-related spending expected to top 20% of gross domestic product by 2025.

Serious illnesses resulting from the progression of chronic health conditions pose particular challenges for health care decision-making. While treatments with curative intent may forestall complications and relieve some symptoms, disease progression ultimately leads to increased disability and symptom burden that compromise quality of life. In addition, among patients with multiple morbidities, treatments for co-occurring conditions may antagonize each other (also known as therapeutic competition), and patients must evaluate tradeoffs among multiple sub-optimal treatment options. As a result, patients' values, preferences, and goals become essential to inform care decisions.

Providing care that is consistent with a patient's values, preferences, and goals is a cornerstone of palliative care, an interdisciplinary, patient-centered approach that aims to improve quality of life for persons with advanced illness and their families. Palliative care focuses on several objectives including relief of symptoms and suffering, communication of prognosis and treatment options in the context of patients' goals, and coordination of care within and across healthcare settings. Palliative care is not synonymous with hospice nor end-of-life care. Rather, these are parts of the spectrum of care for serious illness that is addressed by palliative care from diagnosis through terminal stages of disease. Moreover, palliative care does not necessarily entail withholding or curbing treatment. Relief of symptoms, enhancing quality of life, and many other specific aspects of goal-concordant care may, in fact, involve optimal medical or surgical treatment of disease. Furthermore, proactive approaches to disease management, such as pre-habilitation strategies prior to surgery to improve functional recovery, can be consistent with goal-concordant care. However, without knowing patients' values and preferences, care may be inconsistent or even run counter to patients' goals.

Most evidence for the effectiveness of palliative care to date has been based on a model of consultation or co-management by specialty-trained palliative care clinicians. However, the demand for palliative care specialists far outpaces their supply. Disease-focused specialists may be well-poised to incorporate aspects of palliative care into their practices, such as basic management of pain, anxiety, and depressive and other symptoms, and effective basic patient-centered discussions about prognosis, goals of care, and code status. Research to identify and implement these aspects of care may be particularly suited to such specialties as oncology, cardiology, pulmonary/critical care medicine, nephrology, neurology, and others. Among surgical specialties, typically acute presentations and rapidly shifting health status, potentially burdensome interventions, need for more appropriate outcome measures, and surgical cultural norms pose unique challenges for palliative care research.

Much of the existing evidence base for palliative care has been in hospital settings. Further research should also include other health system and community settings, care delivery models, and relevant outcomes. Such research is needed to identify specific populations or settings for which particular palliative care practices may or may not be appropriate. Research can also guide alternatives for preventable emergency department visits, hospitalizations, and other avoidable utilization among seriously ill patients in the community. Innovative approaches such as tele-medicine may be particularly useful in specific settings such as rural areas where access to healthcare is limited. Finally, as the role of informal caregivers expands alongside current trends toward aging in place, more research is needed on the role of intimate partners and adult children in care and decision-making for older individuals with serious illnesses.

This Funding Opportunity Announcement (FOA) encourages exploratory or developmental research grant applications to develop new tools, methods, and models focused on palliative care in geriatric populations. This FOA covers studies in a variety of settings including hospitals (and specific sites within hospitals including specialty medical or surgical wards, intensive care units, and emergency departments), post-acute care settings, outpatient clinics and doctors' offices, patients' homes and other residential settings, assisted living facilities, nursing homes, hospices, and other healthcare or community settings. This FOA encourages both prospective studies and analyses of existing datasets, health and medical records, claims data, or other sources. Leveraging ongoing cohorts, intervention studies, networks, data and specimen repositories, and other existing research resources and infrastructure are encouraged. Study designs may include observational approaches, quasi-experimental designs, and limited interventional studies where feasible for this R21 mechanism.

Topics of interest among Institutes and Centers (ICs) participating in this FOA are summarized below. Applicants are encouraged to contact the Scientific/Research contact listed in Section VII to ensure that proposed aims are consistent with the mission(s) of the intended IC(s). Where IC topic areas overlap, applicants are especially encouraged to contact the respective IC representatives to discuss appropriate arrangements for dual assignment.

National Institute on Aging (NIA)

The NIA is interested in studies that focus on palliative care in individuals and populations with age-related diseases, conditions, and/or special problems and needs associated with older age, such as multiple chronic conditions, polypharmacy, cognitive impairment/dementia, age-related disabilities, and other geriatric syndromes. Topics of interest include, but are not limited to:

• Development and evaluation of new health care models and approaches aligned with patient values, preferences and goals in seriously ill older adults with multiple chronic conditions, Alzheimer's disease and related dementias, or other age-related conditions.
• Development and evaluation of new assessment tools in older adults with complex care needs; e.g., multiple chronic conditions, frailty/multiple age-related disabilities, cognitive impairment/dementia.
• Development and evaluation of new strategies to incorporate palliative care approaches for aging-related conditions by health care practitioners who are not palliative care specialists, or collaborative approaches between palliative care specialists and clinicians from other disciplines. (See also research objectives of other participating IC's below for specific disciplines.)
• Evaluation of new decision support tools, palliative care consultation triggers, communication aids, and advance care planning approaches for seriously ill older patients and their surrogate decision-makers (when present) or for seriously ill, unbefriended older patients to achieve goal-concordant care, with particular attention to revisiting both shifting goals and differing family member perspectives.
• Evaluation of novel approaches for discontinuing medications or other treatments in older adults with serious illnesses to reduce treatment complexity, mitigate drug interactions and other adverse effects, or achieve preferred treatment tradeoffs, and barriers to such discontinuation among patients, their families, and clinicians.
• Understanding the impact of single or multiple symptoms on function, disease outcomes, quality of life, and decision-making in seriously ill older adults, particularly with multiple morbidities. Symptoms may include pain, fatigue or increased fatigability, dyspnea, nausea/vomiting, constipation, pruritus, anorexia, sleep disturbance, delirium, anxiety, and depressive symptoms. (Applicants are encouraged to see RFA-AG-16-013 for further discussion of fatigability.)
• Development of novel pharmacologic or non-pharmacologic strategies to relieve symptoms (as in previous bullet) in older adults through consideration of aging physiology, concurrent conditions or treatments, altered symptom perception, or other aging-related changes.
• Development of new approaches for understanding and addressing gender, ethnic, geographic, and socioeconomic disparities in access, delivery, and outcomes of palliative care for older adults and/or their caregivers.
• Development of new approaches for incorporating and analyzing patient-centered variables relevant to goal-concordant care in older adults that are not routinely captured in research or clinical care settings; e.g., functional assessment, values and treatment preferences, subjective well-being, social support, financial status, and cultural factors.
• Development of new models for addressing systemic challenges to conducting research studies of palliative care in older adults, such as barriers to care, high rates of disability and mortality, and adherence among patients, caregivers, family members, and clinicians.
• Novel analyses of the effects of coverage policies of Medicare and other care funders on timely access to appropriate palliative care, and of the effects of care coordination, payment bundling, or other organizational and financing innovations on timely access to appropriate palliative care.
• Development and evaluation of novel analytic methods for quasi-experimental and observational studies of palliative care strategies in older adults that address time-dependency, multimodal treatment, matching of control subjects, or other important parameters.

NIA-supported Research Centers may be particularly useful for accessing recruitment resources, analytic capabilities, specimens, specialized expertise, and other aging-related research resources. More information about each of these Centers programs can be found at their respective links: Alzheimer's Disease Research Centers, Centers on the Demography and Economics of Aging, Claude D. Pepper Older Americans Independence Centers, Edward R. Roybal Centers for Translation Research in the Behavioral and Social Sciences of Aging, and Resource Centers for Minority Aging Research.

National Institute of Nursing Research (NINR)

NINR's focus includes science that assists individuals, families and family caregivers in managing the complex experiences of advanced symptoms in serious, advanced illness; to mitigate the effects of advanced symptom burden on individual and caregiver health and well-being; and to optimize planning for end-of-life decision-making and goal-concordant care. NINR is particularly interested in studies that address issues such as management of pain and other advanced symptoms and behavioral, emotional, social, spiritual and informed decision-making support. Interventions that address supportive, palliative, and hospice needs across a continuum of services in coordination with individuals, families and their health care teams are encouraged.

In addition to the overall objectives, examples of specific research topics include, but are not limited to:

• Develop, test and evaluate minimally invasive methods including tools, technologies and assessments to monitor physiological, behavioral and emotional status, including advanced symptoms and individual- and caregiver-reported outcomes, that are effective and acceptable to older adults and their caregivers.
• Identify similarities and differences and/or develop, test and evaluate interventions addressing the needs of older individuals and their family caregivers for advanced symptom management, including behavioral, emotional, social, spiritual and informed decision-making support across populations of advanced diseases such as advanced heart failure and other cardiovascular diseases, advanced renal disease, advanced hepatic disease, advanced respiratory conditions including advanced COPD, and advanced cancers.
• Develop, test and evaluate assessments and interventions during the palliative care period that assess and improve grief, bereavement and loss outcomes for older adults.
• Identify optimal non-pharmacological methods for managing advanced or complex symptoms including, but not limited to, pain dyspnea, fatigue, nausea, delirium, sleep disturbance, pruritus, etc. in older adults with advanced disease.
• Identify multidimensional palliative care needs of older adults and their family caregivers including, but not limited to, physical, psychosocial, behavioral, emotional and spiritual needs and develop, test and evaluate innovative interventions/models of care that address these needs.
• Develop, test and evaluate interventions/models of palliative care that addresses issues associated with frailty in older adults.
• Develop, test and evaluate interventions that address transitions across the palliative and end-of-life care continuum, with the aim of maintaining continuity/coordination of care.
• Evaluate the unique needs related to end-of-life issues in older adults (e.g., management of multiple conditions, assessment and management of advanced or complex symptoms, advance care planning and communication relating to advance care planning).
• Test the acceptability and effectiveness of palliative care strategies across gender or ethno-cultural perspectives among older adults.

Interdisciplinary collaborations that include nurse scientists in the project team are strongly encouraged. Additionally, applicants are encouraged to engage the resources and expertise of existing Palliative Care Networks such as the Palliative Care Research Cooperative Group, when appropriate.

National Institute on Minority Health and Health Disparities (NIMHD)

Racial/ethnic minorities may have unique preferences, decision-making, self-care strategies, access and use of informal or complementary therapies, caregiving, and family and social networks that support geriatric care which affect their choice and use of palliative care. Minorities are less likely to use Advanced Directives and Hospice Care and are more likely to die in hospitals after undergoing aggressive care and accruing financial burdens, and there remains an overall distrust of the health care system and institutions, as well as underutilization of current palliative care services. Minorities are also more likely to have multiple chronic diseases and a greater impact on health-related quality of life based on these diseases, thus requiring more complex care, and they are more likely to experience racially discordant care. Less is known about geriatric palliative care among populations stratified by socioeconomic status independent of race/ethnicity, among those living in underserved rural residences, and among those of sexual and gender minority status.

NIMHD is interested in supporting research on one or more minority or health disparity populations (African Americans/Blacks, Hispanics/Latinos, American Indians/Alaska Natives, Asian Americans, Native Hawaiians and Other Pacific Islanders, socioeconomically disadvantaged populations, underserved rural populations, and sexual and gender minority populations) that focuses on understanding the mechanisms and pathways that contribute to disparities in palliative care by examining the interplay of factors from multiple levels, e.g., individual, family, community, clinician, and health systems. Research may propose using available secondary data, health system data and/or collection of primary data.

Research topics of interest include but are not limited to:

• Identifying values, preferences and goals for race/ethnic minorities or other health disparity populations' patients, families, and caregivers and how these affect palliative care outcomes.
• Understanding the role of individual, family, culture, clinician, health system, and social factors that impede or strengthen palliative care.
• How to effectively address health determinants from environmental, cultural, social and system levels within patient-centered approaches.
• Improvement and exploration of new and existing palliative care indicators/variables able to distinguish the quality, values, preferences and goals that are particular to minority or health disparity populations, such as functional assessment, symptom burden, quality of life, values and treatment preferences, subjective well-being, social support, financial status, cultural factors, and other biological or psychosocial variables.
• Understanding and strengthening patient-clinician interactions, communication, medical decision-making and continuity of care. For example, assessing ways to improve awareness and knowledge of care options, address patient preferences, minimize clinician biases, address trust barriers, address system barriers, increase coordination of care, and manage expectations.
• Understanding the context of care settings (e.g. hospital, clinic, community, and home-based settings), how these effect health outcomes, and what influences the patterns of choice, utilization, and quality of the settings.
• Understanding the role and use of self-management, cultural, traditional, and spiritual approaches among minority and health disparity populations within palliative care.
• Understanding attitudes and preferences regarding advance care planning among minorities and health disparity populations, as well as compliance with advance care planning by clinicians and health care systems.
• Understand how advance care planning models can be improved to address barriers, attitudes, values, and goals for minority and health disparity populations, clinicians, and health care systems.

National Cancer Institute (NCI)

The NCI is interested in studies that focus on advancing the science of geriatric palliative care in the context of cancer patients, cancer populations, and other persons affected by cancer; examples of studies of interest include, but are not limited to:

• Analyze and compare biological, social, and psychological factors that place elderly patients at risk for poor outcomes (decreased survival, serious adverse events) during and following cancer treatment.
• Examine the trajectory of physical and functional abilities during cancer treatment.
• Develop and refine interventions that improve older patients' tolerance of and adherence to cancer therapies.
• Examine physician and patient factors that contribute to treatment decision-making, e.g., enrolling in cancer clinical trials, implementing dose reductions of cancer therapies.
• Develop, test, and evaluate interventions that aim to deliver timely, effective, patient-centered palliative care to older adults diagnosed with cancer.
• Develop, test, and evaluate cancer care delivery models for older adults with cancer, including those that allow for the provision of palliation simultaneously with active treatment, including clinical trial participation.
• Identify and address the palliative care needs of special cancer patient populations who may be medically underserved by palliative care, including older adults with comorbid conditions and individuals being treated for less common cancers and hematologic malignancies.
• Expand knowledge of the efficacy of interventions known to be effective at earlier places along the cancer continuum to manage common cancer symptoms at the end of life.
• Develop and test tools, multilevel interventions, care delivery models, and health IT features that facilitate the communication of advanced care planning documents among primary, specialty, and acute care providers, and the development of shared understanding of the care plan and interdependencies involved among older adults, family members, caregivers, physicians, healthcare practitioners and healthcare organizations who care for older adults with cancer.
• Test the feasibility, acceptability, reach, and effectiveness of telehealth and eHealth palliative care services for older adults diagnosed with cancer, particularly those in medically underserved communities.
• Develop interventions to build and strengthen cancer palliative care capacity among healthcare providers across the spectrum of healthcare delivery settings.
• Develop feasible and effective approaches to collect patient-generated health data, including patient-reported outcomes (PROs) from older adults with advanced cancers, including patients with limited health literacy and technology access, and literacy.
• Develop feasible and effective approaches to evaluate the quality of palliative care provided to older adults with cancer and comorbid conditions.
• Develop and test methods in data collection and data analysis to address missing outcomes data in palliative care intervention studies of older adults with cancer (e.g., missing due to attrition, patient condition precluding completion of PRO measures), including use of proxy outcome evaluators and clinician-rating scales.
• Examine prognostic understanding and awareness among older adult cancer patients (from the initiation of palliative care to end-of-life), as well as how patients' prognostic understanding relates to family members' and caregivers' prognostic understanding, and how patient and family beliefs relate to oncologist-provided prognoses.
• Develop, test, and evaluate intervention approaches implemented across different healthcare systems and community settings that encourage palliative care interventions based on older cancer patient's health status, not age.
• Develop, test, and evaluate intervention approaches (from initiation of palliative care to end-of-life) implemented across different healthcare systems and community settings that are based on older cancer patient's health status, not age.

Applicants are encouraged to enroll subjects who represent accurately the broad range of age, gender, race, ethnicity, health, and functional level in the geriatric population. Applicants are strongly discouraged from excluding subjects with cognitive impairment, frailty, or other age-related complicating conditions without compelling scientific justification. Consideration of social factors is particularly encouraged in clinical studies, as inattention to such issues as socioeconomic status, built environment barriers, and attitudes and behaviors may likely threaten external validity.

Applicants are encouraged to consider using patient-reported outcome measures such as PROMIS , NIH Toolbox, and Neuro-QoL . Applicants may also find useful a searchable database of published instruments to detect cognitive impairment in older adults. Cost-effectiveness and other economics-related outcomes are appropriate provided that studies are consistent with NIH's priorities for health economics research.

Applicants interested in conducting ancillary investigations or secondary analyses of aging-relevant population studies can search the NIA Population Studies Database, National Archive of Computerized Data on Aging, or publicly available databases for aging-related secondary analyses in the behavioral and social sciences.

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

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

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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.
• o 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).

Buttons to access the online ASSIST system or to download application forms 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.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, 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.

Appendix:

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

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

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

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions.

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

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

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 emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.

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

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

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

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?

In addition, for applications proposing clinical trials

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?

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?

In addition, for applications proposing clinical trials

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?

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?

In addition, for applications proposing clinical trials

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?

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?

In addition, for applications proposing clinical trials

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?

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?

In addition, for applications proposing clinical trials

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?

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.

Specific to applications proposing clinical trials

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)?

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.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA. ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain "applicable clinical trials" on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as 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).

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

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 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 http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://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 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 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.

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.

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

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.

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: http://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 Center Telephone: 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

Basil Eldadah, M.D., Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-6761
Email: eldadahb@nia.nih.gov

Jeri L. Miller, Ph.D.
National Institute of Nursing Research (NINR)
Telephone: 301-594-6152
Email: jmiller@mail.nih.gov

Adelaida Rosario, Ph.D.
National Institute on Minority Health and Health Disparities (NIMHD)
Telephone: 301-594-8683
Email: adelaida.rosario@nih.gov

Alexis Bakos, Ph.D., M.P.H., R.N.
National Cancer Institute (NCI)
Telephone:240-276-6609
Email: alexis.bakos@nih.gov

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

Robin Laney
National Institute on Aging (NIA)
Telephone: 301-496-1473
Email: robin.laney@nih.gov

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

Priscilla Grant, J.D.
National Institute on Minority Health and Health Disparities (NIMHD)
Telephone: 301-594-8412
Email: pg38h@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.