Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose:

This funding opportunity announcement (FOA) seeks to support research to understand and reduce disparities in opioid care; and to determine the mechanisms for the variation in the prevalence of Opioid Use Disorder (OUD) in U.S. health disparities populations. NIMHD and the participating Institutes have a specific interest in projects that will focus on health disparities pathways, explaining opioid health outcomes by examining the impact of different determinants (biological, behavioral, socio-cultural, environmental, physical environment, health system) at multiple levels (i.e., individual, interpersonal, community, societal) on health outcomes in health disparity populations (see the NIMHD Research Framework for examples of health determinants of interest).https://www.nimhd.nih.gov/about/overview/research-framework.html.

Background:

The abuse of prescription and non-prescription opioids is one of the greatest public health threats in the US today. Ninety-one Americans die every day from an opioid overdose. Driven by this alarming rate of opioid abuse and misuse, drug overdose is now the leading cause of accidental death in the U.S. Nearly 2.5 million people in the US are suffering from opioid addiction related to prescription drugs for chronic pain. Opioid use disorders (OUD's) were most common among those who were uninsured or unemployed, were low-income individuals, or had behavioral health problems. Seventy-five to eighty-three percent of those reported starting with a prescription drug. Presently, death rates from opioid overdoses in rural areas exceed urban areas, contributing to 63% of all overdose deaths. Those states with the highest opioid prescriptions per capita also have the highest opioid overdose mortality. These staggering rates are overwhelming families, communities, first responders, and healthcare facilities nationwide, with consequences that could reverberate for generations. The complexity of the crisis necessitates a multidimensional and multi-sectoral research effort.

A major consequence of OUD is opioid-associated Neonatal Abstinence Syndrome (NAS) and the considerable pressure on the foster care system generated by NAS. Although the immediate consequences of this crisis are well known, knowledge gaps exist on the long-term consequences of NAS on growth and development, behavioral outcomes, as well as the effect of involvement of dysfunctional parents in the care of opioid-dependent newborns or the alternative of foster care. OUD also increases risk of infectious diseases with co-use of illicit substances by injection especially hepatitis viruses and HIV.

The majority (80%) of persons with OUD had another substance use disorder (SUD). Among persons with OUD, 29% had major depressive episode(MDE), 32% had bipolar disorder, 13% had schizophrenia, 53% smoked cigarettes, 41% had alcohol use disorder (AUD), and 43% had 1 other drug use disorder.

Rates of opioid overdose deaths continued to increase for all racial/ethnic groups. Non-Hispanic Whites (hence, Whites) and American Indian/ Alaskan Natives (AI/AN) have experienced the largest rise in opioid-related fatalities. The American Indian/Alaska Native (AI/AN) communities, historically vulnerable to substance use, have an overdose rate comparable to Whites. Overdose rates increased 63% for Black persons and 43% for Latinos from 1999 to 2015. By comparison, the rate of overdose deaths among White persons increased 240% from 1999 to 2015 and similar increases were noted for AI/AN populations. By 2014, Whites and AI/AN's were dying at double or triple the rates of African Americans and Latinos, respectively. Factors that may contribute to these disparities include preferential opioid prescribing to Whites in specific clinical settings, and possible differences in clinical pharmacogenomics. There may also be undefined social and cultural factors among Latinos and African Americans that contribute to these observed differences. In summary, multiple factors specific to these populations may contribute to racial differences in opioid sensitivity, clinical management and resistance to opioid misuse. Available data indicate that a disproportionate burden of opioid use overdose deaths is borne by persons living in rural areas of less privileged socioeconomic status. There are no data on patterns of opioid use among sexual gender minorities and limited data on Asians, Native Hawaiians, and U.S. Pacific Islanders.

Women of reproductive age (15-44 years) receive more prescription medications than men, which in turn resulted in increased risk of misuse. Presently, a woman reports to the emergency department every three minutes requesting pain medication. The face of the opioid epidemic is increasingly young, White, and female. Among diagnosed OUD in 2015, 0.9 million were men and 1.2 million women, with 3,300 women affected daily. Women who misuse opioids face gender-specific challenges, effectiveness of treatment and outcomes. Unlike men, women commonly report stigma as one of the top reasons they do not seek treatment for substance use disorders. Women seeking treatment report high rates of childhood victimization, histories of sexual abuse, and current danger (47%) from violent partner. In contrast to men, women also tend to enter treatment at a much later stage of addiction, with more serious health complications due to accelerated physiological damage. More research is needed to address the gender-specific challenges posed by the opioid misuse crisis.

Medication-assisted treatment (MAT) is the use of medications, in combination with counseling and behavioral therapies, to provide a "whole-patient" approach to treat and prevent opioid overdose (OUD). MAT has proven effective in combating OUD. The three medications used most in MAT are Methadone, Buprenorphine, and Naltrexone. However, less than 40% of those with OUD have access to treatment. Barriers to access include clinician bias, a lack of resources, insurance restrictions, and a wide disparity in rural-urban supply of trained substance use treatment providers. Efforts to increase education on treatment, particularly in non-traditional treatment settings, would be beneficial to addressing the opioid crisis. Timely population-based data about persons with OUD are needed for improving access to MAT for subpopulations, including underserved racial/ethnic groups, to reduce opioid addiction.

Prescription Drug Monitoring Programs (PDMPs), being statewide databases that gather information from pharmacies on dispensed prescriptions of controlled substances, are associated with significant reductions in opioid prescribing. Prescribing practices for treating pain should be evidence-based, responsive to patients' needs, maintain a "minimize harm" guideline, and implemented carefully by trained professionals in a manner that involves reasonable oversight through pain management regulatory policies. Implementation of the CDC Guidelines on chronic opioid prescribing would include routine urine testing for prescribed medication and other substances, monitoring statewide database for other controlled substance prescriptions and a harm reduction strategy to reduce the morphine equivalent dose of opioids to 90 mg/day or less. More research is needed to understand the influence of these policies and practices across various regions in the U.S and how that influences OUD.

Prevention in the realm of OUD remains a work-in-progress and requires strategies to ameliorate the current crisis. Evidence-based interventions are needed on the opioid crisis in order to promote drug-free communities.

Current community-level interventions include public education, clinician-patient partnerships, and community-based medication disposal programs. Some States now require information about opioids in the health education and medical school curriculum. There is increasing Clinician-Patient Partnerships where patients reach explicit understanding about goals and expectations of treatment with their clinicians. Future evaluation of Community-Based Medication Disposal Programs for unused prescription opioids awaits. Further research investigations are needed to understand the role of economic upheaval, unemployment, inequality, and other systemic sources of despair in increasing the risk for addiction and decreasing the odds of recovery.

In the criminal justice setting, drug treatment courts have been effective in treating individuals with substance use disorders. These courts are specialized problem-solving courts that divert eligible drug-abusing offenders from the traditional court system into court supervised treatment. More research is needed to reduce drug use relapse through risk and need assessments, judicial interaction, monitoring and supervision, graduated sanctions and incentives, treatment, and rehabilitation services.

Research Objectives

This initiative will support multidisciplinary exploratory/developmental research projects that examine the following: sociodemographic, cultural, economic, epidemiologic, and biological factors in opioid care specific to health disparity populations that increase the risk of OUD; the consequences of OUD; ways to improve resource availability among defined health disparity populations to reduce opioid treatment gap; and underlying mechanisms for the variation in the prevalence of OUD in health disparities populations. Research projects are encouraged to utilize rigorous innovative multi multidisciplinary approaches with integration of multiple factors that are known to cause opioid health disparities.

Research Methodology

Research projects are encouraged to utilize rigorous innovative multidisciplinary approaches with integration of multiple factors that are known to cause opioid health disparities.

Projects should include a focus on one or more NIH-designated health disparity populations in the United States, which include Blacks/African Americans, Hispanics/Latinos, American Indians/Alaska Natives, Asians, Native Hawaiians and other Pacific Islanders, socioeconomically disadvantaged populations, underserved rural populations, and sexual and gender minorities.

Examples of research methods could include, but are not limited to:

• Cluster-randomized, randomized or pragmatic clinical trials of the effectiveness of new or existing technologies that involves broad inclusion of patients with OUD and adequately reflects the action on the health determinants.
• Use of large-scale longitudinal data sets, data mining techniques, registries, and integration of quantitative and qualitative analytical frameworks and techniques to address and inform implementation of interventions addressing the opioid crisis.
• The ability to conduct subgroup analysis to determine which interventions work best for specific population groups, including medically underserved and under-represented groups with the intent to focus on reduction of OUD.
• Decision science modeling and analysis in OUD care and outcomes for health disparity populations.
• Use of large-scale longitudinal data sets, data mining techniques, registries, and integration of quantitative and qualitative analytical frameworks and techniques to address and inform implementation of interventions addressing the opioid crisis.
• Participatory engagement of stakeholders (treatment facilities, patients, hospitals, and caregivers, clinicians, community groups, administrators, policymakers) in the formulation of the research and to the extent necessary, in the implementation of the research.
• Descriptive studies using quantitative and qualitative methods to contribute to the understanding of the differences in opioid overdose deaths by race/ethnicity
• Prospective clinical studies that define the continued use of prescription opioids for more than 4 weeks by race/ethnicity and socioeconomic status.

Areas of Research Interest

Applications should be relevant to both the objectives of the funding opportunity announcement and to at least one of the participating Institutes' and Offices' research interests. Researchers are strongly encouraged to review the general research interests of the participating ICs.

National Institute on Minority Health and Health Disparities (NIMHD)

NIMHD is interested in several research priorities that could have significant impact on understanding and addressing the opioid crisis in health disparities populations. The following include potential topic areas but are not limited to:

Treatment and Health Services

• Assess the relationship between access to chronic pain treatment in health disparity populations and OUD.
• Evaluate the relationship between opioid prescribing and OUD demographics, specifically relating to race and ethnicity.
• Evaluate the use of MAT in non-traditional settings: examine multi-disciplinary approach to treatment, including holistic and non-medical models of care; assess the impact of education on prevention and treatment in non-medical settings.
• Assess unique aspects of MAT (opioid-specific treatment) use among diverse racial/ethnic groups with OUD.
• Evaluate the intersection of OUD with mental health disorders.
• Gender-responsive approaches to account for differences associated with OUD.
• Evidence-Based Practices (MAT, CBT, etc.) to address gender specific concerns.
• Research on opioid-dependent newborns: consequences of opioid-related neonatal abstinence syndrome (NAS) on growth & development, stigma and long-term behavioral outcomes; the role of dysfunctional parents in the care of these children; burden on foster home care.
• Assess the role of Medicaid and Medicare and OUD treatment modalities, including enhancing payment for MAT.
• Research on pharmacogenomic testing in OUD treatment.
• Research on identifying the most important barriers to providing healthcare services in rural communities and novel strategies to improve mental health infrastructure in these settings.
• Developing specialized MAT maintenance programs for pregnant women with OUD.
• Studies on mechanisms enhancing Clinician-Patient Partnership in opioid prescribing.

Education:

• Studies on the role of incorporating opioid prevention strategies as part of the health education curriculum and enforcing continuing education on opiates prescribing clinicians.

Epidemiology/Technology:

• The impact of OUD in specific health disparity subpopulations (e.g., by Latino national origin or heritage, by AI/AN tribe, by geographic location).
• Study the role of geographic information system (GIS) and real-time opioid prescription tracking systems in enhancing public health surveillance.
• Develop novel mechanisms to improve opioid overdose surveillance in order to track the rapidly changing illicit opioid market of Fentanyl and its derivatives.
• Assess the impact of fentanyl in opioid overdose deaths, the role of distribution of fentanyl test kits and effects of expanding forensic toxicology testing.

Community Level Interventions:

• Assess the role of Public Education: studies on the impact of bystander Narcan administration on the prevalence of OUD.
• Research on assessing the impact of Community-Based Medication Disposal Programs/ drug take-back efforts on OUD.

National Institute of Aging (NIA)

NIA is interested in applications that address aspects of the opioid crisis in health disparities populations across the life course, including late life. Such topics include (but are not limited to) the following:

• Medicare/Medicaid dual eligible recipients
• Role of disability (including work-limiting disability) on the patterning of pain and opioid use in middle and later life
• Health care delivery and access in rural areas among middle-aged and older Americans
• Opioid use in nursing homes and other residential care facilities
• Behavioral economics techniques integrated with Electronic Health Records (EHRs) to produce low-cost pragmatic interventions designed to improve adherence to recommended pain treatment guidelines
• Effectiveness of health care systems and regulatory actions in distinguishing between appropriate and inappropriate opioid use
• Impact of opioid treatment guidelines on clinical, functional, and quality of life outcomes in older adults across settings, particularly acute, post-acute, palliative care, and end-of-life settings

National Institute of Child Health and Human Development (NICHD)

NICHD's areas of programmatic interest include obstetric and pediatric clinical studies focused on (but are not limited to) the following topics:

• Developing specialized MAT maintenance programs for pregnant women with opioid use disorder (OUD)
• The role of prenatal care in optimizing pregnancy outcomes in women with OUD
• Assessment of fetal well-being during pregnancy in women with OUD to optimize neonatal outcomes
• Studies of postpartum care and support for women with OUD to optimize maternal and neonatal outcomes
• The role of pharmacogenomics in opioid use disorder treatment
• Studies on opioid-dependent newborns and consequences of neonatal abstinence syndrome related to opioid
• Research on safe and effective outpatient management strategies for neonatal opioid withdrawal syndrome including optimal follow-up

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

NIAAA is interested in applications that:

• Address the role of alcohol use in the development of opioid addiction, morbidity, and mortality
• Provide data on opioid and alcohol use presentation to emergency departments and in fatalities.
• Address the potential effectiveness of addiction treatment services, such as for alcohol use disorder, in treating opioid misuse

Office of Research in Women's Health (ORWH)

The Office of research in Women's health is interested in the following:

• Gender-responsive approaches to account for differences associated with OUD
• Evidence-Based Practices (MAT, CBT, etc.) to address gender specific concerns
• Gender specific approaches to address the mental health, reproductive and sexual health, and physical health of women with opioid use disorders.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

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) are not eligible to apply
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not 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.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

Section IV. Application and Submission Information

1. Requesting an Application Package

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.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in 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.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Andrew Louden, Ph.D.
National Institute on Minority Health and Health Disparities (NIMHD)
Telephone: 301-594-9009
Fax: 301-480-4049
Email: andrew.louden@nih.gov

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.

R&R or Modular Budget
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.
The following modifications also apply:

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

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.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

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

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit 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.

Section V. Application Review Information

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

1. Criteria

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

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

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

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 involving 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 New Investigators, or 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 involving 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 involving 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 involving 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 involving 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?RFA/PAR only: Additional Questions may be added and should be explained to the applicant in Section IV.2.

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 involving 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

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

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.

Not Applicable

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.

2. Review and Selection Process

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

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

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

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

3. Anticipated Announcement and Award Dates

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

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the 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.nig.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).
For all Clinical Trial FOAs, use the Clinical Trial text insert.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see 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.

Not Applicable

3. Reporting

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.

Section VII. Agency Contacts

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons 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: 301-710-0267

Andrew Louden, Ph.D.
National Institute on Minority Health and Health Disparities (NIMHD)
Telephone: 301-594-9009
Email: andrew.louden@nih.gov

Benyam Hailu, M.D., M.P.H.
National Institute on Minority Health and Health Disparities (NIMHD)
Telephone: 301-594-8696
Email: benyam.hailu@nih.gov

Judith A. Arroyo, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-402-0717
Email: jarroyo@mail.nih.gov


Victoria Cargill
Office of Research in Women?s Health (ORWH)
Telephone: 301-435-0971
Email: CargillV@od.nih.gov

Sarah Duffy
National Institute on Drug Abuse (NIDA)
Telephone: 301-443-6504
Email: duffys@nida.nih.gov


Rosemary D. Higgins, MD
Eunice Kennedy Shrive National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-7909
Email: higginsr@mail.nih.gov

Amelia Karraker, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-3131
Email: Amelia.Karraker@nih.gov
Weijia Ni, Ph.D
Center for Scientific Review (CSR)
Telephone: 301-594-3292
Email: niw@csr.nih.gov

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


Bryan Clark, MBA
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
Email: clarkb1@mail.nih.gov

Amy Connolly
National Institute on Drug Abuse (NIDA)
Telephone: 301-827-4457
connolla@mail.nih.gov

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

Eva Lawson-Lipchin
National Institute on Aging (NIA)
Telephone: 301-435-2020
Email: eva.lawson-lipchin@nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.