Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

It is critical that applicants follow the instructions in 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 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 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

This Funding Opportunity Announcement (FOA) encourages UG3/UH3 phased cooperative research applications to accelerate implementation of effective non-opioid interventions for pain management in rural and remote populations. Projects include pragmatic, implementation, or hybrid effectiveness-implementation trials to improve pain management and reduce the use of opioid medications. Awards made under this FOA will initially support a milestone-driven planning phase (UG3) of 1 to 2 years, with possible transition to an implementation phase (UH3) of up to 4 years duration (5 years total for the two phases). Only UG3 projects that plan a pilot may request 2 years for the planning phase with up to 3 years for the UH3 implementation phase; all other projects may request 1 year for the UG3 phase with up to 4 years for the UH3 phase. UG3 projects that have met the scientific milestone and feasibility requirements may request a transition to the UH3 phase. The UG3/UH3 application must be submitted as a single application, following the instructions described in this FOA.

The overall goal of this initiative is to support the implementation of effective practices and procedures that may lead to prevention or improved management of chronic pain in rural and/or remote populations, along with a reduction in prescribing and/or using opioids. Results from the trials supported by this funding opportunity announcement (FOA) should inform policy makers, payers, community stakeholders, as well as healthcare providers and patients in the primary care, emergency department, hospital, community health, home health, or dental settings. This FOA requires that the intervention under study be integrated into the health care delivery system that serves individuals who live in a rural or remote community. This does not require the physical setting of the intervention be at a traditional health care facility. Studies can propose to integrate multi-component or multiple interventions that have demonstrated efficacy in other settings.

Trials will become part of and work with the HEAL Pragmatic and Implementation Studies to Improve the Management of Pain and Reduce Opioid Prescribing (PRISM) Program, which has leveraged the infrastructure of the NIH Pragmatic Trials Collaboratory [previously known as the NIH Health Care Systems (HCS) Research Collaboratory]. (See https://rethinkingclinicaltrials.org/.) The PRISM Program has established a Coordinating Center (CC) that is providing national leadership and technical expertise in all aspects of research conducted within the HCS. Awarded applicants will work with the CC (http://rethinkingclinicaltrials.org/about-nih-collaboratory/) to facilitate further planning and refinement of the proposed study in partnership with health care delivery systems. Studies in collaboration with Tribal populations will need to engage in meaningful dialogue to respectfully recognize the sovereignty of each Nation.

For this application, rural is defined according to the Health Resources & Services Administration (HRSA) definition: All non-metro counties, as defined by the Office of Management and Budget; all metro census tracts with Rural-Urban Commuting Area (RUCA) codes 4-10; and large area metro census tracts of at least 400 square miles in an area with population density of 35 or less per square mile with RUCA codes 2-3; and outlying metro counties without a UA. For more detail on the addition of outlying metro counties, read the Federal Register Notice, Revised Geographic Eligibility for Federal Office of Rural Health Policy Grants. The HRSA Rural Health Grants Eligibility Analyzer can be used to determine which counties and locations are rural areas. HRSA also provides data files to identify rural areas by county, census tract, and those using a zip code approximation. Remote areas, defined by USDA Frontier and Remote (FAR) Area Code 4, are considered both rural and remote; therefore, the definition of rural above will be used for eligibility. The USDA provides data files and maps using the FAR codes. Rural and remote areas may include American Indian and/or Alaska Native Tribal populations.

Background

Rural communities have been particularly hard hit by the opioid epidemic and are disproportionately impacted by opioid-related overdoses. However, patients with chronic pain are present across all geographic areas, and recent evidence indicates that the percentage of adults with chronic pain increases as the place of residence becomes more rural. Furthermore, many patients with chronic pain have comorbidities, including mental health conditions, sleep disturbance, and opioid and/or alcohol use disorders that complicate appropriate pain management. There are known disparities in management of pain in rural areas. Rural residents are more likely to be prescribed an opioid analgesic and less likely to use non-opioid interventions such as self-management, or traditional or cultural interventions for pain than those in non-rural areas. Despite evidence for effective non-opioid interventions, these interventions are not optimally implemented in rural areas.

Pain, like other health conditions, is shaped by biological, behavioral, and social determinants of health. To fully address the factors affecting quality pain management, the interrelationships between health policy, healthcare services, biology and genetics, individual behaviors and social factors must be examined. Development and implementation of sustainable, effective non-opioid chronic pain management in rural and remote areas require attention to the social and environmental determinants of health that affect overall health.

In rural settings, primary care practitioners, including physicians, nurse practitioners, and physician assistants are responsible for addressing patients needs for pain management while reducing opioid use. Limited community resources and/or long distances to reach specialists such as behavioral health, pain specialists, and physical therapists increase the challenges of chronic pain management in rural communities. While there have been some promising studies integrating effective, evidence-based pain management in rural settings, there is still a need for coordinated approaches to identify and reduce barriers and accelerate the implementation of high-quality chronic pain care to optimize health and advance health equity.

There are both guidelines published by various government agencies and clinical and professional societies and evidence for supporting the use of nonpharmacologic approaches as first tier treatment and non-opioid approaches for second tier treatment of chronic pain. The Centers for Disease Control and Prevention (CDC) guideline for prescribing opioids for chronic pain, for example, states that "nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain." The Clinical Practice Guideline from the American College of Physicians also recommends noninvasive, nonopioid treatments for acute, subacute, and chronic low back pain.

This FOA will support trials testing methods for management of acute pain if the acute pain requires the intervention of a health care provider for management, such as acute dental/orofacial pain or acute low back pain and are likely to recur, become chronic, or escalate to a more serious complication if not managed appropriately.

Pragmatic, implementation, and hybrid effectiveness-implementation trials, therefore, are needed because policies, clinical practice guidelines, and tools and interventions have not been readily adopted or adapted and implemented in rural and remote settings. Research is needed to study strategies to equitably and efficiently implement effective interventions and evidence-based pain management guidelines in these settings.

To effectively address the barriers to and preferences for implementation in rural communities, community engagement, including identification and integration of one or more community-based partners in the UG3 phase are critical to this initiative. Community partnership(s) will be developed in the UG3 phase, but investigators will need to identify the role and characteristics of desirable community partners in the application. Community partner(s) should be located in the rural or remote community and might be a community organization, faith-based organization, community health worker, local library, school, local patient or consumer advocacy group, community champion, or group representing populations that experience health disparities and/or other relevant community stakeholder groups. Community engagement in clinical studies involves patients, families and/or their representatives, health professionals, and the clinical research team working in active partnership at various levels across the continuum of clinical research. Continued respectful, equitable, and bidirectional knowledge transfer during stakeholder engagement can improve participant retention and adherence to the study protocol. Engagement can help build trust in communities that may be fearful of participating in clinical research because of stigmas and medical mistrust. Community engagement can be used to promote health and health research by reducing barriers and enabling research participation by NIH-designated populations that experience health disparities and populations with limited English proficiency. Community-engaged research (CEnR) is participatory and describes methods to operationalize community engagement within clinical research. Engaging the community in research (CEnR) from study planning to implementation contributes to successful health equity study design that is inclusive of diverse participants and provides infrastructure to ensure culturally appropriate research strategies, tools, bi-directional knowledge transfer, and information dissemination are utilized. Partnering with the community helps with development of sustainable interventions and the translation of study results into practice, potentially improving health outcomes. CEnR has the potential to promote wellness by impacting community health literacy and health behavior through community and participant empowerment. When community members participate in their own health promotion by engaging in the research process, they are able to identify their own health needs and develop a sense of belonging within the scientific and medical research community.

The NIH HEAL Initiative:

This FOA is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management. More information about the HEAL Initiative is available at: https://heal.nih.gov/.

Meeting Attendance:

The NIH HEAL Initiative will require a high level of coordination and sharing between investigators. It is expected that NIH HEAL Initiative awardees will cooperate and coordinate their activities after awards are made by participating in Program Director/Principal Investigator (PD/PI) meetings, including an annual HEAL investigators meeting in the D.C. area, as well as other activities.

In addition, travel to attend two, one-and-a-half-day PRISM/Collaboratory program meetings in the first year and an annual meeting in subsequent years in the greater Washington D.C. area is expected.

Diversity:

In addition to scientific diversity, applicants should strive to incorporate diversity in their team development plan. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogenous teams. Scientists and trainees from diverse backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. There are many benefits that flow from a diverse NIH-supported scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved or health disparity populations participate in and benefit from health research, and enhancing public trust. In spite of tremendous advancements in scientific research, information, educational and research opportunities are not equally available to all. NIH encourages institutions to diversify their student and faculty populations to enhance the participation of individuals from groups that are underrepresented in the biomedical, clinical, behavioral, and social sciences. Please refer to Notice of NIH's Interest in Diversity NOT-OD-20-031 for more details.

For the purpose of this FOA, we define "embedded pragmatic clinical trial" and "implementation research," as follows:

Embedded pragmatic clinical trials are conducted within a health care delivery system that will oversee delivery of care (which may be provided in traditional or non-traditional health care settings including but not limited to clinics, hospitals, mobile care units, community centers, etc.), and are primarily designed to determine the effects of an intervention under the usual conditions in which it will be applied, which is in contrast with explanatory trials that are primarily designed to determine the effects of an intervention under ideal circumstances (http://www.bmj.com/content/350/bmj.h2147). There are three key attributes of pragmatic clinical trials (PCTs): (1) an intent to inform decision-makers (patients, clinicians, administrators, and policy-makers), as opposed to elucidating a biological or social mechanism; (2) an intent to enroll a population relevant to the decision in practice and representative of the patients or populations and clinical settings for whom the decision is relevant; and (3) either an intent to (a) streamline procedures and data collection so that the trial can focus on adequate power for informing the clinical and policy decisions targeted by the trial or (b) measure a broad range of outcomes (http://rethinkingclinicaltrials.org/chapters/pragmatic-clinical-trial/what-is-a-pragmatic-clinical-trial-2/).

Implementation research seeks to understand the behavior of practitioners and support staff, organizations, community and family members, and policymakers in context as key influences on the adoption, implementation, and sustainability of evidence-based health interventions and guidelines (e.g., Community Guide to Preventive Services, U.S. Preventive Services Task Force, and clinical and professional societies' recommendations and guidelines). Implementation research studies should not assume that effective interventions can be integrated into any service setting and for consumer groups and populations without attention to local context, nor that a unidirectional flow of information (e.g., publishing a recommendation, trial, or guideline) is sufficient to achieve practice change. Additional information on implementation research, including frameworks for implementation and hybrid effectiveness-implementation research is available at: https://rethinkingclinicaltrials.org/chapters/dissemination/dissemination-implementation-top/dissemination-and-implementation-frameworks/

The awards supported by this initiative will utilize the existing coordinating center of the PRISM Program, which leverages the infrastructure of the NIH Health Care Systems (HCS) Research Collaboratory, now known as the Pragmatic Trials Collaboratory. The overall goal of the Collaboratory program is to strengthen the national capacity to implement cost-effective large-scale research studies that engage health care providers and delivery systems and patients as research partners. The NIH HCS Research Collaboratory Program established a Coordinating Center (CC) led by Duke University in 2012 (http://rethinkingclinicaltrials.org/about-nih-collaboratory/) that is providing national leadership and technical expertise. In 2019, the HEAL Initiative supported the PRISM Program, which expands the activities of the CC to support the PRISM awards. Awardees from this FOA will work with the NIH and CC to both plan and conduct their pragmatic or implementation trial.

The PRISM program encourages sharing of resources with broad availability of policies, practices, materials, and tools to facilitate collaboration, reuse, and replication. In addition, the PRISM program encourages sharing of study data from projects in a timely manner with appropriate privacy and confidentiality protections, in accordance with the Data Sharing Policy developed by the Steering Committee (https://dcricollab.dcri.duke.edu/sites/NIHKR/KR/Collaboratory.DataSharingPolicy_June232014.pdf). Thus, the HCS Research Collaboratory program requires awardees to implement a Resources and Data Sharing Plan consistent with achieving these program goals.

Common Data Elements (CDEs)

The HEAL Clinical Pain Common Data Element (CDE) Initiative provides an unprecedented opportunity for the pain research community to access quality and meaningful data across pain conditions, diverse populations, and multiple interventions. The HEAL CDE initiative aims to facilitate cross-study comparisons, improve interpretability of findings for patient-reported outcomes, and improve the ability to compare results across trials to quantify the impact of interventions. For studies involving human subjects, projects will be required to use the HEAL Clinical Pain Core CDEs which include measures within nine pain domains and are specific to either adult or pediatric populations and acute or chronic pain conditions. The domains include pain intensity, pain interference, physical functioning/quality of life, sleep, pain catastrophizing, depression, anxiety, treatment satisfaction, and a substance use screener (HEAL CDE Program). Studies that use additional pain screening tools must select from a comprehensive set coded through HEAL or submit their tools for coding to comply with HEAL pain data harmonization. Any outcome measures specific to clinical pain should be validated measures appropriate for the pain condition.

Research Objectives

This FOA solicits applications for UG3/UH3 exploratory/developmental phased award cooperative agreements for projects including efficient, pragmatic, implementation, or hybrid effectiveness-implementation trials addressing chronic pain management in rural or remote populations. Projects addressing multiple levels of NIMHD’s research framework are encouraged.

Applications must specify one or more health care systems (HCS) that will oversee delivery of care. There must be two or more sites within the HCS, or multiple HCS to assure inclusivity and sufficient sample size. Sites may include (but are not limited to) rural hospitals, clinics, provider offices, pharmacies, mobile health units or home health providers. HCS partners include but are not limited to large health care systems, small and rural hospitals, Critical Access Hospitals, Rural Health Clinics, Tribal clinics and hospitals, Federally Qualified Health Centers and Indian Health Service (IHS) federally operated healthcare facilities, as well as visiting nurse services/home health agencies. HCS may also include local primary health care providers (including physician, doctor of osteopathy, dentist, nurse practitioner, physician assistant, nurse-midwife, nurse anesthetist, clinical nurse specialist, emergency medical service providers, etc.) at one or more sites of care. For effectiveness studies, the HCS should be large enough to yield sufficient participants to ensure powering the trial design. The design of the proposed project should maximize external validity of the study while maintaining rigor, by testing generalizability, feasibility, and sustainability of findings across rural and/or remote health care settings and diverse staff and patient populations.

In the UG3 planning phase, one or more additional community-based partners will be identified to participate in the proposed trial. Community partner(s) should be located in the rural or remote community (as described in Part 2, Section I. Background) and might be a community organization, faith-based organization, community health worker, local library, school, local patient or consumer advocacy group, community champion, local group representing populations that experience health disparities, and/or other relevant community stakeholder group. Other potential partners with experience working with rural clinical sites include Area Health Education Centers, Primary Care Associations, State Rural Health Associations, State Offices of Rural Health, Medicare Quality Improvement Organizations. The community-based partner(s) should be fully engaged in the research process from planning through implementation and evaluation.

The research application should specify the type of proposed research, whether pragmatic, implementation, or hybrid effectiveness-implementation, and must meet all the following criteria:

1. The project must test an intervention or coordinate several interventions (which can be treatments, preventive actions, or organizational changes) that are robust, apply broadly to pain patient populations, and can be implemented in rural and remote areas, with the broad goal of determining whether the intervention(s) improves pain outcomes/management and adds value to the utilization of the nation’s health care resources.
2. The results of the question being tested will have a significant impact on pain management in rural and/or remote populations at the individual or systems level.
3. The intervention(s) must be well-characterized and available such that it could be reliably delivered by clinical providers and/or HCS. If an intervention includes a drug, biologic, or medical device, it must be a legally marketed drug, biologic, or medical device in the US, and used as approved/cleared for use by the Food and Drug Administration.
4. The intervention(s) must be reasonably simple and not require a complex structure for implementation or monitoring.
5. As in routine practice, the project must allow for interventions to be implemented with flexibility and by appropriate practitioners.
6. The project outcome measure(s) must be clinically meaningful and important to stakeholders including patients, providers, health care systems, and policy makers. Clinical outcome measures must be defined at the patient, provider, and/or system level. Additional outcome measures, such as use of health care services or medications and other resources may be included.
7. The project design must incorporate rigorous controls, prospectively identified, preferably by randomization. The design may incorporate alternative randomization approaches, such as by cluster or timing of implementation. If another method is used to generate the comparison group, perhaps by staged assignment or staged implementation of the intervention, it should provide comparable rigor and the choice should be justified in the application. More than one health care system partner may be needed to enroll sufficient participants for a rigorous study.
8. Proposed analytic plans for projects that proposed cluster-randomized trials must address adequacy of sample size and study power and employ analytic strategies relevant for such pragmatic trial designs. Applicants are strongly encouraged to consult Collaboratory Biostatistical Guidance documents (http://sites.duke.edu/rethinkingclinicaltrials/biostatistical-guidance-documents/) when developing pragmatic trial analytic plans.
9. The project must enroll patients based on broad eligibility criteria to maximize diversity and minimize intentional or unintentional exclusions based on risk, age, health literacy, demographics, or expected adherence. Projects with a focus on NIH-designated disparity populations in rural and remote areas are encouraged.

Studies addressing effectiveness must include:

• Sufficient HCS partners or sites to realistically enroll a sample to reach 90% power.

Implementation trials must include:

• Sufficient evidence for the proposed intervention to justify implementation or de-implementation or the need for intervention adaptation. A strategy to de-implement care is proposed for low-value interventions where there is evidence of no benefit or there is more harm than benefit for patients.
• Outcomes focused on implementation that are most likely at a system or individual provider level. Patient-level implementation outcomes may be possible if focused on the use of the targeted intervention.
• A conceptual model and theoretical justification of the proposed study design and variables tested with a well-defined strategy and reasonable readiness to adopt if primary outcome is met.

Partnerships with health care delivery systems, providers, and community-based organizations will be critical in conducting this work. Applicants should name the health care system, describe the role of the health care system, the number of sites available, and indicate the rationale for selecting this health care system or organization. Evidence of support and commitment to the project should be included, such as letters of support, budgets for appropriate providers or coordinators, etc. Applicants should NOT name the community-based partner(s) or organization(s), but should describe the role of the community-based partner(s) and the criteria for selection. Budgets for the community-based partner(s) should be included in the UH3 phase. Applicants, who may be from academic institutions or other organizations, should describe experience in successful conduct of clinical or implementation research in partnerships with health care systems.

These projects will be funded as phased awards. Only UG3 projects with a planned pilot may request 2 years for the planning phase with up to 3 years for the UH3 implementation phase; all other projects may request 1 year for the UG3 phase with up to 4 years for the UH3 phase. Applications proposing a 2-year UG3 Phase must propose and justify the need for a pilot study that will inform the design of the UH3 Phase. Activities in both phases will depend on the specific study (e.g., disease domains, types of interventions, experimental design, randomization strategy, and proposed outcome measures).

During the UG3 or planning phase, activities will generally include but will not be limited to the following:

1. Identify project staff that will participate in the PRISM/Collaboratory Work Groups (see Section I.5 Additional Information https://rethinkingclinicaltrials.org/cores-and-working-groups/), which will develop guidelines and practices to be implemented across projects.
2. Work with the Collaboratory to implement approved guidelines and practices for electronic data extraction and quality control methods and tools, as well as for electronic data sharing, when feasible. In the planning phase, this will include developing and validating all electronic data methods and tools within the health care system needed for the project (e.g., electronic health records, electronic methods for patient identification and outcomes assessment, patient reported data, biospecimens, images, high-throughput genomic data, family history data, data abstraction and survey instruments) and complete quality control testing at all sites. If multiple health care systems are included, there may be multiple electronic health record systems from which data need to be collected.
3. Finalize the intervention, including materials and training plans for sites.
4. Assess adequacy and finalize clinically relevant outcome measures with other Collaboratory investigators. Awarded applicants will work with other Collaboratory investigators and NIH to identify HEAL Core Measures (pain severity, pain interference, and pain functioning, as well as others); and will work with the CC and NIH to develop metrics for resource utilization for planning and implementing Collaboratory pragmatic trials. If an award is made, NIH and CC staff will work with the Program Directors/Principal Investigators to facilitate coordination among projects.
5. Refine estimates of requirements with guidance from NIH and the CC for sample size, numbers of sites, site to site heterogeneity, and implementation timetable based on data derived from the partnering HCS.
6. Identify at least one additional community-based partner (not specified in the application) and develop a detailed community partner engagement plan that outlines planned collaborations with community-based study-relevant organizations, patients with lived experience in the community, local patient or consumer advocacy groups, community champions, groups representing populations that experience health disparities, community-based organizations, faith-based organizations and/or other relevant community stakeholder groups. The community engagement plan should:
   1. Describe patient engagement activities and methods to monitor and evaluate outcomes related to engagement
   2. Describe the roles of community partners from planning through implementation and evaluation of the study
   3. Describe the characteristics of desirable community partners
   4. Include linguistic and cultural competence strategies to enable recruitment and retention of populations that experience health disparities
7. Include resources to compensate community partners and support and sustain community engagement.
8. Identity barriers to implementation and patient/provider/community preferences for implementation. Develop detailed plans to address barriers and preferences including participation of community partners in planning and implementation. Examples of issue that may need to be addressed include (but are not limited to) infrastructure needs such as internet or cellular access, appropriate equipment to implement the intervention and monitor patients, transportation issues, etc.
9. Develop detailed plans for site implementation, including site staff, method of identification, randomization (as applicable) and participant recruitment and acquisition and administration/implementation of the intervention if applicable. The plans should include site staff training and support in conducting activities needed for implementation, keeping in mind that community partners may have limited experience with research and its activities.
10. Put strategies in place should enrollment or retention not meet specified metrics.
11. Address all ethical issues and issues related to human subject safety oversight for the project, including the development of informed consent documents or opt-out consent if applicable, and finalize the site of the Institutional Review Board (IRB) review. Applicants must propose a single IRB approach for trial oversight to facilitate both appropriate and timely study implementation, unless review by the proposed single IRB would be prohibited by a federal, Tribal, or state law, regulation, or policy. Address all potential regulatory elements of the proposed trial (if applicable).
12. Develop a detailed budget for conduct and completion of the project, including preparation of a final study report. Budget must include appropriate compensation for community-based partners. Finalize detailed plans for data coordination and quality control for the UH3 phase. The CC will not provide these functions for individual projects. Data coordinating activities for individual projects must be budgeted as part of the UH3 budget. The budget should include any costs for data sharing to meet HEAL requirements (see section IV. 2. Resource Sharing). Data sharing activities with the CC do not require separate budgets.

Project Implementation Phase (UH3): The objective of the two-to-four-year UH3 implementation phase is to conduct the project in accordance with activities planned in the UG3 phase. Implementation activities will depend upon the study, but in general the following goals should be achieved:

• Each project is expected to implement all aspects of the proposed pragmatic trial or implementation research study including the identification and recruitment of proposed sample sizes of patients, practice sites, and clinicians, as well as the execution of the intervention and its implementation, and the assessment of outcomes.
• Each project is expected to provide complete assessment of all issues related to patient, clinician, and site identification, as well as electronic health record (EHR) tools used in these steps.
• Each project is expected to provide definitive information about the execution of the intervention at all sites.
• Each project is encouraged to assess fidelity to the intervention, when possible, and describe if any efforts will be made to address poor or differential fidelity across sites or study arms.
• Each project is to provide detailed and definitive testing of the validity of methods used for monitoring and outcome assessment.

For Pragmatic Trials that aim to evaluate the effectiveness of the intervention Design, Analysis, and Sample Size for Intervention Studies that Assign and/or Deliver Interventions in Groups or Clusters

Special research design and method for analysis and sample size are needed in the following conditions:

• Participants are assigned to study arms in groups or clusters (e.g., families, clinics, schools, worksites, communities, counties, states) and observations taken on individual participants are analyzed for intervention effects.
  • Appropriate intervention study designs include but are not limited to a parallel group- or cluster-randomized trial, a stepped-wedge group- or cluster-randomized trial, a rigorous quasi-experimental design such as group- or cluster-level regression discontinuity design or interrupted time-series design, or a rigorous alternative.
• Participants are assigned individually to study arms but receive at least some of their intervention in a group (in-person or virtual) or through a shared facilitator or provider.
  • Appropriate study designs include an individually randomized group treatment trial, a rigorous quasi-experimental design, such as an individual-level regression discontinuity design, or a rigorous alternative.

Methods consistent with plans for assignment of participants and delivery of interventions should be documented in the application. Additional information and examples are available at https://researchmethodsresources.nih.gov

Milestones and UG3/UH3 Transition
Utilization of milestones is a key characteristic of this FOA. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. This FOA will utilize a two-phase, milestone-driven cooperative agreement (UG3/UH3) mechanism consisting of a start-up phase of one or two years (UG3) and a full enrollment and clinical or implementation trial execution phase (UH3). UG3 projects with a planned pilot may request 2 years for the planning phase, all other projects may request 1 year. Projects must include well-defined milestones for the planning phase (UG3) and annual milestones for the implementation phase (UH3). It is understood that the proposed milestones for the UH3 phase will be revised as activities in the UG3 phase progress. In the event of an award, the PD/PI and NIH staff will negotiate a final list of milestones for each year of support. Milestones for transition to the UH3 phase should be quantitative and support a go/no-go decision.

At the completion of the UG3 planning phase, the applicant will be required to submit a detailed transition request for the UH3 Project implementation phase. UH3 transition requests will undergo an administrative review to determine whether the project will be awarded for the implementation phase (UH3).

• All community-based partners should be named prior to the end of the UG3 award.
• All regulatory approvals should be obtained prior to the end of the UG3 award.
• Training of intervention providers, comparison group providers, or other resources should be planned at the start of the UH3 award to allow for the successful launch and execution of the proposed pragmatic trial or implementation study in the UH3 phase.

Applicants should understand that initial funding of the UG3 phase does not guarantee support of the UH3 phase and transition to the UH3 phase of the project will occur only if an administrative review process recommends that the UG3 planning milestones have been successfully met, that the UH3 phase can proceed with confidence of success, and that there is an availability of funds. Continuation of the award is conditional upon satisfactory progress, including satisfactory enrollment. If, at any time, recruitment falls significantly below the projected milestones for recruitment, the NIH will 1.) implement a corrective action plan and 2.) if necessary, consider ending support and negotiating an orderly phase-out of the award. NIH retains, as an option, periodic external peer review of progress through existing PRISM, NIH Pragmatic Trials Collaboratory and/or HEAL external advisors. NIH staff will closely monitor progress at all stages, milestones, accrual instances, and safety levels.

Research Areas of Interest

Applicants must propose a pragmatic or implementation trial to address one or more critical research questions important for chronic pain management in rural or remote populations.

Applications submitted in response to this FOA are strongly encouraged to: 1) include multi-level interventions with systemic implementation strategies that are scalable and conducive to long-term sustainability (beyond the term of award) and can be rapidly implemented in rural and remote healthcare systems; 2) incorporate efficiencies and utilize existing resources (e.g., NCATS CTSAs, practice-based research networks, electronic health records, administrative databases and/or patient registries, rural health research centers) to increase the efficiency of participant enrollment, retention, and data collection; 3) consider subpopulation analysis to determine which interventions work best for specific population and/or cultural groups (e.g., American Indians/Alaska Natives, Hispanics or Latinos, Pacific Islanders, Veterans, occupations such as mining, agriculture, forestry, etc.) including medically underserved, un- and under-insured, Medicare- or Medicaid-eligible populations, and underrepresented groups, with the intent to focus on reduction of health disparities; and 4) assess social determinants of health using measures available in the Social Determinants of Health Collection of the PhenX Toolkit (www.phenxtoolkit.org) or other widely adopted measures, as appropriate. Depending on study design and preference of the rural community, a plan to make the intervention available to all participants after completion of the trial should be considered. Applicants are encouraged to collect data on patient experiences that may affect their chronic pain including Veteran status, occupation, etc.

Examples of interventions and settings include but are not limited to:

• Interventions in rural and/or remote health care settings, including primary care (offices, clinics, Rural Health Clinics, Community Health Centers, urgent care, dentist office, home health agency, etc.), acute care (emergency rooms, small and rural hospitals, Critical Access Hospitals, surgical centers, etc.), and other traditional and non-traditional health care settings where pain management disparities are well documented.
• Interventions that address a gap in access to non-opioid pain management for rural and/or remote populations (e.g., mobile interventions, telehealth options, delivery of select services in community settings, non-opioid medications, brief training followed by self-care, etc.).
• Non-opioid pain interventions including but not limited to non-opioid medications, self-care or self-management techniques, non-pharmacologic treatments, physical therapy, and/or training in interventions followed by home practice.
• Interventions that address equity in decision-making for pain assessment, management, and follow up (e.g., assessment of preferences for pain care, use of semi-structured interviews to assess and mitigate bias).
• Evidence-based interventions for effective practices for chronic pain management that have not been implemented or tested in rural or remote populations either on their own or in combination with other tested interventions or novel interventions with evidence of efficacy.

The following list provides examples of some of the potential research topics that might be addressed by such trials:

• Studies focused on improving access to specialty pain management and non-pharmacological interventions. These projects may focus on chronic pain or serious acute pain that requires intervention by health care professionals. Examples include (but are not limited to): use of mobile vans travelling to communities, telehealth solutions, decision support tools for patients and primary providers, etc.
• Studies focused on specific pain patient populations to prevent and manage chronic pain including: acute and chronic peri-operative pain, chronic pain management in those who have or are at risk of opioid use disorder, individuals with pain and a co-occurring mental health disorder, individuals with chronic overlapping pain conditions, pain management in older adults, pain management in children, and individuals with multiple chronic conditions.
• Studies to address barriers that affect implementation of evidence-based guidelines and interventions for pain management.
• Studies addressing social determinants of health that affect access to and use of effective non-opioid chronic pain management interventions and practices.
• Multi-level interventions including system level innovations, education at provider, patient, family and community levels to improve understanding and implementation of established guidelines for non-pharmacological and non-opioid approaches to chronic pain management.
• Studies of implementation strategies to support the adoption and adherence to non-opioid chronic pain management strategies and guidelines using community-based partners or champions.
• Studies testing the effectiveness of implementation strategies to reduce health disparities and improve quality of chronic pain management among those who live in rural or remote areas and who are part of a racial/ethnic minority, who have low literacy and numeracy, who represent sex and gender minorities, and/or other underserved populations.
• Studies to address assessment and management of serious acute pain that requires professional assessment and treatment and that may lead to ongoing healthcare needs and/or repeated use of opioid prescriptions. Examples include but are not limited to severe dental/orofacial pain resulting in repeated ER/Urgent Care visits for pain management or pain resulting from a severe injury that requires additional treatment such as physical therapy or surgery.

Specific examples of pain conditions of interest include but are not limited to the following:

• Migraines and other chronic headaches
• Pain from arthritis
• Low back pain
• Pain from injuries requiring health care intervention
• Perioperative pain
• Dental/orofacial pain
• Gynecological pain
• Visceral pain
• Neuropathies and neuropathic pain
• Cancer pain or chronic pain in cancer survivors
• Pain in one or multiple chronic conditions such as lupus, fibromyalgia, sickle cell disease, diabetes mellitus, chronic renal disease, etc.

It is expected that the pragmatic, implementation, or hybrid effectiveness-implementation trials supported under this RFA will recruit women in sufficient numbers to determine sex/gender-specific responses as well as sex/gender differences in trial outcomes. These comparisons have significant clinical relevance given the higher prevalence of pain in women. Studies should, as appropriate, enroll both sexes to better understand the influence of sex/gender as a variable.

Types of Studies Responsive to this FOA

The following types of studies are responsive to this FOA:

• Pragmatic, implementation, or hybrid effectiveness-implementation trials
• Adapting, adopting and/or testing of methods for prevention and management of chronic pain and for management of acute pain if the acute pain requires the intervention of a health care provider for management (e.g., acute dental/orofacial pain or acute low back pain) and is likely to recur, become chronic, or escalate to a more serious complication if not managed appropriately.

Types of Clinical Trials Not Responsive to this FOA

The following types of clinical trials are not responsive to this FOA and applications proposing such activities will be deemed non-responsive and will not be reviewed:

• Studies that do not include human subjects
• Studies that propose to conduct research in animals or in vitro studies
• Phase I (first-in-human) trials whether single or multi-site
• Studies to assess initial feasibility of an intervention
• Studies to understand the mechanism of the intervention that do not include evaluation of health outcomes
• FDA-regulated drug, biologic, or device trial
• Studies that do not focus on populations residing in rural or remote settings as defined above in Part 2, Section I.
• Secondary data analysis
• Studies that are only observational

IC-Specific Areas of Interest

In addition to the above description of the scientific objectives, resources communicating scientific interests of selected NIH Institutes, Centers, and Offices (ICOs) are summarized below. Applicants are encouraged to contact the Scientific/Research contact of the intended I/C to ensure that the aims of the proposed project are consistent with the ICO mission.

National Institute of Nursing Research (NINR)

The National Institute of Nursing Research (NINR) supports research to solve pressing health challenges and inform practice and policy - optimizing health and advancing health equity into the future. NINR discovers solutions to health challenges through the lenses of health equity, social determinants of health, population and community health, prevention and health promotion, and systems and models of care. Drawing on the strengths of nursing’s holistic, contextualized perspective, core values, and broad reach, NINR funds multilevel and cross-sectoral research that examines the factors that impact health across the many settings in which nurses work, including homes, schools, workplaces, clinics, justice settings, and the community.

In the context of this FOA, NINR’s interests include but are not limited to the following topics:

• Studies of prevention and management of chronic pain in rural settings that address health-related social risk factors and social needs within the context of clinical practice and health care delivery
• Implementation studies that incorporate attention to social determinants of health that affect pain management options and outcomes
• Research that identifies and addresses access to quality care, and structural barriers impacting health outcomes, health seeking behaviors, and patient-provider interactions
• Projects focused on improving the health of underserved, uninsured, and under-insured rural and remote populations
• Multidisciplinary, multi-level interventions or multi-component delivery models that fully engage stakeholders and the rural communities where they serve
• Studies that address clinical and organizational challenges to delivery of evidence-based, quality care for chronic pain, especially those studies that bridge clinical and community care services with social factors and health care needs.

National Institute on Aging (NIA)

NIA is interested in applications that focus on adults in middle age and late life with acute and chronic pain conditions. NIA is particularly interested in management of pain in the setting of multiple chronic conditions, polypharmacy, socioeconomic deprivation, and physical functional and cognitive impairment. NIA is especially interested in improving health equity of aging populations suffering with pain. As such, applicants are encouraged to propose research that will investigate or address causal drivers and moderators of disparities in pain experience and pain management operating at multiple levels of analysis and domains of influence and across the lifespan. NIA encourages projects addressing priorities outlined in the NIA Health Disparities Research Framework.

Applications that propose behavioral interventions are encouraged to use the NIH Stage Model for Behavioral Intervention Development, focusing on Stage IV and Stage V. For example, the UG3 Phase may include Stage IV studies focused on establishing necessary relationships in rural communities to establish the effectiveness of efficacious simple interventions (e.g., simple default or nudge interventions, or technology-based interventions that require no training to administer), and the UH3 Phase may include hybrid Stage IV/Stage V studies that examine the Stage IV effectiveness of these interventions in combination with Stage V research examining the mechanisms of action of different implementation strategies.

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

NIAAA has particular interest in applications examining the use of alcohol to self-medicate chronic pain and how alcohol use impacts implementation of proposed interventions to treat chronic pain. Specific considerations relevant to alcohol include but are not limited to: assessment, across healthcare settings, of alcohol use; co-use of alcohol and opioids to self-medicate chronic pain; ability of interventions to reduce alcohol consumption; incorporation of alcohol-related information into patient, provider, family, and community education materials; and differential effects or impacts of alcohol on chronic pain across health disparity populations.

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

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases. In the context of this FOA, the NIAMS is interested in applications that support the "real world" implementation of effective, evidence-based interventions to manage pain in individuals from rural and remote areas with emphasis on pain assessment, treatment, and management in the NIAMS mission-relevant disease areas. Research in community health care settings is particularly encouraged. Note, applications focusing on chronic low back pain (cLBP) will be expected to align with the Back Pain Consortium (BACPAC) Research Program definition of cLBP and collect the BACPAC minimum data set as appropriate. Applicants are encouraged to discuss potential applications with the appropriate NIAMS program director.

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

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is particularly interested in applications that address implementation of evidence-based non-opioid interventions for chronic pain management in rural and remote populations relevant to (a) women with endometriosis, pelvic pain, vulvodynia/vestibulodynia, dysmenorrhea, and other gynecologic pain syndromes, and (b) children, women of reproductive age, pregnant and lactating individuals, people with intellectual and physical disabilities, and health disparity populations (i.e. racial/ethnic groups, sexual and gender minorities, underserved rural and socioeconomically disadvantaged populations).

National Institute of Drug Abuse (NIDA)

NIDA is interested in pragmatic, implementation or hybrid effectiveness-implementation trials that concurrently address chronic pain management and reductions in opioid misuse or opioid use disorder (OUD) in rural communities. For the purposes of this RFA, opioid misuse is defined as taking a medication in a manner or dose other than prescribed; taking someone else’s prescription, even if for a legitimate medical complaint such as pain; or taking a medication to feel euphoria (i.e., to get high). For the purposes of this RFA, the DSM-5 identifies OUD as a problematic pattern of opioid use leading to clinically significant impairment or distress. OUD severity can range from mild (2-3 symptoms), to moderate (4-5 symptoms) and severe (6 or more symptoms). Individuals who are in OUD recovery can also be included in these studies. Of importance, tolerance and withdrawal symptoms represent iatrogenic consequences of chronic opioid consumption and do not meet DSM criteria for mild OUD. Applicants who are interested in measuring reductions in misuse behaviors and/or OUD are encouraged to collect the IMPOWR CDEs and share data with the IMPOWR network.

National Institute of Dental and Craniofacial Research (NIDCR)

In addition to the Research Areas of Interest delineated above, this FOA encourages applications that leverage existing resources and/or identify unique challenges in rural communities affected by the opioid epidemic. NIDCR is interested in clinical trials aimed at reducing the burden of pain in individuals living in rural areas and associated with acute and chronic oral and craniofacial diseases and conditions including temporomandibular disorders (TMD), trigeminal neuropathies, burning mouth syndrome, oral cancer pain, dental/orofacial pain and other conditions. Examples of research topics that would be appropriate to the NIDCR include:

• Testing the implementation of effective opioid use disorder (OUD) screening and referral to treatment models in rural dental care settings;
• Testing evidence-based clinical tools and/or interventions designed to modify dental practitioner opioid prescribing behaviors for individuals living in rural areas, especially for adolescent and young adult patients;
• Testing the implementation of evidence-based opioid risk mitigation strategies in rural dental practice settings;
• Testing the implementation of effective non-opioid pharmacological, non-pharmacological treatments or a combination of these for management of acute and chronic oral and craniofacial pain conditions in individuals living in rural areas;
• Testing evidence-based approaches to assessment and management of acute dental/orofacial pain that may lead to ongoing healthcare needs and/or repeated use of opioid prescriptions;
• Testing effective interventions that target biological, psychological, and/or social determinants/stressors that address disparities in acute and chronic oral and craniofacial disease pain presentation and management;
• Testing the implementation of effective social determinants of health-driven, culturally-tailored interventions that target chronic oral and craniofacial pain and comorbid conditions affecting individuals living in rural settings.

Applicants are encouraged to discuss applications with the NIDCR contact listed in Section VII. Agency Contacts.

National Institute on Minority Health and Health Disparities (NIMHD)

The mission of the NIMHD is to lead scientific research to improve minority health and reduce health disparities. NIMHD projects aimed at reducing the health disparity equity and inequity burden associated with chronic must include a focus on one or more of the following populations that NIH-designates as experiencing health disparities in the United States and its territories: African Americans, Latinos/Hispanics, American Indians and Alaska Natives, Asian Americans, Native Hawaiians and other Pacific Islanders, less privileged socioeconomic groups, underserved rural populations, and sexual and gender minorities (SGM).

In addition to the Research Areas of Interest delineated above, examples of research topics that would be appropriate to the NIMHD include:

• Studies that use multiple domains of influence (e.g., biological, behavioral, sociocultural, environmental, physical environment, health system) and multiple levels of influence (e.g., individual, interpersonal, family, peer group, community, societal) to understand and address health disparities (see the NIMHD Research Framework, https://www.nimhd.nih.gov/about/overview/research-framework.html, for more information)
• Studies that include multidisciplinary, multi-level interventions with engagement of community members and collaborators
• Studies that address SDOH that impact access to care such as structural barriers, medical insurance, racism, discrimination stigma, and bias
• Studies that address cultural humility, literacy, numeracy, misinformation, and family models on perceptions, barriers, and adherence to pain treatment
• Studies that involve group-based innovative models in special populations that include SGM, women, children, and the elderly in rural communities
• Studies that use novel technologies and mechanisms to address chronic pain in diverse rural populations

Applicants are encouraged to discuss applications with the NIMHD contact listed in Section VII. Agency Contacts.

National Institute of Neurological Disorders and Stroke (NINDS)

The National Institute of Neurological Disorders and Stroke (NINDS) commits to reducing the disproportionate burden of neurological diseases experienced by underserved groups of society, including racial and ethnic minorities, rural, and socioeconomically disadvantaged populations, by funding a spectrum of research from basic science through clinical studies and training the next generation of health equity investigators (https://www.ninds.nih.gov/Current-Research/Focus-Tools-Topics/Health-Disparities-Research). Chronic pain including but not limited to migraine and headache is a priority disease area for NINDS. Applicants are strongly encouraged to incorporate community engagement strategies into their study designs from inception to implementation.

NINDS is particularly interested in:

• Studies to address the social determinants of health that affect implementation of evidence-based guidelines and interventions for chronic pain management among those who live in rural or remote areas and who are part of a racial/ethnic minority, low literacy/numeracy, limited English proficiency, and/or other underserved population
• Studies testing the effectiveness of implementation strategies to reduce health disparities and improve quality of chronic pain management among those who live in rural or remote areas and who are part of a racial/ethnic minority, low literacy/numeracy, limited English proficiency, and/or other underserved population
• Studies focused on specific pain patient populations to prevent and manage chronic pain among those who are part of a racial/ethnic minority, low literacy/numeracy, limited English proficiency, and/or other underserved population
• Studies that test implementation of existing evidence-based chronic pain interventions, that impact those who live in underserved rural or remote areas

A letter of intent and communication with NINDS program staff prior to submission of an application are strongly encouraged.

Additional Information

Governance: The awards funded under this FOA will be cooperative agreements (see Section VI.2 Cooperative Agreement Terms and Conditions of Award). Close interaction with the NIH staff and with the CC will be required to accomplish the goals of this program.

HCS Research Collaboratory Work Groups have been established by the CC and the NIH as the core collaborative activity of this program. The Work Groups provide a forum for discussion of challenges and solutions across projects. Harmonized and standardized policies and processes will be vetted in these groups. Work Groups have been established in the following areas: Electronic Health Records, Regulatory /Ethics, Biostatistics & Study Design, Health Care Systems Interactions, Implementation Science, Health Equity, and Patient Reported Outcomes (http://rethinkingclinicaltrials.org/cores-and-working-groups/). Additional Work Groups may be identified as the HCS Research Collaboratory expands with new projects as part of this initiative. Work Groups will comprise individuals from each of the Projects, the Coordinating Center, and staff from the NIH. PD/PIs must identify study staff or investigators that will participate in Collaboratory Work Groups.

A Steering Committee has been established by the CC to address issues that span all projects, provide input into the policies and processes of the PRISM/Collaboratory, and assist in dissemination of policies and processes that enable research in healthcare systems involving their patients and practitioners. At a minimum, the Steering Committee will have one representative from each of the projects, one representative from each Work Group, one representative from the Coordinating Center, NIH Program Officers and Project Scientists for the CCC and Projects. All members are expected to actively participate in all Steering Committee activities. The combined vote of NIH membership may never exceed 40 percent. NIH may convene an external panel of experts to provide advice on the overall program progress.

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

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

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)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• American Indian/Alaska Native Tribal Governments (Federally Recognized)
• American Indian/Alaska Native Trial Governments (Other than Federally Recognized)

Federal Government

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• American Indian/Alaska Native Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Urban American Indian/Alaska Native American Serving 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.

• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their full SAM and Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active 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 diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women 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.

Key Personnel of the NIH HEAL PRISM or Collaboratory Coordinating Center (funded under RFA-AT-19-011 or RFA-AT-22-002) must not be named as PDs/PIs on applications submitted in response to this FOA.

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, per 2.3.7.4 Submission of Resubmission Application. 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 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

For this application, the intervention should be provided to patients living in rural areas, as defined by the Health Resources & Services Administration (HRSA) definition: All non-metro counties, all metro census tracts with Rural-Urban Commuting Area (RUCA) codes 4-10, and large area metro census tracts of at least 400 square miles in an area with population density of 35 or less per square mile with RUCA codes 2-3; and outlying metro counties without a UA. For more details on the addition of outlying metro counties, read the Federal Register Notice, Revised Geographic Eligibility for Federal Office of Rural Health Policy Grants. The HRSA Rural Health Grants Eligibility Analyzer can be used to determine rurality.

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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.

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:

Martina Schmidt, Ph.D.
Telephone: 301-594-3456
Email: [email protected]

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

For this specific FOA, the Research Strategy section is limited to 20 pages, divided between the UG3 and UH3 phases of the project.

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, with the following additional instructions:

Facilities and Other Resources: The application should provide sufficient rationale for the proposed HCS(s) for the Project. Applicants should provide a description of successfully conducted clinical studies within the partnering HCS and describe the infrastructure and expertise (e.g., clinical investigators, informaticists) to implement the proposed pragmatic trial within all proposed HCSs.

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

R&R Budget

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

Budgets for both phases (UG3/UH3) must be included; the UH3 budget will undergo reassessment during the UG3 planning phase.

Budgets must include funds for clinical and data coordination and comply with HEAL data sharing (as described under Section IV. 2. Resource sharing plan).

Minimum effort of personnel: The PD/PI must devote a minimum level of effort of 20% annually (2.4 -person months) to the project. There should be sufficient time and effort from the leadership team to ensure successful conduct of the proposed study. Budgeted effort of other personnel must be appropriate to the needs of the project. The budget should include personnel at all participating health care systems with expertise relevant to the project, which might include clinical investigators and staff with expertise in the administrative aspects of clinical trials oversight. The budget should also include personnel at participating community partners, including community-based organizations, for participation in research design and as well as conduct of the clinical trial.

Applications should budget for study personnel to participate in each of the NIH PRISM/Collaboratory Work Groups. The UH3 budget should include data coordinating activities for individual projects. The budget should include any costs for data sharing to meet HEAL requirements (see section IV. 2. Resource Sharing). Applications must budget for project PD(s)/PI(s) travel to attend two one-and-a-half-day Health Care Systems Research Collaboratory program meetings in the first year, and an annual meeting in subsequent years in the greater Washington D.C. area. In addition, applicants must budget for one PD/PI to attend the annual HEAL Investigators Meeting in the greater Washington D.C. area.

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:

Applications should describe the intervention or coordination of several interventions that are robust, apply broadly to pain patient populations and can be implemented in rural and remote areas, with a goal of determining whether the intervention(s) improves pain outcomes. Applicants should describe how the results of the question being tested will have a significant impact on pain management in rural and/or remote populations at an individual or systems level. The intervention should be clearly described, well-characterized and available such that it could be reliably delivered by clinical providers or HCSs. The intervention should be reasonably simple and not require a complex structure for implementation or monitoring. The application should describe planned implementation flexibilities including implementation by appropriate providers.

To clearly distinguish between the two phases, applicants should specify separate UG3 and UH3 information in each subsection (Specific Aims and Research Strategy) of the PHS 398 Research Plan as appropriate. Activities in both phases will depend on the specific study (e.g., specific pain population, types of interventions, experimental design, randomization strategy and proposed outcome measures). In preparing the application, investigators should consider the fact that applications will be assigned a single impact score for both UG3 and UH3 phases.

Specific Aims: Applicants should address the scientific questions to be answered: what specifically will be done during the proposed funding periods, and what is the impact of addressing the research question on public health. Specific aims should be scientifically appropriate for the distinct phases of the project. Include separate aims, on one page, for both the UG3 and UH3 phase, and clearly label them as UG3 specific aims and UH3 specific aims.

Research Strategy: Within the Research Strategy, applicants should first describe the UG3 Phase and then the UH3 Phase. The Research Strategy section should have a clear demarcation of the UG3 and UH3 phases of the application. It is not necessary to repeat background information or details of methods in the UH3 portion that were provided in the UG3 portion. Applications proposing a two-year UG3 Phase must propose and justify the need for a pilot study that will inform the design of the UH3 Phase. The UH3 Phase must be described in sufficient detail to permit reviewers to assess significance and innovation of the proposed work and the strength of the experimental design. Address how the research question serves the goals of the overall PRISM/Collaboratory program and addresses the urgent need for better pain management.Applications should describe details for the proposed trial or implementation research study including projections for recruitment, attrition, and effect size estimations.

Applications should describe the plan to enroll patients based on broad eligibility criteria to maximize diversity and minimize intentional or unintentional exclusions based on risk, age, health literacy, demographics or expected adherence.

Applications should describe the intervention or coordination of several interventions that are robust, apply broadly to pain patient populations and can be implemented in rural and remote areas, with a goal of determining whether the intervention(s) improves pain outcomes. Applicants should describe how the results of the question being tested will have a significant impact on pain management in rural and/or remote populations at an individual or systems level. The intervention should be clearly described, well-characterized and available such that it could be reliably delivered by clinical providers or HCSs. The intervention should be reasonably simple and not require a complex structure for implementation or monitoring. The application should describe planned implementation flexibilities including implementation by appropriate providers.

Clinically meaningful outcome measures that are important to stakeholders should be described. The level (patient, provider and/or system level) of the outcome measures should be defined. If the study is not randomized, the rigor of the planned controls and justification for the choice of control should be described. All applications should include a clear description of the analytic plan that is appropriate to the type of study (pragmatic, implementation or hybrid effectiveness/implementation). If the project proposes a cluster-randomized trial, explanation of the adequacy of the sample size and study are needed, as well as the planned analytic strategy.

Investigators are encouraged to describe how the approaches, measures, designs, and outcomes proposed are pragmatic or utilize implementation research methods.

If the project proposes to implement evidence-based guidelines, applicants are encouraged to describe the quality and level of evidence for the treatments that will be implemented from the guidelines.

The application should describe the health care system(s) and the investigative team's experience conducting pragmatic, implementation, or hybrid effectiveness-implementation trials within health care systems. In general, all studies must use at least one HCS for implementation, which is identified in the application. Applications proposing effectiveness outcomes should include a sufficient number of participating HCS (at least one) and sites (more than one) to allow for enrollment of participants to allow for a fully powered assessment of effectiveness. The application must provide a rationale for the HCS selected for the project and provide a description of the infrastructure and expertise to implement the proposed trial within all proposed HCSs. Additional community partnerships will be developed in the UG3 phase. A description of the role of the community partner, criteria for selecting a community partner, and plans for developing the partnership in the UG3 phase should be included.

Both the UG3 and the UH3 phases of the Research Strategy must include a summary of the proposed Milestones Plan that is a required Other Clinical Trial-related attachment. The summary should describe the key milestones (e.g., training of study personnel, implementation of EHR and other data collection methods, IRB approval for each site, enrollment targets by gender/race/ethnicity, etc.) that need to be met for each phase of the application (UG3 and UH3) to ensure its success; the methods that will be used to reach the milestones; and a timetable identifying when each of these key milestones will be met. The proposed milestones will be reviewed by the NIH program staff based on recommendations from the peer review panels, and final milestones will be agreed upon and included in the terms of award. Milestones may be revised in the UG3 phase by agreement of the investigators and NIH program staff.

PRISM/Collaboratory Work Groups include participation by individuals from all funded projects, the CC, and the NIH. Applicants should describe how project personnel would participate in the PRISM/Collaboratory Work Groups ([Electronic Health Records, Regulatory /Ethics, Biostatistics & Study Design, Health Care Systems Interactions, Implementation Science (if applicable), Health Equity, and Patient Reported Outcomes http://rethinkingclinicaltrials.org/cores-and-working-groups/]. Applicants should describe their willingness to comply with policies, guidelines, and practices developed by the Work Groups, and to work with the CCC in providing relevant information and materials.

Applicants should not propose work that duplicates efforts already funded or supported by NIH Institutes or Centers, HEAL Initiatives, or the Patient-Centered Outcomes Research Institute (PCORI). Although novel theoretical approaches and methodologies may be needed, when possible, applicants should leverage, adopt, or adapt resources from ongoing NIH-supported and other national efforts including but not limited to the many federal investments in the HMO Research Network, the CTSAs, REDCap, PROMIS, NIH Toolbox, Health Care Innovation Awards, DEcIDE, eMERGE, other networks, CERTs, SHARP, Vaccine Safety Datalink, or the Sentinel Initiative.

Applicants should allow flexibility in determining which patient-reported outcome measures will be used, if possible. The HEAL Initiative has a set of Common Data Elements that includes required or highly recommended measures for collection at baseline and primary follow-up timepoint (https://heal.nih.gov/data/common-data-elements).

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.

NIH intends to maximize the impact of HEAL Initiative-supported projects through broad and rapid data sharing. Consistent with the HEAL Initiative Public Access and Data Sharing Policy (https://heal.nih.gov/about/public-access-data), all applications, regardless of the amount of direct costs requested for any one year, are required to include a Data Management and Sharing Plan, outlining how scientific data and any accompanying metadata will be managed and shared. The plan should describe data types, file formats, submission timelines, and standards used in collecting or processing the data. Data generated by HEAL Initiative-funded projects must be submitted to study-appropriate domain-specific or generalist repositories in consultation with the HEAL Data Stewardship Group to ensure the data is accessible via the HEAL Initiative Data Ecosystem. Guidelines for complying with the HEAL Public Access and Data Sharing Policy can be found at https://heal.nih.gov/data/complying-heal-data-sharing-policy. Resources and tools to assist with data related activities can be found at https://www.healdatafair.org/.

To maximize discoverability and value of HEAL datasets and studies and facilitate data integration and collaboration, applications submitted in response to this FOA are strongly encouraged to incorporate standards and resources where applicable:

• Applicants are encouraged to ensure that data collected by the study conform to Findable, Accessible, Interoperable, and Reusable (FAIR) principles.
• Applicants are specifically encouraged to incorporate into their planning an alignment with the guidelines, principles, and recommendations developed by the HEAL Data Ecosystem, including but not limited to preparing data to store in selected specified repositories, applying minimal metadata standards, and using core HEAL Clinical Data Elements (CDEs) (https://heal.nih.gov/data/common-data-elements) and other necessary requirements to prepare data to connect to the HEAL Data Ecosystem.
• All new HEAL clinical pain studies are required to submit their case-report forms/questionnaires to the HEAL Clinical Data Elements (CDE) Program. The program will create the CDE files containing standardized variable names, responses, coding, and other information. The program will also format the case-report forms in a standardized way that is compliant with accessibility standards under Section 508 of the Rehabilitation Act of 1973 (29 U.S.C 794 (d)), which require[s] Federal agencies to make their electronic and information technology accessible to people with disabilities. HEAL Initiative clinical studies that are using copyrighted questionnaires are required to obtain licenses for use prior to initiating data collection. Licenses must be shared with the HEAL CDE team and the program officer prior to use of copyrighted materials. For additional information, visit the HEAL CDE Program.
• To the extent possible, HEAL awardees are expected to integrate broad data sharing consent language into their informed consent forms and align study consent language with data access and re-use requirements as defined by repository HEAL investigators select to store their HEAL data long-term.

The NIH notices referenced below provide additional NIH guidance that should be considered in developing a strong data management and sharing plan. The list is instructive but not comprehensive.

• Elements of an NIH Data Management and Sharing Plan (NOT-OD-21-014)
• NIH has provided guidance around selecting a repository for data generated by NIH-supported research and has developed desirable characteristics for all data repositories (NOT-OD-21-016).
• NIH encourages the use of data standards including the PhenX Toolkit (www.phenxtoolkit.org) (for example, see NOT-DA-12-008, NOT-MH-15-009).
• Data should be organized according to a standard model that is widely accepted within the field. An example for the clinical research studies would be the OMOP Common Data Model, which has also been successfully adapted for use with observational (including survey) studies more generally. In addition, the HL7 FHIR (Fast Healthcare Interoperability Resources) standard (NOT-OD-19-122) may facilitate the flow of data with EHR-based datasets, tools, and applications.
• NIH encourages clinical research programs and researchers to adopt and use the standardized set of data classes, data elements, and associated vocabulary standards specified in the United States Core Data for Interoperability (USCDI) standards, as they are applicable (NOT-OD-20-146). Use of the USCDI can complement the FHIR standard and enable researchers to leverage structured EHR data for research and enable discovery. In addition to USCDI, OMOP, and FHIR standards for enhanced interoperability, investigators and data centers should align their data collection and management practices with recommended guidance emerging from the HEAL CDE and Data Ecosystem programs.

Awardees conducting research that includes collection of genomic data should incorporate requirements under the NIH Genomic Data Sharing Policy (NOT-OD-14-124, NOT-OD-15-086).

Letters of Support

Applications must include a strong letter of support from each of the HCS partners named in the application that relates their commitment to the proposed research and outlines how the project fits with organizational priorities, and the commitment of their staff to the project. The letter must provide a description of how the project would directly impact the quality of care within their HCS and indicate level of intention to sustain the intervention(s) after the study period, based upon results. The application is expected to include letters from the officials responsible for intellectual property issues at the applicant institutions (including sub-contractor institutions) stating that the institution supports and agrees to abide by the Resources and Data Sharing Plan put forth in the application. These letters should be clear expressions of commitment consistent with achieving the goals of the program.

When involving human subjects research, clinical research, and/or NIH-defined 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.

As all applications will include human subjects, applications must include at least one human subjects study record for the activities of the UH3 project. If the UG3 will include any human subjects research a separate study record should be included for the UG3 human study(ies). As stated in the instructions, investigators must submit a study record for each clinical trial proposed in the application.

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan
Describe the following: 1) the planned recruitment methods including use of contact lists (participants and/or sites), databases or other pre-screening resources, advertisements, outreach, media / social media and referral networks or groups; 2) if there are known participant or study-related barriers to accrual or participation (based on literature or prior experience), please list these barriers and describe plans to address them to optimize success; 3) contingency plans for participant accrual if enrollment significantly lags behind accrual benchmarks; 4) participant retention and adherence strategies; and 5) possible competition from other trials for study participants.

Applicants must provide strong evidence of the availability of appropriate institutional resources and suitable patient populations, providers, clinics, or facilities (depending on unit of randomization). Documentation of availability of eligible participants, clinic sites, or units of randomization, presented in tabular format must be provided. The application must include relevant information that addresses the feasibility of recruiting participants who are eligible for the study. Specifically, applicants must provide evidence that each recruiting center in the study or trial has access to a sufficient number of participants who meet the eligibility criteria and appropriate diversity (gender, race, ethnicity) as defined in the submitted protocol. For multisite applications, information must be provided for each participating site.

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan
In addition to the NIH application requirements for a data and safety monitoring plan for clinical trials, applicants should refer to NIH’s policy on data and safety monitoring (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html).

Section 4 - Protocol Synopsis

4.7 Dissemination Plan
Describe how the investigators will facilitate and support timely publication and dissemination of results in ClinicalTrials.gov and develop tools as appropriate and consistent with achieving the goals of the program.

Section 5 - Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-related Attachments
The following attachments must be included as a part of the cooperative agreement application. Attachments permit expansion of certain elements that cannot be appropriately described in the Research Strategy. All attachments listed below must be provided or the application will not be peer reviewed.

Milestones Plan
A Milestones Plan must be provided as an attachment called "Milestones Plan.pdf", appended with one, two, or three pages, as needed, and must not exceed three pages.

The milestones should be well described, quantifiable, and scientifically justified to allow an assessment of progress. For UG3 milestones, applicants should delineate what they propose to achieve in order to proceed to the UH3 phase. The milestones should also include a timeline, a discussion of the suitability of the milestones for assessing success in the UG3 Phase, and a discussion of the implications of successful completion of these milestones for the proposed UH3 Phase. Annual milestones for the project implementation (UH3) phase, including annual enrollment milestones by gender/race/ethnicity, should also be included in the application, although it is understood that timelines and milestones for implementation in the UH3 phase that are proposed in the application will evolve as activities in the UG3 phase progress, if an award is made.

All applicants must use the following definition of a milestone in their application: a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, achievable, and measurable. Milestones must address overall recruitment and retention goals. The Terms and Conditions under this FOA will include a milestone plan that is mutually agreed upon by the investigators and NIH.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

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

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.

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.

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 How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential fieldof the Senior/Key Person Profile form. 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 unique entity identifier provided on the application is the same identifier 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 and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive 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.

All post-submission materials must be received by the Scientific Review Officer (SRO) no later than 30 calendar days prior to the peer review meeting. In addition to the NIH policy allowed post-submission materials in NOT-OD-19-083, the following post-submission materials are allowed:

• Milestones Plan (e.g., due to the hiring, replacement, or loss of an investigator; change to health care systems participating in the trial; or change in electronic health record or IT infrastructure)

Section V. Application Review Information

1. Criteria

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

For this particular announcement, note the following:

This FOA includes Additional Review Criteria on Milestones, which require comment by reviewers and which are to be considered when determining the overall impact score.

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.

Overall Impact

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).

Scored Review Criteria

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.

Significance

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

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

Specific to this FOA:

Will this project develop effective methods to improve the management of pain in rural or remote populations? For studies that integrate an intervention into health care delivery, how strong is the evidence of efficacy or effectiveness for the intervention? For studies that propose to improve adherence to established guidelines, how strong is the evidence for the guidelines that are being used? Is the proposed study addressing a major public health issue focused on pain management? How well does the application justify the need for the proposed trial to change the management of pain in rural populations? How well does the application propose outcomes that are clinically meaningful to stakeholders? Is there a strong likelihood that the UG3 planning activities and subsequent project implementation in the UH3 phase will achieve significant advances in the ability to implement effective non-opioid management of chronic pain in rural and/or remote populations?

Investigator(s)

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

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

Specific to this FOA:

Do interdisciplinary teams include necessary expertise to conduct the trial? Does the team include appropriate collaborators from the participating HCS(s)? Does the application address the inclusion of team members from different backgrounds that will advance the implementation of the project? Do the PD(s)/PI(s) and key personnel have the necessary expertise in design and implementation of pragmatic, implementation, or hybrid effectiveness-implementation clinical studies in a rural or remote area? Do the PD(s)/PI(s) have extensive experience in performing proposed planning phase activities, and do they have a track record of successful recruitment and retention in prior studies, investigative collaborations, or partnerships with (within) health delivery systems?

Innovation

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

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

Specific to this FOA:

Does the application challenge and seek to impact current conventional approaches to pain management studies by utilizing novel approaches or methodologies that will allow it to be successfully implemented in a rural and/or remote setting? Does the application include mechanisms for leveraging novel collaboration and study oversight strategies?

Approach

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

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

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?

Specific to this FOA:

Is the intervention or coordination of several interventions robust, applicable to pain patient populations and able to be implemented in rural and/or remote areas? Based on the characterization and availability of the intervention can the intervention be reliably delivered by clinical providers and/or HCS? Have the investigators allowed for interventions to be implemented with flexibility and by appropriate practitioners? Will the results of the question being tested have a significant impact on pain management in rural/remote populations, individuals and/or systems level? Are the projections for recruitment, ongoing engagement, attrition and effect size estimations based on data in the proposed HCS? Is the degree of pragmatic aspects of the approaches, measures, design and outcomes well justified for the design elements of the proposed study? Are project outcome measures clearly described, defined as patient, provider, and/or systems level and clinically meaningful? Will the results provide relevant information and adequate data for other communities or HCSs to potentially adopt the intervention? Will rigorous controls be included in the design? Will broad but adequate eligibility criteria be used, as proposed? Can interventions be easily implemented and monitored? Have the investigators proposed reasonable approaches to overcome barriers to research in the rural and/or remote setting? Have the investigators proposed plans to determine patient, provider, and community preferences to implementation? Will the plans for community engagement included in the proposed UG3 phase further the study goals? Are resources included to compensate stakeholders and patients and support and sustain community engagement? Does the proposed analytic plan address study power and employ analytic strategies that are appropriate for the study design (pragmatic, implementation or hybrid effectiveness/implementation? Are there clear and feasible plans for data sharing in the HEAL data ecosystem?

Environment

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

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

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

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

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

Specific to this FOA:

Does the application provide sufficient rationale for the HCS(s) selected for the project? Is commitment from the HCS to the project evident? Has/have the HCS(s) successfully conducted clinical studies, such that there are sufficient infrastructure and expertise (e.g., clinical investigators, informaticists) to implement the proposed pragmatic trial at all proposed sites? If the proposed HCS has not previously participated in research studies, have the investigators proposed methods to work with the HCS to facilitate the proposed research? Will the plans for involving community partner(s) allow for needed recruitment, provide help for implementation, identify implementation barriers, and advance study progress towards the goals?

Additional Review Criteria

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.

Study Timeline

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

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

Milestones

Are the proposed milestones clearly defined, feasible, well developed and quantifiable with regard to specific goals and accomplishments? Are the timeline and criteria appropriate to have community-based partner(s) identified by the end of the UG3 period? Is the timeline for training providers or interventionists appropriate for the successful conduct of the study? Is the timeline for gathering stakeholder feedback regarding meaningful outcome measures, barriers to implementation, and local preferences appropriate to allow implementation in the UH3 phase? Are adequate criteria provided for the UG3 phase that will be utilized in determining milestone completion before proceeding to the next phase of the project? Are the UH3 milestones appropriate for the next phase of the project? Will proposed UG3 activities (including plans for identifying a sufficiently large target patient population) allow for transition to the UH3 phase? Are the goals of the UG3 phase reasonable and, if accomplished, will they provide the basis for the proposed UH3 phase?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable.

Renewals

Not Applicable

Revisions

Not Applicable

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.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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

Resource Sharing Plans

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National Center for Complementary and Integrative Health, 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 will receive a written critique.

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.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

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 submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council for Nursing Research. 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.
• Geographical distribution of awards and study sites.

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 recipient's business official.

Recipients 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 and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient 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).

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, Recipients, and Activities, including of note, but not limited to:

• Federalwide Research Terms and Conditions
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex (including gender identify, sexual orientation, and pregnancy). This includes ensuring programs are accessible to persons with limited English proficiency and persons with disabilities. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.
• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including reasonable accommodations and making services accessible to them, see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.
• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.
• For guidance on administering programs in compliance with applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 and 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 75, 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

1. Overseeing the overall budget, activities and performance of the project. The PD(s)/PI(s) must devote a minimum level of effort of 20% annually (2.4 calendar months) to the project. If a project includes multiple PIs, the total annual PI effort must be at least 20%. The institution must obtain appropriate prior approval for any change in PI effort.
2. Accepting the participatory and cooperative nature of the collaborative research process and complying with policies and practices developed by the PRISM/NIH HCS Research Collaboratory governing structure.
3. Sharing data and resources according to the approved sharing policies for the PRISM/NIH HCS Research Collaboratory program and the NIH HEAL Initiative Public Access and Data Sharing requirements (https://heal.nih.gov/about/public-access-data).
4. Participating in all meetings of the PRISM/Collaboratory Steering Committee. Identifying study team members with relevant expertise to participate in program-wide Work Groups and sub-committees (as appropriate).
5. Cooperating with the PRISM/Collaboratory Steering Committee, Collaboratory Coordinating Center, research partners, and NIH staff in the design and conduct of protocols, analysis of data, and reporting of results of research.
6. Agreeing to accept close coordination, cooperation, and management of the project with NIH, including those outlined below under "NIH Responsibilities."
7. Submitting materials to the NIH Program Director, Coordinating Center, and/or Steering Committee, as requested. This will include regular reports of accomplishments and roadblocks, conference and meeting summaries, and other reports as requested.
8. Submitting materials that meet all subject and formatting requirements.
9. Submitting a detailed transition request for the UH3 Project implementation phase, outlining UG3 progress and how negotiated UG3 Milestones have been met, as well as sending detailed plans, budgets, and annual milestones for the UH3 implementation phase. Note that, funding of the UG3 Project planning phase cooperative agreement does not guarantee support of the UH3 Project implementation phase
10. Any of the above functions may be performed by the applicant organization or by subcontract to the applicant organization.

Recipients(s) will retain custody of and have primary rights to the data and software developed under these awards, subject to Government policies regarding rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff has substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

1. The NIH Project Scientist will work with the PD(s)/PI(s) and the Steering Committee to ensure the objectives of the program are being met. The primary responsibility for the program resides with the recipient, although specific tasks and activities will be shared among the recipient and the NIH Project Scientist.
2. NIH staff will interact with the PD(s)/PI(s) on a regular basis to monitor progress. Monitoring may include: regular communication with the PD(s)/PI(S) and his/her staff, periodic site visits for discussion with the recipients research team, observation of field data collection and management techniques, fiscal reviews, and other relevant stewardship activities.
3. The NIH reserves the right to terminate or curtail the award (or an individual component of the award) in the event of inadequate progress or data reporting.
4. Additional NIH staff may participate in all Work Groups, implementation teams and committees, including the Steering Committee, as appropriate. NIH may designate staff from other federal agencies to participate if advantageous to facilitate the activities of the program.
5. NIH staff will act as a resource and facilitator for activities of the recipient with non-NIH HCS researchers and other NIH, DHHS, or other federally sponsored research networks that may be relevant to this effort.
6. NIH staff will provide input, expert advice, and suggestions in the design, development, and coordination of the infrastructure development and implementation efforts.
7. NIH staff will report periodically on progress of the program to the NIH Common Fund, NIH, and DHHS leaders. NIH may convene an external panel of experts to provide advice on program progress.
8. NIH staff will conduct an administrative review of the UH3 transition request to determine whether the project will transition to UH3 funding and be implemented. Criteria for transition to the UH3 phase used in the NIH administrative review include: successful achievement of the UG3 milestones, potential for successfully meeting the UH3 implementation phase plans and milestones, demonstrated ability of the team to work within the consortium arrangement, and the availability of funds.
9. Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

1. Ensuring that NIH HCS sites and investigators as well as NIH and other research partners fully comply with federal regulatory requirements. This includes but is not limited to those relating to human subjects protections, informed consent, and reporting of adverse events.
2. Jointly developing appropriate confidentiality procedures for data collection as well as processing, storing and analyzing data to ensure the confidentiality of individual patients, health care providers and other institutions involved in any PRISM/Collaboratory research projects.
3. Participating in the PRISM/Collaboratory Steering Committee to address issues that span all projects, providing input into the policies and processes of the HCS Research Collaboratory, and assisting in dissemination of policies and processes that enable research in partnership with health care systems, their patients, and practitioners. At a minimum, the Steering Committee will be composed of one representative from each of the projects, one representative from each Work Group, one representative from the CC, the NIH Program Coordinator, and representatives from various NIH ICs and the Common Fund. The combined vote of NIH membership may never exceed 40 percent of the total committee membership.
4. Participating in the PRISM/Collaboratory Work Groups that have been established as the core collaborative activity of this program. The Work Groups provide a forum for discussion of challenges and solutions across projects; harmonized and standardized policies and processes will be vetted in these groups. Work Groups have been established in the following areas: Electronic Health Records, Regulatory/Ethics, Biostatistics & Study Design, Health Care Systems Interactions, Implementation Science (if applicable), Health Equity, and Patient Reported Outcomes (http://rethinkingclinicaltrials.org/cores-and-working-groups/). Additional Work Groups may be identified as the PRISM/Collaboratory expands with new projects. Work Groups are open to participation by individuals from all funded Projects, the CCC, and the NIH.
5. Recipients will work with other PRISM/Collaboratory investigators and NIH to identify common clinical outcome measures (such as measures of quality of life, physical function, pain, or fatigue). NIH and CCC staff will work with the Principal Investigators to facilitate this aspect of the projects.
6. Establishing an adherence by each Project Team (project grantee, CC grantee, and NIH staff) to a written plan of engagement, with timelines, to ensure timely delivery of the tested implementation plan.
7. Working together with the CC through all phases of the projects, including the implementation and close out, to assure all resources, materials, protocols, data, best practices, program policies, and lessons learned are disseminated broadly through the CC, to inform researchers and health care systems engaged in research in health care settings.

Dispute Resolution:
Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened, having three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. Reporting

When multiple years are involved, recipients 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. NIH FOAs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients 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, application errors and warnings, documenting system problems that threaten submission by the due date, and 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)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

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

Karen Kehl, PhD, RN
National Institute of Nursing Research (NINR)
Telephone: 301-594-8010
Email: [email protected]

Laura Elizabeth Kwako, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Phone: 301-451-8507
E-mail: [email protected]

Denise L Stredrick, PhD
Office of Disease Prevention (ODP)
Phone: 301-594-7553
E-mail: [email protected]

Priscah Mujuru
National Institute on Minority Health and Health Disparities (NIMHD)
Phone: 301-594-9765
E-mail: [email protected]

Devon Oskvig, Ph.D.
National Institute on Aging (NIA)
Phone: 301-827-5899
Email: [email protected]

Alexis Bakos, PhD, MPH, RN
National Cancer Institute (NCI)
Phone: 301-921-5970
Email: [email protected]

Susan Shero, RN, MS
National Heart, Lung, and Blood Institute (NHLBI)
Phone: 301-827-8168
Email: [email protected]

Beda Jean-Francois, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Phone: 202-313-2144
Email: [email protected]

Charles H Washabaugh, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Phone: 301-496-9568
E-mail: [email protected]

Sue Marden, PhD, RN
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6838
Email: [email protected]

Cheryse A. Sankar, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-318-2889
Email: [email protected]

Dena Fischer, DDS, MSD, MS
National Institute of Dental & Craniofacial Research (NIDCR)
Phone: (301) 594-4876
E-mail: [email protected]

Shelley Su
National Institute on Drug Abuse (NIDA)
Phone: 301-402-3869
E-mail: [email protected]

Martina Schmidt, PhD
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3456
Email: [email protected]

Kelli Oster
National Institute of Nursing Research (NINR)
Telephone: 301-594-2177
Email: [email protected]

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Phone: (301) 443-4704
E-mail: [email protected]

Priscilla Grant
National Institute on Minority Health and Health Disparities (NIMHD)
Phone: 301-594-8412
E-mail: [email protected]

Jeni Smits
National Institute on Aging (NIA)
Phone: 301-827-4020
Email: [email protected]

Sean Hine
National Cancer Institute (NCI)
Phone: 240-276-6291
Email: [email protected]

Nina Hall
National Heart, Lung, and Blood Institute (NHLBI)
Phone: 301-435-0710
E-mail: [email protected]

Debbie Chen
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-594-3788
Email: [email protected]

Sahar Rais-Danai
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Phone: 301-594-5032
E-mail: [email protected]

Margaret Young
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-642-4552
Email: [email protected]

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

Diana Rutberg, MBA
National Institute of Dental & Craniofacial Research (NIDCR)
Phone: (301) 594-4798
E-mail: [email protected]

Pamela G Fleming
National Institute on Drug Abuse (NIDA)
Phone: 301-480-1159
E-mail: [email protected]

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.