Part 1. Overview Information

Key Dates

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

This Funding Opportunity Announcement (FOA) seeks grant applications to optimally and sustainably address late-stage implementation research questions to address the delivery of proven-effective prevention and treatment interventions for heart, lung, blood, and sleep (HLBS) comorbid diseases and disorders in people living with HIV (PLHIV) in World Bank designated low- and middle-income countries (LMICs) and Small Island Developing States (SIDS). The NHLBI recognizes that LMICs that have been reclassified as high-income in the past eight years may continue to have low-resource regions and population sub-groups like those in LMICs. Consequently, the NHLBI also encourages applications from these re-classified countries. Throughout the rest of this FOA, the term LMIC is used broadly to denote countries currently designated as LMICs, those countries designated as LMICs prior to January 1, 2011 that have since been re-categorized as high-income by the World Bank, and SIDS. For the purposes of this FOA, late-stage implementation research is defined as research to identify strategies to achieve sustainable uptake of proven-effective interventions in routine clinical, public health, and community-based settings and maximize the positive impact on population health. Each awarded project is to conduct late-stage implementation research within one or more of the following geographical regions: East Asia and the Pacific, Europe and Central Asia, Latin America and the Caribbean, Middle East and North Africa, South Asia, and Sub-Saharan Africa. As a group, awardees will constitute a collaborative alliance for HLBS late-stage implementation research on comorbid diseases and disorders in PLHIV in LMICs with capabilities for answering research questions (within and across regions) aimed at improving population health outcomes. This FOA is intended to support applications from Foreign Institutions only to conduct research that, while carried out in LMICs, results in outcomes that apply to low-resource settings globally.

Background

Globally, an estimated 36.9 million people were living with HIV in 2017. New infections are decreasing worldwide and deaths due to AIDS have also decreased. HIV/AIDS, however, will remain among the top five leading causes of death in low- and middle-income countries (LMICs) for the foreseeable future. With a call to end the global AIDS epidemic by the year 2030, WHO, UNAIDS, PEPFAR and others have called for an increase in the number of persons on antiretroviral therapy (ART) to combat the disease. There is now a push for rapid scale-up of ART utilization in LMICs, and over 70% of the adult population with known HIV status in these countries could be on ART as early as 2020. While this treatment is vital for proper management of HIV symptoms and complications, transmission ability, and viral progression, ART has been shown to increase the risk of heart failure and other cardiopulmonary conditions in high-income countries (HICs). The early appearance of chronic heart, lung, blood, and sleep (HLBS) comorbid disorders in PLHIV in HICs suggests similar HLBS comorbid complications will occur in LMICs and low-resource settings as ART uptake increases, especially as ART-related viral suppression continues to drive a significant increase in the average lifespan of PLHIV around the world. In comparison to those without HIV, PLHIV have a higher prevalence of smoking, and thus the occurrence of pulmonary complications such as COPD and other pulmonary conditions are also increased. Sleep disturbances are also prevalent in PLHIV, along with the increased risk for other comorbid disorders such as stroke, and diabetes. There is a need to strengthen the evidence base on implementation of scalable interventions that have proven effectiveness to promote HLBS health management in PLHIV in LMICs, identify individuals in need of care early in the disease process, intervene early to preempt disease progression, and treat and manage illness and care in these individuals while considering the varying needs of different population groups across the life course. As global health paradigms continue to transition from acute to chronic treatment, integration of care and person-centered care is of increasing interest for creating sustainable health systems, especially with regard to HLBS comorbid care in PLHIV in LMICs. Further opportunities for decreasing siloes between the non-communicable disease (NCD) and infectious disease communities are vital as the burden of NCDs rises disproportionately in LMICs. This requires diverse scientific communities to work closely together and learn new skills across platforms, disciplines, countries, and regions to address integrated health needs.

Implementation research is a vital component of the evolving healthcare paradigm in LMICs for effective, sustainable, contextualized treatment of comorbid diseases. Implementation research evaluates salient research outcomes for evidence-based interventions including acceptability, affordability, and appropriateness of interventions, including feasibility, fidelity, penetration, and sustainability of the intervention in specific contexts. Proven-effective interventions and guidelines exist for HLBS diseases and disorders for PLHIV, (e.g., using chronic care models to manage patients, promoting aspirin therapy, smoking cessation). However, globally these interventions have not been fully implemented and/or scaled up due to a multitude of factors. Because of the earlier and more pronounced onset of non-communicable diseases (NCDs) increasingly being seen in PLHIV, the HIV population presents an ideal opportunity to gain an understanding of how to promote sustainable uptake of proven interventions and integrated care programs that could then be translated to broader populations, including non-HIV populations with NCDs. In addition, the ongoing, highly visible, and widely supported international efforts (e.g., PEPFAR, UNAIDS, WHO’s HIV program, etc.) to rapidly scale-up adequate treatment for PLHIV present a unique opportunity for large-scale, multi-site, multidisciplinary collaborations and integrated care networks to more sustainably address management of HLBS and comorbid chronic illnesses in PLHIV.

Scope and Objectives

The objective of this FOA is to support late-stage (T4) implementation research projects to test strategies for the optimal uptake and continued sustainability of proven-effective interventions that will provide generalizable knowledge to address the delivery of proven-effective prevention and treatment interventions for HLBS comorbid diseases and disorders in PLHIV globally. Applications are expected to propose projects that: (1) capitalize on and leverage current knowledge of the most prevalent HLBS comorbid complications in PLHIV; (2) leverage ongoing global efforts, in combination with NIH-supported research opportunities, to conduct implementation research and study delivery of high priority, proven-effective, evidence-based programs to improve the health of PLHIV in low-resource settings; (3) identify barriers to and facilitators for uptake of proven intervention strategies; and (4) enhance implementation research capacity.

Partnerships:

Research partnerships are key to enhancing resources and improving capacity for global health research in LMICs. A partnership model of research in which LMIC PIs lead research projects with any needed technical support from colleagues in HICs can lead to ownership, sustainability, and the development of local and national research capacity. Cultural and national influences play a large role in the interpretation and application of research findings. Similarly, local and national researchers in LMICs have critical knowledge of the cultural and national influences regarding health problems and systems. Thus, in global health research conducted in LMICs, local and national researchers should engage in partnerships as needed, to provide technical assistance, enhance resources, and build research capacity.

The NIH expects research supported by this FOA to be designed and planned in collaboration with in-country government agencies, non-governmental organizations (NGOs), and health care institutions and organizations so as to be responsive to local needs, interests, and capacities; embrace cultural and health system factors; and to increase likelihood of long-term sustainability. The NIH expects research supported by this FOA to align with commitments or planned commitments at a regional or national level to implement evidence-based interventions (including evidence of cost-effectiveness and affordability) and services for HLBS comorbid diseases and disorders in PLHIV across health or other sectors (e.g., education, information technology). Efforts to make evidence-based health care for HLBS comorbid disorders in PLHIV equitably available at a national, regional, or local level require both infrastructure and partnerships, especially collaborations among researchers, HLBS and HIV/AIDS health service users, HLBS and HIV/AIDS health service providers, non-governmental organizations, and government agencies that will implement and sustain services. As such, this FOA intends to support applications that propose partnerships with representatives from: (1) one or more LMIC research institutions; (2) one or more LMIC non-governmental organizations and/or health care institutions or systems that provide access to service provider and service user viewpoints so as to be responsive to local needs, interests, and capacities; and (3) one or more representatives of an LMIC government agency with a health-related function (e.g., Ministry of Health, Ministry of Social Welfare, Ministry of Public Health, National AIDS Control Program/Agency/Council, etc.) and that have a policy-making, evaluation, or research role within the agency. In addition, the NIH expects the proposed research to provide participating countries, regions, and/or local jurisdictions with the knowledge, tools, and strategies needed to maximize the positive effects of HLBS- and HIV/AIDS-related interventions, to enable and/or strengthen HIV/NCD integrated care systems, to scale up services to broader populations, to sustain delivery of evidence-based care, and/or to foster evidence-based policy and program development for meeting the needs of individuals with HLBS comorbid disorders in PLHIV.

Applications are expected to utilize existing or planned research collaborations in the region of interest (eligible regions defined below) and with relevant expertise. To be considered responsive to this FOA, applications are expected to utilize partnerships within and/or across the geographic region(s) and foster partnerships between the HIV and NCD research and implementation communities.

Applicants must demonstrate that a research partnership currently exists (or can be developed and maintained) between the applicant and the partnership entities listed above via official documentation of the partnership (i.e., letter of support). Partnerships are intended to ensure that the viewpoints of multiple stakeholders contribute to the development and conduct of the research, thereby increasing the likelihood of public health-relevant research findings, and ultimately the uptake and sustainability of the research findings. Partnerships are expected to be integral to the conduct of the research proposed in the application.

Regions:

The NIH expects the proposed research to take place in World Bank-designated LMICs, Small Island Developing States (SIDS), and previously designated LMICs re-categorized by the World Bank as high-income (from LMIC) on or after January 1, 2011. This program is not intended to support research that will be conducted primarily in and/or by the United States or other high-income institutions that do not meet eligibility criteria, although partnership with high-income country collaborators is encouraged. The NIH recognizes that countries reclassified as high-income (from LMIC) in the past eight years may continue to have low-resource regions and population sub-groups like those in LMICs. Consequently, the NIH also encourages countries from these re-classified countries. Throughout this FOA, the term LMIC is used broadly to denote countries currently designated as LMICs, those countries designated as LMICs prior to January 1, 2011 that have since been re-categorized as high-income by the World Bank, and SIDS. Research is expected to take place in the following World Bank regions:

• East Asia and the Pacific
• Europe and Central Asia
• Latin America and the Caribbean
• Middle East and North Africa
• South Asia
• Sub-Saharan Africa

Implementation Research Elements:

The NIH expects that applications will propose a project focused on an implementation aspect of delivering, scaling up, or sustaining proven-effective, evidence-based interventions to prevent or treat HLBS comorbid diseases and disorders in PLHIV at the national, regional, or local level within designated LMIC(s). Projects focused on deimplementation of ineffective practices or other areas of implementation research such as systems modeling are also encouraged.

This FOA is intended to support applications that propose to: (1) employ validated, theoretical, or conceptual implementation research frameworks (e.g., Consolidated Framework for Implementation Research (CFIR); Promoting Action on Research Implementation in Health Services (PARiHS); Pragmatic-Explanatory Continuum Indicator summary (PRECIS); Reach Effectiveness Adoption Implementation Maintenance (RE-AIM); PRECEDE-PROCEED, K2A, etc.); (2) include implementation measures as primary outcome measures (e.g., acceptability, adoption, appropriateness, affordability, costs, feasibility, fidelity, penetrance, scale-up, sustainability, etc.); (3) include implementation research study designs (e.g., experimental, quasi-experimental, observational, modeling, cluster randomization, stepped-wedge; Type III hybrid effectiveness, etc.); and (4) inform understanding of key mediators and mechanisms of action of the implementation, scale-up, or sustainment effort.

The NHLBI encourages research activities that leverage other service delivery systems or platforms (e.g., infectious disease care and treatment, maternal and child health care, education, justice, work places) for delivering evidence-based services for HLBS diseases and disorders. The NHLBI also encourages the use and enhancement of existing, sustainable databases, where possible, in answering study questions.

Applicants proposing to conduct a clinical trial under this FOA must adhere to NIH requirements for clinical trials research.

Research Skills Development:

This FOA will support applications that include plans/strategies/models for future skills/career development designed to increase research capacity to conduct late-stage (T4) implementation research in LMICs, especially to address the HIV epidemic and comorbid HLBS diseases and disorders. It is expected that this capacity building/skills development will allow researchers to conduct late-stage (T4) implementation research in LMICs within the country and/or region in which the research project is proposed to be conducted. As different countries and regions may have various levels of research capacity and readiness for research participation, responsive applications are expected to clearly describe a principled approach to engagement and subsequent skills development activities. Research capacity-building/skills development elements are expected to be suited to the needs of the region, with the goal of significantly enhancing the future capacity for HLBS implementation science research within the region by the end of the project period. These efforts will be aligned throughout the alliance of funded HLB SIMPLe awards, as is feasible, and co-facilitated by the companion HLB SIMPLe Research Coordinating Center (RCC).

Applicants are encouraged to propose innovative models of mentoring, skills development, and career development for investigators from within the region. Skills development activities, in turn, may focus on the development of independent researchers by providing mentorship and supporting research development projects for graduate students, advanced post-doctoral candidates, early career faculty, and investigators who may wish to refocus their careers on HLBS or late-stage (T4) implementation research. Skills development may also focus on clinicians, staff of regional NGOs or Ministries of Health, community health workers, or other technical personnel to learn specialized skills in late-stage (T4) implementation research. While applications should not propose to support an academic degree program, leveraging existing educational infrastructure, such as regional schools of public health, and aligning appropriate areas of emphasis to drive sustained implementation research efforts is appropriate. Additionally, utilization of existing, validated skills development materials and resources is encouraged.

Research skills development activities may include, but are not limited to:

• Short courses on implementation science methodology, dissemination and implementation research designs, and/or mixed methods research
• Summer research institutes to enhance scientific writing skills and increase publication rates
• Establishment of distance learning and research mentoring networks
• Establishment of research fellowships for staff of regional NGOs, Ministries of Health, community health workers, or other technical personnel

Structure

This FOA utilizes a bi-phasic, milestone-driven cooperative agreement (UG3/UH3) mechanism consisting of a study start-up and needs assessment (UG3) phase with possible transition to an implementation (UH3) phase. Awards made under this FOA will support a maximum project period of 5 years, consisting of a 1-2 year UG3 phase and 3-4 year UH3 phase, based on the needs of the proposed research. Only UG3 projects that meet the scientific performance milestones and award requirements of the UG3 phase may transition to the UH3 phase. Applications submitted in response to this FOA must address both the UG3 and UH3 phases and are strongly encouraged to use project management principles as appropriate.

Phases of Award:

The UG3 phase will support planning activities focused on sustainable uptake of proven-effective interventions throughout the community of interest. This phase should include activities such as the identification of the population in which the strategies to deliver and scale up proven-effective interventions will be tested, establishment of collaborative relationships, identification of the strategies to be tested during the UH3 implementation phase, conduct of a health needs assessment, and preparation of all details required for conducting a clinical trial, such as finalization of the protocol and the informed consent/assent document; the development of the manual of operations and procedures, case report forms and other resources necessary to the performance of the protocol; Data and Safety Monitoring Board (DSMB) review of the protocol; and Institutional Review Board approval of the trial

The UH3 phase will support implementation of the proposed research and/or clinical trial beyond the necessary planning and study start-up activities of the UG3 phase. Subject to NHLBI funding availability and scientific priorities, UH3 awards will be made after administrative review with specific attention to the extent to which agreed-upon milestones have been met. If the UH3 is funded, an additional administrative review will be scheduled within the first two years of the UH3 to assess progress toward UH3 milestones or enrollment milestones.

Milestones and Transition to UH3 Phase:

Delineation of milestones is a key characteristic of this FOA. The application is expected to propose a well-defined set of milestones for the UG3 phase as well as the UH3 phase. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be performance-based to enhance the likelihood that the project will be completed on-time and on-budget. It is understood that the proposed milestones for the UH3 phase may be revised as activities in the UG3 phase progress. In the event of an award, the PD/PI and NIH staff will negotiate the final list of milestones for each year of support. At the completion of the UG3 planning phase, which may consist of one or two years of support based on the needs of the proposed research, the applicant will be required to submit a detailed transition request for the UH3 phase. Satisfactory completion of UG3 milestones will be assessed administratively to determine eligibility to transition to the UH3 implementation phase, which may consist of three or four years of support, based on the needs of the proposed research; a maximum project period of five years will apply for all efforts proposed under the UG3/UH3 phased award. The quality of the planning, design, and documentation products for the UH3 phase will be given key consideration when the NIH considers the transition to the UH3 implementation phase. NHLBI policies regarding milestones and relevant clinical research/studies policies are described in NHLBI Accrual of Human Subjects (Milestones) Policy, NHLBI Policy for Inclusion of Women and Minorities in Clinical Research, and NHLBI Policy for Data and Safety Monitoring of Extramural Clinical Studies). If at any time the project fails to make progress toward meeting milestones (e.g., developing a final protocol and/or manual of procedures including a detailed description of study procedures and process details; completing training of study staff, etc.), the NIH may consider ending support and negotiating an orderly close-out of the award.

Applicants and recipients of UG3 funding should note that the UG3 award does not guarantee subsequent UH3 funding.

Examples of projects that are responsive to this FOA

Examples of projects that are of interest to the NHLBI and responsive to this FOA include, but are not limited to those that propose:

• To test implementation strategies for delivering local and national policies/guidelines designed to achieve equitable access to quality services for treatment of HLBS comorbid diseases and disorders in PLHIV across population subgroups (e.g., women, poor, rural, racial/ethnic minorities);
• Implementation of structural interventions (i.e., interventions that alter the social and economic environments in ways that increase availability, acceptability, and/or accessibility of health care) designed to prevent, preempt, treat, and/or manage HLBS comorbid diseases and disorders in PLHIV;
• To test implementation models for improving delivery and quality of care for:
  • Delivering evidence-based interventions for early identification and treatment of HLBS comorbid diseases and disorders in PLHIV;
  • Scaling up of skills development and supervision for providers of health services (including non-specialist health workers) for HLBS comorbid diseases and disorders in PLHIV;
  • Integrating screening for HLBS comorbid diseases into existing delivery platforms for development and expansion of integrated care networks (e.g., primary health care, schools, HIV service delivery systems, work places, etc.);
  • Delivering transdiagnostic interventions for HLBS diseases and disorders in health sector and non-health sector settings affiliated with HIV/AIDS care;
• To test implementation of feedback models for monitoring the reach, accessibility, quality, costs, and/or fidelity of preventive, treatment, or rehabilitative health services for HLBS comorbid diseases and disorders in PLHIV in a given service delivery system (e.g., how models enable data-driven decision-making for optimal delivery of care);
• To test optimal and sustainable systems-level or community-level strategies to deliver care in non-traditional comorbid chronic disease care settings (e.g., workplaces, faith-based settings, schools, etc.) for PLHIV with comorbid HLBS disorders (e.g., using technology and other approaches);
• To test the implementation of evidence-based models of peer-delivered or caregiver-delivered support for PLHIV with comorbid HLBS disorders in LMICs/low-resource settings, including task shifting as a mechanism of integrated care delivery;
• To test the implementation of low-cost, technologically-assisted strategies for supporting providers, delivering care, and/or supporting adherence or engagement with treatment in low-resource settings;
• To test implementation strategies for effectively incorporating NCD-related modules into electronic medical records for integrated chronic care management;
• To test implementation strategies for enhancing the delivery of prevention or treatment services, including effective pharmacotherapies for HLBS diseases and HIV/AIDS, in justice and social service settings.

Applications proposing projects that are considered non-responsive will not be reviewed. Non-responsive applications are those that:

• Propose research to be conducted primarily in and/or by the U.S. or other HICs that do not meet eligibility criteria;
• Do not conduct research on an aspect of the delivery of proven-effective prevention and treatment interventions for heart, lung, blood, and sleep (HLBS) comorbid diseases and disorders in people living with HIV (PLHIV) in World Bank designated LMICs
• Develop or test new intervention(s) that have not yet been proven effective;
• Conduct preclinical studies with animals;
• Conduct research in populations that are not living with HIV/AIDS;
• Do not propose or provide evidence of collaboration among one or more research institutions, one or more LMIC government agencies with a health-related function; and one or more LMIC NGOs and or health care institutions or systems that provide access to provider and service user viewpoints;
• Collect preliminary data on the efficacy of the intervention (such as pilot testing), or collect observational data from humans to support a clinical trial for the effectiveness of an intervention(s);
• Conduct comparative effectiveness trials of various interventions.

Additional Information

This FOA runs in parallel with a companion FOA (RFA-HL-20-026) that encourages applications for an HLB SIMPLe Research Coordinating Center (RCC). Close interaction with the NIH and with the RCC will be required to accomplish the goals of this program. The RCC will assist in dissemination of policies and enable research in partnership with other research sites across the global alliance.

Section II. Award Information

Section III. Eligibility Information

1. Eligible Applicants

• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Only direct applications from foreign institutions in World Bank-designated low- and middle-income countries (LMICs), Small Island Developing States (SIDS), and previously designated LMICs re-categorized by the World Bank as high-income on or after January 1, 2011 will be accepted. Applicants are encouraged to engage partners from any country, including the U.S., that can assist them in meeting the goals of this FOA.

To determine country income categories, please see: http://data.worldbank.org/country

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration , but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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:

Director, Office of Scientific Review
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0279
Email: [email protected]

The attachment listed below must be provided.

1. Milestone Plan. The filename "Milestone Plan" should be used for this attachment. A milestone is defined as: a scheduled event in the project timeline that signifies the completion of a major project stage or activity. The Milestone Plan must describe objective, measurable milestones with separate milestones for the UG3 and UH3 phases. The milestone plan must include clearly stated annual milestones that will be reached at the end of the UG3 planning phase and annual milestones that will be completed during the UH3 implementation phase. The milestone plan should address anticipated challenges to meeting milestones and propose potential mitigation or corrective action strategies.

Milestones may be refined and finalized in consultation with NIH Program Staff at the time of the UG3 phase of the award and before the UH3 phase award, if granted.

• Milestones that may be completed during the UG3 phase include, but are not limited to:
  • Identification of the population in which the strategies to deliver and scale up proven-effective interventions will be tested
  • Demonstration that the necessary study population is available for appropriate testing of implementation research strategy
  • Establishment of collaborative relationships
  • Establishment of skills development programs for practitioners
  • Identification of the strategies to be tested during the UH3 implementation phase;
  • Collection of data to determine feasibility of study procedures and establish a timeline for accrual of study participants
  • Finalization of the health needs assessment
  • Finalization of the statistical analysis plan
  • Finalization of the study protocol
  • Acceptance of the protocol by NIH
  • Preparation of all documents required for conducting the proposed implementation research and/or clinical trial, if proposed, including:
    • Development of case report forms and other resources necessary to the performance of the trial
    • Preparation of informed consent(s), manual of operations, study procedure documents for practitioners, study-specific data management plan, etc.
    • Comprehensive clinical trial project management plan that includes a description of all relevant activities associated with trial launch, conduct, and completion, and on-time and on-budget performance metrics
    • All necessary regulatory approvals, as well as provision of the necessary drugs, devices or other resources
    • Finalization and Institutional Review Board/Data and Safety Monitoring Board approval of the trial protocol and related study documents
  • Study participant enrollment plan
• Milestones that may be completed during the UH3 phase include, but are not limited to:
  • Study activation
  • Enrollment of the first patient participant
  • Enrollment and randomization, if applicable, of 25%, 50%, 75% and 100% of the projected study population
  • Achievement of retention target for the study population
  • Dissemination of research results
• Completion of data collection time period
• Completion of primary outcome data analyses
• Reporting of results in ClinicalTrials.gov, if applicable

Provide evidence that the PD(s)/PI(s) and Key Personnel have:

• The necessary implementation research expertise for the proposed project;
• The necessary expertise for conducting research on chronic HLBS disease management in people living with HIV (PLHIV) in LMICs, and/or low-resource settings;
• The expertise and capacity to form a multidisciplinary team that can facilitate collective efforts to determine best ideas or approaches;
• The capacity to foster and coordinate successful collaborations and manage complex projects, which will contribute to the coordinated completion of the research activities, and therefore, the scientific objectives of the program;
• The evaluative sciences capacity to independently perform data analyses.

Document the relevant experience of each PD/PI and all key personnel, and clearly define their roles and responsibilities in the program.

Applicant teams must include investigators from:

• One or more research institutions;
• One or more LMIC non-governmental organizations and/or health care institutions that provide access to service provider and service user viewpoints, so as to be responsive to local needs, interests, and capacities; and
• One or more representatives of an LMIC government agency with a health-related function (e.g., Ministry of Health, Ministry of Social Welfare, Ministry of Public Health, National AIDS Control Program/Agency/Council) and who have a policy-making, evaluation, or research role within the agency.

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

The operational budget including 8% Facilities and Administrative (F&A) costs should include, but not be limited to the following items:

• PD(s)/PI(s) supervision of day to day operations and oversight of the professional activities during proposed research capacity-building/skills development
• Reasonable administrative costs
• Subcontracts as necessary.

Applicants should also budget for the cost of the PD/ PI and another key person to attend a three-day start-up meeting held by the NHLBI during Year 1 of the award.

Applicants must budget for annual costs of having a PD/PI and two additional team members participate in an annual three-day face-to-face meeting of the global implementation research alliance (international meeting location to vary annually; for budgeting purposes, assume Zurich, Switzerland). Attendance at this meeting is required for the PD/PI and two additional individuals from each awardee team, with participants from the LMIC preferred. Teams are also encouraged to include a junior team member in each annual meeting.

Funds for Skills Development/Research Capacity-Building should not exceed $50,000 in direct costs per year.

If applicable, budgets should include supplemental costs associated with Data Safety and Monitoring Board (DSMB) activities, including preparing materials and/or reports for the DSMB. The associated HLB SIMPLe RCC will convene and manage a global DSMB for oversight of all HLB SIMPLe research programs and oversee clinical study and site monitoring for proper oversight of clinical trials proposed under the HLB SIMPLe FOA.

Specific Aims

The specific aims must be relevant to the NHLBI mission. Describe how the project proposes to design and test optimal and sustainable T4 implementation strategies for the delivery of proven-effective prevention and treatment interventions for HLBS comorbid diseases and disorders in PLHIV in LMICs. Aims must also describe how the proposed project will build T4 implementation research capacity through the development of an in-country cadre of researchers, clinicians, and/or community health workers with the necessary skills to sustainably address the rising burden of non-communicable diseases in PLHIV.

Research Strategy

Applications should address the following:

• Describe how the proposed project addresses comorbid HLBS disorders and HIV sequelae for populations at risk, including PLHIV. Indicate if the proven, evidence-based interventions are ready for scale-up for HLBS diseases and disorders among PLHIV in LMICs.
• Provide evidence that the proposed research is responsive to local needs, governmental priorities/commitments, sociocultural and economic contexts, interests, and capacities.
• Propose the use of indicators and measures of project context, reach, outcomes, and scale up potential. The project should also include assessment of implementation costs as an integral part of the proposed research.
• Describe how the study is designed to inform understanding of key mediators/mechanisms of action of the implementation, scale up, or sustainment effort. Note that applicants proposing to conduct a clinical trial under this FOA must adhere to NIH’s requirements for clinical trials research.
• Describe how the project will accommodate relevant gender and cultural aspects, as well as vulnerable populations.
• Provide a description of how the project is designed to promote a culture of evidence-informed learning and effective uptake of results by embedding real-time monitoring/evaluation throughout the intervention selection and scale-up process, as applicable.
• Describe plans for implementation science and knowledge translation capacity-building, particularly within the countries and across the regions where the research will be conducted.
• Describe how suitable management and government structures will be established to ensure relevant stakeholders are appropriately engaged throughout the research.
• Describe how the proposed research protocol will fully incorporate protections for populations in vulnerable circumstances; how participants will be safeguarded from potential harmful or inequitable impacts of research outcomes; and which mechanisms for protection of sensitive data will be utilized while enabling data sharing for research purposes.
• Provide a plan to ensure that conflicts of interest are appropriately minimized or managed to protect the scientific integrity and credibility of the research and fulfill ethical obligations to research participants, particularly in situations where interventions are supported by the private sector and/or there is the potential for commercial gains.

UG3 Planning Phase:

• Describe the proposed project or trial design. Applications must utilize the most rigorous design possible for the strategies to be tested. This may include randomized controlled trials, including cluster-randomized trials. Other designs or approaches may also be appropriate, including systems and population-based approaches, quasi-experimental strategies, mixed-methods designs, stepped-wedge designs, and the use of adaptive treatments. Describe plans to document and evaluate the fidelity, quality, delivery, and costing of the implementation strategy.
• Clearly describe the target population. Implementation strategies to be developed and tested must target providers and health care delivery systems that serve PLHIV. Demonstrate access to and ability to recruit, as applicable, from a sufficient pool of eligible participants, and provide appropriate documentation . To the extent possible, applications should address disparities in accessibility, use, or outcomes of services due to gender, age, race/ethnicity, geography or other domain of inequity.
• Describe the infrastructure available to implement the project or trial within the proposed setting and population. Describe how suitable management and governance structures will be established and maintained to ensure relevant stakeholders are appropriately engaged throughout the research.
• Describe the planned process of protocol development, including developing collaborations and refining the protocol based on results of the planning period activities
• Provide appropriate justification for the selection of the evidence-based practice, treatment, and/or guidelines that are targeted, and describe how the proposed project is likely to improve delivery of HLBS evidence-based care among PLHIV in LMICs. NHLBI strongly encourages inclusion of plans to extend the reach of the intervention(s) to communities with diverse cultural values, if applicable.
• Outline the proposed implementation framework that will be employed in the research and its potential to improve HLBS comorbid care in PLHIV.
• Describe establishment of successful partnerships with various stakeholders.
• Discuss the potential challenges in preparing and implementing the research protocol and how these will be addressed.

Implementation Strategies:

• Identify the implementation strategies that will be tested during the UH3 phase. Discuss how the proposed implementation strategy represents an improvement over currently used strategies and/or standards of care.
  • Describe the conceptual framework of the proposed implementation strategy. A validated implementation framework that is feasible for the project is preferred.
  • Specify how the proposed implementation strategy will be adaptable and responsive to the context and account for cultural and organizational factors. For example, describe strategies that take a systems approach by including healthcare systems, government partners, existing HIV/AIDS-related infrastructure, non-profit organizations and/or community resources to enable regional providers to improve care, that help providers to efficiently navigate the healthcare systems in which they work, and that include provider interaction with patients to improve adherence to care.
• Identify key implementation facilitators and barriers that could affect the adoption, adaptation, integration, scale-up and future sustainability of the implementation strategy. Include key barriers at the provider, healthcare system, community, and patient levels that impede current implementation efforts, and identify potential methods to facilitate improved wide-scale adoption of practice guidelines in healthcare centers, community clinics, and other relevant and community-based settings.
• Describe plans for investigators to partner closely with the health care systems and community-based settings in which they work to develop the necessary support to carry out the implementation strategy. Describe how the proposed implementation strategy incorporates multi-level methods to facilitate the effective and efficient adoption of evidenced-based care and guidelines.
• Describe plans to consider contextually-relevant implementation elements such as workflow impact, process adjustments, and mitigation strategies.
• Clearly describe the expected primary outcomes of the implementation strategy. Describe plans for data collection, sources of data values, addressing missing data, data analysis, and evaluating and documenting outcomes. Validated outcomes are expected to include process-focused measures such as acceptability, uptake and adoption, affordability, appropriateness and feasibility, costs, fidelity, penetrance, and sustainability.
• Describe plans to document and evaluate the quality and delivery of the implementation strategy.

UH3 Implementation Phase:

• Describe plans to test the implementation strategies for the identified evidence-based intervention(s).
• Provide a detailed plan to assess the consistency and quality of targeted adoption and scale up of the interventions, organizational characteristics most likely to impact fidelity, and contextual factors likely to impact intervention sustainability (positively or adversely).
• Describe plans for assessment of project implementation costs.
• Describe plans for optimizing sustainability of the implementation beyond the funded project period.
• Describe plans for maximizing external validity such as generalizability, feasibility, and sustainability of findings across health care settings, patient populations, and community settings.

Investigators:

Without repeating information from individual biosketches, describe plans for the multi-disciplinary teams of scientists, clinicians, and stakeholders to work together to develop and test models of implementation that are feasible and applicable across diverse community and practice settings and populations of patients. Identify the collaborative process for engagement and involvement of stakeholders and how the expertise and resources of stakeholders will be leveraged.

Outcomes:

Clearly describe primary outcomes and outcome measures relevant to implementation research (e.g., acceptability, adoption, appropriateness, affordability, etc.) that are appropriate for studying and assessing HLBS care among PLHIV in LMICs. Clinical outcomes are secondary outcomes and can be used to assist in determining fidelity. Identify key factors at the provider, healthcare system, community, and patient levels that determine successful implementation of specific evidence-based treatments and strategies for HLBS among PLHIV in LMICs.

Skills Development/Capacity Building:

Applications must describe a plan for outreach, engagement, and collaboration with regional partners in building research capacity. As different countries and regions may have various levels of research capacity and readiness for research participation, applications should clearly describe a principled approach to engagement and subsequent skills development activities. Research capacity building/skills development elements should be suited to the needs of the region, with the goal of significantly enhancing the future capacity for HLBS implementation science research within the region by the end of the project period. Applications should describe the process for recruitment, review, and selection of candidates. Individuals participating in the skills development component must have a mentor and devote at least 6 person months (CY) effort (e.g., at least 50% of a 12-month calendar appointment) to the proposed research project. Do not include descriptions of individual candidate projects in the application.

Letters of Support

To be considered complete, applications must include letter(s) of support from relevant community- based partners, Ministries, NGOs, healthcare provider(s), and other organization(s) related to the proposed project indicating their relevant expertise and commitment to participate.

If partial funding is to be provided by sources other than NHLBI, provide Letter(s) of Support signed by an authorized representative.

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Where applicable, the awardee will work with NIH and the associated research coordinating center on efforts to harmonize data and use common data standards and elements across funded research sites. For instance, NHLBI can partner with the PD(s)/PI(s) to prepare a dataset and documentation for submission to the Biological Specimen and Data Repository Information Coordinating Center (BioLINCC) as described in the NHLBI Policy for Data Sharing from Clinical Trials and Epidemiological Studies and the Guidelines for NHLBI Data Set Preparation. BioLINCC or another mutually agreed upon NIH-based data repository may be used for the wide sharing of study data to enable public access to data.
• Applications should address plans to make available within one year of the end of the NHLBI period of support for the project, data not previously released and other study materials or products not previously distributed to individuals who are not study investigators in accordance with the NHLBI Data Sharing Policy available at http://www.nhlbi.nih.gov/funding/datasharing.htm.

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.

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

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

Applications from foreign organizations must:

• Request budgets in U.S. dollars.
• Contain detailed budgets. See NOT-OD-06-096.

In addition, for applications from foreign organizations:

• Charge back of customs and import fees is not allowed.
• Funds for up to 8% Facilities and Administrative (F&A) costs (excluding equipment and subawards in excess of $25K) may be requested. See https://grants.nih.gov/grants/policy/nihgps/HTML5/section_16/16.6_allowable_and_unallowable_costs.htm

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

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement .

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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.

In addition, for applications involving clinical trials:

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

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?

In addition, for applications involving clinical trials:

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

Specific to this FOA:

• Is the proposed research scientifically compelling, and does it leverage existing programs and platforms, if relevant?
• How fitting is the conceptual framework underlying the proposed implementation research?
• What is the likelihood that successful project implementation will lead to a significantly new understanding that is relevant for scientists and knowledge users?
• How will successful completion of project aims influence potential scientific, technical, and/or organizational challenges and system barriers (health care and other sectors) to implementation of the interventions which drive this field?
• How do the proposed intervention strategies demonstrate relevance to the socio-political, cultural, policy, and economic contexts of the study settings and understanding of the contextual factors affecting implementation?
• Is the proposed research aligned with international, regional, and/or national commitments?
• What is the potential for sustaining the proposed intervention at scale and for translating findings into different settings?
• How has the application demonstrated that proven, evidence-based interventions are ready for scale-up and appropriate for HBLS diseases and disorders among PLHIV in LMICs?

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

In addition, for applications involving clinical trials:

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

Specific to this FOA:

• How strong are the implementation research expertise and capacity of the PD(s)/PI(s) and Key Personnel to foster and coordinate collaborations to test implementation strategies?
• Does the research team demonstrate a high-quality track record in evaluative science as well as fields relevant for the effective implementation of the proposed research?
• How effectively does the application demonstrate that key stakeholders have been actively involved in informing the proposed research, including in the selection and adaptation of the intervention and the research design?
• How well integrated is the proposed research team with the relevant systems and organizations to develop the necessary support to carry out the implementation strategy or strategies?

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

In addition, for applications involving clinical trials:

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

Specific to this FOA:

• To what extent does the proposed implementation strategy incorporate multi-level methods to facilitate the effective and efficient adoption of evidenced-based care, strategies, and guidelines and advance scientific knowledge for scale up?
• How likely is the proposed research to improve delivery of HLBS evidence-based care among PLHIV in LMICs?

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?

In addition, for applications involving clinical trials:

Does the application adequately address the following, if applicable?

Study Design

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

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

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

Data Management and Statistical Analysis

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

Specific to this FOA:

• To what extent will the proposed plans have the potential to optimize sustainability of the implementation delivery strategy beyond the funded project period?
• How clearly does the application identify key barriers at the provider, system, community, and patient levels that could impede current implementation efforts?
• How compelling is the justification for the targeted evidence-base and the need for improvements in delivery of HLBS-related care for PLHIV in LMICs?
• How strong are the plans to document and evaluate the fidelity, quality, delivery, and costing of the implementation strategy?
• Is the design of the UG3 phase likely to enable the intervention delivery strategy to appropriately move forward to the larger UH3 phase?

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?

Specific to this FOA:

• Are sufficient procedures proposed and/or in place for protecting the data and personal confidentiality of clinical trial participants living with HIV?

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

In addition, for applications involving clinical trials:

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed? Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate? If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial? If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Specific to this FOA:

• In what ways will the proposed location, setting and conditions support timely completion of study aims and completion of both the UG3 and UH3 phases?
• How sufficient is the infrastructure to implement the proposed study within the proposed setting and population?
• To what extent will the plans for developing partnerships with stakeholders contribute to adequately testing the implementation strategy?
• Are the potential stakeholders that are available for collaborations appropriate for the proposed study?

Study Timeline

In addition, for applications involving clinical trials:

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

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

Milestones

Are the listed milestones for each phase appropriate for the goals of the project? To what extent are the milestones relevant, measurable, achievable, result-focused and time-bound? How effectively do the risk assessment and management plans identify and describe risks to implementation and how well are contingency plans described?

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.

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.

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

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

Not Applicable

Not Applicable

Not Applicable

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

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

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

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

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 NHLBI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

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

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

3. Anticipated Announcement and Award Dates

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

Section VI. Award Administration Information

1. Award Notices

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

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Specific to applications proposing clinical trials

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

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

2. Administrative and National Policy Requirements

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

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

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.htmlhttps://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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 Part 75, 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 awardees 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 awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

2.A.1. Awardee and Principal Investigator Rights and Responsibilities

The PD(s)/PI(s) will have primary authority and responsibility for defining objectives, approaches, and details of the research within the guidelines of this FOA and retain primary responsibility for the performance of all UG3/UH3 supported research activities. The PD/PI will be responsible for:

• Planning, directing, and executing the proposed research activities, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, dissemination of data, tools, and technologies, and collaboration with other investigators;
• Providing effective leadership and management of all activities under the award;
• Developing and defining the approach, plans, conduct and analysis for a late-stage (T4) implementation research program for the prevention, treatment, and control of HLBS diseases and disorders in PLHIV in LMICs;
• Meeting project goals, timelines, and milestones;
• Assuring compliance with applicable federal, state, and local regulations;
• Assuring compliance with all applicable DHHS/NIH policies for conduct of research and clinical trials.

PD(s)/PI(s) agree to participate in the cooperative research program, including serving on the Steering Committee, participating in Steering Committee meetings and teleconferences, adhering to Steering Committee policies and decisions, attending annual meetings or workshops, and accepting the close coordination, cooperation, participation and assistance of NIH staff in accordance with the guidelines described in Section VI.2.A. Cooperative Agreement Terms and Conditions of Award: NIH Responsibilities.

All awardees proposing clinical research must comply with federal, state, and local regulations regarding clinical research and monitoring of clinical trials and oversee that all training requirements for the protection of human subject are in compliance. All clinical research performed outside of the U.S. must, in addition to U.S. Federal regulations, comply with the host country regulations for protection of human subjects and conduct of clinical research.

The PD/PI will ensure that on-site administrative structure, scientific capacity, and training are available to enable the research team, including local research investigators and partners, to perform the research activities proposed in this grant application.

The PD/PI will ensure that research and associated activities conducted under this cooperative agreement employ an approach that identifies optimal and sustainable strategies to deliver proven-effective interventions into routine clinical and public health practice and community-based settings to achieve maximal population health impact. The PDs/PIs will provide a process for assessing ongoing research and research capacity-building projects and modifying, redirecting, and/or curtailing ongoing research activities to reflect local changes/shifts based on emerging needs or changing epidemiological conditions.

The PD/PI will be responsible for the timely submission of all abstracts, manuscripts and reviews (co)authored by members of the grant and supported in part or in total under this cooperative agreement. Manuscripts shall be submitted to the NIH Program Official within two weeks of acceptance for publication and must comply with the NIH Public Access Policy. Publications or oral presentations of work performed under this cooperative agreement will require appropriate acknowledgement of NIH support. Timely publication of major findings is encouraged.

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

2.A.2 NIH Responsibilities

An NIH Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. The role of the NIH Project Scientist will be to facilitate and not to direct the activities. It is anticipated that the NIH Project Scientist will offer advisory input. The NIH Project Scientist will facilitate liaison activities for partnerships and aid with access to NIH-supported resources and services. Other appropriate NIH program staff assistance will be coordinated by the NIH Project Scientist, which may include Medical Officer(s), clinical operations and regulatory specialists, biostatisticians, and other expertise as required. The NIH Project Scientist, with support of the appropriate staff and expertise, may provide coordination and assistance to the awardees to meet the requirements for clinical protocol content and conduct. The NIH Project Scientist with substantial programmatic involvement may:

• Provide guidance and support in the design of the research activities
• Serve as a resource for protocol design and development
• Provide programmatic support during the accomplishment of the research
• Advise in the selection of sources or resources
• Advise in management and technical performance
• Participate in scheduled meetings and teleconferences to discuss program coordination and/or progress
• Coordinate and facilitate the interactions among the awardees
• Participate as a voting member in Steering Committee meetings
• Facilitate collaboration with other NIH-supported research resources
• Serve as a resource for all major transitional changes that the awardees might propose (e.g., a change in partnership organization) and advise on their appropriateness prior to implementation to assure consistency with the goals of this FOA
• Assist in avoiding unwarranted duplication of effort with other NIH efforts
• Provide technical assistance and advice to the awardees as appropriate
• Interact with the PDs/PIs on a regular basis to monitor progress. Monitoring may include regular communication with the PDs/PIs and study staff, periodic site visits for discussion with the awardee research team, observation of field data collection and management techniques, fiscal reviews, and other relevant stewardship matters.
• Make recommendations for continued funding based on (a) overall research progress; (b) cooperation in carrying out the research (e.g., attendance at Steering Committee meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or (c) maintenance of high-quality research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements.

A network Scientific Advisory Group (NSAG) may be appointed and supported by NIH to review the progress and provide scientific advice for the intersecting and joint activities of all grants that receive funding under this FOA. The NSAG will be comprised of no more than seven federal and non-federal experts selected by the NIH to participate in NSAG activities in an advisory capacity, when appropriate. When convened, the NSAG will meet at the annual meeting of awardees.

The NIH Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The assigned NIH Program Official may not also serve as an NIH Project Scientist. The NIH Program Official will periodically report award progress to NIH leadership including the Directors of the NHLBI and FIC; PD(s)/PI(s) will provide timely assistance in providing relevant updates, documents, and other materials for NIH reporting purposes.

The NIH Program Official will conduct at least two administrative reviews to determine progress toward achievement of milestones included in the mutually-agreed upon milestone plan, one toward the end of the UG3 phase, and one within the first two years of the UH3 phase. If the milestones have not been satisfactorily met, subsequent funding years may not be approved. NIH reserves the right to phase-out or curtail the study (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable protocol, (b) substantial shortfall in subject recruitment milestones, core milestones mutually agreed upon by the recipient organization and PD/PI and the NIH, consortium participation and collaboration with other awardees, (c) substantive changes in the agreed-upon methodologies and tools with which NIH cannot concur, (d) human subject ethical issues that may dictate a premature termination, or (e) results that substantially diminish the scientific value of study continuation.

The government, via the NIH Program Official, will have access to all data generated under this Cooperative Agreement and may periodically review the data and progress reports. NHLBI staff may conduct data analyses and use information obtained from the data for the preparation of internal reports on the activities of the study.

An NIH intramural scientist may not serve as the PD(s)/PI(s) of a project awarded under this FOA but may participate as a collaborator or consultant. An intramural scientist, however, may not receive salary, equipment, supplies, or other remuneration from this FOA. The intramural scientist must obtain written approval of his/her NIH Institute Scientific Director for the amount of resources that may be allocated to the project; this amount must be specified in the letter, and cannot exceed $200,000 in direct costs of intramural resources. The approval must also specify that the conduct of the project will comply with the DHHS regulations for research involving human subjects and with the PHS policy on vertebrate animal research (if applicable). For applications that include NIH intramural components, the involvement of intramural scientists needs to be consistent with NIH policy.

The NHLBI reserves the right to withhold funding for an individual award in the event of a substantive change in, or failure to make sufficient progress toward, the agreed-upon work scope with which the NIH cannot concur or when there are ethical issues that may dictate a premature close-out.

2.A.3 Collaborative Responsibilities

A Steering Committee (SC) will serve as the governing board for awardees. All participants in the program are bound by the policies and procedures developed by the SC; adoption of such policies and procedures requires a majority vote. Awardees under this FOA will be required to accept and implement policies approved by the SC. Membership on the SC will include the PI of each award, or a designated representative in the case of a Multiple PI award. Each member will have one vote. The NIH Project Scientist will be a voting member of the SC. The chair will be chosen by a majority vote of the SC, with years of service as chair determined by the committee. The chair, in collaboration with the associated program coordinating center staff, is responsible for preparing meeting agendas, for scheduling and chairing meetings, and for preparing concise minutes which will be delivered to SC members within 14 days of the meeting. Virtual meetings are appropriate. The NIH Project Scientist may not serve as Chair of the SC.

Steering Committee responsibilities will include:

• Evaluating, reviewing, and recommending new collaborations and resource allocations for projects across awardees
• Coordinating data sharing and collaborative research efforts among awardees (e.g., measures, consultations with staff across awardees), as appropriate
• Developing and conducting shared protocols, when appropriate
• Jointly developing appropriate confidentiality procedures for data collection, processing, storage and analysis to ensure the confidentiality of data
• Cooperating to ensure the timely and broad dissemination of lessons learned to inform researchers and health care systems engaged in scaling up evidence-based interventions at the population level for integrated HLBS/HIV care in LMICs.

2.A.4 Dispute Resolution Process

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. The three members will be: 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 awardee. This special dispute resolution procedure does not alter the awardee'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

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

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

Brad Newsome, PhD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8170
Email: [email protected]

Geetha P. Bansal, PhD
Fogarty International Center (FIC)
Telephone: 301-496-1492
Email: [email protected]

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0270
Email: [email protected]

Lynn Rundhaugen
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-480-4546
Email: [email protected]

Bruce Butrum
Fogarty International Center (FIC)
Telephone: 301-496-1670
Email:[email protected]

Section VIII. Other Information