Part 1. Overview Information

Key Dates

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts ).

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

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background and Purpose

Familial Hypercholesterolemia (FH) is a common genetic disorder, affecting 1 in 250 people in the U.S., that causes high levels of low-density lipoprotein cholesterol (LDL-C) leading to premature coronary heart disease. If left untreated, men with heterozygous FH over the age of 50 have a 50% increased risk of having a fatal or non-fatal coronary event, while women have a 30% increase by the age of 60. Early intervention with cholesterol-lowering medications, such as statins and ezetimibe, along with lifestyle modifications, can significantly reduce the likelihood of future cardiovascular events and death by ~80 percent. Despite the clinical severity, less than 10% of the population with FH is diagnosed, and among those diagnosed, only half are on life-saving therapies. Furthermore, many FH patients do not find out they have the disease until after having a major coronary event, such as a heart attack or stroke. Thus, identifying and diagnosing FH as soon as possible, to initiate therapeutic interventions and reduce cardiovascular events and death, provides great benefit. Given the hereditary nature of FH, (cascade) screening programs directed at family members of newly diagnosed FH patients, or index cases, is highly effective. Cascade screening is the mechanism by which blood relatives of FH index cases are systematically contacted based on their risk according to the pattern of inheritance (i.e., first-degree relatives first, then second-degree relatives and so forth). Relatives are then screened using LDL cholesterol measurements, genetic testing of known mutations in FH associated genes (LDLR, APOB, PCSK9), or hybrid methods. Cascade screening with genetic testing is more cost-effective than broad universal screening mechanisms and has the potential to reduce the mean diagnostic age of FH significantly. Considerable barriers are affecting the successful implementation of cascade screening in the U.S. These barriers include issues navigating HIPAA related privacy policies, inadequacies in the education of clinicians and patients, and geographic limitations affecting patient access to genetic servic es, among others. Additionally, it remains a challenge to sustain a steady pool of index cases for cascade screening approaches that mine clinical and laboratory information in electronic health record (EHR) databases, in order to rapidly identify new high-risk individuals an essential element for robust cascade screening efforts at the population level.

In an effort to address the implementation challenges mentioned above, this Funding Opportunity Announcement (FOA) will support single-site clinical trial applications for research study proposals that: (1) address barriers that impede population-level implementation of case finding and cascade screening; (2) explore implementation science methodologies to assess the uptake, cost-effectiveness, feasibility, and scalability of family-based cascade screening programs for FH; (3) develop or improve machine learning algorithms and data mining techniques to find high-risk individuals using EHRs; and (4) optimize treatment strategies and health outcomes.

Research Objectives

The objective of this Funding Opportunity Announcement (FOA) is to support applications that developand test innovative strategies for accelerating the uptake and sustainment of evidence-based detection, diagnosis, and treatment of adults with familial hypercholesterolemia (FH). This FOA will support research studies that: (1) explore barriers and facilitators to implementing case finding and cascade screening; (2) utilize implementation science methodologies and frameworks to study adoption, sustainability, and scalability of cascade screening programs; and (3) develop innovative approaches to identify high-risk individuals.

Applications that include plans to specify and test mechanisms of change, leverage existing data resources, utilize vigorous reporting requirements, foster sustainability, including re-use of information, and provide information to enable others to adapt successful implementation strategies are strongly encouraged. NIH encourages researchers to explore the use of Fast Healthcare Interoperability Resources (FHIR ) standard to capture, integrate, and exchange clinical data for research purposes (NOT-OD-19-122)

Selected Research Examples

Ideal research examples in response to this FOA are those that use validated implementation research frameworks, models, and evidence-based interventions (i.e., evidence-based practices (EBP), evidence-based guidelines (EBG), or other well-accepted evidence-based interventions) to explore strategies for: (1) finding FH patients; (2) cascade screening for FH; (3) optimizing treatment strategies and health outcomes; and (4) addressing multi-level systems approaches in the overall management of FH.

Examples include but are not limited to those listed below:

• Develop and test generalizable, cost-effective, and sustainable strategies at the local, state, or national levels for finding FH and connecting patients to clinical sources of care.
• Develop and test strategies that leverage data science approaches using electronic health record (EHR), clinical decision tools, machine learning, and clinical algorithms to test models for finding FH index patients, cascade screening, and optimizing treatment strategies across rural and urban areas.
• Develop and test the feasibility, cost-effectiveness, and scalability of case detection and cascade screening strategies across diverse clinical settings.
• Develop and test optimal and sustainable strategies to promote the adoption and sustainability of diagnosis, cascade screening for FH within under-represented populations, rural communities, and low-resource settings.
• Explore facilitators and barriers to cascade screening across key stakeholder groups (patients, providers, communities, health systems, and healthcare payers, and policy makers) using qualitative and qualitative methods.
• Develop and test innovative and generalizable strategies for increasing provider and patient adherence to guideline-based treatment for FH patients with established CHD.
• Develop and test sustainable models for successfully transitioning pediatric patients with FH to appropriate care as young adults.
• Identify novel and generalizable methods for engaging health systems, clinics, communities, and patients for more effective implementation of health interventions.
• Evaluate systems-level approaches, tailored to large community health systems such as the Federally Qualified Health Centers, for sustained improvements in the overall management of patients with FH.
• Develop and test multi-level strategies that influence sustainability and high-fidelity delivery of evidence-based care for FH patients.
• Explore novel, systems-level strategies for implementation of local, state, and/or national policies and guidelines to achieve equitable access to and quality cardiovascular disease and risk factor care across federally-identified vulnerable populations.

Phases of Award

Applications submitted in response to this milestone-driven FOA must address a planning phase (R61) of up to one year, and an implementation research phase (R33) of up to four years for the clinical trial and development and dissemination of an implementation package.

Delineation of milestones by the applicant for the R61 and R33 phases is a key characteristic of this FOA. This FOA will support applications that propose a series of milestones including expected enrollment goals in the R61 and R33 phases and for accomplishing the completion of the clinical trial on-time and on-budget. Applications that address contingency plans to proactively confront potential delays or disturbances in meeting the milestones are strongly encouraged. Satisfactory completion of R61 milestones will be assessed administratively by NHLBI to determine eligibility to transition to the R33 phase.

The R61 phase supports the selection of implementation research frameworks, models, and evidence-based interventions; assessment of organizational readiness for change; quantitative and qualitative assessments of the barriers, facilitators and workflow factors; assessment of organizational/cultural preferences for the type(s) of the implementation strategies; plans for recruitment and retention of participants; development, roll-out, and evaluation plan for the implementation strategy, including infrastructure changes and skills development program, as needed; selection of the implementation and clinical outcome measures and a priori definition of what qualifies as success for these outcomes; the finalization of the informed consent/assent document; the development of the manual of operations and procedures (MOP); case report forms and other resources necessary to document the performance of the implementation strategy clinical trial protocol; establishment of a Data and Safety Monitoring Board and their review of implementation strategy clinical trial protocol; and Institutional Review Board approval of the implementation strategy clinical trial protocol. All necessary regulatory approvals should be obtained in the R61 phase to allow for the successful launch of the proposed implementation strategy clinical trial in the R33 phase. Enrollment into the implementation strategy clinical trial is expected to begin before the end of the R61 phase to optimize the probability of successfully completing the trial on time and on budget.

The R33 phase supports updates to the procedures, documents, execution of, and analyses of the outcomes of the implementation clinical trial. In addition, R33 phase supports the development, refinement, and dissemination of a comprehensive implementation package, which would support sustained use of implementation strategy beyond funding period and/or others' ability to adapt the implementation strategy for their use.

Investigators and NHLBI will mutually agree upon final revised milestones that will be included in the Terms and Conditions of the grant, prior to award. The overall planned enrollment will be agreed upon between the grantee organization (or recipient) and the NHLBI prior to an award. Enrollment of participants into the implementation strategy clinical trial is expected to begin before the end of the R61 phase to optimize the probability of successfully completing the trial on time and on budget. NHLBI will conduct an administrative review approximately 9 months into the R61 phase to determine if there has been adequate progress toward achievement of milestones included in the Notice of Award to transition to the R33 phase. Milestones and timelines for the R33 phase may be revised and finalized at the time of the R61/R33 transition.

Milestones must address timing of overall recruitment/enrollment and retention goals, including accrual goals for women, minorities, and individuals of all ages including children and older adults. It is expected that performance of core milestones, such as planned enrollment goals, will be shared on a regular basis through eConnect, an NHLBI platform that will facilitate transfer of electronic information to NHLBI (an NHLBI clinical dashboard database). Subject to NHLBI funding availability and scientific priorities, R33 awards will be made after administrative review with specific attention to the extent to which all agreed-upon milestones have been met. If the R33 is funded, NHLBI will review the progress of the clinical trial on a regular basis. Slower than anticipated progress towards meeting milestones will result in a re-evaluation of the award by NHLBI including whether the objectives of the trial can be met on time and on budget. If milestones have not been satisfactorily met, subsequent funding years may not be approved and may lead to phasing out of the award.

NHLBI policies regarding milestones and relevant clinical research/studies policies are described in the following: NHLBI Accrual of Human Subjects (Milestones) Policy, NHLBI Policy for Inclusion of Women and Minorities in Clinical Research, NHLBI Policy for Data and Safety Monitoring of Extramural Clinical Studies, and NHLBI Data Sharing Policy.

Clinical Trials Not Supported by This FOA

The following types of clinical trials are not responsive to this FOA, and will not reviewed:

• Phase I (first-in-human) trials
• Observational studies that do not meet the NIH definition of a clinical trial
• Multi-site trials
• Drug or device safety trials, which require an Investigational New Drug (IND) or Device Exemption (IDE) authorization/approval prior to funding

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

• Eligible Agencies of the Federal Government

• U.S. Territory or Possession

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant organizations

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

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) 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.

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

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

Letter of Intent

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

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

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

The letter of intent should be sent to:

Director, Office of Scientific Review
Telephone: 301-435-0270
Email: NHLBIChiefReviewBranch@nhlbi.nih.gov

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed.

Other Attachments: The attachments listed below must be completed and attached or the application will not be peer reviewed.

1. Single-site Justification Plan: A Single-site Justification Plan must be provided as an attachment using the filename "Single-Site Justification Plan.pdf" and may not exceed 2 pages. This plan should describe how all participants for the trial will be enrolled at a single institution and in the allotted time frame.

2. Trial Management Plan: A description of how the proposed trial will be managed must be provided as an attachment using the filename "Trial Management.pdf" and may not exceed 5 pages. Describe the strategy that will be used throughout the project to ensure that management activities of the clinical trial are met, including directly supporting the needs of scientific study leadership to identify barriers, make timely responses to challenges, and optimize the allocation of limited resources to meet pre-defined study objectives. The trial management plan should provide sufficient detail to demonstrate the ability to achieve the goals of the clinical trial on-budget and on-time and to successfully manage and mitigate risks. This plan is expected to include:

• A plan for assessment of organizational readiness for change and engagement with internal and external end-use stakeholders
• A plan for informed selection of the implementation framework and implementation strategy(ies) to be used, including an approach for reconciliation of conflicting preference among personnel involved in the design of the implementation strategy
• Description of the role of the project manager

• Description of the role of the project manager
• A risk assessment plan
• A risk management plan that addresses contingencies in the event that there is inadequate progress toward achieving the R61 and/or R33 core milestones in terms of logistical issues. The plan should identify a range of contingencies that could threaten study progress or feasibility, and propose solutions using project resources.
• Plan for developing a skills development program and means to deploy the skills development program to enable effective delivery of the evidence-based practices (EBP) implementation strategy
• Key methodology and standard operating procedures governing the following:
  • resource management
  • assessment of barriers and facilitators of implementing the evidence-based guidelines (EBG)
  • monitoring and documenting the evolution in development and adaptation of the EBP implementation strategy
  • implementation deployment, operations/execution, and study closure
• Plan for how the clinical trial management team will resolve fiscal issues in a timely manner
• Plan for enabling the implementation strategy to continue beyond the project funding period, if successful, or to shut it down, if not successful
• Plan for development and dissemination of actionable insights, in terms of successful, neutral, and underperforming elements of the implementation strategy used in the project so that others may leverage findings for their own successful EBP implementation strategy
• Processes required for orderly project closure, including how the study will comply with the NIH Data Sharing Policy, and biorepository plans if specimens will be stored after planned study testing and analyses are complete

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

All Key Personnel who are major contributors to the study must provide an NIH Biosketch whether or not they are budgeted. Describe the experience of key scientific personnel in project planning and implementation, including the following:

• Success in meeting milestones and timelines
• Expertise in implementation research
• Adeptness at engaging with and heeding insights from diversified personnel at the study site(s) that will be impacted by the workflow of the EBP implementation strategy
• Expertise in biostatistics, implementation science clinical trials, adaptive designs, skills development programs, and quality improvement programs.

The experience and authority of each PD/PI and all Key Personnel must be carefully documented. Roles and responsibilities, including coordination of the responsibilities of other project team members, must be well defined. Include biosketches for a multidisciplinary team of appropriate personnel (implementation and dissemination research specialist, clinician(s), skills development expert, data manager, study coordinator(s), personnel responsible for the implementation strategy, such as patient navigator, etc.) to facilitate the accomplishment of all aspects of the implementation trial, including recruitment of subjects, design of the implementation strategy, implementation of the trial protocol, development and dissemination of the actionable implementation strategy.

R&R Budget

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

Budgets should request only the costs that will be required for the activities to be performed in a given year.

If applicable, budgets should include all costs associated with Data Safety and Monitoring Board (DSMB) activities, including preparing reports for the DSMB, assessing DSMB member's conflict(s) of interest, meeting reimbursement for DSMB members, and support for at least one DSMB meeting per year.

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

Research Strategy: The research strategy must present an overview of the state of the science for the EBP and the relevance of the implementation trial for the FH condition(s) that will be addressed. Include a detailed discussion of the scientific protocol and the ways in which the population at the research site shares the researchers' conviction that improvement is needed, as well as how the proposed clinical trial of the implementation strategy for the EBP is expected to generate sustainable improvement in health outcomes. The research strategy is not expected to generate findings which are nationally generalizable, but must demonstrate that there is an appropriate end-use stakeholder population to whom the anticipated findings are applicable and can be disseminated.

The following criteria must be addressed:

Significance: The significance of the need to improve compliance with the EBP at the study site(s) must be clearly stated. Describe evidence supporting the need for and timeliness of the study, with emphasis on how the anticipated results will address an evidence gap and therefore advance science.

A plan for estimating the costs for the adaptation of the strategy and costs for on-going implementation are encouraged. Describe plans for evaluating the impact of the implementation strategy on clinical outcomes. Include a description of how results will be configured and disseminated to facilitate adaptation of the strategy by other groups and/or sites.

Innovation: The selection of an extant EBP is a pre-requisite of the FOA. Explain how this project is likely to advance dissemination and implementation research to enable sustainable improvement in clinical practice paradigms, and/or otherwise advance the field of late-stage implementation and dissemination research.

Approach: Describe the conceptual framework of the proposed implementation research strategy (e.g., such as Consolidated Framework for Implementation Research (CFIR); Behavior Change Wheel; 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.) and how the framework will be tailored to the study population and the EBP that will be employed. Discuss the validated organizational and other outcome measures that will be used to assess readiness for and impact of the EBP (e.g., acceptability, adoption, appropriateness, feasibility, implementation costs, penetration, and sustainability in the selected context beyond the project period). Explain how the elements of the implementation strategy will be selected and prioritized based on theoretical or empirically-derived change mechanisms, workflow, and personnel available. Describe how missing data will be handled and how drivers of uncertainty of estimates will be reported and explained. Explain how the sustainability objective will be integrated into the implementation strategy developed and tested. It is particularly important to provide a discussion of how this research will seek to generate and disseminate findings, including National standards for coding and data integration, which promote re-use and minimize reinvention of the implementation strategy.

Supporting Data: Briefly describe the EBP formative clinical studies (including any pilot/feasibility studies) that provide the basis for the proposed implementation clinical trial. Include other research as appropriate to demonstrate that the chosen approach is justified. If the implementation clinical trial is a hybrid or Phase III trial, include relevant data used to determine that the proposed trial includes adequate numbers of subgroups of participants to allow for separate and adequately powered analyses. Conceptualization and planning must have progressed to a stage sufficient to allow for an overall assessment of the likelihood of the success of the trial.

Experimental Approach: Critical features of conducting the clinical trial that are not already submitted as part of the PHS Human Subjects and Clinical Trials Information form must include, but are not limited to, the following:

• A detailed description and rationale for the research hypothesis(es)
• The rationale for the specific design chosen (e.g., pragmatic, adaptive, stepped-wedge, cluster-randomized)
• Evidence to support that the implementation strategy for the EBP will not introduce harm and is not known to be inferior to the existing range of practice (or usual care) at the site, in the community, and described in relevant standards of care
• A detailed rationale explaining why the proposed study population is an appropriate group to answer the research question(s) and likely to enable project completion on time and on budget
• Justification for all assessments including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the primary and secondary research questions. Use of patient-reported outcomes as well as other or non-traditional data collection approaches (e.g., telephone, mobile devices, or web-based systems)
• A description of the planned laboratory evaluations (as appropriate) and plans to implement and monitor Good Clinical Practices (GCP) (see NOT-OD-16-148), Good Laboratory Practices (GLP) and Good Manufacturing Practices (GMP), as appropriate
• A discussion of major challenges in engaging possibly divergent opinions from varying perspectives or types of personnel informing the implementing strategy, and how they will be resolved and monitored for compliance with the implementation protocol
• A discussion of event rates and contingency plans if the effect size or event rate is underestimated
• Participant follow-up procedures

Core Milestones

Propose and justify milestones that will be subject to peer-review. 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 relevant, measurable, results-focused and time-bound. Milestones must address timing of overall recruitment/enrollment and retention goals. The milestones must address accrual goals for women, minorities, and individuals of all ages including children and older adults.

Describe the milestones that will be met in the R33 phase to address the specific aims, and ensure the successful completion of the clinical trial and dissemination of its results.

Core milestones of particular interest include but are not limited to:

Core R61 Trial Milestones

• Plan for and recruitment of representative stakeholders and personnel anticipated to be involved with or impacted by the implementation strategy for the EBP
• Assessment of the organizational readiness for change
• Quantitative and qualitative assessments of the barriers, facilitators, resources and workflow factors needed to inform the design of a successful implementation strategy
• Plan highlighting elements of the implementation strategy, e.g., functional specifications of health IT, standardized data coding, which are specifically designed to foster sustainability and re-use of the implementation strategy for the EBP by others
• Finalization of operationalization of the implementation framework, implementation and clinical outcome measures, and a priori definition of what qualifies as success for these outcomes
• Assessment and pilot testing of the type(s) of implementation strategies (e.g., learning collaborative, tailored implementation strategy, LEAN, systems engineering, skills development, audit and feedback, computerized reminders, facilitation, coaching, unlearning, etc.)
• Finalization of plans for administration of the "intervention," i.e., the form of the implementation strategy
• Definition of the comparison groups in the implementation clinical trial protocol
• Finalized protocol and informed consent documents
• DSMB review and approval of final protocol, template consent(s) and/or assent(s), and data and safety monitoring plan
• IRB approval of final protocol and consent and/or assent
• Enrollment of the first participant during the R61 phase

Core R33 Trial Milestones

• Enrollment of 25%, 50%, 75% and 100% of the projected recruitment for all study participants, including women, minorities and individuals of all ages, including children and older adults (as appropriate)
• Strategy to develop a plan to support the sustainable use of implementation strategy beyond the research project
• Closure and completion plans for the study
• Collection of data related to primary and secondary endpoints and database lock
• Dissemination of results, including preparation of manuscripts for peer-reviewed scientific journal(s), scientific and community-based presentations, etc.
• Development and dissemination of a comprehensive implementation package, which would support the sustained use of the implementation strategy beyond the funding period and/or enable others ability to adapt the implementation strategy

Letters of Support: If appropriate, letters of support which are necessary for the successful conduct of the trial must be provided. If partial funding is to be provided by sources other than NHLBI, provide Letter(s) of Support signed by an authorized organization representative (AOR).

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

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Awardees are expected to comply with the NHLBI Data Sharing Policy.

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide. When involving human subjects research, clinical research, and/or NIH-definedclinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics

2.2 Eligibility Criteria
If applicable, includethe required health status of study participants.

2.5 Recruitment and Retention Plan

The Recruitment and Retention Plan should address: 1) the expertise of the individual(s) responsible for screening, approaching and consenting potential participants; 2) the required characteristics of the study site(s), if applicable; 3) engagement of relevant advocacy groups; 4) the process for identification and screening of study participants; 5) primary and back-up recruitment strategies (e.g., use of electronic health records); 6) participant retention and adherence strategies; 7) possible competition from other trials for study participants; 8) engagement of the clinical community(ies) that will play a critical role in the recruitment and retention; 9) recruitment of groups (e.g., for stepped-wise regression, adaptation trials, or for cluster-randomized trials).

2.7 Study Timeline

Include a table or graph of the overall study timeline. This is expected to be a visual representation (such as a Gantt Chart) of core milestones and key project management activities. A narrative is not expected in this section.

The study timeline should include core milestones that need to be met throughout the lifecycle of the clinical trial (to include both the R61 and R33 phases) to ensure its success, and the subtasks that will be used to reach the milestones. The period of time for the study duration is expected to be displayed in months and must include, but is not limited to, the following:

(a) when the qualitative and quantitative assessment of barriers, facilitators, preferences and workflow factors is expected to be initially and periodically determined

(b) when the target end-use stakeholders are expected to have been identified

(c) when the initial and updated implementation strategies are expected to be determined

(d) when the initial skills development plan is expected to be finalized

(e) when the skills development plan is expected to begin

(d) when the study is expected to be opened to enrollment

(e) when core milestones are expected to be met

(f) when subtasks needed to reach the core milestones are expected to be achieved

(g) when the analysis of the study data is expected to occur

(h) when the submission of the primary study manuscript for publication is expected

(i) when the dissemination of the implementation strategy is expected

3.5 Overall Structure of the Study Team

Include a description of the following:

• Committees needed to manage the complexity of the trial, including any internal or external advisory committees
• The role of any sub-contractors or providers of services, personnel, or facilities
• The coordination between major participants and NHLBI
• Key channels used to reach and inform each stakeholder group and receive feedback
• How disputes will be resolved between all stakeholders

Section 4 - Protocol Synopsis

4.1 Brief Summary
Include protocol title.

4.2.a Narrative Study Description
Describe the protocol to be followed in each arm of the trial. Include a brief description of how the investigators will standardize and optimize adherence to the protocol. Specify concomitant interventions, if applicable. Describe the proposed experimental design including a discussion of the rationale for the particular design chosen (pragmatic, stepped-wedge, cluster-randomized, adaptive, etc.).

4.2.c Interventions - Description
Describe the rationale for the choice of the EBP selected and configuration of the implementation research strategy including such specific information as form, duration, and agent of the implementation strategy, and key characteristics of other forms of proposed approaches such as diagnostic tests and behavioral interventions.

4.4 Statistical Design and Power
Provide a justification for the proposed sample size based on appropriate study assumptions. Explain how the outcome(s) will address the hypothesis(es) being tested. Describe plans for interim and final analyses; methods of bias control; and methods for handling missing data (as applicable). The description should be detailed enough to allow replication of the analysis by an independent statistician.

For Phase III clinical trials, include plans for evaluation of the clinical and all primary outcome(s) by race/ethnicity, sex and gender, and include all relevant data to assess whether or not the trial includes adequate numbers for valid analyses of subgroups. In addition, justify adequacy of power to analyze subgroups of participants. Adaptive designs should include a pre-specified adaptation plan that allows for clear go/no-go decisions and pre-specified analysis boundaries.

Include a description of the approach to data management and validation, including data management systems, methods of data entry and cleaning, event tracking and logistics, case report forms, and methods for monitoring the quality and consistency of the intervention(s) and data collection; policies and methods for ensuring blinding of study results; data confidentiality and subject privacy; adjudication of events (as needed); and data reports.

Section 5 - Other Clinical Trial-Related Attachments

5.1 Other Clinical Trial-related Attachments

The following attachment must be provided or the application will not be peer reviewed. Applicants must provide a detailed table listing the characteristics of trials that demonstrate experience in trial coordination within the last 5 years. The table must be provided as an attachment called "Clinical Trial Research Experience.pdf" and may not exceed 3 pages. If more than one trial will be described, the name of each attachment for a unique trial or study record may be named, "Clinical Trial Research Experience1.pdf, Clinical Trial Research Experience2.pdf", etc.

The table columns should include:

Column A: clinical study title
Column B: applicant's role in the study
Column C: a brief description of the study design
Column D: planned enrollment
Column E: actual enrollment
Column F: whether the studies completed on schedule or not
Column G: publication reference(s)?

Delayed Onset Study

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

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

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

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

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.

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

Section V. Application Review Information

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.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed). Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

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

Specific to this FOA:

To what extent has the identification of significant referent end-use stakeholder population been demonstrated at a national or sub-national population level?

For the purposes of this FOA, 'intervention' refers to the 'implementation strategy' and 'the safety, efficacy or effectiveness of an intervention (implementation strategy)' refers to 'the affordability, acceptability, and sustainability of the strategy.'

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?

Investigator(s)

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

Specific to this FOA:

To what extent does the investigative team include a diversified group of individuals with knowledge and expertise in designing implementation strategies that considers the preferences and variation in available resources, barriers, cultural context, organizational culture variations, and anticipated end-use stakeholders?

How strong is the evidence that an appropriate research team has been identified at the investigational site for the purpose of managing the implementation strategy and conducting clinical outcome assessment, if participants are enrolled from multiple locations/clinics

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?

Innovation

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

Specific to this FOA:

How well has the research plan adequately addressed the distinctive FOA requirement to design, test, and disseminate the implementation strategy(ies) so that the study findings may be sustained beyond the funded research project period, or replicated elsewhere in a streamlined fashion? To what extent has the application provided a compelling approach to leveraging existing resources and promoting reuse of critical aspects of the implementation strategy to enable others to streamline the adaptation of the implementation strategy?

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?

Approach

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

Specific to this FOA:

To what extent do the implementation research objectives accomplish the following:justify the proposed implementation framework and analytical plan, provide plans for interim and final analyses, provide methods of bias control and handling missing data, and enable characterization of the uncertainty of estimates and the drivers of that uncertainty? Does the application adequately discuss how success will be determined?

If applicable, how adequate are the plans for adaptive design of the implementation strategy? How appropriate is the adaptation plan for enabling clear go/no-go decisions and pre-specified outcome measures for success?

Does the application adequately address the following, if applicable.

Study Design

Will the study d?e?s?i?g?n? adequately 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 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 adequate? 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?

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?

Environment

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

Specific to this FOA:

How adequately does the application describe the physical resources, system functionality (e.g., electronic healthcare record (EHR)) and clinical and community environments so that these aspects of the implementation strategy can be translatable or adaptable to other settings?

Are there adequate plans and resources available to coordinate the clinical trial at a single-site?

How strong is the Single-site Justification Plan attachment and how well does it describe how participants for the trial will be enrolled at a single institution and in the allotted timeline? Is there evidence of the ability of the individual 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?

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?

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?

Data and Safety Monitoring

Is the proposed Data and Safety Monitoring Plan (DSMP) appropriate for the proposed clinical trial? What components of the DSMP demonstrate the ability to monitor the site and participating facilities?

Study Timeline

Is the study timeline described in detail, taking into account planning phase, meaningful engagement of stake holders, the anticipated rate of enrollment, and planned follow-up assessment, the preparation and dissemination of meaningful reporting of the findings? 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)?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) 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.

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by 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.

As part of the scientific peer review, all applications:

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

• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA. Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

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

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

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

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that 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

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

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

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

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides 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/fact-sheet-guidance/index.html and https://www.lep.gov. 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 https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

• Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

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

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

Not Applicable

3. Reporting

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement. A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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

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

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threatensubmission by the due date, and post-submission issues)

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

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email:GrantsInfo@nih.gov(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:support@grants.gov

Cheryl Anne Boyce, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-496-1051
Email: cheryl.boyce@mail.nih.gov

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

Andre Walker
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8061
Email: WalkerA@mail.nih.gov

Section VIII. Other Information

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