Part 1. Overview Information

Key Dates

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

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

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

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

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

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background

This concept for a clinical trial was strongly influenced by the NHLBI workshop held in February 2021 entitled “Earlier treatment in adults with high lifetime risk of cardiovascular diseases: What prevention trials are feasible and could change clinical practice?”. The workshop’s discussions helped inform this initiative focused on whether earlier pharmacological intervention on cardiovascular risk factors can reduce or delay the development of subclinical coronary artery atherosclerosis in young adults who have a high lifetime risk of cardiovascular disease (CVD) but a low or borderline 10-year risk, commonly <7.5% as estimated by the ASCVD 10-year risk equation (see https://www.nhlbi.nih.gov/events/2021/early-treatment-high-lifetime-risk-cardiovascular-diseases). We anticipate the trial supported by this NOFO will provide initial evidence that earlier treatment will delay or reduce the onset of clinical CVD in young adults with high lifetime risk of CVD.

The rationale for this clinical trial rests on several premises. CVD mortality is no longer declining and has been rising in the last decade, particularly in younger adults. There is substantial epidemiological evidence that earlier and more aggressive treatment of cardiovascular risk factors might lead to substantially larger reduction in lifetime risk of CVD events. Mendelian randomization studies suggest that lifetime reductions in LDL cholesterol combined with lower systolic blood pressure might reduce CVD events substantially, raising the intriguing hypothesis that earlier treatment in adulthood might have a greater benefit than later treatment, although benefit would not be as large as those suggested by Mendelian randomization studies. Because younger adults (<50 years old) with high lifetime risk often have low 5- and 10- year risk of ASCVD, guidelines do not recommend pharmacologic treatment until these 5- and 10-year risks are much higher. For example, the average non-Hispanic white male does not reach intermediate risk until age 60. The degree of risk reduction over the subsequent decades by initiating treatment many years earlier compared to at initiating it age 60 when the plaque is first identifiable and more malleable and responsive to treatment may be nearly 2-fold greater. Although intensive behavioral interventions (e.g., nutrition and physical activity) can lead to reductions in cardiovascular risk factors, there is a paucity of trial evidence that these behavioral interventions can reduce coronary atherosclerotic progression. However, these interventions are already recommended in clinical guidelines.

The hypothesis that pharmacologic intervention earlier in the disease process when minimal coronary atherosclerosis is present could improve outcomes has been proposed for more than a decade. If true, such intervention could have a large public health impact. In the scientific process to ultimately conduct a large, clinical event-driven trial to reduce major adverse coronary events, a critical knowledge gap is whether and how early coronary atherosclerotic plaque can be successfully treated to halt or reverse progression of atherosclerotic plaque and from developing into at-risk plaques that lead to events. Thus, a clinical trial that demonstrates a substantial impact on coronary atherosclerosis progression and plaque features in high-risk individuals could lead to change in clinical practice and may have some impact on guidelines. Rather than using surrogate biomarkers to measure subclinical coronary atherosclerotic disease, this trial will directly quantify subclinical coronary artery atherosclerotic disease. 

Currently, there is no standard approach for screening asymptomatic adults for coronary artery disease other than with risk calculators using traditional risk factors. Among those who are screened, many young adults may have no or little evidence of coronary artery atherosclerosis. Yet recent studies have suggested that using traditional screening methods for CVD risk factors to identify those with a high lifetime risk and, perhaps supplemented by polygenetic risk scores, could enable the identification of young adults with a greater than 25% chance of having coronary artery atherosclerosis plaques detectable by either coronary artery calcium (CAC) testing or coronary computed tomographic angiography (CCTA). This screening ability provides the rationale for a two-component trial strategy. The first component is the identification of individuals with a substantial probability of having subclinical coronary atherosclerosis, and the second component is the testing of intervention strategies. An alternative approach would be to focus on atherosclerosis in other vascular beds rather than focusing directly on subclinical coronary atherosclerosis; however, this initiative focuses on subclinical coronary atherosclerosis because of its importance in the etiology of angina, myocardial infarction, and a substantial proportion of heart failure.

Purpose

NHLBI seeks to stimulate clinical trial research that efficiently identifies young adults with subclinical coronary atherosclerosis and determines whether early treatment significantly reduces the progression of coronary atherosclerosis. Since women have less coronary artery atherosclerosis before menopause, inclusion of women older than 50 years old may be considered. This NOFO proposes a three-arm clinical trial which is expected to be conducted with a high degree of efficiency, and with streamlined administrative procedures wherever possible.

Note: This DCC NOFO runs in parallel with a companion NOFO (RFA-HL-25-010) for a collaborating Clinical Coordinating Center (CCC). Both a DCC application and a collaborating CCC application must be submitted on the same due date for consideration by NHLBI. DCC (U24) applications submitted without a collaborative CCC (UG3/UH3) application will be deemed incomplete and will not proceed to review.

Phases of Award

The first year of the DCC (this NOFO) will correspond to the UG3 phase of the collaborative CCC application and is intended to support the development of case report forms and other resources necessary to the performance of the clinical trial; further development of study partnerships; finalization of the protocol; and subsequent approval of Data and Safety Monitoring Board; and Single Institutional Review Board (see NOT-OD-16-094) approvals of the trial protocol; and informed consent(s)/assent(s); manual of operations; data management systems and randomization procedures; and finalized integrated project management plans.

The second year of the DCC award is contingent on the successful completion of the UG3 phase of the collaborative CCC application, and corresponds to the first year of the UH3 phase of the CCC. The decision to proceed beyond the first year of the DCC award will be made after administrative reviews of the progress made by both the DCC and the CCC are conducted approximately 9 months into award (i.e., progress report will be due), with particular attention paid to the extent to which agreed-upon milestones have been met and are subject to the availability of funds. Due to the collaborative and parallel nature of these NOFOs, NHLBI will enter into negotiation with the DCC to achieve early phase-out of the award if CCC or DCC progress is deemed inadequate upon administrative review.

For trials using an FDA-regulated product and requiring an IND or IDE application to administer the product to humans, investigators must (1) secure IND authorization or IDE approval and (2) provide documentation of this authorization or approval to NHLBI before a funding decision will be made. Necessary drugs, devices, or other resources must be obtained by the end of the first year of the award to allow for the full execution of the proposed clinical trial. In addition, proposed clinical trials are expected to be able to begin enrollment by the end of the first year of the DCC award.

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, if funded, both the CCC and DCC will be responsible for milestone completion but that only one party, the CCC or the DCC, will be responsible for recording the completion of both CCC and DCC milestones through eConnect, an NHLBI platform that facilitates transfer of electronic information to NHLBI.

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, NIH Single IRB Polic, and NHLBI Data Sharing Policy.

Note: This DCC NOFO runs in parallel with a companion NOFO (RFA-HL-25-010) for a collaborating Clinical Coordinating Center (CCC). Both a DCC application and a collaborating CCC application must be submitted on the same due date for consideration by NHLBI. DCC applications submitted without a collaborative CCC (RFA-HL-25-010, UG3/UH3) application will be deemed incomplete and will not proceed to review. Applicants are encouraged to use the Compendium of Best Practices for Data Coordinating Centers as a reference tool. 

Clinical Studies Not Supported by this NOFO

The following types of clinical studies are not intended to be supported by this NOFO and will not proceed to peer review:

• Phase I (first-in-human) trials, whether single or multi-site
• Single site trials
• Drug or device safety trials
• Multi-site observational studies that do not meet the NIH definition of a clinical trial (see NOT-HL-18-611)
• Mechanistic or Basic Experimental Studies in Humans (BESH) (NOT-HL-19-690)
• Clinical trials with a control arm and only one active intervention arm

Study Design. Given the goal of testing two interventions, an efficient study design is needed to allow for a three-arm study within the NOFO budget. With changes in coronary artery plaque as the primary study endpoint, most trial participants will likely need to have evidence of plaque at trial baseline to have at least 85% power to detect a change in a conservatively defined primary endpoint. Since it is  assumed that evidence of plaque changes with prognostic implications will be more common than the development of new coronary plaques, combinations of new plaques and changes in existing plaque may be proposed as a trial primary outcome measure if scientifically well justified. Most un-selected young adults will likely not have coronary plaques on CCTA imaging; therefore, in order for this trial to successfully test the primary hypothesis of this NOFO, participants should have a high lifetime risk and considerable likelihood of having coronary plaques at randomization. The trial should have two components, both of which are equally important. The first is to identify young adults with a substantial likelihood of having plaque on imaging at baseline randomization, and the second is the intervention component of the trial. The number of potential participants requiring screening is an essential lesson to be learned in the UG3  phase of the trial. Given the large numbers of patients who would need to be pre-screened to meet inclusion and exclusion criteria, applicants should provide a detailed rationale and evidence that rapid, simple screening can be performed efficiently with a pragmatic approach for clinical practice. The first component should start during the first year of the UG3 phase and may continue for up to two years in the UH3 phase. Since screening in the UG3 phase will detect individuals with subclinical atherosclerosis, the intervention trial component should start in the UH3 phase. The participant screening during the UG3 phase is expected to continue in the UH3 phase. The trial recruitment should be completed by the second year of the UH3 phase and follow-up should be completed by the end of the fourth year of the UH3 phase to permit orderly trial closure, and data analysis and publication.

• The screening component. The initial protocol for the screening component may be modified based on initial results of its success. The screening component will allow for testing and determination of the optimal screening methods for detecting a high proportion of individuals with subclinical coronary atherosclerosis. Transition to the UH3 phase will require considerable evidence that the screening approach is effective at identifying many trial participants who meet the inclusion requirements and that the screening approach can be continued to achieve a fully enrolled trial within the funding timeline of the UH3 phase. The study design, if feasible within the budgetary cap set for this RFA, may include use of a central laboratory for analysis and for collection of biological samples for future ancillary studies.
• Effective recruitment and retention of study participants. The study should propose an effective method for identifying which young adults to include in the trial, with the option of an older inclusion criteria for women. The recruitment component may involve a variety of possible screening strategies that use traditional risk factors, polygenetic risk scores, or other biomarkers to identify a subgroup that will undergo imaging to determine their eligibility for trial randomization. There may be other innovative screening approaches that could be used if they have strong scientific justification and evidence of feasibility. The recruitment strategy should address participants' concerns about radiation exposures from imaging techniques. Recruitment strategies should involve more intense community engagement to obtain a trial population that includes individuals from underrepresented racial and ethnic groups, individuals with disabilities, individuals across the lifespan as appropriate to the goals of this RFA, women, and individuals from geographically diverse groups. 
• Trial power and operational aspects. Power calculations will be dependent upon the primary outcome chosen; however, it is anticipated that using coronary imaging to quantify and qualify atherosclerotic plaque for a total of 3 arms (2 intervention arms and 1 control arm) with approximately 500 participants in each arm; a trial with approximately 500 participants in each of the 3 arms (2 intervention arms and 1 control arm) will be feasible. Primary outcomes could be: changes in percent atheroma volume, changes in total plaque volume, changes in non-calcified plaque volume, or combinations of these or another well-established imaging endpoint of coronary atherosclerosis. The primary outcome chosen is strongly recommended to have a strong association with future clinical events. Adherence to the interventions and the dropout rate should be clearly detailed and supported based on existing evidence.  Applicants should consider strategies to reduce cross-over between the control arm and either of the two active arms. This may require masking the results of the screening evaluation at baseline for participants until the end of the intervention period who do not have clinically actionable findings based on current guidelines
• Facilitation of post award follow up. This NOFO’s funding period will only provide support for a limited post-intervention follow-up period and is not intended to support longer-term follow up of trial participants beyond the end of the award. However, longer follow up may be scientifically important; therefore, trial designs that facilitate efficient long-term follow-up of outcomes as well as post-trial use of preventive interventions would be of interest. This may be done by embedding the study within a health system or network that permits ongoing collection of clinical event information.
• Potential for future vs. ancillary studies.  An important potential opportunity is the additional mechanistic information that could be gained from this trial. It is anticipated that numerous intermediate biomarkers and genetic studies could be conducted if blood and serum samples are obtained from participants.

Prior to Submission
Applicants are strongly encouraged to consult with the Scientific/Research contacts for the area of science for which they are planning to develop an application prior to submission. Early contact is encouraged to provide an opportunity for NHLBI staff to discuss the scope and goals, and to provide information and guidance to potential applicants.

Plan for Enhancing Diverse Perspectives (PEDP)

The NIH recognizes that teams comprised of investigators with diverse perspectives working together and capitalizing on innovative ideas and distinct viewpoints outperform homogeneous teams. There are many benefits that flow from a scientific workforce rich with diverse perspectives, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved populations participate in, and benefit from research, and enhancing public trust.

To support the best science, the NIH encourages inclusivity in research guided by the consideration of diverse perspectives. Broadly, diverse perspectives can include but are not limited to the educational background and scientific expertise of the people who perform the research; the populations who participate as human subjects in research studies; and the places where research is done.

This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP), which will be assessed as part of the scientific and technical peer review evaluation.  Assessment of applications containing a PEDP are based on the scientific and technical merit of the proposed project. Consistent with federal law, the race, ethnicity, or sex of a researcher, award participant, or trainee will not be considered during the application review process or when making funding decisions. Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review.

The PEDP will be submitted as Other Project Information as an attachment (see Section IV).  Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance materials.

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

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Governments

• 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 Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply - 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information

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

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including individuals from underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019. 

Notice of NIH's Interest in Diversity 

Every facet of the United States scientific research enterprise—from basic laboratory research to clinical and translational research to policy formation–requires superior intellect, creativity and a wide range of skill sets and viewpoints. NIH’s ability to help ensure that the nation remains a global leader in scientific discovery and innovation is dependent upon a pool of highly talented scientists from diverse backgrounds who will help to further NIH's mission. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogeneous teams. Scientists and trainees from diverse backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. There are many benefits that flow from a diverse NIH-supported scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved or health disparity populations participate in, and benefit from health research, and enhancing public trust. In spite of tremendous advancements in scientific research, information, educational and research opportunities are not equally available to all. NIH encourages institutions to diversify their student and faculty populations to enhance the participation of individuals from groups that are underrepresented in the biomedical, clinical, behavioral and social sciences. See NOT-OD-20-031.

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 How to Apply - Application Guide.

Multiple PDs/PIs are allowed on any single application. PD(s)/PI(s) from each linked application should not be designated as multiple PDs/PIs on each application of a collaborative set.

ESI applicants can be the PI/PD of an application providing they can show support of investigators with appropriate clinical trials experience (as part of a multiple PI team). ESIs are encouraged to be part of the study team, and they should be budgeted for support at a level appropriate for the role on the project. 

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

This NOFO only accepts an application that is part of a collaborative pair of applications. The pair must include one application to this DCC U24 NOFO plus one application to the companion CCC UG3/UH3 NOFO, RFA-HL-25-010.

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 NOFO. 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 How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the How to Apply - 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
National Heart, Lung, and Blood Institute
Email: NHLBIChiefReviewBranch@nhlbi.nih.gov

Page Limitations

All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply – Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

All instructions in the How to Apply - Application Guide must be followed.

Descriptive Title of Applicant's Project: To allow NIH to identify a group of applications as a related set of collaborative applications, the title of each application in the set must have the following format: a “1/N” indicator + Identical Title (e.g., “1/3”, where the 1/3 means this is site 1 of 3 sites in the set. The other sites will be labeled 2/3, etc.) Titles may not exceed 200 characters in length, including the tag, e.g., 1/3, at the beginning of the title.

Cover Letter Attachment: The Cover Letter is one PDF file only. The following collaborative information is required in the Cover Letter: a listing of all the applications that are a part of the set of collaborative applications being submitted, including for each: 1) the PD/PI(s) name(s), 2) the Title (including the tag, e.g., “1/3”), and 3) the Applicant Institution. Each site should submit an identical listing

SF424(R&R) Project/Performance Site Locations

All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the How to Apply - Application Guide must be followed.

Facilities and Other Resources: Describe the facilities and resources available for the coordination of a multi-site clinical trial, including project management tools that will be used. Describe how the infrastructure at the DCC and performance sites will facilitate the efficient operation of the proposed multi-site clinical trial. If applicable, discuss any community participatory agreements and/or stakeholder agreements to support the protocol.

Other Attachments: The attachments listed below that are marked as "Required" must be provided, or the application will not be peer reviewed.

1. Trial Management Plan (Required): A description of how the proposed trial will be managed must be provided as an attachment using the filename "Trial Management Plan.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 performed including directly supporting the needs of scientific study leadership to identify barriers, make timely responses, and optimize the allocation of limited resources to meet pre-defined study objectives. This description should include:

• Description of the project management team and levels of effort.
• Description of how the CCC and DCC project management teams will integrate with one another.   
• A risk assessment plan.
• A risk management plan that addresses contingencies in the event that there is inadequate progress toward achieving the U24 core milestones. The plan should identify a range of contingencies that could threaten study progress or feasibility, and propose solutions using study resources.
• Key methodology and standard operating procedures governing resource management, study deployment, operations/execution, and study closure.
• How the clinical trial management team, in collaboration with the CCC, will resolve fiscal and logistical issues in a timely manner including plans to proactively evaluate and prioritize study risks and issue corrective responses.
• Processes required for orderly project closure including how the study will comply with the NIH Data Management and Sharing Policy, and biorepository plans if specimens will be stored after planned study testing and analyses are complete.

In summary, 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.

2. Clinical Trial Research Experience (CTE) (Required):

Applicants must provide a table listing the characteristics of trials that demonstrate experience from key personnel in trial coordination in the last 5 years. The table must be provided as an attachment called "Clinical Trial Research Experience.pdf" and may not exceed 3 pages.

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: number of sites 
Column G: whether the studies were completed on schedule or not 
Column H: publication reference(s)

3. Network Description (Optional):

A Network Description Plan is optional and should only be provided as an attachment using the filename ““Network Description.pdf”” if the proposed clinical trial is to be conducted using the infrastructure of an existing Network. This attachment may not exceed 6 pages and should include the following description:

• Name of Network.
• Number of years and funding remaining to support the Network infrastructure and any information on the continuance of the Network.
• Plans to replace sites that are under-performing or that are removed through the Network re-competition process. These plans should include contingencies for funding, data recovery, and the follow-up of enrolled trial participants.
• Infrastructure capacity and availability of patient populations considering current ongoing trials within the Network.
• Plans to incorporate the current Network infrastructure into the proposed trial, including participant recruitment, trial implementation, and central coordination through the CCC and data management, data analysis, or statistical analysis through the DCC.
• Plans to utilize master clinical trial agreements and a single IRB.
• Describe the part of the Network that will be leveraged by the CCC and the DCC, respectively. If both the CCC and the DCC applications intend to leverage the infrastructure of an existing network, the DCC application must also include this information.

Plan for Enhancing Diverse Perspectives (PEDP)

• In an "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of actionable strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity.
• Applicants should align their proposed strategies for PEDP with the research strategy section, providing a holistic and integrated view of how enhancing diverse perspectives and inclusivity are buoyed throughout the application.
• The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured.
• The PEDP may be no more than 2 pages in length and should include:
  • Actionable strategies using defined approaches for the inclusion of diverse perspectives in the project;
  • Description of how the PEDP will advance the scientific and technical merit of the proposed project;
  • Anticipated timeline of proposed PEDP activities;
  • Evaluation methods for assessing the progress and success of PEDP activities.

Examples of items that advance inclusivity in research and may be appropriate for a PEDP can include, but are not limited to:

• Partnerships with different types of institutions and organizations (e.g., research-intensive; undergraduate-focused; HBCUs; emerging research institutions; community-based organizations).
• Project frameworks that enable communities and researchers to work collaboratively as equal partners in all phases of the research process.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as human subjects in clinical trials, including those from underrepresented backgrounds.
• Description of planned partnerships that may enhance geographic and regional diversity.
• Outreach and recruiting activities intended to diversify the pool of applicants for research training programs, such as outreach to prospective applicants from groups underrepresented in the biomedical sciences, for example, individuals from underrepresented racial and ethnic groups, those with disabilities, those from disadvantaged backgrounds, and women.
• Plans to utilize the project infrastructure (i.e., research and structure) to enhance the research environment and support career-advancing opportunities for junior, early- and mid-career researchers.
• Transdisciplinary research projects and collaborations among researchers from fields beyond the biological sciences, such as physics, engineering, mathematics, computational biology, computer and data sciences, as well as bioethics.

Examples of items that are not appropriate in a PEDP include, but are not limited to:

• Selection or hiring of personnel for a research team based on their race, ethnicity, or sex.
• A training or mentorship program limited to certain researchers based on their race, ethnicity, or sex.

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see PEDP guidance materials.

SF424(R&R) Senior/Key Person Profile

All instructions in the How to Apply - Application Guide must be followed.

The PD/PI (or Multi-PDs/PIs) of the DCC must be experienced in the coordination and management of multi-center clinical trials, including success in meeting milestones and timelines. The experience of each PD/PI and all Key Personnel must be carefully documented and roles and responsibilities must be well-defined. DCCs require a multidisciplinary team and the application should reflect the team's hands-on involvement in DCC functions, including coordination, tracking, logistics and administration, communications, data management (including quality control), data security and IT infrastructure (including development of public and secure study websites), regulatory support, and biostatistical/analytical support. Applicants must include personnel and corresponding biographical sketches for the DCC only. All Key Personnel who are major scientific contributors to the study must provide an NIH Biosketch whether or not they are budgeted. The PD/PI (or Multi-PDs/PIs) for the DCC cannot be Key Personnel on the CCC application. 

R&R Budget

All instructions in the How to Apply - Application Guide must be followed.

The application must include only its own budget, including any subcontract budgets associated with it. Separate itemized budgets must be prepared for each subcontract. The application must provide detailed annual budgets that will enable the DCC to meet its milestones.

Any cores (e.g., economics/quality of life) must be a subcontract to either the DCC or CCC. Separate itemized budgets must be prepared for each subcontract and/or for each collaborating center or core. If feasible within the budgetary limits, it may be applicable to use a central laboratory for analysis and for collection of biological samples for the clinical trial as well as potential future ancillary studies.

All costs requested and all changes in budgets after the first year should be clearly identified and justified. The DCC budget must be synchronized with the CCC budget. Include costs associated with community engagement activities (e.g., community advisory board(s), infrastructure needs), as applicable.

If parts of the costs of the trial are to be provided by sources other than NHLBI, these contributions must be presented in detail in the budget justification. Third Party support of the proposed research activity (if approved) will be incorporated as a Special Award Condition. Applicants are reminded that although Cost Share is not required, if these types of costs are included in the research application and peer reviewed, it is expected that these costs will not be covered by NHLBI.

The DCC should include in their budget all costs associated with DSMB activities. This includes the costs for preparing reports for the DSMB and meeting reimbursement for the DSMB members. The DCC should assess the need for liability insurance for DSMB members and provide a plan commensurate with the risk of the trial. The budget should include provision for executing the plan proposed. The DCC should also include a plan for assessing DSMB member conflict of interest, and put associated costs in the budget. Additionally, if the DSMB is convened by NHLBI, the DCC should include in their budget coordination of support for at least one DSMB meeting per year in Bethesda, MD and coordinate regular DSMB calls as needed (by teleconference or videoconference).

Include budget support for steering committee meetings whether in person or as a hybrid video conference. Include budget support for publication, dissemination of results, and data sharing.

In addition, budget support for an independent study chairperson who would not be faculty at either institution, including trial clinical sites participating in RFA- HL-25-007 (DCC) and/or RFA-HL-25-010 (CCC).

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

PEDP implementation costs:

Applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7): https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm.

R&R Subaward Budget

All instructions in the How to Apply - Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the How to Apply - Application Guide must be followed.

PHS 398 Research Plan

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Research Strategy: The Research Strategy must present a discussion of the ways in which the DCC plans to provide expert assistance in protocol design and analysis plans, and feasibility assessments.

The following criteria must be addressed:

Significance: Explain why the chosen study design is optimal to answer the scientific questions posed for the trial described in the CCC application. 
 
Innovation: Describe plans to employ unique or novel methodologies that will enhance the clinical trial design, management, or methods of data analysis. Describe how the DCC plans to utilize current best practices to improve the knowledge and/or skills of the multi-site clinical trial it will support.

Approach: Describe how the multi-site clinical trial will be coordinated including plans for providing administrative, operational support and data management and tracking support. Explain the communications strategy including how the DCC will interact with the CCC and individual sites, how data will be transmitted in an accurate and timely fashion, and how the DCC will establish accessible and secure methods of communication. Explain how the DCC will help with the Plans for Enhancing Diverse Perspectives (PEDP) and Community Engagement Plans (CEP) described in the CCC application. Provide plans to assess recruitment feasibility using available data on the target population from registries and prior studies to the extent possible.

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 activity. Milestones must be relevant, measurable, results-focused and time-bound, and should address timing of overall recruitment/enrollment and retention goals. The milestones must address accrual goals for individuals targeted by this RFA, and any other identified requirements for completion of the approved research.

Describe the milestones that will be met to address the specific aims and ensure the successful completion of the clinical trial and dissemination of its results. The U24 core milestones should include but are not limited to:

Core U24 Year 1-2 Trial Milestones

• Complete 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
• sIRB approval of final protocol and consent and/or assent
• Randomization of at least 10% of the screened participants into one of the three trial arms during the UG3 phase as specified in the power calculation
• Activation of at least 50% of trial sites 

Core U24 Year 3 and Beyond Trial Milestones

• Enrollment of the remaining participants in the screening and intervention by the end of the second year of the UH3 phase. Enrollment of 25%, 50%, 75% and 100% of the projected recruitment for all study participants, including individuals targeted by this RFA
• Study closure and completion plans
• Collection of data related to primary and secondary endpoints and database lock
• Submission of primary manuscript to a peer-reviewed scientific journal(s), dissemination of results, and data sharing

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide.

Other Plan(s): Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply - 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 How to Apply - Application Guide must be followed.

The following fields are required:

1.1 Study Title

1.2 Is this Study Exempt from Federal Regulations?

1.3 Exemption Number (if applicable)

1.4 Clinical Trials Questionnaire

2.1 Conditions or Focus of Study

2.4 Inclusion of Women and Minorities

2.5 Recruitment and Retention Plan

2.7 Study Timeline

3.1 Protection of Human Subjects

3.2 Is this a multi-site study that will use the same protocol to conduct non-exempt human subjects research at more than one domestic site?

3.3 Data and Safety Monitoring Plan

3.5 Overall Structure of the Study Team

4.1.a Detailed Description

4.1.c Interventions

4.3 Statistical Design and Power

4.7 Dissemination Plan

5.1 Other Clinical Trial-related Attachments

Section 2 - Study Population Characteristics

2.1 Conditions or Focus of Study
The information provided for Conditions or Focus of Study must be the same as that provided in the collaborating CCC application.

2.3.a Inclusion of Individuals Across the Lifespan

The information provided for Inclusion of Individuals Across the Lifespan must be the same as that provided in the collaborating CCC application.

2.4 Inclusion of Women and Minorities
The information provided for Inclusion of Women and Minorities must be the same as that provided in the collaborating CCC application.

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) engagement of patient advocacy groups; 3) the process for identification and screening of diverse study participants; 4) primary and back-up recruitment strategies (e.g., use of electronic health records); 5) participant retention and adherence strategies; 6) possible competition from other trials for study participants; 7) engagement of the clinical community(ies) that will play a critical role in the recruitment and retention; 8) recruitment of groups for cluster-randomized trials.

Provide a table of the recruiting sites and site PD/PIs showing enrollment goals and number of potential participants available at each site.

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 CCC and DCC are expected to provide the same 2 study timelines in their respective application. Each application should include a timeline for the first year of the trial (UG3 phase) and a separate timeline for subsequent years (UH3 phase). The study timelines should include core milestones that need to be met throughout the lifecycle of the clinical trial. The Study Timelines need to address the relevant components of the PEDP. It is expected that the timelines will clearly indicate which subtasks are needed to reach the core milestones; and which subtasks will be performed by the CCC and which ones will be performed by the DCC. 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) the study opens to enrollment  
(b) core milestones are met  
(c) subtasks needed to reach the core milestones  
(d) when final transfer of the data to the DCC will occur  
(e) database lock and analysis of the study data  
(f) submission of the primary study manuscript for publication

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan

The information provided for the Data and Safety Monitoring Plan must be the same as that provided in the collaborating CCC application. Describe the process that will be utilized to identify unanticipated problems and describe procedures for intervention discontinuation and stopping guidelines.

3.5 Overall Structure of the Study Team

Include a description of the following:

• The role of the Executive Committee and Steering Committee as well as any internal or external advisory committees
• The oversight, responsibilities, communication with, and coordination of any sites or cores proposed
• The role of any sub-contractors or providers of services, personnel, or facilities
• How these functions will integrate with the organizational framework described in the collaborating DCC application
• How the CCC and DCC will coordinate leadership for clinical trial implementation and communications
• The coordination between the separate components and NHLBI
• Channels used to communicate with stakeholder groups and receive feedback
• How disputes will be resolved between the CCC, DCC, and all stakeholders

Section 4 - Protocol Synopsis

4.1.a Detailed Description

Describe the proposed experimental design including a discussion of the clinical trial design and the rationale for the particular design chosen (pragmatic, explanatory, cluster-randomized, adaptive, etc.). Provide details of the randomization scheme, if applicable.

4.1.c Interventions
Describe the rationale for the choice of the intervention including such specific information as dose, period of administration, choice of formulation, device specifications, and key characteristics of other forms of proposed approaches such as diagnostic test and behavioral interventions.

4.3 Statistical Design and Power

Provide content requested with respect to each outcome measure listed in Question 4.3 "Outcome Measures" of the collaborating CCC application. Justify the proposed sample size based on appropriate study assumptions, event rates, and power calculations. It is expected that the effects size will be powered for at least 85% for the primary trial outcome(s) for each active arm of the trial and the statistical methods (with respect to each outcome measure) have been adequately addressed. Justify the event rate and provide contingency plans should the event rate or effect size be underestimated. The calculations must be linked to the study endpoints and to the hypothesis(es) being tested. Explain how the outcome(s) will address the hypothesis(es) being tested. Provide details of the randomization scheme, if applicable. 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.

Adaptive designs should include a pre-specified adaptation plan that allows for clear go/no-go decisions and pre-specified analysis boundaries.

For all clinical trials (unless appropriately justified as not needed), the statistical analysis plans should include a description of an interim monitoring plan including stopping guidelines for safety as well as efficacy and futility.

For Phase III clinical trials, include plans for evaluation of the primary outcome(s) by race/ethnicity and gender, and include all relevant data to assess whether 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.

The approach to data management must include, but is not limited to, a description of:

• Data management systems
• Methods of data entry and cleaning
• Event tracking and logistics
• Biospecimen tracking
• Case report forms
• Methods for quality assurance and quality control
• Methods for monitoring the quality and consistency of intervention(s)
• Test, validate and optimize data capture systems
• Policies and methods for ensuring blinding of study results
• Data confidentiality and subject privacy
• Plans for data and IT security at each site
• Disaster recovery plans
• Adjudication of events (as needed)
• Data analysis reports

4.7 Dissemination Plan

The information provided for Dissemination Plan must be the same as that provided in the collaborating CCC application. 

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 How to Apply - Application Guide must be followed.

PHS Assignment Request Form

All instructions in the How to Apply - Application Guide must be followed.

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

See Part 2. 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. 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply – 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 Section 7.9.1 Selected Items of Cost.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the How to Apply - 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 form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply - Application Guide.

See more tips for avoiding common errors.

Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review.

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

Post Submission Materials

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.

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

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).  As part of the overall impact score, reviewers should consider and indicate how the Plan to Enhance Diverse Perspectives affects the scientific merit of the project.

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.

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

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.

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 policies and practices, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

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

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

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 NOFO. Following initial peer review, recommended applications will receive a second level of review by the National Heart, Lung and Blood  Advisory Council. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project, including the PEDP, 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 2.4.4 Disposition of Applications.

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. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding. 

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

Recipients must comply with any funding restrictions described in Section IV.6. 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 NOFO will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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

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

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

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

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

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

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

If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.

HHS recognizes that NIH 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 NOFO.

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 System for Award Management (SAM.gov) requirements. SAM.gov requires Federal agencies to review and consider information about an applicant in the designated integrity and performance system (currently SAM.gov) prior to making an award. An applicant can review and comment on any information in the responsibility/qualification records available in SAM.gov. NIH will consider any comments by the applicant, in addition to the information available in the responsibility/qualification records in SAM.gov, 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 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

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

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

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

• The recipient PD/PI will have primary and lead responsibilities for the project as a whole, including research design and protocol development, participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, as well as collaborations with other recipient.
• Provide updates at least annually on progress in PEDP implementation. 
• Upon completion of the project, recipients are expected to put their data into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community (see "Areas of Joint Responsibility" below). In-Kind contributions or Cost sharing is not a requirement of this program; however, if cost share is proposed, peer reviewed and accepted by NHLBI it will become a term and condition of award. Third Party involvement or support involving the proposed research activity must be reviewed and concurred by NHLBI staff per policy. If the support involves financial or material aid necessary for the completion of the project, and the support is no longer available and/or is not replaceable in a timely fashion and it will negatively impact the success or progress of the study, then NHLBI may negotiate phasing out the award.
• Recipients 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.

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

The NHLBI Project Scientist will assist with development of research protocols, monitor patient recruitment and study progress, ensure disclosure of conflicts of interest, and ensure adherence to NHLBI policies. 
 
The NHLBI Project Scientist will serve on the Steering Committee and other study committees, when appropriate, as a non-voting member. The NHLBI Project Scientist may work with recipients on issues coming before the Steering Committee such as recruitment, protocol development, follow-up, quality control, adherence to protocol, possible changes to the protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems, such as insufficient participant enrollment. 
 
In addition to the Project Scientist, a separate NHLBI Program Official will be responsible for the normal program stewardship of the cooperative agreement, and will be in the Notice of Award. However, NHLBI may elect to have a dual-role approach where a single individual may act as both the NHLBI Project Scientist and Program Official. Final decision-making authority on matters of budgetary and funding actions, grants management actions, and management of intellectual property issues is assigned to NHLBI staff other than the Project Scientist. The responsibility for final decision making may reside with Senior Institute management, separate organizational components and/or oversight committees. Because it is anticipated that the Program Official will participate in activities that rise to a level of involvement (i.e., additional role as Project Scientist) that results in conflicts of interest, for example, co-publication, other staff members such as direct line supervisors and/or other Senior NHLBI Program management staff will serve as agency Program Officials and will be responsible for the normal scientific and programmatic stewardship of the award. The NHLBI policy on authorship and manuscript review of NHLBI sponsored extramural research protects against conflicts of interest with the Program Officer.

An independent Data and Safety Monitoring Board (DSMB) will be established to oversee participant safety in the clinical trial and provide overall monitoring of interim data and safety issues. As part of the collaborative activities under this cooperative agreement, the NHLBI will collaborate with the recipients to appoint and/or agree upon a single DSMB for monitoring the clinical trial. The DSMB may be appointed by the NHLBI, or with the approval of NHLBI, the DSMB could be an institutional DSMB. At the first meeting, the DSMB will review the recipient’s protocol and potentially recommend modifications. Subsequently, the DSMB will monitor and review recruitment, adverse events, data quality, outcome data, and overall recipient performance. The DSMB has the responsibility to review interim data and final data, and recommend whether the protocol should be modified, and, at each meeting, whether the study should be continued or should be terminated early. An NHLBI scientist other than the NHLBI Program Official or Project Scientist will serve as Executive Secretary to the Board. Because the DSMB serves as an independent group advisory to the NHLBI, study investigators shall not communicate with DSMB members regarding study issues, except as authorized by the Board’s Executive Secretary.

The NHLBI 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 NHLBI, consortium participation and collaboration with other recipients, (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 results that substantially diminish the scientific value of study continuation.

Areas of Joint Responsibility include:

The Authorized Organizational Representative (AOR) is responsible for communicating progress on achievement of each milestone for the collaborative project to the NHLBI Grants and Program Officers listed on the Notice of Award. Award continuation, even during the period recommended for support, is conditional upon satisfactory progress. If, at any time, recruitment, as defined in the NHLBI Accrual of Human Subjects (Milestones) Policy, falls significantly below projections, or core milestones mutually agreed upon by the recipient organization and PD/PI and the NHLBI are not met, the NHLBI may consider ending support and negotiating an orderly phase-out of the award. NHLBI Grants Management and Program Officers will closely monitor progress at all trial stages including milestones, accrual, and safety.

Recipients will retain custody of and have primary rights to their data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. Meetings and calls may be arranged by NHLBI staff to promote sharing of information among investigators regarding state of science technologies, data management techniques, analytical strategies and tools, and data sharing. Support or other involvement of industry or any other third party in the study (e.g., participation by the third party; involvement of study resources or citing the name of the study or NHLBI support; or special access to study results, data, findings or resources) may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NHLBI.

NHLBI will partner with the PD/PI to ensure that the dataset preparation is congruent with requirements for NHLBI data repository datasets and associated documentation for submission to the Biological Specimen and Data Repository Information Coordinating Center (BioLINCC) and the NHLBI Policy for Data Sharing from Clinical Trials and Epidemiological Studies, and is in accordance with the Guidelines for NHLBI Data Set Preparation.

Study investigators are strongly encouraged to publish and to release publicly and disseminate results, tools, resources and other products of the study, in accordance with the study protocols and governance. It is expected that all methods, analyses, software, and algorithms will be made available in a timely manner to the scientific community. A plan for dissemination of study results will be developed by the recipient PD/PI in collaboration with the NIH Project Scientist and incorporated as a Special Term and Condition in the NoA. Within 3 years of the end of the period of NHLBI support for the project, data not previously released and other study materials or products not previously distributed are expected to be made available to individuals who are not study investigators in accordance with the NHLBI Supplement to the NIH Data Sharing Policy.

Dispute Resolution:

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

3. Data Management and Sharing

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

Recipients will provide updates at least annually on implementation of the PEDP.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

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

In accordance with the regulatory requirements provided at 2 CFR Part 200.113 and Appendix XII to 2 CFR Part 200, 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 (Responsibility/Qualification in SAM.gov, formerly 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 2 CFR Part 200 – Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (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: 301-637-3015

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

David Schopfer, M.D., M.A.S.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-402-3833
Email: david.schopfer@nih.gov

Lawrence Fine, M.D., Dr.PH.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0305
Email: lawrence.fine@nih.gov

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute
Email: NHLBIChiefReviewBranch@nhlbi.nih.gov

James Hennigan
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-480-7071
Email: james.hennigan@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 2 CFR Part 200.