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.

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). It is anticipated that 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 CCC NOFO runs in parallel with a companion NOFO (RFA-HL-25-007) for a collaborating Data Coordinating Center (DCC) application. Both a CCC application and a collaborating DCC application must be submitted on the same due date for consideration by NHLBI. CCC (UG3/UH3) applications submitted without a collaborative DCC (U24) application will be deemed incomplete and will not proceed to review.

Phases of Award

Applicants must address objectives for both a two-year UG3 and a five-year UH3 phase and are strongly encouraged to use project management principles, as appropriate. A key characteristic of this NOFO is completion of core milestones. A core milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be performance-based to achieve completion of the trial on time and on budget and must be established for both the UG3 and UH3 phases of the project.

The magnitude of the number of participants successfully screened and recruited into the trial during the UG3 phase will be an important indicator of the likelihood of continued success during the UH3 phase. Confirmation that the trial will have access to a sufficient sized potential trial population for trial completion with adequate statistical power is also another important indicator.

Milestones must address timing of overall recruitment/enrollment and retention goals, including accrual goals for women and minorities, young men ? 50 years old, and the age inclusion criteria for women if different from men. 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.

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 UG3 award to allow for the successful launch and execution of the proposed clinical trial in the UH3 phase.

Applications that address contingency plans to proactively confront potential delays or disturbances in meeting the milestones are strongly encouraged. Investigators and NHLBI will review and mutually agree upon the milestones that will be included in the Terms and Conditions of the award, if awarded. Transition to the UH3 phase is predicated on the successful completion of all UG3 core milestones. NHLBI will review and mutually agree upon the core milestones that must be met during the UG3 phase to allow for completion of the screening component and the trial stage during the UH3 phase. The overall planned enrollment and percentage of active clinical sites expected by the end of the UG3 phase will be agreed upon between the grantee organization (or recipient) and the NHLBI prior to an award.

NHLBI will conduct an administrative review approximately 21 months into the UG3 phase to determine progress toward achievement of milestones included in the Notice of Award. Subject to NHLBI funding availability and scientific priorities, the UH3 award will be made after administrative review with specific attention to the extent to which all agreed-upon milestones have been met.

Milestones and timelines for the UH3 phase may be revised and finalized at the time of the UG3/UH3 transition. Less than satisfactory progress in the UH3 phase may lead to phasing out the award. If the UH3 is funded, NHLBI will review the progress of the clinical trial on a regular basis. Slower than anticipated progress toward 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 the 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, NIH Single IRB Policy and NHLBI Data Sharing Policy.

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 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. 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 trial participants until the end of the intervention period who do not have clinically actionable findings based on current guidelines. 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. This 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.  Because the ability to efficiently identify potential participants is critical for the successful implementation of the intervention trial, the 2-year UG3 phase is intended to provide sufficient time to ensure the screening, and recruitment of appropriate individuals in the intervention component of the trial is adequate before transition to the UH3 phase will be approved.
• Intervention to be tested. The primary goal of the UH3 phase will be to test which intervention(s) are the most efficacious at reducing the onset and slowing the progress of subclinical coronary atherosclerosis. A secondary goal is to compare the two intervention strategies if both are successful. The UH3 Phase will take five additional years. Trial participants with a high risk of developing coronary atherosclerosis or with coronary atherosclerosis present will be randomized to either a control arm or one of two active potential interventions arms. Applicants will select the specific interventions to be used in each arm. Each active arm could have a combination of agents and include combinations of agents and lifestyle interventions. The possible interventions may include some combination of antihypertensive, lipid-lowering, anti-inflammatory, and/or weight loss drugs or any other with sufficient trial evidence of efficacy to prevent progression of coronary atherosclerosis. One active intervention arm will likely use generic drug treatment(s) that have proven efficacy in older populations with higher 10-year risk. The other active intervention arm may have less efficacy trial data in primary prevention including anti-inflammatory agents such as colchicine, or glucagon-like peptide-1 receptor agonists such as semaglutide, or combinations of these alternative agents in a single arm. The interventions will be compared to an enhanced usual care (control) arm. All participants in each arm will be educated on guideline-recommended lifestyle changes. The control arm may include enhanced lifestyle interventions since it is expected that many trial participants will have subclinical coronary atherosclerosis. 
   
  Trial procedures should be suitable for a future efficacy trial using more pragmatic design features and lower costs per patient. A run-in period may be considered to identify optimal participants who will adhere to treatment and improve the cost efficiency of the trial. To increase the efficiency of the study in determining the optimal future intervention in an efficacy trial, this approach will allow individual pharmacological or behavioral or combinations of interventions to be pursued. Any studied intervention should have substantial prior evidence of efficacy in either primary or secondary cardiovascular risk. The study will use the CCTA (or proposed alternative imaging method) to obtain primary trial outcomes regarding plaque volumes and characteristics associated with clinical outcomes. During the trial, biomarkers and changes in CVD risk factors should be used to confirm an acceptable level of adherence and expected level of change in CVD risk in order to demonstrate that there is a clinical difference in the hypothesized mechanisms of efficacy such as LDL between the control and active arms. The platform nature of the trial will also allow for additional interventions to be added and studied if additional funding support becomes available.
• 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 3 total 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 arms 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 highly 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 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.

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. 

Prior to SubmissionApplicants 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. 

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 CCC UG3/UH3 NOFO plus one application to the companion DCC U24 NOFO, RFA-HL-25-007.

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: [email protected] 

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., “1/22”, where the 1/22 means this is site 1 of 22 sites in the set. The other sites will be labeled “2/2, ”.) Titles may not exceed 200 characters in length, including the tag, e.g., 1/22, 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., “1/22”), and 22) 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 CCC 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 and management plan that addresses contingencies in the event that there is inadequate progress toward achieving the UG3 and/or UH3 core milestones. The plan should identify a range of contingencies that could threaten study progress or feasibility, and propose detailed solutions using study resources.
• Key methodology and standard operating procedures governing resource management, study deployment, operations/execution, and study closure.
• How the clinical trial, in collaboration with the DCC, will resolve fiscal and logistical issues in a timely manner, including plans to pro-actively 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 the 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. 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.

4. Community-Engagement Plan (Required):

A description of how the proposed trial addresses community engagement must be provided as an attachment using the filename ““Community-Engagement Plan.pdf”” and may not exceed 1 page. An approach that emphasizes collaboration with community partners, leaders, and knowledge holders, leveraging community resources and local service delivery and/or settings to address the needs of multiple stakeholders is encouraged. Additionally, approaches based on models and or principles such as those used in conducting Community-Based Participatory Research (CBPR) are encouraged whenever feasible and appropriate. Discussion of engagement with different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based) is strongly encouraged. As appropriate, plans may include a Community and Scientific Advisory Board that targets community representation and scientists not directly involved in the project.

5. 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

SF424(R&R) Senior/Key Person Profile

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

The PD(s)/PI(s) of the clinical trial must be experienced in the conduct of multi-center clinical trials including success in meeting milestones and timelines and have expertise in the content area of the proposed clinical trial. The experience of each PD/PI and all Key Personnel must be carefully documented, and roles and responsibilities must be well-defined. In addition, the responsibilities and authority of each PD/PI must be specified. The application must ensure that a multidisciplinary team of appropriate personnel (clinical trialist, clinician, Project Manager, study coordinator(s), etc.) are proposed at the contributing institutions to facilitate the implementation of all aspects of the clinical trial, including recruitment of subjects, design/implementation of the trial protocol, and coordination of roles/responsibilities of the CCC leadership. Applicants must include personnel and corresponding biographical sketches for the CCC only. All Key Personnel who are major scientific contributors to the study must provide an NIH Biosketch whether they are budgeted. The PD/PI (or Multi-PDs/PIs) for the CCC cannot be Key Personnel on the DCC application. 

R&R Budget

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

This application must include only its own budget, including any subcontract budgets associated with it. The application must provide detailed annual budgets that will enable the CCC to meet its milestones. In the budget justification, provide the detailed budget needs (per year for each site and total) and an implementation and cost management plan (e.g., capitation). Include costs associated with community engagement activities (e.g., community advisory board(s), infrastructure needs), as applicable. Do not include budget support for the Data Safety Monitoring Board (DSMB). Budget support for the DSMB should be included in the collaborative DCC application budget only.

Any cores (e.g., imaging) must be a subcontract to either the CCC or DCC. Separate itemized budgets must be prepared for each subcontract and/or for each collaborating center or core. 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 specific term and condition in the Notice of Award. If the Third Party support ceases and the trial is no longer tenable without the Third Party support, a close-out plan may be requested. 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.

Include budget support for personnel to travel to 2 in-person Steering Committee meeting and/or other meeting of investigators and NHLBI program staff to be held in the Washington, D.C. area for both years of the UG3 phase and for an annual in-person meeting thereafter.

Include budget support for publication, dissemination of results, and data sharing.

Budgets should request only the costs that will be required for the activities to be performed in a given year. Generally, the NHLBI expects the requested costs in year 1 (UG3) to be lower than in the following years, depending on recruitment targets. It is also expected that the CCC budget will be lower in the final 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 an overview of the state of the science, current status and relevance of the trial, a detailed discussion of the specific protocol, and the approach to data collection. Provide a brief description of study research objectives.

The following criteria must be addressed:

Significance: The significance of the proposed clinical trial and importance of the question must be clearly stated. It is particularly important to provide a discussion of the evidence supporting equipoise for each of the two intervention arms. The application should make clear the need for and timeliness of the study with emphasis on how the results will address an evidence gap and therefore advance science. The application must justify the proposed screening approaches. Include a description of how results will impact health or clinical care. A discussion of the costs and benefits of the study should be included for evaluation of the trial’s significance.

Innovation: Explain how the application challenges and seeks to shift current research or clinical practice paradigms. This may include tools used during the screening process (first sequential component) as well as during the intervention (second sequential component) that highlight the most contemporary evidence and have the potential to expand our current understanding of the pathophysiology of coronary artery atherosclerosis in young adults and novel treatments to alter its clinical course.

Approach: The research approach section should include a description of the supporting data from the most contemporary evidence and the experimental approach. The rationale for the chosen subclinical or intermediate, primary, and secondary endpoints must have substantial existing evidence of an association with future clinical events in order to support its justification as the endpoint.

Supporting Data: Describe the formative clinical studies (including any pilot studies) that are the basis for the proposed clinical trial. Include other research as appropriate to demonstrate that the approach chosen is justified. 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: Include critical feature of conducting the clinical trial that are not already submitted as part of the PHS Human Subjects and Clinical Trials Information Form, including but not limited to, the following experimental approach items:

• A detailed description and rationale for the research hypothesis(es)
• The rationale for the specific design chosen
• Evidence supporting that: 1) equipoise exists between the arms of the trial and 2) the intervention(s) or control arm(s) tested are not known to be inferior to the range of practice (or usual care) at the sites, in their community, and described in relevant standards of care
• A detailed rationale explaining why the proposed study population of young adults is the most appropriate group to answer the research question(s)
• Justification for all assessments including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the primary and secondary research question; a description of the use of patient reported outcomes as well as non-traditional data collection approaches (e.g., telephone, mobile devices, or web-based systems)
• A description of the laboratory evaluations (as appropriate) and plans to implement and monitor Good Clinical Practices (GCP), Good Laboratory Practices (GLP) and Good Manufacturing Practices (GMP), as appropriate should be provided
• A discussion of major challenges in implementing the study and how they will be addressed, including the potential participant concerns about the adverse consequences of radiation exposure, or adverse consequences of any interventions and the detection of subclinical plaques.
• Discussion of proposed imaging methods should include approaches to limit the radiation exposure to the minimum at each clinical site
• A discussion of event rates and contingency plans if the effect size or subclinical event rate is underestimated

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, and should address timing of overall recruitment/enrollment and retention goals. The milestones must address accrual goals for women, minorities, and individuals of all ages, and any other identified requirements for completion of the approved research. Milestones must be proposed for both the 2 year UG3 and the five year UH3 phases. For the UH3 phase, 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 core milestones of particular interest include, if applicable to the research strategy, but are not limited to:

Core UG3 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% the screened participants in 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 UH3 Trial Milestones

• Enrollment of the remaining participants in the screening and intervention component by the end of the second year of the UH3 phase. Specified goals such as enrollment of 25%, 50%, 75% and 100% of the projected remaining recruitment for all study participants during the first and second year of the UH3 phase, including specified goals for women and minorities by the end of the second year of the UH3 phase with a contingency plan provided if this milestone is not met and justification why this will not adversely impact the power of the three arm trial
• 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

Letters of Support: Letters of support from clinicians or clinical department chairs whose support is necessary to the successful conduct of the trial should be provided and indicate that, and describe how, the trial is in equipoise and that the intervention(s) or control arm(s) tested are not known to be inferior to the range of practice (or usual care) at each site, in their community, and described in relevant standards of care. 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 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.

• 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.

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 DCC 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 study participants that include individuals from diverse groups; 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) most study designs for this trial will likely use individual randomization designs, but if not, recruitment of groups for cluster-randomized trials should be discussed and described and appropriate milestones proposed for UG3 and UH3 phases.

Provide a table of the recruiting sites and site PDs/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 and second year of the trial (UG3 phase) and a separate timeline for subsequent 5 years (UH3 phase). The study timelines should include core milestones that need to be met throughout the life cycle 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 delineate 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 DCC 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 protocol to be followed in each of the three arms of the trial. Include a brief description of how the CCC will standardize and optimize adherence to the protocol at the sites. Specify concomitant interventions, if applicable. Describe the proposed experimental design including a discussion of the clinical trial design and the rationale for the particular design elements chosen (pragmatic, explanatory, cluster-randomized, adaptive, etc.). The proposed trial should rigorously test whether the screening approach efficiently identifies young adults with coronary artery atherosclerosis and if the interventions in each of the two active prevent or reduce the development or progression coronary atherosclerosis.

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
Include a brief statement indicating that the CCC has worked closely with the DCC to ensure that the number of expected participants, the expected effect size, the power of 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. In addition, clearly state that the Statistical Design and Power attachment is being submitted in its entirety as a part of the collaborating DCC application.

4.7 Dissemination Plan
The information provided for Dissemination Plan must be the same as that provided in the collaborating DCC 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. Each application of a collaborative set must be on-time. Considerations for late applications that are based on the institution or PD/PI apply only to his/her individual application. 

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 NHLBI, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed. Each application of a collaborative set must be complete, compliant, and responsive.

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.

For this particular announcement, note the following:

Reviewers will consider the overall feasibility of the project and whether the proposed clinical trial will answer the key scientific NOFO questions and be completed on time and within the proposed budget.

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  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 recipients.
• 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 HHS, PHS, and NIH policies.
• Provide updates at least annually on progress in PEDP implementation. 

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 in the UG3 phase, 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.

 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 disagreement that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed will be convened. It will have three members: 1) a designee selected by the Executive Committee (with the NHLBI member absent from the discussion) or by the individual recipient in the event of an individual disagreement; 2) a second member selected by NIH; and 3) the third designee with expertise in the relevant area selected by the other two. This special dispute resolution does not alter the recipients’ right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations at 42 CFR part 50, subpart D and HHS regulation at 45 CFR part 16.

Multiple PD/PI Dispute Resolution

If a conflict develops between PD(s)/PI(s) in a multiple PD/PI application, the following procedures will apply:

The Departmental administrators representing the PD(s)/PI(s) shall meet and attempt in good faith to settle any dispute, claim or controversy arising out of or relating to the interpretation, performance or breach of this disagreement. However, if the Departmental administrators fail to reach resolution in 30 days then NIH may invoke dispute resolution procedures as described in the above paragraph. 

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: [email protected] (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: [email protected]

David Schopfer, M.D., M.A.S.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-402-3833
Email: [email protected]

Lawrence Fine, M.D., Dr.PH.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0305
Email: [email protected] 

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute
Email: [email protected] 

James Hennigan
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-480-7071
Email: [email protected] 

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.