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

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

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

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



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

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Research Objectives 

The objective of this funding opportunity will be to support investigator-initiated, Phase 0 and I clinical trials (including bridging studies) for diagnosis and therapeutic interventions (e.g., drugs, devices, and biologics, including cells and cell products) for heart, lung, blood, and sleep (HLBS) disorders in adults and children. NHLBI seeks applications that propose to contribute to the evidence base for important health matters of relevance to the research mission of NHLBI and which meet the NIH definition of a clinical trial (see NOT-OD-15-015). In addition to supporting clinical trial start-up and implementation activities, this PAR will provide support for final stage, agent-associated preclinical activities needed for the implementation and conduct of the proposed trial. 

This NOFO is applicable to single or multi-site clinical trials that are Phase I, including bridging studies. For the purposes of this NOFO, the definition of a bridging study is a study performed to provide clinical data that allows extrapolation of the existing data from the population approved to receive the therapeutic or diagnostic into a new population (e.g., from adult subjects into pediatric subjects).

NHLBI seeks to enable early translational research as a means of facilitating and accelerating the development of new clinical interventions. This includes identifying unmet medical needs and opportunities, knowledge and resource gaps, and developing programs that bridge the gaps between mechanistic, discovery, and early translational research. For additional information about the mission, strategic vision, and research priorities of the NHLBI, applicants are encouraged to consult the NHLBI website. In addition to scientific relevance and excellence, these clinical trials are expected to be conducted with a high degree of efficiency and with streamlined administrative procedures wherever possible.

Structure

This NOFO will utilize a bi-phasic, milestone-driven R61/R33 mechanism consisting of a start-up phase (R61) and a clinical trial execution phase (R33). Applicants must address objectives for both the R61 and the R33 phase and are strongly encouraged to use project management principles as appropriate.

Phases of Award

The R61 phase can be up to two years and will support late-stage product development activities required to allow the therapeutic or diagnostic to be administered to humans. Examples of activities that will be allowed include: stability studies, final formulation studies, establishment of shipping and receiving protocols, Investigational New Drug (IND) filing, and Phase 0 clinical trials. Submissions containing animal studies are not permitted for this NOFO. If the project needs additional animal studies or any other activities that are not covered under this NOFO to be ready for the early phase clinical trial, applicants are encouraged to apply for Catalyze grants or Catalyze preclinical services. Information about the Catalyze program can be found here: Catalyze - About (nhlbicatalyze.org)

The R61 phase will also support finalization of the protocol and the informed consent/assent document; the development of the manual of operations, case report forms and other resources necessary to the performance of the protocol; further development of study partnerships; review of the protocol; and Institutional Review Board approval of the trial. All necessary regulatory approvals, as well as source(s) of the necessary drugs, devices or other resources as needed, should be obtained to allow for the successful launch of the proposed clinical trial in the R33 phase. An administrative review of the extent to which peer-reviewed milestones are met in the R61 phase will determine whether the R33 phase award will be issued, subject to NHLBI funding availability. In addition to the primary aim of assessing the safety of the therapeutic/diagnostic product, secondary aims in the R33 phase may include: 1) further testing of the intervention's feasibility, safety, and acceptability; 2) determining the optimal dose for a subsequent trial by assessing dose-response with respect to a functional pharmacodynamic readout of the biological signature in response to multiple doses of the product; 3) determining the pharmacokinetics of the dose and formulation of the product to be used in future trials to justify the frequency of dosing; and 4) developing functional biological signature measures and clinical outcome measures feasible for use in larger efficacy and effectiveness trials. The specific activities appropriate for the R33 phase will depend on the product under study and available preliminary data on the product.

Milestones

Delineation of milestones by the applicant for the R61 and R33 phases is a key characteristic of this NOFO. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. This NOFO will support applications that propose a series of milestones including manufacturing and product development goals in the R61 phase and trial conduct in the R33 phase. Applicants are expected to complete the trial on time and on budget. Applications that address contingency plans to proactively confront potential delays in meeting the milestones are strongly encouraged.

Milestones must address timing of overall recruitment/enrollment and retention goals, including accrual goals for women, under-represented minorities, and individuals of all ages including children and older adults. It is expected that performance of core milestones, such as planned enrollment goals, will be shared on a regular basis through eConnect, an NHLBI platform that facilitates transfer of electronic information to NHLBI. 

After review, NHLBI will determine eligibility to transition to the R33 phase; this includes completion and analysis of any Phase 0 clinical trials. With the entirety of the Phase I clinical trial in the R33 phase, there will be additional administrative review of accrual milestones within this phase. It is expected that the performance of critical milestones such as expected enrollment goals will be shared on a regular basis through an NHLBI clinical dashboard database. Milestones and metrics may include IND or IDE filing, IRB protocol approval, successful transition to R33 phase, timely startup of clinical trial protocol and completion of trial and trial-specific milestones, publication of trial results, and/or specific plan for transition to next appropriate clinical study or returning to basic research studies to refine and improve the approach. 

Additional NHLBI policies relevant to clinical research are the NHLBI Policy for Inclusion of Women and Minorities in Clinical Research, and the  NHLBI Policy for Data and Safety Monitoring of Extramural Clinical Studies.

 Applications Not Responsive to this NOFO

The following types of clinical trials are considered outside the scope of this NOFO, and applications proposing such activities will be considered non-responsive to this NOFO and will be withdrawn without review:

• Phase II or III trials (see PAR-22-189 , PAR-22-192 , or PAR-22-193 or their reissuances for NHLBI NOFOs that support Phase II or III trials)
• Observational studies that do not meet the NIH definition of a clinical trial (see NOT-OD-15-015)
• Trials designed to address hypotheses related to the biology and pathobiology of health and/or diseases. Mechanistic or Basic Experimental Studies in Humans (BESH) (NOT-HL-19-690)
• Animal studies

Specific Areas of Research Interest

Investigators are strongly encouraged to consult with the Scientific/Research Contacts listed in Section VII for the area of science for which they are planning to develop an application prior to submitting an application. Early contact (at least 12 weeks prior to submission) is encouraged. This period of time provides an opportunity for NHLBI staff to discuss the scope and goals, and to provide information and guidance to the applicants.

Diversity Statement

The NIH recognizes that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogeneous teams. There are many benefits that flow from a diverse 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 populations participate in, and benefit from research, and enhancing public trust. For more information, please see NOT-OD-20-031.

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 eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are 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 the 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 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.

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.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the 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).

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 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
National Institutes of Health
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.

Cover Letter: A copy of the NHLBI approval letter to submit a grant application with direct costs over $500,000 in any year must be attached.

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: If the proposed trial is multi-site, describe the facilities and resources available for the coordination of a multi-site clinical trial. Describe how the infrastructure and performance sites will facilitate the efficient operation of the proposed multi-site clinical trial.

Other Attachments: The following attachments marked as "Required" must be provided, or the application will not be reviewed: 

1. Clinical Trial Research Experience: Applicants must provide a detailed listing of projects that demonstrate experience of the proposed team in late translational research and early phase clinical trials in the last 5 years. The table must be provided as an attachment called "Product Development Experience.pdf" and may not exceed 3 pages.

The table columns should include:

Column A: product development program title

Column B: applicant's role in the development program  

Column C: a brief description of the development program

Column D: a brief description of the early phase trial

Column E: planned enrollment

Column F: actual enrollment

Column G: publication reference(s)

2. Project Management Plan: A Project Management Plan must be provided as an attachment called "Project Management Plan.pdf" and may not exceed 3 pages. The Project Management Plan should describe the strategy that will be used throughout the project to ensure that the unique goals of the preparatory work and the clinical trial are met. Project management planning should directly support 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. The project management plan should describe:

• The role of the project manager
• The project's critical path to meet scientific objectives within budgetary limits
• Business roles, executive decision-making, and accountability standards
• The contingency plans in the event that there is inadequate progress toward achieving the R61 and/or R33 milestones
• Key methodology and standard operating procedures governing resource management, study deployment, operations/execution, and study closure
• How the project management team will resolve fiscal and logistical issues in a timely manner including plans to proactively evaluate and prioritize study risks and issue corrective responses
• Processes required for orderly project closure including how data and specimens will be handled

In summary, the project management plan must 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.   

Other Attachments:

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 clinical trial coordination and management, 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 (clinician, statistician, data manager, study coordinator(s), etc.) is proposed to facilitate the implementation of all aspects of the clinical trial, including recruitment of subjects, and design/implementation of the clinical protocol.

R&R Budget

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

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

Include budget support for publication and dissemination of results.

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 that there be a discussion of how the trial will test the proposed hypothesis(es) and the unmet need or gap that is filled with the new therapeutic or diagnostic. 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 our knowledge of theory and practice in this area. Include a description of how results will impact clinical care to improve health. 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.

Approach: The research approach should include detailed descriptions of the supporting data and the experimental approach.

Supporting Data. Describe the preclinical studies that provide the basis for the proposed clinical trial. Include other research as appropriate to demonstrate that the approach chosen is justified. Conceptualization and planning must have progressed to a stage sufficient to allow for an overall  assessment of the likelihood of the success of the trial.

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

• A detailed description and rationale for the research hypothesis(es).
• 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 potential challenges in implementing the research protocol and how they will be addressed.
• An overall summary of the product development plan and the go/no go milestones remaining that will be analyzed in the R61 phase of the application.
• A detailed description of the approach to obtain regulatory approvals.
• A discussion of event rates and contingency plans if the effect size or event rate is underestimated.

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): 

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.
  • Datasets should be prepared in accordance 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 in accordance with the Guidelines for NHLBI Data Set Preparation.

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

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

PHS Human Subjects and Clinical Trials Information

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics

2.2 Eligibility Criteria

If applicable, include the required health status of study participants.

2.5 Recruitment and Retention Plan

The Recruitment and Retention Plan should address: 1) the expertise of the individual(s) responsible for screening, approaching and consenting potential participants; 2) engagement of patient advocacy groups; 3) the process for identification and screening of study participants; 4) primary and back-up recruitment strategies (e.g., use of electronic health records); 5) implementation of the consent and/or assent process(es); 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. Provide a table of the recruiting sites and site PD/PIs showing enrollment goals and number of potential participants available at each site.

2.7 Study Timeline

Applicants must include both a description and a table or graph of the overall study timeline and key milestones.

Overall Study Timeline. Include estimated study duration (in months) including but not limited to (a) when the study opens to enrollment; and (b) when data will be cleaned and ready for analysis. The study timeline should include a description of key milestones that need to be met throughout the lifecycle of the preparatory phases and the clinical trial (R61 and R33 phases) to ensure its success, the processes that will be used to reach the milestones, and a timetable identifying when each of these key milestones will be met.

Key Milestones. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, measurable, results-focused and time-bound. Milestones must address timing of overall recruitment/enrollment and retention goals. The milestones must address accrual goals for women, minorities and children and any other identified requirements for completion of the approved research. Transition to the R33 phase is predicated on the successful completion of the milestones proposed and peer-reviewed for the R61 phase of the application. 

The milestone plan should include key milestones that need to be met during the R61 phase to allow for successful launch of the trial in the R33 phase. The milestone plan also needs to describe the milestones that must be reached in the R33 phase to address the specific aims, and ensure the successful completion of the clinical trial and dissemination of its results. Investigators and NHLBI will review and mutually agree upon a final revised milestone plan that will be included in the Terms and Conditions of the grant (if awarded).

Milestones of particular interest during the R61 phase include but are not limited to:

• Completion of all product formulation studies
• Registration of the trial in ClinicalTrials.gov
• Completion of GCP training
• Final shipping and distribution methods for the experimental therapeutic or diagnostic
• Completion of regulatory approvals
• IRB approval of finalized clinical protocol
• Completion of final Informed Consent(s) and, if applicable, assent form(s)
• Completion of agreements in place for product supply (if applicable)
• Development of a comprehensive laboratory plan
• Pharmacy/Laboratories Identification (as applicable)
• Establishment of contracts/third party agreements (if applicable)
• Training of study staff
• Development of final Management/Communication Plan
• Completion of IRB-approved Data and Safety Monitoring Plan
• Completion of Site Performance Plan
• Completion of Data Completeness and Quality Monitoring Reporting Plan

The application should also include a series of milestones for the completion of the specific aims of the clinical trial (R33) phase and contingency plans. Milestones and timelines for the R33 phase may need to be revised and finalized at the time of the R61/R33 transition meeting. Milestones of interest during the R33 phase include but are not limited to:

• Enrollment of 25%, 50%, 75% and 100% of the projected recruitment for all study participants, including women, minorities and children (as appropriate)
• Assessment of site protocol implementation performance
• Collection of data related to primary and secondary endpoints and database lock
• Submission of primary manuscript to peer-reviewed scientific journal(s) and dissemination of results
• Submission of study results to ClinicalTrials.gov within 12 months of the primary completion date

Section 3 - Protection and Monitoring Plans

3.1 Protection of Human Subjects

1. Risks to Human Subjects

a. Human Subjects Involvement, Characteristics, and Design

Applicants must include a detailed rationale explaining why the proposed study population is the most appropriate group to answer the research question(s).

b. Study Procedures, Materials, and Potential Risks

Include a justification for all assessments including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the primary and secondary research questions. Use of patient reported outcomes as well as non-traditional data collection approaches (e.g., telephone, mobile devices, or web-based systems). Describe participant follow-up procedures.

3.3 Data and Safety Monitoring Plan

Specify criteria for adverse events reporting, intervention discontinuation and stopping guidelines.

3.5 Overall Structure of the Study Team

Include a description of the following:

Section 4 - Protocol Synopsis

4.1.a. Detailed Description

Include protocol title. Summary must represent the protocol that will be implemented at the sites and must describe the intervention to be tested, and the protocol to be followed in each arm of the trial. Describe the proposed experimental design including a discussion of the clinical trial design and the rationale for the particular design chosen.

4.2.c Interventions - Description

Provide a detailed description of the therapeutic or diagnostic to be tested and how it will be administered. 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 tests and behavioral interventions. Specify criteria for intervention discontinuation and stopping guidelines.

4.5 Will the study use an FDA-regulated intervention?

4.5.a If yes, describe the availability of Investigational Product (IP) and the Investigational New Drug (IND)/Investigational Device Exemption (IDE) status.:

Provide evidence of prior communications (letters/emails) and/or the outcomes of the pre-IND or pre-IDE meeting with the FDA. If the protocol is exempt from an IND/IDE, if available, provide a copy of the exemption letter from the FDA.

If communication has not yet been established, describe the process that will be used for attaining all necessary FDA or other applicable regulatory agency approvals necessary for the conduct of the trial and associated timeline. If the protocol is conducted under a non-US regulatory agency, a plan for attaining applicable regulatory approvals should be provided.

See additional requirements regarding IND/IDE submission in Section VI. 

Delayed Onset Study

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

PHS Assignment Request Form

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

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

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

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

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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

Information on the submission process and a definition of on-time submission are provided in the How to Apply-Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the How to Apply Application Guide. Paper applications will not be accepted.

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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.

Requests of $500,000 or more for direct costs in any year

1. Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected].

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

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

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

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Reviewers will evaluate Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate criterion score. 

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

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

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

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

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 appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. 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 the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 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.

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

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

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.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

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

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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.
• 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.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

Not Applicable

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 Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

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.

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 Section 8.6 Closeout. 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.

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: 301-480-7075

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

Sumita Khatri, MD
Division of Lung Diseases 
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-402-9673 
Email: [email protected]

Daniel Frank, PhD
Division of Blood Diseases and Disorders
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-594-9405
Email: [email protected]   

Emily Tinsley, PhD
Division of Cardiovascular Sciences
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0519
Email: [email protected]

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

Ron Caulder 
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8020
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.