PAR-27-011-Full-Announcement.html

Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Heart, Lung, and Blood Institute (NHLBI)

Funding Opportunity Title

Single-Site Investigator-Initiated Clinical Trials (R61/R33 Clinical Trial Required)

Activity Code

R61/R33 Exploratory/Developmental Phased Award

Announcement Type

Reissue of

PAR-25-028

Related Notices

Check for any recent Notices of NIH Policy Changes that may impact application requirements.

Funding Opportunity Number (FON)

PAR-27-011

Companion Funding Opportunity

None

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s)

93.837, 93.838, 93.233, 93.840, 93.839

Funding Opportunity Purpose

This Notice of Funding Opportunity (NOFO) supports applications to develop and conduct investigator-initiated single site clinical trials including efficacy, comparative effectiveness, pragmatic and/or dissemination and implementation science clinical trials. Trials using innovative designs such as platform trials, adaptive, and Bayesian designs are encouraged. These trials may include ones that test different therapeutic, behavioral, dissemination and implementation science clinical trials and/or prevention strategies. Trials for which this NOFO applies must be relevant to the research mission of the NHLBI and meet the NIH definition of a clinical trial (see NOT-OD-15-015). For additional information about the mission, strategic vision, and research priorities of the NHLBI, applicants are encouraged to consult the NHLBI website.

This NOFO will utilize a bi-phasic, milestone-driven mechanism of award. The objective of the application is to present the scientific rationale for the clinical trial and a comprehensive scientific and operational plan that describes it. The application should address project management, participant recruitment and retention, performance milestones, scientific conduct of the trial, and dissemination of results. The multiple PD/PI model is strongly encouraged but not required. Applicants are encouraged to include a PD/PI with expertise in biostatistics, clinical trial design, and coordination. The application should also describe its approaches to increase community engagement from conceptual design of the intervention through implementation and sustainability, close gaps in health outcomes within the US population, and increase health for all.

Funding Opportunity Goal(s)

The Division of Cardiovascular Sciences supports research and training to foster heart and vascular research in the basic, translational, clinical and population sciences, and to foster training to build talented young investigators in these areas, funded through competitive research training grants.

The Division of Lung Diseases supports research and research training on the causes, diagnosis, prevention, and treatment of lung diseases and sleep disorders.

The Division of Blood Diseases and Resources supports and research and training to foster research and research training on the pathophysiology, diagnosis, treatment, and prevention of non-neoplastic blood diseases, including anemias, sickle cell disease, thalassemia; biology of red blood cells, white blood cells, and platelets, hematopoietic stem cells and the bone marrow niche, hemophilia and other abnormalities of hemostasis and thrombosis.

The Center for Translation Research and Implementation Science (CTRIS) plans, fosters, and supports late-stage research to identify promising approaches for ensuring successful integration of evidence and evidence-based interventions within clinical and public health settings, such as health centers, worksites, schools, and communities in the United States and abroad.

The National Center on Sleep Disorders Research (NCSDR) supports research and research training related to sleep disordered breathing, and the fundamental functions of sleep and circadian rhythms.

Key Dates

Posted Date

March 18, 2026

Open Date (Earliest Submission Date)

May 02, 2026

June 02, 2026

July 02, 2026

Not Applicable

April 2027

October 02, 2026

November 02, 2026

Not Applicable

July 2027

February 01, 2027

March 01, 2027

Not Applicable

December 2027

June 02, 2027

July 02, 2027

Not Applicable

April 2028

October 01, 2027

November 01, 2027

Not Applicable

July 2028

February 01, 2028

March 01, 2028

Not Applicable

December 2028

June 01, 2028

June 30, 2028

Not Applicable

April 2029

October 02, 2028

November 02, 2028

Not Applicable

July 2029

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.

Due Dates for E.O. 12372

Not Applicable

Expiration Date

November 03, 2028

Required Application Instructions

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.

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

NOFO Research Objectives This NOFO supports applications to develop and conduct investigator-initiated single-site clinical trials. Clinical trials supported by this NOFO include Phase II and above clinical trials. This NOFO is applicable to single-site clinical trials only, and will utilize a bi-phasic (R61/R33), milestone-driven mechanism consisting of a start-up phase of up to one year (R61), and a full enrollment and clinical trial execution phase of up to four years (R33). Proposed research may utilize a design anywhere along the continuum of efficacy, effectiveness, pragmatic and/or dissemination and implementation research clinical trials. For this NOFO, pragmatic trials are considered those that test an intervention under the usual clinical conditions in which it will be applied, while efficacy trials do so under more idealized circumstances. Implementation trials test strategies to adopt and integrate evidence-based health interventions and change practice patterns within specific settings. These implementation trials can include hybrid implementation/effectiveness studies. Innovative trial designs such as adaptive and Bayesian designs will be considered. The trial design should be appropriate for the study question. Trials for which this NOFO applies are expected to contribute to the evidence base for important health matters of relevance to the research mission of NHLBI, close gaps in health outcomes within the US population, and increase health for all. For additional information about the mission, strategic vision, and research priorities of the NHLBI, applicants are encouraged to consult the NHLBI website.

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 R61 and R33 phases of the project. These clinical trials are expected to be conducted with a high degree of efficiency, with streamlined administrative procedures wherever possible. Applicants are strongly encouraged to employ project management principles as appropriate. Applications that address contingency plans to proactively confront potential delays or disturbances in meeting the milestones are strongly encouraged.

The definition of a single-site clinical trial is one in which the protocol is implemented by one investigational site that conducts and coordinates the protocol. While a single-site clinical trial may enroll participants from multiple locations/clinics within a geographic area, those participants will receive an intervention or undergo outcome assessments under the direction and oversight of one research team at one investigational site.

Phases of Award The R61 phase will support finalization of the protocol and the informed consent/assent document; the development of the manual of operations and procedures, case report forms and other resources necessary to the performance of the trial; further development of study partnerships; establishment of a Data and Safety Monitoring Board (DSMB) and review and approval of the protocol by the DSMB; and Institutional Review Board approval of the trial.

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 R61 award to allow for the successful launch and execution of the proposed clinical trial in the R33 phase.

Investigators and NHLBI will review and mutually agree upon final revised milestones that will be included in the Terms and Conditions of the grant, if awarded. Transition from the R61 to the R33 phase is predicated on the successful completion of all milestones proposed and peer-review for the R61 phase of the application. The core milestones must be met during the R61 phase to allow for successful launch of the full trial in the R33 phase. The overall planned enrollment will be agreed upon between the recipient and the NHLBI prior to an award. Enrollment of participants into the clinical trial is expected to begin before the end of the R61 phase to optimize the probability of successfully completing the trial on time and on budget. NHLBI will conduct an administrative review approximately 9 months into the R61 phase to determine progress toward achievement of milestones included in the Notice of Award. Milestones and timelines for the R33 phase may be revised and finalized at the time of the R61/R33 transition. Less than satisfactory progress in the R33 phase may lead to closing out the award.

R33 milestones must address timing of overall recruitment/enrollment and retention goals, including accrual goals for women, minorities, and individuals of all ages including children and older adults. It is expected that performance of core milestones, such as planned enrollment goals, will be shared on a regular basis through eConnect, an NHLBI platform that facilitates transfer of electronic information to NHLBI. Subject to NHLBI funding availability and scientific priorities, R33 awards will be made after administrative review with specific attention to the extent to which all agreed-upon R61 milestones have been met. If the R33 is funded, NHLBI will review the progress of the clinical trial on a regular basis. Slower than anticipated progress towards meeting milestones will result in a re-evaluation of the award by NHLBI including whether the objectives of the trial can be met on time and on budget. If milestones have not been satisfactorily met, subsequent funding years may not be approved and may lead to closing out the award.

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

Investigators This NOFO encourages investigators experienced in the conduct of clinical research to apply. Early Stage Investigators with clinical research experience are strongly encouraged to apply, provided they will receive scientific support from senior investigators (e.g., as Co-Investigators).

Clinical Trials Not Supported by and Non-Responsive to this NOFO The following types of clinical trials are not intended to be supported by this NOFO and will be considered non-responsive:

Prior to Submission Prior to submitting to this NOFO, all applicants are strongly encouraged to consult with the Scientific/Research contacts for the area of science for which they are planning to develop an application. 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.

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

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

Section II. Award Information

Funding Instrument

Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed

New

Resubmission

Revision

The OER Glossary and the How to Apply Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Clinical Trial?

Required: Only accepting applications that propose clinical trial(s).

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget

Application budgets are not limited but need to reflect the actual needs of the proposed project.

Award Project Period

The scope of the proposed project should determine the requested project award period.

The maximum project period of the combined R61 and R33 phases is 5 years, with up to 1 year for the R61 phase and up to 4 years for the R33 phase.

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

Eligible Organizations

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Local Governments

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)

Foreign Organizations/International Collaborations

Non-domestic (non-U.S.) Entities (Foreign Organizations) are 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.

NIH will no longer issue awards (i.e., new, renewal, or non-competing continuation) to domestic or foreign entities that involve foreign subawards/subcontracts. All NIH-funded research involving foreign subawards/subcontracts must be submitted in response to a NOFO that is specifically designated for funded international collaborations. This new requirement was effective, May 1, 2025.

Applications involving foreign subawards/subcontracts submitted in response to this NOFO will be deemed noncompliant and will not be considered for funding. This policy applies to all monetary international collaborations resulting in foreign subawards/subcontracts, however, it does not preclude unfunded international collaborations or foreign components, funding for foreign consultants, or procurement of unique equipment or supplies from foreign vendors.

Required Registrations

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.

Eligible Individuals (Program Director/Principal Investigator)

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.

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.

ESI applicants can be the PI/PD of an application providing they can show support of senior investigators (e.g., Co-I, Multi-PI (MPI)) with appropriate clinical trials experience. ESIs are strongly 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 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 (in this NOFO, in a policy notice, or other notice from NIH Guide for Grants and Contracts). 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.

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

Instructions for Application Submission

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.

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

Facilities and Other Resources:

Describe how the available infrastructure at the single performance site will be leveraged to facilitate the efficient operation of the proposed clinical trial, including project management tools that will be used. If applicable, discuss any community participatory agreements and/or stakeholder agreements to support the protocol.

Other Attachments: The following attachments marked as “Required" must be provided, or the application will not proceed to peer-review:

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

2. 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.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, making timely responses, and optimizing the allocation of limited resources to meet pre-defined study objectives. This description should include:

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.

3. Clinical Research Experience (CRE) (Required):

The following attachment must be provided, or the application will not proceed to peer-review. Applicants must provide a detailed table listing the characteristics of clinical studies that demonstrate relevant experience in clinical research coordination. The table must be provided as an attachment called "Clinical 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: whether the studies completed on schedule or not Column G: publication reference(s)

4. Community-Engagement Plan (CEP) (Required):

A description of how the proposed trial addresses the quality and consistency of community engagement from conceptual design of the intervention through implementation and sustainability (as applicable) 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 interested collaborators 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, under-resourced, 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. Describe how the efforts discussed in the CEP are expected to meaningfully contribute to innovation. Consideration of how members of the community advisory board and scientific board will be recruited, retained, engaged in and acknowledged is encouraged.

SF424(R&R) Senior/Key Person Profile

All Key Personnel who are major contributors to the study must provide an NIH Biosketch whether they are budgeted. Describe the experience of key scientific personnel in the conduct of clinical trial coordination and management, including success in meeting milestones and timelines, expertise in the content area of the proposed clinical trial, and expertise in biostatistics and clinical trial design. 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 respective responsibilities and authority of each PD/PI must be specified. Include biosketches for a multidisciplinary team of appropriate personnel (clinician, statistician, data manager, study coordinator(s), etc.) 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. Describe the expertise of the project manager and other significant contributors to the project relevant to successful execution of the trial.

R&R Budget

Provide detailed, annual budgets that will enable the trial to meet its milestones. In the budget justification, provide the detailed budget needs (per year 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.

If partial funding is to be provided by sources other than NHLBI, these contributions should be presented in detail in the budget justification. Third Party support of the proposed research activity (if approved) will be incorporated as a Term and Condition 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.

Include budget support, if needed, for any personnel to attend steering committee/executive committee meetings.

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 to be lower than in the following years, depending on recruitment targets.

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

R&R Subaward Budget

PHS 398 Cover Page Supplement

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 should present an overview of the state of the science and relevance of the trial, a detailed discussion of the specific protocol, and the approach to data collection, analysis, and dissemination. In the overview, address the study research objectives and the overall conduct of the clinical trial, including the prioritization of this proposed clinical trial in the context of other overlapping clinical research.

The following criteria should 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. 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. Include a description of how results will impact health or clinical care. A discussion of the risk, cost, 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 section should include detailed descriptions of the supporting data and the experimental approach.

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

Core Milestones Propose and justify milestones that will be subject to peer-review. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, measurable, results-focused and time-bound. Milestones must address timing of overall recruitment/enrollment and retention goals. The milestones must address accrual goals for women, minorities, and individuals of all ages including children and older adults, and any other identified requirements for completion of the approved research. Milestones need to be proposed for both the R61 and R33 phases. For the R33 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.

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

The core milestones of particular interest include, but are not limited to:

Core R61 Trial Milestones

Core R33 Trial Milestones

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. The letters should 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 the 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):

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.

Additionally, applicants should consult and incorporate the NHLBI Supplement to the NIH Policy for Data Management and Sharing into their DMSP as applicable. This includes, but is not limited to, plans to share scientific data through existing NIH-supported Scientific Data Repositories, Ancillary Studies, and the Data Freeze Approach.

Data Repositories NHLBI-supported researchers are expected to share scientific data through existing NIH-supported Scientific Data Repositories or other repositories that have the desired characteristics described in the Supplemental Information to the NIH Policy for Data Management and Sharing: Selecting a Repository for Data Resulting from NIH-Supported Research. NHLBI encourages submission of data into NHLBI BioData Catalyst (BDC), especially for data from studies that must comply with NHLBI’s Accrual of Human Subjects (Milestones) Policy and for those projects supported by funding opportunity announcements that encourage data deposition into BDC. NHLBI also encourages the submission of data into BDC for NHLBI projects and ancillary studies to NHLBI parent studies subject to the NIH GDS Policy. For data submitted to repositories other than BDC, an appropriate globally-unique, persistent identifier with sufficient metadata should be shared with NHLBI to promote FAIR principles and populate a master index for data generated from all NHLBI-supported research.

NHLBI discourages the deposition of data in multiple places, which may incur issues of version control and excess storage costs. If researchers need to deposit data generated from NHLBI support into more than one repository, the rationale for this need should be provided within the Data Preservation, Access, and Associated Timelines element in DMS Plans. When approved for deposition in multiple repositories by appropriate NHLBI staff, for data deposited in repositories other than BDC, an appropriate globally-unique, persistent identifier for each repository, with sufficient metadata, should be provided to the NHLBI to promote FAIR principles.

Ancillary Studies NHLBI defines ancillary studies as studies that collect new data or derive data for purposes that are separate from the main “parent” study. The goal of ancillary studies is to extend scientific knowledge beyond the parent study’s original scope. NHLBI ancillary studies are primarily supported by NIH funds but may also be funded, in part or whole, by other sources such as non-profit and private sector organizations. Studies approved as ancillary, regardless of funding sources, to an NHLBI-funded parent observational study or clinical trial (including studies co-funded by multiple institutes, centers, and offices or to which NHLBI provides administrative oversight) are required to adhere to the parent study’s data sharing policies as a condition of approval. The requirements of data sharing agreements between NHLBI-funded parents and their ancillary studies should be consistent with the principles of the NIH DMS Policy.

Data sharing requirements are outlined in the agreement between the parent and respective ancillary study, and it is the responsibility of the ancillary study principal investigator to state in writing to the parent study steering committee any special circumstances that would preclude or limit data sharing. As specified in contract terms or award terms, designees from the parent studies shall submit updated and new ancillary data to an NHLBI-approved data repository on the same data submission timeline as the parent data (for example, core exam data, annual event surveillance, etc.). Ancillary study principal investigators should get advance approval from the parent study steering committee for any plans to share data with other repositories which have characteristics consistent with those described in the Supplemental Information to the NIH Policy for Data Management and Sharing: Selecting a Repository for Data Resulting from NIH-Supported Research.

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

Section 2 - Study Population Characteristics

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) participant retention and adherence strategies; 6) possible competition from other trials for study participants; 7) engagement of the clinical community(ies) that will play a critical role in the recruitment and retention; 8) recruitment of groups for cluster-randomized trials.

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, including but not limited to study start-up including regulatory approvals, enrollment, intervention phase, follow-up phase, data analysis and dissemination of results. A narrative is not expected in this section.

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

(a) when the study opens to enrollment

(b) when core milestones are met

(c) when subtasks needed to reach the core milestones are achieved

(d) when the analysis of the study data will occur

(e) when the submission of the primary study manuscript for publication is expected Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan

3.5 Overall Structure of the Study Team

Include a description of the following:

Section 4 - Protocol Synopsis

4.1 Study Design

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

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 Calculation

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

For Phase III clinical trials, include plans for evaluation of the primary outcome(s) by race/ethnicity and sex, and include all relevant data to assess whether the trial includes adequate numbers for valid analyses of subgroups. Adaptive designs should include a pre-specified adaptation plan that allows for clear go/no-go decisions and pre-specified analysis boundaries.

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

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

Foreign Organizations Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the How to Apply- Application Guide.

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…