It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. 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

This FOA supports applications to develop and implement a Clinical Coordinating Center (CCC) for investigator-initiated multi-site clinical trials (Phase II and beyond). Multi-site clinical trials are defined as trials that enroll from two or more recruitment sites. Trials for which this FOA applies are expected to contribute to the evidence base for important health matters of relevance to the research mission of 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: http://www.nhlbi.nih.gov. In addition to scientific relevance and excellence, these clinical trials are expected to be conducted with a high degree of efficiency, with streamlined administrative procedures wherever possible.

Proposed clinical trials may utilize a design anywhere along the continuum between explanatory and pragmatic. For this FOA, pragmatic trials are considered those that test an intervention under the usual clinical conditions in which it will be applied, while explanatory trials do so under more idealized circumstances. The trial design should be appropriate for the study question.

This CCC FOA runs in parallel with a companion FOA (PAR-18-410) that encourages applications for a collaborating Data Coordinating Center (DCC). Both a CCC application and a collaborating DCC application must be submitted on the same due date for consideration by NHLBI. CCC applications submitted without a collaborative DCC (U24) application will be deemed incomplete and will not proceed to review.

Applications submitted to this FOA are expected to be Phase II or above clinical trials. This FOA will utilize a bi-phasic, milestone-driven cooperative agreement (UG3/UH3) mechanism consisting of a start-up phase of up to one year (UG3) and a full enrollment and clinical trial execution phase (UH3). Applicants must address objectives for both a UG3 and a UH3 phase and are strongly encouraged to use project management principles as appropriate.

Phases of Award

The UG3 phase will support the development of case report forms and other resources necessary to the performance of the trial; further development of study partnerships; finalization and Institutional Review Board/Data and Safety Monitoring Board approval of the trial protocol, informed consent(s), manual of operations, and clinical trial project management plans. Applications that address a comprehensive clinical trial project management plan that includes consideration of feasibility of trial launch, conduct, and completion, and also on-time and on-budget performance milestones are strongly encouraged. All necessary regulatory approvals, as well as provision of the necessary drugs, devices or other resources, should be obtained by the end of the UG3 award to allow for the successful launch and execution of the proposed clinical trial in the UH3 phase. In addition, it is expected that enrollment into the clinical trial will begin by the end of the UG3 phase or sooner. Subject to NHLBI funding availability and scientific priorities, UH3 awards will be made after administrative review with specific attention to the extent to which agreed-upon milestones have been met. If the UH3 is funded, an additional administrative review will be scheduled within the first two years of the UH3 to assess progress toward UH3 milestones or enrollment milestones.

Milestones

Delineation of milestones is a key characteristic of this FOA. 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 performance-based to achieve completion of the trial on time and on budget. Milestones must be established for both phases of the project. Satisfactory completion of UG3 milestones will be assessed administratively to determine eligibility to transition to the UH3 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.

This FOA will support applications that include a series of milestones for completion of the clinical trial (UH3 phase) and provide contingency plans to proactively confront potential delays or disturbances in meeting the milestones. NHLBI staff in collaboration with the awardee will closely monitor progress at all stages, including milestones, accrual, and safety. If, at any time, recruitment falls significantly below the projected milestones for recruitment, NHLBI may consider ending support and negotiating a phase-out of the award. Continuation of the award is conditional upon satisfactory progress in meeting milestones and subject to the availability of funds.

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

Clinical Trials Not Supported by this FOA

The following types of clinical trials are not intended to be supported by this FOA:

• Phase I (first-in-human) trials, whether single or multi-site
• Single site trials
• Drug or device safety trials
• Multi-site observational studies that do not meet the NIH definition of a clinical trial

Prior to submitting to this FOA, 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.

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

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

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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) 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.

Applicant Organizations

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

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

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

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

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

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

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

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

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

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

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

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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
6701 Rockledge Drive, Room 7214
Bethesda, MD 20892-7924 (Express Mail Zip: 20817)
Telephone: 301-435-0270
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

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

If the direct costs of the combined CCC and DCC budgets equal or exceed $500,000 in any given year, a copy of the NHLBI approval letter must be attached.

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

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

Facilities and Other Resources: Describe the facilities and resources available for the coordination of a multi-site clinical trial, including project management software that will be used. Describe how the infrastructure at the CCC and performance sites will facilitate the efficient operation of the proposed multi-site clinical trial.

All instructions in the SF424 (R&R) Application Guide must be followed. Applicants must include personnel and corresponding biographical sketches for the CCC only. All Key Personnel who are major contributors to the study must provide an NIH Biosketch whether or not they are budgeted. The PD/PI (or Multi-PDs/PIs) for the CCC cannot be Key Personnel on the DCC application.

The PD(s)/PI(s) of the clinical trial must be experienced in the conduct of multi-center 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.) are proposed at the contributing institutions to facilitate the implementation of all aspects of the clinical trial, including recruitment of subjects, design/implementation of the clinical protocol, and coordination of roles/responsibilities of the CCC leadership.

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

This application must include only its own budget, including any subcontract budgets associated with it. Separate itemized budgets must be prepared for each subcontract. The application must provide detailed annual budgets that will enable the CCC to meet its milestones. In the budget justification, provide the detailed budget needs (per year for each site and total) and an implementation and cost management plan (e.g., capitation).

Any cores (e.g., economics/quality of life) must be a subcontract to either the CCC or DCC. Separate itemized budgets must be prepared for each subcontract and/or for each collaborating center or core.

If parts of the costs of the trial are to be provided by sources other than NHLBI, these contributions must be presented in detail in the budget justification. Third Party support of the proposed research activity (if approved) will be incorporated as a 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 personnel to travel to a yearly in-person Steering Committee meeting and/or other meeting of investigators and NHLBI program staff to be held in the Washington, D.C. area.

Include budget support for publication and dissemination of results.

Note: Do not include budget support for the DSMB. Budget support for the DSMB should be included in the collaborative DCC budget only.

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

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

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

Research Strategy: The Research Strategy must present an overview of the state of the science, 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 hypotheses and why there is clinical 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 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 section should include a description of the supporting data and the experimental approach.

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)
• The rationale for the specific design chosen (e.g., pragmatic, explanatory, cluster-randomized)
• A detailed rationale explaining why the proposed study population is the most appropriate group to answer the research question(s).
• A detailed description and 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
• 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.
• A discussion of event rates and contingency plans if the effect size or event rate is underestimated
• Participant follow-up procedures

Supporting Data. Describe the formative clinical studies (including any pilot studies) that are the basis for the proposed clinical trial. Include other research as appropriate to demonstrate that the approach chosen is justified. 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.

Letters of Support: Letters of support from clinicians or clinical department chairs whose support are necessary to the successful conduct of the trial should be provided.

If partial funding is to be provided by sources other than NHLBI, provide Letter(s) of Support signed by an authorized organization representative (AOR).

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

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Blank copies of the consent forms must be included in the Appendix. The consent forms must contain the appropriate information to define risks and benefits of the study.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics

2.1 Conditions or Focus of the Study

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

2.2 Eligibility Criteria

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

2.4 Inclusion of Women, Minorities, and Children

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

2.5 Recruitment and Retention Plan

The Recruitment and Retention Plan should address: 1) the expertise of the individual(s) responsible for screening, approaching and consenting potential participants; 2) engagement of patient advocacy groups; 3) the process for identification and screening of study participants; 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) participant retention and adherence strategies; 7) the safeguards for vulnerable populations as appropriate (e.g., children, pregnant women); 8) possible competition from other trials for study participants; 9) engagement of the clinical community(ies) that will play a critical role in the recruitment and retention; 10) recruitment of groups for cluster-randomized trials;

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

2.7 Study Timeline

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

Overall Study Timeline. Include estimated time of study duration (in months) including but not limited to when: (a) the study opens to enrollment; and (b) final transfer of the data to the DCC will occur. The study timeline should include a description of key milestones that need to be met throughout the lifecycle of the clinical trial (UG3 and UH3 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. The aim of the CCC milestone plan is to describe the milestones that need to be met by the CCC in coordination with the activities of the DCC.

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 UH3 phase is predicated on the successful completion of the milestones proposed and peer-reviewed for the UG3 phase of the application.

The milestone plan should include key milestones that need to be met during the UG3 phase to allow for successful launch of the full trial in the UH3 phase of the clinical trial. The overall enrollment and site participation expected by the end of the UG3 phase will be agreed upon between the investigators and the NHLBI prior to an award. It is generally expected that at least one participant will be enrolled by the end of the UG3 phase as well as about 25% of participating sites activated so that accrual targets can be met on time during the UH3 phase. The milestone plan also needs to describe the milestones that need to be reached in the UH3 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). CCC milestones of particular interest during the UG3/UH3 phases should include but are not limited to:

• Complete finalized clinical protocol
• Finalize informed consent(s) and, if applicable, assent forms
• Agreements in place for product supply (if applicable)
• Comprehensive laboratory plan
• Pharmacy/Laboratories Identification (as applicable)
• Contracts/Third Party Agreements (if applicable)
• Training of sites
• Final Management/Communication Plan
• Final Data and Safety Monitoring Plan
• Site Performance Plan
• Data Completeness and Quality Monitoring Reporting Plan
• Completion of regulatory approvals
• 25% of sites activated
• Enrollment of the first subject during the UG3 period
• UG3/UH3 transition meeting
• 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(s) 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

Enrollment into the clinical trial is expected to begin in the UG3 phase to allow for an evaluation of early enrollment feasibility and the probability of successfully completing the trial on time and on budget. Near the end of the UG3 phase, NHLBI will conduct an administrative review of the extent to which milestones (including enrollment milestones) have been met. If trial performance is deemed to be sufficient, the UH3 phase will be awarded subject to NHLBI funding availability. NHLBI will conduct at least two administrative reviews to determine progress toward achievement of milestones included in the mutually agreed upon milestone plan: the first towards the end of the UG3 phase, and the second within the first two years of the UH3 phase. Milestones and timelines for the CCC UH3 phase may be revised and finalized at the time of the UG3/UH3 transition meeting. Investigators and NHLBI will review and mutually agree upon a final revised UH3 milestone plan that will be included in the Terms and Conditions of the UH3 grant (if awarded).

Section 3 - Protection and Monitoring Plans

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

If Yes, describe the single IRB Plan

The information provided for the Single IRB plan must be the same as that provided in the collaborating DCC application.

3.3 Data and Safety Monitoring Plan

The information provided for the Data and Safety Monitoring Plan must be the same as that provided in the collaborating DCC application. 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:

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

Section 4 - Protocol Synopsis

4.1 Brief Summary

Include protocol title. Summary must represent the protocol that will be implemented at the sites.

4.2.a Narrative Study Description

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

4.2.c Interventions - Description

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. Specify criteria for intervention discontinuation and stopping guidelines.

4.4 Statistical Design and Power

As an attachment, include a brief statement indicating that the CCC has worked closely with the DCC to ensure that the number of expected subjects, the expected effect size, the power, and the statistical methods (with respect to each outcome measure) have been adequately addressed. In addition, clearly state that the Statistical Design and Power attachment is being submitted in its entirety as a part of the collaborating DCC application.

4.6 Will the study use an FDA-regulated intervention?

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

Provide evidence of prior communications (letters/emails) and/or the outcomes pre-IND or pre-IDE meeting, with the FDA. If the protocol is exempt from an IND/IDE and, 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 6.

4.7 Dissemination Plan

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

The dataset 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.

Section 5 - Other Clinical Trial Related

5.1 Other Clinical Trial-related Attachments

Attachments listed below must be provided or the application will not be peer reviewed.

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

The table columns must include:

Column A: clinical trial title

Column B: applicant's role in the trial

Column C: a brief description of the trial design

Column D: planned enrollment

Column E: actual enrollment

Column F: number of sites

Column G: whether the trial(s) were completed on schedule or not

Column H: publication reference(s)

2. CCC Project Management Plan: A Project Management Plan must be provided as an attachment called "CCC 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 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 UG3 and/or UH3 milestones;
• Key methodology and standard operating procedures governing resource management, study deployment, operations/execution, and study closure;
• How the project management team, in collaboration with the DCC, will resolve fiscal and logistical issues in a timely manner including plans to pro-actively evaluate and prioritize study risks and issue corrective responses;
• Processes required for orderly project closure including how 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.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

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

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

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

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

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

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

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

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.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization's profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 8 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.

This policy applies when the combined budget for the collaborative DCC and CCC applications exceeds $500,000 in direct costs in any year.

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

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research 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.

For this particular announcement, note the following:

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

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

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

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Specific to this FOA:

If the primary outcomes of the trial are achieved, how critical will the information be with regard to addressing the evidence gap and advancing knowledge of theory and practice? How likely is it that the trial results will contribute critical clinical knowledge? How likely are the results to contribute to the improvement of clinical care?

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

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Specific to this FOA

How strong is the Clinical Trial Experience attachment in demonstrating the expertise of the personnel to conduct the proposed trial? How well defined are their roles and responsibilities? What evidence is provided to ensure that the clinical site will employ the appropriate personnel to recruit subjects and design/implement the clinical protocol? How strong is the project management expertise represented among the key personnel? How strong is the leadership to coordinate a multi-site clinical trial? How adequate are the descriptions of roles/responsibilities of the Project Manager and other key personnel?

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

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

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

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Specific to this FOA

What strengths and weaknesses are there in the study design? How strong is the evidence for equipoise? How well does the Protocol Synopsis describe the necessary elements of the clinical trial and how likely is it that the protocol can be efficiently implemented at all of the sites? Are the endpoints clearly defined and how appropriately is the intervention characterized? Is the study timeline appropriate to complete the goals, meet the milestones, and address the scientific question(s)? Are adverse events appropriately captured and monitored? How effectively does the Project Management Plan attachment identify and describe risks to implementation and how well are contingency plans described? How strong is the discussion of event rates and are these realistic? Does the application propose to use existing available resources, as applicable? Does the application adequately address Good Clinical Practices (GCP), Good Laboratory Practices (GLP), and good Manufacturing Practices (GMP) compliance if applicable?

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

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Specific to this FOA

Are appropriate facilities and resources available to adequately coordinate a multi-site clinical trial? Is there strong evidence that the institutions have the available resources needed to conduct a multi-site trial at the CCC and the performance sites?

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

Study Timeline

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Specific to this FOA

Are the listed milestones for each phase appropriate for the goals of the project? To what extent are the milestones relevant, measurable, achievable, result-focused and time-bound?

Data and Safety Monitoring

Specific to this FOA

Is the proposed Data and Safety Monitoring Plan appropriate for the proposed clinical trial? What is the quality of the DSM Plan to monitor the site and participating facilities (labs, pharmacies)?

Do the consent forms contain the appropriate information to communicate risks and benefits of the study?

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

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

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

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

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

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

For Renewals, the committee will consider the progress made in the last funding period.

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

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.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

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

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NHLBI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

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

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

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

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.

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

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

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

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

Additionally, ICs may specify any special reporting requirements for the proposed clinical trial to be included under IC-specific terms and conditions in the NoA. For example: If the proposed clinical trial has elevated risks, ICs may require closer programmatic monitoring and it may be necessary to require the awardee to provide more frequent information and data as a term of the award (e.g., to clarify issues, address and evaluate concerns, provide documentation). All additional communications and information related to programmatic monitoring must be documented and incorporated into the official project file. 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 of all trials

whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/.

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

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

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

For trials using an FDA regulated product and requiring an IND or IDE application, the IND application or IDE application must be submitted to the FDA more than 30 days prior to when a grant award would be expected to be made so that documentation of the FDA determination regarding the application is available to NHLBI prior to a possible award. If the protocol is conducted under a non-US regulatory agency, equivalent determinations must be provided to NHLBI prior to award.

If progress is deemed satisfactory in the first phase, milestones and timelines for the second phase (execution of the trial) may stay the same as originally agreed upon. In certain cases the milestones and timelines may need to be revised and finalized prior to transitioning into the second phase of the award. If revision of the milestone plan is needed, investigators and NHLBI staff will review and mutually agree upon a revised milestone plan for the second phase of the trial.

If the DCC is terminated early for cause (i.e., failure to comply with terms and conditions of their award) it would leave the CCC unable to complete the objectives of its grant, but not because of any fault on the part of the CCC. In such a case, NHLBI will enter into negotiation with the CCC awardee to achieve mutually agreed-upon early phase-out of the award per 45 CFR 75.372.

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

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person's race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator's scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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

Cooperative Agreement Terms and Conditions of Award

Not The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75 and other HHS, PHS, and NIH grant administration policies.

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

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

The awardee PD/PI will have primary and lead responsibilities for the project as a whole, including research design and protocol development, participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, as well as collaborations with other awardees.

Upon completion of the project, awardees are expected to put their data into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community (see section 3 below "Collaborative Responsibilities").

Third Party support of the proposed research activity (if proposed, accepted and approved) will be incorporated as a Special Award Condition in the NoA. Awardees will be responsible for ensuring third party compliance and if the 3rd party support is no longer available, and not replaceable in a timely fashion negotiated phase-out of the award may occur.

Cost Share is not a requirement for this program; however, if cost share is proposed, peer reviewed and accepted by NHLBI it will become a Special Award Condition in the NoA.

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

The NHLBI Project Scientist will assist with development of research protocols, monitor patient recruitment and study progress, ensure disclosure of conflicts of interest, and ensure adherence to NHLBI policies. NHLBI will appoint the Data and Safety Monitoring Board (DSMB).

The NHLBI Project Scientist will serve on the Steering Committee and other study committees, when appropriate, as a non-voting member. The NHLBI Project Scientist may work with awardees on issues coming before the Steering Committee such as recruitment, protocol development, follow-up, quality control, adherence to protocol, possible changes to the protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment.

In addition to the Project Scientist, a separate NHLBI Program Official will be responsible for the normal program stewardship of the cooperative agreement, and will be in the Notice of Award. However, NHLBI may elect to have a dual-role approach where a single individual may act as both the NHLBI Project Scientist and Program Official. Final decision-making authority on matters of budgetary and funding actions, grants management actions, and management of intellectual property issues is assigned to NHLBI staff other than the Project Scientist. The responsibility for final decision making may reside with Senior Institute management, separate organizational components and/or oversight committees. Because it is anticipated that the Program Official will participate in activities that rise to a level of involvement (i.e., additional role as Project Scientist) that results in conflicts of interest, for example, co-publication, other staff members such as direct line supervisors and/or other Senior NHLBI Program management staff will serve as agency Program Officials and will be responsible for the normal scientific and programmatic stewardship of the award.

Final decision-making authority on matters of budgetary and funding actions, grants management actions, and management of intellectual property issues is assigned to NHLBI staff other than the Project Scientist. The responsibility for final decision making may reside with senior Institute management, separate organizational components and/or oversight committees. Because it is anticipated that the Project Scientist will participate in activities that rise to a level of involvement that results in conflicts of interest, for example, co-publication, etc., other staff members such as direct line supervisors and/or other Senior NHLBI Program management staff will serve as agency Program Officials and will be responsible for the normal scientific and programmatic stewardship of the award.

The NHLBI policy on authorship and manuscript review of NHLBI sponsored extramural research protects against conflicts of interest with the Program Officer.

An independent Data and Safety Monitoring Board (DSMB) will be established to oversee participant safety in the clinical trial and provide overall monitoring of interim data and safety issues. As part of the collaborative activities under this cooperative agreement, the NHLBI will collaborate with the awardees to appoint and/or agree upon a single DSMB for monitoring the clinical trial. The DSMB may be appointed by the NHLBI, or with the approval of NHLBI, the DSMB could be an institutional DSMB. At the first meeting in the UG3 phase, the DSMB will review the awardee's protocol and potentially recommend modifications. Subsequently, the DSMB will monitor and review recruitment, adverse events, data quality, outcome data, and overall awardee performance. The DSMB has the responsibility to review interim data and final data, and recommend whether the protocol should be modified, and, at each meeting, whether the study should be continued or should be terminated early. An NHLBI scientist other than the NHLBI Program Official or Project Scientist will serve as Executive Secretary to the Board. Because the DSMB serves as an independent group advisory to the NHLBI, study investigators shall not communicate with DSMB members regarding study issues, except as authorized by the Board's Executive Secretary.

NHLBI will conduct at least two administrative reviews to determine progress toward achievement of milestones included in the mutually-agreed upon milestone plan, one towards the end of the UG3 phase, and one within the first two years of the CCC UH3 phase. If either the DCC or the CCC milestones have not been satisfactorily met, subsequent funding years may not be approved.

The NHLBI reserves the right to phase-out or curtail the study (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable protocol, (b) substantial shortfall in subject recruitment milestones, core milestones mutually agreed upon by the recipient organization and PD/PI and the NHLBI, consortium participation and collaboration with other awardees, (c) substantive changes in the agreed-upon methodologies and tools with which NIH cannot concur, (d) human subject ethical issues that may dictate a premature termination, or (e) results that substantially diminish the scientific value of study continuation.

Areas of Joint Responsibility include:

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

Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The Principal Investigator of this award will be required to participate in periodic meetings and telephone conference calls with other investigators performing large-scale genome wide association studies supported by the NHLBI. These meetings and calls will be arranged by NHLBI staff to promote sharing of information among investigators regarding state of science technologies, data management techniques, analytical strategies and tools, and data sharing. Support or other involvement of industry or any other third party in the study (e.g., participation by the third party; involvement of study resources or citing the name of the study or NHLBI support; or special access to study results, data, findings or resources) may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NHLBI.

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

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

Dispute Resolution:

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

Multiple PD/PI Dispute Resolution

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

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

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

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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

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

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 registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Division of Blood Diseases and Resources

Nancy DiFronzo, PhD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0065
Email: [email protected]

Division of Cardiovascular Sciences

Yves Rosenberg, MD, MPH
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0550
Email: [email protected]

Division of Lung Diseases

Gail Weinmann, MD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0233
Email: [email protected]

Keary A. Cope, PhD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0287
Email: [email protected]

Anthony Agresti
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8014
Email: [email protected]

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.