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

Background

According to the American Heart Association’s most recent report (Heart Disease and Stroke Statistics 2017 Update), approximately 92.1 million American adults are living with some form of cardiovascular disease, including the after-effects of stroke. At least half of this population is age 60 years or older. Total health expenditures and lost productivity costs of cardiovascular diseases and stroke in the US averaged approximately $316.1 billion annually in 2012 to 2013 and are projected to be approximately $804 billion in 2020. Cardiothoracic surgical treatments have been instrumental in addressing many of the most prominent cardiovascular conditions, including coronary artery disease, congestive heart failure, atrial fibrillation (AF) and valvular disease, among others. Coronary artery bypass grafting (CABG), cardiac valve repairs, mechanical circulatory support devices, and arrhythmia surgery have extended survival and improved quality of life for many patients. However, the accelerating pace of innovation in surgical practice, including the utilization of new approaches and technologies and the extension of surgical approaches to older patients with greater co-morbidities, continues to outpace the ability of randomized controlled trials (RCTs) to provide an evidence base for establishing improved outcomes and benefit. Additionally, the advances made in interventional cardiology (e.g., transcatheter-based interventions), particularly over the last decade, compound this issue.

The primary goal of the Cardiothoracic Surgical Trials Network (CTSN) is to design, conduct, and analyze multiple, collaborative clinical trials and studies that evaluate novel products, surgical interventions, and related management approaches, for the treatment of cardiovascular disease in adult patients. An important objective of the CTSN is to continue to increase the efficiency of clinical research by providing a clinical laboratory in which multiple clinical trials can be conducted without having to create a new infrastructure for each one. This initiative proposes a transition from a traditional research network model to a flexible clinical trials platform accessible to the research community, industry, foundations, professional societies, and international research entities.

The CTSN has been a successful and impactful clinical research enterprise since 2007, building a cadre of cardiac surgical trials investigators, and a platform for broad collaboration among allied specialties, foundations, professional societies, and industry. Currently the CTSN includes cardiac surgical academic centers across the US, Canada, and Germany.

The CTSN has been instrumental in addressing scientific and public health questions in cardiothoracic surgery, and has proven to be an ideal interdisciplinary infrastructure to link cardiothoracic surgeons with other medical research specialties, including neurology, anesthesiology, and all areas of cardiology. Moreover, the CTSN is moving into the new area of implementation research, to go beyond adding to scientific knowledge to translate and sustain benefits to populations. The inclusion of implementation research is needed to determine optimal strategies for delivering RCT-proven effective therapies and cardiac surgical approaches to populations, in order to improve CV outcomes in communities.

The key achievements that speak to the importance of this Network include completion and reporting of six RCTs and three large observational studies and multiple ancillary and sub studies, with over 2,000 randomized patients and more than 14,000 observed patients participating. These trials have been conducted efficiently and at considerable cost savings to the government, as compared to individual investigator-initiated or industry-sponsored trials. The Network has a broad research agenda that includes valvular heart disease, arrhythmias, heart failure, coronary artery disease, and reducing complications of surgery. The trials have spanned early translation, RCTs in the comparative effectiveness realm to large observational studies. The Network has produced numerous high impact publications. Findings from the CTSN trials have advanced knowledge and influenced professional society guidelines in the US, Canada and Europe.

Previous Network studies have fallen into three domains: (1) randomized clinical trials in the comparative effectiveness arena; (2) exploratory and proof of concept trials; and (3) observational studies directed at quality improvement. Three trials are currently ongoing as are several ancillary studies. There is ongoing consideration of new trial concepts from both inside and outside the CTSN as well as efforts to develop new protocols of clinically meaningful questions that address important public health issues. Additional CTSN trial information can be found at http://www.ctsurgerynet.org/.

Purpose

This Funding Opportunity Announcement (FOA) seeks multi-PD/PI applications for Linked Clinical Research Centers (LCRCs) to support the CTSN. The National Heart, Lung, and Blood Institute (NHLBI) expects applications with highly innovative clinical trial strategies, novel approaches to patient recruitment and retention for challenging cardiothoracic surgical trials, and the ability to build clinical research capacity in areas of need. The LCRCs add a new paradigm to the CTSN model. Each LCRC will consists of an experienced academic cardiac surgical clinical trial site ("primary site") linked with a less experienced academic cardiac surgical clinical site in a high cardiovascular disease burden area ("affiliate site"), and will also include a Clinical and Implementation Research Skills Program which will be integrated across the two sites. It is expected that a single application will be proposed with two PDs/PIs; one PD/PI from the primary site and one PD/PI from the affiliate site.

An LCRC primary site is expected to demonstrate a strong track record of prior trial performance and clinical research mentoring; the provision of a developmental platform for junior clinical researchers and implementation scientists; and support for novel techniques and strategies to disseminate study results to impact the care of individuals and improve the burden of disease.

An LCRC affiliate site must have conducted fewer than three NHLBI-funded randomized controlled trials per year in cardiac surgery and received less than $3 million in NHLBI total grant funding to the institution in 2017. The affiliate site should be one that would benefit from research mentoring and a collaborative clinical research opportunity, and be located in a high cardiovascular (CV) disease burdened part of the US or Canada to build capacity in these areas. For the purposes of this FOA, a high CV disease burdened area is broadly defined as an area or region of the US or Canada that has a preponderance of CV disease including hypertension, obesity, diabetes, and stroke, or other unique disease burden characteristic. These areas might include the geographic regions incorporating the Mississippi Delta, Appalachia, and the Stroke Belt (South East US), Stroke Buckle (coastal plains areas of the Carolinas and Georgia), Newfoundland/Labrador (Canada), rural or inner-city locales, or involve predominantly minority or low socioeconomic status populations.

A separate solicitation seeks applications for a Limited Competition: Data Coordinating Center (DCC) that will support the Network (RFA-HL-19-010).

Objectives

To achieve budget efficiencies, while at the same time enhancing the output and scope of the enterprise, the CTSN infrastructure will be modified to include a new clinical research paradigm that will be comprised of an experienced academic cardiac surgical clinical trial site ("primary site") linked with a less experienced academic cardiac surgical clinical site ("affiliate site") in a high cardiovascular disease burden area as a multi-PD/PI application. The intent is for the experienced primary site to mentor the new, less experienced affiliate site in the conduct of RCTs, including but not limited to: screening, enrolling, randomizing and retaining participants, as well as obtaining informed consent, capturing timely and complete data and maintaining complete, current auditable records. This will provide an opportunity for the affiliate site to collaborate on impactful cardiac surgical trials and thereby expand clinical research capacity in areas where it is most needed. Funds to support protocol costs associated with the RCTs will be provided through the CTSN DCC award (RFA-HL-19-010), outside investigator-initiated grants, industry and foundations.

An important component of the new CTSN paradigm is that it will establish a develomental platform for the next generation of clinical and implementation researchers. The NHLBI expects that LCRC applications will propose a plan for a Clinical and Implementation Research Skills Program (CIRSP) to expand the skills and knowledge of junior investigators who have the potential to transition into research leadership roles. It is anticipated that the CIRSP will be integrated across both the primary site and the affiliate site. Applications that propose to address needed diversity within the cardiac surgical clinical research workforce by proposing to include underrepresented minorities are of high programmatic interest.

This FOA seeks applications for LCRCs with the ability to:

• Work cooperatively within CTSN to design impactful cardiothoracic surgical trials and to conduct the trials with rigorous good clinical practice
• Identify, enroll and retain participants in sufficient number to complete trials in a timely and efficient manner
• Interface with a variety of cardiovascular databases and registries and incorporate these resources into innovative trial designs
• Assemble the resources necessary for optimal conduct and support of CTSN activities and studies
• Integrate questions and endpoints into the design of RCTs that can inform subsequent implementation activities to enhance adoption by the surgical community post study and bolster translation of findings
• Provide skills development opportunities in the conduct of cardiothoracic surgical trials and clinical research and implementation science, contributing to the development of the next generation of clinical and implementation researchers

Network Organization and Governance

In this funding cycle, the CTSN will be a cooperative Network of up to five academic LCRCs, a DCC, a rotating Network Chair (cardiothoracic surgeon) and rotating Co-Chair (cardiologist), a Vice Chair for Strategic Development, a Vice Chair for International Collaboration, and NHLBI.

Linked Clinical Research Centers (LCRCs) are responsible for proposing and developing protocols, recruiting participants, entering data into the web-based data entry system, assuring good clinical practice, developing skills of junior investigators in both clinical research and implementation science, and disseminating research findings. All LCRCs are required to participate in a cooperative and interactive manner with one another and with the Data Coordinating Center.

The Data Coordinating Center, described in more detail in RFA-HL-19-010, coordinates, administers, and supports all Network clinical research, operational, and administrative and statistical activities. Briefly, these activities include but are not limited to supporting protocol development; developing manuals of procedures and electronic case report forms; providing sample size calculations, statistical advice, common questionnaires, and data analysis; supporting manuscript preparation; and providing overall study coordination and quality assurance, including support for the Data and Safety Monitoring Board (DSMB), the Protocol Review Committee (PRC), the Steering Committee, and other standing committees meetings/conference calls. Funds to support execution of the protocols at the clinical centers are part of the DCC cooperative agreement (hereafter referred to as award ) and are distributed to the clinical centers (both LCRCs and Consortium Centers) by the DCC on a per-patient basis and according to the approved protocol budgets. For some protocols the DCC conducts long-term patient follow-up.

Consortium Center (CC) sites are subcontracted through the DCC to enhance trial enrollment, protocol development, manuscript preparation, and other key Network activities. These sites are reimbursed on a per-capita basis and do not receive infrastructure funding. It is anticipated that up to 40 CCs in the US, Canada, and Europe will participate.

The Steering Committee (SC) is the main governing body of the CTSN. The SC comprises the Principal Investigators (PDs/PIs) from the LCRCs and the DCC, the Network Chair, co-Chair, Vice Chairs, and NHLBI staff. Voting members of the SC include the Chair (a cardiothoracic surgeon) and Co-Chair (a cardiologist), the Vice Chairs and the remaining PD/PIs of the LCRCs and DCC, and the NHLBI Program Official. The Chair and Co-Chair positions may be rotated among the LCRC Investigators and others as appropriate. The SC has primary responsibility for the general organization of the CTSN, the approval of clinical protocols and protocol changes, the conduct and monitoring of studies, and the expeditious reporting of study results. All major scientific and administrative decisions are determined by majority vote of the SC, which meets in-person an average of twice a year and by teleconference on a monthly basis. This Committee ensures that all decisions are reported to the Investigators Committee.

Committees and Subcommittees of the SC, such as the Operations Committee and subcommittees for Protocol Development, Protocol Operations, Publications and Biorepository have been established and may be continued or added to at the discretion of the SC.

The Investigators Committee (IC) consists of all CTSN investigators and study coordinators from the LCRCs and Consortium Centers, staff members from the DCC and NIH, and the CTSN Chair, co-Chair and Vice Chairs. The Network Chair, Co-Chair and Vice-Chairs are named by NHLBI to oversee and guide SC and IC activities. The IC meets in-person an average of twice a year and by teleconference on a monthly basis. Subcommittees are established as necessary and membership includes physician and nurse investigators from the LCRCs and CCs, representatives from the DCC, and members from NIH.

The NHLBI is responsible for organizing and providing overall support for the CTSN. The NHLBI Program Office and Office of Grants Management are responsible for the federal stewardship of the award (management, financial and administrative oversight). In addition to regular award oversight, the NHLBI Project Scientists will be involved substantially with the awardees as a partner, consistent with the Cooperative Agreement mechanism. The NHLBI will appoint the Protocol Review Committee, the Data Safety and Monitoring Board, and the Network Chair, Co-Chair, and Vice Chairs. The Study Chairs are independent of the DCC and are responsible for ensuring that there are well-documented policies and procedures in place to guide all aspects of Network activities and operation. In collaboration with NHLBI staff, the Chairs facilitate Network activities, oversee its functions, and conduct SC and IC meetings.

An independent Protocol Review Committee (PRC) is appointed by and advisory to the NHLBI. It consists of a chairperson and clinicians and scientists with expertise in basic and clinical cardiothoracic surgery research, clinical trial design, biostatistics, enabling technologies, outcome measures, and other areas of expertise as needed. The PRC will evaluate protocols approved by the SC based on the following criteria: importance of the question to be addressed, the scientific merit of the experimental design and approach, feasibility, appropriateness for the Network, and consistency with NHLBI mission and policies. All new study protocols performed by the CTSN that have not previously been peer reviewed must be approved by the PRC before referral to the Data and Safety Monitoring Board.

An independent Data and Safety Monitoring Board (DSMB) is appointed by and advisory to the NHLBI, in accordance with established policies to ensure data quality and participant safety. All CTSN protocols must be approved and monitored by the DSMB, generally after their approval by the PRC, or peer review. The DSMB will be responsible for providing independent advice to the NHLBI regarding the progress of each trial and the appropriateness of continuing each study. The DSMB will meet approximately every six months, with interim meetings as necessary.

An independent External Review Committee with expertise in areas such as cardiothoracic surgery, cardiology, cellular therapy, as well as clinical trial management and regulatory oversight will review the CTSN during the fourth or fifth year of the Network and advise the NHLBI (and Steering Committee) on opportunities to improve operations and future scientific directions.

Specific Areas of Research Interest and Experimental Approaches Being Sought

This FOA focuses on clinical studies in the proof-of-concept/early feasibility/early translation area, RCTs in the comparative effectiveness realm, and innovative trials leveraging registry data and electronic medical records, among others approaches. The Network has identified a range of timely and clinically important questions in cardiac surgery, which will require further development. Clinical trial/study protocols being contemplated and/or developed in the Network fall into two categories: 1) actively underway and 2) ready for implementation.

The following three high-priority research questions are actively underway by the Network at the current time: 1) long-term neurological and cognitive outcomes following AVR; 2) bundled payment and 90-day readmissions after CABG surgery; and 3) patient-centered outcomes and the creation of a patient alliance.

The Network has identified four high-priority research areas to develop trial protocols that may be ready for implementation after the start of the funding period:

1. Preventing and Managing Thrombo-Embolic Risk: In follow-up of the CTSN Neuroprotection Trial (NCT02389894), the Network investigators in conjunction with Industry (should there be funding interest) are considering developing cerebral embolic protection trial protocols for novel interventions, such as second-generation embolic protection devices, new drugs and/or biologicals, such as nitric oxide.

2. Anticoagulation Management Strategies for Bioprosthetic Valves and AF: Many questions remain regarding the post-operative management of several cardiac surgical patient subsets, particularly those with AF and/or valve repairs or replacements. A future CTSN trial may evaluate when it is safe to start an alternative direct oral anticoagulant (e.g., apixaban) in non-mechanical heart valve patients with an indication for anticoagulation after CT surgery. Patient groups could include those with post-operative AF and/or bioprosthetic heart valve replacements or annuloplasty repairs. A particular area of intense interest involves the recent recognition of bioprosthetic leaflet thrombosis and the comparative efficacy of antiplatelet versus anticoagulant agents for its prevention and treatment.

3. Valvular Heart Disease: Several important trials can be developed in the valvular heart disease realm. A trial focused on relative merits and long-term outcomes of SAVR versus TAVR in bicuspid aortic valve disease is under consideration. Bicuspid aortic valve disease has been excluded from TAVR pivotal trials, but TAVR is increasingly used in this population, despite a relatively weak evidence base. Another potential study in collaboration with TVT investigators might seek to evaluate QOL after SAVR versus TAVR, leveraging registry data.

4. Circulatory Assist Devices and Cardiac Regeneration: The Network has built expertise in conducting stem cell trials in LVAD patients, and could conduct a follow-up trial of the nearly-completed LVAD MPC II Trial (NCT02362646), or expand our portfolio by evaluating new biologicals, such as cardiosphere-derived cells, exosomes, or human embryonic stem cells derived from cardiomyocytes. Optimizing outcomes in patients receiving circulatory support alone remains an important goal. A randomized trial of a constellation ( bundle ) of management strategies versus standard therapy to reduce complications in LVAD patients is under consideration. Finally, cardiogenic shock remains a high-mortality condition, and the Network investigators are exploring trials of both ECMO and percutaneous VADs to improve the fate of this patient population.

Multiple trials will be conducted during the project period. Trial protocols that are under development in the CTSN will be considered for Network funding by the CTSN Steering Committee once the funding period for this FOA has commenced. It is anticipated that each protocol will be implemented in all of the LCRCs and in the Consortium Centers that have the appropriate patient populations. Specific protocol reimbursement will be determined for each protocol and negotiated with the participating centers.

During this award cycle, trials will be supported with CTSN funds, individual investigator-initiated grant awards and through industry and foundation collaborations. While a finite number of trials will be supported directly through CTSN funding, the Network expects to complete between 7-10 trials due to the utilization of new revenue streams. Outside independent investigators and small businesses wishing to collaborate with the CTSN will have the opportunity to submit grant applications through the NHLBI multi-center clinical trial FOAs (PAR-18-407 and PAR-18-410) which will in turn support CTSN infrastructure and provide protocol reimbursement costs. Other entities, such as industry, foundations and international research entities who share scientific research priorities, similarly will be encouraged to approach the CTSN Leadership to sponsor/fund and conduct collaborative trials and studies. Collaborations with the Patient Centered Outcomes Research Institute (PCORI) and the Centers for Medicare and Medicaid Services (CMS) addressing patient-centered outcomes, patient advocacy, and cost effectiveness will be strongly encouraged. Cardiovascular device trials in collaboration with the FDA Center for Devices and Radiological Health utilizing innovative approaches and statistical designs will also be strongly encouraged.

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 from 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:

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

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
• Foreign Institutions and foreign components based only in Canada

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply but only if they are based in Canada.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply except for Canadian components.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the 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.

Multi-PD/PI applications are required in response to this FOA. It is expected that a single application will be proposed with two PDs/PIs; one PD/PI from the primary site and one PD/PI from the affiliate site. Applications that do not use a Multi-PD/PI application will be considered non-compliant and will not proceed to peer review.

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
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7214, MSC 7924
Bethesda, MD 20892-7924 or Bethesda, MD 20817 (express mail)
Telephone: 301-435-0270
Email: NHLBIChiefReviewBranch@nhlbi.nih.gov

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

The Research Strategy must consist of the following subsections with the indicated page limits:

A. Clinical and Clinical Research Capabilities, required; 12 pages.

B. Mentoring Plan for the Affiliate Site, required; 12 pages.

C. Clinical and Implementation Research Skills Program Plan, required; 6 pages.

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.

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: Applications should include sources of research support through Clinical and Translational Science Awards (CTSAs), departments, institutions, etc. Applications from institutions that have a CTSA funded by NIH should identify the resources that could be available to support the proposed LCRC, commenting particularly on those aspects that will enhance their programmatic and scientific efficiency. In such a case, a description of the CTSA and how the applicant proposes interacting with it should be included. Given the fiscal limitations and costs of clinical research, applicants with additional research support for clinical studies or projects are of special interest.

Other Attachments:

The application must include the following documents, uploaded as separate pdf files with the names indicated below. The attachments listed below must be provided or the application will not be peer reviewed.

1. Population Available for Cardiac Surgical Clinical Trials and Studies (Required)

The filename "Population Cardiac Trials.pdf" must be used and will be reflected in the final image bookmarking for easy access for reviewers.

For both the primary site and the affiliate site, detail the following per year for 2015 through 2017:

• Age, demographics and proximity to the institution of cardiac surgical patients
• Number of the following cardiac surgical procedures:
• Open heart cardiac surgical procedures
• Minimally invasive cardiac procedures
• Single CABG
• CABG with other procedures
• Mitral valve repairs and replacements, aortic valve repair and replacements
• Placement of mechanical circulatory support devices
• Number of TAVR, both with and without embolic protection
• Number of Mitraclip procedures

2. Clinical Research History (Required)

Applicants must provide a table that demonstrates both the primary and affiliate sites' prior experience with multi-center collaborative clinical research in cardiac surgery and cardiovascular disease by listing all trials and studies conducted at both the primary and affiliate site from 2015 through 2017. The table must be provided as an attachment with the filename "Clinical Research History.pdf". The table columns should include:

• Column A: name of the study/trial
• Column B: a brief description of the study/trial
• Column C: funding source(s) (NIH, industry and/or foundation/other)
• Column D: time from initiation to completion of contracting process
• Column E: time from protocol receipt by the trial PD/PI (or time protocol finalized if local trial) to IRB approval
• Column F: time from IRB approval to first patient enrolled
• Column G: planned monthly enrollment for the site
• Column H: actual monthly enrollment at the site.

Note: A scorecard with the above information must be provided and certified by the DCC for CTSN trials.

3. Affiliate Site Unique Characteristics (Required)

The filename "Affiliate Site.pdf" must be used and will be reflected in the final image bookmarking for easy access for reviewers.

The following documentation and descriptions of the affiliate site must be provided:

• High burden of cardiovascular disease (e.g., diabetes, stroke, and/or obesity) or unique patient population
• Any unique population or features associated with the affiliate site that would make a compelling case for inclusion in the CTSN.
• Documentation of total NIH research funding in 2017.
• Number and name of cardiac surgeons and cardiologists

4. Data Integration Capabilities (Required)

The filename "Data Integration.pdf" must be used and will be reflected in the final image bookmarking for easy access for reviewers.

• Describe the site's involvement with various cardiac surgical and cardiovascular databases and registries. Demonstrate how interactions with these databases and registries may be leveraged to facilitate clinical research through the CTSN.
• Describe participation in one or more national quality improvement activities. Specify which system and provide a detailed description of variables collected, quality control, and management of the data system.
• Describe efforts to integrate data across multiple data sources to create resources for research. Data integration efforts may be intra-institutional and/or inter-institutional.
• Describe what institutional technical and personnel capabilities exist at the site to support data integration efforts.
• Provide an illustrative use case for how an integrated data resource can support a clinical trial.

5. Special Strengths (Required)

The filename "Special Strengths.pdf" must be used and will be reflected in the final image bookmarking for easy access for reviewers.

• Describe special or unique strengths that may be relevant to CTSN research. This can include state-of-the art scientific capabilities that may be shared or may be available and which may develop and expand the scientific productivity of the CTSN.
• Special administrative strengths or experience and participation in administrative aspects of clinical research (e.g., IRBs, data and safety monitoring committees, advisory board for clinical research, clinical research committees) should be highlighted.

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

The PDs/PIs must have expertise in adult cardiac surgery and must describe their clinical, research, administrative and academic commitments in the Biosketches.

Collaborators must be designated at both the primary and the affiliate site and be either a cardiologist or neurologist. In addition, Collaborators must describe their experience participating in collaborative clinical trials and their clinical, research, administrative and academic commitments in the Biosketches.

A clinical research Nurse or Study Coordinator must be designated at both the primary and the affiliate site, and an accompanying biographical sketch must be included.

A Director for the Clinical and Implementation Research Skills Program (CIRSP) must be designated and an accompanying biographical sketch must be included for this role. The CIRSP Director, in addition to clinical research mentoring experience, must demonstate familiarity with integration of late-stage (T4-translation to populations) implementation.

All instructions in the SF424 (R&R) Application Guide must be followed. LCRC awards will be for core infrastructure costs only and may not exceed $400,000 in direct costs per year. NHLBI strongly encourages that the following staffing plan be implemented.

• Primary site PD/PI: at least 1.2 person-months (10 percent effort over 12 months) effort, and co-Investigator at least 1.2 person-months (10 percent effort over 12 months) effort; co-Investigator must be a cardiologist or neurologist.
• Affiliate site multiple PD/PI support: at least 1.2 person-months (10 percent effort over 12 months) effort, and Collaborator at 1.2 person-months (10 percent effort over 12 months) effort; co-Investigator must be a cardiologist or neurologist.
• Clinical and Implementation Research Skills Program Director: up to 6 person-months (50 percent over 12 months); may be Primary Site PD/PI.
• Research or Nurse Coordinator: at least 9 person-months (75 percent effort over 12 months) at both primary and affiliate site.
• Additional Research or Nurse Coordinator or Research Assistant: up to 3 person-months (25 percent effort over 12 months) may be proposed at both primary and affiliate site.
• Travel: Up to 8 trips per Network team, as appropriate. In-person Steering Committee meetings are held twice each year. Meetings will take place in Bethesda, MD and other locations based on geographical distribution of the LCRCs. The PD/PI or designee and full-time Research or Nurse Coordinator are required to attend the meetings in their entirety.
• Clinical and Implementation Research Skills Program (CIRSP): A separate budget page for the CIRSP must be submitted and may request up to $100,000 in direct costs each year for the entire project period. Allowable costs include salary support for the CIRSP Director (up to 50%) and other senior investigators and staff participating in mentoring activities; travel costs for new investigators; supplies and equipment to support developmental activities; and costs for courses, seminars, workshops, and other activities directly related to the CIRSP program. All costs requested should be justified with respect to developmental activities and may not be used to supplement the costs of research proposed in the rest of the LCRC application. Salary support for the new investigators is neither needed nor allowable, since the CIRSP is intended to serve new clinical investigators who occupy positions and receive salary support from other sources.

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: Applicants must provide a description of the primary site's capabilities in multi-center collaborative cardiac surgical clinical trials and clinical research. Detailed knowledge of the conduct of multi-center randomized controlled clinical trials and studies in the field of cardiac surgery directed at cardiovascular disease must be demonstrated. The Research Strategy must contain the three sections (A-C) described below.

A. Clinical and Clinical Research Capabilities

• Using studies outlined in the "Clinical Research History.pdf" attachment (or other recent studies), describe up to five trials/studies that struggled with recruitment and/or retention of participants and how this challenge was handled, including lessons learned. In addition, describe up to five trials/studies that were a success.
• Discuss strategy for recruiting various types of populations into trials/studies, i.e., through use of social media, patient engagement, collaboration with foundations and patient advocacy groups.
• Without repeating information from individual biosketches, describe plans to ensure dedicated coordinator staff and other research personnel are acquired such as research echo technicians with experience in adult cardiac surgical and cardiovascular trials.
• Describe capabilities for patient recruitment on nights and weekends.
• Describe ability to engage in a central IRB model.
• Describe a plan to provide complete, accurate, and timely transmission of data to the CTSN DCC (described in RFA-HL-19-010). Describe processes for responses to data entry edits and audits, including suggested timelines for responses.
• Provide a detailed description of the clinical attributes of the program, including clinical services provided, availability of applicable subspecialists, non-invasive imaging capabilities, exercise laboratory, and neurologic assessment capabilities.
• Describe how implementation science/T4-type data collection will be integrated into future trial designs and plans for the ultimate translation and uptake of clinical findings to populations with high disease burden.

B. Mentoring Plan for Affiliate Site

• Provide a mentoring and management plan intended to support development of research experience and capacity at the affiliate site. This plan should include: supervision, skills development, in-service, certification, data handling, quality assurance, cost-effective management, and communication.
• Describe plans for expanding the capacity of the affiliate site in the conduct of cardiac surgical RCTs, including but not limited to: screening, enrolling, randomizing and retaining patients, as well as obtaining informed consent, capturing timely and complete data and maintaining complete, current auditable records and establishing collaborations across the institution with cardiologists, neurologists and anesthesiologists.
• Describe expected synergies between the primary and affiliate sites that will contribute to successful collaboration and strong participation in CTSN trial activities by both sites.

C. Clinical and Implementation Research Skills Program Plan

The CIRSP is intended for staff investigators at both the primary and affiliate sites with limited clinical research experience, including fellows and junior faculty members. Applications must:

• Describe plans for fostering the next generation of clinical researchers so that they are versed in late-stage (T4-translation to populations) implementation research.
• Propose a plan for recruiting high quality CIRSP participants, including recruitment of women and minorities; a description of the experience level of potential participants;
• Describe the needs or gaps for cardiothoracic surgeons/researchers that this program will address; the type of research-intensive experiences to be provided involving CTSN trials;
• Provide plans for skills development of participants (including didactic preparation) that will promote progress to more independent researcher status; the nature and extent of mentoring; a plan for coordinating activities and progress of participants across sites; coordination of activities of participating senior investigators; avoidance of overlap or duplication of existing opportunities at the applicant institutions; and development of evaluation measures for the success of the program.
• Detail the strategy for integration of late-stage (T4-translation to populations) implementation research skills development into the clinical research activities and outline how this effort will be targeted to impact CV disease burden. Partnership and collaborations between the CIRSP and professional societies, foundations, and private sources are strongly encouraged, as are leveraging of other resources at the LCRC institution and affiliated sites, CTSA infrastructure, DCC, as well as distance-learning opportunities. NHLBI has established a cadre of K12-level T4 Implementation Science research centers in 2017 which may offer an excellent opportunity to leverage their training and experiences in T4 implementation science research capabilities. Details about these K12 T4 centers can be accessed directly via this link.

Consortium/Contractual Arrangements: Applicants from the Primary site are required to link to an affiliate site. Documentation of this affiliation is mandatory as is a mentoring plan (see Research Strategy Section/Mentoring Plan for Affiliate Site above). Collaboration and interaction among institutions must be clearly documented in the application including the investigator responsible at the collaborating site(s).

Management plans including supervision, training, certification, data handling, quality assurance, cost effective management, and communication are required for linked centers.

Letters of Support: Letters of institutional and departmental support for participation in the CTSN are required, which must include assurances that in the case of studies competing for the same patient population, NHLBI-funded studies will take priority. Applicants must discuss their willingness, and that of their institutions involved, to accept fee for service reimbursement from the DCC for patient care costs as approved by the Executive Committee and NHLBI for each protocol.

Applications from institutions that have a CTSA funded by NIH must include a letter of agreement from either the CTSA Program Director or PD/PI.

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:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) 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 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

2.4 Inclusion of Women, Minorities, and Children

Describe plans to include both genders, and racial and ethnic minorities as appropriate for the scientific goals of the research within the CTSN.

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.

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.

Specific to this FOA:

• Awards issued under this FOA will be incrementally funded for up to 7 years. These will not be Multi-Year Funded.
• Awards issued under this FOA will be excluded from automatic carryover. All carryover actions will require NHLBI prior approval.
• Awards issued under this FOA will not be provided the authority to automatically extend the final budget period. All extensions, including the first, will require NHLBI prior approval.
• Awards issued under this FOA will be excluded from SNAP.

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 and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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

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.

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?

Specific to this FOA:
How strongly does the application demonstrate that the Linked Clinical Research Center will be able to successfully conduct randomized controlled trials that are meaningful and impactful to cardiovascular disease and cardiac surgery and translate those findings in areas of high disease burden?

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?

Specific to this FOA:
What experience do the PDs/PIs have in multi-center research that makes the site likely to succeed in the Network? How well does the application demonstrate that the Linked Clinical Research Center has the expertise to recruit and retain the population under study? How strong is the applicant's prior experience with multi-center collaborative clinical research in adult cardiac surgery? Does the application demonstrate that the Linked Clinical Research Center and its research team will be able to achieve the goals of the CTSN? Do the PDs/PIs demonstrate an adequate track record of conducting multi-center clinical trials and in managing multi-disciplinary research teams? Does the research team express willingness to work as part of the CTSN, with the DCC and with the NHLBI Project Scientists? How well does the applicant describe adequate involvement of the Research or Nurse Coordinator? How well does the Clinical and Implementation Research Skills Development Program Director demonstrate adequate engagement across the Linked Clinical Research Center?

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?

Specific to this FOA:
Does the application include state-of-the art scientific capabilities that may develop and expand the scientific productivity of the CTSN?

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?

Specific to this FOA:

What potential problems, alternative strategies, and benchmarks for success are most likely to advance the clinical trial and collaborative activities of the Linked Clinical Research Center and the Network broadly? What are the strengths in this application demonstrating that the Linked Clinical Research Center has the appropriate processes in place to recruit and retain the population under study? How thoroughly does the applicant discuss previous successes and challenges in recruiting and retaining patient populations, establishing necessary collaborations for the identification of eligible patients and the collection of rigorous and timely data? What plans are proposed by the applicant for participating in a central IRB model and are they adequate ? What data systems are outlined in the clinical research center application that would allow the site to integrate data across multiple data sources for research purposes? What is the quality of the applicant's approaches to data integration? How is implementation science integrated as a research concept into trial design and what plans are provided for translation of clinical findings to populations with high disease burden? What plans are described for including eligible populations for both genders, for minorities and their subgroups, and are these appropriate for the goals of the CTSN? What are the plans for recruitment and retention of subjects and are they adequately described?

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?

Specific to this FOA:
Does the Linked Clinical Research Center have the research capabilities to fully participate in the activities of the CTSN? Does the application demonstrate adequate institutional resources and multi-disciplinary expertise to successfully carry out the research protocols? Does the Linked Clinical Research Center demonstrate that it has the administrative and clinical resources necessary to meet the broad goals of mentoring the affiliate site and contributing to the scientific aims of the CTSN? Does the applicant describe adequate clinical attributes of the centers? Does the applicant demonstrate that adequate patient populations exist at the clinical centers for CTSN trials and studies? Does the application demonstrate adequate institutional resources and expertise to facilitate data integration across multiple registries and other databases? Does the applicant make a compelling case that the affiliate site is in an area of high disease burden that will benefit from translation and implementation activities? Has the affiliate site documented a high burden of CV disease or unique patient population?

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.

Clinical and Implementation Research Skills Program (CIRSP) Plan

Is there a plan to recruit high quality participants, including plans to recruit women and other underrepresented groups? Does the plan identify the needs or training gaps of cardiothoracic surgeons in clinical and implementation science research, as well as a tailored mentoring plan (both research and didactic) to address those needs and training gaps, and to achieve independence? Does the plan adequately recognize institutional and cultural gaps between the LCRC sites and implement a well-conceived coordinated plan across the linked institutions as well as the CTSN? Is there a component to evaluate the effectiveness of the proposed CIRSP as well as the progress of individual trainees? Do the credentials and track records of the PD/PI, CIRSP Project Leader, and other participating senior investigators provide confidence in a good outcome?

Mentoring Plan for Affiliate Site

Is the site mentoring plan robust enough to build research experience and capacity at the affiliate site? Does the plan address supervision, skills development, in-service, certification, data handling, quality assurance, cost-effective management and communication? Does the plan provide for specific mentoring in the conduct of cardiac surgical RCTs including but not limited to: screening strategies, enrolling approaches, randomizing and retaining patients as well as regulatory and operations guidance in a way sufficient to support successful participation in cardiac surgical trials? Are the described synergies between the primary and affiliate site likely to result in a successful collaboration and strong participation in CTSN trial activities by both sites?

Collaboration

Is there documentation of institutional collaboration and support on both the part of the primary site and the affiliate site?

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.

Not Applicable

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

Not Applicable

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 the 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.

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

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. 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.

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 http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.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 http://www.hhs.gov/ocr/civilrights/understanding/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 http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.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

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 the primary responsibility for:

MILESTONE ACCRUAL PLAN (MAP)

Upon review and recommendation of the protocol(s) by the Protocol Review Committee (PRC) or Data and Safety Monitoring Board (DSMB) and approval by the Steering Committee (SC), the Grantee shall submit a Milestone Accrual Plan (MAP) within 90 days to the NHLBI Grants Officer with a copy to the Program Officer. The MAP must be signed by the Authorized Organization Official and acceptance of the MAP will be demonstrated in a letter from NHLBI indicating acceptance of the plan.

CLINICAL STUDIES

The Grantee Institution and Principal Investigators will have the primary responsibility in all aspects of CTSN trials and studies, including proposing protocols, participating in their overall development, preparing protocol budgets in collaboration with the DCC, modifying proposals if indicated, recruiting study participants, conducting the trial and collecting the relevant data, assuring quality of study participant care and protocol adherence, assuring the accurate and timely transmission of data collected in conjunction with the DCC, analyzing and interpreting data, preparing publications, and working with the DCC and NHLBI to disseminate research findings. LCRC PDs/PIs will also be responsible for working with the DCC to develop common definitions and standardization across protocols wherever appropriate. PDs/PIs are responsible for ensuring that Clinical Sites follow approved protocols and maintain quality control of data in accordance with the Data Safety and Monitoring Board guidance and recommendations and policies of the CTSN. Any problems concerning the compliance of clinical sites in following the protocol or quality control of data should be reported immediately by the awardee to the NHLBI Program Official. Support or other involvement of industry or any other third party in trials or studies conducted through the CTSN, e.g., participation by the third party in study resources, citing the name of the study, 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.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

The NHLBI Project Scientists will monitor patient recruitment and study progress, ensure disclosure of conflicts of interest and ensure adherence to NHLBI policies. NHLBI will appoint the Network Chairs, all members of the PRC, and the DSMB.

The NHLBI Project Scientist will serve on the Steering Committee and other study committees, when appropriate, and will have one vote. The NHLBI Project Scientists may work with awardees on issues coming before the SC and as appropriate, other committees, e.g., recruitment intervention, follow-up, quality control, adherence to protocol, assessment of problems affecting the study and possible changes in 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.

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

The NHLBI reserves the right to terminate or curtail the trial or study (or an individual award) in the event of: failure to develop or implement a mutually agreeable collaborative protocol; substantial short in participant recruitment, follow-up, data reporting, or quality control; major breach of the protocol or substantive changes in the agreed-upon protocol with which NHLBI cannot concur; attaining of a major study endpoint before schedule with persuasive statistical significance; or human subject ethical issues that may dictate a premature termination.

NHLBI-APPOINTED DSMB

A DSMB will be established for this Network to monitor data and oversee patient safety. The DSMB is appointed by the Director, NHLBI. Similarly, an independent PRC, will be established by the NHLBI and will provide peer review for each Network protocol not otherwise peer reviewed. An NHLBI scientist, other than the NHLBI Project Scientist, shall serve as Executive Secretary (ES) to the Boards. Because the Boards serve as independent groups advisory to the NHLBI, study investigators will not communicate with Board members regarding study issues, except as authorized by the ES.

The Study Chair, the Director and senior staff of the Coordinating Center, and representatives from the NHLBI will participate as non-voting members. The DSMB is scheduled to convene two times per year, and the SC on an as needed basis.

Areas of Joint Responsibility include:

Awardees agree to the governance of the study through a SC. The SC will have primary responsibility for the conduct of protocols and the preparation of publications, SC voting membership shall consist of all PD/PI awardees, one NHLBI Project Scientist, and the Chairs. Each full member will have one vote.

Network participants will be required to accept and implement policies approved by the SC.

The NHLBI Project Scientists, DCC, and Network Chairs will be responsible for ensuring that there are well-documented policies, procedures, and bylaws to guide all aspects of Network activities and operations.

Dispute Resolution:

Any disagreements 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 of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Marissa A. Miller, DVM, MPH
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-594-1542
Email: millerma2@mail.nih.gov

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0270
Email: NHLBIChiefReviewBranch@nhlbi.nih.gov

Tyrone Smith
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8053
Email: smithty@mail.nih.gov

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.