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

The Cardiothoracic Surgical Trials Network (CTSN) has been a successful and impactful clinical research enterprise since 2007, building a cadre of cardiac surgical trial investigators and a platform for broad collaboration among allied specialties, foundations, professional societies and industry. The CTSN includes cardiac surgical academic centers across the U.S., Canada, and Germany. The CTSN has become a critical resource to the cardiac surgery, cardiology, and neurology communities.

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 delivery of randomized controlled trial-proven effective therapies and cardiac surgical approaches to populations in order to improve cardiovascular outcomes in communities.

During this funding cycle, the CTSN will 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. In this transition, funding of the enterprise will be shared by government and other sources wanting to leverage the infrastructure and collaborate on important scientific research questions.

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 ctsurgerynet.org.

Purpose and Objectives

This limited competition Funding Opportunity Announcement (FOA) is intended to support a Data Coordinating Center (DCC) to conduct the activities of the Cardiothoracic Surgical Trials Network (CTSN). The DCC will consist of two collaborating components including a Data Management and Analytics Center (DMAC) and a Clinical Coordination Center (CCC). NHLBI strongly encourages multi-PD/PI applications with two PDs/PIs; one PD/PI for the DMAC and one PD/PI for the CCC.

The primary responsibility of the DCC is to oversee the conduct of multiple randomized clinical trials in the CTSN. The DCC will support regulatory and administrative activities, data collection and management, and statistical analysis and reporting of trial results in a timely manner. The DCC will promote collaboration and communication among CTSN investigators and the broader research community and coordinate outreach activities including engaging foundations, research entities, and industry in trials of mutual interest and public health importance. The DCC is responsible for integrating the efforts of individual CTSN Linked Clinical Research Centers, Consortium Center sites, core laboratories, and other collaborators, and conducting long-term follow-up centrally via telephone follow-up at the DCC. The NHLBI anticipates that the DCC will collaborate strategically with the Clinical and Implementation Research Skills Program component of the LCRCs to enhance the development of junior investigators by facilitating their involvement in protocol development (including clinical trial design and statistical approaches), publication committees, and by providing datasets for secondary analyses.

This FOA runs in parallel with a separate FOA that solicits applications for the CTSN Linked Clinical Research Centers (LCRCs), described in detail in RFA-HL-19-009.

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), described in more detail in RFA-HL-19-009, are responsible for proposing and developing protocols, recruiting participants, entering data into the web-based data entry system, assuring good clinical practice, mentoring 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 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 (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 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.

Requirements for the CTSN Data Coordinating Center

The DCC will coordinate all trials to be run in the Network facilitating use of the collaborative infrastructure. DCC planning should consider protocols to be completed in a two-to five-year time frame (awardees shall not assume that follow-up will occur outside of the lifetime of the award with Federal support). The DCC will facilitate protocols and new concepts being reviewed and prioritized through the CTSN SC process after LCRC cooperative agreement awards are made. Protocols that are voted by the SC to be developed will be supported by protocol development committees coordinated by the DCC and comprised of membership from LCRCs, CCs, the DCC, and NIH. The DCC will coordinate all CTSN conducted peer review of protocols through the PRC in collaboration with the NHLBI.

The DCC will consist of two collaborating components including:

1) a Data Management and Analytics Center (DMAC)

2) a Clinical Coordination Center (CCC).

Data Management and Analytics Center (DMAC)

NHLBI expects that the DMAC component will work in close collaboration with the CCC and that the DMAC will have primary responsibility for:

• Overall management and coordination of the Network

Management of overall funding of the DCC grant award, Network project timelines, and the CTSN website to ensure that it is updated at regular intervals; Overall coordination of Network activities across all components (i.e., the CCC, LCRCs, CCs, core laboratories, Network leadership, industry collaborators, and NIH); and provide coordination and leadership in the early identification and resolution of issues arising within the Network.

• Administrative Management

Administrative support to the Network Chairs, scientific leadership, and other stakeholders as needed, including but not limited to drafting Network meeting/teleconference agendas and minutes, manuscripts, and presentations, as well as publicizing ongoing clinical trials via appropriate advertising venues; Coordination and facilitation of meetings, teleconferences, and training among study personnel, committees, subcommittees, oversight bodies such as the DSMB, industry and other collaborators. Additional responsibilities of the DMAC include developing, negotiating, and executing agreements and subcontracts such as investigator agreements, subcontracts with LCRCs, CCs and core laboratories identified by the CCC, materials transfer agreements, agreements with industry and other collaborators.

• Trial/Study Design and Protocol Development

Trial/study design, statistical and biomedical/scientific writing expertise to Protocol Development Committees (PDCs), including defining sample size requirements and randomization schemes, assisting in the determination of trial endpoints and analytical approaches, as well as developing trial stopping rules, as appropriate, for NHLBI review and DSMB approval. It is also expected, the DMAC will facilitate PDC meetings/teleconferences, to ensure that protocols are developed within Network timelines and coordinate protocol review by the NHLBI-appointed PRC and DSMB in collaboration with the Executive Secretaries of each. The DMAC will also oversee data management-related document development and finalization for each trial/study in collaboration with the CCC.

• Data Management and Analysis

Development, maintenance, and/or refinement of data dictionaries and a 21CRF Part 11-compliant electronic data capture system (EDC) for clinical research trials and studies conducted by the Network, assuring high data quality through edit/validation checks; Serving as a central repository for trial/study data and acquired large data sets (e.g., CMS and other relevant data sets) pertinent to Network trials and studies. Additional DMAC responsibilities are expected to include overseeing secure data collection, storage, and, when appropriate, transfer of LCRC-, core laboratory-, and ancillary study-generated data; preparing confidential data analyses and reports as requested by the NHLBI, Network leadership, SC, the DSMB, and regulatory agencies in collaboration with the CCC; and coordinating data analysis, reporting, and publishing of Network research, the latter in high quality peer-reviewed journals.

Clinical Coordination Center (CCC)

NHLBI expects that the CCC, working in close collaboration with the DMAC, will have responsibility for:

• Enrolling Clinical Centers

Identification of CCs and administration of their corresponding subcontracts/investigator agreements; Administration of LCRC investigator agreements and site subcontracts and agreements including providing reimbursement for patient care costs as a fee for service arrangement after a protocol has been approved and the NHLBI has approved the funds for distribution; Integration of activities of all awarded LCRCs and subcontracted CCs to minimize duplication of effort and to maximize resources by utilizing existing resources whenever possible; Establishment and tracking of site enrollment targets, encourage recruitment, and development of strategies to encourage referrals from other specialty areas. Additionally, the NHLBI anticipates the CCC will prepare, distribute for review, finalize, and then distribute protocols, protocol amendments, manuals of procedures (MOPs), and other materials necessary for study implementation. In collaboration with the DMAC, the CCC will provide protocol training as an integral part of site initiation activities and as needed throughout the trial.

• Biorepositories, Core and Collaborating Laboratories

Identification and administration of subcontracts with biorepositories and core laboratories and investigators as needed; Administration of subcontract and agreement including providing reimbursement to these facilities as applicable and/or ensuring transfer of biospecimens to collaborating laboratories in a timely manner, training of clinical center personnel, as well as distribution of materials and supplies furnished by core laboratories. Within the scope of these the CCC will also coordinate with biorepositories to ensure accurate inventories of fluid and tissue specimens for laboratory studies and their transfer to collaborating laboratories. The CCC is expected to assist biorepositories and core laboratories as needed with the preparation of procedures manuals and their distribution to clinical centers.

• Study Products

Administration of agreements with manufacturers and arrangement and tracking of the supply of study products, including drugs, biologics, devices and/or combination products, to clinical centers, and coordinate study product training of clinical center personnel, as needed.

• Clinical Research Activities

Long-term follow-up of trial participants through centralized telephone visits at key time points. Activities may include obtaining vital status, the occurrence of protocol-specified adverse events (e.g., major adverse cardiovascular and cerebrovascular events, other cardiovascular and neurological events), hospitalizations, and quality of life; Entering data obtained into the electronic data capture system and maintain GCP-compliant records of all telephone visits; Collection of source documentation pertaining to serious adverse events as defined by the protocol and upload the documents into the EDC for review by the Events Adjudication Committee.

• Network Activities

Participation in Network activities to provide clinical trial operational guidance including SC, IC, and coordinator meetings and teleconferences, trial-specific operations teleconferences, and trial-specific training workshops

• Human Subjects Protection

Overseeing Human Subjects Protection within the Network by preparation of informed consent templates and patient-centered materials (e.g., brochures and letters) for review by the trial/study sponsor(s); Ensuring that all DCC, LCRC, CC, and core laboratory personnel are properly trained on protocol-specific procedures (including the informed consent process), CTSN policies, applicable regulations, and Good Clinical Practice (GCP), in collaboration with the DMAC. Additional CCC responsibilities include evaluating screening logs and patient eligibility, as well as triaging unexpected adverse events regardless of the clinical center investigator’s determination for further assessment by independent Medical Monitors.

• Regulatory Affairs

Facilitation of interactions with regulatory authorities such as the Food and Drug Administration (FDA), Health Canada, CMS, and other agencies; Appointment of a qualified staff member to serve as the ClinicalTrials.Gov Responsible Party and Sponsor of Investigational New Drug applications (INDs) and Investigational Device Exemptions (IDEs); Reporting and tracking of unexpected adverse events and unanticipated problems to NHLBI, other study sponsors, oversight bodies, and regulatory agencies. Moreover, after triage, CCC staff will coordinate adverse event review by Network Medical Monitors, the Events Adjudication Committee, and IND/IDE safety monitors (the latter for IND/IDE trials). Additional CCC responsibilities are expected to include preparing and submitting all regulatory documents (e.g., briefing packages, initial regulatory applications, amendments to regulatory applications, responses to regulatory authority inquiries, etc.) to regulatory agencies, as well as CMS applications for coverage of IND/IDE trials to CMS.

• Regulatory Compliance

Assuring compliance with the Health Insurance Portability and Accountability Act (HIPAA) within the CTSN in accordance with 45 CFR Parts 160, 162, and 164 or corresponding regulations for Canadian and other international clinical centers; Implementation and supervision of the revised Common Rule (45 Part 46) within the CTSN, including the use of a single-IRB review for federally-funded, multi-institutional studies conducted in the United States. In addition, the CCC will be expected to register and report results of clinical studies and trials in ClinicalTrial.Gov as required by 42 CFR Part 11. In collaboration with the DMAC, the CCC will be expected to establish and maintain written procedures for all internal processes within the DCC. To supplement the monitoring program discussed below, the CCC will have independent auditing to assure regulatory compliance within the Network, as needed.

• Monitoring Program

Developing, organizing and conducting a monitoring program for all enrolling clinical centers, core laboratories, biorepositories, and other collaborators participating in CTSN research to ensure high quality clinical research. The monitoring program will include preparing and providing trial-specific monitoring plans to the trial sponsor(s) and monitoring study execution at clinical centers, core laboratories, and biorepositories to assure compliance with the protocol, MOP, CTSN policies, applicable regulations and guidelines throughout the duration of the trial. Additionally, the CCC will be responsible for conducting site initiation, interim and close-out visits (central/remote or on-site) in accordance with the monitoring plan; preparing monitoring reports for the trial sponsor (e.g., the NHLBI) and monitoring letters for enrolling clinical centers, core laboratories, and biorepositories after completion of monitoring visits and in accordance with required timelines; and providing monthly monitoring schedule updates/trackers to the trial sponsor (e.g., the NHLBI). The CCC will be expected to identify underperforming centers and laboratories as early as possible, develop corrective and preventative action plans in consultation with the NHLBI, and oversee the implementation of the corrective and preventative action plan.

DCC key personnel will be expected to participate in site evaluation visits conducted with the NHLBI, and Network Chairs for each LCRC at least once during the 7-year funding period. The entire CTSN program will be reviewed by an External Review Committee during Year 4 or 5, and the DCC will be responsible for developing and providing relevant materials to the External Review Committee for this review.

Applications submitted in response to this FOA must propose one or more delayed onset clincial trial studies. The delayed onset clinical trial studies represent future 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 to be conducted by the CTSN and should not provide specific details about the proposed clinical studies.

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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

NHLBI strongly encourages multi-PD/PI applications with at least two PDs/PIs; one PD/PI for the DMAC and one PD/PI for the CCC.

Only past awardees from RFA-HL-13-022 are eligible for this FOA.

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: [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.

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.

Key personnel should include:

• The PD/PI of the DMAC, with responsibility over the entire DCC (signified below by DMAC/DCC), and the PD/PI of the CCC are both required to have doctoral degrees in a field relevant to biomedical research; expertise in the evaluation of surgical, biologic and device trials; and leadership expertise in NIH Network or Cooperative Group-based clinical trials to seamlessly orchestrate DCC activities involved in conducting the multiple, multi-center clinical trials and studies performed within the Network.
• The PD/PI of the DMAC/DCC must have a comprehensive understanding of the measurement of the long-term clinical outcomes and economic impact of clinical interventions; patient safety and quality of care research; policy analysis; innovative trial design, methodology and conduct of complex surgical and device trials; the assessment of quality of life and economic analysis of clinical procedures, and volume-outcome studies; and policy studies on technological change; as well as an understanding of translational research and implementation science.
• The PD/PI of the CCC must be certified as a clinical research professional (CCRP), or have equivalent experience with a comprhensive understanding of human subjects protection; safety and pharmacovigilance in drugs, biologics, devices and combination products to ensure timely, complete, and accurate reporting to oversight bodies and regulatory agencies; applicable regulatory requirements; electronic data capture and database development; as well as the technical background to review comprehensive IND and IDE risk assessments and safety reports.
• Medical Officer/Senior Cardiologist (i.e., MD, DO or equivalent doctoral degree) specializing in adult cardiology with expertise in heart failure, electrophysiology, and/or interventional cardiology. The Medical Officer should be experienced in the area of safety and pharmacovigilance in drugs, biologics, devices, and combination products to review and evaluate information relevant to the safety of these products.
• Senior Regulatory Professional to organize and manage all regulatory affairs and compliance activities. This individual must have a Masters or higher degree with Regulatory Affairs Certification (RAC) or equivalent experience and comprehensive experience supervising other regulatory professionals, medical writers, clinical trial monitors and clinical trial auditors/auditing consultants.
• Senior Regulatory/Medical Writer with a Master's degree and more than 5 years of medical writing or doctoral degree with more than 2 years of medical writing experience to conduct thorough literature searches, prepare complete and accurate regulatory documents (e.g., briefing packets, initial INDs/IDEs, IND/IDE amendments, responses to regulatory authorities, etc.), reports to oversight bodies and regulatory authorities, formal meeting minutes, clinical study reports, and other types of regulatory documents).
• Senior Clinical Research Professional with an RN, BSN, or higher degree in a relevant field and certification as a clinical research professional or equivalent experience to manage the day-to-day activities of clinical operations. This individual must have at least 10 years of clinical research experience and supervisory experience managing other clinical research professionals (e.g., clinical trial project managers and supporting staff), as well as substantial experience working with clinical center research coordinators and other clinical center staff. Comprehensive knowledge of GCP, data-driven development of trial accrual benchmarks, arranging the supply of study products, development of case report forms, and administration of agreements with clinical centers, core laboratories, industry and other collaborators is also required.
• Senior Biostatistician with a doctoral degree in biostatistics and at least 5 years of experience supervising data management and statistical analysis staff to manage the day-to-day activities of data management and analysis, ensuring all timelines are met. This individual should have at least 10 years of experience in multisite clinical trial design and analysis, expertise in project management, the ability to work collaboratively as part of a multidisciplinary team as well as to meet timelines.
• Information Technology Professional with a Bachelor's degree or higher in computer science, informatics, or other relevant field to manage research informatics activities. This individual should have in-depth experience developing large-scale, web-based, clinical trial data management systems and support systems (e.g., web-based document management and tracking systems), data systems validation, as well as experience supervising research informatics staff including website designers.

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

Application budgets must plan for the following:

For all non-protocol costs:

• Limits for budget amounts that applicants may request for all non-protocol costs are listed in Section II Award Information, Award Budget.
• A suggested 9 person-months for the PDs/PIs for the DMAC/DCC and the CCC. 
• Medical Officer/Senior Cardiologist at suggested 3 person-months
• Senior Regulatory Professional at suggested 9 person-months
• Senior Regulatory/Medical Writer at suggested 4 person-months
• Senior Clinical Research Professional at suggested 9 person-months
• Senior Biostatistician at suggested 5 person-months
• Information technology professional at suggested 3 person-months
• For other Investigators/staff, the effort should be commensurate with the oversight required.
• Expenses related to managing the DSMB will include approximately eight and up to ten members with meetings occurring in-person in Bethesda, Maryland, annually and an additional two to three times per year by conference call.
• Expenses related to managing the Protocol Review Committee will include approximately five to seven members with one meeting occurring in-person in Bethesda, Maryland, and additional meetings occurring on an as needed basis by conference call. 
• Steering Committee and All Investigators Committee expenses will include an average of twice a year in-person meetings and monthly conference calls and monthly subcommittee calls for each active protocol subcommittee.  Travel for LCRC staff to meetings will be budgeted by the LCRCs; however, DCC staff travel to Steering Committee and All Investigators Committee meetings should be included in the DCC budget.
• Coordinators Group expenses include an average of three in-person meetings per year and bi-weekly conference calls.  Travel for LCRC coordinating staff to meetings will be budgeted by the LCRCs; however, DCC staff travel to Coordinators Group meetings should be included in the DCC budget.
• Site monitoring visit expenses include costs for site initiation, interim monitoring, and close-out monitoring activities that will be conducted via centralized monitoring to the extent possible.  On average, the DCC will visit each actively accruing clinical site in accordance with the trial monitoring plan, which takes into account the level of risk and established policies and regulations; these on-site monitoring visits will be dependent on the number of ongoing CTSN trials, trial accrual rate(s), applicable regulations, and findings from centralized monitoring and previous site visits. 
• Site evaluation visit expenses include a minimum of one site visit to each LCRC (up to five) during the up to 7-year grant period and conference call expenses for one or two conference calls per enrolling clinical center to follow up on any recruitment issues. 
• Expenses associated with identifying, contracting and overseeing up to 40 Consortium Centers. One reverse site visit for up to 40 Consortium Centers should also be included
• Costs associated with training to include costs related to the design and implementation of web-based training and assessment for protocols and annual Good Clinical Practice training for all investigators and study coordinators.  NOTE: In-person training for coordinators and investigators should be addressed above in the tri-annual and bi-annual in-person committee meetings, respectively.   
• Support for the Network Chair, Co-Chair and Vice Chairs at 1.2 person-months (10% effort) each, travel to five meetings a year, and modest administrative expenses.
• Costs related to the design and implementation and maintenance of the CTSN public and private websites and development of web-based programs for financial management of the Network.
• Support for independent medical monitors experienced in cardiothoracic surgery, as well as an independent Events Adjudication Committee with expertise in cardiothoracic surgery and cardiology.
• Center costs also should include the costs of updating the Network Administrative Manual of Operations and Procedures, trial-specific manuals of procedures and of developing questionnaires, forms, and marketing activities and materials (brochures, videos, seminars). 
• Other expenses as appropriate.

Protocol associated funds will be awarded to the DCC for subsequent distribution to the clinical centers, core labs, and satellite sites on the following schedule: Year 1 - $3,200,500; Year 2- $3,201,500; Year 3 - $3,201,500; Year 4 - $2,500,000; Year 5 - $2,399,500; Year 6 - $2,399,500; Year 7 - $0.  Future year amounts will depend on annual appropriations. The budget justification for protocol associated costs for each year should include a table that apportions the direct costs among the following categories:  patient care costs, core lab costs, biorepository costs, clinical consortium, and site sub contracts.  The DCC applicant should assume that two to three protocols will be active in the first year and seven to ten total protocols will be developed and begin active recruitment during the award period covered by this FOA. The budget should include, but is not limited to:

• Protocol associated costs (e.g. clinical costs that are not part of routine clinical care such as laboratory tests, sample and data collection, supplies)
• Expenses associated with drug or device acquisition and distribution when required, and application to the Food and Drug Administration (FDA) for Investigational New Drugs (INDs) and Investigational Device Exemptions (IDEs).
• Expenses associated with procuring and operating centralized laboratories will include the expense of transferring the data or specimens to the central lab(s), training technicians to obtain the data in a uniform manner, and instituting quality control measures (e.g., provision for re-reading a proportion of the studies to determine accuracy of interpretation) will be included in the DCC budget.  Expenses associated with obtaining the specimens or data will be included in the LCRC.
• Costs to engage an single IRB (sIRB) for up to 10 CTSN-led trials.

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 describe the following:

• Plans for leading and coordinating complex multi-center clinical cardiothoracic surgical studies and trials.
• Experience with representative studies from CTSN as a means of discussing the proposed approach to the design and conduct of cardiothoracic and/or cardiovascular surgical protocols, maximize recruitment and retention, and minimize logistical, operational, and regulatory issues, all in the context of multiple trials running simultaneously. Include a description of novel clinical research approaches and innovative technologies that can be applied to the clinical trial enterprise.
• Proposed strategy to conduct long-term follow-up of trial participants at the DCC.
• Plans for how the DCC will cooperate and interact with all CTSN components to achieve coordination of all Network activities. Include strategies to manage and support electronic and other communications; support regulatory affairs and compliance, human subjects protections, site/core lab and data monitoring, clinical operations and administrative activities; conduct data collection, management, statistical analysis and reporting of clinical trial results in a timely manner.
• The DCC's proposed role in the development of clinical and implementation research junior investigators in collaboration with the LCRCs. Where appropriate, discussion of developed and implemented best practices should be included.
• Plans for conducting outreach activities including engaging foundations, international research entities and industry in trials of mutual interest and public health importance.

Research Team

Provide an overview of the overall organization of personnel in the Research Team of the DCC and describe the ability and commitment of the investigators to function as a coordinated research team, to work efficiently and expeditiously with, and to enhance the research goals of, the CTSN.

A sound rationale should be provided as to why the research team is the most appropriate, and likely to generate an exceptionally high impact if successful. Provide an overview of the DCC team member roles and responsibilities in light of the requirements of concurrently managing multiple studies at various stages of study design, conduct, and closeout.

Clinical and Translational (CTSA) Organizations

The NHLBI encourages academic centers participating in the CTSN to partner with the CTSA, if one exists at the applicant institution, to enhance the scientific and operational aspects of the Network.

If applicable, describe how the CTSN DCC will interface with a CTSA structure including plans for leveraging bioinformatic, clinical trial design and biostatistics expertise. Describe how the CTSA network may be leveraged to establish strong and interactive relationships with local communities and clinics, and to enhance recruitment of clinically and ethnically diverse patient populations. If appropriate, describe how the CTSN DCC might partner with translational investigators in the CTSA to create state-of-the art mechanistic and translational sub-studies that could be conducted within the Network’s clinical protocols.

Multiple PD/PI Leadership Plan

Describe plans for how the DMAC/DCC PD/PI and the CCC PD/PI will work collaboratively together to lead the identified multidisciplinary team. Include a description of planned strategies for effective communications between and within the DMAC and CCC.

Letters of Support

Provide documentation of departmental and institutional commitment to supporting cardiothoracic surgery research and to prioritization of Network research. This can be in the form of letters or memoranda provided to the Program Directors/Principal Investigators, and by citing evidence of past support. These assurances to provide support should address areas such as fiscal administration, personnel management, space allocation, procurement, planning, equipment, and budgeting.

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

• 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.

Delayed Onset Study

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

Applications must include one or more delayed onset Studies.

Justification Attachment. Provide a brief description (must be no more than one page) of potential delayed onset study(ies) to be conducted by the CTSN that represent future proof-of-concept/early feasibility/early translation studies, RCTs in the comparative effectiveness realm, and/or innovative trials leveraging registry data and electronic medical records.

The CTSN has established data and safety monitoring principles and processes for all studies conducted within the Network and according to Good Clinical Practices.  Applicants are only required to provide a statement that the Data and Safety Monitoring Plan for the CTSN trials is to adhere to the standard CTSN policies and procedures for data and safety monitoring.

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

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.

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

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

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:

How compelling are the experiences from representative studies and trials, and in what ways do these experiences likely predict the ability to successfully conduct high impact multi-center collaborative randomized controlled trials and studies that evaluate cross specialty team-based care, interventions and novel therapies in the context of cardiac surgery but with relevance to cardiovascular disease in this funding period? How are the proposed approaches relevant to recruitment and retention, and operational issues addressing unique challenges to cardiac surgical trial conduct? How strong is the applicant's plan for cooperation and interaction of components to achieve the goals of the Network? To what extent will the coordination activities support the complex structure and activities of the Network? How likely is it that the outreach plans will result in strong collaborations and new revenue sources to support trials of public health importance?

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:
Do the DMAC/DCC PD/PI and CCC PD/PI have complementary and integrated expertise; and to what extent is the leadership approach, governance and organizational structure appropriate for the overall DCC? How likely is it that the investigators have sufficient expertise to conduct the DCC as proposed? To what extent are the PD/PIs and any key investigators likely to be able to accomplish all the objectives in a highly collaborative, fair, and flexible manner, appropriate to the roles described in this FOA?

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?

Specific to this FOA:
What novel organizational concepts, management strategies, or electronic and information technologies to support clinical research conduct are being proposed and are these likely to succeed? Which innovative and useful approaches to project coordination and logistical support are most likely to work in a cardiac surgical clinical trial arena?

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? 

Does the application adequately address the following, if applicable

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

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 are the strengths and weaknesses of the application in terms of: (1) overall management of clinical research and scientific activities such as study development, trial launch and results dissemination across a complex Network; (2) management of CTSN core administration activities; (3) overall support for trial design, protocol development, data management and analytic activities; (4) coordination of clinical operations, including centralized long-term follow-up of trial participants at the DCC; (5) oversight of human subjects protections, regulatory affairs and compliance support; (6) the ability to monitor all clinical centers and participating laboratories; (7) participation in the development of clinical and implementation research junior investigators in collaboration with the LCRCs; and (8 the ability to report results in high impact journals and translate findings to populations with high disease burden.

To what extent are the overall strategy, operational plan, and organizational structure appropriate to accomplish the specific aims of the DCC and are they well-reasoned? What potential problems, alternative strategies, and benchmarks are presented that lead you to believe the DCC will be successful? To what extent will the proposed approaches accomplish the major goals of coordinating multiple protocols running simultaneously-specifically, managing study development, launch and dissemination of results, managing core CTSN operations, and coordinating logistics and other support services? How likely is it that the proposed plan will promote collaboration across the DCC and all components of the CTSN? Where appropriate, is the proposed program developing or utilizing latest best practices to improve the knowledge and/or skills of the Network and what are these?

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:
To what extent do the proposed data management systems indicate the flexibility required to accommodate the changing needs of the program over time? How strong are the examples that intend to show that the applicant has adequate capability to utilize electronic technology to meet the coordination goals of the DCC?

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)?

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.

Not Applicable

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.

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 . 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.

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).

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 OMB administrative guidelines, HHS 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:

The DCC PDs/PIs play an important role in all aspects of CTSN studies, including participating in protocol development, preparing protocol budgets in collaboration with the Clinical Research Centers, modifying proposals if indicated, monitoring recruitment of study participants, assuring the quality of study participant protocol adherence, assuring the accurate and timely transmission of data, analyzing and interpreting data, preparing publications, and working with the LCRC and enrolling CCs and NHLBI to disseminate research findings.  The DCC will also be responsible for working with the LCRC PDs/PIs and Study Chairs to develop common definitions and standardization across protocols wherever appropriate.  Awardees must agree to the governance of the study through a Steering Committee.   Investigators will be required to project patient enrollment for a specific protocol during a specified time frame; continuation and level of funding will be based on actual recruitment and the DCC will monitor this in collaboration with the NHLBI.

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.

PIs are encouraged to publish and disseminate results and other products of the study in accordance with study protocols and governance.  For applicable studies, data not previously released and other study materials or products not previously distributed are to be made available to individuals who are not study investigators, within three years of the end of the period of NHLBI support, provided such release is consistent with the study protocol and governance.  Awardees will retain in custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

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 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 Study Chairs, Protocol Review Committee (PRC) and the Data and Safety Monitoring Board (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, such as: 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.

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 the NHLBI Project Scientist and Project Officer.  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/Program Official will participate in activities that rise to a level of involvement that results in conflicts of interest, for example, co-publication, other staff members such as direct line supervisors and/or other Senior NHLBI Program management staff will serve as agency Program Officials and will be responsible for the normal scientific and programmatic stewardship of the award.

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

Areas of Joint Responsibility include:

• Awardee(s) agree to the governance of the study through a Steering Committee.  The Steering Committee will have primary responsibility for identification of priority areas for research, the conduct of protocols, data analysis and the preparation of publications and dissemination products. Steering Committee voting membership shall consist of all Principal Investigators (i.e., cooperative agreement awardees), one NHLBI Project Scientist, and the Protocol Chairs.  Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.
• Awardee(s) agree to collaboratively develop achievable/feasible agreed-upon metrics to evaluate the overall success of the CTSN during review by the NHLBI appointed External Review Committee during years 4 or 5. Metrics should include stakeholder feedback and modifications to enhance the efficiency and scientific rigor of the program. 
• Awardee(s) agree to negotiate mutually agreed upon milestones during the development of each clinical research protocol and may include such things as time to IRB approval, time to subcontract finalization, first patient screened, first patient enrolled, etc.
• A Data and Safety Monitoring Board will be appointed by the Director, NHLBI to provide overall monitoring of interim data and safety issues.  An NHLBI scientist, other than the NHLBI Project Scientist, shall serve as Executive Secretary 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 Board’s Executive Secretary.

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 regulations 42 CFR Part 50, Subpart D and HHS regulations 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: [email protected]

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

Marissa A. Miller, DVM, MPH
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0513
Email: [email protected]

Director, Office of Scientific Review
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0270
Email: [email protected]

Tyrone Smith
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8053
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.