Department of Health and Human Services

Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Heart, Lung, and Blood Institute (NHLBI)
National Institute of Neurological Disorders and Stroke (NINDS)

Funding Opportunity Title

Limited Competition: Data Coordinating Center for Cardiothoracic Surgical Trials Network (CTSN) (U01)

Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

Reissue of RFA-HL-06-005

Related Notices

Funding Opportunity Announcement (FOA) Number

RFA-HL-13-022

Companion FOA
Number of Applications

See  Section III. 3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.837

FOA Purpose

The purpose of this limited Funding Opportunity Announcement (FOA) is to invite applications to support the Data Coordinating Center (DCC) for the Cardiothoracic Surgical Trials Network (CTSN).  A separate FOA (RFA-HL-13-017) seeks applications for Network Core Clinical Centers. 

The goal of the CTSN is to evaluate surgical interventions and related management approaches to improve the treatment of cardiovascular disease and conditions in adult patients.  The DCC provides administrative and statistical support to maintain an infrastructure to develop, coordinate, and conduct multiple collaborative surgical trials designed to improve cardiovascular outcomes and optimize post-operative neurological function. 

Key Dates
Posted Date

March 28, 2012

Open Date (Earliest Submission Date)

May 13, 2012

Letter of Intent Due Date
Application Due Date(s)

June 13, 2012, by 5:00 PM local time of applicant organization.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

October/November 2012

Advisory Council Review

January  2013

Earliest Start Date(s)

April 1, 2013

Expiration Date

June 14, 2012

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (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.

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Nature of the Research Opportunity

This funding opportunity announcement (FOA) issued by the National Heart, Lung, and Blood Institute (NHLBI) invites applications to support a component of the Cardiothoracic Surgical Trials Network (CTSN).  The CTSN focuses on research of newer surgical techniques, technologies, devices, and innovative pharmaceutical and bioengineered products to improve the health of adults with cardiovascular disease.  Core Clinical centers will be funded through a companion FOA (RFA-HL-13-017).

This FOA is a limited competition solicitation to continue operation of the CTSN Data Coordinating Center.  Only the current CTSN Data Coordinating Center awardee is eligible to apply in response to this FOA.  In the research plan of this announcement, the applicant should describe innovative strategies to recruit, randomize, and retain patients, as well as to handle logistical and regulatory challenges for randomized controlled trials of up to 300 subjects, proof-of-concept/first in human trials of RFA-HL-13-017 solicits applications from all qualified applicants.) 

In 2007, the NHLBI, in collaboration with the Institute of Circulatory and Respiratory Health (ICRH) of the Canadian Institute for Health Research (CIHR) and the National Institute for Neurologic Disorders and Stroke (NINDS), launched the CTSN, a cooperative clinical research network of academic centers with clinically active cardiothoracic surgeons.  The network provides support to maintain an infrastructure to develop, coordinate, and conduct multiple collaborative clinical trials designed to improve cardiovascular disease outcomes in the adult population.  The Network currently consists of one data coordinating center (DCC), eight core clinical research centers (grantee sites), two clinical skills development cores, four clinical core laboratories (all managed by the DCC), a specimen biorepository (subcontracted to the DCC), and 26 clinical consortium centers (subcontracted to enhance trial enrollment and other key Network activities).  Leadership and scientific oversight is provided by the Chair (a CT surgeon), Co-Chair (a cardiologist), and an NHLBI-appointed Protocol Review Committee and Data and Safety Monitoring Board.  A Steering Committee serves as the governance structure.  The Network is funded predominantly by NHLBI, with contributions from the NINDS and the CIHR.

The DCC leads and coordinates all aspects of the conduct and operations of multicenter trials, including site contracts with collaborating clinical sites and core laboratories, regulatory compliance, recruitment monitoring, patient safety and adverse event reporting, manuals of procedures preparation, and training.  The DCC also provides a data management and statistical function, providing support of protocol development; database development; and data collection, quality, and integrity; expertise in statistical analyses; and manuscript preparation.  Another important function is administrative coordination including managing and distributing protocol and core laboratory funds, organizing meetings and providing support to the Steering Committee and Chairs.

Background

Cardiovascular disease (CVD) constitutes a large morbidity and mortality burden in the United States, and consumes a large portion of the health care bill.  According to disease statistics in 2007, CVD caused 814,000 deaths, or 34 percent of all deaths. This cost the nation $286 billion in healthcare expenditures including $167 billion in direct health expenditures and $119 billion in indirect cost of mortality (source: NHLBI Disease Statistics). Cardiothoracic surgery is an important therapeutic tool in addressing many of the most prominent cardiovascular conditions, including coronary artery disease, congestive heart failure and valvular disease, among others. Cardiothoracic surgery has been very innovative in addressing these disease challenges. Coronary artery bypass grafting (CABG), cardiac valve repairs, ventricular assist devices, artificial hearts, and arrhythmia surgery have extended survival and improved the quality of life for many patients. The accelerating pace of innovation in cardiothoracic surgical practice, including the utilization of new approaches and technologies and the extension of surgical approaches to older patients with greater co-morbidity, has outstripped the ability of randomized clinical trials to provide an evidence base to establish improved outcomes and benefit.

The mandate of the Institute of Circulatory and Respiratory Health’s (ICRH) of the Canadian Institutes for Health Research amplifies the need for a growing number of clinician scientists and clinicians to contribute to the global health enterprise.  There are approximately 140 cardiac surgeons in Canada.  Those cardiac surgeons who also conduct research require adequate time, funding, mentoring, access to facilities and technology, and linkages with accomplished collaborators.  The CTSN is an effective model for bringing together cardiac surgeons with many other health professionals and researchers to design new clinical trials that will speed the transfer of new knowledge into clinical practice.

The CTSN also aligns with at least two key priorities within ICRH’s recently updated strategic plan.  In 2011, the ICRH of the CIHR identified the development of research networks, and the development of patient oriented research, as two key strategic priorities.  In fact, ICRH was an enabling force in developing the Canadian Institutes of Health Research – Strategy for Patient-Oriented Research, as well as contributing to CIHR’s position on research networks.  Working together with many partners, CIHR aims to transform Canada's capacity for patient-oriented research by:  developing and sustaining the next generation of clinician-researchers, improving the infrastructure and funding for patient-oriented research, and supporting the development of relevant value-added research networks. This Network complements CIHR’s focus on development of patient-oriented research teams, platforms, networks and centers.

The CTSN is dedicated to fostering a culture of rigorous scientific comparisons; to promoting the evaluation of newer surgical techniques, technologies, devices and innovative pharmaceutical and bioengineered products directed at cardiovascular disease and interventions to improve neurological and neurocognitive outcomes of cardiothoracic surgery; and to ensuring that the public has access to the best procedures determined by careful assessment. The Network also provides the administrative and operational infrastructure for conducting randomized clinical trials and studies that would provide a strong evidence base to inform surgical practice and to disseminate those findings to the broader scientific community.

The CTSN has developed a diverse and impressive portfolio of surgical research projects that evaluate clinically meaningful questions and address important public health issues, with input from the Steering Committee, the broader surgical community through the CTSN and American Association for Thoracic Surgery websites, and through scientific meeting interactions and individual collaborations. 

The clinical research portfolio for the initial grant period falls into three areas: randomized clinical trials, observational prospective studies, and proof-of-concept trials.

The following trials are active and anticipated to complete randomization during the current grant period:

1.  Surgical Interventions (CABG vs. CABG plus mitral valve repair) for Moderate Ischemic Mitral Regurgitation (MMR)

2.  Evaluation of Outcomes Following Mitral Valve Repair/Replacement in Severe Chronic Ischemic Mitral Regurgitation (SMR)

3.  Surgical Ablation Versus No Surgical Ablation for Patients with Persistent or Longstanding Persistent Atrial Fibrillation Undergoing Mitral Valve Surgery (AF)

•  Observational Prospective Studies

The following studies are completed:

1.  Management Practices and the Risk of Infections Following Cardiac Surgery (Infections Registry)

2.  Discrete Choice Study to Evaluate Patient Preference for Surgical vs. Non-surgical Procedures in Patients Undergoing Coronary Revascularization

•  Proof-of-Concept Trials

The following trial is being conducted as a collaboration with the Cardiovascular Cell Therapy Research Network (CCTRN) and leverages both intellectual and infrastructure resources from the two Networks to accelerate the translation of a novel “off the shelf” product for heart failure patients.  This CTSN-CCTRN collaboration is designed as a two-stage trial with Stage 1 randomization  to begin in the current grant period.  Provided the results of Stage 1 show that the protocol is feasible and the intervention is safe, Stage 2 will be conducted during the second grant period.

LVAD Therapy:  Exploring the Effect of Intramyocardial Injection of Mesenchymal Precursor Cells on Myocardial Function (LVAD-MPC) - Stage 1

Specific Research Objectives and Experimental Approaches Being Sought

The primary goal of the CTSN is to conduct multiple, collaborative, randomized clinical trials, proof-of-concept trials, and observational prospective clinical study protocols to evaluate surgical interventions and related management approaches to improve the treatment of cardiovascular disease and conditions in adult populations.   Also of interest are strategies to reduce neurological complications, such as stroke, and optimize long-term cognitive and functional outcomes after CT surgery by evaluating neuroprotective approaches.  Secondary objectives of the Network are to:

The CTSN emphasizes small translational, proof of concept and Phase 1 and 2 clinical investigations and trials.  Phase 3 trials are outside the scope of this program.  The Network is expected to be able to manage multiple trials and observational studies concurrently, and complete four to six Phase 1/2 trials and/or observational studies during the 5-year funding period.

Network Organization

The CTSN is a cooperative Network of Core Clinical Centers, a DCC, a rotating Network Chair (cardiothoracic surgeon) and rotating Co-Chair (cardiologist), NHLBI, NINDS and ICRH Project Scientists.

Core Clinical Centers (CCC) are responsible for proposing and developing protocols, recruiting study subjects, entering data into the web-based data capture system, assuring good clinical practice, mentoring junior investigators, and disseminating research findings.  All individual CCCs are required to participate in a cooperative and interactive manner with one another and with the Data Coordinating Center and to enroll into all CTSN sponsored trials and studies.  Up to eight CCCs will be funded through RFA HL-13-017, and up to 30 clinical consortium centers will be subcontracted through the DCC to enhance trial enrollment, protocol development, manuscript preparation, and other key Network activities.

The Data Coordinating Center (DCC) 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 by the DCC on a per patient basis and according to the approved protocol budgets.  The DCC identifies and subcontracts with clinical consortium centers, core laboratories and biorepositories.

The Steering Committee (SC) is the main governing body of the CTSN.  The SC is comprised of the Principal Investigators from the CCCs and the DCC, the Network Chairs, NIH and CIHR staff.  Voting members of the SC include the Chair (a cardiothoracic surgeon) and Co-Chair (a cardiologist), the principal investigators of the CCCs and DCC, and the NHLBI Program Official.  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 at 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 consists of all CTSN investigators and study coordinators from the core clinical and clinical consortium centers, staff members from the DCC and NIH, and the CTSN Chairs.  The Network Chair and Co-Chair 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 CCCs, representatives from the DCC, and members from NIH.

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 and Co-Chair.  The Study Chairs are independent of the DCC and CCCs 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 Investigators meetings.

NINDS, as a co-funding Institute, will participate on the SC.  The NHLBI and NINDS will share responsibilities with the Network for developing the neurology- and neurocognitive-specific content of the program.  The NHLBI will also share all communications, verbal or otherwise, including progress reports and correspondence, concerning this program.

ICRH will provide and administer a portion of the protocol funds for the CCC awarded to a successful academic institution located in Canada.  ICRH staff will work with NHLBI to assess responsiveness, collaborate with the NHLBI concerning the peer review process and administration, and advise the NHLBI on matters related to the Network.

An independent Protocol Review Committee (PRC) is appointed by and advisory to the NHLBI in consultation with ICRH. 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 missions and policies. All new study protocols performed by the CTSN must be approved by the PRC before referral to the DSMB.  The PRC may be copied on minor protocol amendments or low-burden ancillary studies.

An independent Data and Safety Monitoring Board (DSMB) is appointed by and advisory to the NHLBI in consultation with the ICRH, in accordance with established policies to ensure data quality and participant safety.  All network protocols must be approved and monitored by the DSMB, generally after their approval by the PRC (except in cases of minor protocol amendments, low-burden ancillary studies or secondary analyses of approved trials).  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 third year of the network and advise the NHLBI (and SC) on opportunities to improve operations and in future scientific directions.

Requirements for the CTSN Data Coordinating Center

The CTSN conducts clinical research with multiple trials and studies active at any given time.  During the second phase of funding, the emphasis will continue to be on research that is relevant to the mission of the NHLBI and NINDS, and is based on a thorough evaluation of the most important public health issues affecting adults and compelling scientific opportunities.  Studies to be run in the Network should require the collaborative infrastructure of the CTSN, and should be able to be completed in a 2-to 4-year time frame (awardees shall not assume that follow-up will occur outside of the lifetime of the award with Federal support).  CTSN pipeline protocols and new concepts will be reviewed and prioritized through the CTSN SC process after CCC cooperative agreement awards are made.  Protocols that are voted by the SC to be developed will be supported by protocol development committees made up of membership from CCCs, the DCC, and NIH.  All protocols unless otherwise peer reviewed, will undergo peer review by an independent CTSN Protocol Review Committee.

The DCC plays an important statistical, clinical, and administrative coordination role for the CTSN.  This includes a role in study design, conduct, and analysis as well as overseeing the broad scope of CTSN research and integrating the efforts of individual CTSN CCCs (HL-13-017), clinical consortium centers, and core laboratories.  Administrative activities include but are not limited to administrative support for the Network Chair and Co-Chair, scientific leadership, and committees, as well as organization of SC, investigator, coordinator, protocol development, DSMB, PRC, and other relevant meetings and conference calls, as well as publicizing ongoing clinical trials via appropriate advertising.

The DCC develops, maintains and refines the data management system for the Network.  This requires electronic data capture for each of the studies undertaken by the Network as well as assuring high data quality.  The data management system must be compatible with that used in the original award period and compliant with applicable regulations for computerized systems, including 21 CFR Part 11.

The DCC prepares protocols for submission to the PRC, DSMB, FDA, Centers for Medicare and Medicaid Services (CMS), or other government agencies as required, including defining sample size requirements and randomization schemes, and assisting in determining primary and secondary outcomes and analytical approaches.  The DCC develops trial stopping rules as appropriate, for NHLBI review and DSMB approval and prepares confidential data analyses and reports for the DSMB. The DCC also supports manuscript preparation through data analysis, statistical consultation, editorial support, and meeting coordination. 

Importantly, the DCC must operate under Good Clinical Practice guidelines, which includes preparation and maintenance of policies and standard operating procedures for all major activities.  The DCC develops procedures for quality control, training and certification, and data management. It monitors the quality and quantity of data received from the CCCs (including clinical consortium centers), biorepositories and core laboratories; provides relevant reports, including adverse events and unanticipated problems, to the NHLBI, clinical centers, and SC; and serves as a central repository for study data.  The DCC develops and maintains an electronic data capture system and manuals of procedures. The DCC also provides regulatory support and facilitates interactions with regulatory authorities. 

The DCC is responsible for clinical monitoring site visits (site initiation, interim monitoring, and close-out visits) necessary for training, quality control, data management in accordance with Good Clinical Practices.  The DCC is also responsible to ensure that all clinical sites are monitored in concert with the NHLBI Milestone Accrual Policy (MAP) - http://www.nhlbi.nih.gov/funding/policies/accrual_guidelines.htm

and that appropriate action is taken in a timely manner to evaluate underperforming sites.  To the extent possible, the DCC will:

In addition, DCC site monitors will visit each actively accruing clinical site at appropriate intervals depending on the number of ongoing CTSN trials at the site, trial accrual rate(s), applicable regulations, and findings from centralized monitoring as well as any previous site visits.  DCC key personnel will participate in site evaluation visits conducted with the NHLBI and Study Chair and Co-Chair to each core clinical site at least once during the 5-year funding period.

Administrative responsibilities include managing and distributing protocol funds to participating clinical centers as a fee for service arrangement after a protocol has been approved and the NHLBI has released the funds for distribution.  The DCC identifies, manages and distributes funding for centralized core laboratories, and clinical consortium centers through subcontracts.  It may also subcontract with suppliers, as needed.

The CTSN DCC is expected to integrate activities of all of the awarded CCCs and subcontracted clinical consortium centers to minimize resources/effort duplication and utilize existing resources available.  The entire CTSN program, including the DCC and CCCs, will be reviewed by an External Review Committee (ERC) during Year 3 and the DCC will be responsible for developing and providing relevant materials to the ERC for this review.

The applicant organization must have appropriate professional expertise and experience in the areas defined above. The applicant institution must have the necessary facilities to meet the special requirements mentioned in the FOA.  A minimum time commitment of 9 person months is expected from the Principal Investigator.

Section II. Award Information
Funding Instrument

Cooperative Agreement

Application Types Allowed

Renewal

The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

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

One (1) DCC will be funded by this award.

It is estimated that approximately $41,520,000 (Total Costs) will be awarded to the DCC over a five (5) year period.   Funding for core laboratories, consortium clinical sites, biorepositories, and protocol reimbursement will be provided according to the instructions in this announcement. 

The following NIH Components intend to commit the following amounts in FY2013: 

NHLBI: $8,104,000 (Total Costs)

NINDS:  $200,000 (Total Costs)

Award Budget

The DCC may request up to $2,000,000 direct costs each year for basic infrastructure costs.  Funding for core laboratories, biorepositories and protocol reimbursement should be requested separately and will be administered by the DCC in the following amounts (direct costs), year 1:  $2,472,941 and years 2-5:   $2,178,823.

Award Project Period

The total project period for an application submitted in response to this funding opportunity may not exceed 5 years.  

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement , are not allowed.

Required Registrations

Applicant organizations must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 4-6 weeks prior to the application due date.

Eligible Individuals (Program Director/Principal Investigator)

Eligible Program DirectorPrincipal Investigators (PD/PI) include those with the experience and expertise to conduct randomized clinical trials, proof-of-concept trials and prospective observational clinical studies in cardiothoracic surgery.  A minimum time commitment of 9 person months is anticipated from the PD/PI and this individual is expected to be readily available to respond directly to questions about CTSN matters on a daily basis, preferably through e-mail and should indicate this in the application.  An additional Investigator with expertise in statistics is strongly recommended, but not subject to the 9 person months commitment.  The disciplines and expertise that are appropriate for this program are cardiothoracic and cardiovascular surgery, cardiology, cardiovascular imaging, , cardiovascular physiology, health policy, clinical trials management, project management, regulatory affairs and biostatistics.  To ensure that data analysis is performed independently of data acquisition, the PD/PI for the DCC may not be a PD/PI for a CCC and vice versa.  The same institution may apply for both a CCC and DCC award; however, applications must identify different and independent groups of investigators for each.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed.     

Section IV. Application and Submission Information

1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the “Apply for Grant Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the 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.

Required and Optional Components

The forms package associated with this FOA includes all applicable components, mandatory and optional.  Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.

Page Limitations

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

SF424 (R&R) Research Plan Component

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

Qualifications and Experience

The CTSN is a collaborative effort requiring the DCC to participate in a cooperative and interactive manner with all components.  The DCC must demonstrate experience leading and coordinating complex multi-center clinical cardiothoracic surgical studies and trials, including activities such as:

The DCC must have the ability to provide online resources including a website for collaborative writing and communicating, must outline a plan for obtaining robust regulatory consultation, and must have the ability to apply for and hold any Investigational Device Exemptions (IDEs) and Investigational New Drug applications (INDs) required for new studies.

Additionally, departmental and institutional commitment to supporting cardiothoracic surgery research and to prioritization of Network research should be clearly documented by the leadership in the form of letters or memoranda provided to the Principal Investigator, 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.

Applicants must agree, if awarded, to accept the “Cooperative Agreement Terms and Conditions of Award” in Section VI. 2. A. “Award Administration Information.”  Awards will be subject to administrative review annually. 

The Research Strategy, and scientific and performance requirements must follow the instructions in the PHS 398 application form, http://grants.nih.gov/grants/funding/phs398/phs398.html and should not exceed 12 pages total.

Research Strategy

The research plan should demonstrate knowledge of the conduct of multi-center clinical trials and studies in the field of cardiothoracic surgery.  It should include the following components:

Research Team

Program Director/Principal Investigator must have a demonstrated track record of successful leadership of a multi-disciplinary team, including the ability to communicate with and ensure collaboration among all CTSN entities.  The major strengths and critical expertise of the DCC team members should be described in sufficient detail to demonstrate the ability to manage multiple studies at various stages of study design, management and closeout as outlined in the section below.

Study Design and Management

The DCC applicant should describe their experience with representative studies from CTSN as a means of discussing their approach to the design and conduct of cardiothoracic and/or cardiovascular surgical protocols, in order to maximize recruitment and retention as well as minimize logistical and regulatory issues.  Aspects to be considered within a Network setting where multiple trials are active at any given time include:

The applicant should also describe experience with cardiothoracic surgery and cardiovascular medicine and their ability to provide leadership in these areas to support the types of clinical studies conducted within the CTSN, i.e., randomized, controlled, blinded trials of up to 300 subjects, proof-of-concept/first in human trials of

For the purposes of this application, the DCC applicant should describe how they will identify, secure, and manage any and all necessary central laboratories for newly approved protocols, as well as plans to maintain any current central laboratories.

Protection of Human Subjects:  In the Form 398 section on Human Subjects, the data and safety monitoring plan requirements may be addressed as follows:

The CTSN has established data and safety monitoring principles and processes for all studies conducted within the Network and according to Good Clinical Practices.  These principles and processes include stringent adverse event reporting procedures, medical monitoring, and an independent CTSN DSMB that is established and operated by the NHLBI.  For the sub-section on the Data and Safety Monitoring Plan, the applicant may simply state that the Data and Safety Monitoring Plan for the study is to adhere to the standard CTSN policies and procedures for data and safety monitoring.

Budget Plans

Budgets should be prepared for five 12 month periods and request no more than $2,000,000 in direct costs per year for basic infrastructure costs.   In addition, 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.  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 - $2,472,941; Years 2-5 - $2,178,823..  Future year amounts will depend on annual appropriations. The DCC applicant should assume that two to three protocols will be active in the first year and four to six total protocols will be developed and begin active recruitment during the award period covered by this renewal FOA.  The budget should include, but is not limited to:

The award will be subject to administrative review annually.  It is expected that all protocols will be performed in a manner consistent with International Conference on Harmonisation Regulations:  Guideline for Good Clinical Practice E6(R1) and applicable federal regulations.

CTSN and 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.

There are many potential ways that a CTSN DCC could interface with a CTSA structure. Specific examples include leveraging bioinformatic, clinical trial design and biostatistics expertise. Since one of the goals of the CTSA network is to establish strong and interactive relationships with local communities and clinics, there may be potential for enhanced recruitment of clinically and ethnically diverse patient populations through the CTSA.  DCCs 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.

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

Appendix

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

Foreign Institutions

Foreign (non-US) institutions are not eligible for this limited funding opportunity but are eligible to apply for the companion funding opportunity RFA-HL-13-017.

3. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via 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.

Applicants are responsible for viewing their application 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.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

6. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF 424 (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.

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 SF 424(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.

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 Central Contractor Registration (CCR). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Applications must be received on or before the due dates in Part I. Overview Information.  If an application is received after that date, it will not be reviewed.

Section V. Application Review Information

1. Criteria

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.

Overall Impact

Reviewers will provide an overall impact/priority 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).

Scored Review Criteria

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? 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?  

Investigator(s)    

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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(s)/PI(s), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation

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?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? 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? 

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Environment

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? 

Additional Review Criteria

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/priority score, but will not give separate scores for these items.

Protections for Human Subjects

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 Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children 

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

Not Applicable

Biohazards

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.

Resubmissions

 Not Applicable.

Renewals

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

Revisions

Not Applicable.

Additional Review Considerations

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/priority score.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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).

Resource Sharing Plans

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) Genome Wide Association Studies (GWAS).

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the Office of Scientific Review, Division of Extramural Research Activities, NHLBI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

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 where applicable. Following initial peer review, recommended applications will receive a second level of review by the NHLBI Advisory Council. The following will be considered in making funding decisions:

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD(s)/PI(s) will be able to access his or her Summary Statement (written critique) via the eRA Commons

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

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 the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include 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.

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 Parts 74 and 92 (Part 92 is applicable when state and local governments are eligible to apply), 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 PD/PI will be responsible for the overall function of the DCC, which is to coordinate, administer, and support all CTSN research and training activities.  The DCC PD/PI will be responsible for oversight of protocol development, drug and device acquisition and distribution, data collection, data safety and confidentiality, quality assurance, data analysis, coordination of data distribution, and implementation of all data sharing plans.  The DCC PD/PI will be responsible for the distribution of protocol funds to the CCCs.  The DCC PD/PI will be responsible for coordinating manuscript preparation, coordination of the activities of the Steering and All Investigators Committees, Study Committees, other Subcommittees established by the CTSN, the PRC, and the DSMB.

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, or provision of routine goods and services within normal business operations that are ancillary to the operation of the research program, support or involvement of any third party will occur only following notification of and concurrence by NHLBI. 

Study investigators are encouraged to publish and to release publicly 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 3 years of the end of the period of NHLBI support, provided such release is consistent with the study protocol and governance.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current 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 and NINDS Project Scientists will monitor patient recruitment and study progress, ensure disclosure of conflicts of interest, and ensure adherence to NHLBI policies.  NHLBI will appoint the Network Chair, Co-Chair, all members of the PRC, and the DSMB.  The Network Chair and Co-Chair will be responsible for ensuring that there are well-documented policies, procedures, and bylaws to guide all aspects of Network activities and operations. 

The NHLBI and NINDS Project Scientists will serve on the SC and other study committees, when appropriate.  The NHLBI and NINDS Project Scientists may work with awardees on issues coming before the SC and, as appropriate, other committees, e.g., recruitment, intervention, follow-up, quality control, adherence to protocol, assessment of problems affecting the study and possible changes in protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment (see http://www.nhlbi.nih.gov/funding/policies/accrual_guidelines.htm).

The NHLBI reserves the right to phase out or curtail the study (or an individual award) in the event of  (a) failure to develop or implement a mutually agreeable collaborative protocol; (b) substantial shortfall in participant recruitment, follow-up, data reporting, or quality control; (c) major breach of the protocol or substantive changes in the agreed-upon protocol 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 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 SC.   The SC will have primary responsibility for the conduct of protocols and the preparation of publications. SC voting membership shall consist of all Principal Investigators (i.e., cooperative agreement awardees), one NHLBI Project Scientist, the Chair and the Co-Chair.  Each full member will have one vote. Awardee members of the SC will be required to accept and implement policies approved by the SC.

An independent PRC, established by the NHLBI, will provide peer review for each network protocol.  A DSMB 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(s), 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 through the chain of command to the Associate Director, Basic and Early Translational Research Program for resolution.

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, 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.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.     

Application Submission Contacts

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Scientific/Research Contact(s)

NHBLI

Marissa A. Miller, D.V.M., M.P.H.
Division of Cardiovascular Sciences
National Heart, Lung, and Blood Institute
National Institutes of Health
6701 Rockledge Drive, Room 8214, MSC 7940
Bethesda, MD 20892-7940
Telephone: 301-594-1542
Email: millerma2@mail.nih.gov

NINDS

Claudia S. Moy, Ph.D.
Program Director, Office of Clinical Research
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 2214, MSC 9520
6001 Executive Blvd.
Bethesda, MD 20892
Telephone: 301-496-2789
FAX: 301-480-1080
Email: moyc@ninds.nih.gov

Peer Review Contact(s)

Director, Office of Scientific Review
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute
National Institutes of Health
6701 Rockledge Drive, Room 7214, MSC 7924 
Bethesda, MD 20892-7924 (Express: 20817)
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: nhlbichiefreviewbranch@nhlbi.nih.gov

Financial/Grants Management Contact(s)

Ms. Tamara Kees
Grants Management Specialist, Office of Grants Management
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute
National Institutes of Health
6701 Rockledge Drive, Rm 7174, MSC 7926
Bethesda, MD 20892-7926
Telephone: 301-435-0169
Email: tkees@mail.nih.gov

Section VIII. Other Information

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

Authority and Regulations

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 Parts 74 and 92.


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