National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Funding Opportunity Title
Data Coordinating Center for the Cardiovascular Cell Therapy Research Network (CCTRN) (UM1)
UM1 - Cooperative Agreements - Multi-Component Research Project Cooperative Agreements
Reissue of RFA-HL-06-001
Funding Opportunity Announcement (FOA) Number
|RFA-HL-12-026, UM1 Multi-Component Research Project Cooperative Agreements|
Catalog of Federal Domestic
Assistance (CFDA) Number(s)
The purpose of this FOA is to request applications for participation as a Data Coordinating Center (DCC) in a continuation of the Cardiovascular Cell Therapy Research Network (CCTRN). A separate solicitation (RFA-HL-12-026) seeks applications for network Regional Clinical Centers (RCCs).
The goal of the CCTRN is to promote evaluation of novel cell-based treatment strategies for individuals with cardiovascular disease. The network provides support to maintain an infrastructure to develop, coordinate, and conduct multiple collaborative clinical trials designed to improve cardiovascular disease outcomes.
April 20, 2011
Letter of Intent Due Date
May 22, 2011
Application Due Date(s)
June 22, 2011
AIDS Application Due Date(s)
Scientific Merit Review
Advisory Council Review
Earliest Start Date(s)
June 23, 2011
Due Dates for E.O. 12372
Required Application Instructions
It is critical that applicants follow the instructions in the PHS398 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. While some links are provided, 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 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
Nature of the Research Opportunity
This solicitation requests applications for a Data Coordinating Center (DCC) to support a Renewal of the Cardiovascular Cell Therapy Research Network (CCTRN). A separate solicitation (RFA-HL-12-026) seeks applications for Regional Clinical Centers (RCCs) that operate within the network. The CCTRN provides a unique environment for academic leaders in the field to form collaborative partnerships to develop and implement well-designed cell-based clinical studies.
The CCTRN was initiated in January, 2007, to provide the organizational, technical and clinical infrastructure necessary to conduct early, proof-of-concept studies designed to provide new knowledge in the field of cell-based therapies for the treatment of cardiovascular diseases. Currently, the CCTRN consists of a DCC and five RCCs, some of which have added satellite centers to enhance patient recruitment. The CCTRN also maintains a biorepository and core labs to manage imaging data (MRI, SPECT, and echocardiography) and functional capability data (exercise testing), plus a training program for clinician-scientists interested in cell-therapy research. Beginning in 2012 with the next funding period, it is anticipated that the network will expand to 6 RCCs and up to 12 satellite centers. As this is a Renewal, applications from the current DCC and RCCs will be evaluated in addition to applications from institutions not presently in the network.
The DCC leads and manages all aspects of the conduct of multicenter trials, including site contracts with core laboratories, regulatory compliance, recruitment monitoring, patient safety and adverse event reporting, protocol development, manuals of operations, and training. The DCC also provides a data management function, with expertise in statistical analyses in support of protocol development and manuscript preparation, database development, data collection, quality, and integrity.
Heart disease is the leading cause of death in North America. In 2006, cardiovascular diseases caused 831,000 deaths, representing 34 percent of all deaths in the United States. Each year about 785,000 Americans have a first heart attack, and another 470,000 have a second (or higher) attack. Approximately 500,000 new heart failure cases are diagnosed every year, and an estimated five million Americans suffer from heart failure. The estimated cost of cardiovascular disease for 2010 is approximately $503 billion: $324 billion in direct health expenditures, $42 billion in indirect cost of morbidity and $137 billion in indirect cost of mortality (Source: NHLBI Disease Statistics).
Recently published data from multiple epidemiologic studies show that about 8 million Americans above the age of 40 have peripheral arterial disease. Prevalence increases dramatically with age and disproportionately affects blacks (Source: American Heart Association).
Improved medical and surgical management in the past 30 years has produced a decline in the death rate due to cardiovascular heart disease. In certain groups, left ventricular assist device (LVAD) implantation may provide short- to intermediate-term benefit. However, damage from hypertension, myocardial infarction, valvular disease, and cardiomyopathy often leads to remodeling of cardiac tissue, which can progress to heart failure. Accelerated ventricular remodeling is a probable contributor to the increased mortality observed after myocardial infarction in hypertensive patients. Current therapy cannot reverse the harmful remodeling and loss of myocytes that accompanies injury. In light of the limited efficacy and poor side effect profile of current treatment options, there is an unmet need for alternative long-term therapeutic strategies. If therapies could be developed to reverse or repair heart damage, an enormous public health burden would be ameliorated.
During the past ten years there has been a growing body of evidence suggesting that regeneration strategies such as cell-based therapies may provide viable approaches to repairing damaged myocardial tissue and restoring cardiac function. A variety of adult stem cells, including bone marrow mononuclear cells, endothelial progenitor cells and mesenchymal stem cells have demonstrated improved ventricular function in animal models of acute myocardial infarction. However, the mechanism(s) by which regeneration may occur in humans remain largely unknown, with the possibilities including both direct (e.g., stem cell differentiation) and indirect (paracrine) effects. Investigators are working to understand stem cell plasticity, mechanisms of stem cell engraftment and survival, and effects on organ function in order to refine approaches that can be utilized in clinical settings.
Research aimed at preventing the progression and consequence of cardiovascular disease, and reversing the disease process through repair and regeneration of damaged tissues, has provided the basis for a new and exciting paradigm of cardiovascular disease treatment. Small exploratory studies and larger randomized clinical trials of cell therapy in patients with myocardial infarctions or chronic heart failure currently are underway in the CCTRN and elsewhere. Both animal and human studies indicate that cell therapy may be able to improve cardiac function and replace damaged or diseased tissue. Early clinical studies suggest that infusion of autologous bone marrow cells is safe and may improve cardiac function in human disease as well.
Thus, three major factors – a compelling clinical need, supportive preclinical data, and promising early clinical experience – underscore the opportunity for cell-based therapy to dramatically alter the treatment of cardiovascular disease.
Ongoing Clinical Trials
Currently the CCTRN is supporting three clinical trials, which are expected to complete randomization of patients by the end of 2011:
1. TIME Transplantation in Myocardial Infarction Evaluation . A Phase II, Randomized, Controlled, Double-Blind Trial Evaluating the Effect of Timing on the Administration of Bone Marrow Mononuclear Cells versus Placebo in Patients with Acute Myocardial Infarction.
2. LateTIME: A Phase II, Randomized, Controlled, Double-Blind Trial Evaluating the Safety and Effect of Administration of Bone Marrow Mononuclear Cells Two to Three Weeks Following Acute Myocardial Infarction.
3. FOCUS: A Randomized, Controlled, Phase II, Double-Blind Trial of Intramyocardial Injection of Autologous Bone Marrow Mononuclear Cells under Electromechanical Guidance for Patients with Chronic Ischemic Heart Disease and Left Ventricular Dysfunction.
These studies are expected to provide new scientific knowledge regarding the feasibility and effectiveness of delivering cells to cardiac tissue for the purpose of improving cardiac function and patient outcomes. Additional scientific knowledge is expected from studies of patient samples stored in a network biorepository, and from other patient-related data.
Specific Areas of Research Interest and Experimental Approaches Being Sought
The primary goal of the Network is to conduct multiple network-wide clinical trials to evaluate cell-based therapies for the treatment of cardiovascular diseases and related syndromes such as angina and peripheral arterial disease. Secondary objectives of the Network are to:
The CCTRN emphasizes early Phase I and II clinical investigations. Studies may involve autologous or allogeneic cells, new strategies for cell delivery, techniques for screening and localizing transplanted cells, and standardization of cell and therapeutic procedures. Phase III trials are outside the scope of this program. The Network is expected to be able to manage multiple trials concurrently, and complete five to eight Phase I/II trials during the seven-year funding period.
Potential research protocols include, but are not limited to, randomized clinical trials that:
Study endpoints that include pulmonary function measurements in addition to cardiac function are encouraged.
The CCTRN will be funded as a Cooperative Agreement consisting of a DCC and up to six RCCs with associated satellites, a biorepository, up to four core laboratories and up to four skills-development training programs for investigators and nurse coordinators. The DCC awarded under this FOA will be expected to work collaboratively with the current DCC for the transition of these responsibilities.
Funds will be provided for up to 12 satellite centers within the network. Inclusion of satellite centers in RCC applications (see RFA-HL-12-026) is encouraged, but optional. Failure to include satellite centers will not adversely affect proposal scoring. Foreign sites are not allowable due to the logistics of cell processing.
The network will use a governance structure consisting of a NHLBI-appointed steering committee Chair, a steering committee comprised of RCC principal investigators, and NHLBI staff.
Scientific and Performance Requirements for the DCC
DCCs will be evaluated on the strength of their scientific application as well as their record of success supporting previous cardiovascular clinical trials. The DCC will be expected to manage multiple concurrent protocols. Accordingly, the PD/PI of the DCC is expected to have demonstrated scientific leadership in the conduct of cardiovascular cell therapy-based clinical research. DCC key personnel must demonstrate both clinical science excellence and specialized expertise in cardiovascular disease monitoring, with a strong background in clinical trials management, research, pharmacovigilance, human subjects protection, and regulatory affairs.
As noted earlier, the DCC coordinates, administers, and supports all Network clinical research activities. These activities include administrative support for the Network Chair, scientific leadership and committees, reimbursement for patient accrual, and organization of investigator meetings. The DCC assists in final protocol development, provides statistical leadership for each study design, and prepares operational timetables. The DCC develops and maintains a data collection system and manuals of procedures, determines sampling and randomization schemes, and assists in defining primary and secondary outcomes and analytical approaches for the protocols. The DCC also provides regulatory guidance and facilitates interactions with regulatory authorities.
Importantly, the DCC must operate under GCP guidelines, which includes preparation and maintenance of policies and standard operating procedures for all major activities.
The DCC must identify a highly qualified expert in regulatory affairs in its listing of key personnel. In addition, the DCC must identify a highly qualified cardiology medical/safety officer, separate from and independent of the PD/PI, in its listing of key personnel.
The DCC subcontracts with external laboratories and consultants as needed, coordinates with suppliers of cells, and arranges for standardization and quality control measures to ensure adequacy and comparability of cellular products across RCCs. The DCC manages and distributes funding for centralized core laboratories, patient care and training programs.
The DCC develops procedures for quality control, training and certification, and data management. It monitors the quality and quantity of data received from the RCCs (including Satellite centers), biorepositories and core laboratories, provides relevant reports, including adverse events, to the NHLBI, RCCs, and Steering Committee (SC), and serves as a central repository for study data. In addition, the DCC establishes quality control measures for cell preparations to ensure the isolation, preparation, viability, and characteristics of the cell preparations from RCCs are comparable, standardized and clinical grade cell products.
The DCC is responsible for clinical monitoring site visits (site initiation, interim monitoring, and close-out visits) necessary for training, quality control, data management and at a minimum will visit each actively accruing site at least twice yearly during the study period. In addition, DCC key personnel will participate in site evaluation visits conducted with the NHLBI and Study Chair at least twice during the 7-year funding period.
The DCC prepares protocols for submission to the Protocol Review Committee, and to the FDA, Centers for Medicare and Medicaid Services (CMS), or other government agencies as required, and prepares confidential data analyses and reports for the Data and Safety Monitoring Board (DSMB). The DCC, with NHLBI and DSMB support and approval, develops stopping rules as appropriate. The DCC also supports manuscript preparation through data analysis, statistical consultation, editorial support, and meeting coordination. The DCC schedules and makes arrangements for all meetings of established committees and boards. The DCC manages and distributes 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 is subject to annual administrative review. Also, it is anticipated that the entire CCTRN program, including the DCC and RCCs, will be reviewed by a panel of experts during year -04.
Steering Committee (SC)
The SC is the main governing body of the network. Voting members of the SC include, at a minimum, the Network Chair, the PD/PIs of the DCC and RCCs (or their designated alternates), and the NHLBI Program Officer. The network Chair is independent of the DCC and RCCs, and will be appointed by NHLBI. The network Chair will plan network activities, oversee its functions, conduct SC meetings, and be a voting member of the Steering Committee. The SC will develop and ensure compliance with network policies and procedures, identify and prioritize topics for investigation, evaluate protocols proposed by the RCCs, and develop consensus protocols for submission to protocol review committees (PRCs). The SC also participates in the selection and oversight of Network core laboratories and biorepositories. The SC will ensure that studies are properly conducted and monitored, that data are analyzed and interpreted appropriately, and that study results are reported in the scientific literature in a timely manner and disseminated to those directly involved in the care of cardiovascular disease patients. The SC typically meets three times per year, with bi-weekly conference calls and ad hoc meetings as required. All major scientific decisions will be determined by majority vote of the SC, subject to final approval by NHLBI. The SC has final responsibility for approving the protocol before review by the PRC or Data and Safety Monitoring Board (DSMB).
Subcommittees of the SC, such as the Executive Committee, and subcommittees for Publications and Presentations, Research Coordinators, Cell Processors, and Quality Control, have been established and may be continued or added to at the discretion of the SC. The Publications and Presentations Subcommittee facilitates and supervises preparation of manuscripts prior to submission for publication. The Research Subcommittee recommends research ideas and develops network research protocols for review identified by the SC. The Quality Control Subcommittee is responsible for developing standards for specific laboratory tests and other measures to be used in the network protocols.
Protocol Review Committee (PRC)
An independent PRC is appointed by and advisory to the NHLBI. It consists of a chairperson and scientists with expertise in basic and clinical cell therapy research, clinical trial design, biostatistics, enabling technologies, outcome measures, and other areas of expertise as needed. The PRC will evaluate protocols proposed 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 network must be approved by the PRC before referral to the DSMB. Minor protocol amendments or low-burden ancillary studies or secondary analyses of approved trials may be submitted directly to the DSMB for consideration.
Data and Safety Monitoring Board (DSMB)
An independent DSMB is appointed by and advisory to the NHLBI 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.
Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed
The OER Glossary and the PHS398 Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards
The number of awards is contingent upon NIH appropriations, and the submission of a sufficient number of meritorious applications. Only one (1) DCC will be funded by this award.
The total amount of funding (direct and indirect costs) that will be available through this and the companion announcement (RFA-HL-12-026) is up to $63 million over a seven-year period to support the CCTRN. It is estimated that approximately $10.5 million direct costs will be awarded to the DCC. Additional funds for core laboratories (imaging, echocardiology, etc.), biorepositories, and protocol reimbursement will be provided according to the instructions in this announcement.
The DCC may request up to $1.5M direct costs in each year for basic infrastructure costs. Funding for core laboratories (imaging, echocardiology, etc.), cell preparation, biorepositories, and protocol reimbursement should be requested separately and will be administered by the DCC.
Award Project Period
The total project period for an application submitted in response to this funding opportunity may not exceed seven 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.
Higher Education Institutions:
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
For profit Organizations
Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply. Foreign (non-U.S.) components of U.S. Organizations are not allowed.
Applicant organizations must complete the following registrations as described in the PHS398 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 Directors/Principal Investigators (PD/PIs) 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 four (4) weeks prior to the application due date.
Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Project Director/Principal Investigator (PD/PI) 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 PHS398 Application Guide.
Eligible PD/PIs include those with the experience and expertise to conduct clinical studies in cardiovascular diseases. The disciplines and expertise that may be appropriate for this program are cardiology, cardiovascular surgery, cardiovascular imaging, cardiovascular nursing, cardiovascular physiology, stem cell biology, clinical trials management, project management, regulatory affairs and biostatistics. To ensure that data analysis is performed independently of data acquisition, the PD/PI for a DCC may not be a PD/PI for a RCC, and vice-versa. The same institution may apply for both a RCC and DCC award, but the applications must identify different and independent groups of investigators for each.
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.
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.
Applicants are required to prepare applications according to the current PHS 398 application forms in accordance with the PHS 398 Application Guide.
It is critical that applicants follow the instructions in the PHS398 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.
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 research
Name, address, and telephone number of the PD(s)/PI(s)
Names of other key personnel
Number and title of this funding opportunity
The letter of intent should be sent to:
Director, Office of Scientific Review
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7214, MSC 7924
Bethesda, MD 20892-7924 (Express Mail: 20817)
Telephone: (301) 435-0270
FAX: (301) 480-0730
Applications must be prepared using the PHS 398 research
grant application forms and instructions for preparing a research grant
application. Submit a signed, typewritten original of the application,
including the checklist, and three signed photocopies in one package to:
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)
At the time of submission, two additional paper copies of the application and all copies of the appendix files must be sent to:
Director, Office of Scientific Review
Division of Extramural Affairs National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7214, MSC 7924
Bethesda, MD 20892-7924 (Express Mail: 20817)
Telephone: (301) 435-0270
FAX: (301) 480-0730
All page limitations described in the PHS398 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:
All instructions in the PHS398 Application Guide must be followed, with the following additional instructions:
General Requirements for the DCC
The Network is a collaborative effort requiring the DCC to participate in a cooperative and interactive manner with all components. Applicants should explicitly indicate their willingness to:
Additionally, departmental and institutional commitment to supporting cardiovascular cell therapy research and to prioritization of Network research should be clearly documented by the leadership in the form of letters or memoranda provided to the PD/PI, 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 and should include Institutional Review Board (IRB) assurance of a willingness to consider participation in cell therapy research.
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.
Budget guidelines for the DCC
Applicants should prepare operating budgets for seven one-year periods with maximum allowable direct costs for DCC operations not to exceed $1.5 million per year. The budget should include a minimum of 6 calendar months effort for the PD/PI, and a minimum half-time position should be budgeted to cover the costs associated with the management and distribution of approved Protocol Funds to the RCCs, satellites and core laboratories. Other key personnel should include project managers, clinical trial monitors, a qualified regulatory affairs specialist, a cardiology medical/safety officer and supporting staff for administrative, financial and information technology support.
Operating budgets should include costs of statistical, operational and administrative support for up to six RCCs and up to four concurrent clinical trials. These functions include, but are not limited to, the costs of developing trial-specific manuals of procedures, electronic data forms, means of electronic transmission, data collection and organization tools, and quality improvement tools for the tracking of data collection and site performance. The DCC also is responsible for procuring pharmaceuticals and devices, preparing and managing INDs or IDEs, and monitoring the approximately 18 participating clinical sites (including both the RCCs and their satellites). Semi-annual visits by relevant DCC personnel to each of these sites for site management and training should be budgeted. The DCC budget also must include support for the NHLBI-appointed Network Chair for the seven years (2.4 calendar months) effort and travel expenses), as well as costs for managing/supporting meetings of the DSMB, PRC, and SC. The DSMB, which consists of 14 members, is expected to meet approximately every 6 months, with interim calls as required. The PRC meets on an irregular schedule, but should be budgeted for at least one meeting per year, with interim calls as required. The Steering Committee is expected to meet in person three times per year, with biweekly teleconferences throughout the project period. Costs for other committee support, including that which may be required for event adjudication, also should be included.
The budget justification for each year must include a table that apportions the total cost request among the following categories: 1) Center infrastructure costs (to include personnel, equipment, supplies and travel), and 2) Study support costs (to include biorepository, core laboratories, cell preparation) and protocol costs (to include patient care and cell processing costs). Center infrastructure costs should include support for essential personnel and facilities and the costs for meetings in Bethesda, Maryland, of the PRC (8 members, 1 meeting per year, with 2 to 4 conference calls per year) and the DSMB (14 members, 2 meetings per year with 2 conference calls).In addition the DCC will support travel and expenses for approximately 15 RCC clinical coordinators and DCC project managers to meet on a quarterly basis. The DCC budget must include support for the Network Chair over the 7 years (2.4 calendar months plus travel expenses), and also for two site visits made to each of the (up to six) RCCs during the 7-year interval. The total first year budget request should provide for the organization of all administrative aspects of the Network and for the development of at least two protocols. Budget requests for years 2-7 should assume that additional protocols will be initiated and that 5-7 protocols requiring up to 490 patients will be implemented during the grant period. Center costs also should include the costs of updating the Network Administrative Manual of Operations, trial-specific manuals of procedures and of developing questionnaires, forms, and database structures, website development and maintenance, and marketing activities and materials (brochures, videos, seminars, food).
Study support costs should include the costs of pharmaceutical and device management, patient travel (mileage reimbursement, public transportation, lodging, ambulances) data entry and analysis, quality control, and manuscript preparation. Patient care costs should be requested at the following amounts: year 1 - $630,000; year 2 -$1.89 million, and years 3-7 at $1,26M per year. Over the 7 year project period, the following direct cost amounts should also be requested: $980,000 for GMP cell preparation; $1.26M for the biorepository; and $4.2M for up to 4 core imaging laboratories. The funds released for DCC operations in each year will be based in part on the number of protocols actually carried out by the network and may be more or less than the budget requested in the application.
As noted earlier, the total amount of funding (direct and indirect costs) that will be available through this and the companion funding opportunity announcement (RFA-HL-12-026 is up to $63 million. Of this amount, the NIH expects to provide a total of up to $5.2 million (direct costs) to the network for fiscal year 2012. If the incumbent DCC is not selected, additional funds (approximately $100,000) will be awarded in Year -01 to support the transition to the new DCC.
CCTRN and Clinical and Translational Award (CTSA) Organizations
The NHLBI encourages academic centers participating in the CCTRN 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 CCTRN DCC could interface with a CTSA structure. Specific examples include utilizing some of the educational and mentoring programs within the CTSA organization to enhance a Clinical Research Skills Development Core. 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 PHS398 Application Guide, with the following modifications:
Do not use the appendix to circumvent page limits. Follow all instructions for the Appendix (please note all format requirements) as described in the PHS398 Application Guide.
Foreign (non-US) organizations are not eligible for this funding opportunity.
Part I. Overview Information contains information about Key Dates.
Information on the process of receipt and determining if
your application is considered “on-time” is described in detail in the PHS398
Applicants may track the status of the application in the eRA Commons, NIH’s electronic system for grants administration.
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
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
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
Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness byNHLBI, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.
The following items must be satisfactorily addressed for an applicant to be eligible as the DCC for the CCTRN program: Relevant past performance, personnel qualifications; overall strategies and plans to manage multicenter clinical trials; procedures for developing trial protocols and timelines; procedures for coordination of network activities; procedures for data and biospecimen management and monitoring; communication plans; financial management; departmental and institutional support, and a transition plan.
Applicants must provide evidence of skills, ability, and research productivity as the DCC in previous or ongoing multi-institutional clinical trials. Specific areas to address should be related to the role of the data coordinating center described in Section I of this FOA. In particular, applicants should describe their previous experience in:
a. Coordinating and supporting the conduct and management of Phase I/II clinical trials including accrual planning and monitoring, and evaluation of trial performance.
b. Overseeing and coordinating concept and protocol development for multicenter Phase I/II clinical trials, trial design, review and approval of protocols and their amendments; procedures to implement approved study concepts at clinical sites.
c. Statistical support for Phase I/II clinical trial design and monitoring; generating and presenting reports for multicenter trials to DSMBs.
d. Data management and quality assurance.
e. Phase I/II clinical trial data analysis and dissemination of findings.
f. Planning and managing fiscal activities for a DCC and for a multicenter program; developing and managing protocol budgets; generating financial reports, distributing funds to multiple sites on a per-patient basis.
g. Negotiating contracts with outside sponsors, pharmaceutical companies or foundations to provide agents and/or financial or in-kind support for a clinical trial.
The DCC should have flexibility in staffing to meet the variation in work scope of the Network. Staffing may need to be adjusted based on changing study requirements.
The applicant should outline their strategies and approach for the following:
a. Implementing a management structure required to simultaneously conduct and complete Phase I/II clinical trials, including estimation of resources needed for different aspects of trial management; coordination of center activities; oversight required for timely protocol development and implementation; monitoring of accrual; on-site and off-site monitoring; and hiring of appropriate personnel.
b. Promoting collaboration between the CCTRN and other cooperative clinical trials groups, where appropriate.
c. Identifying and training qualified non-Core (Satellite) centers and collaborators with patient populations eligible for CCTRN studies that warrant additional patients; identifying and implementing practices to streamline and improve efficiency and productivity of clinical research processes for collaborative trials, including implementing procedures for data capture and sharing.
d. Identifying, standardizing and harmonizing common data elements, procedures and outcome measures for cell therapy data capture and reporting.
e. Leveraging available resources at the applicant’s institution, as appropriate.
The applicant should describe previous experience in the following areas:
a. Concept development and feasibility assessment, protocol design and analysis plans, and implementation of multicenter trials involving cardiovascular cell therapy. Include timeline expectations for various aspects of trial implementation indicated above. The clinical trials are expected to be conducted and completed within the timeframe of this FOA.
b. Meetings and communications for multicenter trials: Planning, arranging for, and supporting meetings of the Steering Committee and its subcommittees, PRC, and DSMB. Prepare minutes and distribute to members.
c. Website(s): Developing and maintaining a secure website for electronic data capture, distribution of study documents, forms, and information, including metrics (textual and graphical) of study progress and performance (e.g., expected vs. actual subject accrual indexed by Clinical Center). Developing and maintaining an open-access website that provides information about the CCTRN to the public and prospective research subjects. NHLBI expects that the open-access website will contain information about each trial, including a summary of study aims, design, and eligibility criteria; a link to the study registered in ClinicalTrials.gov (http://clinicaltrials.gov/) and a link to the NHLBI public website (http://www.nhlbi.nih.gov/index.htm). The public website must comply with all applicable Federal regulations, including Section 508 of the Rehabilitation Act of 1973 (29 USC 794d). See http://www.section508.gov and http://www.nih.gov/icd/od/ocpl/resources/wag/.
d. Creation and maintenance of secure and robust data management systems to compile, quality check, track, and manage all data collected about subjects enrolled on CCTRN trials, including procedures for data quality control/improvement, and training and certification.
e. Creation and maintenance of standard operating procedures that describe network support activities.
f. Phase I/II Clinical trials oversight activities including clinical monitoring visits by DCC staff or contractors.
Departmental and institutional commitments to participate as the DCC for the CCTRN Program should be clearly documented with letters of support from appropriate individuals. Evidence of past support also may be cited. Support in areas of grants management, personnel management, space allocation, procurement, data coordination and confidentiality, and equipment as well as general support of the Network’s research should be specified and may be more fully detailed in the Resources section of the application (Section 4.7).
Applicants must clearly express their intent to participate in a cooperative manner with NHLBI and other components of the CCTRN program, as outlined in this FOA.
All applicants should provide a plan to ensure an orderly transition of data sets/files, databases, manuals, and forms developed by the current program to the DCC awarded through this FOA or as directed by the Federal Government. At the end of the seven-year program supported by this FOA, the DCC must transfer all CCTRN acquired data, and forms and manuals developed by the CCTRN to the Federal Government, or as directed by the Federal Government.
Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.
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
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).
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? 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 PD/PIs, 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/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Does the application provide evidence of investigator success in carrying out or managing cardiovascular clinical trials, as measured by meeting study recruitment goals or managing study documentation requirements and producing peer-reviewed publications?
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?
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?
Does the research plan demonstrate understanding of the scientific, statistical, logistical, and technical issues underlying multi-center clinical trials, including the assessment of outcomes relating to treatment and management of cardiovascular patients? Does the DCC demonstrate leadership in study design, data acquisition and management, data quality, and data analysis?
Does the DCC management demonstrate that an administrative framework has been developed and implemented to facilitate the design, implementation, review and management of cell therapy trial protocols? Does the DCC management demonstrate an ability to assist RCCs with recruitment problems, and to subcontract with non-RCC central laboratories and consultants, if needed, to meet overall goals and study needs? Are there feasibility and clarity of plans for prioritizing the use of shared resources, for allocating availability to the proposed research activities, and for ensuring that the scientific resources and facilities are used to their fullest extent? Does the DCC demonstrate leadership in organizing Network meetings and conference calls, study training and study oversight? Does the DCC demonstrate that staff has the expertise, training, and experience to effectively coordinate multiple protocols in a Network? Are adequate expertise, time and effort devoted for effective Network functions? Is adequate medical and regulatory expertise available to handle the highly regulated area of cell therapy? Does the DCC demonstrate an ability to participate in collaborative research and cooperate with a Network Steering Committee, RCC staff, and the NHLBI? Does the DCC demonstrate willingness to continue with the same level of participation? Does the applicant acknowledge potential problem areas and consider alternative tactics?
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?
Does the DCC demonstrate that the facilities, equipment, and organizational structure are present to effectively coordinate CCTRN activities, assist RCCs in implementing the CCTRN study protocols, collect, securely store and analyze study data? This includes but is not limited to conducting studies, and obtaining study and investigational agents and devices. Are standard operating procedures consistent with GCP and applicable regulations in place? Does the DCC have a fully functional and validated electronic data capture system in place for data management? Does the DCC demonstrate an ability to assist by contracting with non-RCC centers for the development of repositories or central laboratories, arranging and coordinating the conduct of laboratory tests and studies, and obtaining and coordinating the distribution of study and investigational agents and devices?
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.
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
For Renewals, the committee will consider the progress made in the last funding period.
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
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.
Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group convened by the Office of
Scientific Review, Division of Extramural Research Activities, NHLBI (assignments
will be shown in the eRA Commons), in accordance with NIH peer
review policy and procedures, using the stated review
As part of the scientific peer review, all applications:
Applications will be assigned to the NHLBI and will compete for available funds with all other recommended applications submitted in response to this FOA . Following initial peer review, recommended applications will receive a second level of review by the NHLBI Advisory Council. The following will be considered in making funding decisions:
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.
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
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 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.
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.
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
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
The Clinical Center Principal Investigators will have the primary responsibility in all aspects of CCTRN studies, including proposing protocols, participating in their overall development, preparing protocol budgets in collaboration with the DCC, modifying proposals if indicated, recruiting study participants, conducting the research, assuring quality of study participant care and protocol adherence, assuring the accurate and timely transmission of data collected in conjunction with the DCC, analyzing and interpreting data, preparing publications, and working with the DCC and NHLBI to disseminate research findings. Clinical Center PIs will also be responsible for working with the DCC to develop common definitions and standardization across protocols wherever appropriate. Awardees must agree to the governance of the study through a Steering Committee.
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.
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 three years of the end of the period of NHLBI support, provided such release is consistent with the study protocol and governance.
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 Project Scientists will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
The NHLBI Project Scientists will monitor patient recruitment and study progress, ensure disclosure of conflicts of interest, and ensure adherence to NHLBI policies. NHLBI will appoint the Network Chair, all members of the Protocol Review Committee (PRC), and the Data and Safety Monitoring Board (DSMB). The Network 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 Project Scientists 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 Steering Committee 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.
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.
In addition to the Project Scientits, a separate NHLBI Program Officia will be responsible for normal stewardship of the cooperative agreement, and will be named in the Notice of Award.
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 the conduct of protocols and the preparation of publications. Steering Committee voting membership shall consist of all Principal Investigators (i.e., cooperative agreement awardees), one NHLBI Project Scientist, and the Chairperson. 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.
independent Protocol Review Committee, established by the NHLBI, will provide
peer review for each network protocol. 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.
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 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 Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.
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.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
GrantsInfo (Questions regarding application instructions and
process, finding NIH grant resources)
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)
Sonia Skarlatos, PhD, FAHA
Deputy Director, Division of Cardiovascular Sciences
National Heart, Lung, and Blood Institute
National Institutes of Health
6701 Rockledge Drive, Room 8124, MSC 7940
Bethesda, MD 20892-7940
Director, Office of Scientific Review
Division of Extramural Affairs
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
Ms. Beckie Chamberlin
Grants Management Specialist
Division of Extramural Affairs
National Heart, Lung, and Blood Institute (NHLBI)
National Institutes of Health
6701 Rockledge Drive, Room 7144, MSC 7926
Bethesda, MD 20892-7926
Telephone: (301) 435-0166
FAX: (301) 451-5462
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 Parts 74 and 92.
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