Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)

Components of Participating Organizations
National Heart, Lung, and Blood Institute (NHLBI), (http://www.nhlbi.nih.gov)

Title: Cardiovascular Cell Therapy Research Network

Announcement Type
New

Update: The following update relating to this announcement has been issued:

Request For Applications (RFA) Number: RFA-HL-06-001

Catalog of Federal Domestic Assistance Number(s)
93.837, 93.839

Key Dates
Release Date: August 16, 2005
Pre-submission Meeting : October 12, 2005
Letters of Intent Receipt Date(s): February 10, 2006
Application Receipt Dates(s): March 10, 2006
Peer Review Date(s): June-July, 2006
Council Review Date(s): October 2006
Earliest Anticipated Start Date: December 1, 2006
Additional Information To Be Available at: http://www.nhlbi.nih.gov/funding/inits/cellnetwork-faq.htm
Expiration Date: March 11, 2006

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

Table of Contents

Part I. Overview Information

Part II. Full Text of Announcement

 Section I. Funding Opportunity Description
   1. Research Objectives

 Section II. Award Information
   1. Mechanism(s) of Support
   2. Funds Available

 Section III. Eligibility Information
   1. Eligible Applicants
     A. Eligible Institutions
     B. Eligible Individuals
   2. Cost Sharing or Matching
   3. Other - Special Eligibility Criteria

 Section IV. Application and Submission Information
   1. Address to Request Application Information
   2. Content and Form of Application Submission
   3. Submission Dates and Times
     A. Receipt, Review and Anticipated Start Dates
       1. Letter of Intent
     B. Sending an Application to the NIH
     C. Application Processing
   4. Intergovernmental Review
   5. Funding Restrictions

 Section V. Application Review Information
   1. Criteria
   2. Review and Selection Process
     A. Additional Review Criteria
     B. Additional Review Considerations
     C. Sharing Research Data
     D. Sharing Research Resources
   3. Anticipated Announcement and Award Dates

 Section VI. Award Administration Information
   1. Award Notices
   2. Administrative and National Policy Requirements
     A. Cooperative Agreement Terms and Conditions of Award
       1. Principal Investigator Rights and Responsibilities
       2. NIH Responsibilities
       3. Collaborative Responsibilities
       4. Arbitration Process
   3. Reporting

 Section VII. Agency Contact(s)
   1. Scientific/Research Contact(s)
   2. Peer Review Contact(s)
   3. Financial/ Grants Management Contact(s)

 Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement


Section I. Funding Opportunity Description

1. Research Objectives

The purpose of this Request for Applications (RFA) is to establish a Cardiovascular Cell Therapy Research Network (CCTRN) that will accelerate research in the use of cell-based therapies for the management of cardiovascular diseases, in order to improve outcomes through the development and application of cell-based therapies and evaluation of these novel therapies. The network will provide the necessary infrastructure to develop, coordinate, and conduct multiple collaborative clinical protocols to facilitate application of emerging scientific discoveries into clinical investigations. Results of Network studies are expected to be widely disseminated and to improve the scientific basis of care for affected individuals.

Nature of the Research Opportunity:

Heart disease is the leading cause of death in North America. In 2002, cardiovascular diseases accounted for 927,000 deaths in the United States with an estimated 942,000 inpatient hospitalizations for acute coronary syndrome: 818,000 for acute myocardial infarction (MI) as a primary diagnosis and 124,000 for unstable angina. Approximately 500,000 new heart failure cases are diagnosed every year, and an estimated five million Americans suffer from heart failure. The projected economic cost in 2005 for cardiovascular diseases in the United States is expected to be $393 billion.

Improved medical and surgical management in the past 30 years has produced a decline in the death rate due to cardiovascular heart disease. However, damage to the heart from hypertension, myocardial infarction, valvular disease, and cardiomyopathy often leads to remodeling of the heart. Left ventricular remodeling can progress to heart failure, and 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 accompany injury. In light of the limited efficacy and poor side effect profile of current treatment options, alternative long-term therapeutic strategies are needed. If therapies could be developed to reverse or repair heart damage, they could ameliorate an enormous public health burden.

Small exploratory studies and larger randomized clinical trials of cell therapy in patients with myocardial infarctions or chronic heart failure are currently underway, mostly outside of the United States. At the same time, stem cell biologists and cardiovascular basic researchers have made interesting observations that raise the hope that cell therapy can be a viable treatment for various cardiovascular conditions. These 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.

Cell therapy has the potential to treat a wide range of diseases. The concept of preventing the progression and consequence of disease, as well as reversing the disease process through repair and regeneration of damaged tissues, has introduced a new and exciting paradigm of cardiovascular disease treatment. Both animal and human studies indicate that cell therapy may be able to improve cardiac function and replace damaged or diseased tissue. A variety of adult stem cells, including bone marrow mononuclear cells, endothelial progenitor cells and mesenchymal stem cells, used in animal models of acute myocardial infarction have demonstrated improved ventricular function under some experimental conditions. Early clinical studies suggest that transplantation 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. In recognition of the need to facilitate the clinical implementation of cell-based therapies for cardiovascular disease, the National Heart, Lung, and Blood Institute (NHLBI) held a Working Group on Translation of Cell-Based Therapies for Cardiovascular Disease (August 2004, http://www.nhlbi.nih.gov/meetings/workshops/translation.htm). In considering how best to translate cardiovascular cell therapy into the clinical arena, the Working Group determined that cell therapy can be implemented more quickly and effectively through an integrated approach and recommended that the NHLBI establish a research network to conduct clinical studies of novel cell based therapies.

Pertinent Background Information Establishing Need for the Research:

Rapid and effective implementation of cardiovascular cell therapy in the clinical setting requires an integrated approach and a stable infrastructure that can test cell-based therapeutic protocols based on and modified by sound preclinical studies to improve outcomes for cardiovascular patients. An investment in technology development, cell production, and core methodologies is a prerequisite to the translation of science into the clinic. The Network infrastructure will include clinical investigators to conduct multi-center clinical trials, facilities to characterize cells and markers and develop new methodologies, core laboratories to isolate and prepare cells for therapeutic use, and imaging specialists to measure efficacy and track the fate of cells. The research network approach is a flexible way to study adequate numbers of patients utilizing these novel therapeutic approaches to form a sound basis for the clinical implementation of cell-based therapies for cardiovascular disease.

Scientific Knowledge to be Achieved Through Research Supported by This Program:

The primary goal of the Network is to conduct multiple collaborative proof-of-concept clinical protocols to evaluate cell-based strategies to improve the treatment of cardiovascular disease. Secondary objectives of the Network are to:

Types of Research and Experimental Approaches:

The emphasis will be on early Phase I and II clinical investigations that help identify optimal cell therapy to improve ventricular function and structure. Therapeutic studies may involve autologous and 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.

Examples of Research Topics:

Applications should propose two clinical research protocols pertaining to a cell-based therapy approach to treat heart disease. Proposals to study the treatment of peripheral vascular disease or gene therapy approaches to treat cardiovascular disease are outside the scope of this RFA and will not be considered. Specific projects should be included based on their importance in the field, need for a multi-center approach, and feasibility.

Some examples of research topics appropriate for this RFA include, but are not limited to, the following:

THESE ARE EXAMPLES ONLY. APPLICANTS ARE NOT LIMITED TO THE TOPICS MENTIONED ABOVE AND ARE ENCOURAGED TO SUBMIT OTHER TOPICS PERTINENT TO THE OBJECTIVES OF THE RFA. Multiple studies will be conducted simultaneously. CCTRN studies may be selected from those proposed by the successful applicants, but a decision to fund a particular Clinical Center will not commit the CCTRN to develop that group's clinical protocol.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Organization of the Cardiovascular Cell Therapy Research Network:

The Cardiovascular Cell Therapy Research Network (CCTRN) will be a cooperative clinical network consisting of up to five Clinical Centers (CC), a single Data and Coordinating Center, and the NHLBI. The responsibilities of each component of the Network are described below:

NHLBI:

The NHLBI will oversee the organization of the Network and thus will be substantially involved with the awardees in a partnership. The NHLBI Program Scientist will monitor patient recruitment and study progress, ensure disclosure of conflicts of interest, and ensure adherence to NHLBI policies. NHLBI will appoint the Network Chairperson, all members of the protocol review committee (PRC), and the data and safety monitoring board (DSMB). The Network Chairperson will be responsible for ensuring that there are well-documented policies, procedures, and bylaws to guide all aspects of Network activities and operations.

Clinical Centers (CCs):

CCs will propose protocols, participate in their overall development, recruit patients, conduct the protocols, and disseminate research findings. All individual CCs will be required to participate in a cooperative and interactive manner with one another and with the DCC in all aspects of the CCTRN. CCs will likely be major medical centers with existing relationships with private or community hospitals and physician practices. It is expected that individual CCs will vary in nature and experience, and thus may represent both different patient populations and unique expertise in the area of cell therapy. The CC must demonstrate clinical science excellence, ability to clinically isolate and prepare Good Manufacturing Practices (GMP) grade cell products, and a proven ability to recruit patients from various racial/ethnic groups. This last requirement might necessitate partnerships with local primary care practice groups. As a whole, the Network intends to enroll patients from tertiary referral centers and to perform clinical interventions on the range of cardiovascular diseases. Potential applicants should review the additional information contained in Section IV, Application Submission Instructions.

The Principal Investigator (PI) at each CC will be responsible for proposing protocols, estimating their costs, and participating in their overall development; conducting the research; participating in standardized cell isolation and preparation procedures, including the submission of samples of cellular products to a central quality control laboratory; assuring quality of patient care and protocol adherence; assuring the accurate and timely transmission of data collected in conjunction with the DCC; and disseminating research findings. Each CC will be subject to annual administrative review.

Data and Coordinating Center (DCC):

The DCC will coordinate, administer, and support all Network clinical research activities. These activities include, but are not limited to, administrative support for the Network Chair, scientific leadership and committees; reimbursement for patient accrual; and organization of investigator meetings. The DCC will assist in final protocol development, provide statistical leadership for each study design, and prepare operational timetables. The DCC will develop a data collection system and manuals of operations, determine sampling and randomization schemes, and assist in defining primary and secondary outcomes and analytical approaches for the protocols. The DCC will also provide regulatory guidance and facilitate interactions with regulatory authorities. The DCC will subcontract with external laboratories as needed, coordinate with suppliers of cells, and arrange for standardization and quality control measures to ensure adequacy and comparability of cellular products across CCs. The DCC will manage and distribute all funding for centralized core laboratory(ies).

The DCC will develop procedures for quality control, training and certification, and data management. It will monitor the quality and quantity of data received from the CCs, provide relevant reports to the NHLBI, CCs, and Steering Committee (SC), and serve as a central repository for study data. In addition, the DCC will establish quality control measures for cell preparations to ensure the isolation, preparation, viability, and characteristics of the cell preparations from CCs are comparable, standardized and clinical grade cell products. The DCC is responsible for any site visits necessary for training, quality control, data management and at a minimum will visit each site once in the course of the study period. The DCC will prepare protocols for submission to the PRC, and to the FDA, Centers for Medicare and Medicaid Services (CMS), or other government agencies as required, and prepare confidential data analyses and reports for the DSMB. The DSMB, with the DCC support, will develop stopping rules. The DCC will support manuscript preparation through data analysis, statistical consultation, editorial support, and meeting coordination. It will schedule and make arrangements for all meetings of established committees and boards. The DCC will manage and distribute 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 will be subject to annual administrative review.

Steering Committee (SC):

The SC will be the main governing body of the Network. Voting members of the SC include, at a minimum, the Network Chair, the PIs of the CCs and of the DCC (or their designated alternate) and the NHLBI Project Scientist. The Network Chair 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 CCs, and develop consensus protocols for submission to the PRC. The SC will ensure that studies are properly conducted and monitored, that data are appropriately analyzed and interpreted, 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 may meet as often as three to six times in the first 12 months of the study, two to four times per year thereafter, and by telecomference on a biweekly basis. All major scientific decisions will be determined by majority vote of the SC. The Steering Committee has final responsibility for approving the protocol before review by the PRC or DSMB.

Subcommittees of the SC will be established as necessary, and will include, at a minimum, a Publications and Presentations Subcommittee, a Research Subcommittee, and a Quality Control Subcommittee. The Publications and Presentations Subcommittee will facilitate and supervise preparation of manuscripts prior to submission for publication. The Research Subcommittee will recommend research ideas and develop network research protocols for review identified by the SC. The Quality Control Subcommittee will be responsible for developing standards for specific laboratory tests and other measures to be used in the Network protocols.

Protocol Review Committee (PRC):

The independent PRC will be appointed by and be advisory to the NHLBI. It will consist 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 exact number and duration of protocols supported in the five-year program will depend on the nature and extent of the investigations proposed by the SC.

The PRC will evaluate protocols proposed by the SC based on the importance of the question to be addressed, scientific merit of the experimental design and approach, feasibility, appropriateness for the Network and consistency with NHLBI missions and policies. The PRC will provide a written critique of each proposal and a final recommendation to the NHLBI. All study protocols performed by the Network must be recommended by the PRC and approved by the NHLBI before initiation. Each CC is expected to participate in at least two protocols per year after the first year.

Data and Safety Monitoring Board (DSMB):

NHLBI will establish a DSMB in accordance with established policies to ensure data quality and participant safety and to provide independent advice to the NHLBI regarding progress and the appropriateness of continuing each study (see http://www.nhlbi.nih.gov/funding/policies/dsmb_inst.htm). In addition, the DSMB will provide a critique of risk to NHLBI before protocol initiation. Funds for the expenses related to managing the DSMB will be budgeted in the DCC.

Clinical Research Skills Development Core

The Network presents a rich environment for young clinical investigators to be exposed to and develop additional research skills. To assist new clinical investigators, the NHLBI will permit applicants for a CC to request up to $100,000 in direct costs per year for a Clinical Research Skills Development Core. The objective of the Core is to support activities to assist new clinical investigators in progressing to more senior status by enhancing their research skills. This support is in addition to the direct costs budget for the CC.

A Clinical Research Skills Development Core is not required, however, and its absence will not disadvantage an applicant. The quality of the Clinical Research Skills Development Core, if proposed, will be evaluated based on the specific components listed below. The priority score on the Core will have no effect on the overall score of an application.

Developmental opportunities that provide experience with new technologies and skills are encouraged for inclusion in the Core. Innovative strategies should be proposed for cross-disciplinary career development to achieve the goal of exposing new clinical investigators to additional research techniques and opportunities. Examples include a program of seminars focusing on scientific topics that include basic and clinical cell therapy studies or the development and/or improvement of core courses designed as in-depth instruction in the fundamental skills, methodology, and theory necessary for the well- trained, independent, clinical researcher. In addition to developing the research skills of new clinical investigators, the Cores must ensure that the participating new clinical investigators receive the mentoring they need to foster their research careers. The Clinical Research Skills Development Core is intended for staff investigators with limited clinical research experience, including fellows and junior faculty members. Investigators who have had a previous K series award are not eligible to participate as new investigators under this program. Individuals with an active K grant can participate until the end of the award period for the K grant, but may not receive salary on the Skills Development Core. The Core should also address other skills necessary for a successful research career, such as grant writing, ethical conduct of research, and clinical trial design.

If a Clinical Research Skills Development Core is proposed, it must be directed by an investigator with strong educational and mentoring credentials who will devote a minimum of 5 percent effort as its Leader. To facilitate mentoring and multidisciplinary developmental activities, active involvement by the principal investigator and other senior investigators within the Network is strongly encouraged. An application for a Clinical Research Skills Development Core will be evaluated in terms of its potential effectiveness in developing the skills and research capabilities of new clinical investigators as reflected in the following required elements of the application:

Attaining independent status should be an objective of the Core activities so participating new investigators should be encouraged to apply for a Career Development Award, a patient-oriented regular research grant, or any other source of independent research or career development support. Although the participating new investigators will be expected to devote essentially full-time effort to research during this period, they may devote an appropriate percentage of their time to maintaining clinical skills.

An application for a Clinical Research Skills Development Core will be evaluated in terms of its potential effectiveness in developing the skills and research capabilities of new clinical investigators as reflected in the required application components identified above.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the Cooperative Agreement (U01) award mechanism.

This funding opportunity uses the just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application.

The NIH U01 is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award." Plans to continue this RFA beyond the current funding opportunity are indefinite.

2. Funds Available

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NHLBI provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution 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 programs.

2. Cost Sharing or Matching

This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing.

3. Other-Special Eligibility Criteria

Awards for a Clinical Center and a Data Coordinating Center will not be made to the same Principal Investigator to ensure that data analysis is performed independently of data acquisition. The same institution may apply for both a Clinical Center and a Data Coordinating Center award, but the applications for each must be from different individuals and must be submitted as separate applications.

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form, and the YES box must be checked.

Special Requirements

The Network will be a collaborative effort that will require all individual clinical centers (CC) to participate in a cooperative and interactive manner with each other, the data coordinating center (DCC), and with the NHLBI. Applicants should explicitly indicate their willingness to:

Clinical Center Applicants

Expectation of Cooperation: To promote development of a collaborative program among the award recipients, the issues discussed below need to be addressed in each application for a CC. Applicants must indicate their willingness and ability to participate in the stated aspects of the Network.

Departmental and Institutional Commitments: The local department and institutional commitment to collaborative cardiovascular cell therapy research and to the prioritization of Network research must be clearly documented by providing letters to the PI and by citing evidence of past support. This institutional assurance 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.

Clinical Centers (CCs):
Each CC applicant should propose a research plan that includes two protocols as models that could potentially be used in the Network environment. Applicants must outline the rationale and background of each proposed study. In addition, each CC should propose supplying clinical grade products produced in a manner that is compliant with all regulatory requirements (see below). The clinical protocols should demonstrate knowledge of current issues in the use of cell therapy for the treatment of cardiovascular disease and, where necessary, discuss patient benefit and risk for any procedures proposed. An applicant must provide the relevant end point(s), and number and type of patients required for each proposed study based on sample size calculations. Inclusion of a registry within an experimental protocol to monitor patient outcomes is acceptable, provided that the registry falls within the time constraints of the RFA. The protocol budget for each proposal must include an estimated per patient enrollment cost. However, protocol costs should be excluded from the requested main CC budget.

Each CC applicant must demonstrate the ability to supply clinical grade cell products that are produced in a manner that will be compliant with regulatory requirements and are prepared according to commonly agreed standards and procedures for Network protocols. Clinical cell processing laboratories must scale up the processes developed in the research laboratory using reagents approved for use in humans and using good manufacturing practices (GMP). The establishment of cellular processing facilities within each CC is proposed as a method to combine the consulting, manufacturing, and regulatory duties that are necessary for the development of novel cellular therapies. It is envisioned that cell processing facilities will provide the actual cellular products utilized by investigators of the CC along with the assurance that it is clinical grade, is produced in a manner that is compliant with all regulatory requirements, and produced in a standardized manner that will allow comparability with cellular products from other CCs when subjected to quality control testing. Some of the preclinical tasks of a cell processing facility include the qualification and testing of reagents, scale-up of methods, development of Standard Operating Procedures (SOPs), ongoing process validation, and the provision of controlled GMP infrastructure. CC applicants may utilize existing cell processing facilities at their institution, propose the development of new processing capabilities, provided the new capabilities can be demonstrated to be available within the first year, or subcontract with an appropriate cell processing facility within close geographical proximity. Applicants should be aware of a resource that could be utilized for these purposes. NHLBI supports three NHBLI Somatic Cell Therapy Processing Facilities (RFP under BAA-HB-03-06) and for the development of clinical, Good Manufacturing Practices (GMP) grade cell products (http://www.nhlbi.nih.gov/funding/inits/archive/hb03-06a1.htm). More information regarding the NHLBI facilities for Production Assistance for Cellular Therapies (PACT) can be obtained from the PACT website (http://www.pactgroup.net).

The Research Plan must follow the instructions in the PHS 398 application form, (revised 5/2001; http://grants.nih.gov/grants/forms.htm). The Research Plan (Items A – D: Specific Aims, Background and Significance, Preliminary Studies/Progress Report, and Research Design and Methods) should not exceed 25 pages. Within the total page limits designated in the PHS 398 application form for the Research Plan the application should include: a one-page overview that presents the key research objective and a diagram depicting the initiation and duration over a 5-year period for both of the two proposed clinical investigations; a description of each of the two protocols that includes the rationale, research aims, outcome measures, and study design; a description of the patient populations with an estimate of the expected distribution of minority and female patients, and assurances of the applicant's access to the patient population.

Qualifications and Experience

Applicants for Clinical Centers must have demonstrable experience and expertise to conduct complex multi-center clinical studies in acquired heart disease and a history of previous successful clinical research. Prospective Clinical Centers must have an established research program in the scientific areas of interest and demonstrated access to a sufficient number of patients to accomplish their portion of the proposed protocols. The applicant must have an established program with experience in identifying and treating cardiovascular disease patients and a designated facility for this purpose. CC applicants should also discuss clinical studies and trials conducted in last two years, particularly those related to cell therapy. Applicants should be well-versed in the science of cellular therapy and represent an institution (or partner with such an institution) able to manufacture quality-controlled cell-based products in compliance with FDA regulations and preparation standards defined for Network protocols. The applicant must demonstrate the willingness and the ability to participate in a cooperative manner with other CCs, the DCC, and the NHLBI in the development of research protocols, statistical methods, uniform data collection and data transfer.

A minimum time commitment of 25% is expected from the physician leadership (Principal Investigator and any Co-investigators) at each Clinical Center. The Principal Investigator or another member of the physician investigative team is expected to be readily available to respond directly to questions about CCTRN matters on a daily basis, preferably through e-mail, and should indicate this in the application. The 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 cardiologists, cardiothoracic surgeons, nurses, and other related sub-specialists. Each CC must designate a research coordinator with adequate percent effort as described below. A description of this individual's training, experience and involvement in clinical research should be provided.

Study Population

The applicant must indicate for each clinical cell therapy protocol how many patients are available in the applicant's center and how many will be required from the entire Network. In the discussion of outcome measures, it will be important to describe appropriate objective measures of primary and secondary outcomes. Applicants are encouraged to explore, within the context of their proposed protocols and the cost limitations outlined elsewhere in this RFA, cell isolation and characterization procedures, new technologies to monitor the fate of transplanted cells, and/or new and improved cell delivery methodologies. The relevant technology should be available for each protocol proposed.

Applicants are expected to provide information regarding the nature of the available patient population including numbers of new MI or heart failure cases and out-patient visits per year over the past five years. A critical element for selecting CCs is the adequacy of patient resources available. In order for reviewers to assess recruitment capacity, applicants must describe fully the cardiovascular patient population available and actual visits at their facilities during 2004. Applications which provide the number of patients available, but do not detail the patient population and actual visits will be judged non-responsive and not eligible for review.

Clinical Trial Agreement (CTA): When a pharmaceutical or device collaborator (third party) provides a study agent/device to the Network, a CTA will be negotiated describing respective responsibilities and rights. The agreement will include, but is not limited to, Investigational New Drug/Investigational Device Exemption (IND/IDE) sponsorship, safety and data monitoring, and access to data. Third party agreements must be developed and implemented with the NHLBI.

Budget Information

For purposes of the grant application, Clinical Centers will be asked to submit budgets for core infrastructure budget costs as well as for patient care costs to conduct the protocol proposed. The patient care budget is to be included as an example only to facilitate peer review of the application. During the grant cycle covered by this RFA, all patient care costs will be awarded to the DCC, which will then be responsible for distributing them to Clinical Centers once per-patient budgets are approved for each protocol and recruitment begins.

Clinical Center infrastructure budget costs may not exceed $300,000 direct costs, and include:

Clinical Research Protocols

Estimated clinical protocol implementation costs should be based on the proposals presented in the applicant's research plan, but should not be included in the CC budget request. A table must be included showing estimated costs per patient for conducting each proposed protocol. The budget for each protocol must be developed on a cost-per-patient basis and include all direct costs and the associated protocol facilities and administrative costs. Costs of drugs or laboratory tests that are not clinically indicated (i.e., are not eligible for third-party reimbursement as part of routine clinical care) should be part of the per-patient cost of conducting a protocol. Applications should clearly identify the potential source(s) for any cells, drugs or substances that are being considered for clinical protocols that are currently unavailable commercially. It should be noted that funds will not be provided for the purchase of expensive medical equipment, such as echocardiographic or magnetic resonance imaging systems. It is anticipated that the cost associated with patient enrollment care will be included in the CC budget. If any of the protocols proposed by CC applicants include obtaining blood or tissue samples, the applicant should delineate how such specimens will be handled and analyzed. In the event that a central laboratory is required to analyze specimens, the CCs will be responsible for obtaining the sample(s) and the cost of obtaining them will be part of the CCs per-patient expense. The cost of shipping, analyzing, and storage, as well as training of personnel and quality control will be the responsibility of the DCC. Costs to implement the protocol should be identified in the research plan. It is anticipated that the first year will be devoted to protocol development and staff training, with patient recruitment commencing in the second year. This should be considered in the proposed budget structure.

Patient care costs include expenses associated with the conduct of a specific protocol, such as:

Tests and clinic visits performed as part of routine clinical care can be incorporated into a research protocol, but their costs will be billed to third-party payers. The pool of patient care funds, including funds to cover the administrative costs associated with protocol activities will be part of the Data Coordinating Center grant. A per-patient budget for each CCTRN protocol will be developed by NHLBI and CCTRN investigators. The Data Coordinating Center will be responsible for apportioning the per-patient monies among the Clinical Centers in proportion to recruitment. Nevertheless, Clinical Centers are asked to develop a per-patient budget for their proposed protocol as part of their application. Investigators should prepare budgets only for their own Clinical Center to conduct the proposed protocols and not for the entire Cardiovascular Cell Therapy Research Network.

Note that ongoing annual budgets for protocols will be based on the protocols approved by the PRC and the Network SC. Continuation and level of funding for each CC will be based on actual recruitment and overall performance. The precise number of protocols conducted over the five years will be determined by the Network SC and will depend on a number of factors, including scientific priority, availability of funds, complexity and protocol requirements, length of the protocols, and ease of enrollment. It is anticipated that after the first year, at least two protocols would be active each year.

The applicant should plan and budget for two members of the investigative team to attend up to six Steering Committee (SC) meetings in Bethesda, MD, in year one, and up to three SC meeting per year thereafter. Each meeting will be approximately two days in length.

Awards will be subject to administrative review annually.

Data and Coordinating Center (DCC)

Qualifications and Experience

Applicants for a Data Coordinating Center must demonstrate experience in the conduct of multi-center clinical studies, coordinating all phases of multi-center clinical studies, protocol and manual of operations development, data collection and management, data safety and confidentiality, adverse events, quality assurance, data analysis, distributed data entry, electronic communications, and administrative management and coordination.

Study Design and Management

Data Coordinating Center applicants should discuss various aspects of study design that would be important in developing clinical protocols, for example: eligibility criteria; baseline and outcome measures; methods of randomization; important considerations for making sample size and power calculations; methods and frequency of data collection and entry; monitoring accuracy of data collection; quality control procedures including training and certification for multiple protocols, some of which may occur simultaneously; managing labeling and handling of blood and cell samples (see below); and plans for statistical analysis. In addition, they should describe their plans for administrative management of the DSMB, the Protocol Review Committee, the Steering Committee, and associated subcommittees. A plan also should be included for the development and maintenance of a web site with both public and secure components that would include information for patients and investigators.

Most CCTRN protocols will require central laboratories for uniform interpretation of key study data, such as cell preparation or imaging studies. Extensive quality assurance and quality control procedures through a central laboratory under the auspices of the DCC should be instituted across Clinical Centers to ensure to the quality and standardization of cell isolation and preparation and to allow comparisons of cellular preparation across the CCs. This will include development of a Manual of Operations, training of staff members from Clinical Centers, and certification of techniques for cell isolation and preparation. Additional specific central lab(s) may be needed depending on the protocols ultimately selected. However, for purposes of the application, Data Coordinating Center applicants should describe in detail how they will conduct quality control laboratory procedures to ensure the quality and standardization of cell isolation and preparation at each CC. In addition, they should describe how they will identify and secure the necessary central lab(s) once specific protocols are approved.

Regulatory Issues

Clinical studies of cellular therapy for cardiac disease require submission of an Investigational New Drug (IND) application to the Food and Drug Administration (FDA). The initial submission must contain adequate information about the cellular product and adequate preclinical data to support the safety of administering the cell therapy to humans. In early clinical trials the FDA is chiefly concerned with subject safety. Therefore, coordination between DCC, NHLBI, and FDA is important to make sure that the kinds of data required for human trials to move forward is understood and collected, speeding development of these potentially important therapies. In most cases, the DCC will be the sponsor of the IND application to the FDA. Applicants should describe their experience with providing regulatory guidance and facilitating interactions with regulatory authorities.

Budget Information

Budgets should be prepared for five 12-month periods. The budget justification for each year should include a table that apportions the direct costs among the following categories: core costs, costs of protocol initiation, and costs of protocol support as described in the RFA. Data Coordinating Center applicants should assume that one to two protocols will be initiated and active in the second year and that at least three protocols will be developed and begin active recruitment during the grant period covered by this RFA. Studies begun in this grant period will not necessarily be concluded by the end of the grant period. Data Coordinating Center budgets should include, but are 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 United States Food and Drug Administration guidelines.

Applicants for the DCC should prepare budgets for five one-year periods with maximum allowable direct costs for the DCC limited to $1,200,000 in the first year and $1,750,000 per year in years two through five. Additionally, DCC applicants will receive a total budget of $8,266,000 to conduct protocols for the five-year study period. The protocol funds will be used to reimburse the CCs for the costs of recruitment, patient care, cells, devices, and/or drugs used in the protocols, as well as costs associated central laboratory assessments (if required). It is expected that patient care costs will be greatest in years two through five.

The DCC should request not more than $500,000 in year 1 and $1,941,500 per year in years 2 through 5 in the patient care category for the distribution of approved protocols. The final amount will be determined by NHLBI. These funds will be managed by the DCC and distributed to each participating CC as a fee for service arrangement after a protocol has been approved and the NHLBI has released the funds for distribution.

The budget justification for each year must include a table that apportions the Total Cost request among the following categories: 1) center costs, 2) costs of protocol initiation (per protocol), and 3) costs of protocol support (per protocol). Center costs should include support for essential personnel and facilities and the costs for meetings in Bethesda, Maryland, of the PRC (8 members, 2 meetings per year) and the DSMB (8 members, 3 meetings per year). Costs of protocol initiation should include the costs of expanding the manual of procedures and of developing questionnaires, forms, and database structures. Protocol support costs should include the costs of pharmaceutical handling, data entry and analysis, quality control, and manuscript preparation. The DCC budget must include support for the Network Chair over the 5 years (20% effort needed and travel expenses), and also for two site visits made to all the clinical centers during the 5- 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 one protocol. Budget requests for years 2-5 should assume that additional protocols will be initiated and that 3-4 protocols will be active (i.e., recruiting subjects and collecting data) during the grant period. 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.

For budget purposes, DCC applicants should assume that in the first year all administrative aspects of the Network will be organized and at least one protocol will be developed. For subsequent years, applicants may assume that at least two protocols a year will be active (either in the protocol development, implementation, or analysis and writing phase). DCC applicants must include costs for coordinating the DSMB, the PRC, and the SC, including the cost of DSMB calls and meetings (DSMB meetings will be held two times per year in Bethesda, Maryland), the cost of PRC conference calls and meetings, and the administrative expenses of weekly SC conference calls and up to six SC meetings in Bethesda, Maryland, in year one and three meetings per year thereafter. Costs allowed for the participation of the Network Chair include salary support (up to 20% of the NIH cap), travel expenses, and administrative support. The DCC also needs to include costs for site visits of each of the CCs over the five-year study period, assuming up to five CCs and a five-member site visit team for purposes of budget preparation, and costs for special functions requiring committee activities, such as an event (morbidity and mortality) classification committee. Cost for financial administration to prepare protocol budgets and to distribute and monitor funds should also be addressed.

DCC applications will describe methods to coordinate study planning, implementation and the dissemination of study results. The DCC must include a budget and justification for any additional costs of this collaborative effort.

Applications that do not include a dissemination of study results plan will be considered non-responsive and not eligible for review. The awards will be subject to annual administrative review. It is expected that all protocols will be performed in a manner consistent with United States FDA guidelines.

Clinical Research Skills Development Core (Core)

The Network presents a rich environment for young investigators to be exposed to and develop additional research skills. To assist the Network awards in enhancing the developmental environment for their new clinical investigators, NHLBI will permit applicants for a CC to request up to $100,000 in direct costs per year for a Clinical Research Skills Development Core. A Core is not a required component of a CC and its absence will not disadvantage an applicant. The priority score on the Core will have no effect on the overall score of an application. If a Network application includes an application for a Core, then the Core should be mentioned in both the Abstract and the Table of Contents. Up to four additional pages may be used to describe the proposed Clinical Research Skills Development Core. The Core proposal should be inserted in the Network application at the end of the Research Plan. This text will not be counted toward the 25-page limit for the total Research Plan (items A-D) specified by the Form 398 instructions. Requests for Core funds should not be included in the body of Network applications as it is expected that this aspect of the Network will be supported by supplemental funds. Thus, applicants should provide a separate budget page for the Core and add the cost of the Core as a line item into the total request for funds. Applicants should read the specific requirements and other instructions for applying at http://www.nhlbi.nih.gov/funding/policies/ntwk_skill.htm.

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

Proposed research should provide a unique research opportunity not available in the U.S.

3. Submission Dates and Times
Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates

Pre-submission Meeting : October 12, 2005
Letters of Intent Receipt Date(s): February 10, 2006
Application Receipt Dates(s): March 10, 2006
Peer Review Date(s): June-July, 2006
Council Review Date(s): October 2006
Earliest Anticipated Start Date: December 1, 2006

3.A.1. Pre-Submission Meeting

A pre-submission meeting will be conducted on October 12, 2005 in Bethesda, Maryland to which all prospective applicants are invited. At the meeting, presentations by NHLBI and other NIH staff will be provided to explain the goals and objectives of the Cardiovascular Cell Therapy Research Network and to answer questions. This meeting will take place beginning at 8:00 a.m. on the morning of October 12, 2005 at the Bethesda Marriott Suites Hotel, 6711 Democracy Boulevard, Bethesda, MD 20817 (telephone: 301-897-5600). A limited number of rooms have been reserved for attendees. Travel to this meeting and associated costs such as lodging will be the responsibility of attendees and will not be provided by the NHLBI. I nformation regarding meeting arrangements and FAQs and other information from the meeting will be available at the following URL: http://www.nhlbi.nih.gov/funding/inits/cellnetwork-faq.htm.

3.A.2. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

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 NHLBI staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Two Rockledge Center, Room 7214
6701 Rockledge Drive
Bethesda, MD 20892-7924 (Express 20817)
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: NHLBIchiefreviewbranch@nhlbi.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 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)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Two Rockledge Center, Room 7214
6701 Rockledge Drive
Bethesda, MD 20892-7924 (Express 20817)
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: NHLBIchiefreviewbranch@nhlbi.nih.gov

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form, and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NHLBI. Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

4. Intergovernmental Review
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. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.

6. Other Submission Requirements

Dissemination Section:

Applicants must include in their application/proposal a plan for dissemination of research results and such a plan should include:

Field/clinical center applicants must include a statement of willingness to work collaboratively after award with the other funded sites to prepare a joint dissemination plan. The DCC application/proposal should describe methods to coordinate the dissemination planning and implementation. The DCC must include a budget and justification for any additional costs of this collaborative effort.

When study results are available, the Principal Investigators (and if appropriate, other personnel from their project) and Program and NHLBI Office of Prevention, Education, and Control (OPEC) staff will meet (e.g., face-to-face, teleconference) to:

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

All applicants must include a plan for sharing research data in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.

The following will be considered in making funding decisions:

2. Review and Selection Process

Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. Incomplete and/or non-responsive applications will not be reviewed.

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHLBI in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

Collaboration: Do the investigators state their willingness to participate in joint meetings, share methods and data resources, and embark on collaborative efforts to decide overall research direction? Is the research plan flexible enough to accommodate further refinement and integration with other efforts? While it will be a group decision to actually engage in any particular proposed collaborative activities, do the applicants show an understanding of how joint collaborative activities can be conducted in a consortium of this type?

Additional Review Considerations for Clinical Centers:

Reviewers will be evaluating Clinical Center applications on the basis of the specific research protocol proposed, as well as the overall ability to participate in a multi-center Network. In addition to the above criteria, in accordance with NIH policy, all Clinical Center applications will also be reviewed with respect to the following:

Additional Review Considerations for Data and Coordinating Center (DCC) Applications:

In addition to the general criteria above, the applications will also be reviewed with respect to the following:

Review Criteria for Clinical Research Skills Development Cores:

The Clinical Research Skills Development Core will receive a priority score based on the review criteria below, but the priority score will not enter into the overall Network application priority score. The Clinical Research Skills Development Core will be evaluated for its effectiveness in developing the skills and clinical research capabilities of new investigators. This will include an evaluation of:

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data may be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The funding organization will be responsible for monitoring the data sharing policy. http://grants.nih.gov/grants/policy/data_sharing.

2.D. Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates
Not applicable

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the Principal Investigator will also receive a written critique called a Summary Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 14 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

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. See Also Section IV.5. Funding Restrictions.

The NoA will include the statement that the “Terms and Conditions of this award incorporate the operating guidelines in RFA-HL-06-001” .

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the Notice of Award. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official at the time of award.

2.A. 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 U01 , 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 above.

2.A.1. Principal Investigator Rights and Responsibilities

The Cardiovascular Cell Therapy Research Network (CCTRN) will be a cooperative clinical network consisting of up to five Clinical Centers (CC), a single Data and Coordinating Center, and the NHLBI and include a Steering Committee, Protocol Review Committee (PRC), Data and Safety Monitoring Board (DSMB) and Clinical Research Skills Development Core(s).

The awardee(s) will have lead responsibilities in all aspects of the study, including any modification of study design; conduct of the study; quality control; data analysis and interpretation; preparation of publications; and collaboration with other investigators, unless otherwise provided for in these terms or by action of the Steering Committee. Awardee(s) agree to the governance of the study through a Steering Committee.

The Clinical Center Principal Investigators will be responsible for proposing protocols, estimating their costs, participating in their overall development, conducting the research, assuring quality of patient care and protocol adherence, assuring the accurate and timely transmission of data collected in conjunction with the Data Coordinating Center, and disseminating research findings.

The Data Coordinating Center Principal Investigator will be responsible for oversight of protocol development, data collection, data safety and confidentiality, quality assurance, data analysis and distributed coordination.

A Clinical Research Skills Development Core may be included in an award to support activities to assist new clinical investigators in progressing to more senior status by enhancing their research skills.

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.

The collaborative protocol and governance policies will call for the continued submission of data centrally to the coordinating center for a collaborative database; the submittal of copies of the collaborative datasets to each principal investigator upon completion of the study; procedures for data analysis, reporting and publication; and procedures to protect and ensure the privacy of medical and genetic data and records of individuals. The NHLBI Project Scientist, on behalf of the NHLBI, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the 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. Within three years of the end of the period of NHLBI support for the project, data not previously released and other study materials or products not previously distributed are to be made available to individuals who are not study investigators, provided such release is consistent with the study protocol and governance and with the above paragraph. In addition, study investigators must establish a plan for making data sets and materials available to the scientific community and to the NHLBI immediately upon completion of the three-year period following the end of the period of NHLBI support.

Upon completion of the project, awardees are expected to put their intervention materials and procedure manuals into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community and the NHLBI, for the conduct of research at no charge other than the costs of reproduction and distribution.

2.A.2. NIH Responsibilities

The NHLBI will oversee the organization of the Network and thus will be substantially involved with the awardees in a partnership. NHLBI will appoint the Network Chairperson, all members of the protocol review committee (PRC), and the data and safety monitoring board (DSMB). The Network Chairperson will be responsible for ensuring that there are well-documented policies, procedures, and bylaws to guide all aspects of Network activities and operations.

A NIH Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. The NHLBI Program Official will monitor patient recruitment and study progress, ensure disclosure of conflicts of interest, and ensure adherence to NHLBI policies.

The NHLBI Project Scientist will serve on the Steering Committee; he/she or other NHLBI scientists may serve on other study committees, when appropriate. The NHLBI Project Scientist (and other NHLBI 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 terminate or curtail the study (or an individual award) in the event of

(1) failure to develop or implement a mutually agreeable collaborative protocol; (2) substantial shortfall in participant recruitment, follow-up, data reporting, or quality control; (3) major breach of the protocol or substantive changes in the agreed-upon protocol with which NHLBI cannot concur; (4) attaining of a major study endpoint before schedule with persuasive statistical significance; or (5) human subject ethical issues that may dictate a premature termination.

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

2.A.3. Collaborative Responsibilities

Awardee(s) agree to the governance of the study through a Steering Committee. Steering Committee voting membership shall consist of the Principal Investigators (i.e., cooperative agreement awardees), the NHLBI Project Scientist, and the Chairperson. Meetings of the Steering Committee will ordinarily be held by telephone conference call or in the metropolitan Washington Area. 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.

An independent Protocol Review Committee (PRC), established by the NHLBI, will provide peer review for each network protocol. Because the Board serves as an independent group advisory to the NHLBI, study investigators will not communicate with Board members regarding study issues, except as authorized by the Board's Executive Secretary. The independent PRC will be appointed by and be advisory to the NHLBI. It will consist 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 exact number and duration of protocols supported in the five-year program will depend on the nature and extent of the investigations proposed by the SC. The PRC will evaluate protocols proposed by the SC based on the importance of the question to be addressed, scientific merit of the experimental design and approach, feasibility, appropriateness for the Network and consistency with NHLBI missions and policies. The PRC will provide a written critique of each proposal and a final recommendation to the NHLBI. All study protocols performed by the Network must be recommended by the PRC and approved by the NHLBI before initiation. Each CC is expected to participate in at least two protocols per year after the first year.

A Data and Safety Monitoring Board will be appointed by the Director, NHLBI to provide overall monitoring of interim data and safety issues; the Steering Committee will nominate members for this Board. Meetings of the Data and Safety Monitoring Board will ordinarily be held in Bethesda. An NHLBI scientist, other than the NHLBI Project Scientist, shall serve as Executive Secretary to the Board.

2.A.4. Arbitration Process

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 arbitration. An Arbitration 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 arbitration procedure in no way affects 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.

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement. The Data Coordinating Center will compile site visit reports, monthly and quarterly subject enrollment reports, meeting summaries, quarterly Research Unit performance and progress reports, and other reports as needed for the Steering Committee, DSMB, other participating NIH sponsors, and Advisory Board.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Sonia Skarlatos, Ph.D.
Deputy Director
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Two Rockledge Center, Suite 9158, MSC 7940
6701 Rockledge Drive
Bethesda, MD 20892-7940
Telephone: (301) 435-0477
FAX: (301) 480-7971
Email: skarlats@mail.nih.gov

Denis Buxton, Ph.D.
Associate Director, Heart Research Program
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Two Rockledge Center, Suite 9188, MSC 7940
6701 Rockledge Drive
Bethesda, MD 20892-7940
Telephone: (301) 435-0516
FAX: (301) 480-1454
Email: buxtond@mail.nih.gov

2. Peer Review Contacts:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Two Rockledge Center, Room 7214
6701 Rockledge Drive
Bethesda, MD 20892-7924 (Express 20817)
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: NHLBIchiefreviewbranch@nhlbi.nih.gov

3. Financial or Grants Management Contacts:

David Reiter
Grants Operations Branch
National Heart, Lung, and Blood Institute
2 Rockledge Center, Room 7172, MSC 7926
6701 Rockledge Drive
Bethesda, MD 20892-7926 (Express 20817)
Telephone: (301) 435-0177
Fax: (301) 480-3510
Email: reiterd@nhlbi.nih.gov

Section VIII. Other Information

Required Federal Citations

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); and efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions on issues related to institutional policies and local IRB rules, as well as local, state and federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research” (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research, updated racial and ethnic categories in compliance with the new OMB standards, clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398, and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: (1) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and (2) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://www.nih.gov/about/publicaccess/ and view the Policy or other Resources and Tools including the Authors' Manual (http://www.nih.gov/about/publicaccess/publicaccess_Manual.htm).

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information," the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 Parts 52 and 63a, and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.


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