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Heart Failure Clinical Research Network

RFA Number: RFA-HL-05-003 (FAQs available, see NOT-HL-05-110)

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/)

Announcement Type
New

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

Catalog of Federal Domestic Assistance Number(s)
93.837

Key Dates

Release Date: December 7, 2004
Letters of Intent Receipt Date: July 19, 2005
Application Receipt Date: August 16, 2005
Peer Review Date: February/March 2006
Council Review Date(s): May 2006
Earliest Anticipated Start Date: July 1, 2006
Additional Information To Be Available Date (URL Activation Date): Not applicable
Expiration Date: August 17, 2005

Due Dates for E.O. 12372
Not Applicable

Executive Summary

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

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
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
A. Receipt and 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
6. Other Submission Requirements

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

Section VI. Award Administration Information
1. Award Notices
2. Administrative 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. Award Criteria
4. 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 Heart Failure Clinical Research Network that will accelerate research in the diagnosis and management of heart failure, in order to improve outcomes through optimal application of existing therapies and evaluation of novel therapies. The network will provide the necessary infrastructure to develop, coordinate, and conduct multiple collaborative clinical protocols to facilitate application of emerging basic science discoveries into clinical investigations. The network will design and conduct multiple concurrent studies accommodating a wide scope of clinical research. The scientific aim of the network is to translate new basic science findings, or novel uses for known therapeutic agents or interventions, into clinical testing. For example, trials may evaluate cell-based treatments, treatments using novel classes of drugs such as immunomodulators, or genetic or other new biomarkers for early diagnosis and assessment of therapy. This RFA will establish and maintain (1) the infrastructure required for a network of up to eight regional clinical centers to perform multiple clinical studies, and (2) a Data Coordinating Center for the Network.

Nature of the Research Opportunity:

Heart failure (HF), in contrast to other cardiovascular diseases, is increasing in prevalence and incidence, and is a major cause of morbidity and mortality. This is a particularly important public health issue as the population ages and interventions for heart disease improve survival. HF is the most common hospital discharge diagnosis in patients over age 65. Approximately 500,000 new HF cases are diagnosed every year, and an estimated 5 million Americans suffer from HF, including up to 1.2 million patients with New York Heart Association (NYHA) class III-IV symptoms. In addition, health care costs related to HF are estimated to be as high as $23 billion annually. Although medical therapy has been successful in controlling symptoms, improved survival may require heart transplantation or mechanical circulatory assistance. Both interventions are costly and available for a relatively low number of patients.

In recognition of the need to advance diagnosis and treatment of HF, the National Heart, Lung, and Blood Institute (NHLBI) held two working groups. A major recommendation of the first working group, Strategic Directions in Congestive Heart Failure , which convened in July 2003, was to create a research network that would conduct clinical studies of novel strategies to improve outcomes for patients with heart failure (see http://www.nhlbi.nih.gov/meetings/hrt_fail.htm). The second working group, convened in November 2003 considered the need and utility of a network and made recommendations concerning the size and scope of such a program (see http://www.nhlbi.nih.gov/meetings/workshops/chf_execsum.htm). Participants of both working groups agreed that current clinical HF research is impeded by a lack of infrastructure to allow enrollment of an adequate number of patients and overcome the substantial initial investment required for conducting patient-oriented research. Other barriers to HF research include the lack of mechanisms to facilitate rapid testing and implementation of promising experimental approaches in the clinical arena, and the absence of uniform definitions of disease or outcomes.

Pertinent Background Information Establishing Need for the Research:

There is a need for rapid translation and clinical application of promising basic science results that have the potential to reduce mortality and morbidity of HF. The major advantages of this proposed HF network program include expeditious evaluation of new approaches to HF; shared resources, including adequate number of patients; standardized and central monitoring for quality in data collection, management, and interpretation; collaboration among clinical and basic scientists; and enhanced ability for rapid dissemination of new findings to the health care community.

In summary, despite many advances in treatment, the incidence and prevalence of HF continues to increase and the long-term prognosis for patients with HF is poor. Substantial progress has been made in developing mechanical circulatory support devices, but current systems are appropriate for only a small subset of patients with end-stage disease. Novel strategies to repair or restore myocardial function are emerging, improved mechanical systems are evolving, and new targets for novel drugs are emerging -- all will require systematic clinical evaluation. Hence, the development of new therapeutic strategies is necessary, but there are obstacles associated with conducting clinical investigations of novel treatments. Single center studies often lack the resources to combine biotechnical expertise with experienced clinicians or appropriate patient populations and are therefore small and lack statistical power. The results of multiple single center studies are difficult to pool for meta-analysis because of differences in endpoints and methods of collection. Industry-driven therapeutic trials frequently establish a transient infrastructure for multi-center studies, but are limited to investigation of therapies with immediate commercial value, and leave concepts without such advocacy, but with potential benefit, untested. These obstacles thwart the capacity to conduct collaborative clinical research at a time when novel strategies for the treatment of HF are burgeoning. The Network offers the opportunity to do important proof-of-concept studies that industry is not likely to pursue. Furthermore, the Network also offers an opportunity to create a three-way partnership among the clinical community (both academic and private physicians), NHLBI, and industry, for conducting patient-oriented HF research.

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 strategies to improve HF treatment. Secondary objectives of the Network are to:

Types of Research and Experimental Approaches:

The emphasis will be on early phase clinical investigations that help identify optimal diagnosis, evaluation, and therapy to improve ventricular function and structure. Therapeutic trials and studies may involve investigational drugs, new strategies for currently used drugs, cell-based therapies, devices, and surgical techniques. Phase III trials are outside the scope of this program. All clinical investigations must be completed within the five-year period.

Examples of Research Topics:

The purpose of the network is to translate new basic science findings, or novel uses for known therapeutic agents or interventions, into clinical testing. Proposed research areas may include, but are not limited to, the following scientific needs and considerations:

Since this RFA focuses on translation of new basic science findings, protocols focused on behavioral and lifestyle interventions, large Phase III clinical trials, or epidemiologic studies are not responsive to this solicitation.

THESE ARE EXAMPLES ONLY. APPLICANTS SHOULD NOT FEEL LIMITED TO THE TOPICS MENTIONED ABOVE AND ARE ENCOURAGED TO SUBMIT OTHER TOPICS PERTAINING TO THE OBJECTIVES OF THIS RFA. It is not the intent of the network to provide support for one or two large protocols that run the entire five years. Multiple studies will be conducted, possibly concurrently during each year. It is anticipated that in the initial year, studies will be selected from those proposed by the successful applicants. However, a decision to fund a particular Regional Clinical Center (RCC) will not commit the Network to develop that group's clinical protocol.

Each RCC applicant should propose a research plan that includes two protocols as models that could potentially be used in the Network environment. The protocols should demonstrate knowledge of current issues in the management of HF. 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 Research plan must follow the instructions in the PHS 398 application form, (revised 5/2001; http://grants.nih.gov/grants/forms.htm) and must include a one page overview of the two proposed investigations that presents the key research objective of each investigation and a diagram depicting the initiation and duration of the two investigations over a 5-year period; a description (within the total page limits designated in the PHS 398 application form) 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, ages; and assurances of the applicant's access to the patient population. The Research Plan, including the overview and description for both protocols, should not exceed 25 pages total.

The applicant must indicate for each 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, new technologies to monitor disease progression and/or improve response to therapy. The relevant technology should be available for each protocol proposed. It is also important to include strategies to assure adherence to therapy as a part of a protocol.

Project Organization:

The Heart Failure Clinical Research Network will be funded as a cooperative agreement and consist of up to eight RCCs, a single Data and Coordinating Center (DCC), and the NHLBI. The responsibilities of each component of the Network are described below:

I. 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 Official will monitor patient recruitment and study progress, ensure disclosure of conflicts of interest, and ensure adherence to NHLBI policies. The plan will have an early collaboration with the Food and Drug Administration (FDA) in developing protocols. NHLBI will appoint the Study Chair, all members of the protocol review committee (PRC), and the data and safety monitoring board (DSMB). The Study Chair will be responsible for ensuring that there are well-documented policies, procedures, and bylaws to guide all aspects of Network activities and operations.

II. Regional Clinical Centers (RCCs):

RCCs will propose protocols, participate in their overall development, recruit patients, conduct the protocols, and disseminate research findings. All individual RCCs will be required to participate in a cooperative and interactive manner with one another and with the DCC in all aspects of the HF Clinical Research Network. RCCs will likely be major medical centers with existing relationships with private or community hospitals and physician practices. It is expected that individual RCCs will vary in nature and experience, and thus may represent both different patient populations and unique expertise in the area of HF. The RCC must demonstrate both clinical science excellence and specialized expertise in HF management, a strong background in HF research, and a proven ability to recruit HF patients that include 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 private practice offices, and to perform clinical interventions on the full range of heart failure diseases. Potential applicants should review the additional information contained in Section IV, Application Submission Instructions.

The Principal Investigator (PI) at each RCC 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 DCC, and disseminating research findings. Each RCC will be subject to annual administrative review.

III. 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 the enhancing of the developmental environment for their new clinical investigators, the NHLBI will permit applicants for a new RCC 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 RCC.

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 an integration of basic and clinical studies or an "exchange" program wherein clinical investigators spend time in basic science laboratories. 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.

IV. 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 Study 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 subcontract with external laboratories as needed, coordinate with suppliers of drugs, and arrange for the preparation and packaging of medications. The DCC will manage and distribute all protocol funds, including a funding of centralized core laboratory(ies), if such activity will be deemed critical for conducting research agenda.

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 RCCs, provide relevant reports to the NHLBI, RCCs, and Steering Committee (SC), and serve as a central repository for study data. 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. There will be early collaboration with FDA in developing protocols. 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 be subject to annual administrative review.

V. Steering Committee (SC):

The SC will be the main governing body of the Network. Voting members of the SC include, at a minimum, the Study Chair, the PIs of the RCCs and of the DCC (or their designated alternate), and the NHLBI Project Scientist. The Study Chair will be appointed by NHLBI. The Study Chair will plan network activities, oversee its functions, conduct SC meetings, and cast tie-breaking votes in that committee. The SC will develop and ensure compliance with Network policies and procedures, identify and prioritize topics for investigation, evaluate protocols proposed by the RCCs, and develop consensus protocols for submission to 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 HF patients. The SC may meet as often as three to six times in the first 12 months of the study, and two to four times per year thereafter. All major scientific decisions will be determined by majority vote of the SC.

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.

VI. Protocol Review Committee (PRC):

The independent PRC will be appointed by and be responsible to the NHLBI. It will consist of a chairperson and scientists with expertise in basic and clinical HF 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 RCC is expected to participate in at least two protocols per year after the first year.

VII. 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).

See also Section VIII Other Information-Required Federal Citation.

Section II. Award Information

1. Mechanism(s) of Support

The NIH U01 is a cooperative award mechanism. In the cooperative agreement mechanism, the PI 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 PI, as described under the Section VI. 2. A. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award . Specifically, after award, scientific or program staff will assist, guide, coordinate, or participate in project activities. At this time, it is not known if this RFA will be reissued. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is July 1, 2006. Applications that are not funded in the competition described in this RFA may be resubmitted as new investigator-initiated applications using the standard receipt dates for new applications described in the instructions to the PHS 398 application.

This RFA uses just-in-time concepts. 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.

2. Funds Available

The NHLBI, intends to commit approximately $5.5 million dollars in FY2006, and up to $37.5 million dollars (total costs) to fund eight RCCs and one DCC for a period of five years. Budget information for RCC and DCC applicants is contained in the sections on budget requirements below. For the purpose of the RFA it is expected that maximum allowable costs for the DCC is limited to a direct cost of $800,000 in the first year and $1,000,000 each year for years two through five. An additional budget of $12,850,000 for protocols for the five year study period is anticipated. For the RCCs, excluding the cost of implementing the proposed protocols which will be funded through the DCC, direct costs may not exceed $250,000 per year. The maximum allowable direct costs for the clinical research skills development cores is $100,000.

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 IC(s) 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. It is not known if competing renewal applications will be accepted. Fiscal and administrative (F&A) costs are not included in the direct cost limitation, see NOT-OD-04-040.

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

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
Each applicant may submit only one application in response to this RFA.

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. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: [email protected].

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

2. Content and Form of Application Submission

Applications must be prepared using the PHS 398 research grant application instructions and forms. Applications must have a Dun and Bradstreet (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.

Supplementary Instructions

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 RCC. This material is in addition to the submission of a research plan as described in the section entitled, Types of Research and Experimental Approaches.

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 HF 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 HF research.

Special Requirements

The Network will be a collaborative effort that will require all individual regional clinical centers (RCC) 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:

Regional Clinical Centers (RCCs):

Application Requirements for Regional Clinical Center (RCC):

It is anticipated that each RCC may have different expertise in HF interventions, with some RCCs providing expertise in cell-based therapies or device investigations, while others may have expertise in HF pharmacotherapy or the ability to recruit a given patient population. It is NOT anticipated that a single RCC will have all expertise sought in the network. However, it is expected that RCC submitting protocols in specific strategies, such as cell-based therapy would have the necessary expertise and provide leadership in that field.

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

Two protocol proposals are requested to serve as an indicator of the applicant's ability to participate in the development and design of protocols for cooperative clinical investigations. Research plans should propose protocols that meet the objectives of the program, and demonstrate the investigators' strength and expertise in HF. Protocols should be written specifically for this Network and will serve as a key factor in evaluation of the application.

Applicants must outline the rationale and background of each proposed study. Study design, endpoints, target population, sample size, and power calculations need to be discussed. RCC applicants must describe how their disciplinary and methodological perspectives could contribute to such a cooperative research effort. The protocol budget for each proposal must include an estimated per patient enrollment cost. However, protocol costs should be excluded from the requested main RCC budget.

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 by the NHLBI.

Budget Requirements for RCC Applications: For each year, each RCC should request non-protocol budget costs only. For the purpose of the RFA, the direct costs budget for the RCC may not exceed $250,000 per year.

Estimated protocol implementation costs should be based on the proposals presented in the applicant's research plan, but should not be included in the RCC 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 drugs or substances (such as cell based therapies) 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 RCC budget. If any of the protocols proposed by RCC 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 RCCs will be responsible for obtaining the sample(s) and the cost of obtaining them will be part of the RCCs 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.

Investigators should prepare protocol budgets considering costs for their own RCC to conduct the proposed protocols, and not for the entire Network. However, if the protocol requires other centers to enroll patients into their protocol, the budget should include a cost per patient enrolled, and how many patients the RCC plans to recruit in their own center. Thus, the yearly protocol budget for the applicant's center should include: a) the number of patients available for each of the proposed protocols at the applicant's center; and b) costs for recruitment and retention of the specified number of patients, including a separate cost per patient and the cost of the proposed therapy/intervention. 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 RCC will be based on actual recruitment and overall performance.

RCC applicants should consider the following additional issues regarding budgets. The RCC center's effort is essential to maintain the infrastructure required to perform multiple clinical trials. It is estimated that the individual RCC will require a minimum level of effort to sustain the organizational aspects of the Network. It is also expected that the type and complexity of each RCC may vary. Each RCC applicant should submit a request for a center budget which may include up to 1 FTE for investigator time, an additional 1 FTE for a research coordinator, and 0.5 FTE for administrative assistant. It is anticipated that half of the first year will be devoted to protocol development and staff training, with patient recruitment commencing in the second half of the first year. This should be considered in the proposed budget structure. Requests must be submitted with appropriate justification. It is anticipated that this center budget will include the following personnel categories: PI and Co-Investigators, Study Coordinators, Data Management Coordinator, and Secretary/Administrator. A minimum of 25% effort for the PI at each RCC is required. Appropriate effort for other key personnel, travel costs for two people to attend SC meetings in Bethesda, Maryland, and other travel related to Network operations (such as DSMB meetings and site visits) should be included with appropriate justification.

In addition to the RCC budget, each RCC will be provided funds for protocol implementation and participation (enrollment) by the DCC. This support will be provided for each protocol on a per-patient basis. 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.

A separate budget table to identify the per-patient costs and total costs should be included with each protocol proposal. These budgets should be based on the two specific protocols proposed in the application and reflect anticipated costs for simultaneous implementation in the first year. Applicants should indicate for each protocol how many patients are available in the applicant's center and how many will be required from the network. The center's estimate of eligible patients should be based on the actual number of patients with that particular clinical problem treated in the year 2004. Protocol Direct Costs should include agents, drugs, devices, or laboratory tests that are not clinically indicated, or are not eligible for third-party reimbursement as a part of routine clinical care. Applicants should clearly identify the potential source(s) for all agents, drugs, or devices involved in the protocols. If donations from a pharmaceutical company are anticipated, applicants should provide documents that indicate the commitment or willingness of the source to contribute to the study and should also describe contingency plans and anticipated extra costs should the arrangements not develop as expected. Funding may not be requested for the purchase of expensive equipment. Distribution of protocol funds will be based on the approved protocols actually carried out by the network and may be more or less than the budget identified in the application. Protocol funds are not to be included in the budget requests for the operation of clinical sites. They are to be identified as proposed costs in a separate table. Therefore, the total costs on the application face page should reflect the RCC center costs. Protocol funds will be distributed by the DCC once the per patient costs have been established for approved protocols.

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 RCC 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 an RCC 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 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.

Data and Coordinating Center (DCC): Application Requirements for Data and Coordinating Center include:

Budget Requirements for DCC Applications: Applicants for the DCC should prepare budgets for five one-year periods with maximum allowable direct costs for the DCC limited to $800,000 in the first year and $1,000,000 per year in years two through five. Additionally, DCC applicants will receive a total budget of $12,850,000 to conduct protocols for the five year study period. The protocol funds will be used to reimburse the RCCs for the costs of recruitment, patient care, devices, agents 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 $1,050,000 in year 1 and $2,950,000 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 RCC as a fee for service arrangement after a protocol has been approved and the NHLBI has released the funds for distribution.

A half-time position should be budgeted to cover costs associated with the management and distribution of approved protocol dollars to each RCC for all five years. 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 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 and initiation of at least two protocols. 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). 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 and enrollment started. 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 Study 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 RCCs over the five-year study period, assuming up to eight RCCs 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.

3. Submission Dates
Applications must be mailed on or before the receipt date described below (Section IV.3.A).

3.A. Receipt, Review and Anticipated Start Dates

Letter of Intent Receipt Date: July 19, 2005
Application Receipt Date(s): August 16, 2005
Peer Review Date: February/March 2006
Council Review Date: May 2006
Earliest Anticipated Start Date: July 1, 2006

3.A.1. 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 IC 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
2 Rockledge Center, Room 7214
6701 Rockledge Drive
Bethesda, MD 20892-7924 (Express 20817)
Telephone: (301) 435-0270
Fax: (301) 480-0730
Email: [email protected]

3.B. Sending an Application to the NIH

Applications must be prepared using the PHS 398 research grant application instructions and forms as described above. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

At the time of submission, two additional 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
2 Rockledge Center, Room 7214
6701 Rockledge Drive
Bethesda, MD 20892-7924 (Express 20817)
Telephone: (301) 435-0270
Fax: (301) 480-0730
Email: [email protected]

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 listed in the heading of this funding opportunity. If an application is received after that date, it will be returned to the applicant without review. Applications will be evaluated for completeness by CSR.

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 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 (see also Section VI.3. Award Criteria).

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
Not applicable.

Section V. Application Review Information

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

2. Review and Selection Process

Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. Incomplete and/or nonresponsive 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's 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.

1. 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?

2. 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?

3. 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?

4. 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)?

5. 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?

6. 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?

Review Criteria for Regional Clinical Center (RCC) Applications:

Review Criteria for Data and Coordinating Center (DCC) Applications:

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).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

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: Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a data sharing plan in their application. 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
Not applicable.

3. Anticipated Announcement and Award Dates
The anticipated award date is July 1, 2006.

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 Grant Award (NGA) will be provided to the applicant organization. The NGA signed by the grants management officer is the authorizing document.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NGA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Notification will be made electronically to the designated institutional business official.

2. Administrative Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the notice of grant 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 cooperative agreement is an award instrument establishing an assistance" relationship (in contrast to an "acquisition" relationship) between NHLBI and a recipient, in which substantial NHLBI scientific and/or programmatic involvement with the recipient is anticipated during performance of the activity. The purpose of NHLBI involvement is to support and/or stimulate the recipient's activity by acting as a "partner", while avoiding a dominant role, direction, or prime responsibility. The terms and conditions below elaborate on these actions and responsibilities, and the awardee agrees to these collaborative actions with the NHLBI Project Scientist to achieve the project objectives. It is anticipated that these terms and conditions will enhance the relationship between the NHLBI staff and the principal investigator(s), and will facilitate the successful conduct and completion of the study. These agreements will be in addition to, and not in lieu of, the relevant NIH procedures for grants administration. The terms will be as follows:

1. 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.

1a. Regional Clinical Centers (RCCs):

RCCs will propose protocols, participate in their overall development, recruit patients, conduct the protocols, and disseminate research findings. All individual RCCs will be required to participate in a cooperative and interactive manner with one another and with the DCC in all aspects of the HF Clinical Research Network. The Principal Investigator (PI) at each RCC 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 DCC, and disseminating research findings. Each RCC will be subject to annual administrative review.

1b. 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 Study 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 subcontract with external laboratories as needed, coordinate with suppliers of drugs, and arrange for the preparation and packaging of medications. The DCC will manage and distribute all protocol funds, including a funding of centralized core laboratory(ies), if such activity will be deemed critical for conducting research agenda.

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 RCCs, provide relevant reports to the NHLBI, RCCs, and Steering Committee (SC), and serve as a central repository for study data. 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. There will be early collaboration with FDA in developing protocols. 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 be subject to annual administrative review.

2. 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. A NHLBI Program Official will be responsible for normal program stewardship of the award, will monitor patient recruitment and study progress, ensure disclosure of conflicts of interest, and ensure adherence to NHLBI policies.

3. Awardee(s) agree to the governance of the study through a Steering Committee. Voting members of the SC include, at a minimum, the Study Chair, the PIs of the RCCs and of the DCC (or their designated alternate), and the NHLBI Project Scientist. The Study Chair will be appointed by NHLBI. The Study Chair will be responsible for ensuring that there are well-documented policies, procedures, and bylaws to guide all aspects of Network activities and operations. The Study Chair will plan network activities, oversee its functions, conduct SC meetings, and cast tie-breaking votes in that committee. The SC will develop and ensure compliance with Network policies and procedures, identify and prioritize topics for investigation, evaluate protocols proposed by the RCCs, and develop consensus protocols for submission to 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 HF patients. The SC may meet as often as three to six times in the first 12 months of the study, and two to four times per year thereafter. All major scientific decisions will be determined by majority vote of the SC. 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. Meetings of the Steering Committee will ordinarily be held by telephone conference call or in the metropolitan Washington Area.

4. 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. An independent Protocol Review Committee, 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. All study protocols performed by the Network must be recommended by the PRC and approved by the NHLBI before initiation.

5. Awardees will retain custody of and have primary rights to their data 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.

6. 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.

7. 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 paragraph 6. 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.

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

9. 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.

10. Any disagreement that may arise in scientific/programmatic matters (within the scope of the award) between award recipients and the NHLBI may be brought to arbitration. An arbitration panel will be composed of three members--one selected by the Steering Committee (with the NHLBI member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NHLBI, and the third member selected by the two prior members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR part 50, Subpart D and HHS regulation at 45 CFR part 16, or the rights of NHLBI under applicable statutes, regulations and terms of the award.

11. These special terms of award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74, and other HHS, PHS, and NIH grant administration policy statements.

3. Award Criteria

The following will be considered in making funding decisions:

4. 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.

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:

George Sopko, M.D., M.P.H.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
II Rockledge Center, Suite 9176, MSC 7940
6701 Rockledge Drive
Bethesda, MD 20892-7940
Telephone: (301) 435-0515
FAX: (301) 480-1336
Email: [email protected]

2. Peer Review Contacts:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
2 Rockledge Center, Room 7214
6701 Rockledge Drive
Bethesda, MD 20892-7924 (Express 20817)
Telephone: (301) 435-0270
Fax: (301) 480-0730
Email: [email protected]

3. Financial or Grants Management Contacts:

Mr. David Reiter
Grants Operations Branch
National Heart, Lung, and Blood Institute
2 Rockledge Center, Room 7142, MSC 7926
6701 Rockledge Drive
Bethesda, MD 20892-7926 (Express 20817)
Telephone: (301) 435-0144
Fax: (301) 480-3310
Email: [email protected]

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); 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, June 12, 1998: 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.

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: a) 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 b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

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.

Public 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 public 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 PA 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.

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 52 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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