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: Pediatric Heart Network

Announcement Type
New

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

Request For Applications (RFA) Number: RFA-HL-05-010

Catalog of Federal Domestic Assistance Number
93.837

Key Dates
Release Date: March 7, 2005
Letters of Intent Receipt Date: August 26, 2005
Application Receipt Date: September 23, 2005
Peer Review Date: February–March, 2006
Council Review Date : June 15, 2006
Earliest Anticipated Start Date: September 1, 2006
Expiration Date: September 24, 2005

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 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
      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

Purpose

The purpose of this RFA is to support the Pediatric Heart Network (PHN) whose mission it is to improve the health of children and adults with structural congenital heart defects, as well as children with inflammatory heart disease, heart muscle disease, and arrhythmias. The objectives of the PHN are to provide an infrastructure for multi-center collaborative clinical research; to evaluate medical, interventional, and surgical therapies; and to serve as a clinical trials training ground for fellows and junior faculty. Results of Network studies are expected to be widely disseminated and to improve the scientific basis of care for affected individuals.

Background

Congenital cardiovascular malformations affect approximately 40,000 infants in the United States each year and are one of the leading causes of infant mortality. Improved medical and surgical management in the past 20 years has produced a growing number of adults with congenital heart disease, whose numbers are now estimated at between one and two million. In addition, a significant number of children suffer from acquired heart disease due to inflammatory cardiac conditions, primary cardiac muscle disease, and arrhythmias. Affected individuals experience morbidity and mortality that generate health and economic consequences out of proportion to their numbers. The medical, social and economic consequences of pediatric heart disease include frequent medical monitoring and the need for invasive procedures, high medical care expenses, disruption of family life, loss of potential productive years of life when a child or young adult dies, and loss of parental productivity and wages.

Treatment of congenital and acquired pediatric heart disease involves medical, surgical, and catheter-based approaches. Great strides have been made in diagnosing and treating congenital and acquired heart disease, but important clinical questions remain unanswered. Few therapies now used as "standard therapy" in the treatment of pediatric heart disease have been tested in randomized controlled trials.

The major barriers to clinical studies in pediatric heart disease include the heterogeneity of conditions, the small numbers of individuals with a particular malformation or condition at any one center, differences in treatment approaches to particular problems between centers, the absence of systematic centralized databases, and the lack of resources to provide national coordination of collaborative efforts. The Network approach is an effective, flexible way to study adequate numbers of patients with uncommon conditions. The efficiency of conducting research through a common infrastructure for recruiting, monitoring, and following patients whose conditions can be characterized in a standard fashion has been demonstrated during the first funding period of the PHN.

Scientific Knowledge to be Achieved Through Research Supported by this Program

Applications should propose research pertaining to congenital heart disease in children or adults, inflammatory cardiovascular disease in childhood, cardiac muscle disease in childhood, or arrhythmias. Proposals to study childhood prevention of adult cardiovascular disease are outside the scope of this RFA. Specific projects should be included based on their importance in the field, need for a multi-center approach, and feasibility.

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

THESE ARE EXAMPLES ONLY. APPLICANTS SHOULD NOT FEEL 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. PHN studies may be selected from those proposed by the successful applicants, but a decision to fund a particular Clinical Center will not commit the PHN to develop that group's clinical protocol.

Organization of the Pediatric Heart Network (PHN)

The PHN is a cooperative Network of Clinical Centers; a Data Coordinating Center; a Network Chair; and the Division of Heart and Vascular Diseases, NHLBI. Clinical Centers are responsible for proposing and developing protocols, conducting the research, and disseminating research findings. All individual Clinical Centers are required to participate in a cooperative and interactive manner with one another and with the Data Coordinating Center. The Data Coordinating Center supports protocol development; provides sample size calculations, statistical advice, common questionnaires, and data analysis; supports manuscript preparation; and provides overall study coordination and quality assurance, including coordination of the activities of the Data and Safety Monitoring Board (DSMB), the Protocol Review Committee (PRC), the Steering Committee, and other standing committees.

The Steering Committee is the main governing body of the PHN. The Steering Committee is composed of the Principal Investigators of the Clinical Centers, the Network Chair, the Data Coordinating Center, and the NHLBI Project Scientist, each of whom shall have one vote. The Network Chairperson is named by NHLBI to oversee and guide Steering Committee activities. The Steering Committee will meet in person an average of three times a year and by teleconference on a biweekly basis. All major scientific decisions will be determined by majority vote of the Steering Committee. The Steering Committee will have primary responsibility for the general organization of the PHN, the approval of clinical protocols and protocol changes, the conduct and monitoring of studies, and the expeditious reporting of study results. Topics for new protocols are reviewed and prioritized by the Steering Committee. For each protocol, one Clinical Center investigator will take the lead responsibility for drafting the protocol, assisted by a subcommittee composed of representatives of every Clinical Center. The Steering Committee has final responsibility for approving the protocol before review by the PRC or DSMB.

Subcommittees are established as necessary and currently include the Publications, Presentations and Ancillary Studies Committee, the Core Laboratory Selection Committee, the Nurse Coordinators Committee, and the individual protocol subcommittees. Committee membership includes physician and nurse investigators from the Clinical Centers, representatives from the Data Coordinating Center, and ex officio members from NHLBI.

An independent Protocol Review Committee, established by the NHLBI, provides scientific peer review for each protocol. A DSMB, also established by the NHLBI, monitors patient safety and reviews performance of each study. As a part of its monitoring responsibility, the DSMB submits recommendations to the NHLBI regarding the conduct and continuation of each protocol.

As specific protocols are developed, support will depend on the availability of funds and will be provided on a per-patient basis. All of the Clinical Centers must be willing to pursue this funding arrangement for each new protocol conducted. Clinical protocols must be approved by local Institutional Review Boards. The exact number and duration of protocols supported in the five-year program will depend on the nature and extent of the protocols developed.

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

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the Cooperative Agreement (U01) award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

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." After the initial five-year award period, future funding opportunities are unknown.

2. Funds Available

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. A minimum time commitment of 10% is expected from the physician leadership (Principal Investigator and any Co-investigators) at each clinical site. A minimum time commitment of 50% is expected from the individual Principal Investigator at the Data Coordinating Center.

2. Cost Sharing or Matching
Cost sharing is not required under this program.

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.

Clinical Center Applicants

Clinical Center applicants will be judged on the basis of the research plan proposed and on the ability to participate in multi-center clinical trials as indicated by the information in the application as a whole. Application to participate in the PHN should not be undertaken lightly, as it entails a significant commitment in terms of time, organizational skills, and administrative ability.

Each applicant should propose a research plan that includes a single protocol that could potentially be used in the Network environment and conducted in a 3-5 year time frame. The research plan should demonstrate detailed knowledge of the conduct of multi-center clinical trials in the field of pediatric cardiology and should involve sufficient subjects to require the use of a network with multi-center participation. Applicants should indicate knowledge of the number of patients required for the study based on sample size calculations. Inclusion of a registry to monitor patient outcomes within a protocol is acceptable, provided that the registry falls within the time constraints of the RFA.

The research plan should include: a one-page overview of the proposed investigation that presents the key research objective and a diagram depicting the initiation and duration over a 5-year period; a description of the protocol that includes the background and rationale, hypothesis being tested, specific research aims, primary and secondary endpoint or outcome measures, and study design. The research plan, including the overview and description, should not exceed 25 pages in total.

Applications from Centers that are not currently PHN Clinical Centers ALSO should address how they would participate in the PHN Single Ventricle Reconstruction Trial. This is a randomized trial comparing two surgical strategies for infants with single ventricle physiology which will continue into the next funding period. The protocol can be obtained from

Dr. Pearson, whose contact information is in Section VII. Because any new Centers that join the PHN will be expected to contribute patients to this trial, such applicants should address specific issues including: screening and recruitment methods, clinical equipoise, expertise to conduct the trial, imaging capability, estimated time to IRB approval, and any other pertinent issues. An additional 5 pages, beyond the 25-page limit for the research plan, can be included for this purpose.

Qualifications and experience

Applicants for Clinical Centers must have demonstrable experience and expertise to conduct complex multi-center clinical studies in congenital cardiac disease and acquired pediatric heart disease. 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. A minimum time commitment of 10% 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 PHN 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 pediatric cardiologists, pediatric cardiothoracic surgeons, nurses, and other related subspecialists.

For applications from current PHN Clinical Centers, reviewers will be provided with the most recent grant progress report, which will include the PHN's formal Site Assessment Report completed by the DCC. This report contains:

For other Clinical Center applicants, the application should include the following information, based on prior experience with clinical studies:

Study population

Clinical Center applicants should have sufficient patients to support recruitment in a variety of studies in the PHN. Applications should include a table with the following information for each of the past three years: the total number of open-heart surgical cases, the total number of cardiac catheterizations performed, the number of echocardiograms performed, including fetal echocardiograms, the number of infants with single-ventricle physiology encountered, and the proportion of surgical patients who do not live in the hospital's local geographic area and thus would find it difficult to return to the center for protocol follow-up testing. As a rough guide and in order to have sufficient patients to participate in PHN protocols, it is estimated that a minimum of 300 open surgical cases per year would be necessary.

Patient access may be accomplished by establishing links with other groups in addition to the applicant's institution. If this is planned, there must be a well-described plan for the coordination of PHN activities among the linked entities.

The application should include detailed sample-size calculations based on the primary end point or outcome for the proposed study as a whole. Each Clinical Center applicant is expected to contribute approximately 1/7 of the patients. Applications should include, for their site only, the number of patients with the applicable characteristics that are seen each year for the past three years, and also the proportion of these patients who would meet the inclusion criteria for actual enrollment in the study.

Applicants from institutions that have a General Clinical Research Center (GCRC) Applicants from institutions that have a GCRC funded by the NIH National Center for Research Resources are expected to make every effort to use the GCRC as a resource for conducting the proposed research. A letter of agreement from the GCRC Program Director or Principal Investigator should be included with the application.

Willingness to participate in the Pediatric Heart Network

Applicants should state their general support of collaborative research and interaction with other Clinical Centers, the NHLBI, and the Data Coordinating Center through this Network concept. Letters of institutional and departmental support for participation in the PHN are requested, which should include assurances that in the case of studies competing for the same patient population, NHLBI-funded studies will take priority. Clinical Center applicants must be able to interact with the Data Coordinating Center to transmit and edit data and should discuss their capability to participate in a distributed data entry system.

Budget Information

For purposes of the grant application, Clinical Centers will be asked to submit budgets for core 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.

Core budget costs may not exceed $200,000 direct costs, and include:

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 PHN protocol will be developed by NHLBI and PHN 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. Applications should identify the potential source(s) for any drugs or substances that are being considered for clinical protocols that are currently unavailable commercially. If the protocol proposed by a Clinical Center applicant includes 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 Clinical Centers will be responsible for obtaining the sample(s) and the cost of obtaining them will be part of the Clinical Center's per-patient expense. Investigators should prepare budgets only for their own Clinical Center to conduct the proposed trial and not for the entire Pediatric Heart Disease Clinical Research Network.

Awards will be subject to administrative review annually.

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 clinical center applicants 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 to lead the Clinical Skills Development Cores must be investigators with strong educational and mentoring credentials who will devote a minimum of 5 percent effort to the Core. To facilitate multidisciplinary developmental activities and appropriate mentoring, active involvement by the Principal Investigator and other senior investigators within the applicant center is strongly encouraged. Applicants should read the specific requirements and other instructions for applying at http://www.nhlbi.nih.gov/funding/policies/ntwk_skill.htm.

Data Coordinating Center Applicants

Qualifications and experience

Applicants for a Data Coordinating Center must demonstrate experience in the conduct of multi-center clinical pediatric 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 samples (see below); and plans for statistical analysis. Applicants also should describe their experience with pediatrics or pediatric cardiology and their ability to provide leadership in pediatric cardiology to support the clinical studies envisioned under this RFA. 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 families and investigators.

Most PHN protocols will require central laboratories for uniform interpretation of key study data, such as laboratory samples or imaging studies. The specific central lab(s) needed will depend on the protocols ultimately selected. However, for purposes of the application, Data Coordinating Center applicants should describe in detail how they will identify and secure the necessary central lab(s) once specific protocols are approved. Because most, if not all protocols will include pediatric echocardiography, Data Coordinating Center applicants should describe the development and maintenance of a central lab for echocardiography. The application also should describe how blood or tissue specimens would be stored and shipped for central interpretation.

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 active in the first year (continuing from the current grant period), 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.

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

Letters of Intent Receipt Date: August 26, 2005
Application Receipt Date: September 23, 2005
Peer Review Date: February–March, 2006
Council Review Date : June 15, 2006
Earliest Anticipated Start Date: September 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 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
6701 Rockledge Drive
Two Rockledge Centre, Room 7214, MSC 7924
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 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
6701 Rockledge Drive
Two Rockledge Centre, Room 7214, MSC 7924
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. Personal deliveries of applications are no longer permitted.

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 (see also Section VI.3. Reporting).

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/archive/grants/policy/nihgps_2003/index.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:

Clinical center applicants must include a statement of willingness to work collaboratively with the other funded sites to prepare a joint dissemination plan after award. 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

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.

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?

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

Additional Review Considerations 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 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. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

2.D. Sharing Research Resources
Not Applicable

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/archive/grants/policy/nihgps_2003/index.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. See Also Section IV.5. Funding Restrictions.

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

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 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/archive/grants/policy/nihgps_2003/index.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/archive/grants/policy/nihgps_2003/index.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 below.

2.A.1. Principal Investigator Rights and Responsibilities

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.

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 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.

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

An 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. NHLBI will appoint the Network Chair, all members of the protocol review committee (PRC), and the data and safety monitoring board (DSMB). The Network Chair will be responsible for ensuring that there are well-documented policies, procedures, and bylaws to guide all aspects of Network activities and operations.

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

Additionally, an agency program official 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.

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.

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. NHLBI policy requires that the Data Coordinating Center report quarterly on recruitment in all Network Studies that propose to enroll more than 150 patients.

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:

Gail Pearson, M.D., Sc.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 9182
Bethesda, MD 20892-7940
Telephone: (301) 435-0510
FAX: (301) 480-1454
Email: Pearsong@mail.nih.gov

2. Peer Review Contacts:

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

3. Financial or Grants Management Contacts:

Ms. Marsha Mathis
Grants Operations Branch
National Heart, Lung, and Blood Institute
2 Rockledge Center, Room 7158, MSC 7926
6701 Rockledge Drive
Bethesda, MD 20892-7926 (Express 20817)
Telephone: (301) 435-0170
Fax: (301) 480-3510
Email: mathism@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); 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.

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.

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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