PEDIATRIC HEART DISEASE CLINICAL RESEARCH NETWORK Release Date: May 24, 2000 RFA: HL-00-013 National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: September 20, 2000 Application Receipt Date: November 20, 2000 More information on this initiative can be found on the Pediatric Heart Disease Clinical Research Network web pages. PURPOSE The National Heart, Lung, and Blood Institute (NHLBI) invites applications to participate in the establishment of a Pediatric Heart Disease Clinical Research Network (Network) of interactive pediatric clinical research centers. This Network will promote the efficient evaluation of novel treatment methods and management strategies having potential benefit for children with structural congenital heart disease, inflammatory heart disease, heart muscle disease, and arrhythmias. Pediatric heart disease will be understood here to refer to these conditions; specifically excluded for purposes of this focused RFA are preventive cardiology issues such as pediatric hypertension and dyslipidemias, and adults with congenital heart disease. It is anticipated that one outcome of the Network will be to promote rapid dissemination of the findings from these clinical studies to the medical community. This Request for Applications (RFA) will establish and maintain (1) the infrastructure required for a Network of up to six clinical centers to perform multiple clinical studies in the focused areas of pediatric heart disease, and (2) a Data Coordinating Center for the Network. This is a one-time solicitation to support a Pediatric Heart Disease Clinical Research Network for five years. 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 RFA, Pediatric Heart Disease Clinical Research Network, 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/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic or Canadian for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. All current policies and requirements that govern the research grant programs of the National Institutes of Health (NIH) will apply to grants awarded under this RFA. Among the disciplines and expertise that may be appropriate for this program are pediatrics, pediatric cardiology, pediatric cardiovascular surgery, pediatric critical care, pediatric anesthesiology, pediatric cardiovascular imaging, pharmacology, therapeutic development, clinical trials management, and biostatistics. 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 the Data Coordinating Center award, but the applications for each must be from different individuals, and must be submitted as separate applications. MECHANISM OF SUPPORT This RFA will use the cooperative agreement (U01) administrative and funding mechanism of support. Under the cooperative agreement, the NIH assists, supports, and/or stimulates, and is substantially involved with recipients in conducting a study by facilitating performance of the effort in a "partner" role. Details of the responsibilities, relationships, and governance of a study funded under a cooperative agreement are discussed later in this document under the section entitled SPECIAL REQUIREMENTS. The total project period for an application submitted in response to this RFA may not exceed five years. This RFA is one-time solicitation. The anticipated award date is August 1, 2001. It is anticipated that the award for the Data Coordinating Center will be approximately $1,500,000 total costs per year and the maximum award for each Clinical Center will be $510,000 total costs per year. The amount awarded to each Clinical Center per year will depend on the protocol(s) underway. FUNDS AVAILABLE A maximum of six awards for Clinical Centers and one award for a Data Coordinating Center will be made under this RFA. A maximum of about $22.8 million (total costs) over a five-year period will be awarded for the Clinical Centers and the Data Coordinating Center. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of an award will also vary in all years. Future year costs will be distributed based on the final, approved protocols. Although the financial plans of the NHLBI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of appropriate scientific and technical merit. Designated funding levels are subject to change at any time prior to final award, due to unforeseen budgetary, administrative, or scientific developments. It is not known if competing renewal applications will be accepted or if this RFA will be reissued. RESEARCH OBJECTIVES Background Approximately 32,000 infants are born each year in the United States with congenital cardiovascular malformations, the most common congenital anomaly, and one of the leading causes of infant mortality. The incidence of congenital heart disease is at least triple that of childhood cancers, and substantially greater than pediatric AIDS. A significant number of additional children experience medical problems from inflammatory cardiac conditions, heart muscle disease, and arrhythmias. Affected children experience morbidity and mortality that generate health and economic consequences out of proportion to their numbers. In spite of recent improvement, the mortality rate for structural congenital malformations varies from less than 1% to as high as 50%, depending on the condition. The medical, social and economic consequences of pediatric heart disease are profound, and include frequent medical monitoring and the need for invasive procedures, high medical care expenses, disruption of family life, the high cost of potential productive years of life lost when a child 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 pediatric heart disease since 1944, when the first operation for palliation of tetralogy of Fallot was performed, but important clinical questions remain unanswered. Medical therapy is employed widely to treat various pediatric heart diseases including arrhythmias, heart failure, myocarditis, and coronary artery aneurysms arising after Kawasaki Disease. Few drugs used as "standard therapy", however, have been tested in randomized controlled trials in pediatrics. For example, standard pharmacological agents used in the treatment of adult heart failure, such as diuretics, digitalis, angiotensin-converting enzyme (ACE) inhibitors, and beta-blockers, are used in children, but have not been studied in a systematic fashion. Emerging adult therapies, such as immune modulation in heart failure, may benefit children but are virtually untested in pediatric populations. In addition, pediatric heart failure can arise from multiple causes, including structural heart defects, heart muscle disease and inflammation, post-operative injury and edema, and poorly-controlled arrhythmias. Standard and novel pharmacological agents may have different effects in specific types of heart failure. As another example, immunosuppressive therapy, commonly used to treat pediatric myocarditis, has never been evaluated in a prospective, randomized trial. Many structural congenital heart abnormalities are successfully corrected surgically. However, the optimal timing and approach for complex congenital structural malformations including the several malformations that lead to single ventricle physiology are not known, and the risks and benefits of devices compared to surgical repair of certain defects have not been studied systematically. In addition, the acute and chronic post-operative course can be complicated by conditions such as post-cardiopulmonary bypass syndrome (especially in infants), arrhythmias including those implicated in sudden death, neurodevelopmental deficits, ventricular dysfunction and heart failure, and coagulapthy leading to the need for reoperation. Treatment strategies for these conditions are not supported by systematic prospective clinical studies. A prime example is sudden cardiac death associated with repair of complex cyanotic congenital heart disease. Many of these survivors are adolescents who have arrhythmias that may not be clinically apparent, and may require invasive testing to discern. However, the correlation between results from invasive testing and sudden death is not clear, so it is difficult to risk-stratify surgical survivors for implantable defibrillator placement. As the number of such survivors grows, there is increased urgency to answer this question. Like heart failure, pediatric arrhythmias can occur in several settings, such as abnormal electrical pathways in structurally normal and abnormal hearts, postoperative edema and injury, inflammatory and heart muscle conditions, and ventricular dysfunction. Therapeutic approaches include medical, interventional, and surgical strategies, which have improved the care of affected children. As with other pediatric heart conditions, however, important treatment questions remain. Most treatment decisions concerning these and other pediatric heart disease are not evidence-based. In the past 25 years, fewer than 40 randomized clinical trials have been conducted, of which nearly half dealt with patent ductus arteriosus in preterm infants. 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, 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 diseases, such as congenital cardiovascular malformations. Efficiencies will be achieved through a common infrastructure for recruiting, monitoring, and following patients whose conditions will be characterized in a standard fashion. A network also can serve as a platform to train junior investigators in pediatric clinical research, and as a vehicle for rapid and wide-spread dissemination of findings. A collaborative effort through a clinical research network is the most scientifically sound and cost-effective way to overcome the current barriers and provide the information needed to bring evidence-based medicine to bear on children with heart disease. Organization of the Pediatric Heart Disease Clinical Research Network The Pediatric Heart Disease Clinical Research Network will be a cooperative network of 5-6 Clinical Centers, one Data Coordinating Center, and the Division of Heart and Vascular Diseases, NHLBI. Clinical Centers will be responsible for proposing protocols, participating in their overall development, conducting the research, and disseminating research findings. All individual Clinical Centers will be required to participate in a cooperative and interactive manner with one another and with the Data Coordinating Center in all aspects of the Pediatric Heart Disease Clinical Research Network. The separate Data Coordinating Center will support protocol development; provide sample size calculations, statistical advice, common questionnaires, and data analysis; support manuscript preparation; and provide overall study coordination and quality assurance, including coordination of the activities of the Data and Safety Monitoring Board (DSMB), the Protocol Review Committee, the Steering Committee, and other standing committees. A Steering Committee will be the main governing body of the Pediatric Heart Disease Clinical Research Network. At a minimum, the Steering Committee will be composed of the Principal Investigators of the Clinical Centers and the Data Coordinating Center. The NHLBI Project Scientist will serve as an ex officio member. By the end of the second meeting of the Steering committee, the NHLBI will name a Study Chairperson, who may not be associated with any of the Clinical Centers or the Data Coordinating Center and is not an NHLBI staff member, to oversee and guide Steering Committee activities. Each Clinical Center, the Data Coordinating Center, and the Study Chair will have one vote. The Steering Committee 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 Steering Committee. The first meeting of the Steering Committee will be convened by the NHLBI Project Scientist. The Steering Committee will have primary responsibility for the general organization of the Pediatric Heart Disease Clinical Research Network, finalizing common clinical protocols, facilitating the conduct and monitoring of studies, and reporting study results. Topics for the protocols will be proposed and prioritized by the Steering Committee. For each protocol, one Clinical Center will take the lead responsibility for drafting the protocol, although the Steering Committee will provide input and will be responsible for assuring development of a common protocol to be implemented by the Clinical Centers. Subcommittees of the Steering Committee will be established as necessary, but 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 by the Steering Committee. The Quality Control Subcommittee will be responsible for developing standards for specific laboratory tests and other measures to be used in Network protocols. All will be chaired by a Clinical Center Principal Investigator, and include representation from the Data Coordinating Center and NHLBI. An independent Protocol Review Committee, established by the NHLBI, will provide peer review for each protocol. A DSMB, also established by the NHLBI, will monitor patient safety and review performance of each study. As a part of its monitoring responsibility, the DSMB will submit recommendations to the NHLBI regarding the 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 and the Pediatric Heart Disease Clinical Research Network Protocol Review Committee before initiation. 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 Network Steering Committee. Research Scope The objective of this RFA is to establish a Pediatric Heart Disease Clinical Research Network that will accelerate research in the diagnosis and management of congenital and acquired pediatric heart disease as defined earlier, standardize existing treatments, and evaluate new therapies. The emphasis will be on clinical studies that help identify optimal diagnosis, monitoring, and therapy. Therapeutic trials and studies may involve investigational drugs, drugs already approved but not currently used, and drugs currently used, as well as devices, interventional procedures, and surgical techniques. All projects must be completed within the five-year duration of this RFA. This Network cannot answer all scientific questions pertaining to pediatric heart disease. However, the urgent clinical problems that fit within the limits of the proposed Network science and structure, and the time-frame of this program are expected to be considered. Specific projects should be included based on their importance in the field, as indicated by numbers of patients affected, medical and economic burden, and problems with current management. Some examples of topic areas in which to pose research questions dealing with diagnostic and treatment strategies appropriate for this RFA include, but are not limited to, the following: o The diagnosis and medical management of congenital cardiovascular malformations and acquired pediatric heart disease, including the role of novel imaging techniques (3-D echo, cardiac MRI) in determining cardiac structure and function; evaluation of standard and novel therapy for pediatric heart failure arising in the setting of structural malformations, cardiac inflammation, and heart muscle disease; and therapy for acquired conditions such as myocarditis or coronary artery aneurysms in Kawasaki Disease. o Surgical strategies for single-ventricle physiology, optimal timing of surgery for various defects, evaluations of combined surgical and interventional strategies for complex congenital heart disease, and optimal approach to severe right- and left-heart obstructions. o Postoperative issues, including ventricular support, myocardial preservation and post-cardiopulmonary bypass syndrome, neurodevelopmental outcome, post- operative pulmonary artery hypertension and dysfunction, post-operative coagulopathy or clot formation leading to reoperation, and postoperative acute and chronic arrhythmias. 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. It is not the intent of this Network to provide support for only one or two protocols that run for the entire five years. Multiple studies will be conducted, possibly two to four a 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 Clinical Center will not commit the Pediatric Heart Disease Clinical Research Network to develop that group's clinical protocol. Each Clinical Center 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 in the field of pediatric heart disease. Each protocol 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 each study based on sample size calculations. One protocol must be a short-term (two years or less) and one a long-term (more than two years, but completed within the overall five-year time frame of the RFA) investigation of congenital or acquired pediatric heart disease. 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 follow the instructions in the PHS 398 application form, (revised 4/98; https://grants.nih.gov/grants/forms.htm) and should include: a one-page overview of the proposed two 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 populations. The Research Plan, including the overview and description for both protocols, should not exceed 25 pages in total. The applicant should 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 indicate appropriate objective measures of primary and secondary outcome. 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 response to therapy. The relevant technology should be available for each protocol proposed during the five years of funding. It also will be important to include strategies to assure adherence to therapy as part of the protocol. SPECIAL REQUIREMENTS Terms and Conditions of Award 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 NHLBI purpose is to support and/or stimulate the recipient=s activity by involvement in and otherwise facilitating the activity in a "partner" role, but 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 toward achieving 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. 2. The NHLBI Project Scientist will serve on the Steering Committee; he/she or another NHLBI scientist may serve on other study committees, when appropriate. The NHLBI Project Scientist (and the other cited 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 potential changes in the 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. 3. 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 Study Chair. 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. 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 protocol. 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 (i.e., cooperative agreement awardees). 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. Awardees are encouraged to publish and to publicly release and disseminate results, data and other products of the study, concordant with the study protocol and governance, and the approved plan for making data and materials available to the scientific community and to the NHLBI. However, during or within three years beyond the end date of the project period of NHLBI support, unpublished data, unpublished results, data sets not previously released, or other study materials or products are to be made available to any third party only with the approval of the Steering Committee and in accordance with paragraph 6. 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, quality control, or other major breach of the protocol, (c) substantive changes in the agreed-upon protocol with which NHLBI cannot concur, (d) reaching a major study endpoint substantially before schedule with persuasive statistical significance, or (e) human subject ethical issues that may dictate a premature termination. 9. 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 Program 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. 10. 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. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDIES It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided 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 research involving human subjects should follow the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and in the NIH Guide for Grants and Contracts of March 18, 1994, Volume 23, Number 11 and are available on the web at: https://grants.nih.gov/grants/guide/notice-files/not94-100.html. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. 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" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html. This Network will, by definition, include children. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit, by September 20, 2000, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. 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 faxed, E-mailed, or mailed to the Deputy Director, Division of Extramural Affairs, NHLBI, at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-710-0267, E-mail: GrantsInfo@nih.gov. The PHS 398 application kit is also available on the Internet at https://grants.nih.gov/grants/forms.htm NHLBI will operate a web site in support of this RFA that will include supplemental information, frequently asked questions, and other pertinent details. It can be accessed through the NHLBI public web site, http://www.nhlbi.nih.gov. Applicants are encouraged to check this site frequently as they are preparing their applications. Material to Include in the Application Clinical Center Applicants: To promote development of a collaborative program among the award recipients, the issues discussed below need to be addressed in each application for a Clinical Center. This material is in addition to the submission of a research plan, as described in the section entitled Research Scope. o Qualifications and experience. Participation in this Network will be a complex and time-consuming undertaking. Applicants for Clinical Centers must have experience and expertise to conduct clinical studies in congenital and acquired pediatric heart disease. Prospective Clinical Centers must have an established research program in the area of congenital heart defects, and demonstrated access to a sufficient number of patients to accomplish their portion of the proposed protocols. A minimum time commitment of 25% is expected from the physician leadership (Principal Investigator and any Co-investigators) at each Clinical Center. o Study population. The application should include a description of the pool of potential study participants, including the age range, ethnic/racial and gender distribution, estimated distribution of patients with different types of congenital and acquired pediatric heart disease, and recruitment sources. It is not anticipated that all eligible patients will be enrolled in research protocols at any one time, and it is possible that an individual patient may be enrolled in more than one study. 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 to link the individual Clinical Centers with other community health care providers, such as pediatric cardiology practices, pediatricians, and health maintenance organizations, as appropriate, to ensure adequate numbers of patients for clinical studies. o Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC Program Director or Principal Investigator should be included with the application. o Willingness to participate in the Pediatric Heart Disease Clinical Research 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. Applicants should discuss their willingness, and that of the institutions involved, to pursue a per- patient basis (capitation) of operational costs for each protocol. 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. Data Coordinating Center Applicants o Qualifications and experience. Applicants for a Data Coordinating Center must demonstrate experience in the area of pediatrics and/or cardiovascular medicine and in coordinating multi-center clinical studies in all phases: protocol and manual of operations development, data collection and management, data safety and confidentiality, quality assurance, data analysis, distributed data entry, electronic communications, administrative management and coordination. A minimum time commitment of 25% is expected from the Principal Investigator of the Data Coordinating Center. o 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. The proposed Data Coordinating Center budgets should stipulate and justify the amount included for managing the DSMB and other Committees. Travel expenses to attend the Steering Committee will be included in the budgets prepared by the Clinical Centers. o The Data Coordinating Center should describe how laboratory specimens (e.g., blood or tissue samples) will be handled. Laboratories responsible to the Data Coordinating Center will manage specimens and laboratory studies as required by the Steering Committee. The costs of performing specific laboratory tests that are not clinically indicated (i.e., will not be reimbursed through third-party payers as part of routine clinical care) will be budgeted as a part of the per- patient costs of each Clinical Center. The costs of specimen shipment as well as laboratory data acquisition and management will be a part of the budget of the Data Coordinating Center. Estimated shipping and handling expenses for specimens should be justified and included in the budget of the Data Coordinating Center. For the purposes of planning, the Data Coordinating Center should assume 2,000 patients over the course of the 5-year study period. o The Data Coordinating Center will be responsible for one or more central labs that will analyze data from clinical testing, such as echocardiograms, electrocardiograms, Holter monitor tracings, electrophysiology studies, and angiograms. It is understood that 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. In addition, 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 (including fetal, transthoracic, and transesophageal components). The costs of performing specific tests (i.e., tests that are not eligible for third-party reimbursement) will be budgeted as a part of the per-patient costs of each Clinical Center. The format of transfer of data to the Data Coordinating Center should be specified. For example, will the central echocardiography lab review tapes or digitally-archived information? The expense of transferring the data on the clinical studies to the central lab(s), training technicians to obtain the data in a uniform manner, and instituting quality control measures (e.g., provision for re-reading a proportion of the studies to determine accuracy of interpretation) will be included in the Data Coordinating Center budget. BUDGET AND RELATED ISSUES Applicants should complete the budget information as directed in the PHS 398 application form. Clinical Center Applicants: Clinical Center applicants should consider the following additional issues regarding budgets. The underlying concept of the Pediatric Heart Disease Clinical Research Network is that a core effort is essential to maintain the infrastructure required to perform multiple clinical trials. Based on this approach, it is estimated that the individual Clinical Centers will require a minimum level of effort to sustain the organizational aspects of the Pediatric Heart Disease Clinical Research Network. Therefore, individual Clinical Centers should submit requests for a CORE BUDGET not to exceed $175,000 total costs per year. It is anticipated that this core budget will cover a minimum of 25% effort for the combined physician leadership (Principal Investigator and any Co- investigators), and appropriate percentages of effort for other key personnel (e.g., clinical coordinator, data entry clerk), and travel costs for approximately eight trips each year to attend Steering Committee meetings in Bethesda, MD, and other travel related to Network operations. These costs should include appropriate justification. Total costs for the core budget can be escalated at three percent annually for future years. It should be noted that funds will not be provided for the purchase of expensive equipment such as echocardiographic or magnetic resonance imaging systems. In addition to the core budget, each Clinical Center will be provided funds for implementation of protocols. This support will be provided for each protocol on a per-successfully-enrolled-patient basis. The precise number of protocols conducted over the five years will be determined by the Pediatric Heart Disease Clinical Research Network Steering Committee and will depend on a number of factors including availability of funds, length of the protocols, and ease of recruitment. It is anticipated that after the first year, two to four protocols may be active each year. Clinical Centers should request protocol enrollment funds as PATIENT CARE costs not to exceed $335,000 per year. This amount should be placed in the patient care category. Patient care costs can be escalated at three percent annually for future years. Maximum allowable total costs for each clinical center (core costs, costs per patient to conduct the protocols, and facilities and administrative costs) will be $510,000 a year. Applicants for the Clinical Centers should present the following information: o For each year, the Clinical Centers should include the core budget costs (not to exceed $175,000 total costs) and patient care costs (not to exceed $335,000 total costs). Estimated protocol implementation costs for Year 1 should be based on the two proposals presented in the applicant=s research plan. A table should be included showing estimated costs per patient for conducting each protocol. o The budget for each clinical protocol in the PATIENT CARE category should be developed on a cost-per-patient-basis and include all direct costs and the associated protocol facilities and administrative costs at a rate not to exceed 28%. 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 identify the potential source(s) for any drugs or substances that are being considered for clinical protocols that are currently unavailable commercially. If either of the protocols 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. The cost of shipping, analyzing, and storing them, as well as training of personnel and quality control will be the responsibility of the Data Coordinating Center. o 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. The applicant should state the total number of patients required by the entire Network to complete each proposed trial. The yearly budget for the applicant's Center should include the number of patients available for the proposed protocol at the applicants center. A budget based on the costs per patient for recruiting and maintaining the specified number of subjects at the applicant's Center should be included for each protocol. Note that ongoing annual budgets for protocols will be based on the protocols approved by the Protocol Review Committee and the Pediatric Heart Disease Clinical Research Network Steering Committee. The individual Clinical Centers will be expected to project patient enrollment for a specific protocol during a specified time frame; continuation and level of funding for each Clinical Center will be based on actual recruitment and overall performance. Awards will be subject to administrative review annually. Data Coordinating Center applicants: Applicants for the Data Coordinating Center should prepare budgets for five 12- month periods that roughly correspond with the standard coordinating center responsibilities outlined elsewhere in this RFA. For budget purposes, Data Coordinating Center applicants should assume that in the first year, all administrative aspects of the Pediatric Heart Disease Clinical Research Network will be organized and at least one protocol will be developed and started. For subsequent years, applicants may assume that two to four protocols a year will be active; i.e., either in the protocol development, implementation, or analysis and writing phase. Data Coordinating Center applicants should include costs for managing the DSMB, the Protocol Review Committee, and the Steering Committee including the cost of DSMB meetings two times per year in Bethesda, the cost of Protocol Review Committee conference calls and meetings, and the administrative expenses of Steering Committee conference calls and meetings. Travel of Steering Committee members will be budgeted by Clinical Centers. The Data Coordinating Center also should include costs for site visits of each of the Clinical Centers over the five-year study period, assuming six Clinical Centers throughout the U.S., and a five-member site visit team, for purposes of budget preparation. 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. APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW. The RFA label available in the PHS 398 (rev. 4/98) application form 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 types on line 2 of te face page of the application form and the YES box must be marked. The sample RFA label available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to the Deputy Director, Division of Extramural Affairs, NHLBI, at the address listed under INQUIRIES. Applications must be received by November 20, 2000. If an application is received after this date it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of an application already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness by NHLBI. Incomplete and/or nonresponsive applications will be returned to the applicant without further consideration. 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 Division of Extramural Affairs, NHLBI, in accordance with the review criteria stated below. The roster of the initial review group will be posted on the NHLBI home page approximately two weeks prior to the review. As part of the initial merit review, all applications will receive a written critique and undergo a review in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second-level review by the National Heart, Lung, and Blood Advisory Council. Review Criteria Clinical Centers: The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application 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 the 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. o Significance: Do the proposed studies address important problems? If the aims of the application are achieved, how will scientific knowledge and care of the child with congenital or acquired pediatric cardiovascular disease be advanced? What will be the effect of these studies on the concepts or methods that drive this field? o Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? o Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? o Investigator: Is the Principal Investigator 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? o Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of a strong tradition of pediatric cardiovascular research and clinical care and ability to recruit the required number of patients? Is there evidence of institutional support for the proposal? o Clinical Center Issues: Does the application demonstrate access to patients and a willingness to work as part of the Pediatric Heart Disease Clinical Research Network and with the NHLBI Project Scientist(s)? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. Data Coordinating Center: Considerations for the review of Data Coordinating Center Applicants include the following issues: o Understanding of the scientific, statistical, logistical, and technical issues underlying multi-center studies, including issues relating to treatment and management of pediatrics and pediatric cardiovascular conditions, and taking a leadership role in the area of study design, statistics, logistics, data acquisition and management, patient confidentiality, handling of laboratory specimens, quality control, data analysis, and Network coordination. o Adequacy of the proposed plans for acquisition, transfer, management, and analysis of data, quality control of data collection and monitoring, and overall coordination of Pediatric Heart Disease Clinical Research Network activities. o The expertise, training, and experience of the investigators and staff, including the administrative abilities of the Principal Investigator, co-investigator, and the time they plan to devote to the program for the effective coordination of the Pediatric Heart Disease Clinical Research Network. o The administrative, supervisory, and collaborative arrangements for achieving the goals of the program, including willingness to cooperate with the participating Clinical Centers and the NHLBI. o Facilities, equipment, and organizational structure to coordinate Clinical Research Network activities effectively, and to assist Clinical Centers in implementing the Pediatric Heart Disease Clinical Research Network protocols, providing for specialized laboratory testing, and collecting data. o Appropriateness of the budget for the work proposed. Schedule Letter of Intent Receipt Date: September 20, 2000 Application Receipt Date: November 20, 2000 Peer Review Date: March, 2001 Council Review: June 14-15, 2001 Anticipated Award Date: August 1, 2001 AWARD CRITERIA Factors that will be considered in making awards include: a) the scientific merit of the proposed program as determined by peer review, the multi- disciplinary nature of the proposed studies, and the quality of the response to the special requirements stated in this RFA; b) relevance to the overall programmatic balance and priorities of the NHLBI and sufficient compatibility of features proposed in the research plan and qualifications of the investigators to make a collaborative program within the Pediatric Heart Disease Clinical Research Network a reasonable likelihood; and c) the availability of funds. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Gail D. Pearson, M.D., Sc.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 9044, MSC 7940 Bethesda, MD 20892-7940 Bethesda, MD 20817 (for express/courier service) Telephone: (301) 435-0524 FAX: (301) 480-1335 Email: gp62n@nih.gov Direct inquiries regarding review issues to: James Scheirer, Ph.D. Deputy Director, Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7216, MSC 7924 Bethesda, MD 20892-7924 Bethesda, MD 20817 (for express/courier service) Telephone: (301) 435-0266 FAX: (301) 480-3541 Email: js110j@nih.gov Direct inquiries regarding fiscal matters to: Mr. Kevin Keating Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive Suite 7136, MSC 7926 Bethesda, MD 20892-7926 Bethesda, MD 20817 (for express/courier service) Telephone: (301) 435-0177 FAX: (301) 480-0422 Email: kk29g@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.837. Awards are made under authorization of Sections 310 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or a Health Systems Agency Review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-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.
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