SPECIALIZED CENTERS OF CLINICALLY ORIENTED RESEARCH (SCCOR) IN PEDIATRIC HEART DEVELOPMENT AND DISEASE RELEASE DATE: March 21, 2002 RFA: HL-02-027 National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) LETTER OF INTENT RECEIPT DATE: December 16, 2002 APPLICATION RECEIPT DATE: January 16, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The primary objective of the Specialized Centers of Clinically Oriented Research (SCCOR) programs is to foster multidisciplinary research on clinically relevant questions enabling basic science findings to be more rapidly applied to clinical problems. The clinical and basic research supported through this RFA will be related to congenital and acquired pediatric heart diseases. It is expected that results from these SCCOR grants will have a positive effect on the prevention, diagnosis, and treatment of congenital cardiovascular malformations, pediatric disorders of myocardial function, pediatric arrhythmias and conduction disturbances, and acquired pediatric cardiac diseases such as Kawasaki Disease and myocarditis. RESEARCH OBJECTIVES The National Heart, Lung, and Blood Institute (NHLBI) revised the Specialized Centers of Research (SCOR) program, based primarily on recommendations from the National Heart, Lung, and Blood Advisory Council. The new program is called the Specialized Centers of Clinically Oriented Research (SCCOR) program. The original SCOR program required both basic and clinical research, but the preponderance of funded projects were in the basic science arena. The new title and the revisions to the program reflect the Institute=s desire to capitalize on basic research advances by encouraging their translation to the clinical arena. The guiding principle of the new SCCOR program is the central focus on clinically relevant research, and the key change to achieve this goal is the requirement that at least one-half of funded projects be clinical. The specific components of the new SCCOR program are detailed in this RFA. Pediatric heart disease is an important public health problem that comprises several major categories: congenital cardiovascular malformations, disorders of myocardial function and electrical conduction, and acquired heart disease. Congenital Cardiovascular Malformations. In the nearly 60 years since the first Ablue baby@ operation, there has been a revolution in the diagnosis and treatment of congenital cardiovascular malformations. Advances in echocardiography permit in utero diagnosis of congenital cardiovascular malformations as early as the first trimester of pregnancy; advances in surgery, bypass and myocardial preservation have made repair of complex cardiac malformations possible in tiny infants; and advances in interventional cardiology have made minimally-invasive treatment of certain lesions a reality. As a result, the mortality rate for children with heart disease has decreased considerably. Unfortunately, however, birth defects remain the leading cause of infant mortality, and cardiovascular malformations remain the largest contributor to birth-defect-related-mortality. In addition, as the number of survivors increases, it is becoming clear that attention must be paid to long- term morbidities, especially in those children with non-cardiac malformations. Enormous strides also have been made in understanding the molecular and morphogenetic underpinnings of normal and abnormal cardiovascular development. In the past 15 years, the role that multiple transcription factors play in the developmental process has been elucidated, several genes and proteins that govern left-right cardiac asymmetry and specify cardiac valves and chambers have been identified, and aspects of molecular regulation of coronary artery development have been worked out. Much remains to be learned, however, and work is required in order to translate the progress that has been made at the bench to the bedside. The pulmonary circulation is integral to congenital heart disease and is also inextricably linked to cardiac development. Many patients with congenital heart disease also have abnormal pulmonary vasculature that persists even after the initial cardiac malformation has been repaired. Because the pulmonary circulation is one of the few vascular beds in which the most expansive growth occurs in the perinatal and postnatal period, it offers a potentially accessible target for therapeutic intervention. However, further study into the mechanisms regulating cardiopulmonary vascular development and remodeling are required before rational therapy can be designed. Because children grow and artificial valves and conduits do not, pediatric patients who receive heart valve or blood vessel replacements require subsequent operations to replace their bioprostheses. Investigators have begun using tissue engineering technology to attempt to develop cardiac tissue substitutes that are durable, biocompatible, and grow with young patients. Their approaches, such as growing cells on biodegradable scaffolds configured to the shape of heart valves or conduit vessels, are still in their infancy, but provide hope for the development of cardiovascular tissue substitutes, which would reduce the need for multiple surgeries for children with congenital cardiac lesions. Tissue engineered structures may also reduce the risks of infection and thrombosis associated with prosthetic and bioprosthetic materials, thereby reducing the need for anticoagulant and anti-platelet therapies with their attendant risk of bleeding. Other cell-based therapies may have potential for treatment of cardiomyopathy and structural heart disease. For example, it may be possible to combine gene and stem cell therapies by genetically modifying stem cells with vectors that program the expression and secretion of therapeutic proteins. Disorders of myocardial function and electrical conduction. In addition to structural abnormalities, children=s heart disease also includes primary and secondary disorders of myocardial function such as heart failure, cardiomyopathy and arrhythmias. Heart failure can be acute or chronic, and can occur in a variety of circumstances in pediatrics including congenital cardiovascular malformations before and after repair, cardiac infection or inflammation, cardiomyopathy, and arrhythmia. Understanding the molecular, cellular, and myocardial components of heart failure in children may lead to improvements in therapy for both children and adults. As in adults, cardiomyopathies can be dilated, hypertrophic, and restrictive, and can be due to primary abnormalities in muscle or structural proteins, or can arise secondary to diverse causes such as cardiac infections or inflammation, cardiotoxic drugs, or systemic illnesses such as lupus. The etiology of many cardiomyopathies remains obscure although some are due to genetic mutations of contractile proteins, connective tissue proteins, or ion channels. Treatment of cardiomyopathy is typically supportive and of variable effectiveness. Novel treatment paradigms are needed to improve the outcome for these conditions. The conduction system arises during late cardiac development and is essential for normal electrophysiological function throughout life. Knowledge about normal and abnormal conduction system development has lagged behind discoveries concerning cardiac structural development. Arrhythmias such as supraventricular tachycardia, congenital and acquired heart block, and ventricular tachycardia are substantial causes of morbidity and occasionally mortality in children. Recent advances in delineating the molecular genetic basis of the Long QT Syndrome, congenital heart block, and the Brugada syndrome suggest that mutations in sodium, potassium, and calcium channel genes predispose patients to these life-threatening arrhythmias. However, environmental and structural factors, including interactions with common drugs, may also affect conduction in relationship to these particular ion channels and may result in lethal arrhythmias. Acquired Heart Disease. Some children with previously normal hearts subsequently develop heart disease. The most common cause of acquired heart disease in children is Kawasaki Disease, an inflammatory disorder of unknown etiology that affects the coronary vasculature. Current treatment is aimed at minimizing the inflammatory process and results in decreases in coronary artery involvement. Identification of a specific etiology and an understanding of genetic and environmental influences on outcome, however, would permit more focused therapy. Rheumatic carditis and myocarditis are two additional forms of acquired heart disease that affect the pediatric population for which improved understanding of the pathyphysiology may identify novel treatment options. The objective of the Pediatric Heart Development and Disease SCCOR is to stimulate clinically relevant, multidisciplinary collaborations leading to clinical and basic science research efforts on important public health problems for children with congenital or acquired heart disease. The translation of knowledge into clinical practice should be a goal of applications submitted in response to this initiative. Recent advances in understanding the molecular biology of cardiovascular development offer new directions for the study of normal and abnormal heart formation, the development of early diagnostic tools, potential risk stratification based on genotype as well as phenotype, and many other endeavors related to clinical problems in pediatric cardiology. The following examples of research topics are intended to provide a perspective on the scope of research that would meet the objectives of this program. It is not required that all or any of these topics be included; investigators are encouraged to consider other topics that are relevant to the goals of the new Pediatric Heart Development and Disease SCCOR program. A unified program of clinical and basic research is needed to address such areas as: o stem cell differentiation, proliferation, and interactions during development to provide the basis for their use as potential sources of cardiomyocytes, endothelial cells, and vascular smooth muscle cells to treat cardiovascular disease in childhood; o novel therapeutic approaches, including cell-based therapies, improved myocardial and pulmonary preservation, improved neurological preservation, and biomechanical advances to treat cardiovascular disease in childhood; o the influence of genomic variation, genotype-phenotype correlations, modifier genes, and gene-environment interactions on the development and progression of pediatric heart disease, and on therapeutic success and the incidence of adverse clinical events; o relationships between congenital cardiovascular disease and pulmonary vascular malformations; o relationships between congenital cardiovascular disease and extracardiac malformations; and o normal and abnormal mechanisms of cardiac development, including both structure and cardiac conduction, emphasizing multidisciplinary approaches and new animal models as well as new technologies such as gene profiling or proteomic approaches. The SCCOR mechanism provides both the incentive and the structure to maintain critical collaborative cores or other resources necessary for translational research. For example, the SCCOR mechanism affords the ability to establish and maintain a large clinical/DNA sample database of patients with congenital heart disease. Clinical Research Skills Development Core The newly developed Specialized Centers of Clinically Oriented Research (SCCOR) program mechanism requires clinical and basic scientists with a broad range of skills to work together on a unified theme. It, therefore, presents a rich environment for young clinical investigators to be exposed to and develop additional research skills. The individual centers can be expected to include among their research staffs clinical personnel who are newly trained and relatively inexperienced in research. To assist the SCCOR grants in enhancing the developmental environment for their new clinical investigators, the NHLBI will permit applicants for a new SCCOR to request up to $100,000 in direct costs per year for a Clinical Research Skills Development Core. The objective of the Core is to support activities to assist new clinical investigators in progressing to more senior status by enhancing their research skills. This support is in addition to the usual cap on the SCCOR mechanism that is updated annually. A Clinical Research Skills Development Core is not required, however, and its absence will not disadvantage an applicant. The quality of the Clinical Research Skills Development Core, if proposed, will be evaluated based on the specific components listed below. The priority score on the Core will have no effect on the overall score of an application. Developmental opportunities that provide experience with new technologies and skills are encouraged for inclusion in the Core. Innovative strategies should be proposed for cross-disciplinary career development to achieve the goal of exposing new clinical investigators to additional research techniques and opportunities. Examples include a program of seminars focusing on scientific topics that include an integration of basic and clinical studies or an Aexchange@ program wherein clinical investigators spend time in basic science labs. In addition to developing the research skills of new clinical investigators, the Cores must ensure that the participating new clinical investigators receive the mentoring they need to foster their research careers. The Clinical Research Skills Development Core is intended for staff investigators with limited clinical research experience, including fellows and junior faculty members. Investigators who have had a previous K series award are not eligible to participate as new investigators under this program. Individuals with an active K grant can participate until the end of the award period for the K grant. The Core should also address other skills necessary for a successful research career, such as grant writing, ethical conduct of research, and clinical trial design. If a Clinical Research Skills Development Core is proposed, it must be directed by an investigator with strong educational and mentoring credentials who will devote a minimum of 5 percent effort as its Leader. To facilitate mentoring and multidisciplinary developmental activities, active involvement by the principal investigator and other senior investigators within the SCCOR is strongly encouraged. An application for a Clinical Research Skills Development Core will be evaluated in terms of its potential effectiveness in developing the skills and research capabilities of new clinical investigators as reflected in the following required elements of the application: 1. A summary of the types of skills that would be developed and a description of proposed project-specific activities; 2. A detailed discussion of how mentoring and the professional development of the new clinical investigators will be achieved, including their progression to more independent status; 3. The credentials and track records of the Clinical Research Skills Development Core Leader, the Principal Investigator, and other participating senior staff in developing new investigators; 4. A plan for coordinating the activities of participating senior investigators; 5. A plan for monitoring the progress of the new clinical investigators; 6. A description of existing opportunities within the applicant=s institution for supporting investigator development and steps taken to avoid overlap with or duplication of these efforts; and 7. A detailed development plan for each proposed new investigator (or a representative plan and proposals for tailoring it to needs of multiple new investigators) including required course work and scientific enrichment activities such as special lectures, visiting scientist symposia, seminars, and workshops. Costs allowable for inclusion within the $100,000 direct costs per year limit for the Clinical Research Skills Development Core include salary support for the Core Leader and other participating senior investigators and staff, travel costs for new investigators, supplies and equipment to be used in support of developmental activities, and costs for courses, seminars, workshops, and other activities directly related to the development plan. All costs requested in this Core must be justified with respect to developmental activities and may not be used to supplement the costs of research proposed in the rest of the SCCOR. Since the Core is intended to serve new clinical investigators who occupy positions and receive salary support from the SCCOR grant, salary support for the new investigators is neither needed nor allowable as a Core cost. All new clinical investigators supported by the SCCOR grant should be eligible to participate in Core-sponsored activities so long as they have not attained independent status. However, attaining independent status should be an objective of the Core activities so participating new investigators should be encouraged to apply for either a Career Development Award, a patient-oriented regular research grant, or any other source of independent research or career development support. Although the participating new investigators will be expected to devote essentially full-time effort to research during this period, they may devote an appropriate percentage of their time to maintaining clinical skills. An application for a Clinical Research Skills Development Core will be evaluated in terms of its potential effectiveness in developing the skills and research capabilities of new clinical investigators as reflected in the required application components identified above. MECHANISM OF SUPPORT This RFA will use the NIH P50 award mechanism. All applications received in response to the Pediatric Heart Development and Disease SCCOR program will be considered as new applications and must meet the requirements for the new SCCOR program. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. The anticipated award date is January 1, 2004. Each NHLBI SCCOR program is limited to 10 years of support. Exceptions to this policy will be made only if a thorough evaluation of needs and opportunities, conducted by a committee composed of non-federal experts, determines that there are extraordinarily important reasons to continue a specific SCCOR program. Under this policy, a given SCCOR grant is awarded for a 5-year project period following an open competition. Only one 5-year competing renewal is permitted, for a total of 10 years of support, unless the SCCOR program is recommended for extension. The NHLBI comprehensive evaluation of the Pediatric Heart Development and Disease SCCOR program will be conducted during the second project period according to the following timetable: Program Announced: FY 2002 Project Period (First Competition): FY 2004 through FY 2009 Program Reannounced: FY 2007 Project Period (Second Competition): FY 2009 through FY 2014 Letter to Principal Investigators Regarding SCCOR Evaluation Plans: FY 2010 (mid-way through year 02 of 2nd project period) SCCOR Evaluation Meeting: FY 2011 (late in year 02 of 2nd project period) The NHLBI does not limit the number of SCCOR applications in a given SCCOR program from one institution. However, each application must have a different principal investigator and must be self-contained and independent of the other(s). Institutions envisioning more than one application should discuss their plans with the program contact listed under Inquiries. FUNDS AVAILABLE NHLBI intends to commit approximately $11,625,000 in fiscal year 2004 to fund three to four new grants in response to this RFA. An applicant should request a project period of five years and may request up to $2.5 million direct costs, not including indirect costs for collaborating institutions, in the first year. All applications will be considered as new applications. An increase of no more than 3 percent may be requested in each additional year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size of each award will also vary. Although the financial plans of the NHLBI provides support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. Consortium Arrangements If a grant application includes research activities that involve institutions other than the grantee institution, the application will be considered a consortium effort. Such applications are permitted, but it is imperative that the application be prepared so that the programmatic, fiscal, and administrative considerations are explained fully. However, at least 50 percent of the projects (including at least one clinical project) and 50 percent of the cores must be located at the applicant institution. The published policy governing consortia is available in the business offices of institutions that are eligible to receive Federal grants-in-aid and should be consulted before developing the application. For clarification of the policy, contact Mr. Anthony Agresti, Grants Operations Branch, NHLBI, (301) 435-0186. Applicants for SCCOR grants should exercise great care in preserving the interactions of the participants and the integration of the consortium project(s) with those of the parent institution, because synergism and cohesiveness can be diminished when projects are located outside the group at the parent institution. Indirect costs paid as part of a consortium agreement are excluded from the limit on the amount of direct costs that can be requested. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are 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. SPECIAL REQUIREMENTS 1. The overall concept of a SCCOR program focuses on clinical and basic scientific issues related to diseases and disorders relevant to the mission of the NHLBI. To be considered responsive to this announcement, all applications must include both clinical and basic research and at least 50 percent of the projects must be clinical. For example, if an application has a total of three projects, two of the projects must be clinical. In addition, interactions between clinical and basic scientists are expected to strengthen the research, enhance the translation of fundamental research findings to the clinical setting, and identify new research directions. Translation of findings from basic to clinical studies is an important focus of the SCCOR program. 2. In order for a project to be considered clinical for the purposes of responsiveness to this RFA, the research must fit the definition of clinical research in the PHS398 (http://grants.nih.gov/grants/funding/phs398/phs398.html, parts 1 and 2, but not part 3). That is, the research must be either patient- oriented research, or an epidemiologic or behavioral study. For patient-oriented research, this is Aresearch conducted with human subjects (or material of human origin such as tissues, specimens and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects.@ To be responsive, clinical investigations may include studies of subjects with the disease of interest as well as normal healthy subjects. In studies involving the use of human specimens, the investigators must have direct interaction with the subject or patient and relate the research results to the patient status or outcome for this to be considered a clinical project. It is intended that the requirement for investigator interaction with the study participants will eliminate research involving archived tissue. Human biomedical and behavioral studies of etiology, pathogenesis, prevention and prevention strategies, diagnostic approaches, and treatment of diseases, disorders or conditions are also responsive. Small population-based epidemiologic studies, where the research can be completed within 5 years, may also be proposed. However, clinical research projects focused on large epidemiologic studies or Phase III clinical trials will be considered unresponsive to this RFA. Clinical research projects, whether on human subjects or human specimens, will be subject to the standard NHLBI policies and procedures regarding human subjects monitoring. 3. The number of clinical projects in each NHLBI SCCOR must be equal to or greater than the number of basic science projects, at the time of submission, award, and throughout the 5-year project period. Neither a clinical component in a basic science project nor a clinical core fulfills the requirement for a clinical project. However, a single project can integrate basic and clinical research. If the majority of the project is clinical, it will be considered a clinical project; if the majority is basic, it will be considered a basic project. Because a SCCOR grant is a 5-year program, an applicant should submit a 5-year plan for all the projects. 4. Each awarded SCCOR must consist of three or more projects, all of which are directly related to the SCCOR program topic. At least 50 percent of the projects and 50 percent of the cores must be located at the applicant institution and at least one of the clinical projects must be at the applicant institution. All basic research projects must be related to the overall clinical focus of the SCCOR. Each component project, whether clinical or basic, requires a well-described clinically relevant hypothesis, preliminary data, and a time-table for conducting the proposed investigations. 5. The relationship of each core to each component project should be described. A core must provide services to two or more projects. 6. Applicants are encouraged to establish links with existing resources, including General Clinical Research Centers, the NHLBI Program in Genomic Applications, and NHLBI clinical research networks, as appropriate. 7. Each SCCOR must have a well-delineated organizational structure and adminis- trative mechanism that foster interactions between investigators, accelerate the pace of research, accelerate translation of basic research findings to clinical applications, and ensure a productive research effort. 8. Applicants should provide a detailed data and safety monitoring plan for the clinical research proposed; the monitoring plan will be considered as part of the peer review of the application. This plan should address informed consent, recruitment, reporting of adverse events, patient safety, oversight of clinical issues in the protocols, storage and analysis of confidential data, and dissemination of any research results. There may be isolated cases when the Institute may wish to convene a Data and Safety Monitoring Board to oversee the clinical projects in a SCCOR program. This will be determined after review and selection of the SCCOR centers. 9. The principal investigator should be an established research scientist with the ability to ensure quality control and the experience to administer both clinical and basic research effectively and integrate all components of the program. A minimum time commitment of 25 percent is required for this individual. The principal investigator must be the project leader of one of the component research projects. If this project is not recommended by peer review, the overall SCCOR application will not be considered further. If this project is judged by peer review to be of low scientific merit, this will markedly reduce the overall scientific merit ranking assigned to the entire application. 10. Project leaders should have significant research experience and must agree to commit at least 20 percent effort to each project for which they are responsible. Leaders of clinicaI projects should have experience in clinical research as defined in Item 2, above. Investigators with minimal research experience, but promising credentials, may participate; however, it is expected that most of the project leaders will be investigators with significant research experience. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA 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: o Direct your questions about scientific/research issues to: Gail D. Pearson, MD, ScD Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Rockledge II, Room 9200 Bethesda, MD 20892 Telephone: (301) 435-0510 FAX: (301) 480-1454 Email: pearsong@nhlbi.nih.gov o Direct your questions about peer review issues to: Anne Clark, Ph.D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Dr., Room 7178 (MSC 7924) Bethesda, MD 20892-7924 (20817 for Courier) Telephone: (301) 435-0270 FAX: (301) 480-0730 Email: ClarkA@nhlbi.nih.gov o Direct your questions about financial or grants management matters to: Mr. Anthony Agresti Division of Extramural Affairs National Heart, Lung, and Blood Institute Rockledge II, Room 7138 Bethesda, MD 20892 Telephone: (301) 435-0186 Email: agrestia@nhlbi.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to Dr. Anne Clark at the address listed under Where to Send Inquires. SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: Because of the size and complexity of a SCCOR, prospective applicants are urged to consult with the staff of the Division of Heart and Vascular Diseases early in the preparation of the application (see INQUIRIES Section). Special instructions are needed for preparing a SCCOR application and are available from the program contact listed under Where to Send Inquiries or at http://www.nhlbi.nih.gov/funding/inits/dhvdsccor.htm. To provide opportunity for such interactions, the time frame for implementation of this program includes an ample interval between the release of this RFA and the receipt date for applications. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 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 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/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: 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 Dr. Anne Clark at the address listed under Where to Send Inquires. Please note that applications delivered by individuals are no longer accepted; all applications must either come via courier delivery or the USPS (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html). APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that 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 applications already reviewed, but such applications must include an Introduction addressing the previous critique. Principal investigators should not sent supplementary material without first contacting the Scientific Review Administrator (SRA). The SRA will be identified in the letter sent to you indicating that your application has been received. If you have not received such a letter within three weeks after submitting the application, contact Dr. Anne Clark at the address listed under Where to Send Inquires. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. Incomplete and/or non-responsive 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 NHLBI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Heart, Lung, and Blood Advisory Council. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. Factors to be considered in the evaluation of each application will be similar to those used in the review of traditional clinical and basic research grant applications and, in addition, will include overall proposed interactions between clinical and basic research projects. The review panel will include a majority of clinical researchers who will receive special instructions to place emphasis on strong clinical components. Major factors to be considered in the evaluation of applications include: 1. Scientific merit of the proposed clinical and basic research projects including significance, importance, clinical relevance and appropriateness of the theme; innovation, originality, and feasibility of the approach; and adequacy of the experimental design. 2. Leadership, scientific stature, and commitment of the principal investigator; competence of the investigators to accomplish the proposed research goals and their time commitment to the program; clinical research experience among the investigators; and the feasibility and strength of consortium arrangements. 3. Collaborative interaction between clinical and basic research components, the required number of clinical projects, and plans for transfer of potential findings from basic to clinical studies. 4. Adequacy of the environment for performance of the proposed research including clinical populations and/or specimens; laboratory facilities; quality of the support cores; proposed instrumentation; quality controls; administrative structure; institutional commitment; and, when needed, data management systems. 5. Adequacy of the data and safety monitoring plan for the clinical research proposed. Each project will receive a priority score. Each core (except the Clinical Research Skills Development Core) will be Recommended or Not Recommended based on whether the core is essential for the proposed research and has the capability to fulfill the proposed function. Reviewers will evaluate the number of projects serviced by the core; strengths and weaknesses of the proposed approaches, resources, and interactions; whether the investigators are qualified for their role(s) in the core; and whether the proposed budget for the core is appropriate. Each application will receive an overall priority score based on the review criteria listed above. 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 priority score. Review Criteria for Clinical Research Skills Development Core 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: 1. Credentials and track record of the Principal Investigator, Clinical Research Skills Development Core Project Leader, and other participating senior investigators. 2. Methods by which new investigators are to be recruited and selected including plans to recruit women and minority individuals. 3. Plans for developing the skills of new investigators; the types of skill and technologic development proposed. 4. Means by which the new investigators' professional development will be achieved. ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: 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. o INCLUSION: 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. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: December 16, 2002 Application Receipt Date: January 16, 2003 Peer Review Date: June/July, 2003 Council Review: September 4-5, 2003 Earliest Anticipated Start Date: January 1, 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). 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 AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice- files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are 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 RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy 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 is available at 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 proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice- files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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 RFA 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 No. 93.837, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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.


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