SPECIALIZED CENTERS OF CLINICALLY ORIENTED RESEARCH (SCCOR) IN CARDIAC DYSFUNCTION AND DISEASE RELEASE DATE: October 23, 2002 RFA: HL-03-009 National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) LETTER OF INTENT RECEIPT DATE: August 11, 2003 APPLICATION RECEIPT DATE: September 11, 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 dysfunction and disease of the myocardium. It is expected that results from the SCCOR grants in this area will have a positive effect on the prevention, diagnosis, and treatment of cardiac disorders, including ischemic and other cardiomyopathies, left ventricular dysfunction, metabolic abnormalities, congestive heart failure, and rhythm disturbances. Because some segments of the population suffer from heart disease disproportionately, there will be an emphasis on research that addresses issues of health disparity. 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. Cardiac Dysfunction and Disease Diseases affecting the myocardium, such as ischemic and other cardiomyopathies, metabolic abnormalities, rhythm and electrical disturbances, heart failure, and inflammatory disorders, often develop as a continuum that begins with injury and progresses over time to overt dysfunction and failure. As the heart responds to such an injury, various critical events are initiated. A remodeling process is initiated at both the cellular and structural level. Sections of the myocardium may become ischemic and demonstrate contractile dysfunction through stunning, hibernation or cell death. In order to maintain cardiac output in the face of injury or stress, the heart may compensate by increasing muscle mass through a hypertrophic process. However, such compensatory mechanisms can eventually lead to decompensation, dilation, and pump failure. Moreover, functional and structural remodeling can lead to disturbances in the normal conduction of electrical impulses, resulting in rhythm abnormalities, culminating in lethal arrhythmias. Thus, an understanding the disease process within the myocardium requires a multidisciplinary approach that can integrate molecular, structural, mechanical, and electrical elements into a cohesive picture. In light of this need, a SCCOR program focusing on cardiac dysfunction and disease, which allows for a natural and logical integration of disciplines and science, can result in advancements in scientific understanding that will have a maximum impact on clinical practice and serve the needs of the research community. During the past 5 decades, new knowledge has developed about the biological mechanisms underlying the pathobiology of cardiovascular disease. This knowledge, coupled with the emergence of new technologies and new pharmacological, interventional, and surgical therapies, has contributed to a substantial decline in mortality from heart disease. Improvements in acute care for heart attack victims have resulted from understanding the basic physiological principles of myocardial oxygen supply and demand. The concept of infarct size limitation ultimately provided the rationale for early thrombolytic and reperfusion therapies and the use of beta-blockers. Still there is a need for improved treatment strategies to diminish the incidence of future cardiac events and death in infarct patients particularly as they age and are at increased risk due significant comorbidities. Pharmacological therapies other than angiotensin-converting enzyme inhibitors and beta-blockers, aimed at attenuating left ventricular remodeling and preventing the development of heart failure, are critical to progress. Thus, in spite of enormous strides made in treating a myocardial infarction and its consequences, new strategies for diagnosis and treatment of cardiac disorders are needed. The current treatment for acute myocardial infarction includes the prompt restoration of coronary blood flow through the use of either thrombolytic agents or percutaneous coronary interventions. Although restoration of blood flow to the jeopardized myocardium is a perquisite for myocardial salvage, reperfusion itself may lead to accelerated and additional myocardial injury, termed reperfusion injury, beyond that generated by ischemia alone. In addition, an inflammatory response, with the migration of inflammatory macrophages and myofibroblasts, that initiates extensive fibrotic remodeling may result from the initial ischemic insult to the heart. However, we do know that cardiac myocytes can be protected from prolonged ischemia and reperfusion if exposed to a prior sublethal ischemic insult or certain pharmacological agents. The potential for clinical application of such a protective phenomenon has generated interest in identifying and understanding the underlying intracellular signaling pathways, with the aim of pharmacologically exploiting these mechanisms to develop therapeutic strategies that can enhance myocardial tolerance to ischemia- reperfusion injury in patients with coronary artery disease. The application of these findings to the clinical setting depends not only on the proof of safety and efficacy when compared with other strategies for protecting the myocardium, but also on the identification of well-defined cohorts of patients who stand to benefit from treatment with such cardioprotective strategies. The development of protective therapies, which may be given at the time of reperfusion, that would delay or prevent the harmful consequences of ischemia and/or reperfusion is likely to have a great impact on the morbidity and mortality from an acute myocardial infarction. Sudden cardiac death and rhythm abnormalities represent a public health threat that accounts for approximately half of all cardiovascular deaths in the United States. From the perspective of both the clinician and bench scientist, sudden cardiac death remains a difficult problem. Except for the use of implantable defibrillators for some subsets of patients, therapeutic interventions for the prevention of arrhythmias have not been successfully targeted to specific mechanisms of sudden cardiac death. However, discoveries with regard to cardiac electrical conduction at the molecular level, neural-electrical modulation, and local neural remodeling provide powerful new approaches for the development of novel antiarrhythmic strategies. Much of the early work on sudden cardiac death prediction has focused almost exclusively on risk factors that reflect coronary disease, or alterations in myocardial structure and function, rather than on more discrete indicators of the immediate causes and triggers of electrical instability. Accumulating information indicates there may be molecular, genetic, and biophysical or biochemical indicators of ventricular arrhythmia risk that could be useful in screening. Thus, major research opportunities remain in establishing sensitive and specific risk markers of sudden cardiac death, so necessary for optimizing therapeutic strategies and allocating scarce resources. Predicting and preventing sudden cardiac death remains a major public health goal for which new strategies are needed, and understanding the causes of sudden cardiac death represents an enormous challenge for clinical and basic cardiovascular science. This challenge can be met by understanding the fundamental causes of lethal arrhythmias, through new basic and clinical research findings. Dilated, hypertrophic, and restrictive cardiomyopathies often arise from primary abnormalities in muscle or structural proteins, or can arise from such diverse causes such as cardiac infections, inflammation, metabolic disturbances, or cardiotoxic drugs. Dilated cardiomyopathy is heterogeneous in both its pathogenesis and its morphology, but with the common feature of a poorly contracting dilated left ventricle with a normal or reduced left ventricular wall thickness. In most cases of dilated cardiomyopathy, no definite cause is identifiable, although the most prevalent toxic cause of DCM is alcohol. Single gene mutations in either the structural proteins of the myocyte, such as dystrophin, metavinculin, and lamin, or of mitochondrial DNA are recognized causes of DCM. Hypertrophic cardiomyopathy is a relatively common genetic disease (1in 500) and is heterogeneous with respect to presentation, prognosis, underlying mutations, and treatment strategies. It is the most common cause of sudden death in the young. Hypertrophic cardiomyopathy often represents a dilemma to primary care clinicians and cardiovascular specialists, owing to its marked heterogeneity in clinical expression, natural history, and prognosis. Controversy abounds with regard to diagnostic criteria, clinical course, and management for which difficult questions often arise, particularly among practitioners infrequently engaged in the evaluation of HCM patients. Treatment of cardiomyopathies is of variable effectiveness. A better understanding of the underlying pathophysiology of cardiomyopathies at the molecular, cellular, and organ level could provide important directions for effectively treating these diseases. Myocarditis is an insidious inflammatory disorder of the myocardium. While patients with myocarditis can be asymptomatic early in the disease process, as the disease progresses, it may produce significant clinical sequelae, ultimately leading to heart failure and death. In postmortem studies, myocarditis has been shown to account for up to 20 percent of sudden, unexpected death in adults under the age of 40. It appears to be far more common in children than in adults. There are numerous causes including infection (viral, bacterial and protozoan), systemic diseases, and toxins. Myocarditis defies traditional diagnostic tests. While myocardial biopsy is currently regarded as the gold standard for diagnosis, there is a need for a more specific and sensitive means to detect this disease. The first line of therapy is general support of myocardial function. Treatment options include immunosuppressive therapy, anti- viral agents, immunoabsorption of antibodies, and anti-cytokine therapy. But, there is no consensus on treating the inflammation or preventing long-term sequelae, such as ventricular arrhythmias. Animal models have provided the majority of information known about the pathology of the disease. While an immune response is essential to clearing the infectious agent (e.g. coxsackievirus), depending on the timing, intensity, and duration of the immune response, it can be either protective or injurious. A greater understanding of the immune response underlying the pathogenesis of myocarditis and other cardiomyopathies should provide a foundation for more rational approaches to therapy. Congestive heart failure is a major public health problem. Approximately 4.8 million Americans have heart failure, and 400,000 new cases are diagnosed each year. Between 1970 and 2000, the hospitalization rates for congestive heart failure of patients 45 years of age or older tripled. While the death rate for congestive heart failure has stabilized in recent years, it may be expected that heart failure will become a more prevalent problem due to the aging of the population , increased survival from heart attacks and better control of high blood pressure. This highlights the need for a better understanding of the progression from left ventricular dysfunction to failure. Such an understanding must include a clearer delineation of subclinical markers of disease and the relationship of asymptomatic to symptomatic left ventricular systolic dysfunction. There is also a growing recognition that congestive heart failure is not solely caused by systolic dysfunction, but may also result from an abnormalities in diastolic function. Heart failure with preserved left ventricular systolic function (diastolic heart failure) is common, particularly in women and the elderly, and is also associated with significant morbidity and mortality. The development of truly effective therapy for all forms of heart failure depends on gaining a clear understanding of the basic mechanisms that alter systolic and diastolic function and the ability to efficiently target these mechanisms to correct the abnormalities. While new pharmacological treatments have been developed over the last two decades, which reduce morbidity and prolong survival, once overt heart failure is diagnosed the prognosis is poor. Innovative, effective treatment strategies are needed which can improve outcomes and increase survival for patients with heart failure. Health Disparities Despite remarkable progress in health care over the last few decades, minorities still bear a disproportionate share of death and disability, and the gap appears to be widening for some diseases. For example, African Americans have the highest overall mortality rate from coronary heart disease of any ethnic group in the United States. Data also show that approximately one-fourth of all deaths among Latinos are attributed to heart disease. Although age-adjusted heart disease death rates are lower among Latinos than among the general population, the decline in heart disease mortality rates observed in the general population in recent years has occurred to a much lesser extent among Latinos than in the total population. Moreover, the rates of obesity and diabetes, both of which greatly increase the risk of cardiovascular disease, are greater among Mexican-Americans than in the general population. Although previously American Indians had very low cardiovascular disease rates, cardiovascular disease is now the leading cause of death among American Indians. Approximately 30 percent of American Indian deaths for all ages is associated with diseases of the heart, and the number of American Indians ages 45 years and older with heart disease exceeds the next three leading causes of death (cancer, diabetes, and injuries) combined. Ethnic and racial differences in the clinical manifestations of cardiovascular disease may be explained by the inherent heterogeneity of the cardiac syndromes, socioeconomic factors, and the high prevalence and severity of hypertension, obesity, and type 2 diabetes. Although all of the reasons for the excess coronary heart disease mortality among African Americans have not been elucidated, it is clear that there is a high prevalence of certain coronary risk factors, delay in the recognition and treatment of high-risk individuals, and limited access to cardiovascular care. Identification of high-risk individuals for vigorous risk factor modification, especially in the control and/or regression of left ventricular hypertrophy, the suppression of rhythm abnormalities, control of metabolic disturbances, and the treatment of heart failure, is key for successful risk reduction and prevention. Further research is needed to evaluate the traditional approaches to risk stratification, therapeutic response, and diagnostic testing in minority populations. A better understanding of the role that biological and physiological differences within these groups plays in the presentation, progression and treatment of disease is needed. Understanding genetic or biologic differences can provide a rationale and basis for developing treatments that are directed at the specific clinical manifestations of disease within a particular ethnic or racial group. In order to ensure that these SCCOR programs contribute to reducing health disparities, applicants are strongly encouraged to consider a research emphasis on health disparities and the translation of this research to clinical practice for affected minority populations. Since a primary aim of research is to provide scientific evidence leading to a change in health policy or a standard of care, it is imperative to determine whether the intervention or therapy being studied affects women or members of minority groups and their subpopulations differently. At a minimum, women and minority individuals should be included in the same proportions as in the U.S. population having the disease entity being studied. If prevalence is unknown, the NHLBI standard for evaluation of the proposed study population is the composition of the population of the United States, which, according to the 2000 census, is 51% women and 25% minorities. When designing and developing a clinical research study or trial involving a treatment or intervention, the investigator must evaluate all relevant data to assess whether or not the study or trial should include adequate numbers of subgroups of participants to allow for separate and adequately powered analyses. Even if no such evidence is available, the study must include sufficient numbers of women and minorities to conduct valid analyses (that is, unbiased assessment) of subgroup effects. Before any SCCOR in Cardiac Dysfunction and Disease is funded, this aspect will be considered by NHLBI staff. During the conduct of a clinical study, success in enrolling appropriate numbers of women and minorities will be monitored by NHLBI staff. Finally, it is expected that the investigators will perform the necessary analyses and include the results in submitted publications. It is through such a consideration of minority and gender representation that health disparities can be understood and eliminated. Research Topics The objective of the SCCOR in Cardiac Dysfunction and Disease is to stimulate clinically relevant, multidisciplinary collaborations leading to clinical and basic science research efforts on important public health problems for individuals with 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 genetic, molecular and physiologic underpinnings of cardiac muscle function and pathophysiology of disease offer new directions for the study of normal and abnormal heart function, the development of early diagnostic tools and markers, potential risk stratification based on genetic and molecular markers, and many other endeavors related to clinical problems in cardiac dysfunction and disease. 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. Applicants are encouraged to consider other topics that are relevant to the goals of the new Cardiac Dysfunction and Disease SCCOR program. A unified program of clinical and basic research is needed to address such topics as: o Develop novel drug or modulatory targets for the prevention or management of arrhythmias, ischemic heart disease, and congestive heart failure; o Explore the role of complementary and alternative medicine in treating cardiac disorders; o Identify sex differences in cardiac function and response to disease and elucidate mechanisms responsible for sex differences; o Delineate the role of oxidative stress and metabolic alterations in cardiac disease; o Identify genotype-phenotype correlations, modifier genes, and genetic variation that influences therapeutic success, as well as the incidence of adverse clinical events; o Elucidate molecular, cellular and physiologic processes involved in the progression from asymptomatic to symptomatic ventricular dysfunction and failure; o Elucidate the underlying pathophysiology of heart failure with preserved systolic function (diastolic heart failure) and develop new approaches to its diagnosis and treatment; o Develop imaging and biomarker tools which can aid in the detection and diagnosis of cardiac diseases; o Elucidate mechanisms involved in the initiation of ventricular and atrial arrhythmias and develop improved approaches to manage their occurrence and sequelae; o Identify racial/ethnic differences in the causes and pathogenesis of cardiac disease and the response to treatment; o Develop improved markers of subclinical left ventricular dysfunction, including genetic and proteomic determinants that can be of benefit in detecting and diagnosing cardiac dysfunction early in the disease process; o Develop novel therapeutic approaches to treat cardiac injury, including cell- based and gene therapies, tissue regeneration and engineering, and improved myocardial preservation and protection; o Identify and validate suitable measures and instruments to assess disease outcomes in women and minority populations; o Understand the basis and treatment of atrial fibrillation; o Develop more specific and sensitive tests to detect myocarditis that are less invasive. 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 various types of heart disease, such as dilated cardiomyopathy, heart failure or rhythm disturbances. 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 "exchange" program wherein clinical investigators spend time in basic science laboratories. In addition to developing the research skills of new clinical investigators, the Cores must ensure that the participating new clinical investigators receive the mentoring they need to foster their research careers. The Clinical Research Skills Development Core is intended for staff investigators with limited clinical research experience, including fellows and junior faculty members. Investigators who have had a previous K series award are not eligible to participate as new investigators under this program. Individuals with an active K grant can participate until the end of the award period for the K grant, but may not receive salary on the Skills Development Core. The Core should also address other skills necessary for a successful research career, such as grant writing, ethical conduct of research, and clinical trial design. If a Clinical Research Skills Development Core is proposed, it must be directed by an investigator with strong educational and mentoring credentials who will devote a minimum of 5 percent effort as its Leader. To facilitate mentoring and multidisciplinary developmental activities, active involvement by the principal investigator and other senior investigators within the 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: o A summary of the types of skills that would be developed and a description of proposed project-specific activities; o 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; o 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; o A plan for coordinating the activities of participating senior investigators; o A plan for monitoring the progress of the new clinical investigators; o 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 o 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 Cardiac Dysfunction 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, 2005. 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 Cardiac Dysfunction and Disease SCCOR program will be conducted during the second project period according to the following timetable: Program Announced: FY 2003 Project Period (First Competition): FY 2005 through FY 2009 Program Reannounced: FY 2007 Project Period (Second Competition): FY 2010 through FY 2014 Letter to Principal Investigators Regarding SCCOR Evaluation Plans: FY 2011 (mid-way through year 02 of 2nd project period) SCCOR Evaluation Meeting: FY 2012 (late in year 02 of 2nd project period) The NHLBI does not limit the number of applications for a given SCCOR program from one institution. However, each SCCOR application from the institution must have a different principal investigator and must be self-contained and independent of other SCCOR applications for the same institution. Institutions envisioning more than one application are encouraged to discuss their plans with the program contact listed under Inquiries. FUNDS AVAILABLE NHLBI intends to commit approximately $18,500,000 in fiscal year 2005 to fund five to six 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 Facilities and Administrative (F&A) costs for collaborating institutions, in the first year. In addition, applicants for a new SCCOR may request up to $100,000 in direct costs per year above the usual cap ($2.5 million direct costs) for a Clinical Research Skills Development Core. 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. 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. 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 NIH 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) 435-0171. 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 If you are a domestic institution, 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 Faith-based or community-based organizations 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. 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. The number of clinical research 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. For example, if an application has a total of three projects, two of the projects must be clinical research projects. 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 research within a project is clinical, it will be considered a clinical project; if the majority of the research within a project 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. 3. In order for a project to be considered clinical research for the purposes of responsiveness to this RFA, the research must be patient-oriented research. Patient-oriented research is research in which an investigator (or colleague) directly interacts with patients having a disease or condition of interest. Normal healthy subjects may be included, but only in combination with studies involving patients. In studies involving the use of human specimens, the investigators must have direct interaction with the patient from whom the specimen is obtained 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. Applicants are encouraged to pursue patient-oriented research on topics related to health disparities and the translation of this research to clinical practice for affected minority populations. At a minimum, clinical research projects must include women and minorities in the study population in representative numbers, unless such inclusion can be demonstrated to be inappropriate. Clinical studies involving interventions or treatments must give consideration to including sufficient numbers of women and minorities to conduct valid analyses of subgroup effects. Human biomedical and behavioral studies of etiology, pathogenesis, prevention and prevention strategies, diagnostic approaches, and treatment of cardiac diseases, disorders or conditions are responsive. However, epidemiologic studies or Phase III clinical trials will be considered unresponsive to this RFA. 4. Each awarded SCCOR must consist of three or more projects, all of which are directly related to the overall clinical focus of the SCCOR. 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. Component projects not located at the applicant institution may be at a foreign institution, but must conform to NIH policy regarding the protection of human subjects 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. Each SCCOR must have a well-delineated organizational structure and administrative mechanism that foster interactions between investigators, accelerate the pace of research, enable translation of basic research findings to clinical applications, and ensure a productive research effort. 7. 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. After a decision has been made regarding SCCOR awards, the Institute will determine whether to convene a Data and Safety Monitoring Board to oversee one or more clinical projects in a SCCOR program. 8. 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. 9. 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 clinical 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. 10. Applicants are encouraged to establish links and utilize existing resources, including the NHLBI Program in Genomic Applications, NHLBI clinical research networks, and General Clinical Research Centers, as feasible and appropriate. If applicants propose to utilize such resources, a letter of agreement from the program director or principal investigator of the resource should be included with the application. 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: John Fakunding, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Rockledge II, Room 9170 Bethesda, MD 20892 Telephone: (301) 435-0544 FAX: (301) 480-1336 Email: fakundij@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 7214 (MSC 7924) Bethesda, MD 20892-7924 (20817 for express/courier service) 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) 435-0171 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 https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, 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/cardiacsccor.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: https://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 (https://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 send 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: o 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. o Leadership, scientific expertise, experience, 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. o 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. o 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. o 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: o Credentials and track record of the Principal Investigator, Clinical Research Skills Development Core Project Leader, and other participating senior investigators. o Methods by which new investigators are to be recruited and selected including plans to recruit women and minority individuals. o Plans for developing the skills of new investigators; the types of skill and technologic development proposed. o 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: August 11, 2003 Application Receipt Date: September 11, 2003 Peer Review Date: February/March, 2004 Council Review: May 13-14, 2004 Earliest Anticipated Start Date: January 1, 2005 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: https://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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://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 https://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 https://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 https://grants.nih.gov/grants/stem_cells.htm and at https://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 https://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 https://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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