SPECIALIZED CENTERS OF CLINICALLY ORIENTED RESEARCH (SCCOR) IN HEMOSTATIC AND THROMBOTIC DISEASES RELEASE DATE: January 30, 2004 RFA: RFA-HL-04-016 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.938, 93.939 LETTER OF INTENT RECEIPT DATE: August 24, 2004 APPLICATION RECEIPT DATE: September 21, 2004 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 focus on diseases and function related to hemostasis and thrombosis. It is expected that the results from these SCCOR grants will have a positive impact on the prevention, diagnosis, and treatment of thrombotic and bleeding disorders. 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 clinical settings. 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. Formation of a blood clot and the resulting ischemia leading to tissue damage is the major cause of disability or death in the United States. The application of innovative technologies in molecular biology, immunology, genetics and protein chemistry has contributed to elucidation of the regulatory pathways of hemostasis and the risk factors related to thromboembolic disease. Further research is necessary to translate these advances to clinical care. The long term goal of this SCCOR program is integration of science and clinical medicine in the prevention and treatment of thrombotic and hemostatic disorders. Five specific areas of emphasis are detailed below. Arterial and Venous Thrombosis The molecular basis of the involvement of inflammation and immune mediators in thrombosis remains unclear and methods of predicting thrombotic disease associated with abnormalities of these interactive pathways remain to be determined. Many proteins, which are integral components of the coagulation cascade, are also potent activators of leukocytes and endothelial cells. Platelets are key mediators of inflammation. Microparticles from platelets/leukocytes/endothelium may be an important source of tissue factor for thrombus formation. Thus, studies that address the interaction of inflammation and thrombosis, and the associated clinical sequelae are timely. Thrombosis and Cancer Thrombosis in cancer remains a significant problem in clinical medicine. Coagulation mechanisms appear to be involved in metastasis and cancer progression. The basic mechanisms underlying cancer related thrombosis, the optimal treatment of the hypercoagulable state associated with malignancy, and the role of the hemostatic system in cancer progression remain to be defined. Despite prospective clinical trials suggesting that anticoagulants alter the course of cancer, the nature of this effect remains uncertain. Better understanding of the relationship between the coagulation system, fibrinolysis, angiogenesis and their roles in tumor progression and host resistance to thrombosis is needed. Thrombotic Stroke Ischemic stroke involves thrombosis, inflammation and reperfusion injury. Little is known about the interactions of blood cells and proteins, the vascular structures and the neuronal/glial compartment in normal and ischemic conditions. New insights into mechanisms and risk factors may come from studies of genetic polymorphisms linked to stroke and the level of expression of different genes. The development of coagulant activity and the interaction of platelets with the brain vasculature is a priority area of study. Better means of intervention for acute stroke and stroke prophylaxis are needed. Clinical studies of aspirin resistance in ischemic stroke patients may give insights into both mechanisms and improved therapeutics for stroke. Thrombolytic therapy with tissue plasminogen activator (t-PA) has proved beneficial, but, only a small group of patients qualify and the treatment may increase the risk of bleeding and neuronal damage. Decreased levels of circulating activated protein C (APC), compared with controls, may be a marker for increased risk for post-infection ischemic stroke. Recombinant APC, approved for treating severe sepsis, exerts important biologic activities in vivo in addition to its known anticoagulant activity. Studies in animal models show that APC may have anti-inflammatory and anti-apoptotic activities, and it is neuroprotective in ischemic stroke. Anti-platelet agents, such as an ecto ADPase (CD39), and chimeric agents that block P-selectin and complement, have been reported to produce beneficial results after stroke. These agents, as well as the t-PA inhibitor, neuroserpin, are attractive candidates for combination therapy of ischemic stroke. Disorders of fibrinolytic system Fibrinolysis plays an important role in the regulation and limitation of clinical thrombosis. Hereditary deficiencies in these pathways are poorly defined. The fibrinolytic system also has broad functions and its components may be involved in angiogenesis and obesity-related thrombosis. Significant opportunities for clinical studies might include in the development of more efficient and specific thrombolytics, cell-based and targeted delivery of these agents, and the efficacy/safety of catheter- directed thrombolysis. The interrelated roles of fibrinolysis and inflammation require further investigation. Bleeding Disorders The molecular definition of the defects in the VWF gene or the protein in Von Willebrand Disease (VWD) remain unclear. Gene therapy trials are continuing in patients with hemophilia. Opportunities for additional patient-oriented research include novel sites of FVIII/FIX synthesis or inducing synthesis of modified factors that increase survival or efficacy of the expressed gene product. Factors that affect the incidence or prevalence of inhibitors and modulating their clinical impact are also important areas of investigation. Defects in platelet function are diagnosed using assays that are essentially similar to those that were in place 25-30 years ago. We have not developed clinically- relevant measures of platelet function with the exception of structural definitions of glycoprotein receptor deficiencies such as Glanzmann Thrombasthenia and Bernard- Soulier syndrome. With the advent of proteomics and gene arrays, opportunities exist to define new clinical syndromes and novel therapeutics for platelet disorders. Studies on the bleeding complications of uremia are also encouraged. Research Topics The objective of the SCCOR in Hemostatic and Thrombotic Diseases is to stimulate multidisciplinary collaborations leading to clinical and basic science research efforts in thrombotic and bleeding disorders. The following examples of research topics are intended to provide a perspective on the scope of research that could 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 this new SCCOR program. Large clinical trials will not be supported under this program. o Study genetic and environmental risk factors, modifier genes, and disease outcome in thrombotic and / or bleeding disorders utilizing proteomic, genomic and other tools; o Perform translational studies on anticoagulant and antiinflammatory agents; evaluate pharmacogenetics, biomarkers, and monitoring of drugs; o Define the molecular properties of the brain vasculature, its expression of coagulant activity and platelet adhesion mechanisms; potential markers of ischemic injury and methods to prevent neuronal damage; o Explore age-dependent regulation of hemostasis, identify genetic switches, and possible development of hypercoagulable state; o Elucidate molecular and signal transduction processes involved in the activation of platelets; develop assays of platelet function, and perform translational studies on platelet inhibitors as potential therapeutic agents; o Define the role of the fibrinolytic enzymes, their activators and inhibitors in thrombosis / bleeding with special attention to obesity and diabetes; o Elucidate the underlying pathophysiology of immune-mediated thrombosis or bleeding and develop new approaches to its diagnosis and treatment; o Develop imaging tools, assays and identify biomarkers of the subclinical prothrombotic state that can be useful in early detection and diagnosis of the disease process; o Study the role of thrombosis in cancer and malignancy; evaluate drug therapy targeted to hemostatic factors in the prevention of cancer-related morbidity and mortality. The SCCOR mechanism provides both the incentive and the structure to maintain critical collaborative cores or other resources necessary for translational research. 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 staff 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; 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. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing continuation applications based on this project will compete with all investigator initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is February 1, 2006. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions of the PHS 398 application. This RFA uses just-in-time concepts. It also uses the modular budgeting as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm. Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format. Otherwise follow the instructions for the non-modular budget research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. FUNDS AVAILABLE The NHLBI intends to commit approximately $8,000,000 in fiscal year 2006 to fund two to four new grants in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs up to $2.5 million, 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. 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. 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 Faith-based or community-based organizations o Foreign institutions are not eligible to apply INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. 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, minorities and children to conduct valid analyses of subgroup effects. Human biomedical and behavioral studies of etiology, pathogenesis, prevention and prevention strategies, diagnostic approaches, and treatment of thrombotic and bleeding 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 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. 11. 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. 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: Pan Ganguly, Ph.D. Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute Rockledge II, Room 10176 Bethesda, MD 20892 -7950 (20817 for courier / express service) Telephone: (301) 435-0070 FAX: (301) 480-1046 Email: gangulyp@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: Ms. Mary Baylor Division of Extramural Affairs National Heart, Lung, and Blood Institute Rockledge II, Room 7126 Bethesda, MD 20892 Telephone: (301) 435-0152 FAX: 301-480-3310 Email: baylorm@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). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS: Because of the size and complexity of a SCCOR, prospective applicants are urged to consult with the staff of the Division of Blood Diseases and Resources early in the preparation of the application. Special instructions for preparing a SCCOR application are available from the program contact listed under WHERE TO SEND INQUIRIES or at http://www.nhlbi.nih.gov/funding/policies/sccor_desc.htm . 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 Hemostatic and Thrombotic Diseases SCCOR program will be conducted during the second project period according to the following timetable: Program Announced: FY 2004 Project Period (First Competition): FY 2006 through FY 2011 Program Reannounced: FY 2009 Project Period (Second Competition):FY 2011 through FY 2016 Letter to Principal Investigators Regarding SCCOR Evaluation Plans: FY 2012 (mid-way through year 02 of 2nd project period) SCCOR Evaluation Meeting: FY 2013 (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 from the same institution. Institutions envisioning more than one application are encouraged to discuss their plans with the program contact listed under Where to Send Inquiries. 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/labels.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 and all copies of the appendix material must be sent to Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRES. APPLICATION PROCESSING: Applications must be received on or before 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. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. Incomplete and/or nonresponsive applications will not be reviewed. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHLBI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: 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 written critique 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. In the written comments, reviewers will be asked to evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. o SIGNIFICANCE; Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? o APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? o INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? o INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? o ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of the unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score. 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, minorities and children. 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. PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protection from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below) INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH; If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. DATA SHARING: The adequacy of the proposed plan to share data. ADDITIONAL REVIEW CONSIDERATIONS Sharing Research Data Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html for guidance. 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 24, 2004 Application Receipt Date: September 21, 2004 Peer Review Date: January / February, 2005 Council Review: September, 2005 Earliest Anticipated Start Date: February 1, 2006 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 HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm DATA AND SAFETY MONITORING PLAN: 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). SHARING RESEARCH DATA; Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing. Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state, and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - 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://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the Standards for Privacy of Individually Identifiable Health Information the Privacy Rule, on August 14, 2002. The Privacy Rule is a Federal regulation under the Health Insurance Portability and Accountability Act (HIPPA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as covered entities ) must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on Am I a covered entity? Information on the impact of the HIPPA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions , cost principles and other considerations described in the NIH Grants Policy Statement.. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro- Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


NIH Office of Extramural Research Logo
   Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS) 		  USA.gov - Government Made Easy
NIH... Turning Discovery Into Health®


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.