Full Text HL-96-002 COMPREHENSIVE SICKLE CELL CENTERS NIH GUIDE, Volume 24, Number 39, November 3, 1995 RFA: HL-96-002 National Heart, Lung, and Blood Institute P.T. 04 Keywords: Blood Diseases Pathophysiology Biomedical Research, Multidiscipl Letter of Intent Receipt Date: March 1, 1996 Application Receipt Date: September 18, 1996 PURPOSE The Division of Blood Diseases and Resources (DBDR) of the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), invites applications for the support of Comprehensive Sickle Cell Centers to focus on multidisciplinary programs of basic, applied, and clinical research, and also to include relevant service activities in diagnosis, counseling and education concerning sickle cell disease and related disorders. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Comprehensive Sickle Cell Centers, is related to the priority areas of chronic disabling conditions and maternal and infant health. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Applicant organizations must be associated with an established medical institution with facilities and patient populations available for clinical investigations in sickle cell disease. Awards will not be made to foreign institutions. However, subprojects to foreign institutions may be considered for research of unusual merit, programmatic need, unique potential, and documented evidence of effective collaborative arrangements. Applications from minority individuals, women, and persons with disabilities are encouraged. Minority health professional institutions are strongly encouraged to apply. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) Comprehensive Center (P60) mechanism. Sickle Cell Center grants are identifiable units within sponsoring institutions that are organized around a group of investigators and other health professionals engaged in ongoing basic and clinical research and community service related to sickle cell disease. Centers provide support for multi disciplinary programs of basic, clinical and behavioral research; for core resources such as laboratory and data analysis; and for quality service activities including diagnosis, counseling, and education. A Center is headed by a Program Director who is responsible for and provides leadership to all Center components, and who may also be principal investigator on one or more of the projects contained within the Center. Although individual components may enjoy a certain amount of autonomy in the conduct of a specific project, each is directly accountable to the Center Program Director, who has overall responsibility for program coordination, implementation, and evaluation. The Program Director must maintain close contact with NHLBI program administrators and grants management officers responsible for each grant. Committees, internal and external, which provide scientific and fiscal overview of Center activities are required. In addition, a formal ongoing agreement between the sponsoring institution and the Center must be developed spelling out the commitment of each to the other. In particular, the sponsoring institution should make a formal commitment of financial support to all components of a proposed Center specifically defining the resources for the salaries, equipment, supplies, and facilities that will be available to the investigators for the entire project period. Under the guidance of the Program Director, each of the required program components and services (research, education, diagnosis, and counseling) should be coordinated and integrated to strengthen the overall program, enhance transfer of new findings to the clinical setting, and identify new research directions. Such interaction should be frequent, formalized, and documented to facilitate continuous exchange of relevant information between projects and components, thus contributing to greater program productivity and effectiveness. Regular meetings of project directors, seminars, poster sessions, and staff lectures are excellent mechanisms for fostering communication and interaction among Center staff. Finally, each Program Director will be expected to develop a mechanism for the ongoing evaluation of the effectiveness and impact of the activities constituting the Center program. While NHLBI will continue to assess the quality and performance characteristics of the program through periodic peer review and staff evaluation, each of the Centers must consider approaches by which it can demonstrate how the local program has influenced understanding and practice in matters related to sickle cell disease. Only by establishing and validating the benefits of the Center program can the long term support of this approach be justified. FUNDS AVAILABLE The FY 95 fiscal support for the Centers program is $19.3 million. Although the NHLBI will consider a modest expansion of this program, it should be noted that the availability of FY 98 funding is contingent on the provision of money through the appropriation process. It is anticipated that ten grants will be awarded under this program. The specific number to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. RESEARCH OBJECTIVES Background Sickle cell disease is a worldwide health problem and is one of the most common inherited disorders of man. This genetic blood disorder is probably the best understood disease at the molecular level and Linus Pauling coined the term "molecular disease" over forty years ago in ascribing the abnormality to the globin portion of the hemoglobin molecule. Almost ten years later, the specific molecular defect was identified as a single amino acid substitution of valine for glutamic acid at position 6 of the beta-globin polypeptide chain. With the advent of recombinant DNA technology, investigators were able to further define this genetic mutation in the globin gene as a change in the codon GAG to GTG. The substitution of glutamic acid by valine results in a loss of two negative charges on the surface of the molecule making sickle hemoglobin less soluble than normal hemoglobin upon deoxygenation. This abnormal hemoglobin aggregates and forms fibers within the red cells, leading to morphological changes that subsequently affect the ability of the cells to traverse the microvasculature, causing occlusion of these small vessels that results in acute pain, and acute as well as chronic organ damage. In addition, sickle red cells are less resilient than normal cells, leading to their early destruction and thus a chronic anemia. This cascade of events caused by the abnormal cell morphology affects the structure and function of the red cells, blood flow through tissues and organs throughout the body, and abnormal interaction of these cells with the microvasculature. The complex pathophysiology of this disorder is a direct consequence of the change in morphology of red cells containing sickle hemoglobin. Despite the distinction of being the first described molecular disease, there is no cure or effective treatment currently available. The NIH established the Comprehensive Sickle Cell Center Program in 1972, in response to a Presidential initiative and Congressional mandate. After an open competition, ten Centers were funded in 1972 and five additional Centers in 1973. Subsequent RFAs were announced in 1977, 1978, 1983, 1988, and 1993. Ten Comprehensive Sickle Cell Centers are currently funded. With this RFA, the Sickle Cell Disease Scientific Research Group, Blood Diseases Program, Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute, announces its plan to fund 10 Comprehensive Sickle Cell Centers, for the period 1998-2003. Research Opportunities Although significant progress has been made over the past two decades in understanding the pathophysiology of sickle cell disease, many unresolved problems remain. Research in the Center's program should take advantage of new scientific advances to address the broad and interdisciplinary spectrum of research questions about sickle cell disease that will ultimately lead to improvement in treatment and prevention of complications of this disorder. The scope of research is unlimited, however, emphasis is placed on the development of innovative approaches, and new hypotheses applied to understanding this disease process. While a Center must devote its major effort to basic and clinical research, it must also provide supporting activities in diagnosis, education and counseling. It is anticipated that the total program, i.e., all ten Centers combined, will achieve a mix of outstanding projects that are two-thirds research oriented and one-third devoted to supporting activities. The actual balance between research and other activities will vary from Center to Center and will depend on local circumstances and competencies. Examples of ongoing research and/or new areas of opportunity in basic, clinical, behavioral, and other services include, but are not limited to, the following: Basic Research o Gene therapy, including the development of methods to improve the propagation of hematopoietic stem cells and alternative gene delivery systems o Study of the regulation of globin gene expression, including the regulation of fetal to adult globin gene switch environment of the red cells in sickle cell disease o Analysis of the pathogenesis/pathophysiology of red cell adhesion and of the microenvironment of the red cells in sickle cell disease o Examination of the pathogenesis/pathophysiology of vaso-occlusion o Study of non-red cell contributors to sickle cell disease pathophysiology, including clotting factors, cytokines, white cells, endothelial cells, free radicals, etc. o Analysis of the role of genetic polymorphism on phenotypic expression in sickle cell disease o Improving animal and cellular model systems to clarify pathogenesis and to evaluate new approaches to treatment Clinical Research o Collaborative clinical research - Joint efforts are strongly encouraged to develop, design, implement, conduct, and publish findings from clinical studies for sickle cell disease; to foster the development of standardized approaches for the care of patients; and to support centralized data and statistical services for clinical research. Collaborative clinical research among Center applicants can be proposed as a part of the original application. It may also be planned following the Center competition. Research areas appropriate for single center or collaborative approaches to clinical studies include, but are not limited to: o Development of disease severity indices o Drug therapies o Central nervous system disease o Pulmonary disease o Renal disease o Immune system dysfunction o Pain management - pharmacologic interventions Behavioral Research o Pain management - non-pharmacologic interventions o Newborn (or perinatal/neonatal) medicine - e.g., outcome evaluation of early intervention in newborn screening o Adolescent medicine - e.g., assessing barriers to treatment, enrolling in clinical trials o Adult medicine - e.g., achieving optimal transition from pediatric/adolescent to adult care modes o Patient compliance with treatment regimens o Outcomes research - e.g. assessing the impact of different health care systems (e.g. managed care organizations) on patterns of care for sickle cell patients o Evaluating the effectiveness of intervention strategies to achieve optimal adjustment of the patient and family to sickle cell disease Other Supporting Activities A number of ancillary integrated activities are needed for the successful implementation of the sickle cell center concept. These other activities include education, counseling, and diagnostic testing. The provision of community outreach programs is also encouraged. Although supporting activities are not research projects, they should be well described with objectives and methodology. o Diagnostic Testing - providing facilities where accurate diagnosis including hemoglobin genotyping can be performed o Counseling - all counseling should be non-directive and aimed at helping counselees to make informed decisions about health-related and/or family planning issues that they believe to be in their best interest o Education - sponsoring activities that provide training and information about sickle cell disease to health care professionals at the Center and in the community or region that the Center serves; and to patients, their families and communities o Community Outreach - developing a liaison between the Center and the community which would inform the community about Center programs and provide community input into their development New Components In May 1995, the Division of Blood Diseases and Resources convened a Concept Review Committee that included active participation by current Sickle Cell Center Directors to make recommendations to the NHLBI that would facilitate and enhance the operations of the Comprehensive Sickle Cell Centers and offer opportunities for career development. As a result of Committee deliberations, the following new components have been incorporated into this Center competition: Data Management Core (Data Coordinating Center) This central resource core will provide data management and statistical needs for specific aspects of the Centers program sharing common clinical protocols, as well as for information related to health services utilization and health outcomes. This core will coordinate the clinical collaboration between the ten centers and will serve as the primary unit to collect, manage, statistically analyze, and store clinical data obtained from the individual Centers. This will require the full range of coordinating center activities including study design and protocol development; preparation of forms and Manual of Operations; training center staff in data collection procedures; maintaining the study database; monitoring clinical center performance; providing patient accrual reports; performing appropriate statistical analyses of study data; and participating in the preparation of study publications. It is anticipated that the centers will share two to three clinical research protocols each year; however, it is unlikely that all centers will participate in each clinical study. For health services data, a standardized reporting format would be developed across all centers that would permit accurate annual reporting to the Institute. Centers wishing to apply for the data management core will submit a separate document with an application face page, budget, and project description, which will be reviewed separately from the main application. The maximum possible total costs for this facility will be $300,000. This will be supplemental to the allowable funding cap for each Center and will be covered within the total funds allocated to the Centers for each year. (See Document on "Special Instructions"). Because of the Data Management Center, large separate data cores will not be funded at individual Centers. However, support can be requested in the administrative core for statistical expertise and data services related to research projects at each Center. Sickle Cell Research Scholars Program This component offers modest career development support for up to three years in the field of basic or clinical sickle cell research to a young scientist at the institution where a Comprehensive Sickle Cell Center is located. Each Center will set aside $100,000 per year for the exclusive purpose of providing partial salary and research support for a Scholar who would be chosen by a panel of principal investigators at each Center with final approval from the Institute. These funds cannot be rebudgeted by the Program Director for other purposes. The Sickle Cell Research Scholar is expected to spend at least 75 percent of his/her effort in sickle cell anemia-related research under the guidance of an established investigator at the Center. Pilot Projects Pilot studies will be allowed (i.e., "seed money") for the pursuit of promising, but untested innovative research that emerges during the project period for established scientists who did not previously work in sickle cell related research or new investigators with state-of- the-art core technologies that will enable them to be competitive in the field. Pilot projects, with funding up to $25,000 in direct costs (within the total cost allocation), will be purely optional and will be reviewed and selected by experts within each Center. Progress will be reported to the Institute upon completion. Center Program Directors are also encouraged to use the Scholars Program and Pilot Projects to attract young minority scientists into biomedical research. Collaboration Active cooperation among Centers is required. Collaborative efforts among Center projects and between Centers enhance productivity and facilitate technology transfer between research and clinical application. Center Program Directors shall meet annually to review their progress and to plan new approaches for future collaborative work. Thus, the accomplishments of Centers will be shared freely and expeditiously. Exclusions Studies of the clinical course ("natural history") of sickle cell disease are currently being conducted in a multi-institutional collaborative Cooperative Study of Sickle Cell Disease. Therefore, applications to pursue such investigations are not appropriate for this competition. Applications lacking any of the required components (basic and clinical research; supporting services for education, diagnosis, and counseling; and the Scholars Program) will be considered as non-responsive to this RFA and will not be accepted. SPECIAL REQUIREMENTS 1. Application Funding Levels: a. New Center Applications: New applications may request up to $1.17 million direct costs (exclusive of indirect costs on subcontracts) in the first year with a maximum increase of no more than four percent for each additional year requested in that application. Applications that exceed these limits will be returned to the applicant. Requests for expensive pieces of equipment that cause the application to exceed these limits, will be considered on an individual basis. However, applicants should make every attempt to include all equipment in the ceiling amount and must discuss any equipment requests that cause the application to exceed the ceiling with NHLBI staff early in the planning phase of the application. Such requests for equipment will require in-depth justification and will be carefully considered throughout the review process. Final decisions will depend on the nature of the justification and the Institute's fiscal situation. b. Competing Renewal Center Applications: Competing renewal applications whose total costs currently exceed $2.0 million will be allowed to apply to apply for up to $2.2 million in total costs for the first year, with a maximum increase of no more than four percent in each succeeding year. Other competing renewals can request 10 percent above the recommended direct costs of the last noncompeting year or up to $1.6 million in total costs, whichever is greater, with a maximum increase of no more that four percent in each succeeding year. The same policy regarding equipment, which is described under "New Applications" applies to competing renewals. Applications that exceed these limits will be returned to the applicant. 2. NHLBI-sponsored annual meetings will be held to encourage the exchange of information among investigators who participate in this program. In the preparation of the budget for the grant application, applicants should request additional travel funds for one meeting each year to be held at various locations where there are Comprehensive Sickle Cell Centers. Applicants should also include a statement in the applications indicating their willingness to participate in such meetings. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103- 43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations) which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research", which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators may obtain copies from these sources or from the program staff or contact person listed below. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by March 1, 1996, a letter of intent that includes a descriptive title of the proposed research , the name, address, and telephone number of the Principal Investigator, the identities of other key personnel, and identification of any other participating institutions. The letter should also indicate any interest in applying for the Data Management Core. Such letters are requested only for the purpose of providing an indication of the number and scope of applications to be received; therefore their receipt is usually not acknowledged. A letter of intent is not binding, and it will not enter into the review of any application subsequently submitted, nor is it a necessary requirement for the application. This letter of intent is to be sent to: Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3541 Email: james_scheirer@nih.gov APPLICATION PROCEDURES Applications are to be submitted on the research grant application form PHS 398 (rev. 5/95). This form is available in an applicant institution's office of sponsored research and from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 6701 Rockledge Drive, Room 3034, MSC 7762, Bethesda, MD 20892-7762 telephone (301) 710-0267, email: girg@drgpo.drg.nih.gov. Use the conventional format for research grant applications and ensure that the points identified in the section on REVIEW CONSIDERATIONS are fulfilled. The page limitations described in the form PHS 398 (rev. 5/95) instructions are to be considered as applicable to all subprojects. Supplemental application guidelines for Comprehensive Sickle Cell Center applications may be obtained from Dr. Junius Adams at the address listed under INQUIRIES. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. If collaborative arrangements involve sub-contracts with other institutions, Ms. Jane R. Davis of the NHLBI Grants Operations Branch (telephone: (301) 435-0166) should be consulted regarding procedures to be followed. The RFA label available in the PHS 398 (rev. 5/95) application form must be affixed to the bottom of the face page of the application. 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 (Comprehensive Sickle Cell Center -HL-96-002) must be typed on line 2 of the face page of the application form and the YES box must be marked. Send or deliver the completed application and three signed, exact photocopies of it to the following, making sure that the original application with the RFA label attached is on top: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for courier/overnight mail service) Send an additional two copies of the application to the Chief, Review Branch at the address listed under LETTER OF INTENT. It is important to send these two copies at the same time as the original and three copies are sent to the Division of Research Grants. Otherwise the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by September 18, 1996. If an application is received after that date, it will be returned to the applicant without review. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the DRG and responsiveness by the NHLBI. Incomplete applications will be returned to the applicant without further consideration. If NHLBI staff determine that the application is not responsive to the RFA, it 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 in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Applications should be prepared so that they can be reviewed without the necessity of interaction between the applicants and the reviewers, since no site visit or reverse site visit will be part of the technical review. Review Criteria Criteria for evaluation of the application will include: 1. The qualifications, experience and commitment of the Center Director and the ability to devote adequate time and effort to provide effective leadership. 2. The scientific merit and quality of the proposed projects. Each project will be assigned a priority score based on scientific merit and relevance to the goals of the Center. 3. The competence of the senior personnel to accomplish the proposed goals of the Center, their commitment, and time they will devote to the project. 4. The adequacy of the facilities to conduct the proposed research including laboratory and clinical facilities, access to patients, instrumentation and data management systems, when needed. 5. The nature of the overall structure and management of the Center, including scientific and fiscal management, integration of the parts, and quality control. 6. The appropriateness of the budget in relationship to the proposed program. 7. The committee structure, both internal and external, and process for ongoing evaluation of the Center's effectiveness. 8. The institutional commitment to the program as evidenced by provision of resources, and the appropriateness of the institutional resources and policies for the administration of a center program of the type proposed. 9. The willingness of the Center leadership to work cooperatively with other Sickle Cell Centers and with the NHLBI. Criteria for the evaluation of the Data Management Center will include: 1. Adequacy of the plans for data management, analysis, and coordination of clinical protocols 2. Qualifications, experience and commitment of the Data Management Core Director to provide effective leadership 3. Competence of the senior personnel to accomplish the proposed goals of the Data Management Core, their commitment, and time they will devote to the project 4. The adequacy of the facilities to conduct data management, analysis, and coordination of clinical protocols 5. Overall structure and management of the Core including fiscal management and quality control 6. Appropriateness of the budget in relationship to the proposed program 7. Institutional commitment to the Data Management Core as evidenced by provision of resources, and the appropriateness of the institutional resources and policies for the administration of a Data Management Core of the type proposed 8. Willingness of the Core leadership to work cooperatively with all Sickle Cell Centers and the NHLBI. AWARD CRITERIA The anticipated date of award is April 1, 1998. Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program needs and balance, and the availability of funds. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues and requests for the program guidelines may be directed to: Dr. Junius G. Adams, III Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7950 Bethesda, MD 20892-7950 Telephone: (301) 435-0055 FAX: (301) 480-0868 Email: ja33m@nih.gov For fiscal and administrative matters, contact: Ms. Jane R. Davis Blood Division Grants Management Section National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0166 FAX: (301) 480-3310 Email: jane_davis@nih.gov AUTHORITY AND REGULATIONS The programs of the Division of Blood Diseases and Resources, NHLBI, are described in the Catalog of Federal Domestic Assistance No. 93.839. Awards will be made under the authority of the Public Health Service Act, Section 301 (42 USC 241) and administered under PHS grant policies and Federal regulations, most specifically 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372, or to Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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