Sickle Cell Disease Research Program

Sickle Cell Disease Research Program is sponsored by National Institutes of Health (NIH). Funds research projects aimed at understanding the pathophysiology of sickle cell disease and developing new treatments.

Expired RFA-HL-01-015: COMPREHENSIVE SICKLE CELL CENTERS This notice has expired. Check the NIH Guide for active opportunities and notices. Release Date: December 5, 2000 RFA: HL-01-015 (Reissued as RFA-HL-06-008 ) National Heart, Lung, and Blood Institute ( http://www.

nhlbi. nih. gov ) Letter of Intent Receipt Date: March 20, 2001 Application Receipt Date: September 25, 2001 The National Heart, Lung, and Blood Institute (NHLBI) invites applications for support as Comprehensive Sickle Cell Centers that will offer interactive, state-of-the-art programs in basic and translational sickle cell disease research.

The primary objective of this Request for Applications (RFA) is to support ten Comprehensive Sickle Cell Centers, and a Statistics and Data Management Center, to carry out research focused on the development of cures or significantly improved treatments for sickle cell disease.

This research will include basic research efforts, inter-center collaborative clinical research, and local clinical research, with all three focused on the most promising therapeutic modalities on the horizon today, and each interactive with the others.

In addition to their primary focus in research, Comprehensive Sickle Cell Centers will also support career development of young investigators in sickle cell disease research, and support patient service activities that are focused on the implementation into clinical practice of the best current models of care and treatment for sickle cell 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, Comprehensive Sickle Cell Centers, 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/ . 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.

At least one, and preferably more than one organization listed on each application must be associated with an established medical institution with facilities and patient populations available for clinical investigations in sickle cell disease. Underrepresented minority individuals, women, and persons with disabilities are encouraged to apply as Awards will not be made to foreign institutions.

However, basic science or clinical projects from foreign institutions may be submitted as subcontracts if they have unusual scientific merit, unique resources, or documented evidence of successful collaborative arrangements.

In accordance with NIH policy, facilities and administrative (F&A) costs will not be paid to a All current policies and requirements that govern the research grant programs of the National Institutes of Health (NIH) will apply to grants awarded under this RFA.

Among the disciplines and expertise that may be appropriate for this program are hematology, pediatrics, medical genetics, pharmacology, therapeutic development, and clinical trials management. Awards for a Comprehensive Sickle Cell Center and for the Statistics and Data Management Center made under this RFA will not be made to the same Principal Investigator to ensure that data analysis is done independently of data acquisition.

The same institution may apply for both a Comprehensive Sickle Cell Center and Statistics and Data Management Center award, but the applications for each must be from different Principal Investigators. The Principal Investigator of a Statistics and Data Management Center application cannot be listed in any capacity under personnel on a Center application.

Statistics and Data Management Center applications need not be from an institution submitting a Center application. This RFA will use the NIH cooperative agreement (U54) administrative and funding mechanism of support. Under the cooperative agreement, the NIH assists, supports, and/or stimulates, and is substantially involved with recipients in conducting a study by facilitating performance of the effort in a "partner" role.

Details of the responsibilities, relationships, and governance of a study or research funded under a cooperative agreement are discussed later in this document under the section entitled SPECIAL REQUIREMENTS (Terms and Conditions of Award).

Comprehensive Sickle Cell Centers 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 multidisciplinary programs of basic, clinical and behavioral research, for core resources such as laboratory and data analysis, and for quality service activities including counseling, education, and community outreach.

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 be somewhat autonomous 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 specialists 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 with an explicit statement of 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, 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 principal investigators, 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 the NHLBI will continue to assess the quality and performance characteristics of the program through periodic outside 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. The total project period for an application submitted in response to this RFA will be five years.

The anticipated award date is April 1, 2003. The NHLBI intends to commit approximately $22,000,000 in FY 2003 to fund ten grants for Comprehensive Sickle Cell Centers, one new grant for a Statistics and Data Management Center, and per-patient costs for inter-Center collaborative clinical studies in response to this RFA.

Comprehensive Sickle Cell Center applicants may request a project period of five years and a budget for total costs (direct costs plus facilities and administrative (F&A) costs) of up to $1,770,000 per year. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary.

Statistics and Data Management Center applicants may request a project period of up to five years and a budget for total costs (direct costs plus facilities and administrative (F&A) costs) of up to $700,000. Statistics and Data Management Center applications must be submitted separately from Comprehensive Sickle Cell Center applications.

In addition to the $1,770,000 in total costs per year that may be requested in the application, approximately $3,600,000 of additional total costs per year will be available program-wide for reimbursement of Comprehensive Sickle Cell Centers based on patient entry into inter-Center collaborative clinical studies (see Program Structure below for additional funding caps for required program components).

Although the financial plans of the NHLBI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds. Requests for expensive pieces of equipment that cause the application to exceed the budget limits cited above 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 during the review process.

Final decisions will depend on the nature of the justification and the Institute"s fiscal situation. When a grant application includes research activities that involve institutions other than the grantee institution, it is considered a consortium effort.

Such activities may be included in a grant application, but it is imperative that a consortium application be prepared so that the programmatic, fiscal, and administrative considerations are explained fully. Facilities and Administrative costs paid as a part of a consortium agreement are included in the limit on the amount of total costs that can be requested.

The published policy governing consortia is available in the business offices of institutions that are eligible to receive Federal grants-in-iad. Consult the latest published policy governing consortia before developing the application. If clarification of the policy is needed, contact Ms. Mary Page at the address 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-five 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 funded in 1977, 1978, 1983, 1988, 1993, and 1998. 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 ten Comprehensive Sickle Cell Centers, for the period 2003-2008.

In May 2000, the Division of Blood Diseases and Resources convened a Midstream Evaluation Committee, comprised of experts from outside the funded NHLBI Comprehensive Sickle Cell Centers, to evaluate the current program and advise the NHLBI on the future structure of this program.

In their deliberations, the committee made recommendations based on the criteria of needs within the sickle cell disease research community, and of facilitating and enhancing the operations of the Comprehensive Sickle Cell Centers. These recommendations were then considered by the NHLBI Sickle Cell Disease Advisory Committee in June 2000.

As a result of deliberations by these two committees, new or modified components have been incorporated into this Center competition. The program will be comprised of ten Centers and a separate Statistics and Data Management Center.

In addition, Centers will be required to have at least one basic research project, at least one clinical research project, and in two new required components, at least one collaborative clinical research project (not included in the budget cap), and a clinical core.

Details on each of these Statistics and Data Management Center This central, completely independent resource core will provide data management and statistical needs for Centers sharing common clinical protocols, as well as supply statistical support for all research projects (clinical or basic science in nature) within the Comprehensive Sickle Cell Center program.

The Statistics and Data Management Center will coordinate and organize 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 organization of program communications through websites, e-mail listservs, conference calls and the like, 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.

The Statistics and Data Management Center will continue to maintain, expand, and improve the existing common patient database initiated in the prior funding cycle. The common patient database contains data from patients making clinic visits to Centers within the program.

This database will be used as a tool for the Steering Committee to plan collaborative clinical studies during the funding cycle, and the samples will be used in these, as well as potentially many other types of research projects, as determined by the Steering Committee.

A separate database and sample repository may also be developed for each collaborative clinical research study carried out within the program, depending on the nature of the study, as judged by the Steering In addition to the traditional duties of a clinical data and coordination center, the Statistics and Data Management Center will have the following additional new responsibilities: o Implement, and/or develop and maintain web-based information technology to facilitate secure data entry, and data analysis for collaborative clinical o Oversee and manage a repository of patient samples (linked to the common patient database), to be stored at the NHLBI Biological Specimen Repository in Gaithersburg, Maryland.

Access to these samples will be controlled by the o Coordinate, with the NHLBI Project Scientist, the activities of the Steering Committee, the Data and Safety Monitoring Board, and independent Protocol o Develop and maintain a database within the Comprehensive Sickle Cell Center program with data on the social and financial burden of living with sickle cell disease.

This "quality of life" database will include any information relevant to the daily quality of the life experienced by individuals living with sickle cell disease, as well as costs associated with current standard medical care for this disease o Collect within the Comprehensive Sickle Cell Center program information related to health services utilization, and health outcomes.

To facilitate this, a standardized reporting format will be developed across all Centers that will permit accurate annual reporting to the Institute Center applicants wishing to also apply for the Statistics and Data Management Center will submit a completely separate application. Because of the existence of the Statistics and Data Management Center, large separate data cores will not be funded at individual Centers.

Statistical support, where necessary for any Center project, must be obtained from the central Statistics and Data Management Center.

Statistical support may not be requested in the administrative core for local statistical expertise and data services for Comprehensive Sickle Cell Centers Collaborative Clinical Research There is at present a great need in the sickle cell disease research and patient communities for a reliable mechanism to carry out multicenter translational research.

Sickle cell disease is a relatively rare disease, thus patients from many centers are often required to acquire sufficient data to allow the statistical significance necessary to produce meaningful results in clinical studies. A great number of promising preclinical therapies, and approaches to therapy face significant barriers to study in human subjects, and so remain untested.

In the past, the vast majority of multi-Center clinical sickle cell disease research has been done outside of the Comprehensive Sickle Cell Center program. While collaboration on research projects was encouraged within the program, this was not sufficient to engender a significant level of collaborative efforts.

In this competition, the Comprehensive Sickle Cell Center program will include for the first time a collaborative clinical research component for inter-Center collaborative clinical studies, comprised of ten Centers, one Statistics and Data Management Center (Data Coordinating Center), and the NHLBI Project Scientist.

Centers will be responsible for proposing protocols that could be adapted by the network, participating in their overall development, conducting the research, and disseminating research findings.

For the 2003-2008 funding cycle, Center applications must include a clinical core to implement the collaborative protocols (included in the budget cap, see description below), and must include at least one inter-Center collaborative clinical research project.

All such projects submitted by applicants, that receive Center awards, will be considered for implementation by the Steering Committee (see description below) in a process described in the following paragraphs. The budget requested for an inter-Center collaborative clinical research project may not exceed $360,000 total costs, and this will not be included in the overall Center cap of $1,770,000 total costs.

In addition, this project must include two or more NHLBI Comprehensive Sickle Cell Centers, depending on the number of patients required, with the identities of participating Centers unknown (by necessity) at the time of application. The clinical studies proposed should be phase I, II, or III studies of relatively short duration, requiring no more than two years from start to finish.

Example topics for these projects are listed below under Research Scope for Center Applicants (Clinical Research). Center applicants will submit with each collaborative clinical research project a well-justified budget request for implementation of that project (patient care costs only) for the single applicant Center.

See APPLICATION PROCEDURES below for information on how to obtain detailed instructions for preparation of applications (and budgets) for collaborative clinical research projects. After the Center awards are made, a Steering Committee (see description below) will meet and consider all inter-center collaborative clinical research projects submitted by funded applicants.

Two to three collaborative projects will be selected for inter-Center collaborative studies, and these will be carried out using the clinical cores of the participating Centers as infrastructure, with each Center reimbursed on a per-patient basis for patient entry from funds dedicated to this purpose (outside of per-Center budget caps, see Funds Available above).

The intent of this RFA is to use these capitation supplements (i.e. per-patient costs for implementation of protocols) as incentives for participation in inter-Center collaborative clinical research. Capitation supplements will be made at the discretion of NHLBI Program and Grants Management staff, with input from the Statistics and Data Management Center.

Approximately $3,600,000 total costs per year will be available program-wide for reimbursement of Comprehensive Sickle Cell Centers based on patient entry into inter-Center collaborative clinical projects.

It is expected that three to six collaborative clinical studies will be completed over the course of the five year funding cycle, with followup collaborative projects (to the initial two to three studies) developed during the funding cycle by the Steering Committee, which includes at a minimum the Director from each Center.

The exact number of protocols supported in the five year program will depend on the nature and extent of the investigations proposed by the Comprehensive Sickle Cell Center Steering Committee.

Depending on each Center"s ability to compete for patient capitation costs, it is anticipated, based on the NHLBI"s estimate of available funds for the collaborative clinical research component (see FUNDS AVAILABLE above), that up to 30% of the total financial resources of each Center could be dedicated to multi-Center collaborative translational research.

A separate Statistics and Data Management Center (see below) will support protocol development and provide sample size calculations, statistical advice, common questionnaires, data analysis, and coordinate the activity of the Data and Safety Monitoring Board, The Protocol Review Committee and overall study coordination and quality assurance.

All individual Centers will be required to participate in a cooperative and interactive manner with one another, and with the Statistics and Data Management Center in all aspects of collaborative The Steering Committee will be the scientific governing body for all inter- Center collaborative clinical research efforts in the Comprehensive Sickle Cell Center program, and, at a minimum, will be composed of the Directors of the individual Comprehensive Sickle Cell Centers and Statistics and Data Management Center, the NHLBI Project Scientist, and a Grants Management Specialist.

The Steering Committee may meet as often as four times in the first 12 months of the study, and three times per year thereafter. All major scientific decisions will be determined by majority vote of the Steering Committee. Each Clinical Center, the Statistics and Data Management Center, and the NHLBI will have one vote.

The Chairperson, who will be someone other than an NHLBI staff member and may be someone from outside the NHLBI Comprehensive Sickle Cell Center program, will be selected by the Director, NHLBI, by the end of the second meeting of the Steering Committee. The first meeting of the Steering Committee will be convened by the NHLBI Project Scientist.

The Steering Committee will have primary responsibility for the general organization of the collaborative clinical component of the Comprehensive Sickle Cell Center program, finalizing common clinical protocols, facilitating the conduct and monitoring of the studies, and reporting study results. Topics for the protocols may be proposed and prioritized by the Steering Committee.

For each protocol, one Center will take the lead responsibility for drafting the protocol, although the Steering Committee will provide input and will be responsible for assuring development of a common protocol to be implemented by the Centers.

Subcommittees of the Steering Committee will be established as necessary, for example, it is envisioned that a Publications and Presentations Committee will facilitate and supervise preparation of manuscripts prior to submission for publication. An independent Protocol Review Committee, established by the NHLBI, will provide peer review for each protocol.

A Data and Safety Monitoring Board (DSMB), also established by the NHLBI, with input from the Steering Committee, will monitor patient safety and review performance of each study. As a part of its monitoring responsibility, the DSMB will submit recommendations to the NHLBI regarding the continuation of each study.

As specific protocols are developed, support will depend on the availability of funds and will be provided on a per-patient basis. All the Centers must be willing to pursue this funding arrangement for each new protocol conducted. Clinical protocols must be approved by local institutional review boards and the Comprehensive Sickle Cell Center Protocol Review Committee before initiation.

In this Center competition, the clinical core will be a required key component of the collaborative research effort, as it will constitute the collaborative clinical research infrastructure, including personnel, at each Center.

A minimum part-time data coordinator must be requested in the clinical core of each Center application to coordinate electronic data entry and analysis with the central Statistics and Data Management Center staff.

In addition, the clinical core will continue to serve its traditional functions of applying the best current models of clinical care to pediatric and adult patients with sickle cell disease, and of collecting patient samples for research studies to be carried out at that Center.

The clinical core will provide partial salary support for physicians, nurses, nurse-coordinators, data coordinators, and secretarial staff who staff the clinics where sickle cell disease patients receive medical care.

Thus the clinical core will both provide state-of-the- art treatment to clients with sickle cell disease (as it has throughout the history of this program), and implement the collaborative clinical research protocols adopted by the Steering Committee. Centers are allowed to submit requests for a clinical core budget not to exceed $400,000 total costs (direct costs plus facilities and administrative (F&A) costs) per year.

Research Projects and Laboratory Cores In addition to at least one inter-Center collaborative clinical research project (not included in the budget cap, as defined above), at least one basic science project, and at least one clinical project (included in the budget cap, may be collaborative) are required. Laboratory cores that will serve basic science and/or clinical projects are optional.

With these requirements, the Comprehensive Sickle Cell Center program supported through this solicitation will meet the need for translational research in sickle cell disease, and will continue to support basic science research as well. The scope of possible research projects is described below under Research Scope.

Sickle Cell Scholar Component This component is a requirement of this solicitation, and offers career development support in basic or clinical sickle cell disease research to young investigators, or new investigators trained in other fields.

Candidates for Sickle Cell Scholars should have at least two years of postdoctoral experience, and may propose to work at any institution participating in a Comprehensive Sickle Cell Center (i.e. the parent institution, or an institution participating through a consortium arrangement).

Sickle Cell Scholars are 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. The duration of support will be a maximum of five years.

Each Center will set aside $90,000 per year in direct costs for the exclusive purpose of providing partial salary and research support for a Sickle Cell Scholar who will be chosen by a panel of Principal Investigators at each Center with final approval from NHLBI. These funds will be restricted in that they cannot be rebudgeted by the Program Director for other purposes.

Because the application receipt date is one and one half years before the Center award date, Sickle Cell Scholars must not be nominated in the Center applications. However, a career development plan will be required in each Center application. See APPLICATION PROCEDURES below for a detailed description of what is required in this application.

The NHLBI Comprehensive Sickle Cell Center program will be best served by allowing additional time for recruitment of Sickle Cell Scholars after the application receipt date. For applications that fall in the funding range after the merit review, the deadline for submission of Sickle Cell Scholar nomination packages to NHLBI will be approximately six months before the Center award date.

See APPLICATION PROCEDURES below for further information on instructions for delayed submission of Sickle Cell Scholar nomination packages to NHLBI. Inclusion of patient service activities such as sickle cell disease education, counseling, community outreach, or hemoglobin diagnosis remains a requirement in this program for the 2003-2008 funding cycle. Funds for these services should be organized and requested in a patient service core.

The scope of possible responsive activities is described below under Research Scope. Research Scope for Center Applicants Although significant progress has been made over the past two decades in understanding the pathophysiology of sickle cell disease, many unresolved questions remain.

Basic and clinical research projects in the Comprehensive Sickle Cell Centers program should take advantage of new scientific advances to address the broad and interdisciplinary spectrum of research hypotheses related to sickle cell disease that will ultimately lead to routine cures, or to improvement in modalities for routine treatment and prevention of complications of this disorder. The scope of responsive research areas is broad.

However, emphasis is placed on therapeutic modalities likely to have an impact on patient care in the near-term, and on the development of innovative approaches in these areas. Research projects for Sickle Cell Scholars should be developed after submission of the Center application, and can be related to any of the clinical or basic research areas listed above, as long as they are consistent with the overall goals of this solicitation.

Basic research projects (using in vitro, cell culture systems, or animal models of sickle cell disease) in the following priority areas are encouraged: o Anti-adhesion therapy (vascular pathobiology of sickle cell disease) o Hematopoietic stem cell transplantation o Vascular therapy (e.g. using nitric oxide, or other vasoactive agents) o Fetal hemoglobin induction therapy o Gene transfer as a potential therapeutic modality o Anti-inflammation therapy, including study of the role of white blood cells in sickle cell disease vaso-occlusion o Red blood cell hydration therapy (ion transport therapy) o Study of non-red cell contributors to sickle cell disease pathophysiology, such as the blood coagulation system o The development of new methods for improved hemoglobin diagnosis THESE ARE EXAMPLES ONLY.

INVESTIGATORS SHOULD NOT FEEL LIMITED TO THE TO THE OBJECTIVES OF THE RFA. At least one collaborative, inter-Center clinical research project (not included in the budget cap) is required in Center applications. These projects should include two or more NHLBI Comprehensive Sickle Cell Centers, and should include phase I, II, or III studies of relatively short duration, to be completed within two years (start to finish).

In addition to this requirement, at least one clinical research project (included in the budget cap) is also required in Center applications. This second requirement may be met with clinical studies that are either single-Center or multi-Center in origin. Multi-Center clinical studies may include any sickle cell Center (comprehensive or not) that can contribute clients and investigators to carry out clinical studies.

Subcontract Centers may be from outside the NHLBI Comprehensive Sickle Cell Center program.

For both the collaborative clinical, and clinical research requirements, focused projects in the following priority areas of clinical sickle cell disease research are o Evaluation of nonmyeloablative conditioning regimens for hematopoietic stem cell transplantation in pediatric clients with sickle cell disease o Evaluation of vasoactive agents (e.g. nitric oxide