Centers for Reducing Sickle Cell Disease Disparities (U54)

Centers for Reducing Sickle Cell Disease Disparities (U54) is sponsored by National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health. Comprehensive center mechanism to reduce health disparities in SCD through multidisciplinary research, including basic mechanisms (e. g.

, TLR4‑mediated inflammation), clinical studies, and community‑engaged implementation.

Expired RFA-HL-06-008: Comprehensive Sickle Cell Centers (U54) This notice has expired. Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Participating Organizations National Institutes of Health (NIH ), Components of Participating Organizations National Heart, Lung, and Blood Institute (NHLBI), (http://www.

nhlbi. nih. gov/) Title: Comprehensive Sickle This is a r enewal of RFA-HL-01-015 which was previously released December 5, 2000.

Update: The following update relating to this announcement has been issued: November 8, 2006 (NOT-HL-06-137) - See Notice NOT-HL-06-137 for Clarifications, Correction, and Addenda to RFA-HL-06-008.

Request For Applications (RFA) Number: Catalog of Federal Domestic Assistance Number(s) Release Date: July 21, 2006 Letters of Intent Receipt Date(s): December Application Receipt Date(s): January Peer Review Date(s): August Council Review Date(s): February, Earliest Anticipated Start Date: April Additional Information To Be Available Date (Url Activation Additional Overview Content The National Heart, Lung, and Blood Institute (NHLBI) invites applications for the renewal of the Comprehensive Sickle Cell Center program, whose purpose is to conduct comprehensive research, training, and education efforts related to sickle cell disease.

Comprehensive Sickle Cell Centers will conduct research to improve our understanding of sickle cell disease pathophysiology, and to develop cures or improved medical management modalities for this disease. Multi-center clinical research projects will be required. In addition, early stage clinical research or basic research (at least one of the two) will be required.

Finally, translational research, health services research and high-risk, short-term basic research will be new required components Up to $118. 4 million (total costs) will be awarded over 5 years. It is anticipated that ten awards will be made for Comprehensive Sickle Cell Centers and one award for a Statistics and Data Management Center.

The Specialized Center, cooperative agreement (U54) funding mechanism will Eligible organizations include 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, Faith-based or community-based organizations, Indian/Native American Tribal Government (Federally Recognized), Indian/Native American Tribal Government (Other than Federally Recognized), and Indian/Native American Tribally Designated Organization.

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.

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 Eligible principal investigators include those with the experience and expertise to conduct research studies in sickle cell disease.

The disciplines and expertise appropriate for this program include adult and pediatric hematology, pulmonary medicine, transfusion medicine, emergency medicine, blood or marrow transplantation, neurology, nephrology, genetics, genomics, molecular biology, biochemistry, and clinical trials management and biostatistics.

Underrepresented minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators . Each Principal Investigator may be listed on only one application for a Clinical Center or the Statistics and Data Management Center. One institution may apply for both awards with different Principal Investigators, but in this case two separate applications must be submitted.

See Section IV. 1 for application materials. Telecommunications for the hearing impaired is available at: TTY 301-451-5936 Part II Full Text of Announcement Section I.

Funding Opportunity Section II. Award Information 1. Mechanism(s) of Support Section III.

Eligibility Information 2. Cost Sharing or Matching 3. Other - Special Eligibility Criteria Section IV.

Application and Submission 1. Address to Request Application Information 2. Content and Form of Application Submission 3.

Submission Dates and Times A. Receipt and Review and B. Sending an Application C.

Application Processing 4. Intergovernmental Review 6. Other Submission Requirements Section V.

Application Review 1. Review and Selection Process A. Additional Review Criteria B.

Additional Review Considerations D. Sharing Research Resources 3. Anticipated Announcement and Award Section VI.

Award Administration 2. Administrative and National Policy A. Cooperative Agreement Terms 1.

Principal Investigator Rights and Responsibilities Section VII. Agency Contact(s) 1. Scientific/Research Contact(s) 2.

Peer Review Contact(s) 3. Financial/ Grants Management Contact(s) Section VIII. Other Information - Required Federal Citations Part II - Full Text of Announcement Section I.

Funding Opportunity Description Nature of the Research Opportunity : The purpose of this Request for Applications (RFA) is to renew a network of ten Comprehensive Sickle Cell Centers (CSCCs) and a Statistics and Data Management Center (SDMC) to carry out research focused on improvement of the understanding of the pathophysiology of sickle cell disease (SCD), and the development of cures or significantly improved treatments for this disease.

This program will provide the necessary infrastructure to conduct multiple inter-Center Phase II clinical protocols, and will support intra-Center basic, translational, clinical, and patient services research. It will also support limited patient services at each center, extensive research training at the high school through junior faculty career levels, and high-risk, short-term basic research projects.

CSCC research activities will be coordinated with those of NHLBI’s other SCD research programs, such as the Sickle Cell Disease Clinical Research Network (that is focused on Phase III clinical trials) and the Thalassemia Clinical Research Network.

The results of all CSCC research efforts will be widely disseminated Pertinent Background Information that Establishes the SCD 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.

Linus Pauling coined the term "molecular disease" over fifty years ago in ascribing the abnormality seen in this condition 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 chronic The cascade of events caused by the abnormal morphology of the red blood cells affects the function of those 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 its distinction of being the first described molecular disease, there is no universal cure currently available, and the limited therapies that are available do not benefit all patients.

Recent research has been focused on blood and marrow transplantation, fetal hemoglobin induction, vasodilation through the nitric oxide pathway, the role of inflammation and white blood cells, hemoglobin gene regulation, gene transfer, genetic modifiers of disease severity, ion channel blockade in red blood cells, combination therapies, pain management, and psychosocial aspects of living with this disease.

While progress has clearly been made, none of these research areas has yet reached fruition in terms of a major impact on clinical wellness or on the quality of life of sickle cell disease patients. Much research remains to be done. In 1972, the NIH established the CSCC Program in response to a Presidential initiative and Congressional mandate.

After an open competition, ten CSCCs were funded in 1972 and five additional CSCCs in 1973. Subsequent RFAs were funded in 1977, 1978, 1983, 1988, 1993, 1998, and 2003. Ten CSCCs and one SDMC are currently funded.

With this RFA, the Hemoglobinopathies & Genetics Scientific Research Group, Blood Diseases Program, Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute, announces its plan to fund ten CSCCs and one SDMC for the period 2008-2013.

Scientific Knowledge to be Achieved Through Research Supported by the Special Program : Applications should propose research to develop cures for SCD, to improve medical management strategies in children or adults, or to increase understanding of the pathophysiology of this disorder. Research to investigate short-term and long-term outcomes for specific patient services or treatments is also required.

Specific projects proposed should be based on their scientific merit, their timeliness, and their feasibility.

Types of Research and Experimental Approaches : This program will support six different types of research inter-Center clinical trials intra-Center clinical studies patient services (outcomes) research translational research (bringing basic research discoveries to human application) high-risk, short-term basic research Inter-Center Clinical Projects These projects can be interventional or epidemiologic in nature and should be chosen and planned such that a minimum of three NHLBI CSCCs are required to meet study objectives.

These must be studies that require a network (3-20 clinical sites) to implement. Phase I studies involving less than 20 patients are not appropriate for this category. These projects should be phase II clinical studies of 1-4 years duration.

Up to four years of funding may be requested. Some examples of appropriate research topics include, but are not limited to, the following: Validation of early genetic predictors for specific complications of SCD, or for a composite measure of SCD severity. Comparison of fetal hemoglobin inducing agents with respect to their effect on the rate of vaso-occlusive pain crises or other end points.

Evaluation of anti-inflammatory or anti-adhesion agents on specific complications Evaluation of vasoactive agents (e.g. the nitric oxide or endothelin pathways) as potential therapeutic agents for specific complications of SCD, such as acute chest syndrome, or pulmonary hypertension. Evaluation of nonmyeloablative conditioning regimens for hematopoietic stem cell transplantation in pediatric patients with SCD.

Evaluation of combination therapies (e.g. a regimen that would include fetal hemoglobin induction and red cell hydration). Evaluation or comparison of iron chelation regimens for transfusional iron overload; Improved medical management of sickle cell pain. Improved treatment of specific complications of SCD- e.g. pulmonary hypertension, acute chest syndrome, renal disease, priapism, osteonecrosis.

In the prior funding cycle (2003-2008), the following eight inter-Center projects either have been implemented or are likely to Oral arginine supplementation in children and adults to stimulate the nitric oxide pathway and improve red cell hydration. Neurocognitive function, neuroimaging, and transfusion in adults. The Collaborative Data registry and DNA/plasma repository (all CSCC patients).

The epidemiology of priapism in children and adults. Hydroxyurea plus magnesium in adult and pediatric hemoglobin SC patients to improve red cell hydration. Dexamethasone for Acute Chest Syndrome in children and adults.

Phase II study of decitabine for fetal hemoglobin induction in adults. Oral methadone for stable pain control in children and adults. Intra-Center Clinical Projects These projects can be interventional or epidemiologic in nature and should be chosen and planned such that one or two clinical sites are required to meet study objectives.

Additional clinical sites outside of the home institution may be included as subcontracts. These projects may be early-stage, phase I interventional clinical studies, or may be epidemiologic or psychosocial in nature. Five years of funding may be requested.

In addition to the example topics shown above for multicenter clinical studies, many of which may apply in this category as well, the following are appropriate example Evaluation of the effect of red blood cell ion transport inhibitors (hydration agents) on specific complications of SCD.

Evaluation of combination therapies with more than one mechanism of action Evaluation of gene transfer for SCD using lentiviral globin vectors and autologous blood or marrow transplantation. Phase I studies of new approaches to nonmyeloablative blood or marrow transplantation Evaluation of the effect of nutritional supplements on growth rates, and resting energy expenditure in SCD patients.

Phase I evaluation of new fetal hemoglobin inducing agents. Evaluation of the effect of transfusion therapy on specific complications Collection of data on behavioral and social issues linked to severe SCD, and interventions to modify coping skills. Collection of epidemiologic data on the prevalence of significant, understudied medical complications of SCD.

Evaluation of improved drugs or regimens for pain control in SCD patients. Patient Services Research Projects A patient services core (described below) is again required in this CSCC competition. In a new component, patient services research is also required.

Each CSCC application must include at least one patient services research project to be conducted over the five-year funding cycle. These projects may address the short-term or long-term outcomes linked to specific interventions, therapies, education and other activites conducted by a CSCC’s patient services core. Outcomes may include assessments of quality-of-life or performance status.

Plans to disseminate research results must be described in detail in patient service project applications. Psychosocial projects may be included. Additional clinical sites outside of the home institution may be included via subcontract.

These projects should be 1-5 years in duration, and a cumulative total of five years of funding may be requested across all patient services projects.

The following are appropriate examples of topics for patient services research projects: Methodologic studies to measure patient-centered outcomes specific to SCD as a function of community-based interventions such as support groups, work incentives, and life skills education (e.g. effectiveness of support groups in reducing visits to the emergency department). Barriers to the utilization of hydroxyurea.

Assessment of the level of satisfaction of patients with participation in Development and field testing of life skills training. Outcome evaluation of early interventions such as newborn screening. Cost-utility analyses to demonstrate the economic benefits of different interventions and their impact on quality of life.

Comparison of different self-care management strategies or approaches to transition patients from pediatric to adult care. Behavioral research studies on: pain management and coping skills (non-pharmacologic interventions); adolescent medicine - e.g., assessing barriers to treatment, enrolling in clinical trials; adult medicine - e.g., achieving optimal transition from pediatric/adolescent to adult care modes.

Patient compliance with treatment regimens; evaluating the effectiveness of intervention strategies to achieve optimal adjustment of the patient and Translational Research Projects These should be projects directed toward the application of new basic science advances in humans. Five years of funding may be requested.

These projects must include both pre-clinical basic investigation and patient-oriented clinical research (see definition below under Special Requirements) over the five-year project duration, with the duration of the basic and clinical portions dictated by the nature of the project. Epidemiologic studies and studies of archived tissues do not qualify for patient-oriented research in this category of research.

Example topics include: Gene transfer for SCD (pre-clinical and pilot clinical New inducers of fetal hemoglobin (pre-clinical and pilot clinical studies). New iron chelators (pre-clinical and pilot clinical studies). Anti-inflammatory agents (pre-clinical and pilot clinical studies).

Blood or marrow transplantation (pre-clinical and pilot clinical studies). Red blood cell hydration agents (pre-clinical and pilot clinical studies). These should be R01-like, basic science investigations for which 5 years of funding may be requested.

Significant preliminary data will be required for these projects. Basic research projects (using in vitro, cell culture systems, research animals, or animal models of sickle cell disease) in the following priority areas are encouraged: The identification in animals of genetic factors with the potential to affect the severity of SCD in humans.

Hematopoietic stem cell transplantation and other cell-based therapies with The development of improved assay systems for high-throughput drug screening with applications to SCD.

Vascular therapy (e.g. utilizing the nitric oxide pathway or other vaso-active Hemoglobin switching (gene regulation) with an eye toward fetal hemoglobin Anti-inflammation therapy, including study of the role of white blood cells Red blood cell hydration therapy (ion transport therapy). Studies of lentiviral globin gene transfer vectors in large animal models.

Studies on the pathophysiology of SCD, e.g. key adhesion events; role of the blood coagulation system; role of redox biology. High-Risk, Short-Term Projects These should be R21-like, high-risk and high-return basic science investigations for which 2 1/2 years of funding may be requested.

These projects should include in vitro, cell culture, or animal investigations directed toward the development of cures or drugs to vastly improve medical management of sickle cell disease. These projects should not include human subjects, but may include human samples, and minimal preliminary data will be required. THESE PROJECTS ARE NOT TO BE SUBMITTED WITH CSCC APPLICATIONS.

Proposals for projects in this category will be selected via a process described below. Examples of appropriate research topics are: High-throughput drug discovery research (chemical genomics) using assays relevant to SCD pathophysiology. Development of non-viral genetic tools and methods to correct the SCD mutation in situ (e.g. by triple helical DNA approaches, homologous recombination etc.).

Novel approaches to modify the regulation of developmental hemoglobin switching (e.g. gamma-globin regulation) for therapeutic purposes in SCD. Pilot investigations of human computational genetics approaches to the identification of genetic risk profiles for certain SCD complications, or for overall disease severity (e.g. whole-genome SNP analysis, Bayesian networks).

The use of comparative genomic approaches to identify and characterize in non-human model organisms (e.g. zebrafish, mice, non-human primates) genetic polymorphisms or loci with therapeutic potential for human SCD (e.g. genes that control known risk factors for SCD such as white blood cell count). Identifying and modeling the effect of genetic modifiers of SCD in the mouse. Modeling novel cell-based therapies for SCD in animal models.

These are examples only. Investigators should not feel limited to the subjects mentioned above, and are encouraged to submit other topics pertinent to the objectives of the RFA. In addition to the six types of research projects for established investigators, the CSCC program will support within the per-Center budget cap one training project for up to five years.

This is the Sickle Cell Scholar project for a single trainee at the senior fellow or junior faculty level. As in the prior competition in 2000 and as with the high-risk, short-term projects in the present competition, Scholar research applications should not be submitted with the main Center application.

Rather, they should be developed upon the announcement of centers in the funding range approximately six months before funding of CSCC applications (i.e. in September, 2007). These supplementary applications will be due to NHLBI staff on February 1, 2008. Scholar research projects 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.

A Scholar career development plan is required in all CSCC applications. The Scholar component, Scholar career development plan, and Scholar eligibility are described in more detail below. See Section VIII, Other Information - Required Federal Citations , for policies related to this announcement.

Organization of the Comprehensive Sickle Cell Center Program for the 2008-2013 Funding Cycle: In May 2005, the Division of Blood Diseases and Resources convened a Midstream Evaluation Committee, comprised of experts from outside the funded NHLBI CSCCs, to evaluate the current CSCC program (2003-2008 funding cycle) and advise the NHLBI on the future structure of this program.

The committee made recommendations based on the criteria of meeting needs within the SCD research community, improving research productivity and breadth, and offering comprehensive care to SCD patients served by this program. These recommendations were subsequently considered by the NHLBI Sickle Cell Disease Advisory Committee in June 2005.

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

CSCC applications will be required to have: at least one inter-Center clinical research project; at least one intra-Center clinical or basic research project; a Scholar (training) career development plan for a senior fellow or junior faculty member to be named later; an administrative core; a clinical core; and a patient services core (other cores are optional).

In addition, in this competition, CSCC applications will be required to have two new components: at least one translational research project and at least one patient services research project. Details on each of these program components follow.

Statistics and Data Management This central, completely independent coordinating center will provide data management and statistical services for all inter-Center clinical protocols in development and active protocols. In addition, the SDMC will be responsible for all statistical and data management services for all intra-Center clinical research projects within the CSCC program.

The SDMC will coordinate and organize the clinical collaboration between the ten centers and their subordinate clinical sites, 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 a Manual of Procedures for collaborative clinical trials; 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 SDMC will continue to maintain, expand, and improve the existing Collaborative Data clinical registry initiated in the prior (2003-2008) funding cycle. The registry contains de-identified, protected health information, as well as quality-of-life, health services utilization, and health economics information collected from patients making clinic visits to Centers within the program.

It will be used as a tool for the Steering Committee to plan collaborative clinical studies during the funding cycle, and to develop standard definitions for the clinical complications of SCD. The SDMC will also oversee (see detail below) a linked DNA and plasma repository which will eventually contain samples for all patients followed in this program who consent to sample donation for research purposes.

The CSCC Collaborative Data registry and repository will be accessible to any interested investigator outside the CSCC program who proposes a legitimate research use. A separate database and sample repository may also be developed for some collaborative (inter-Center) clinical studies carried out within the program, depending on the nature of the study, at the discretion of the Steering Committee.

The SDMC will have the following additional responsibilities: Develop and maintain a secure CSCC-only website for data entry and analysis, for posting of the Manual of Procedures for inter-Center clinical trials, key study documents, and enrollment updates, for multi-author document management, and other miscellaneous uses to be defined by the Steering Committee.

Develop and maintain a public CSCC website that is linked to the NHLBI public homepage, and linked to all ten websites for the individual CSCCs. Develop standards for CSCCs to use for website design, and work with local CSCC web designers (required, see below) to build websites compliant with NHLBI, NIH, and DHHS website policies.

Develop, maintain, and support customized software as needed for CSCC applications on inter-Center clinical projects (e.g. for remote entry of clinical or laboratory data, or for specimen tracking). Execute and pay study-specific subcontracts for central facilities or required specialists in inter-Center clinical projects.

Provide salary support for elected CSCC officers (Chair and Vice-Chair) of the Steering Committee at a level specified by NHLBI. Manage a repository of patient samples (linked to the database for the Collaborative Data project), to be stored at the NHLBI Biological Specimen Repository in Gaithersburg, Maryland.

Coordinate the collection and shipment to the NHLBI repository of DNA and plasma samples for all consenting patients entered into the Collaborative Data registry. Coordinate the management of access to samples by the Steering Committee.

Coordinate the distribution of samples to CSCC and non-CSCC investigators proposing a legitimate research Coordinate, with the NHLBI Project Scientist, the activities of the Steering Committee (SC), independent Protocol Review Committee (PRC), and Data and Safety Monitoring Board (DSMB). Assist CSCC staff in the preparation of protocol and consent documents from inter-Center clinical projects for review by the PRC.

Take responsibility for writing/revising the data management and statistical sections of the clinical protocol.

Assist CSCC staff in the preparation of protocol and consent documents from all funded intra-Center clinical projects for review by the PRC and DSMB; hold a special training session on PRC and DSMB approval processes for all Principal Investigators of funded CSCC intra-Center clinical projects; take responsibility for writing/revising the data management and statistical sections of the clinical protocol; prepare standard protocol and consent form templates to be used for all clinical projects (inter-Center or intra-Center) undergoing DSMB review, and ensure the timely preparation of all final documents for DSMB review; take responsibility for all statistical and data management aspects of all CSCC clinical projects in front of the With the assistance of the Steering Committee, integrate, coordinate and standardize to the extent feasible the funded patient services research and service activities taking place within the patient services cores Coordinate abstract preparation and submission for the annual meeting of the National Sickle Cell Disease Program held in the Prepare statistical and safety reports for all active CSCC clinical projects per the schedule set by the DSMB.

Meet all Food and Drug Administration (FDA) reporting requirements for any inter-Center CSCC clinical projects conducted under IND, including adverse event reporting. For intra-Center clinical projects, this will be a joint effort between the SDMC and local CSCC staff.

Assume responsibility for adverse event reporting on all CSCC clinical studies according to NHLBI, DHHS Office of Human Subjects Protections (OHRP), and DSMB rules and timelines. Assume responsibility for limited clinical monitoring of each clinical site participating in each inter-Center clinical study.

Develop a monitoring plan for each inter-Center study that includes review of compliance with the protocol, compliance with regulatory issues as appropriate, and review Appoint and support as a consultant an independent medical monitor to review adverse event reports in real time.

Assist the Steering Committee and CSCC staff with the preparation of research abstracts and publications Maintain a controlled document facility, and a secure data storage facility with data and power backup plans in case of computer At the direction of the Steering Committee will assist representatives of the new Sickle Cell Disease Clinical Research Network with collaborative activities as needed.

CSCC applicants wishing to also apply for an SDMC award will submit a completely separate application. Because of the existence of the SDMC, large separate data cores will not be funded at individual CSCCs. Statistical support, where necessary for any CSCC project, must be obtained from the central Statistics and Data Management Center.

Funds may not be requested in the administrative core for local statistical expertise and data services for projects at each CSCC. Comprehensive Sickle Cell Centers Collaborative Clinical Research There remains a great need in the SCD research and patient communities for a reliable mechanism to carry out multicenter translational research.

In the next funding cycle, the CSCC program will continue to have a clinical research network-like collaborative clinical research component , with a governing Steering Committee (see formal description below) comprised of ten CSCCs and their subordinate clinical sites, one SDMC (Data Coordinating Center), and the NHLBI Project Scientist.

This part of the program will be responsible for implementing the inter-Center clinical studies prioritized by the Steering Committee. As in the last competition, CSCCs will be responsible for proposing inter-Center protocols that can be adapted by the network, participating in their overall development, conducting the research, and disseminating research findings.

For the 2008-2013 funding cycle, CSCC applications must include a clinical core (included in the budget cap; see description below) to implement locally the collaborative protocols, and must include at least one proposal for an inter-Center collaborative clinical research project.

All such projects submitted by applicants that ultimately receive CSCC awards will be considered for implementation by the Steering Committee when it first meets in April, 2008. The budget requested for an inter-Center collaborative clinical research project may not exceed $400,000 total costs per year at the applicant’s Center, and this will not be included in the per-CSCC budget cap (see below).

In addition, this project must be suitable for inclusion of three or more NHLBI CSCCs, depending on the number of patients required, with the identities of participating centers unknown (by necessity) at the time of application.

Interventional clinical projects proposed should generally be phase II studies of relatively short duration, requiring two-three years to complete (from first enrollment to when the last patient completes the protocol). Epidemiologic studies are allowed. Example topics for these projects are listed above under Examples of Research Topics.

CSCC applicants will submit with each collaborative clinical research project a well-justified budget request for implementation of that project (patient care costs only, without personnel costs) for the single applicant Center. See Application and Submission Information below for more detailed information on the preparation of budgets for inter-Center collaborative clinical research projects.

After the CSCC awards are made, a Steering Committee will meet and consider all inter-Center proposals 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 CSCCs 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 below).

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 SDMC. Approximately $3.

6 million total costs per year will be available program-wide for reimbursement of CSCCs based on patient entry into inter-Center collaborative clinical trials. Additional follow up collaborative projects will be developed during the funding cycle by the Steering Committee, which will include at a minimum the Director from each Center.

It is expected that four to eight collaborative clinical studies will be completed over the course of the five-year funding cycle. The exact number of protocols completed will