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:

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 research topics:

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:

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:

Basic Research Projects

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:

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:

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 Center

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:

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 depend on the nature and extent of the investigations proposed by the Steering Committee. Depending on each CSCC’s ability to compete for patient capitation costs, it is anticipated that up to 30% of the total financial resources of each CSCC may be dedicated to multi-Center collaborative clinical research. The independent SDMC (described above) will support protocol development and implementation. All CSCCs will be required to participate in a cooperative and interactive manner with one another, and with the SDMC in all aspects of collaborative clinical research.

The Steering Committee will be the scientific governing body for all inter-Center collaborative clinical research efforts in the CSCC program, and, at a minimum, will be composed of the Directors of the individual CSCCs and SDMC and the NHLBI Project Scientist. The Steering Committee will meet four times in person in the first year of the program (2008-2009), and three times in person per year thereafter. These meetings will be one or two days in duration. All major decisions regarding the commitment of inter-Center protocol funds will be reached by majority vote of the Steering Committee. Each CSCC, the SDMC, and the NHLBI will have one vote. However, the NHLBI will not vote on the prioritization of inter-Center projects. The Chair and Vice-Chair of the SC, neither of whom will be an NHLBI staff member but both of whom may be from outside the NHLBI CSCC program, will be elected by the Steering Committee at its first meeting, to 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 CSCC program, finalizing common clinical protocols, facilitating the conduct and monitoring of the studies, and reporting study results. Topics for the protocols will be proposed and prioritized by the Steering Committee. For each protocol, one Center will take the lead responsibility for drafting the protocol, although the SC will provide input and be responsible for assuring development of a common protocol to be implemented by the Centers. Subcommittees of the SC will be established as desired or necessary; for example, it is envisioned that a Publications and Presentations Committee will facilitate and supervise preparation of manuscripts prior to submission for publication.

Protocol Review Committee and Data and Safety Monitoring Board

An independent Protocol Review Committee (PRC), established by the NHLBI, will provide peer review for each inter-Center clinical protocol proposed by the Steering Committee. In a new function, the PRC will also review all intra-Center clinical protocols in the 2008-2013 funding cycle. While intra-Center projects will be peer-reviewed as a part of competing CSCC applications, that review does not include a detailed review of clinical protocols.

A separate and independent Data and Safety Monitoring Board (DSMB), also established by the NHLBI, will monitor patient safety and review performance for all clinical research studies supported by this program (including all inter-Center, intra-Center, translational, patient services, and Scholar projects). As a part of its monitoring responsibility, the DSMB will submit recommendations to the NHLBI regarding the initiation and continuation of each study. The DSMB will also participate in the development of case report forms for each study, assisting the SDMC. As specific protocols are developed, support for inter-Center protocols will depend on the availability of funds and will be provided on a per-patient basis. All inter-Center and intra-Center clinical protocols must be approved by the PRC, DSMB, and local institutional review boards (IRBs), usually in that order, before they can be initiated. Three to four months will be required to complete all of these review steps. All CSCCs must be willing to accept these approval and funding processes for clinical research protocols.

Clinical Core

In this CSCC 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 new requirement for the 2008-2013 funding cycle is that the clinical core must include both pediatric and adult clinics. However, none of these clinics need be located at the home institution. This new requirement will increase the capacity of the CSCC program to complete trials focused on adult patients, and will also bring the program closer to offering comprehensive (adult plus pediatric) care). Support for one or more data coordinators must be requested in the clinical core of each CSCC application to coordinate electronic data entry and analysis with the central SDMC 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 SCD, 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 SCD patients receive medical care. Thus the clinical core will have a dual function: 1) to provide state-of-the-art treatment to clients with SCD (as it has throughout the history of this program), and 2) to implement inter-Center, collaborative clinical research protocols adopted by the Steering Committee. CSCC applicants may request a clinical core budget of up to $500,000 total costs (direct costs plus facilities and administrative (F&A) costs) per year.

Administrative Core

An administrative core is required in CSCC applications. The administrative core will be responsible for management, coordination, and support of local CSCC activities, including oversight and travel costs for internal and external advisory committees, travel costs for CSCC staff, and support for key personnel such as the Center Director and an administrative assistant. The administrative core application must contain a written plan for management of the CSCC. This plan should address in detail how these complex centers will be governed, and how important decisions will be made. It should include a description of the roles of the CSCC Director, the Internal Advisory Committee, and the External Advisory Committee in the governance of the CSCC. It must also address both collaborative, inter-Center activities and non-collaborative, intra-Center activities. Additionally, in a new requirement for this competition, each CSCC application will be required to request in the administrative core support for a web designer to develop, maintain, and support a public access website that is linked to the CSCC public website developed by the SDMC, that is in turn linked to the NHLBI homepage. Local web designers will work with SDMC staff to develop CSCC websites compliant with existing NHLBI, NIH, and DHHS policies.

Research Projects and Laboratory Cores

In addition to at least one inter-Center collaborative clinical research project (not included in the Center budget cap; as defined above), the following types and numbers of projects will be required in CSCC applications: at least one translational research project; at least one intra-Center clinical or basic research project; and at least two patient services research projects. The budgets for all required projects except inter-Center projects are included in the per-Center budget cap. Laboratory cores that will serve basic science, translational, and/or clinical projects are optional and should only be proposed if they serve at least two projects.

Patient Services Core

As in the prior funding cycle, a patient services core is required in this CSCC competition. Ancillary, but integrated service activities are needed for the successful implementation of the CSCC concept, and additional clinical sites outside of the home institution may be included via subcontract.. The following are examples of responsive patient support activities:

These activities should be well described in CSCC applications, with stated objectives and methodology. All CSCC patient services core activities and patient services research will be coordinated and integrated in the 2008-2013 funding cycle with the assistance of the SDMC.

Translational Research

In a new component, translational research is formally required in CSCC applications. The CSCC program is the centerpiece of the NHLBI’s translational SCD research portfolio, and it offers tremendous opportunities to develop new therapies for SCD. Successful translational research will require close collaboration of clinical and basic researchers at CSCCs, something which has occurred only to a limited extent in the past. The partners in these translational teams can be located far apart from one another, so that geographic proximity is not a limitation. The NHLBI is interested in soliciting and supporting the best possible translational SCD projects possible, involving the best basic research, and the best translationally-oriented clinical centers in the world, regardless of their location. The appropriate scope and some example research topics for translational projects are described above.

High-Risk, Short-Term Research

In order to accelerate the pace of progress towards new therapies for SCD, high-risk, short-term research projects will be included in the CSCC program for the 2008-2013 funding cycle. The appropriate scope and duration, and some example research topics for high-risk, short-term projects are described above. THESE PROJECTS ARE NOT TO BE SUBMITTED WITH CSCC APPLICATIONS. Each of the ten CSCCs to be funded in this competition will be notified in September 2007 of the requirement to submit one of these projects to NHLBI staff on February 1, 2008. These projects will be reviewed by the CSCC Steering Committee (plus ad hoc basic science reviewers) in April 2008 for possible funding shortly thereafter. This process will be repeated at the mid-way point of the five-year funding cycle (approximately August, 2010). Thus each funded CSCC will have the opportunity to conduct two of these pilot research projects during the five-year funding cycle. Approximately $1.5 million total costs (program-wide) will be set aside for this purpose each year.

Sickle Cell Scholar Component

The Sickle Cell Scholar training component will remain a key component of the CSCC in the 2008-2013 funding cycle. It offers career development support in basic or clinical SCD 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 CSCC (i.e. the parent institution, or an institution participating through a consortium arrangement). A Scholar is expected to spend at least 75 percent of his/her effort in SCD-related research under the guidance of an established investigator at the CSCC. The duration of support for a Scholar will be five years maximum. Each CSCC will set aside up to $105,000 per year in direct costs (within its budget cap) for partial salary and research support for a Scholar, to be chosen by a panel of Principal Investigators at each CSCC and with final approval from NHLBI. These funds will be restricted in that they cannot be rebudgeted by the Center Director for other purposes.

Because the CSCC application receipt date precedes the CSCC award date by one and one-half years, Sickle Cell Scholar nominations and research proposals must not be included in CSCC applications. The CSCC program will be best served by allowing additional time for recruitment of Sickle Cell Scholars after the application receipt date. A Scholar career development plan is required in each CSCC application. See Application and Submission Information below for a detailed description of what is required in the Scholar career development plan. A call for Scholar nominations and Scholar research proposals will be issued to all CSCC applicants in the funding range in September, 2007. Detailed instructions will be provided at that time. These materials will then be due to NHLBI on February 1, 2008, two months before the CSCC award date. See Application and Submission Information below for further information on instructions for delayed submission of Sickle Cell Scholar nomination packages to NHLBI.

Sickle Cell Summer for Science Program for High School Students

The Sickle Cell Summer for Science program for high school students will be continued in the 2008-2013 funding cycle. Funds will be available for each CSCC to support summer research experiences for up to three qualified and interested high school students per year. Approximately $222,750 total costs (program-wide) will be set aside for this purpose each year. CSCCs will submit applications for each high school candidate to NHLBI in May or June of each year. NHLBI staff will then review the applications, and funds will be released to CSCCs for each approved application. Detailed instructions will be provided to funded CSCCs in April 2008. In continuing this program, the NHLBI hopes to continue to foster in high school students an interest in a career in SCD research.

With these requirements, the NHLBI is confident that the CSCC program supported for the 2008-2013 funding cycle will meet the need for biomedical research in SCD, patient services and patient services research, and research training/career development for new investigators.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the Cooperative Agreement (U54) award mechanism.

This funding opportunity uses the just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application.

The NIH U54 is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements (Section VI.2), "Cooperative Agreement Terms and Conditions of Award." Plans to continue this RFA beyond the current funding opportunity are indefinite.

As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

2. Funds Available

• The NHLBI intends to commit approximately $23.7 million (total costs) in FY 2008 to fund ten new and/or competing continuation CSCC awards, and one new or competing SDMC award for a period of five years in response to this RFA.
• It is anticipated that the annual awards for CSCCs will be $1,043,000 direct costs maximum (excludes funds for inter-Center clinical protocols and high-risk, short-term research projects). An additional budget of $3,620,000 total costs per year will be available for inter-Center protocol implementation, and $1.5 million total costs per year will be available for high-risk, short-term research. There will be no annual cost escalation within any of these CSCC budget categories. It is anticipated that the annual award for the SDMC will be approximately $1,564,000 direct costs maximum (excluding funds for inter-Center clinical protocol implementation held within the SDMC award, as described below). There will be no annual cost escalation allowed for the SDMC award. Although NHLBI remains committed at this time to funding at the recommended levels, fiscal restraints may necessitate future adjustments in each fiscal year.
• The average amount of CSCC funding per award was $1,017,372 direct costs in FY 2004.
• The anticipated start date of the awards is April 1, 2008.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) new or renewal application(s) if your organization has any of the following characteristics:

• For-profit organizations
• Non-profit organizations
• Public or private institutions, such as universities, colleges, hospitals, and laboratories
• Units of State government
• Units of local government
• Eligible agencies of the federal government
• Domestic institutions
• Foreign institutions are not eligible to apply on their own but they may participate as subcontractors to a domestic institution
• Faith-based or community-based organizations
• Indian/Native American Tribal Government (Federally Recognized)
• Indian/Native American Tribal Government (Other than Federally Recognized)
• Indian/Native American Tribally Designated Organization

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 SCD.

Foreign institutions may participate as subcontractors if they have unique patient or laboratory resources, unusual scientific merit, or documented evidence of prior successful collaborative arrangements. According to current NIH policy, foreign institutions may request up to 8% facilities and administrative (F&A) costs.

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

2. Cost Sharing or Matching

This program does not formally require cost sharing as defined in the current NIH Grants Policy Statement at: http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing

3. Other-Special Eligibility Criteria

Awards for a CSCC and for the SDMC 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 CSCC and SDMC award, but the applications for each must be from different Principal Investigators. The Principal Investigator of a SDMC application cannot be listed in any capacity under personnel on a Center application. SDMC applications need not be from an institution submitting a Center application.

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-0088.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

Special Requirements

The formation within CSCC applications of consortium arrangements between institutions separated by any geographic distance (“virtual centers”) is strongly encouraged, so as to facilitate the assembly of the highest quality SCD research teams and projects possible. Consortium arrangements can also be included in the clinical cores to expand patient access. The intent of this RFA is to support the highest quality SCD research in those research areas with the greatest potential for routine cure or improved treatment of sickle cell disease within 10 years. While consortium arrangements are encouraged, it is incumbent upon the applicants to present evidence that the proposed consortium is feasible, and that it can function well as a productive team. At a minimum, a Center’s administrative core should reside at the parent institution. The clinical core and/or patient service core can either be located at the parent institution, or a subcontract site, or both. The assembly of teams with prior collaborative experience is encouraged but not required. Submission of a schedule of planned meetings, and/or a plan to develop web- or e-mail-based electronic communications infrastructure is encouraged.

Translational projects are here defined as projects that include at least some patient-oriented research. They may include only patient -oriented research, or a combination of basic research and patient-oriented research. Patient-oriented research is research in which an investigator (or colleague) directly interacts with SCD patients. Normal healthy subjects may be included, but only in combination with studies involving patients. In studies involving the use of human specimens, the investigators must have direct interaction with the patient from whom the specimen is obtained and relate the research results to the patient status or outcome for this to be considered a translational project. It is intended that the requirement for investigator interaction with the study participants will eliminate research involving archived tissue. Applicants are encouraged to pursue patient-oriented research on topics related to the development of cures or significantly improved medical management of SCD. Human biomedical studies of completely new or variant treatments, of the etiology of disease severity, or of diagnostic approaches for disease severity will all be considered responsive to the requirement for a translational project. Other types of responsive projects are possible. However, epidemiologic studies or Phase III clinical trials will be considered unresponsive to this requirement..

All research projects that include human subjects must include women and minorities in the study population in representative numbers, unless such inclusion can be demonstrated to be inappropriate. Clinical studies involving interventions or treatments must give consideration to including sufficient numbers of women, minorities and children to conduct valid analyses of subgroup effects.

For CSCC applicants and SDMC applicants, prior experience in collaborative clinical studies is required, and will be used to evaluate the potential of the applicant to work as part of a successful collaborative team.

Center applications that do not include documentation of plans for access to at least 300 patients total with sickle cell syndromes, and access to at least 100 adult patients above 21 years of age (with sickle cell syndromes), will be considered unresponsive to this solicitation, and will be returned to the applicant. Access to this number of patients must be possible within the first year of the funding cycle. In addition, the clinical core must include proposals for both pediatric and adult SCD clinics, and must provide access to both age groups of patients.

SDMC applications must be submitted separately from CSCC applications. SDMC applications submitted within CSCC applications will not be accepted.

CSCC applications that lack a career development plan for a Sickle Cell Scholar will be judged unresponsive and will be returned to the applicant. Likewise any applications lacking any of the other required components (a collaborative clinical research project; patient service research projects; basic, translational and clinical research projects; high-risk, short-term research projects; a clinical core; an administrative core; or a patient service core) or formatting described below will be considered unresponsive to this solicitation, and will not be accepted.

CSCC applications that do not conform to the budget guidelines or budget caps described below will be returned to the applicant without further review..

Applicants should include a statement in the application (and a linked request for travel funds) indicating their willingness to participate in up to 4 meetings per year of the SC, and up to 9 conference calls per year.

Each CSCC will have an Internal Advisory Committee to facilitate internal governance and operations, and to oversee collaborative arrangements among Center investigators. Research collaborations among Center investigators are strongly encouraged. This Internal Advisory Committee should be comprised of the Center Director and the Principal Investigators of its various projects and cores. The Internal Advisory Committee Committee should meet quarterly at a minimum.

Each CSCC will have an External Advisory Committee to periodically review that Center’s progress, and advise the Center staff on optimal Center performance. This committee should must meet at least once per year, and should be comprised of at least three completely independent SCD investigators with no direct connection whatsoever to that Center. Proposed members for this committee should not be named in the Center application.

The CSCC SC will act as a collaborative clinical research unit that will require all individual CSCCs to participate in a cooperative and interactive manner with each other, the SDMC, and the NHLBI. Applicants should explicitly indicate their willingness to:

CSCC Applications

Format

CSCC applications should contain the following elements:

Center Overview

To promote development of a collaborative program among the award recipients, the issues listed below need to be specifically addressed and clearly labeled in the Center Overview section of each CSCC application. This material is in addition to the completed PHS 398 packages for the various research projects and core components listed above.

The local SCD study population should be described in the clinical core application, not in the Center Overview.

Inter-Center Research Projects

Each CSCC applicant should propose at least one inter-Center research project as a model that could potentially be implemented as a collaborative project. Applicants must outline the rationale and background of each proposed study, should demonstrate knowledge of current issues in the medical management of SCD, and, where necessary, should discuss patient benefits and risks for any procedures proposed. An applicant must provide the relevant end point(s), and number and type of patients required for each proposed study based on sample size calculations. Each inter-Center project must contain a budget for implementation of the protocol at the applicant’s center only. This budget must include a detailed reasonable and current estimate of the per-patient cost of implementing the complete protocol. See more detail on budget below.

All inter-Center clinical proposals must contain a complete description of all active, pending, or planned local SCD trials to allow reviewer assessment of competing trials. This includes trials submitted for the NHLBI Sickle Cell Disease Clinical Research Network to be funded in April 2006.

When a pharmaceutical or device collaborator (third party) provides a study agent/device to the Network, a Clinical Trial Agreement (CTA) will be negotiated describing the responsibilities and rights of all parties. The agreement will include, but is not limited to, Investigational New Drug/Investigational Device Exemption (IND/IDE) sponsorship, safety and data monitoring, and access to data. Third party agreements such as this must be developed and implemented in collaboration with the NHLBI.

Scholar Career Development Plan

For the Sickle Cell Scholar component, Scholar candidates must not be nominated in Center applications. However, a career development plan must be submitted with the Center application that includes: a proposed mentor, a description of the proposed mentor’s research experience, relevant mentoring experience, and qualifications to train a young/new scientist; a statement from the proposed CSCC Director of commitment to mentorship for the Sickle Cell Scholar; a description of the local facilities and opportunities for research career development and enhancement at the institution where the Sickle Cell Scholar will work; a description of the proposed career development plan to foster a long-term career in sickle cell disease research; and a detailed recruitment plan, with a timeline, to attract the best candidate possible well in advance of the Center awards date. The Scholar career development plan should be included in the form of one completed PHS 398 package. The Scholar candidate must be at least two years past an M.D., Ph.D., or M.D., Ph.D. degree, and have had some research experience by the Center award date. In addition, the candidate must devote at least 75% effort to the Sickle Cell Scholar project, that will include research and research career development. Proposed mentors must be the Principal Investigator of a subproject or core within the proposed Center, and must devote a minimum 5% effort to mentoring the Sickle Cell Scholar. Since applicants will not know the identity of their Scholar candidate at the time of application submission, and thus will not know if a clinical or basic project will be proposed, it is allowable for both a clinical and laboratory mentor to be proposed in the Scholar career development plan. The proposed mentor(s) must submit a statement of commitment to mentoring the Sickle Cell Scholar, and a statement of commitment to the required 5% minimum level of effort. Funds for the mentor’s effort should be requested within the mentor’s subproject or core, or in the administrative core, but not in the Scholar budget.

While Sickle Cell Scholars must not be nominated in the Center application, for applications in the funding range after the merit review, Scholar nomination packages will be due to NHLBI two months before the anticipated start date (February 1, 2008). This will allow additional time to recruit the best candidates for a long-term career in sickle cell disease research.

Guidelines for CSCC Application Assembly

CSCC Applications must be assembled in the following order:

1- Application face page

2- Composite budget page(s) for whole CSCC, detailed for year 1 and total direct costs only for years 2-5

3- Center Overview

4- Project(s) Numbered 1 (as defined under Format above)

5- Project (s) Numbered 2- if included (intra-Center clinical project)

6- Project (s) Numbered 3

7- Project (s) Numbered 4- if included (basic project)

8- Project (s) Numbered 5

9- Core Labeled A

10- Core Labeled B

11- Core Labeled C

12- Core(s) Labeled D- optional

Plan Numbered 1

Plan Numbered 2

Plan Numbered 3

Plan Numbered 4

APPLICATIONS NOT CONFORMING TO THESE GUIDELINES FOR APPLICATION ASSEMBLY WILL BE CONSIDERED UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED TO THE APPLICANT WITHOUT FURTHER REVIEW.

Budget Information

Budget Guidelines for CSCC Applications- Within the Per-CSCC Budget Cap

For preparation of the budget, CSCC applicants should present a composite budget for all five years of support. This composite budget should include the direct costs for all required CSCC components included in the per-CSCC budget cap of $1,043,000 direct costs per year. These components, and any applicable component budget caps, are listed below:

Annual cost escalation will not be allowed. For each project and core included in the composite budget, a PHS Form 398 packet must be completed (please note that only one PHS Form 398 packet should be used to capture all patient services projects). Detailed budgets should be provided on form pages 4 and 5. The budget pages should be clearly labeled as to which Center activity they address. Applicants should provide adequate budget justification, and all applicable direct costs, and facilities and administrative costs (F&A) for consortium arrangements should be included. In addition, the utilization relationships between research projects and any optional laboratory core(s) that serve those projects should be presented in a table of direct costs, with the columns being the projects and the rows being the core(s).

A CSCC Director is not required to be the Principal Investigator of a subproject but must be listed as the Principal Investigator of the administrative core, where he/she is required to devote a minimum of 15% effort. The minimum level of effort for Principal Investigators of intra-Center clinical, translational, patient services, and basic science research projects, as well as the clinical core, is 20%. A Scholar’s minimum level of effort is 75%, and for his/her mentor is 5%. The minimum level of effort at one site for the local Principal Investigators of inter-Center clinical research projects (listed under personnel in that CSCC’s clinical core) is 10%; however, the actual level of effort required could be much higher depending on which inter-Center projects are approved by the Steering Committee. This should be carefully considered by applicants, and supplemental funding for Lead Principal Investigators from inter-Center protocol funds (outside the per-center cap) may be possible. For any core other than the clinical core, the minimum level of effort for Principal Investigators is 10%.

The following costs should be listed in the administrative core:

Laboratory cores, when proposed, must include a table of direct costs showing the percentage utilization relationships for research projects served by the core, with the columns being the projects and the rows being the core(s).

The patient services core (providing services) should have a budget separate from that for the patient services projects (conducting research).

Five years of funding should be requested for all CSCC components under the per-CSCC budget cap.

Budget Guidelines for CSCC Applications- Outside the Per-CSCC Budget Cap

The budget for the inter-Center collaborative clinical research project(s) is required in CSCC applications but should not be included in the composite CSCC budget. It should be prepared separately, as follows. The budget requested for one such project should not exceed $400,000 total costs, and this is not counted toward the budget cap of $1,043,000 direct costs for year one. Inter-Center project budgets must include costs necessary to implement the proposed inter-Center collaborative project at the applicant’s CSCC only. Costs for collaborating Centers should not be included. This budget should generally not include personnel costs, but compensation for required medical specialists may be included. Support for other necessary personnel (e.g. study Principal Investigator, nurse coordinators and data managers) should be requested in the clinical core. The budget should be based on estimated per-patient costs for implementing the proposed clinical protocol (e.g. for recruitment, study maintenance, clinical lab tests, and drugs) and on the number of subjects that center can enroll in the study. For example, if it is estimated to cost $6,000 direct costs per patient per year to complete the proposed study, and estimated that 20 patients can be recruited at this one Center, then ($6,000 X 20), or $120,000 of patient costs may be requested to complete the study in one year. Per-patient project costs may be requested in the form of patient care costs. This amount should be placed in the Patient Care category on budget page 4 in PHS Form 398. Patient care costs may not be escalated in future years. Applicants should request facilities and administrative (F&A) costs (negotiated institutional rate) for costs placed in the Patient Care category. Applicants should also identify the potential source(s) for any drugs or substances that are unavailable commercially but are being considered for use in the collaborative study. Applicants should explicitly state the number of patients available for the proposed protocol at the applicant‘s CSCC and the total number required throughout the inter-Center collaborative team to complete the study. Per-patient cost estimates should be justified in detail, and up to $400,000 total costs per year may be requested in any inter-Center collaborative clinical research project, depending on the number of patients to be recruited. For inter-Center clinical research projects, one to four years of funding may be requested. The combined allowable maximum for each Center’s clinical core plus protocol implementation costs will be approximately $900,000 total costs per year.

Patient care costs include expenses associated with the conduct of a specific collaborative protocol, such as:

During the grant cycle covered by this RFA, all patient care costs will be awarded to the SDMC, which will then be responsible for distributing them to CSCCs once per-patient budgets are approved for each protocol and recruitment begins.

Note that ongoing annual budgets for inter-Center collaborative projects will be based on the protocols approved by the CSCC Steering Committee and actual awards for inter-Center collaborative clinical projects will be calculated on a per-successfully-enrolled-patient (capitation) basis. Individual CSCCs will be expected to project patient enrollment for a specific protocol during a specified time frame; continuation and level of funding for each Center will be based on actual recruitment and overall performance.

Applications and budget information for high-risk, short-term research projects should not be submitted in CSCC applications.

The award will be subject to administrative review annually.

APPLICATIONS NOT CONFORMING TO THESE BUDGET GUIDELINES WILL BE RETURNED TO THE APPLICANT WITHOUT FURTHER REVIEW.

SDMC Applications

SDMC applications should contain or address the following elements:

Budget Information

Applications should include budgets prepared using Budget Form pages 4 and 5 of PHS Form 398 and should be completed for five budget periods of 12 months each. Maximum allowable direct costs for the SDMC are limited to $1,564,000 per year (excluding patient care costs and costs for high-risk, short-term research projects). There will be no cost escalation allowed in future years. In addition, the SDMC will be actively involved in the distribution of patient care funds for implementation of inter-Center clinical research protocols, and of funds for high-risk, short-term research projects reviewed by the Steering Committee. Approximately $18,100,000 total costs will be available for inter-Center protocols over the five-year funding cycle to support these protocols. SDMC applicants should request $500,000 total costs in the patient care category in year one, and $4,400,000 total costs in the patient care category in each of years two through five to implement inter-Center clinical research protocols. There will be no annual inflationary escalation of patient care costs. It is expected that patient care costs will be greatest in years two through five. Approximately $1.5 million total costs will be available in each year for high-risk, short-term research projects, with no annual cost escalation. These funds will be managed by the SDMC and distributed to each participating CSCC as a fee-for-service arrangement after a protocol or project has been approved and the NHLBI has released the funds for distribution. Genuine protocol costs include the costs of recruitment, patient care, devices, and/or drugs used in the protocols, as well as costs for associated central laboratory assessments (if required). Applicants should provide adequate budget justification, and all applicable direct costs, and facilities and administrative costs (F&A) should be included.

The budget justification should include a comparison of the costs of support of inter-Center versus intra-Center clinical studies.

The minimum level of effort for the Principal Investigator of the SDMC will be 20%. Travel costs for key personnel to attend the annual meeting of the National Sickle Cell Disease Program, and for two people to attend four two-day meetings of the Steering Committee in Bethesda, MD in the first year, and three such meetings in subsequent years, should be requested. In addition, approximately $65,000 direct costs per year should be requested for managing the DSMB and PRC (includes board member honoraria, travel, meeting expenses, and conference calls). Estimated direct costs of $5,000 per year for limited shipping of laboratory specimens and related supplies should also be included in the budget of the SDMC. The costs of document distribution and laboratory data acquisition and management should be included in the SDMC budget. These funds are not intended to cover all shipping costs for all collaborative clinical studies. Any approved study which includes significant additional costs for shipping of samples will have included in the study budget supplemental funds for the SDMC to coordinate study-specific shipping. SDMC applicants should request estimated direct costs of $50,000 per year to provide partial salary support for the elected Chair and Vice-Chair of the CSCC SC, travel support for the Chair to attend two DSMB meetings per year, and limited administrative support.

For budget purposes, SDMC applicants should assume that in the first year, all administrative aspects of the collaborative clinical research component of the program will be organized, and one protocol will be developed and started. For subsequent years, applicants may assume that three to five protocols a year will be active, i.e. either in the protocol development, implementation, or analysis and writing phase.

SDMC applicants should include travel costs for two site visits to fifteen major participating CSCC clinical sites over the five-year funding cycle (assuming one SDMC traveler per visit), and costs for any special functions requiring Protocol Team activities. The goal will be to schedule these visits so as to combine monitoring for multiple active protocols at a given site. Not all protocols may require site visits, and the SC will decide this issue. Costs to the SDMC for financial administration to prepare individual protocol budgets (in collaboration with NHLBI staff), to be the sole distributor of protocol funds, and to monitor in a limited way the use of those funds at clinical sites should also be addressed.

SDMC applicants should request costs for the publication and dissemination of study results.

Budget Guidelines for SDMC Applications- Within the SDMC Budget Cap

The following items must be included or addressed in the SDMC budget cap of $1,564,000 direct costs for year one:

Budget Guidelines for SDMC Applications- Outside the SDMC Budget Cap

The following items must be included in the SDMC budget request (in all years or as noted) but should not be included within the SDMC budget cap:

The award will be subject to administrative review annually.

APPLICATIONS NOT CONFORMING TO THESE BUDGET GUIDELINES WILL BE RETURNED TO THE APPLICANT WITHOUT FURTHER REVIEW.

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

• Charge back of customs and import fees is not allowed.
• Format: every effort should be made to comply with the format specifications, which are based upon a standard US paper size of 8.5" x 11."
• Funds for up to 8% administrative costs (excluding equipment) can now be requested (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-028.html)
• Organizations must comply with federal/NIH policies on human subjects, animals, and biohazards.

• Organizations must comply with federal/NIH biosafety and biosecurity regulations. See Section VI. 2. “Administrative and National Policy Requirements".
• Additional information regarding foreign grants is available in the NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260).

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.

3. Submission Dates and Times