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) 710-0267, Email: [email protected].

Telecommunications for the hearing impaired: TTY 301-451-5936.

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

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates

Letters of Intent Receipt Date(s): December 22, 2006
Application Receipt Date(s): January 23, 2007
Peer Review Date(s): August to September, 2007
Council Review Date(s): February, 2008
Earliest Anticipated Start Date: April 1, 2008

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed research
• Name, address, and telephone number of the Principal Investigator
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.
The letter of intent should be sent to:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Two Rockledge Center
6701 Rockledge Drive
Bethesda, MD 20892-7924 (Express 20817)
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: [email protected]

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Two Rockledge Center
6701 Rockledge Drive
Bethesda, MD 20892-7924 (Express 20817)
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: [email protected]

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NHLBI. Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at: https://commons.era.nih.gov/commons/.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.

6. Other Submission Requirements

CSCC applicants should have the ability to enroll up to 50 patients with sickle cell syndromes per year in inter-Center collaborative clinical protocols.

All awardees under this program must agree to the Cooperative Agreement Terms and Conditions of Award in Section VI.2, Administrative and National Policy Requirements.

Dissemination Section:

All Applicants must include in their application a plan for dissemination of research results and such a plan should include:

CSCC applicants should include a statement of willingness to work collaboratively after award with the other funded sites to prepare a joint dissemination plan. SDMC applicants should describe methods to coordinate the dissemination planning and implementation. The SDMC should include a budget and justification for any additional costs of this collaborative effort.

Plan for Sharing Research Data

All applicants must include a plan for sharing research data in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.

The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Section V. Application Review Information

1. Review and Selection Process

Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness by the NHLBI. Incomplete, and/or non-responsive applications will not be reviewed.

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NHLBI in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

• Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score.
• Receive a written critique.
• Receive a second level of review by the National Heart, Lung, and Blood Advisory Council (NHLBAC).

Only the review criteria described in Section V.2 below will be considered in the review process.

In order to be considered for funding, CSCC applications must at a minimum have both a clinical research project and a basic research project with priority scores fundable at the time of the September, 2007 NHLBI Advisory Council meeting. The following will also be considered in making funding decisions for CSCC applications:

• The overall scientific merit of the proposed CSCC as determined by peer review according to the criteria listed below in Section V.2.
• The willingness to collaborate and share data.
• The potential to be a strong contributor to a collaborative clinical research consortium.
• The balance of different types of required subprojects (i.e. clinical , basic, translational, patient services research) among those with high scientific merit.
• Relevance to the overall programmatic balance and priorities of the NHLBI.

The following will be considered in making funding decisions for SDMC applications:

2. Criteria

CSCC Applications

Each CSCC application will receive an overall priority score. That score will be derived based on the following. All research subprojects numbered 1-5 (inter-Center clinical, intra-Center clinical, patient services, basic, and translational respectively) within a CSCC application will receive separate priority scores based on the applicable subproject review criteria listed below. Cores A-D (administrative, clinical , patient services, and any laboratory cores), and the Scholar career development plan (plan 1) within a CSCC application will not receive priority scores, but will either be recommended, or not recommended. Reviewers will assign overall priority scores to CSCCs based on all subproject scores, the CSCC-specific review criteria listed below, and reviewer assessment of the quality of the cores.

The required, separate plans for dissemination of research results (plan 2), data sharing (plan 3), and resource sharing (plan 4) should be assessed by reviewers but should not be considered in assessing scientific merit or assigning priority scores (see below).

Review Criteria for CSCCs

The following review criteria will apply to CSCCs:

Overall Scientific Merit: What is the composite scientific merit of the overall application, including all scored subprojects and cores, based on the detailed review criteria listed below? What is the potential for synergy within the proposed collaborative research program?

Performance in Collaborative Sickle Cell Disease Clinical Trials: Adequacy of the track record of the Principal Investigator in conducting clinical research (enrolling and completing patients on research protocols) and in managing multi-disciplinary teams. For currently funded CSCCs, the reviewers will be provided with the most recent NHLBI Progress Report (Type 5) and a formal Site Visit Report prepared by the currently funded SDMC. For CSCC applicants not currently funded, assessment of track record will be based on the elements included in the Center Overview section described above in Section IV(2). For renewal applications, has the applicant center enrolled a significant number of patients in collaborative CSCC clinical trials in the prior CSCC funding cycle (for the reporting period June, 2004 - February, 2007)? For new applications, does the applicant center have a track record of success enrolling patients in prior multicenter collaborative clinical sickle cell trials?

Participation and Collaboration in Sickle Cell Disease Clinical Trials: For renewal applications, how many collaborative CSCC clinical trials has the applicant center participated in during the prior CSCC funding cycle? For new applications, how many collaborative clinical sickle cell trials has the applicant center participated in during the last ten years? Is the applicant center likely to be a strong team player in the CSCC clinical research consortium? Does the present overall application reflect a willingness to collaborate on the part of the applicant center?

Review Criteria for Inter-Center Clinical Projects

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Does this study address an important clinical issue in the management of SCD? Are the results likely to have a significant positive impact on standards of patient care?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

Innovation: Is the project original and innovative? For example: Does the project challenge existing clinical practice; address an innovative hypothesis or critical barrier to clinical management of SCD? Does the project develop or employ novel approaches, drugs, or devices?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers?

Environment: Does the clinical research infrastructure in which the work will be done contribute to the probability of success? Are adequate numbers of patients available at this center to make a significant contribution toward completion of the proposed trial? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

Competing Trials: Are there now, or are there likely to be in the future active local trials that will compete for patients with the proposed study? Will this have a negative impact on the feasibility of the proposed study?

Collaboration: Do the investigators state their willingness to participate in joint meetings, share methods and data resources, and embark on collaborative efforts to decide overall research direction? Is the research plan flexible enough to accommodate further refinement and integration with other efforts? While it will be a group decision to actually engage in any particular proposed collaborative activities, do the applicants show an understanding of how joint collaborative activities can be conducted in a consortium of this type?

Review Criteria for Intra-Center Clinical Research Projects

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: What is the potential of the proposed study to reduce the clinical severity of SCD and improve quality of life? Does this study address an important clinical issue in the management of SCD? Does this study address a clinical complication of SCD for which we have little data regarding prevalence or severity? What is the likelihood that this study will lead to others that will have a positive impact on patient care?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

Innovation: Is the project original and innovative? For example: Does the project challenge existing clinical practice; address an innovative hypothesis or critical barrier to clinical management of SCD? Does it take advantage of historical research strengths at this center? Does the project develop or employ novel approaches, drugs, or devices?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers?

Environment: Does the clinical research infrastructure in which the work will be done contribute to the probability of success? Are adequate numbers of patients available to answer the questions asked? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

Review Criteria for Patient Services Projects

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Do the proposed projects address a demonstrated unmet need of that Center's local SCD patient population, including family members? Do they address issues important to the larger U.S. SCD patient population? Does this study address an important problem related to the quality of life of SCD patients? If the aims of the application are achieved, how will standards for SCD health services be advanced? How important is this work compared to other related, ongoing SCD health services research the reviewer is aware of?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies within the health services research area as applied to SCD?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Are there personnel listed with expertise in behavioral sciences, social sciences and/or allied health? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project?

Environment: Does the clinical research environment in which the work will be done contribute to the probability of success? Are adequate numbers of patients available to answer the questions asked? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

Dissemination of Results: Are there adequate plans for dissemination of information about effectiveness of the tested interventions or approaches?

Review Criteria for Basic Research Projects

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: What is the potential of the proposed research to lead to a cure for sickle cell disease in the long term? What is its potential to lead to significantly improved medical management of sickle cell disease in the long term? Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

Innovation: How innovative is the proposed research compared to other related, active SCD research the reviewer is aware of? Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

Review Criteria for Translational Research Projects

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: What is the potential of the proposed study to cure or significantly reduce the clinical severity of SCD? Does this study address an important clinical issue in the management of SCD? What is the likelihood that this study will lead to others that will have a positive impact on patient care?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

Innovation: Is the project original and innovative? For example: Does the project address an innovative hypothesis or critical barrier to clinical management of SCD? Does it take advantage of basic research strengths at this center? Does the project develop or employ novel approaches, drugs, or devices?

Investigators: What is the track record of the Principal Investigator in translational research? Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers?

Environment: What is the track record of this institution in translational research? Does the clinical research infrastructure in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Are adequate numbers of patients available to answer the questions asked? Is there evidence of institutional support?

SDMC Applications

The following criteria will be used to assign priority scores to SDMC applications:

2.A. Additional Review Criteria:

In addition to the above criteria, the items listed below should be considered by reviewers in the determination of scientific merit and the priority score for all scored CSCC components when applicable as noted:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).
Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. However, the priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data may be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

2.D. Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates

Not applicable

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the NIH eRA Commons.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

The NoA will include the statement that the Terms and Conditions of this award incorporate the operating guidelines in RFA-HL-06-008.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement U54, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined above.

2.A.1. Principal Investigator Rights and Responsibilities
The Comprehensive Sickle Cell Center (CSCC) program will include non-collaborative, intra-Center functions as well as collaborative, inter-Center functions involving interactions between individual CSCCs. The rights and responsibilities of CSCC Principal Investigators are different for these two types of functions.

CSCCs- Non-Collaborative, Intra-Center Functions

CSCC Principal Investigators (PIs) will be responsible for managing CSCCs. This will include ensuring that all required components for individual CSCCs are in place and functioning, and that all subprojects and cores are making satisfactory progress on approved specific aims. PIs will be responsible for the following CSCC components: high-risk, high-return research, basic research, translational research, patient services research, intra-Center clinical research, all cores, the Scholar, and the Sickle Cell Summer for Science program. All research projects and cores (except high-risk, high-return research), and the Scholar career development plan will be peer reviewed by the ad hoc Special Emphasis Panel that reviews all competing CSCC applications. Nominations for the Scholar and Sickle Cell Summer for Science program will be reviewed by NHLBI staff. High-risk, high-return research will be reviewed by the Steering Committee, with ad hoc experts added as necessary. The PRC will not be involved in peer review of any non-collaborative CSCC components. The DSMB will be involved in approval and oversight of clinical protocols within non-collaborative, intra-Center clinical research projects. The Steering Committee will hold no responsibility for oversight of non-collaborative, intra-Center components. PIs will assemble and convene on a quarterly basis the internal CSCC advisory committee that is the governing body of individual CSCCs and is comprised of the PI , subproject PIs, and core PIs, They will also assemble and convene on an annual basis the external CSCC advisory committee comprised of outside SCD experts. PIs will be responsible for implementing the management plan included in their administrative core applications. The NHLBI Program Official will not be substantially involved in the management of individual CSCCs, He/she will review the progress of each CSCC annually, but will not participate in the design or prioritization of non-collaborative CSCC research. Likewise, the SDMC will not be substantially involved with non-collaborative, intra-Center CSCC components. The SDMC will play an assistive, optional role in the design of non-collaborative CSCC research, but will be responsible for assisting with the preparation and presentation of all intra-Center clinical research protocols before the DSMB. CSCC PIs will be responsible for ensuring that the SDMC is provided protocol information in a timely manner to facilitate this process.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to government rights of access consistent with current HHS, PHS, and NIH policies.

CSCCs- Collaborative, Inter-Center Functions

The CSCC program will include a cooperative, collaborative clinical network consisting of ten individual CSCCs, a single SDMC, and the NHLBI. The network will include a governing Steering Committee, and a dedicated PRC and DSMB. The awardee(s) will have lead responsibilities in all aspects of research design, including any modification of study design; conduct of the study; quality control; data interpretation; preparation of publications; and collaboration with other investigators, unless otherwise provided for in these terms or by action of the Steering Committee. Awardee(s) agree to the governance of all collaborative studies through a Steering Committee. CSCC PIs will be responsible for proposing collaborative, inter-Center research protocols, estimating their costs, participating in their overall development, conducting the research, assuring the quality of patient care and protocol adherence, assuring the accurate and timely transmission of data to the SDMC, and disseminating research findings. CSCCs will submit data to the central SDMC for all collaborative studies, will follow Steering Committee procedures for. data,reporting and publication, and will follow Steering Committee procedures to protect and ensure the privacy of medical and genetic data and records of individuals. The NHLBI Project Scientist, on behalf of the NHLBI, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the Steering Committee.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to government rights of access consistent with current HHS, PHS, and NIH policies.

Support or other involvement of industry or any other third party in the study -- e.g., participation by the third party; involvement of study resources or citing the name of the study or NHLBI support; or special access to study results, data, findings or resources -- may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NHLBI.

Study investigators are encouraged to publish, release publicly and disseminate results and other products of the study in accordance with study protocols and governance. Within three years of the end of the period of NHLBI support for the project, data not previously released and other study materials or products not previously distributed are to be made available to individuals who are not study investigators, provided such release is consistent with the study protocol and governance and with the above paragraph. In addition, study investigators must establish a plan for making data sets and materials available to the scientific community and to the NHLBI immediately upon completion of the three-year period following the end of the period of NHLBI support.

Upon completion of the project, awardees are expected to put their intervention materials and procedure manuals into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community and the NHLBI, for the conduct of research at no charge other than the costs of reproduction and distribution.

SDMC

The Principal Investigator of the SDMC will be responsible for organization, facilitation, and coordination of all collaborative, inter-Center clinical research studies within the CSCC program. This will include protocol development, form development, data collection, identification of vendors and additional clinical sites, data safety and confidentiality, quality assurance, and data analysis. The SDMC will distribute copies of all collaborative datasets to each Principal Investigator upon completion of each study, will follow Steering Committee procedures for data analysis, reporting and publication, and will follow Steering Committee procedures to protect and ensure the privacy of medical and genetic data and records of individuals. The SDMC will make logistical arrangements for meetings of the PRC, DSMB, and Steering Committee. The SDMC will reimburse for travel expenses and disburse honoraria to members of the PRC and DSMB. The SDMC will be responsible for direct payment of patient care funds to all clinical sites participating in collaborative, inter-Center research upon authorization by the NHLBI Program Official. Funds for high-risk, high-return research will be held restricted within the SDMC award and will be awarded by NHLBI staff. The SDMC will hold no responsibility for distribution of these funds.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to government rights of access consistent with current HHS, PHS, and NIH policies.

2.A.2. NIH Responsibilities

The NHLBI, NIH will oversee the organization of the CSCC program for the 2008-2013 funding cycle and thus will be substantially involved with the awardees in a partnership. NHLBI will appoint all members of the PRC and DSMB, and NHLBI staff will serve as Executive Secretaries of these committees. The CSCC Steering Committee Chairperson will be responsible for ensuring that there are well-documented policies, procedures, and bylaws to guide all aspects of Steering Committee activities and operations.

An NHLBI, NIH Project Scientist will have substantial programmatic involvement in collaborative, inter-Center aspects of this program that is above and beyond the normal stewardship role in awards, as described below. The NHLBI Project Scientist will serve on the Steering Committee; he/she or other NHLBI scientists may serve on other study committees, when appropriate. The NHLBI Project Scientist (and other NHLBI scientists) may work with awardees on issues coming before the Steering Committee and, as appropriate, other committees, e.g., recruitment, intervention, follow-up, quality control, adherence to protocol, assessment of problems affecting the study and possible changes in protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment. The NHLBI Project Scientist will not have substantial programmatic involvement in the non-collaborative, intra-Center aspects of this program. There will be one NHLBI Project Scientist for the group of ten CSCC awards.

The NHLBI reserves the right to terminate or curtail the study (or an individual award) in the event of (1) failure to develop or implement a mutually agreeable collaborative protocol; (2) substantial shortfall in participant recruitment, follow-up, data reporting, or quality control; (3) major breach of the protocol or substantive changes in the agreed-upon protocol with which NHLBI cannot concur; (4) attaining of a major study endpoint before schedule with persuasive statistical significance; or (5) human subject ethical issues that may dictate a premature termination.

The NHLBI Program Official will be responsible for the normal scientific and programmatic stewardship of the award (including non-collaborative, intra-Center and collaborative, inter-Center aspects), and will be named in the award notice. He/she will monitor patient recruitment and study progress, ensure disclosure of conflicts of interest, and ensure compliance with NHLBI policies. There will be one NHLBI Program Official for the group of ten CSCC awards, and he/she may be the same person as the NHLBI Project Scientist described above. NHLBI staff (a group of 3-5 individuals) will be responsible for reviewing nominations for the CSCC Scholar and Sickle Cell Summer for Science components.

2.A.3. Collaborative Responsibilities

Awardee(s) agree to the governance of the study through a Steering Committee. Steering Committee voting membership shall consist of the Principal Investigators (i.e., cooperative agreement awardees) of all CSCCs and the SDMC, the NHLBI Project Scientist, and the Chairperson (if not a Principal Investigator). Meetings of the Steering Committee will be held by telephone conference call or in person at one of the CSCC locations or in Bethesda, MD . Each full member will have one vote. There will be twelve votes total with an internal Chairperson, and thirteen votes total with an external Chairperson.

Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

The Steering Committee will be responsible for electing a Chair and Vice-Chair of the Steering Committee. The Chair may be a CSCC Principal Investigator or may be from outside the funded CSCC program. The Steering Committee will be responsible for reviewing high-risk, high-return research proposals, with ad hoc experts added as needed.

An independent Protocol Review Committee (PRC), established by the NHLBI, will provide peer review for each proposed collaborative clinical protocol after awards are made. The PRC will only be responsible for review of collaborative clinical protocols. It will not be responsible for reviewing any other CSCC components. The PRC will meet by telephone conference call. Because the PRC serves as an independent group advisory to the NHLBI, study investigators will not communicate with PRC members regarding study issues, except as authorized by the PRC's Executive Secretary. The independent PRC will be appointed by and be advisory to the NHLBI. It will consist of scientists and physicians with expertise in sickle cell disease research, clinical trial design, biostatistics, enabling technologies, outcome measures, and other areas of expertise as needed. The exact number and duration of protocols supported in the five-year program will depend on the nature and extent of the investigations proposed by the Steering Committee. The PRC will evaluate protocols proposed by the SC based on the importance of the question to be addressed, scientific merit of the experimental design and approach, feasibility, appropriateness for a multicenter clinical network and consistency with NHLBI missions and policies. The PRC will provide a written critique of each proposal and recommendations to the NHLBI. All study protocols performed by the CSCCs must be recommended by the PRC and approved by the NHLBI before initiation. Each CSCC is expected to participate in at least two protocols per year after the first year.

A Data and Safety Monitoring Board (DSMB) will be appointed by the Director, NHLBI to provide overall monitoring of data and patient safety issues related to all CSCC clinical studies; the Steering Committee may suggest potential DSMB members to the NHLBI Project Scientist. Meetings of the Data and Safety Monitoring Board will ordinarily be held in Bethesda, MD. An NHLBI scientist, other than the NHLBI Project Scientist, shall serve as Executive Secretary to the Board.

2.A.4. Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement. The SDMC will compile site visit reports, monthly and quarterly subject enrollment reports, meeting summaries, quarterly Research Unit performance and progress reports, and other reports as needed for the Steering Committee, DSMB, and any other participating NIH sponsors.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Greg Evans, Ph.D.
Leader, Hemoglobinopathies and Genetics Scientific Research Group
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Two Rockledge Center, Suite 10042, MSC 7950
6701 Rockledge Drive
Bethesda, MD 20892-7950
Telephone: (301) 435-0056
FAX: (301) 480-0868
Email: [email protected]

For questions concerning patient services research projects and patient services cores, please contact:

Ellen Werner, Ph.D.
Health Scientist Administrator
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Two Rockledge Center, Suite 10042, MSC 7950
6701 Rockledge Drive
Bethesda, MD 20892-7950
Telephone: (301) 435-0077
FAX: (301) 480-0868
Email: [email protected]

2. Peer Review Contacts:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Two Rockledge Center, Room 7214
6701 Rockledge Drive
Bethesda, MD 20892-7924 (Express 20817)
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: [email protected]

3. Financial or Grants Management Contacts:

Rob Vinson
Grants Operations Branch
National Heart, Lung, and Blood Institute
2 Rockledge Center, Room 7156, MSC 7926
6701 Rockledge Drive
Bethesda, MD 20892-7926 (Express 20817)
Telephone: (301) 435-0166
Fax: (301) 480-3310
Email: [email protected]

Section VIII. Other Information

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of Data and Safety Monitoring Boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central ( PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_Manual.htm).

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002 . The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.

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NIH Funding Opportunities and Notices

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