and Human Services (HHS)
EXPIRED
COMPREHENSIVE SICKLE CELL CENTERS
Release Date: December 5, 2000
RFA: HL-01-015 (Reissued as RFA-HL-06-008)
National Heart, Lung, and Blood Institute
(http://www.nhlbi.nih.gov)
Letter of Intent Receipt Date: March 20, 2001
Application Receipt Date: September 25, 2001
PURPOSE
The National Heart, Lung, and Blood Institute (NHLBI) invites applications for
support as Comprehensive Sickle Cell Centers that will offer interactive,
state-of-the-art programs in basic and translational sickle cell disease
research. The primary objective of this Request for Applications (RFA) is to
support ten Comprehensive Sickle Cell Centers, and a Statistics and Data
Management Center, to carry out research focused on the development of cures
or significantly improved treatments for sickle cell disease. This research
will include basic research efforts, inter-center collaborative clinical
research, and local clinical research, with all three focused on the most
promising therapeutic modalities on the horizon today, and each interactive
with the others. In addition to their primary focus in research,
Comprehensive Sickle Cell Centers will also support career development of
young investigators in sickle cell disease research, and support patient
service activities that are focused on the implementation into clinical
practice of the best current models of care and treatment for sickle cell
disease.
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 RFA, Comprehensive Sickle Cell
Centers, is related to one or more of the priority areas. Potential
applicants may obtain a copy of "Healthy People 2010" at
http://www.health.gov/healthypeople/.
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible agencies of
the Federal government. At least one, and preferably more than one
organization listed on each application must be associated with an established
medical institution with facilities and patient populations available for
clinical investigations in sickle cell disease. Underrepresented minority
individuals, women, and persons with disabilities are encouraged to apply as
Principal Investigators.
Awards will not be made to foreign institutions. However, basic science or
clinical projects from foreign institutions may be submitted as subcontracts
if they have unusual scientific merit, unique resources, or documented
evidence of successful collaborative arrangements. In accordance with NIH
policy, facilities and administrative (F&A) costs will not be paid to a
foreign institution.
All current policies and requirements that govern the research grant programs
of the National Institutes of Health (NIH) will apply to grants awarded under
this RFA. Among the disciplines and expertise that may be appropriate for
this program are hematology, pediatrics, medical genetics, pharmacology,
therapeutic development, and clinical trials management.
Awards for a Comprehensive Sickle Cell Center and for the Statistics and Data
Management Center made under this RFA will not be made to the same Principal
Investigator to ensure that data analysis is done independently of data
acquisition. The same institution may apply for both a Comprehensive Sickle
Cell Center and Statistics and Data Management Center award, but the
applications for each must be from different Principal Investigators. The
Principal Investigator of a Statistics and Data Management Center application
cannot be listed in any capacity under personnel on a Center application.
Statistics and Data Management Center applications need not be from an
institution submitting a Center application.
MECHANISM OF SUPPORT
This RFA will use the NIH cooperative agreement (U54) administrative and
funding mechanism of support. Under the cooperative agreement, the NIH
assists, supports, and/or stimulates, and is substantially involved with
recipients in conducting a study by facilitating performance of the effort in
a "partner" role. Details of the responsibilities, relationships, and
governance of a study or research funded under a cooperative agreement are
discussed later in this document under the section entitled SPECIAL
REQUIREMENTS (Terms and Conditions of Award).
Comprehensive Sickle Cell Centers are identifiable units within sponsoring
institutions that are organized around a group of investigators and other
health professionals engaged in ongoing basic and clinical research and
community service related to sickle cell disease. Centers provide support for
multidisciplinary programs of basic, clinical and behavioral research, for
core resources such as laboratory and data analysis, and for quality service
activities including counseling, education, and community outreach. A Center
is headed by a Program Director who is responsible for and provides leadership
to all Center components, and who may also be Principal Investigator on one or
more of the projects contained within the Center. Although individual
components may be somewhat autonomous in the conduct of a specific project,
each is directly accountable to the Center Program Director, who has overall
responsibility for program coordination, implementation, and evaluation. The
Program Director must maintain close contact with NHLBI program administrators
and grants management specialists responsible for each grant. Committees,
internal and external, which provide scientific and fiscal overview of Center
activities are required. In addition, a formal ongoing agreement between the
sponsoring institution and the Center must be developed with an explicit
statement of the commitment of each to the other. In particular, the
sponsoring institution should make a formal commitment of financial support to
all components of a proposed Center specifically defining the resources for
the salaries, equipment, supplies, and facilities that will be available to
the investigators for the entire project period.
Under the guidance of the Program Director, each of the required program
components and services (research, education, and counseling) should be
coordinated and integrated to strengthen the overall program, enhance transfer
of new findings to the clinical setting, and identify new research directions.
Such interaction should be frequent, formalized, and documented to facilitate
continuous exchange of relevant information between projects and components,
thus contributing to greater program productivity and effectiveness. Regular
meetings of project principal investigators, seminars, poster sessions, and
staff lectures are excellent mechanisms for fostering communication and
interaction among Center staff. Finally, each Program Director will be
expected to develop a mechanism for the ongoing evaluation of the
effectiveness and impact of the activities constituting the Center program.
While the NHLBI will continue to assess the quality and performance
characteristics of the program through periodic outside review and staff
evaluation, each of the Centers must consider approaches by which it can
demonstrate how the local program has influenced understanding and practice in
matters related to sickle cell disease.
The total project period for an application submitted in response to this RFA
will be five years. The anticipated award date is April 1, 2003.
FUNDS AVAILABLE
The NHLBI intends to commit approximately $22,000,000 in FY 2003 to fund ten
grants for Comprehensive Sickle Cell Centers, one new grant for a Statistics
and Data Management Center, and per-patient costs for inter-Center
collaborative clinical studies in response to this RFA. Comprehensive Sickle
Cell Center applicants may request a project period of five years and a budget
for total costs (direct costs plus facilities and administrative (F&A) costs)
of up to $1,770,000 per year. Because the nature and scope of the research
proposed may vary, it is anticipated that the size of each award will also
vary. Statistics and Data Management Center applicants may request a project
period of up to five years and a budget for total costs (direct costs plus
facilities and administrative (F&A) costs) of up to $700,000. Statistics and
Data Management Center applications must be submitted separately from
Comprehensive Sickle Cell Center applications. In addition to the $1,770,000
in total costs per year that may be requested in the application,
approximately $3,600,000 of additional total costs per year will be available
program-wide for reimbursement of Comprehensive Sickle Cell Centers based on
patient entry into inter-Center collaborative clinical studies (see Program
Structure below for additional funding caps for required program components).
Although the financial plans of the NHLBI provide support for this program,
awards pursuant to this RFA are contingent upon the availability of funds.
Requests for expensive pieces of equipment that cause the application to
exceed the budget limits cited above will be considered on an individual
basis. However, applicants should make every attempt to include all equipment
in the ceiling amount and must discuss any equipment requests that cause the
application to exceed the ceiling with NHLBI staff early in the planning phase
of the application. Such requests for equipment will require in-depth
justification and will be carefully considered during the review process.
Final decisions will depend on the nature of the justification and the
Institute"s fiscal situation.
Consortium Arrangements
When a grant application includes research activities that involve
institutions other than the grantee institution, it is considered a consortium
effort. Such activities may be included in a grant application, but it is
imperative that a consortium application be prepared so that the programmatic,
fiscal, and administrative considerations are explained fully. Facilities and
Administrative costs paid as a part of a consortium agreement are included in
the limit on the amount of total costs that can be requested. The published
policy governing consortia is available in the business offices of
institutions that are eligible to receive Federal grants-in-iad. Consult the
latest published policy governing consortia before developing the application.
If clarification of the policy is needed, contact Ms. Mary Page at the address
listed under INQUIRIES.
RESEARCH OBJECTIVES
Background
Sickle cell disease is a worldwide health problem and is one of the most
common inherited disorders of man. This genetic blood disorder is probably
the best understood disease at the molecular level and Linus Pauling coined
the term "molecular disease" over forty-five years ago in ascribing the
abnormality to the globin portion of the hemoglobin molecule. Almost ten
years later, the specific molecular defect was identified as a single amino
acid substitution of valine for glutamic acid at position 6 of the beta-globin
polypeptide chain. With the advent of recombinant DNA technology,
investigators were able to further define this genetic mutation in the globin
gene as a change in the codon GAG to GTG. The substitution of glutamic acid
by valine results in a loss of two negative charges on the surface of the
molecule making sickle hemoglobin less soluble than normal hemoglobin upon
deoxygenation. This abnormal hemoglobin aggregates and forms fibers within
the red cells, leading to morphological changes that subsequently affect the
ability of the cells to traverse the microvasculature, causing occlusion of
these small vessels that results in acute pain, and acute as well as chronic
organ damage. In addition, sickle red cells are less resilient than normal
cells, leading to their early destruction and thus a chronic anemia. This
cascade of events caused by the abnormal cell morphology affects the structure
and function of the red cells, blood flow through tissues and organs
throughout the body, and abnormal interaction of these cells with the
microvasculature. The complex pathophysiology of this disorder is a direct
consequence of the change in morphology of red cells containing sickle
hemoglobin. Despite the distinction of being the first described molecular
disease, there is no cure or effective treatment currently available.
The NIH established the Comprehensive Sickle Cell Center Program in 1972, in
response to a Presidential initiative and Congressional mandate. After an
open competition, ten Centers were funded in 1972 and five additional Centers
in 1973. Subsequent RFAs were funded in 1977, 1978, 1983, 1988, 1993, and
1998. Ten Comprehensive Sickle Cell Centers are currently funded. With this
RFA, the Sickle Cell Disease Scientific Research Group, Blood Diseases
Program, Division of Blood Diseases and Resources, National Heart, Lung, and
Blood Institute, announces its plan to fund ten Comprehensive Sickle Cell
Centers, for the period 2003-2008.
Program Structure
Background
In May 2000, the Division of Blood Diseases and Resources convened a Midstream
Evaluation Committee, comprised of experts from outside the funded NHLBI
Comprehensive Sickle Cell Centers, to evaluate the current program and advise
the NHLBI on the future structure of this program. In their deliberations,
the committee made recommendations based on the criteria of needs within the
sickle cell disease research community, and of facilitating and enhancing the
operations of the Comprehensive Sickle Cell Centers. These recommendations
were then considered by the NHLBI Sickle Cell Disease Advisory Committee in
June 2000. As a result of deliberations by these two committees, new or
modified components have been incorporated into this Center competition. The
program will be comprised of ten Centers and a separate Statistics and Data
Management Center. In addition, Centers will be required to have at least one
basic research project, at least one clinical research project, and in two new
required components, at least one collaborative clinical research project (not
included in the budget cap), and a clinical core. Details on each of these
follow.
Statistics and Data Management Center
This central, completely independent resource core will provide data
management and statistical needs for Centers sharing common clinical
protocols, as well as supply statistical support for all research projects
(clinical or basic science in nature) within the Comprehensive Sickle Cell
Center program. The Statistics and Data Management Center will coordinate and
organize the clinical collaboration between the ten centers, and will serve as
the primary unit to collect, manage, statistically analyze, and store clinical
data obtained from the individual Centers. This will require the full range
of coordinating center activities including organization of program
communications through websites, e-mail listservs, conference calls and the
like, study design and protocol development, preparation of forms and Manual
of Operations, training center staff in data collection procedures,
maintaining the study database, monitoring clinical center performance,
providing patient accrual reports, performing appropriate statistical analyses
of study data, and participating in the preparation of study publications.
The Statistics and Data Management Center will continue to maintain, expand,
and improve the existing common patient database initiated in the prior
funding cycle. The common patient database contains data from patients making
clinic visits to Centers within the program. This database will be used as a
tool for the Steering Committee to plan collaborative clinical studies during
the funding cycle, and the samples will be used in these, as well as
potentially many other types of research projects, as determined by the
Steering Committee. A separate database and sample repository may also be
developed for each collaborative clinical research study carried out within
the program, depending on the nature of the study, as judged by the Steering
Committee.
In addition to the traditional duties of a clinical data and coordination
center, the Statistics and Data Management Center will have the following
additional new responsibilities:
o Implement, and/or develop and maintain web-based information technology to
facilitate secure data entry, and data analysis for collaborative clinical
studies
o Oversee and manage a repository of patient samples (linked to the common
patient database), to be stored at the NHLBI Biological Specimen Repository in
Gaithersburg, Maryland. Access to these samples will be controlled by the
Steering Committee
o Coordinate, with the NHLBI Project Scientist, the activities of the Steering
Committee, the Data and Safety Monitoring Board, and independent Protocol
Review Committee
o Develop and maintain a database within the Comprehensive Sickle Cell Center
program with data on the social and financial burden of living with sickle
cell disease. This "quality of life" database will include any information
relevant to the daily quality of the life experienced by individuals living
with sickle cell disease, as well as costs associated with current standard
medical care for this disease
o Collect within the Comprehensive Sickle Cell Center program information
related to health services utilization, and health outcomes. To facilitate
this, a standardized reporting format will be developed across all Centers
that will permit accurate annual reporting to the Institute
Center applicants wishing to also apply for the Statistics and Data Management
Center will submit a completely separate application. Because of the existence
of the Statistics and Data Management Center, large separate data cores will
not be funded at individual Centers. Statistical support, where necessary for
any Center project, must be obtained from the central Statistics and Data
Management Center. Statistical support may not be requested in the
administrative core for local statistical expertise and data services for
projects at each Center.
Comprehensive Sickle Cell Centers
Collaborative Clinical Research
There is at present a great need in the sickle cell disease research and
patient communities for a reliable mechanism to carry out multicenter
translational research. Sickle cell disease is a relatively rare disease,
thus patients from many centers are often required to acquire sufficient data
to allow the statistical significance necessary to produce meaningful results
in clinical studies. A great number of promising preclinical therapies, and
approaches to therapy face significant barriers to study in human subjects,
and so remain untested. In the past, the vast majority of multi-Center
clinical sickle cell disease research has been done outside of the
Comprehensive Sickle Cell Center program. While collaboration on research
projects was encouraged within the program, this was not sufficient to
engender a significant level of collaborative efforts. In this competition,
the Comprehensive Sickle Cell Center program will include for the first time a
collaborative clinical research component for inter-Center collaborative
clinical studies, comprised of ten Centers, one Statistics and Data Management
Center (Data Coordinating Center), and the NHLBI Project Scientist.
Centers will be responsible for proposing protocols that could be adapted by
the network, participating in their overall development, conducting the
research, and disseminating research findings. For the 2003-2008 funding
cycle, Center applications must include a clinical core to implement the
collaborative protocols (included in the budget cap, see description below),
and must include at least one inter-Center collaborative clinical research
project. All such projects submitted by applicants, that receive Center
awards, will be considered for implementation by the Steering Committee (see
description below) in a process described in the following paragraphs. The
budget requested for an inter-Center collaborative clinical research project
may not exceed $360,000 total costs, and this will not be included in the
overall Center cap of $1,770,000 total costs. In addition, this project must
include two or more NHLBI Comprehensive Sickle Cell Centers, depending on the
number of patients required, with the identities of participating Centers
unknown (by necessity) at the time of application. The clinical studies
proposed should be phase I, II, or III studies of relatively short duration,
requiring no more than two years from start to finish. Example topics for
these projects are listed below under Research Scope for Center Applicants
(Clinical Research). Center applicants will submit with each collaborative
clinical research project a well-justified budget request for implementation
of that project (patient care costs only) for the single applicant Center.
See APPLICATION PROCEDURES below for information on how to obtain detailed
instructions for preparation of applications (and budgets) for collaborative
clinical research projects.
After the Center awards are made, a Steering Committee (see description below)
will meet and consider all inter-center collaborative clinical research
projects submitted by funded applicants. Two to three collaborative projects
will be selected for inter-Center collaborative studies, and these will be
carried out using the clinical cores of the participating Centers as
infrastructure, with each Center reimbursed on a per-patient basis for patient
entry from funds dedicated to this purpose (outside of per-Center budget caps,
see Funds Available above). The intent of this RFA is to use these capitation
supplements (i.e. per-patient costs for implementation of protocols) as
incentives for participation in inter-Center collaborative clinical research.
Capitation supplements will be made at the discretion of NHLBI Program and
Grants Management staff, with input from the Statistics and Data Management
Center. Approximately $3,600,000 total costs per year will be available
program-wide for reimbursement of Comprehensive Sickle Cell Centers based on
patient entry into inter-Center collaborative clinical projects. It is
expected that three to six collaborative clinical studies will be completed
over the course of the five year funding cycle, with followup collaborative
projects (to the initial two to three studies) developed during the funding
cycle by the Steering Committee, which includes at a minimum the Director from
each Center. The exact number of protocols supported in the five year program
will depend on the nature and extent of the investigations proposed by the
Comprehensive Sickle Cell Center Steering Committee. Depending on each
Center"s ability to compete for patient capitation costs, it is anticipated,
based on the NHLBI"s estimate of available funds for the collaborative
clinical research component (see FUNDS AVAILABLE above), that up to 30% of the
total financial resources of each Center could be dedicated to multi-Center
collaborative translational research.
A separate Statistics and Data Management Center (see below) will support
protocol development and provide sample size calculations, statistical advice,
common questionnaires, data analysis, and coordinate the activity of the Data
and Safety Monitoring Board, The Protocol Review Committee and overall study
coordination and quality assurance. All individual Centers will be required
to participate in a cooperative and interactive manner with one another, and
with the Statistics and Data Management Center in all aspects of collaborative
clinical research.
The Steering Committee will be the scientific governing body for all inter-
Center collaborative clinical research efforts in the Comprehensive Sickle
Cell Center program, and, at a minimum, will be composed of the Directors of
the individual Comprehensive Sickle Cell Centers and Statistics and Data
Management Center, the NHLBI Project Scientist, and a Grants Management
Specialist. The Steering Committee may meet as often as four times in the
first 12 months of the study, and three times per year thereafter. All major
scientific decisions will be determined by majority vote of the Steering
Committee. Each Clinical Center, the Statistics and Data Management Center,
and the NHLBI will have one vote. The Chairperson, who will be someone other
than an NHLBI staff member and may be someone from outside the NHLBI
Comprehensive Sickle Cell Center program, will be selected by the Director,
NHLBI, by the end of the second meeting of the Steering Committee. The first
meeting of the Steering Committee will be convened by the NHLBI Project
Scientist. The Steering Committee will have primary responsibility for the
general organization of the collaborative clinical component of the
Comprehensive Sickle Cell Center program, finalizing common clinical
protocols, facilitating the conduct and monitoring of the studies, and
reporting study results. Topics for the protocols may be proposed and
prioritized by the Steering Committee. For each protocol, one Center will
take the lead responsibility for drafting the protocol, although the Steering
Committee will provide input and will be responsible for assuring development
of a common protocol to be implemented by the Centers. Subcommittees of the
Steering Committee will be established as necessary, for example, it is
envisioned that a Publications and Presentations Committee will facilitate and
supervise preparation of manuscripts prior to submission for publication.
An independent Protocol Review Committee, established by the NHLBI, will
provide peer review for each protocol. A Data and Safety Monitoring Board
(DSMB), also established by the NHLBI, with input from the Steering Committee,
will monitor patient safety and review performance of each study. As a part
of its monitoring responsibility, the DSMB will submit recommendations to the
NHLBI regarding the continuation of each study. As specific protocols are
developed, support will depend on the availability of funds and will be
provided on a per-patient basis. All the Centers must be willing to pursue
this funding arrangement for each new protocol conducted. Clinical protocols
must be approved by local institutional review boards and the Comprehensive
Sickle Cell Center Protocol Review Committee before initiation.
Clinical Core
In this Center competition, the clinical core will be a required key component
of the collaborative research effort, as it will constitute the collaborative
clinical research infrastructure, including personnel, at each Center. A
minimum part-time data coordinator must be requested in the clinical core of
each Center application to coordinate electronic data entry and analysis with
the central Statistics and Data Management Center staff. In addition, the
clinical core will continue to serve its traditional functions of applying the
best current models of clinical care to pediatric and adult patients with
sickle cell disease, and of collecting patient samples for research studies to
be carried out at that Center. The clinical core will provide partial salary
support for physicians, nurses, nurse-coordinators, data coordinators, and
secretarial staff who staff the clinics where sickle cell disease patients
receive medical care. Thus the clinical core will both provide state-of-the-
art treatment to clients with sickle cell disease (as it has throughout the
history of this program), and implement the collaborative clinical research
protocols adopted by the Steering Committee. Centers are allowed to submit
requests for a clinical core budget not to exceed $400,000 total costs (direct
costs plus facilities and administrative (F&A) costs) per year.
Research Projects and Laboratory Cores
In addition to at least one inter-Center collaborative clinical research
project (not included in the budget cap, as defined above), at least one basic
science project, and at least one clinical project (included in the budget
cap, may be collaborative) are required. Laboratory cores that will serve
basic science and/or clinical projects are optional. With these requirements,
the Comprehensive Sickle Cell Center program supported through this
solicitation will meet the need for translational research in sickle cell
disease, and will continue to support basic science research as well. The
scope of possible research projects is described below under Research Scope.
Sickle Cell Scholar Component
This component is a requirement of this solicitation, and offers career
development support in basic or clinical sickle cell disease research to young
investigators, or new investigators trained in other fields. Candidates for
Sickle Cell Scholars should have at least two years of postdoctoral
experience, and may propose to work at any institution participating in a
Comprehensive Sickle Cell Center (i.e. the parent institution, or an
institution participating through a consortium arrangement). Sickle Cell
Scholars are expected to spend at least 75 percent of his/her effort in sickle
cell anemia-related research under the guidance of an established investigator
at the Center. The duration of support will be a maximum of five years. Each
Center will set aside $90,000 per year in direct costs for the exclusive
purpose of providing partial salary and research support for a Sickle Cell
Scholar who will be chosen by a panel of Principal Investigators at each
Center with final approval from NHLBI. These funds will be restricted in that
they cannot be rebudgeted by the Program Director for other purposes.
Because the application receipt date is one and one half years before the
Center award date, Sickle Cell Scholars must not be nominated in the Center
applications. However, a career development plan will be required in each
Center application. See APPLICATION PROCEDURES below for a detailed
description of what is required in this application. The NHLBI Comprehensive
Sickle Cell Center program will be best served by allowing additional time for
recruitment of Sickle Cell Scholars after the application receipt date. For
applications that fall in the funding range after the merit review, the
deadline for submission of Sickle Cell Scholar nomination packages to NHLBI
will be approximately six months before the Center award date. See
APPLICATION PROCEDURES below for further information on instructions for
delayed submission of Sickle Cell Scholar nomination packages to NHLBI.
Patient Service Cores
Inclusion of patient service activities such as sickle cell disease education,
counseling, community outreach, or hemoglobin diagnosis remains a requirement
in this program for the 2003-2008 funding cycle. Funds for these services
should be organized and requested in a patient service core. The scope of
possible responsive activities is described below under Research Scope.
Research Scope for Center Applicants
Although significant progress has been made over the past two decades in
understanding the pathophysiology of sickle cell disease, many unresolved
questions remain. Basic and clinical research projects in the Comprehensive
Sickle Cell Centers program should take advantage of new scientific advances
to address the broad and interdisciplinary spectrum of research hypotheses
related to sickle cell disease that will ultimately lead to routine cures, or
to improvement in modalities for routine treatment and prevention of
complications of this disorder. The scope of responsive research areas is
broad. However, emphasis is placed on therapeutic modalities likely to have
an impact on patient care in the near-term, and on the development of
innovative approaches in these areas. Research projects for Sickle Cell
Scholars should be developed after submission of the Center application, and
can be related to any of the clinical or basic research areas listed above, as
long as they are consistent with the overall goals of this solicitation.
Basic Science Research
Basic research projects (using in vitro, cell culture systems, or animal
models of sickle cell disease) in the following priority areas are encouraged:
o Anti-adhesion therapy (vascular pathobiology of sickle cell disease)
o Hematopoietic stem cell transplantation
o Vascular therapy (e.g. using nitric oxide, or other vasoactive agents)
o Fetal hemoglobin induction therapy
o Gene transfer as a potential therapeutic modality
o Anti-inflammation therapy, including study of the role of white blood cells
in sickle cell disease vaso-occlusion
o Red blood cell hydration therapy (ion transport therapy)
o Study of non-red cell contributors to sickle cell disease pathophysiology,
such as the blood coagulation system
o The development of new methods for improved hemoglobin diagnosis
THESE ARE EXAMPLES ONLY. INVESTIGATORS SHOULD NOT FEEL LIMITED TO THE
SUBJECTS MENTIONED ABOVE AND ARE ENCOURAGED TO SUBMIT OTHER TOPICS PERTINENT
TO THE OBJECTIVES OF THE RFA.
Clinical Research
At least one collaborative, inter-Center clinical research project (not
included in the budget cap) is required in Center applications. These
projects should include two or more NHLBI Comprehensive Sickle Cell Centers,
and should include phase I, II, or III studies of relatively short duration,
to be completed within two years (start to finish). In addition to this
requirement, at least one clinical research project (included in the budget
cap) is also required in Center applications. This second requirement may be
met with clinical studies that are either single-Center or multi-Center in
origin. Multi-Center clinical studies may include any sickle cell Center
(comprehensive or not) that can contribute clients and investigators to carry
out clinical studies. Subcontract Centers may be from outside the NHLBI
Comprehensive Sickle Cell Center program. For both the collaborative
clinical, and clinical research requirements, focused projects in the
following priority areas of clinical sickle cell disease research are
encouraged:
o Evaluation of nonmyeloablative conditioning regimens for hematopoietic stem
cell transplantation in pediatric clients with sickle cell disease
o Evaluation of vasoactive agents (e.g. nitric oxide gas) as potential
therapeutic agents for specific complications of sickle cell disease, such as
acute chest syndrome, or pulmonary hypertension
o Evaluation of new fetal hemoglobin inducing agents with respect to their
effect on the rate of vasoocclusive pain crises
o Evaluation of anti-adhesion agents (e.g. monoclonal antibodies) on specific
complications of sickle cell disease
o Evaluation of gene transfer in the context of autologous hematopoietic stem
cell transplantation as a potential therapeutic modality
o Evaluation of existing anti-inflammatory agents (now in use for other
conditions) as potential therapeutic agents for specific complications of
sickle cell disease
o Evaluation of the effect of nutritional supplements on growth rates, and
resting energy expenditure in clients with sickle cell disease
o Evaluation of the effect of red blood cell ion transport inhibitors on
specific complications of sickle cell disease
o Evaluation of the effect of transfusion therapy on specific complications of
sickle cell disease
o Evaluation of improved iron chelators in the context of transfusion therapy
o Preliminary comparison of existing therapeutic modalities for specific
complications of sickle cell disease
o Validation of early predictive markers for specific complications of sickle
cell disease
o Behavioral research studies on: pain management (non-pharmacologic
interventions), newborn (or perinatal/neonatal) medicine - e.g., outcome
evaluation of early intervention in newborn screening, adolescent medicine -
e.g., assessing barriers to treatment, enrolling in clinical trials,
adult medicine - e.g., achieving optimal transition from pediatric/adolescent
to adult care modes,
patient compliance with treatment regimens, evaluating the effectiveness of
intervention strategies to achieve optimal adjustment of the patient and
family to sickle cell disease
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.
Patient Service Core Activities
Ancillary but integrated service activities are needed for the successful
implementation of the Comprehensive Sickle Cell Center concept. These other
activities include education, counseling, community outreach, or hemoglobin
diagnosis. The following are examples of responsive patient support
activities:
o Education - sponsoring activities that provide information about sickle cell
disease to health care professionals at the Center and in the community or
region that the Center serves, and to patients, their families and communities
o Community Outreach - developing a liaison between the Center and the
community which would inform the community about Center programs and provide
community input into their development
o Counseling - all counseling should be non-directive and aimed at helping
counselees to make informed decisions about health-related and/or family
planning issues that they believe to be in their best interest
o Diagnostic Testing - providing facilities where accurate diagnosis,
including hemoglobin genotyping, can be performed
Although patient service cores will not carry out research projects, their
proposed activities should be well described in Center applications, with
stated objectives and methodology.
SPECIAL REQUIREMENTS
For Center applicants, and Statistics and Data Management Center 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 150 clients with sickle cell syndromes (including at least 100
clients with SS homozygous sickle cell disease) will be considered
unresponsive to this solicitation, and will be returned to the applicant.
Access to this number of clients must be possible within the first year of the
funding cycle. In addition, planned access within the clinical core to both
pediatric and adult sickle cell disease clients within a single Center is
encouraged.
Statistics and Data Management Center applications must be submitted
separately from Center applications. Statistics and Data Management Center
applications submitted within Center applications will not be accepted.
The formation 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 sickle cell disease 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 sickle cell disease 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.
Center 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, basic and clinical research projects,
a clinical core, or a patient service core) will be considered unresponsive to
this solicitation, and will not be accepted.
Center applications that do not conform to the budget guidelines, format, and
caps described in APPLICATION PROCEDURES will be considered unresponsive, and
will not be accepted.
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 Steering Committee, and up to 9 conference calls per
year.
Each Comprehensive Sickle Cell Center 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.
Each Comprehensive Sickle Cell Center 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 sickle
cell disease investigators with no direct connection whatsoever to that
Center. Proposed members for this committee should not be named in the Center
application.
Terms and Conditions of award
The cooperative agreement is an award instrument establishing an "assistance"
relationship (in contrast to an "acquisition" relationship) between NHLBI and
a recipient, in which substantial NHLBI scientific and/or programmatic
involvement with the recipient is anticipated during performance of the
activity. The NHLBI purpose is to support and/or stimulate the recipient"s
activity by involvement in and otherwise facilitating the activity in a
"partner" role, but avoiding a dominant role, direction, or prime
responsibility. The terms and conditions, below, elaborate on these actions
and responsibilities, and the awardee agrees to these collaborative actions
with the NHLBI Project Scientist toward achieving the project objectives. It
is anticipated that these terms and conditions will enhance the relationship
between the NHLBI staff and the Principal Investigator(s), and will facilitate
the successful conduct and completion of the study. These agreements will be
in addition to, and not in lieu of, the relevant NIH procedures for grants
administration. The terms will be as follows:
1. The awardee(s) will have lead responsibilities in all aspects of their
protocols, including any modification of study design, conduct of the study,
quality control, data analysis and interpretation, preparation of
publications, and collaboration with other investigators, unless otherwise
provided for in these terms or by action of the Steering Committee.
2. The NHLBI Project Scientist will serve on the Steering Committee, he/she or
another NHLBI scientist may serve on other study committees, when appropriate.
The NHLBI Project Scientist (and the other cited 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, standards and methods, adherence to protocol, assessment of
problems affecting the study and potential changes in the 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.
3. 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) and the NHLBI Project
Scientist. Meetings of the Steering Committee will ordinarily be held by
telephone conference call or in the Washington DC Metropolitan Area.
4. A Data and Safety Monitoring Board will be appointed by the Director, NHLBI
to provide overall monitoring of interim data and safety issues, the Steering
Committee may nominate members for this Board. Meetings of the Data and
Safety Monitoring Board will ordinarily be held in Bethesda, MD. The NHLBI
Project Scientist shall serve as Executive Secretary to the Board. An
independent Protocol Review Committee, established by NHLBI, will provide peer
review for each protocol.
5. Awardees will retain custody of and have primary rights to their data
developed under these awards, subject to Government rights of access
consistent with current HHS, PHS, and NIH policies. The collaborative
protocol and governance policies will call for the continued submission of
data centrally to the coordinating center for a collaborative database, the
submittal of copies of the collaborative data sets to each Principal
Investigator upon completion of the study, procedures for data analysis,
reporting and publication, and 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 (i.e. cooperative agreement awardees).
6. Support or other involvement of industry or any other third party in the
study -- e.g., participation by the third party, involvement of project
resources or citing the name of the project or the NHLBI support, or special
access to project 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..
7. Awardees are encouraged to publish and to publicly release and disseminate
results, data and other products of the study, concordant with the study
protocol and governance and the approved plan for making data and materials
available to the scientific community and the NHLBI. However, during or
within three years beyond the end date of the project period of NHLBI support,
unpublished data, unpublished results, data sets not previously released, or
other study materials or products are to be made available to any third party
only with the approval of the Steering Committee and in accordance with
paragraph 6.
8. The NHLBI reserves the right to terminate or curtail the study (or an
individual award) in the event of (a) failure to develop or implement a
mutually agreeable collaborative protocol, (b) substantial shortfall in
participant recruitment, follow-up, data reporting, quality control, or other
major breach of the protocol, (c) substantive changes in the agreed-upon
protocol with which NHLBI cannot concur, (d) reaching a major study endpoint
substantially before schedule with persuasive statistical significance, or (e)
human subject ethical issues that may dictate a premature termination.
9. Upon completion of the project, Field Center 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.
10. Any disagreement that may arise in scientific/programmatic matters (within
the scope of the award), between award recipients and the NHLBI may be brought
to arbitration. An arbitration panel will be composed of three members--one
selected by the Steering Committee (with the NHLBI member not voting) or by
the individual awardee in the event of an individual disagreement, a second
member selected by NHLBI, and the third member selected by the two prior
members. This special arbitration procedure in no way affects the awardee"s
right to appeal an adverse action that is otherwise appealable in accordance
with the PHS regulations at 42 CFR part 50, Subpart D and HHS regulation at 45
CFR part 16, or the rights of NHLBI under applicable statutes, regulations and
terms of the award.
11. These 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 part 74, and other HHS, PHS, and NIH grant
administration policy statements.
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of the NIH that women and members of minority groups and
their sub-populations must be included in all NIH-supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification are 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 research involving human subjects should read the
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research," published in the NIH Guide for Grants and Contracts on
August 2, 2000
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html),
a complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The
revisions relate to NIH defined Phase III clinical trials and require: a) all
applications or proposals and/or protocols to 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) all
investigators to report accrual, and to conduct and report analyses, as
appropriate, by sex/gender and/or racial/ethnic group differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.
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 that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html.
Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES. Program staff may also provide additional relevant
information concerning the policy.
URLS IN NIH GRANT APPLICATIONS OR APPENDICES
All applications and proposals for NIH funding must be self-contained within
specified page limitations. Unless otherwise specified in an NIH
solicitation, internet addresses (URLs) should not be used to provide
information necessary to the review because reviewers are under no obligation
to view the Internet sites. Reviewers are cautioned that their anonymity may
be compromised when they directly access an Internet site.
LETTER OF INTENT
Prospective applicants for Comprehensive Sickle Cell Centers, or for the
Statistics and Data Management Center, are asked to submit by March 20, 2001 a
letter of intent that includes a descriptive title of the proposed research,
the name, address, and telephone number of the Principal Investigator, the
identities of other key personnel and participating institutions, and the
number and title of the RFA in response to which the application may be
submitted. 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 NHLBI staff to estimate the potential review workload
and plan the review.
The letter of intent is to be FAXed or mailed to Dr. Deborah Beebe at the
address listed under INQUIRIES.
APPLICATION PROCEDURES
The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants. These forms are available at most institutional
offices of sponsored research and may be obtained from the Division of
Extramural Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-710-0267, E-mail: GrantsInfo@nih.gov. The PHS 398 application kit is also
available on the Internet at http://grants.nih.gov/grants/forms.htm. The
page limitations described in the form PHS 398 (rev. 4/98) instructions are to
be considered as applicable to all clinical and basic science proposals or
subprojects, cores (administrative, clinical, patient service, and any
laboratory cores), and for the career development plan for Sickle Cell
Scholars (see below).
Material to Include in the Application:
Center Applicants
o at least one inter-Center collaborative clinical research project (whose
budget will not be counted toward the applicant"s budget cap)
o at least one clinical research project (included in the budget cap, and can
be multi-Center, or single-Center in nature)
o at least one basic science research project
o a career development plan for a Sickle Cell Scholar
o a description of external and internal advisory committees (naming of
members of the external advisory committee is not required)
o statement of willingness to participate in Steering Committee meetings up
to 4 times per year
o a clinical core (with a minimum part-time data manager, and documented
access to at least 150 clients with sickle cell syndromes)
o an administrative core
o a patient service core
Laboratory cores will be optional.
Research projects for Sickle Cell Scholars must not be submitted with the
Center application.
Applications should be assembled in the following order: application face
page, composite budget page(s), then the PHS Form 398 packages for the inter-
Center collaborative clinical research project, other clinical project(s),
basic science project(s), administrative core, clinical core, patient service
core, any other cores, and lastly the Sickle Cell Scholar career development
plan.
To promote development of a collaborative program among the award recipients,
the issues discussed below need to be addressed in each Center application.
This material is in addition to the submission of a research plan for the
basic science and clinical research projects addressed in the section entitled
Research Scope above.
o Qualifications and experience. Applicants for Centers must have experience
and expertise to conduct clinical studies in sickle cell disease. Prospective
Centers must have an established research program in the area of sickle cell
disease
o Study population. Center applicants must have access to at least 150
persons with sickle cell syndromes in the first year of the funding cycle. Of
these, at least 100 must have the SS (homozygous sickle cell disease)
genotype. Clinical research study populations should include children and
approximately 50 percent females. The application should include a
description of the pool of potential study participants--the age range,
ethnic/racial distribution, estimated distribution of patients with different
variants of sickle cell disease, and recruitment source. Access to at least
150 patients for various protocols over the five year period is expected, but
it is not anticipated that all 150 patients will be enrolled in research
protocols at any one time, and it is possible that an individual patient may
be enrolled in more than one study. Patient access may be accomplished by
establishing links with other groups besides the applicant institution. There
must be a well described plan to link the individual Centers with community
health care providers such as HMOs, clinics, or private practice physicians to
ensure adequate numbers patients for clinical studies of therapeutic agents
and management strategies
o Willingness to participate in collaborative clinical research. Applicants
should state their general support of collaborative research and interaction
with other Centers, the NHLBI, and the Statistics and Data Management Center
through the program structure described in this solicitation. Applicants
should discuss their willingness, and that of the institutions involved, to
pursue a per-patient basis (capitation) of operational costs for each
protocol. Center applicants must be able to interact with the Statistics and
Data Management Center (through the peripheral data coordinator in each
Center"s clinical core) to transmit and edit data and should discuss their
capability to participate in a distributed data entry system
o Institutional resources for patient care and follow-up including personnel,
space, and special laboratory facilities should be described. Applicants from
institutions that have a General Clinical Research Center (GCRC) funded by the
NIH National Center for Research Resources may wish to identify the GCRC as a
resource for conducting the proposed research. If so, a letter of agreement
from either the GCRC Program Director or Principal Investigator should be
included with the application
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 Comprehensive Sickle Cell Center 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
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.
The proposed mentor must be the Principal Investigator of a subproject within
the proposed Center, and must devote a minimum 5% effort to mentoring the
Sickle Cell Scholar. The proposed mentor 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.
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 approximately 6 months before the
anticipated start date. This will allow additional time to recruit the best
candidates for a long-term career in sickle cell disease research.
Statistics and Data Management Center Applicants
The issues discussed below need to be specifically addressed in each
application for the Statistics and Data Management center:
o Qualifications and experience. Applicants for a data coordinating center
must demonstrate experience in the area of hematology and demonstrated
expertise coordinating multi-Center clinical trials in all phases: protocol
and manual of operations development, staff training in study procedures,
research instrument development, data collection and management, quality
assurance, data analysis, distributed data entry, electronic communications,
administrative management and coordination
o Study design and management. Statistics and Data Management Center
applicants should discuss various aspects of study design that would be
important in developing clinical protocols, for example: eligibility criteria,
baseline and outcome measures, methods of randomization, important
considerations for making sample size and power calculations, methods and
frequency of data collection and entry, monitoring accuracy of data
collection, quality control procedures including training and certification
for multiple protocols, some of which may occur simultaneously, managing
labeling and handling of blood samples, and plans for statistical analysis.
Applicants should also describe their familiarity with sickle cell disease and
plans for managing the Data and Safety Monitoring Board and the Protocol
Review Committee
o The Statistics and Data Management Center should delineate how laboratory
specimens will be handled. Laboratories responsible to the Statistics and
Data Management Center will manage specimens and laboratory studies as
required by the Steering Committee. The costs of performing specific
laboratory tests will be budgeted as a part of the per-patient costs of each
Center. The costs of specimen shipment as well as laboratory data acquisition
and management will be a part of the budget of the Statistics and Data
Management Center
Budget and Related Issues
Centers
For preparation of the budget, the applicant should present a composite budget
for all five years of support. This composite budget should include the
direct costs for each required Center component included in the Center cap of
$1,770,000 (i.e. basic and clinical research projects, the Sickle Cell
Scholar, the clinical core, and all other cores). The budget for the inter-
Center collaborative clinical research project(s) should not be included in
the composite Center budget, it should be prepared separately as described
below. Budget Form pages 4 and 5 of PHS Form 398 should be completed for each
Center component listed in the composite budget. 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 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 Comprehensive Sickle Cell Center Director will be required to be the
Principal Investigator of at least one subproject at a minimum of 20% level of
effort. The Director will also be required to devote a minimum of 15% effort
in the administrative core. The minimum level of effort for basic science
Project Directors, single-Center clinical Project Directors, and Core
Directors will be 20%. The minimum level of effort at one site for Principal
Investigators of collaborative clinical research projects (supported though
that Center"s clinical core) will be 10%. Travel costs for key personnel to
attend the annual meeting of the National Sickle Cell Disease Program, and for
two people to attend four meetings of the Steering Committee in Bethesda, MD
in the first year, and three meetings in subsequent years, should be
requested. In addition, travel costs for the minimum three members of the
External Advisory Committee should also be requested.
Budget Check List and Format for Comprehensive Sickle Cell Center applicants:
The following components must be included in the Center budget cap of
$1,770,000 total costs, and each should have its own budget pages 4 and 5 from
PHS Form 398 in the Center application:
o Basic Research Project(s) - a minimum of one basic science project is
required
o Clinical Research Project(s) - a minimum of one clinical project is
required. This project can be multi-Center or single-Center in nature
o Sickle Cell Scholar - this component is required and provides $90,000 direct
costs plus facilities and administrative (F&A) costs which will be restricted
for use only to support the Sickle Cell Scholar (minimum effort 75%)
o Clinical Core - this component is required and may not exceed $400,000 in
total costs including F&A costs. This component must provide partial support
for a clinic physician, a principal investigator of a collaborative clinical
research project (minimum effort 10%), and a data manager (minimum part-time).
In addition, the clinical core must support any other personnel (e.g. nurse
coordinator, research nurse, technician, or secretary) or infrastructure
needed to carry out the inter-Center collaborative clinical project(s)
included in the application. The budget prepared for the clinical core should
reflect the infrastructure costs at the applicant Center only of carrying out
the inter-Center collaborative clinical research project submitted
o Administrative Core - this component is required and should include support
for the Center Director (minimum effort 15%) and any secretarial staff. Costs
for travel of Center personnel to Steering Commitee and program meetings (see
details above) may be included here or distributed among the individual
component budgets in the application. In addition, costs in support of
external advisory committee activities must be included here
o Patient Service Core - this component is required and should include support
for personnel and other costs anticipated for the proposed patient support
activities at the applicant Center
o Laboratory Core - this component is optional, and when proposed, must
include a table of direct costs showing the utilization relationships between
research projects and any core(s) that serve those projects, with the columns
being the projects and the rows being the core(s)
In addition to the components included in the Center cap of $1,770,000, each
Center must include at least one inter-Center collaborative clinical research
project. The budget for this project is not counted toward the budget cap of
$1,770,000, and it must include costs necessary to implement the proposed
inter-Center collaborative project. The budget should reflect the costs at
the applicant Center only of carrying out the study. Costs for collaborating
Centers should not be included. 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 required to complete the study. For example, if it is
estimated to cost $6,000 per patient per year to complete the study proposed,
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. 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 be escalated at three percent
for future years. Applicants should request facilities and administrative
(F&A) costs of 28% 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. Budgets for inter-Center collaborative clinical projects
must not include personnel, study personnel are to be supported through the
clinical cores of participating Centers. Applicants should explicitly state
the number of patients available for the proposed protocol at the applicant
Center 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 $360,000 total costs per year may be requested in any inter-
Center collaborative clinical research project, depending on the number of
patients to be recruited. The combined allowable maximum for each Center"s
clinical core plus protocol implementation costs will be approximately
$760,000 a year.
Note that ongoing annual budgets for inter-Center collaborative projects will
be based on the protocols approved by the Comprehensive Sickle Cell Center
Steering Committee and actual awards for inter-Center collaborative clinical
projects will be calculated on a per successfully enrolled patient
(capitation) basis. Individual Centers 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.
The award will be subject to administrative review annually.
APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED
UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW.
Statistics and Data Management Center
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. Applicants should provide adequate budget justification, and all
applicable direct costs, and facilities and administrative costs (F&A) should
be included. The minimum level of effort for the Principal Investigator of
the Statistics and Data Management Center 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 meetings of the Steering Committee
in Bethesda, MD in the first year, and three meetings in subsequent years,
should be requested. In addition, approximately $30,000 direct costs per year
should be requested for managing the Data and Safety Monitoring Board and the
Protocol Review Committee (includes board member travel). Estimated shipping
and handling direct costs of $25,000 per year for clinical study specimens
should also be included in the budget of the Statistics and Data Management
Center. The costs of specimen shipment as well as laboratory data acquisition
and management will be a part of the budget of the Statistics and Data
Management Center.
For budget purposes, Statistics and Data Management Center 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 two to four protocols a year will be active, i.e. either in the protocol
development, implementation, or analysis and writing phase.
It is expected that all protocols will be performed in a manner consistent
with United States Food and Drug Administration guidelines.
Budget Check List and Format for Statistics and Data Management Center
applicants:
The following items must be included in the Statistics and Data Management
Center budget cap of $700,000 total costs:
o Partial support for the principal investigator (minimum effort 20%), and
support for any other key personnel (e.g. biostatistician, coordinator,
secretarial staff, data manager, and/or information technology professional)
o Travel costs for key Data Center personnel to attend the annual meeting of
the National Sickle Cell Disease Program (various locations), and for two
people to attend four meetings of the Steering Committee in Bethesda, MD in
the first year, and three meetings in subsequent years
o $30,000 direct costs per year for management of the Data and Safety
Monitoring Board, and Protocol Review Committee, including travel for
board/committee members to two meetings in Bethesda, MD per year
o $25,000 direct costs per year for shipping and handling of laboratory
specimens
The award will be subject to administrative review annually.
APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED
UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW.
The RFA label available in the PHS 398 application form must be affixed to the
bottom of the face page of the application. Failure to use this label could
result in delayed processing of the application such that it may not reach the
review committee in time for review.
In addition to identifying the application as a response to this RFA, check
"YES" in item 2 of page 1 of the application and enter the title "
Comprehensive Sickle Cell Centers HL-01-015."
The sample RFA label available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to
allow for this change. Please note this is in pdf format.
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
BETHESDA, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the application must be
sent to Dr. Deborah Beebe at the address listed under INQUIRIES.
Applications must be received by September 25, 2001. If an application is
received after this date it will be returned to the applicant without review.
The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application. This
does not preclude the submission of substantial revisions of an application
already reviewed, but such applications must include an introduction
addressing the previous critique.
REVIEW CONSIDERATIONS
Upon receipt, applications will be reviewed for completeness by the CSR and
for responsiveness by NHLBI. Incomplete and/or nonresponsive applications
will be returned to the applicant without further consideration. Applications
that are complete and responsive to the RFA will be evaluated for scientific
and technical merit by an appropriate peer review group convened by the
Division of Extramural Affairs, NHLBI, in accordance with the review criteria
stated below. The roster of the initial review group will be available via
the NHLBI home page approximately two weeks prior to the review. As part of
the initial merit review, all applications will receive a written critique and
undergo a review in which only those applications deemed to have the highest
scientific merit will be discussed, assigned a priority score, and receive a
second level review by the National Heart, Lung and Blood Advisory Council.
Review Criteria
Centers:
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. Each
of the following components of Comprehensive Sickle Cell Center applications
will receive a separate priority score, and will thus be considered in
assigning the overall priority score: collaborative clinical research projects
(including two or more Centers), local clinical research projects, and basic
science projects. The basic science and clinical projects will be reviewed
using criteria described below. Proposed cores (administrative, clinical ,
patient service, and any laboratory cores), and the career development plan
for Sickle Cell Scholars, will not receive priority scores, but will either be
recommended, or not recommended.
Basic Science and Clinical Research Projects
Basic science and clinical research projects will be reviewed according to the
following criteria. In the written comments, reviewers will be asked to
discuss the following aspects of the application 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 the 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.
o Significance: Do the proposed studies address important problems? If the
aims of the project are achieved, how will scientific knowledge, and/or care
of the client with sickle cell disease be advanced? What will be the effect
of these studies on the concepts or methods that drive this field?
o Approach: Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project? Does the applicant acknowledge potential problem areas and consider
alternative tactics?
o Innovation: Does the project employ novel concepts, approaches or method?
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?
o Investigator: Is the investigator 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 (if any)?
o Environment: Does the scientific environment in which the work will be
done contribute to the probability of success? Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements? Is there evidence of a strong tradition of
sickle cell disease research? For clinical projects, is there a strong
tradition of clinical care and ability to recruit the required number of
patients? Is there evidence of institutional support for the project?
The following additional review criteria will be applied to the overall Center
applications:
o Demonstrated willingness on the part of the investigators to work as part
of the collaborative clinical research component of the Comprehensive Sickle
Cell Center program, and with the NHLBI Project Scientist.
o Access to patients for collaborative clinical research.
o Multidisciplinary nature of the proposed studies.
In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:
o The adequacy of plans to include both genders, minorities and their
subgroups, and children as appropriate for the scientific goals of the
research. Plans for the recruitment and retention of subjects will also be
evaluated.
o The reasonableness of the proposed budget and duration in relation to the
proposed research.
o The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project
proposed in the application.
Statistics and Data Management Center:
Considerations for the review of Statistics and Data Management Center
Applicants include the following:
o Evidence of understanding of the scientific, statistical, logistical, and
technical issues underlying multi-Center clinical studies, including issues
relating to treatment and management of sickle cell disease, study design,
statistics, logistics, and handling of laboratory specimens, and overall
coordination of the activities of the collaborative clinical component of the
Comprehensive Sickle Cell Center program (including activities of the Steering
Committee, Data Safety and Monitoring Board, and Protocol Review Committee).
This should include the adequacy of the proposed plan to organize
communications within the program via websites, e-mail listservs, conference
calls, and the like.
o Adequacy of the proposed plans for data entry, transfer, management,
security, and analysis, and for quality control (data collection and
monitoring).
o Adequacy of the proposed plan to supply biostatistical support to the entire
Comprehensive Sickle Cell Center program.
o Adequacy of the proposed plan to manage the common patient database and
linked patient sample repository for the Comprehensive Sickle Cell Center
program, to be stored at the NHLBI Biological Specimen Repository in
Gaithersburg, Maryland.
o Adequacy of the proposed plan to collect program-wide quality of life
information on clients living with sickle cell disease, develop and manage a
database containing this information, and disseminate this information widely
o Adequacy of the proposed plan to collect program-wide health services
utilization, and health outcomes data on clients living with sickle cell
disease, develop and manage a database containing this information, and
disseminate this information widely
o The expertise, training, and experience of the investigators and staff in
the areas of biostatistics and clinical study coordination, including the
administrative abilities of the Principal Investigator, co-investigator, and
the time they plan to devote to the program for the effective coordination of
the collaborative clinical component of the Comprehensive Sickle Cell Center
program.
o The administrative, supervisory, and collaborative arrangements for
achieving the goals of the program, including willingness to cooperate with
the participating Centers and the NHLBI.
o Facilities, equipment, and organizational structure to effectively
coordinate the activities of the collaborative clinical component of the
Comprehensive Sickle Cell Center program, and assist Centers in implementing
the collaborative clinical protocols, providing for specialized laboratory
testing, and collecting data.
o Appropriateness of the budget for the work proposed.
Schedule
Letter of Intent Receipt Date: March 20, 2001
Application Receipt Date: September 25, 2001
Peer Review Date: February/March, 2002
Council Review: May, 2002
Earliest Anticipated Start Date: April 1, 2003
AWARD CRITERIA
Factors that will be considered in making awards include:
o the scientific merit of the proposed program as determined by peer review,
the multidisciplinary nature of the proposed studies, and the quality of
meeting the special requirements stated in this RFA, especially the
willingness to collaborate and to share data
o relevance to the overall programmatic balance and priorities of the NHLBI
and sufficient compatibility of features proposed in the research plan, and
qualifications of the investigators, to make a successful collaborative
clinical component of this program a reasonable likelihood
o the availability of funds.
INQUIRIES
Inquiries concerning this RFA are strongly encouraged. The opportunity to
clarify any issues or answer questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
Greg Evans, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room10152, MSC 7950
Bethesda, Maryland 20892-7950
Telephone: (301) 435-0055
FAX: (301) 480-0868
E-Mail: EvansG@ nih.gov
Direct inquiries regarding review matters, address the letter of intent, and
send two copies of the application to:
Deborah Beebe, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7178, MSC 7924
Bethesda, Maryland 20892-7924
Telephone: (301) 435-0270
FAX: (301) 480-3541
E-mail: BeebeD@nhlbi.nih.gov
Direct inquiries regarding fiscal matters to:
Mary Page
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7162, MSC 7926
Bethesda, MD 20892-7926
Telephone: (301) 435-0152
FAX: (301) 480-3310
E-mail: PageM@nih.gov
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance No.
93.839. Awards are made under authorization of Sections 301 and 405 of the
Public Health Service Act as amended (42 USC 241 and 284) and administered
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts
74 and 92. This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency review.
The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and promote the non-use of all tobacco products. In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care, or early childhood
development services are provided to children. This is consistent with the
PHS mission to protect and advance the physical and mental health of the
American people.
Weekly TOC for this Announcement
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