and Human Services
9000 Rockville Pike
Bethesda, Maryland 20892
PREVENTION AND TREATMENT OF TYPE 2 DIABETES IN CHILDREN AND
ADOLESCENTS-–COORDINATING CENTER
Release Date: October 5, 2000
RFA: DK-01-011 - (Reissued as RFA-DK-08-502)
National Institute of Diabetes and Digestive and Kidney Diseases
Letter of Intent Receipt Date: March 20, 2001
Application Receipt Date: April 17, 2001
PURPOSE
The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) invites cooperative agreement applications for a Coordinating
Center to support clinical trials for the primary prevention and
treatment of type 2 diabetes in children in the U.S. and Canada.
Type 2 diabetes has been traditionally viewed as a disease of adults.
Recent epidemiological data reveals an increasing number of cases of type
2 diabetes in the pediatric population, especially among adolescents and
in certain minority populations. The rise in type 2 diabetes in children
and adolescents is presumed to be a consequence of widespread obesity and
decreased physical activity. Clinical trials to develop effective
primary prevention strategies for this age group are needed. In
addition, the drugs currently available for the treatment of type 2
diabetes in adults have not been used widely in children and need to be
studied in this population. A complementary RFA (DK-01-010) is being
issued to solicit applications for clinical trials for the prevention and
treatment of type 2 diabetes in the pediatric population. The intent of
this RFA is to create a Coordinating Center (CC) to provide clinical
center coordination and analytical and statistical support for the
clinical trials. In addition, the CC will work with the NIDDK and the
clinical centers as part of a Steering Committee to design the actual
trial protocols.
An institution or organization can apply to be the CC, as well as submit
a proposal for a clinical trial. Separate applications are required for
these components, which must be administratively and fiscally distinct.
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,
Prevention and Treatment of Type 2 Diabetes in Children and Adolescents,
is related to the priority area of diabetes and chronic disabling
conditions. 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. This geographic constraint
is necessary because of the need for close communication and frequent
meetings among members of the Steering Committee, and possible site
visits to ensure adequate recruitment, retention, and the use of
standardized procedures across the studies. Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to apply
as principal investigators.
Awards for the clinical centers and for the Coordinating Center will not
be made to the same Principal Investigator, to ensure that data analysis
is done independently of data acquisition. An institution or
organization can apply to be the CC, as well as submit a proposal for a
clinical trial, however, separate applications are required for these
components, which must be administratively and fiscally distinct.
MECHANISM OF SUPPORT
The administrative and funding instrument to be used for this program
will be a cooperative agreement (U01), an assistance mechanism (rather
than an acquisition mechanism), in which substantial NIH scientific
and/or programmatic involvement with the awardee is anticipated during
performance of the activity. Under the cooperative agreement, the NIH
purpose is to support and/or stimulate the recipient"s activity by
involvement in and otherwise working jointly with the award recipient in
a partner role, but it is not to assume direction, prime responsibility,
or a dominant role in the activity. Details of the responsibilities,
relationships and governance of the study to be funded under cooperative
agreement(s) are discussed later in this document under the sections
“Objectives and Scope,” “Special Requirements,” and "Terms and Conditions
of Award."
The total project period for applications submitted in response to the
present RFA should be seven years. The anticipated award date is
September 30, 2001.
This RFA is a one-time solicitation. At this time, the NIDDK has not
determined whether or how this solicitation will be continued beyond the
present RFA.
FUNDS AVAILABLE
This collaborative effort will be divided into three phases 1) planning,
2) recruitment and study, and 3) analysis. It is anticipated that the
planning phase will take 12 months, and $1.25 million is available to
support the Coordinating Center during the first year. Substantially
greater funds will be available in subsequent years to support the
conduct of the trials. The exact dollar amount will depend, in part, on
the final design of the trials. Costs are expected to decrease in the
final year of each trial, which will be devoted to data analysis and
reporting of results.
It is anticipated that one award for the Coordinating Center will be made
and that 6-10 awards for clinical trial sites will be made. The CC budget
for personnel, supplies, equipment, communications, and travel should not
exceed $1.25 million in total costs during the first year. After the
planning phase, awards in subsequent years will depend on the
requirements of the specific studies designed by the Steering Committee.
The CC will receive funds to support its personnel, supplies, equipment,
communication, and travel. In addition, it will receive money to pay for
centralized laboratories and reading centers, as needed by the trials.
Although this program is provided for in the financial plans of the
NIDDK, awards pursuant to this RFA are contingent upon the availability
of funds for this purpose. Awards and level of support depend on receipt
of a sufficient number of applications of high scientific merit.
RESEARCH OBJECTIVES
Background
Type 2 diabetes is characterized by insulin resistance and impaired
insulin secretion, although its precise etiology and pathogenesis are
only incompletely understood. The public health impact of type 2
diabetes is enormous.
Clearly associated with aging and obesity, type 2 diabetes has
traditionally been considered a disease of adults. Children presenting
with diabetes are usually assumed to have type 1 diabetes, an autoimmune
disease. In recent years, however, it has become apparent that an
increasing number of children who present with hyperglycemia actually
have type 2 diabetes. In general, population-based screening data are
not available. However, data culled from diabetes clinics in several
locations suggest that the percentage of children diagnosed with diabetes
who are classified as having type 2 diabetes has risen from less than 5%
(prior to 1994) to 20-30% (after 1994).
Not surprisingly, the available published data reveal that one of the
major risk factors for type 2 diabetes in children is obesity. Indeed,
the increase in reports of type 2 diabetes among children parallels a
similar rise in the adult population as obesity has become a major public
health concern. In children, the rise in the incidence in type 2
diabetes appears to be concentrated largely in minority populations-–
African Americans, Hispanic Americans, and Native Americans. Indeed,
type 2 diabetes (in all age groups) is one of the major chronic diseases
where significant racial/ethnic health disparities exist.
Data from NHANES III suggests that up to 1/3 of adults who have type 2
diabetes may go undiagnosed. A similar situation may exist with
children. In fact, the diagnosis of type 2 diabetes in children is often
made because of routine laboratory screening being conducted as part of a
school physical and not because the child presents to a health care
provider with specific complaints. Thus, many children who do not
receive such screening may go undiagnosed until they become symptomatic,
at which time they may have been hyperglycemic for many years and are at
high risk for developing diabetic micro- and macrovascular complications.
In addition, significant numbers of children may not have frank diabetes,
but may be at high risk of developing diabetes based on the presence of
impaired fasting glucose or impaired glucose tolerance. Furthermore, the
combination of insulin resistance, hypertension and dyslipidemia
(syndrome X), which is being documented with increasing frequency among
obese adolescents, is associated in adults with the development of
accelerated cardiovascular disease. It is, therefore, imperative to
establish appropriate screening criteria and effective primary prevention
programs to avoid a potential major public health burden.
The NIDDK is currently funding a large, randomized, multicenter trial
(The Diabetes Prevention Program, DPP) to study the efficacy of
interventions designed to delay or prevent the onset of diabetes in high
risk adults. These interventions may not be directly applicable to the
pediatric population. The majority of children with type 2 diabetes are
in the pre-adolescent or adolescent age range. The adolescent period
presents special challenges to health care providers and families when
attempting to promote behavior and life style changes. Prevention and
treatment programs must also consider cultural differences among racial
and ethnic groups that may influence acceptance of medical regimens.
This is especially important for type 2 diabetes in children, which
currently disproportionately affects minority groups. In addition,
children represent a unique “target” population that may be amenable to
population-based, public health interventions through schools or other
community organizations.
When children develop diabetes, efficacious therapy is needed to maintain
euglycemia in order to prevent the development of complications.
Diabetes is currently estimated to cost the U.S. health care system
approximately $98 billion annually. Much of the cost is related to the
micro- and macrovascular complications of diabetes. Since the
development of complications is related, in part, to the duration of
diabetes, children represent a population at high risk. Indeed, studies
have documented that from 30-50 percent of children with type 2 diabetes
already have adverse cardiovascular risk profiles at the time of
diagnosis. Unfortunately, the drugs currently approved for use in adults
with type 2 diabetes have not been systematically studied in children.
Thus, treatment options for those children diagnosed with type 2 diabetes
are restricted by the lack of data on the use of such pharmacological
agents.
Optimal treatment of type 2 diabetes in children, as well as in adults,
should go beyond merely achieving euglycemia. Ideally, therapy would
reverse insulin resistance and preserve or improve beta cell function.
Lifestyle modifications may be helpful in increasing insulin sensitivity,
and recent advances in the drug treatment of type 2 diabetes have focused
on insulin sensitizing agents. However, little is known about whether one
particular class of agents used to treat type 2 diabetes might be
advantageous in helping to maintain insulin secretion, and prevent the
inexorable slide to insulin treatment which ultimately characterizes type
2 diabetes. Preserving beta cell function in children with impaired
glucose tolerance or type 2 diabetes is of critical importance. Thus,
clinical trials are needed to establish appropriate and effective
treatment regimens for children with type 2 diabetes.
It would be desirable in conducting clinical trials for the prevention
and treatment of type 2 diabetes in children to create an infrastructure
to standardize clinical and outcome measures which will be used in these
clinical trials, so that these studies can be compared and utilized to
impact on health care, both for the individual patient and physician, as
well as at the public health level.
A separate RFA (DK-01-010) will solicit applications for clinical trials
for the prevention and treatment of type 2 diabetes in children (ages 6-
18 years). Based on peer review, those proposals judged to be of high
scientific merit will be chosen for funding. A Steering Committee will
then be created, comprised of the Principal Investigator of each study
site, the head of the Coordinating Center, as well as an NIDDK
representative. The Steering Committee will meet during the planning
phase of the cooperative agreement to design the intervention protocols,
and develop standardized tools, assays, tests and analysis techniques
that will be utilized in all the funded trials.
This RFA solicits applications for a Coordinating Center to participate
in the collaborative planning process and to provide administrative,
analytical and statistical support for the clinical trials.
Objectives and Scope
Applicants should read the companion RFA (DK-01-010) for the clinical
centers to fully understand the objectives and scope of the clinical
trials to be conducted. The Steering Committee, which will include the
Principal Investigator of the CC, will meet during the planning phase of
the cooperative agreement to design the actual study protocols.
It is anticipated that the Steering Committee will develop one, multi-arm
trial for the treatment of type 2 diabetes in children to be carried out
in multiple sites, to ensure geographic and racial/ethnic diversity.
Treatment trials may include lifestyle interventions and/or
pharmacological therapy.
At least one but possibly more primary prevention protocols will be
developed. The prevention trials may involve a standard protocol with
variations based on the need for cultural sensitivity at different sites,
or the Steering Committee may opt for several distinct prevention trials.
Prevention trials will focus on cost-effective, school- or community-
based interventions with the potential for broad, public health
application.
In addition to establishing the intervention protocols, the Steering
Committee will also develop standardized tools, assays, tests and
analysis techniques that will be utilized in all the funded trials.
The CC will have both scientific and administrative functions. The first
objective of the CC is to participate in the design of the intervention
protocols and the development of standardized measures to be used in the
clinical trials for the prevention and treatment of type 2 diabetes in
the pediatric population. The Principal Investigator of the CC will serve
on the Steering Committee, which will meet during the planning phase to
design and approve protocols and establish standardized tests, analytical
methods and outcome measures to be used in all trials (see below, Special
Requirements). During the planning phase, the CC, in particular, will
provide input to determinations of sample size and statistical analysis.
The CC will also be responsible for arranging meetings and conference
calls, generating meeting agendas and minutes of meetings, developing
manuals of operation, questionnaires and data collection forms, and
facilitating communication among Steering Committee members. The CC will
also generate materials to be used in recruiting study participants.
The second objective of the CC is to be a data management center. The CC
will receive data from all study sites. The application should provide
details for the establishment of a data transmission system and database,
it should detail the procedures for data transmission and record keeping,
including methods to validate data and check for discrepancies and
missing data/forms. Trial sites must be informed of incomplete or missing
information. It is expected that CC staff will travel to clinical trial
sites to monitor data collection and quality control procedures. The CC
will provide for central registration of all study participants, maintain
records on all enrolled participants and track participant status. The CC
will randomize patients, when required by a particular study. The
application should describe the system for patient registration, tracking
and randomization, and should detail methods to protect patient
confidentiality. For multi-center trials, the CC will coordinate
interactions between study centers. The CC will process, review and
analyze all data transmitted from the clinical trials and will provide
statistical reports at all Steering Committee meetings on progress of the
trials. In addition, the CC will provide reports and analyses for review
by an independent Data Safety and Quality Monitoring Board (DSQ, see
“Study Organization,” below).
The third objective of the CC is to provide analytical and statistical
support for the trials. The CC will be responsible for all data
management and statistical analysis for the various clinical trials. The
CC will review all proposed protocols and develop statistical designs for
studies, analyze study results, and review all manuscripts for
statistical design considerations.
The fourth objective of the CC is to assist in the performance of all
standardized measures. The CC will establish centralized laboratories and
reading centers, possibly through subcontracts, and provide for shipment
of samples between study sites and these centralized facilities, as
dictated by the needs of the various clinical trials. These standardized
tests (see below, “Special Requirements”) will be determined by the
Steering Committee during the planning phase. The CC staff will, as
necessary, train clinical and/or laboratory staff, and certify the
qualifications of personnel or laboratories to perform assays and tests.
The CC will monitor quality control of all centralized laboratory tests
and clinical measures. Examples of the types of centralized laboratory
functions that may be required include assays of blood glucose, insulin,
glycosylated hemoglobin, lipid and lipoproteins, islet cell antibodies
and various hormone measurements (e.g., IGF-1, IGFBPs, leptin, sex
steroids). Other tests might include anthropomorphic measures (e.g.,
height, weight, BMI, skin fold thickness), determination of insulin
sensitivity and insulin secretion, and assessment of body composition.
Reimbursement for laboratory tests will be done by the CC, via
subcontracts to centralized laboratories and/or reading centers. This
will require tracking all clinical tests performed and maintaining
necessary files, and generating reimbursement reports. The CC will be
responsible for soliciting proposals from, and helping to select, such
central laboratories and reading centers.
The CC must conform to the guidelines of the Office of Human Research
Protection (OHRP) by obtaining an assurance, having an institutional
review board (IRB) and obtaining IRB approval annually. In addition, the
CC will maintain a centralized file of all IRB approval forms for the
various trials. The CC, in conjunction with the Principal Investigator
of each study site, must establish and implement a plan for monitoring
and reporting all adverse events to the NIDDK and the DSQ.
Because of its role in generating materials to be used in recruiting
patients, the CC should demonstrate evidence of cultural sensitivity and
the ability to develop culturally competent protocols and train
appropriate staff.
SPECIAL REQUIREMENTS
A goal of this RFA is to develop an infrastructure for conducting studies
related to the prevention and treatment of type 2 diabetes in the
pediatric population. In particular, it is intended to create a series
of standardized measurement tools and analytical procedures that will be
used in all the clinical trials funded under the companion RFA, DK-01-
010, and that may serve as a framework for future studies. For example,
all the trials should utilize the same test to assess such parameters as
glucose homeostasis, insulin sensitivity, insulin secretion, or body
composition. Laboratory tests (e.g., insulin, glycosylated hemoglobin,
lipids) should be performed by a single laboratory. Uniform surveys or
questionnaires (e.g., for family history, dietary history, or physical
activity assessment) should be developed. Surrogate markers and outcome
measures should be standardized across the trials.
To promote the development of a collaborative program among the award
recipients, a Steering Committee will be formed, composed of the
Principal Investigator of each study site and of the Data Coordinating
Center, as well as the NIDDK program official. It is expected that the
Steering Committee will meet a minimum of six times at the NIH and have
frequent contact by telephone during the planning phase, which is
expected to take one year. Once the trials are initiated, the Steering
Committee will continue to meet at least twice each year and have
frequent conference calls. It is anticipated that, during these meetings
and calls, issues related to study protocol will be discussed and ideas
will be exchanged to enhance study progress. The Steering Committee may
create subcommittees to accomplish its goals.
Each application must designate a Director and Deputy Director. The CC
Director should be an experienced biostatistician, epidemiologist,
physician or other professional with experience in directing a
coordinating center for a large collaborative clinical trial or other
large-scale epidemiological research project. Staff needs may be
modified based on the final protocols established by the Steering
Committee, however, statisticians, systems analysts, programmers,
statistical assistants, clerks and administrative assistants must be
available. It is expected that senior statistical staff will devote time
to developing data analysis methods for use in the trials.
Since the treatment trials may involve the use of drugs not currently
approved for use in children, the CC must have the capability to obtain
and maintain an Investigational New Drug application.
Study Organization
The cooperative agreement will have three phases: 1) planning (12
months), 2) recruitment and study (5 years), and 3) analysis (final year
of each trial).
Each clinical trial center will receive funding through a separate U01
award mechanism. When the individual U01s are awarded, each center will
receive direct funds to cover the cost of personnel, equipment, supplies,
communication, travel and patient care costs associated with the study.
Reimbursement of laboratory tests will be done through the Coordinating
Center via subcontracts to centralized laboratories and/or reading
centers.
The Principal Investigator of each center will, in collaboration with
other Steering Committee members, develop the study protocol and uniform
data collection forms. Each center will have direct responsibility for
identifying eligible study participants, assessing eligibility, promoting
adherence to study design, conducting baseline and follow-up visits,
obtaining blood, urine and other physical measurements, and sending
samples and data to the Coordinating Center, reading centers and
laboratories, as appropriate, according to time frames set by the
Steering Committee.
The Coordinating Center will have primary responsibility for the
biostatistical analyses and data management aspects of the clinical
trials. The CC will have both scientific and administrative functions.
The CC will review all proposed protocols and help develop the
statistical design for each study, analyze study results and review all
manuscripts for statistical considerations. The CC will prepare and
update protocols, manuals of operation and all forms to be used in data
collection, and will provide materials to aid in patient recruitment.
The CC will be responsible for establishing a database to accommodate
data generated by each trial, developing a data transmission system, and
assessing data quality and completeness throughout each study. The CC
will provide for central registration and randomization, when necessary,
of all individuals enrolled in trials. The CC will establish, via
subcontracts, central laboratories and reading centers, as determined by
the Steering Committee. The CC will provide statistical reports on the
progress of trials at Steering Committee meetings, oversee the patient
care cost reimbursement system, and facilitate communication among
investigators, including scheduling meetings and conference calls,
developing agendas and documenting minutes, and maintaining membership
rosters and committee lists. The director of the CC will be a member of
the Steering Committee and cannot have any responsibility for recruitment
or follow-up of study participants.
The Steering Committee will have overall responsibility for the design of
the studies performed. The Steering Committee will design the prevention
and treatment interventions, and develop standardized testing methods and
outcome measures, as described above, to be utilized in the various
clinical trials. The Steering Committee will approve all protocols,
changes to protocols, and manuals of operation. Responsibility for the
execution of each trial will rest with the Principal Investigator of each
study site, who will provide progress reports to the Steering Committee.
The Steering Committee will also develop policies relating to access to
patient data and specimens, and ancillary studies. The Steering Committee
will establish guidelines for presentations at scientific meetings and
for writing and publishing manuscripts on the findings of the study. The
Steering Committee will meet initially to develop the protocols and
subsequently to discuss the progress of the study. The NIDDK will select
a chairperson from among the non-federal Steering Committee members or
other experts in diabetes clinical trials. The chairperson of the
Steering Committee must not have responsibility for recruitment or
follow-up of study participants. If a study investigator is chosen as
chairperson, he/she must designate a replacement investigator at his/her
institution. The chairperson must have proven evidence of leadership
ability and be able to make an adequate time commitment to the
cooperative agreement.
The Data Safety and Quality Monitoring Group (DSQ) is an external
oversight committee that will be appointed by the NIDDK. It will be
composed of diabetes and clinical trial experts not directly involved in
any of the clinical trials. Prior to the initiation of a trial, the DSQ
will review the protocols to ensure proper scientific design and
protection of human subjects. The studies will move forward into the
recruitment phase only with the concurrence of the awardees, the DSQ and
the NIDDK. The DSQ will monitor each trial for safety and efficacy, with
authority to recommend protocol or procedural changes or early
termination of any trial. The DSQ is advisory to both the NIDDK and the
Steering Committee. The Chairperson of the Steering Committee and the
Principal Investigator of the CC will attend DSQ meetings, which will
take place at least twice a year.
The following terms and conditions will be incorporated into the award
statement and provided to the Principal Investigator(s) as well as the
institutional official at the time of award.
TERMS AND CONDITIONS OF AWARD
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 Parts 74 and 92, and other HHS and
NIH Grant Administration policy statements.
The administrative and funding instrument used for this program is a
cooperative agreement (U01), an "assistance" mechanism (rather than an
"acquisition" mechanism) in which substantial NIH scientific and/or
programmatic involvement with the awardee is anticipated during
performance of the activity. Under the cooperative agreement, the NIH
purpose is to support and/or stimulate the recipient"s activity by
involvement in and otherwise working jointly with the award recipient in
a partner role, but it is not to assume direction, prime responsibility,
or a dominant role in the activity. Consistent with this concept, the
dominant role and prime responsibility for the activity resides with the
awardee(s) for the project as a whole, although specific tasks and
activities in carrying out the studies will be shared among the awardees
and the NIDDK Project Scientist.
1. Awardee Rights and Responsibilities
Awardees will have primary and lead responsibilities for the project as a
whole, including research design and protocol development, participant
recruitment and follow-up, data collection, quality control, interim data
and safety monitoring, final data analysis and interpretation, and
preparation of publications, with assistance from the NIDDK Project
Scientist. Awardees will collaborate with other investigators
participating in this project and agree to follow common protocols
developed by the Steering Committee. The awardees also agree to provide
progress reports to the Steering Committee. The inability to meet
performance requirements may result in an adjustment of funding,
withholding of support, restriction of funds already awarded, or
termination of the award.
All awardees (including the CC) must be able to demonstrate that there is
a current, approved Assurance on file with the NIH Office of Human
Research Protections (OHRP), that each protocol and informed consent is
approved and reviewed annually by the Institutional Review Board (IRB) of
record, and that each subject has given written, informed consent. The
Principal Investigator must agree and assure that adequate records will
be available, to enable outside monitors to assess compliance with
applicable federal laws and regulations.
The Coordinating Center will have primary responsibility for clinical
center coordination, and the biostatistical analyses and data management
aspects of the clinical trials. The CC will have both scientific and
administrative functions. The CC will review all proposed protocols and
help develop the statistical design for each study, analyze study results
and review all manuscripts for statistical considerations. Based on input
from the Steering Committee, the CC will prepare and update protocols and
manuals of operation, and will provide materials to aid in patient
recruitment. The CC will be responsible for establishing a database to
accommodate data generated by each trial, developing a data transmission
system, and assessing data quality and completeness throughout each
study. The CC will provide for central registration and randomization,
when necessary, of all individuals enrolled in trials. The CC will
establish, via subcontracts, central laboratories and reading centers, as
determined by the Steering Committee. The CC will provide statistical
reports on the progress of trials at Steering Committee meetings, oversee
the patient care cost reimbursement system, and facilitate communication
among investigators, including scheduling meetings and conference calls,
developing agendas and documenting minutes, and maintaining membership
rosters and committee lists. The director of the CC will be a member of
the Steering Committee and cannot have any responsibility for recruitment
or follow-up of study participants.
The CC and study investigators must agree to implement an adverse event
tracking system, as designed by the Steering Committee.
Awardees must conform to the guidelines pertaining to the accrual of
women and minorities as subjects in clinical research, and the reporting
of results in these subgroups, as specified below under “Inclusion of
Women and Minorities in Research Involving Human Subjects.”
In addition to periodic financial and administrative reports required by
NIH for administration of cooperative agreements, awardees must agree to
furnish reports documenting recruitment and follow-up activity. The CC,
together with the study Principal Investigators, must achieve and
maintain quality data in accordance with the common protocols and manuals
of operation specified by the Steering Committee.
Prompt presentation and publication in the scientific literature of study
findings is required. Awardees must agree to acknowledge NIDDK support
in the publications and oral presentations resulting from research
conducted under this cooperative agreement. Manuscripts and
presentations will be written and reviewed according to policies
established by the Steering Committee.
Awardees will retain custody of and have primary rights to the data
developed under these awards, subject to Government rights of access
consistent with current HHS and NIH policies. The CC will be expected to
put all study intervention materials and procedure manuals in the public
domain and/or make them available to other investigators. The NIDDK also
expects that biologic samples and associated clinical data will be made
available to the scientific community at an appropriate juncture, for
further studies related to understanding, preventing and/or treating type
2 diabetes in children and adolescents.
2. NIDDK Staff Responsibilities
The NIDDK Project Scientist will provide scientific support to the
awardees’ activities, including protocol development and modification,
quality control and performance monitoring, interim data monitoring,
final analysis, and preparation of publications. Consistent with the
cooperative agreement nature of this study, the NIDDK Project Scientist
will be substantially involved as an active partner in all aspects of the
scientific and technical management of the trials. This level of
involvement will be above and beyond the level required for
administration of traditional research grants.
The NIDDK Project Scientist will have voting membership on the Steering
Committee and, will participate, as appropriate, on its subcommittees.
The NIDDK reserves the right to terminate or curtail the study (or an
individual award) in the event of substantial shortfall in participant
recruitment, follow-up, data reporting, quality control, or other major
breach of the protocol. The NIDDK can also terminate or curtail a study
if a major study endpoint is reached substantially before schedule with
persuasive statistical significance, if futility in reaching a
significant difference between the treatment groups is realized, if there
is emergence of new information that diminishes the scientific importance
of the study, or if human subject safety or ethical issues dictate a
premature termination. The NIDDK may also terminate the project if there
is failure to develop or implement a mutually agreeable collaborative
protocol.
3. Collaborative Responsibilities
The Steering Committee, which will be the main governing board of the
study, will be composed of the Principal Investigator of each study site,
the Principal Investigator of the CC, and a representative of the NIDDK,
with each member having one vote. The Steering Committee will have
primary responsibility for developing common research designs, protocols
and manuals, facilitating the conduct and monitoring of studies, and
reporting study results. The Steering Committee will design the
prevention and treatment interventions, and develop standardized testing
methods and outcome measures, as described above, to be utilized in the
various clinical trials. The Steering Committee will approve all
protocols, changes to protocols, and manuals of operation. Responsibility
for the execution of each trial will rest with the Principal Investigator
of each study site, who will provide progress reports to the Steering
Committee. The Steering Committee will also develop policies relating to
access to patient data and specimens, and ancillary studies. The Steering
Committee will establish guidelines for presentations at scientific
meetings and for writing and publishing manuscripts on the findings of
the study. The Steering Committee will meet initially to develop the
protocols and subsequently to discuss the progress of the study. The
NIDDK will select a chairperson from among the non-federal Steering
Committee members or other experts in diabetes clinical trials. The
chairperson of the Steering Committee must not have responsibility for
recruitment or follow-up of study participants. If a study investigator
is chosen as chairperson, he/she must designate a replacement
investigator at his/her institution. The chairperson must have proven
evidence of leadership ability and be able to make an adequate time
commitment to the cooperative agreement.
To promote the development of a collaborative program among awardees,
Principal Investigators are expected to attend Steering Committee
meetings and participate in conference calls on a regular basis. In the
first, planning year, it is anticipated that at least six meetings will
be required, to establish common measurements and outcomes. Once patient
recruitment has started, at least two Steering Committee meetings will
occur annually, with communication by conference call continuing on a
regular basis to discuss emerging issues.
The Data Safety and Quality Monitoring Group (DSQ) is an external
oversight committee which will be appointed by the NIDDK. It will be
composed of diabetes and clinical trial experts not directly involved in
any of the clinical trials. Prior to the initiation of a trial, the DSQ
will review the protocol to ensure proper scientific design and
protection of human subjects. The studies will move forward into the
recruitment phase only with the concurrence of the awardees, the DSQ and
the NIDDK. The DSQ will monitor each trial for safety and scientific
validity, with authority to recommend protocol or procedural changes or
early termination of any trial. The DSQ is advisory to both the NIDDK and
the Steering Committee. The chairperson of the Steering Committee and the
Principal Investigator of the CC will attend DSQ meetings, which will
take place at least twice a year.
4. Arbitration
Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award), between award recipients and the NIDDK
may be brought to arbitration. An arbitration panel will be composed of
three members: one selected by the Steering Committee (with the NIDDK
member not voting) or by the individual awardee in the event of an
individual disagreement, a second member selected by the NIDDK, and the
third member selected by the two prior selected 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.
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.
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.
Under the statute, when an NIH defined Phase III clinical trial is
proposed, evidence must be reviewed to show whether or not clinically
important gender and/or race/ethnicity differences in the intervention
effect are to be expected. This evidence may include, but is not limited
to, data derived from prior animal studies, clinical observations,
metabolic studies, genetic studies, pharmacology studies, and
observational, natural history, epidemiology and other relevant studies.
The NIDDK believes that prior studies neither strongly support nor negate
significant differences in expected intervention effects by sex/gender
and/or race/ethnicity. In this case, the NIH Phase III clinical trial
will be required to include sufficient and appropriate entry of gender
and/or racial/ethnic subgroups, so that valid analysis of the
intervention effect in subgroups can be performed. However, the trial
will not be required to provide high statistical power for each subgroup.
The Research Plan in the application or proposal must include a
description of plans to conduct the valid analyses of the intervention
effect in subgroups. The final protocol(s) approved by the IRB(s) must
include these plans for analysis. The award will require that the
results of subset analyses must be reported to NIH in Progress Reports,
Competitive Renewal Applications, and in the required Final Progress
Report.
Inclusion of the results of subset analyses is strongly encouraged in all
publication submissions. If the analysis reveals no subset differences,
a brief statement to that effect, indicating the subsets analyzed, will
suffice.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN
SUBJECTS
It is the policy of the 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 or 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.
LETTER OF INTENT
Prospective applicants are asked to submit, by March 20,2001, a letter of
intent that includes a descriptive title of the proposed research, name,
address, and telephone number of the Principal Investigator, 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 subsequent applications, the information allows
NIDDK staff to estimate the potential review workload and to plan the
review.
The Letter of Intent is to be sent to:
Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 653 MSC 5452
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone: (301) 594-8885
FAX: (301) 480-3505
APPLICATION PROCEDURES
The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these awards. These forms are available at most
institutional offices of sponsored research, from the GrantsInfo,
Division of Extramural Outreach and Information Resources, National
Institutes of Health, 6701 Rockledge Drive, Suite 6095, Bethesda, MD
20892-7910, telephone 301-435-0714, email: GrantsInfo@nih.gov.
Additional Materials to Include in the Application
Applicants must describe plans to achieve the stated “Objectives and
Scope,” “Special Requirements,” and “Terms and Conditions of Award”
stated in this RFA. In addition, applicants should address the following
issues that are important to the successful development of a
collaborative program.
Applicants must document their willingness to participate on the Steering
Committee and appropriate subcommittees, work cooperatively with other
members of the Steering Committee and follow the common protocols
established cooperatively by the Steering Committee. Applicants must
address the following responsibilities of the CC: 1) participation in the
design of the final protocols and development of the manuals of
operation, data collection forms, and questionnaires, 2) development and
implementation of systems for communication among Steering Committee
members, and among study sites, 3) data collection, editing, processing,
analysis and reporting, 4) monitoring of adherence to protocols and of
data quality, and 5) establishment of procedures that insure the safety
and confidentiality of all records.
Applicants must describe plans for maintaining effective collaboration
and communication among investigators. They should provide information
on prior experience participating in diabetes research and clinical
trials. Applicants must describe their ability to 1) provide fiscal
management and administrative support for the clinical trials established
by the Steering Committee, and 2) design, support, conduct and provide
statistical expertise for clinical trials. The CC must have the ability
to handle an IND application.
A description of appropriate facilities, personnel, equipment and
institutional support must be provided. Experience handling numerous
subcontracts should be documented. Examples of forms and correspondence
useful for coordinating tasks should be included. A thorough description
of experience and methods for tracking patient care costs and reimbursing
multiple study sites must be given. The applicant should describe the
approach that would be used for soliciting and evaluating proposals for
centralized laboratories and/or reading centers.
Applicants should describe their physical facilities, data management and
computer resources, and facilities for data retrieval and storage.
Examples of data forms, questionnaires and software/computer programs
should be included and described. Methods for sending and receiving
data, and maintaining data should be described. Data management and
quality control procedures must be detailed. Applicants must include a
plan for randomization of patients into protocols. Methods for assuring
privacy and maintaining confidentiality should be included. There must be
a data and safety management plan. Applicants must state their plans for
reporting accrual by gender, race and ethnicity and for the reporting of
results that examine differences in treatment effects across these
subgroups (see above, “Inclusion of Women and Minorities in Research
Involving Human Subjects”).
Applicants must document their willingness to participate in Steering
Committee and DSQ activities, including meetings at the NIH and regular
conference calls, and should state their willingness to follow the common
protocol agreed to during the planning phase.
Evidence of strong institutional support must be provided.
Applications should not exceed 35 pages, excluding appendices, which may
contain copies of pertinent forms or examples of correspondence useful
for coordinating tasks.
Budget Information
Applicants should submit an adequately justified budget for the entire
anticipated project period. The budget should be divided into three
phases: 1) planning (12 months), 2) recruitment and study (five years),
and 3) analysis (final year of each trial). The application should
contain a detailed budget for each phase.
The planning phase will be for the development of the protocols and the
manuals of operation by the Steering Committee. The budget should
contain costs for personnel, supplies, equipment, communication and
travel. In addition, the NIDDK will supply funds for the reimbursement of
laboratory tests, which will be distributed by the CC to centralized
laboratories and reading centers through appropriate subcontracts. The
actual budget awarded will be determined following the design of the
various clinical trials.
The RFA label available in the PHS 398 (rev. 4/98) 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, the RFA title and number must be typed on line 2a of the face
page of the application form and the YES box must be marked.
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 20827 (for express/courier service)
At the time of submission, two additional copies of the application must
also be sent to:
Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 653 MSC 5452
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone: (301) 594-8885
FAX: (301) 480-3505
Applications must be received by April 17, 2001. If an application is
received after that date, it will be returned to the applicant without
review. Supplemental materials for the application must be received by
May 21, 2001. Material received after that date will not be accepted.
All supplemental material should be sent to:
Scientific Review Administrator
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
The name of the SRA will be provided to the applicant in the letter
acknowledging receipt of the application.
The Center for Scientific Review (CSR) will not accept any application in
response to this announcement that is essentially the same as one
currently pending initial review, unless the applicant withdraws the
pending application. The CSR will not accept any application that is
essentially the same as one already reviewed. This does not preclude the
submission of a substantial revision of an application already reviewed,
but such an application must follow the guidance in the PHS Form 398
application instructions for the preparation of revised applications,
including an introduction addressing the previous critique.
REVIEW CONSIDERATIONS
All applications will be judged on the basis of the scientific merit of
the proposed project and the documented ability of the investigators to
meet the RESEARCH OBJECTIVES of the RFA. Although the technical merit of
the proposed protocol is important, it will not be the sole criterion for
evaluation of a study. Other considerations, such as the expected
scientific and intellectual contributions to the collaborative effort,
will be part of the evaluation criteria.
Upon receipt, applications will be reviewed for completeness by the CSR
and responsiveness by the NIDDK. Incomplete and/or non-responsive
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 NIDDK in accordance with the review criteria
stated below. As part of the initial merit review, all applications will
receive a written critique and undergo a process in which only those
applications deemed to have the highest scientific merit, generally the
top half of the applications under review, will be discussed, assigned a
priority score, and receive a second level review by the National
Diabetes and Digestive and Kidney Diseases Advisory Council.
Review Criteria
Applicants are encouraged to submit and describe their own ideas about
how best to meet the goals of the cooperative study and their specific
protocols, and are expected to address issues identified under SPECIAL
REQUIREMENTS of the RFA.
Applications will be reviewed for scientific and technical merit using
the following criteria:
o Approach: Is there an adequate understanding of the scientific agenda
of the cooperative agreement? Can the CC contribute to the goals and
enhance the study group as a whole? Does the applicant have a thorough
understanding of the complexities of administering and monitoring a
large-scale clinical trial and of maintaining effective communication and
collaboration among study group members? Does the applicant illustrate
the ability to design, support, conduct and provide statistical expertise
in clinical trials? Does the application contain an appropriate plan to
capture. monitor, transmit, store, ensure security and otherwise manage
clinical data on large-scale clinical trials? Does the applicant
describe a reasonable plan for distributing drug in large-scale, multi-
centered clinical trials in a masked manner, and des rive appropriate
procedures for unmasking drug, if necessary? Is there an efficient and
reliable plan for tracking patient tests that are performed at the
clinical sites? Are there appropriate plans to protect confidentiality of
data? Is there an appropriate data and safety monitoring plan? Does the
applicant’s approach conform to NIH guidelines for inclusion of women and
minorities as human subjects in clinical research? Is there evidence that
the CC staff can develop culturally sensitive study materials?
o Investigator: Are the investigators appropriately trained and well
suited to carry out this work? Is the scientific, technical and
administrative work proposed appropriate to the experience level of the
principal investigator and other staff? Prior experience in the
collection of data from multiple sites, as well as experience monitoring
the quality of such data must be demonstrated. Is the investigator
likely to contribute intellectually to the collaborative effort? Is
there evidence of prior experience working collaboratively in carrying
out a standard protocol involving multiple study sites? Is there
evidence of willingness to work collaboratively on the Steering Committee
to develop and follow unified protocols? Is there an appropriate amount
of time planned for effective collaboration?
o Environment: Does the scientific environment in which the work will be
done contribute to the probability of success? Are the available
facilities adequate for coordination of multiple clinical trials, for
data acquisition, management and analysis, and for fiscal administration
of a multi-site study? Is there evidence of institutional support?
In addition to these criteria, in accordance with NIH policy, all
applications will be reviewed with respect to the reasonableness of the
proposed budget and the adequacy of the proposed protection for human
subjects.
AWARD CRITERIA
Applications recommended by the NDDK Advisory Council will be considered
for award based upon (a) scientific and technical merit, (b) program
balance, including in this instance, sufficient compatibility of features
to make a successful collaborative program a reasonable likelihood, and
(c) availability of funds.
Schedule
Letter of Intent Receipt Date: March 20,2001
Application Receipt Date: April 17, 2001
Peer Review Date: June 2001
Council Review: September 2001
Earliest Anticipated Start Date: September 30, 2001
INQUIRIES
Written and telephone inquiries concerning this RFA are encouraged. The
opportunity to clarify any issues or questions from potential applicants
is welcome.
Direct inquiries regarding programmatic issues to:
Barbara Linder, M.D., Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
NIDDK
6707 Democracy Boulevard, Rm. 699
Bethesda, MD 20892-5460
Telephone: (301) 594-0021
FAX: (301) 480-3503
E-mail: linderb@extra.niddk.nih.gov
Direct inquiries regarding fiscal matters to:
Kim Law
Division of Extramural Activities
NIDDK
6707 Democracy Boulevard, Rm. 639 MSC 5456
Bethesda, MD 20892-5456
Telephone: (301) 594-8869
FAX: (301) 480-3504
E-mail: lawk@extra.niddk.nih.gov
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance
No. 93.847. Awards are made under authorization of the Public Health
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public
Law 99-158, 42 USC 241 and 285) 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 NIH strongly encourages all grant and contract 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
NIH Funding Opportunities and Notices
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