and Human Services
9000 Rockville Pike
Bethesda, Maryland 20892
PREVENTION AND TREATMENT OF TYPE 2 DIABETES IN CHILDREN AND
ADOLESCENTS—CLINICAL CENTERS
Release Date: October 5, 2000
RFA: DK-01-010 - (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 to develop 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, however, recent epidemiological data
reveal an increasing number of cases of type 2 diabetes in the pediatric
population, especially among adolescents and in certain minority
populations. The increase of type 2 diabetes in children and adolescents
is presumed to be a consequence of widespread obesity and decreased
physical activity.
Clinical trials to develop both effective primary prevention strategies
and treatment regimens for this age group are needed. The intent of this
RFA is to focus on community or school-based primary prevention programs
that can be applied in a cost-effective manner to decrease risk factors
for type 2 diabetes and lower the incidence of the disorder. In
addition, the drugs currently available for the treatment of type 2
diabetes in adults have not been used widely in children. Treatment
options need to be studied in this population to determine the most
efficacious, safe, and cost-effective strategies to achieve euglycemia in
the pediatric age group.
The purpose of this RFA is to 1) solicit proposals for clinical trials
for the prevention and treatment of type 2 diabetes in the pediatric
population, and 2) create an infrastructure for the conduct and analysis
of such clinical trials. Applicants may submit a proposal for a primary
prevention trial or a treatment trial. An institution wishing to propose
both a prevention trial and a treatment trial may do so, but must submit
two separate applications. It is anticipated that the final cooperative
agreement award will fund 1) one multi-center, multi-arm treatment trial
and 2) at least one, but possibly more, primary prevention trials, to be
conducted at multiple sites. Applicants selected on the basis of a
proposal for either a treatment or prevention trial may have the
opportunity to participate in both types of trials.
A complementary RFA (DK-01-011) will be issued to create a Coordinating
Center (CC) to provide administrative, analytical and statistical support
for the studies conducted. An institution or organization can apply to be
the CC, as well as submit an application 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 institutions in the United States,
Puerto Rico and Canada. This geographic constraint is necessary because
of the need for close communication and meetings among members of the
Steering Committee (see Objectives and Scope). Applicants may be for-
profit or 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.
Racial/ethnic minority individuals, women, and persons with disabilities
are encouraged to apply as principal investigators.
Applicants may submit a proposal for a primary prevention trial or a
treatment trial. An institution wishing to propose both a prevention
trial and a treatment trial may do so, but must submit two separate
applications.
Awards for the clinical trial centers and for the Coordinating Center
will not be made to the same Principal Investigator to insure that data
analysis is performed independently of data acquisition. An institution
or organization can apply to be the CC as well as submit an application
for a clinical trial.
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
titled “Objectives and Scope,” and "Terms and Conditions of Award."
The total project period for applications submitted in response to the
present RFA should be 7 years. The anticipated award date is September
30, 2001.
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.
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
The collaborative effort which the NIDDK will support 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.
Approximately $1.75 million are available to support the clinical trial
sites during the planning year of this cooperative agreement.
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 6-10 awards for clinical trial sites will be made.
The exact number of sites for each of the trials will depend on the
sample size needed and the potential for recruitment at individual sites.
The budget for the planning year is expected to support the salary and
travel of the principal investigator and other appropriate key personnel
at each study site. Once the trials begin, the NIDDK will provide funds
directly to each center to support personnel, supplies, equipment,
communication, travel and patient care costs associated with the study.
Additional funds will be provided to the Coordinating Center to support
subcontracts to centralized laboratories and/or reading centers, as
required by the trials. After the planning phase, awards in subsequent
years will depend on the requirements of the protocols ultimately
designed under this cooperative agreement. Because the nature and scope
of each clinical trial will vary, it is anticipated that the size of each
award will also vary.
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. In fact,
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 suggest 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 of 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
insulin resistance, 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
disproportionately affects minority groups. In addition, children
represent a unique “target” population, which 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 preventing 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.
Objectives and Scope
This RFA is designed to 1) solicit applications for clinical trials for
the prevention and treatment of type 2 diabetes in children, and 2)
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 population level.
To accomplish its objectives, this RFA solicits investigator-initiated
clinical trial proposals for the primary prevention and treatment of
children (6-18 years of age) with type 2 diabetes. Investigators are
invited to submit a detailed proposal containing the study design he/she
believes best addresses the needs of his/her patient population. The
trial proposed should involve either primary prevention or treatment, and
the application must contain a rationale for the intervention chosen. An
institution may propose both a prevention trial and a treatment trial,
however, separate applications must be submitted for each trial. This
Objectives and Scope section outlines the scientific goals of the RFA.
Additional details regarding the content of the application are outlined
under “Application Procedures.”
While the study population at any one site may vary based on local
demography, an overall goal of this RFA is to address the prevention and
treatment of type 2 diabetes in children and adolescents from minority
groups, including African Americans, Hispanic Americans, and Native
Americans. The final demographic composition of the trial will reflect
the high rates of type 2 diabetes among minority children. To accomplish
this goal, investigators are encouraged to develop collaborations with
care providers who have access to underserved minority populations. It is
highly desirable for investigators to establish meaningful mentorships
with such caregivers, who may not be trained as scientific investigators.
This collaboration might involve a university appointment for a
collaborator located outside the institution and opportunities for this
individual to obtain experience as a clinician-scientist. Also encouraged
is participation of newly trained physicians. It is desirable to provide
opportunities and experiences that may lead such individuals to develop
as clinical investigators. In addition, all applicants must address the
issue of the cultural sensitivity of the intervention proposed.
Based on peer review, awards will be made to those centers whose
proposals are judged to be of high scientific merit (see Review Criteria
and Award Criteria, below). A Steering Committee will then be created,
comprised of the Principal Investigator of each study site, the head of
the Coordinating Center (to be recruited through a companion RFA, DK 01-
011), as well as an NIDDK representative. The Steering Committee will
meet during the planning phase of the cooperative agreement to design the
actual study protocols. The Steering Committee will be the main governing
board of the studies and will have primary responsibility for developing
common research designs, protocols and manuals, facilitating the conduct
and monitoring of studies, and reporting study results.
1. Treatment Trial
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
at multiple sites, to insure an adequate sample size, as well as
geographic and racial/ethnic diversity. Investigators who proposed a
primary intervention trial will also be eligible to participate in the
treatment trial. However, any one funded clinical site may not
necessarily participate in all conducted protocols, depending on the need
for patient numbers and diversity.
The treatment trial may involve lifestyle intervention and/or drug
therapy. It is desirable for the designed trial to assess
pathophysiological issues, such as preservation of beta cell function, in
addition to simply measuring glucose control. The inclusion of a board-
certified pediatric endocrinologist among the trial personnel or as a
consultant is encouraged.
2. Prevention Trial
At least one, but possibly more, primary prevention protocols will be
developed. The prevention trial ultimately designed by the Steering
Committee 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. If multiple
prevention trials at different sites are carried out, the Steering
Committee will establish standardized entry criteria, clinical
assessments and outcome measures so that all the trials can be compared.
Thus, 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
(see below).
Primary prevention trials should focus on cost-effective, school- or
community-based interventions with the potential for broad, population-
wide application. Other (i.e., non school-based) community-based
interventions are also acceptable. However, the intervention cannot
consist of a one-on-one intervention between a health care provider (or
other adult) and a child. Physician- or clinic-based primary prevention
trials will not be accepted.
Applicants may propose an intervention designed to alter risk factors for
type 2 diabetes, improve insulin sensitivity, decrease development of
impaired glucose tolerance, or prevent conversion to frank diabetes.
While it is expected that interventions will focus on lifestyle
modifications and may, therefore, include assessment of weight, BMI or
physical fitness, the protocol must include measures of insulin
sensitivity and glucose homeostasis. The final design of the prevention
trial will rest with the Steering Committee.
The prevention trial must represent a collaborative, multidisciplinary
effort between a physician (who need not be the Principal Investigator)
and appropriate qualified personnel, as required by the needs of the
study designed (e.g., epidemiologist, psychologist, nurse, nutritionist,
exercise specialist, etc.). The inclusion of a board-certified pediatric
endocrinologist among the trial personnel or as a consultant is
encouraged. It is anticipated that the design of the prevention trial
may be labor intensive because of the need to assess insulin sensitivity
or glucose homeostasis to establish that the intervention is efficacious.
However, the actual intervention must be one that ultimately could be
widely applied to a large population of children.
3. Steering Committee
In addition to designing the clinical trial protocols, the Steering
Committee is also expected 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 this RFA, 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, and 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.
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 will establish subcommittees, as necessary, to
accomplish its goals. 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.
4. Study Organization
The cooperative agreement will have three phases: 1) planning (12
months), 2) recruitment and study (five years), and 3) analysis (final
year of each trial).
Each clinical trial center will receive funding through a separate U01
award. When the individual U01s are awarded, each center will receive
direct funds to cover the cost of personnel, equipment, supplies, travel,
communication, and patient care costs associated with the study.
Reimbursement for laboratory tests will likely be done by the
Coordinating Center, via subcontracts to centralized laboratories and/or
reading centers. If additional sites are needed to recruit adequate
numbers of patients, subcontracts may be added to individual study sites.
The Principal Investigator of each center will, in collaboration with
other Steering Committee members, develop the study protocols 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 (recruited through a separate RFA DK-01-011) 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 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 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.
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. Clinical Center awardees will collaborate with other
investigators participating in this cooperative agreement and agree to
follow common protocols developed by the Steering Committee. The
awardees also agree to meet patient recruitment goals, to transmit data
in a timely manner to the CC, as determined by the Steering Committee,
and 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.
The Steering Committee will develop and maintain specific measures to
ensure the safety and protection of the rights of study patients. The
Principal Investigator of each study site will assume and accept primary
responsibility for ensuring that studies are conducted in compliance with
all federal regulations. These include but are not limited to Title 21
CFR 50, 56, 312 and Title 45 CFR 46. All awardees 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 (recruited through a separate RFA DK-01-011)
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.
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.
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, PHS, 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.
A study site and its institution may not be involved simultaneously in
other studies involving the treatment or prevention of type 2 diabetes in
the pediatric population if enrollment criteria overlap between the
studies and if the studies are actively recruiting participants.
Applicants will forego participation in studies that would compete for
recruitment of the same study population.
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, as appropriate, will participate in 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 mutually agreeable collaborative
protocols.
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 year, it is anticipated that at least six meetings will be
required, to design the protocols and establish common measurements and
outcomes. Once patient recruitment has started, at least two Steering
Committee meetings will occur annually, with additional communication by
conference call 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 (1) both males and females and (2)
members of minority groups and their subpopulations 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 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
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 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.
Instructions for Applicants
Applications responding to this RFA should not use the modular grant
format.
All applicants should provide a detailed description of the design of the
study, including what eligibility, baseline, and follow-up tests are to
be done, what surrogate markers and endpoints will be examined, and the
duration of follow-up. Examples of data forms and questionnaires
proposed should be given. The process for biologic sample collection,
storage and handling needs should be included. A description of the
laboratory tests that are needed with appropriate methods for performing
them should be provided. If multiple tests are available to assess a
parameter (e.g., assessment of insulin sensitivity), a justification for
the chosen method should be included. Also included should be the
methods that would be used to ensure privacy and maintain confidentiality
of data. There must be a data and safety monitoring plan.
1. Treatment Trial
Applicants should provide a detailed description of the target population
to be studied with justification including a definition of the cohort by
age, sex and race. The ability to recruit this target population and the
methods to be used should be described, with an estimation of the
potential number of patients who fit the eligibility criteria and
expected accrual rates. Sample size needs and the assumptions and
calculations used to estimate sample size should be detailed. Because
the ultimate trial carried out under this RFA will be a collaborative
effort, an investigator may propose an intervention that requires more
patients than can be recruited from within his/her institution. In this
case, the investigator should provide a detailed description of the total
sample size needed as well as the number of patients that could be
recruited from his/her own site. 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”).
The application must provide a detailed account of the local population
pool from which patients will be recruited, including the gender and
racial/ethnic make-up of the population and the expected numbers of
patients from each group that could be recruited. While the study
population for any individual trial may vary based on local demography,
an overall goal of this RFA is to address the prevention and treatment of
type 2 diabetes in children and adolescents from minority groups,
including African Americans, Hispanic Americans, and Native Americans. A
plan for recruitment and retention of participants must be provided.
Subcontracts may be used to recruit patients from additional local sites
not a part of the parent institution. In this case, the Principal
Investigator must include a detailed description of the patient pool at
these additional sites, as well as letters of cooperation from potential
subcontractors. It must be made clear that, depending on the final
design of the clinical trial, not all potential subcontractors will be
needed. Applicants must demonstrate evidence of cultural competency.
(2) Prevention Trial
The prevention intervention must be carried out at a school or other
community-based setting. The application must provide a detailed account
of the local population pool from which patients will be recruited,
including the gender and racial/ethnic make-up of the population and the
expected numbers of patients from each group that could be recruited.
While the study population for any individual trial may vary based on
local demography, an overall goal of this RFA is to address the
prevention and treatment of type 2 diabetes in children and adolescents
from minority groups, including African Americans, Hispanic Americans,
and Native Americans. A plan for recruitment and retention of
participants must be provided, with an estimation of the potential number
of patients who fit the eligibility criteria and expected accrual rates.
Sample size needs and the assumptions and calculations used to estimate
sample size should be detailed. The applicant must provide letter(s) of
agreement from the school or community group that will be targeted. The
letter(s) must be provided in the application or be sent to the
Scientific Review Administrator no later than July 2, 2000. If the
applicant is unable to provide letter(s) of agreement by July 2, he/she
must contact the Scientific Review Administrator before that date.
Applications that do not have appropriate letter(s) of agreement will not
be reviewed.
There must be a data and safety monitoring plan. The applicant must
demonstrate evidence of cultural competency. 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”).
(3) Budget Information
Detailed budget information should be provided for the proposed trial.
The budget should be divided into 3 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. It is anticipated that
during the planning phase, the budget will primarily support the salary
and travel of the Principal Investigator and other key personnel. Once
the award is made, each study site will directly receive costs for
personnel, supplies, equipment, communication, travel, and patient care
costs associated with the study. The application should detail these
costs as dictated by the study that is proposed. The actual budget
awarded will be determined once the Steering Committee finalizes the
protocols. Each site does not have to participate in every trial actually
conducted. Therefore, the final awards may vary among sites. Costs for
laboratory tests will be reimbursed using subcontracts through the CC, at
rates determined by the NIDDK.
(4) Issues To Be Addressed By All Applicants
Qualifications and Experience. Applicants must include a description of
their experience and expertise to conduct a clinical trial and
participate in a multi-center collaborative effort. In addition, the
application must provide evidence of the Principal Investigator’s ability
to contribute to the scientific effort of this cooperative agreement.
Institutional Support. There should be evidence of strong institutional
support for the proposed study, including adequate space, resources and
facilities for patient care and follow-up.
Willingness to Collaborate. Applicants must document their willingness to
participate in Steering Committee 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.
Applicants must describe plans to accommodate stated program requests,
criteria and staff involvement.
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 (not to exceed 3 pages) for the
application must be received by May 25, 2001. Material received after
that date will not be accepted. Twenty copies of 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
General 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 importance and
timeliness of the proposed clinical trial(s), access to patients, and
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.
Those applications that are complete and responsive will undergo
scientific merit review in accordance with the criteria stated below for
scientific/technical merit by an appropriate peer review group convened
by the NIDDK. Those applications deemed to have the highest scientific
merit, generally the top half of applications under review, will be
discussed, assigned a priority score, and receive a second level of
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.
The review group will assess the scientific merit of the protocols and
related factors, including:
o Significance: Does this study address an important problem? If the
aims of the application are achieved, how will scientific and/or medical
knowledge 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? Is there evidence of the ability to
recruit, enroll and maintain subjects in a randomized trial? This
includes an adequate description of the racial, ethnic and gender
composition of the proposed cohort and documentation of access to an
adequate patient population who may be approached in finding potentially
eligible study participants.
Are there adequate plans to ensure accurate collection and timely
transmission of study data to the CC and/or central laboratories and
reading centers? 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?
o Innovation: Does the project employ novel concepts, approaches or
methods? 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)? Is the investigator likely to make a significant intellectual
contribution to the collaborative effort? Is there evidence of prior
experience in working collaboratively to carry out a clinical trial or
standard protocol? Is there evidence of willingness to work cooperatively
on the Steering Committee to develop and follow unified protocols?
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 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 humans.
AWARD CRITERIA
Applications recommended by the NDDK Advisory Council will be considered
for award based on the scientific merit of the proposed project and the
ability of the investigators to meet the research objectives of this RFA.
In addition, other considerations, including program balance will be
considered. Additional considerations might include the racial and ethnic
composition of the populations being studied, the geographical location
of the trial, and the type of intervention being proposed. Awards are
also contingent upon the 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
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 PHS 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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