COOPERATIVE MULTICENTER RESEARCH NETWORK TO TEST GLUCOSE SENSORS IN CHILDREN 
WITH TYPE 1 DIABETES MELLITUS

Release Date:  February 22, 2001

RFA:  RFA-HD-01-009

National Institute of Child Health and Human Development
 (http://www.nichd.nih.gov)
National Institute of Diabetes and Digestive and Kidney Diseases
 (http://www.niddk.nih.gov)

Letter of Intent Receipt Date:  March 27, 2001
Application Receipt Date:       May 11, 2001

PURPOSE

The National Institute of Child Health and Human Development (NICHD) and the 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
invite cooperative agreement applications for participation in a 
collaborative research consortium that will utilize new continuous glucose 
monitoring devices to:  (1) evaluate glycemic control and the incidence, 
magnitude, and duration of hypoglycemia in a contemporaneous population of 
children with type 1 diabetes mellitus; and (2) to evaluate glucose 
homeostasis in children without diabetes.  This research consortium may also 
evaluate the value of providing data from these devices to health care 
professionals with regard to achieving glycemic control and minimizing 
hypoglycemia in children with type 1 diabetes mellitus. 

In addition to applications for Clinical Centers (CC), which will recruit 
subjects, and develop and implement a common protocol, separate applications 
are invited for support of a Data Coordinating Center (DCC).  The DCC will 
have primary responsibility for Clinical Center coordination, and the 
biostatistical analyses and data management aspects of the clinical trials.

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 Request for 
Applications (RFA) is related to one or more of the priority areas.  
Potential applicants may obtain “Healthy People 2010” at 
http://www.health.gov/healthypeople/. 

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and North American, 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.  The need for continuous and active 
communication among sites dictates that only institutions in the United 
States and North America are eligible to apply.  Racial/ethnic minority 
individuals, women, and persons with disabilities are encouraged to apply as 
Principal Investigators.
 
MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) cooperative 
clinical research (U10) award mechanism, 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 stimulate the recipients’ activity by involvement in the activity 
and otherwise working jointly with the award recipients 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 agreements are 
discussed below under “Terms and Conditions of Award.” 

FUNDS AVAILABLE

The NICHD and NIDDK intend to commit approximately $2 million in total costs 
[Direct plus Facilities and Administrative (F & A) costs] in FY 2001 to fund 
four Clinical Center applications and one Data Coordinating Center 
application in response to this RFA.  Applicants for the Clinical Centers and 
for the Data Coordinating Center may request a project period of up to five 
years and a budget for total costs of up to $400,000 per year.  Although the 
financial plans of NICHD and NIDDK provide support for this program, awards 
pursuant to this RFA are contingent upon the availability of funds and the 
receipt of a sufficient number of meritorious applications.

RESEARCH OBJECTIVES
 
Background
 
Hypoglycemia is the major limitation to implementation of intensive glycemic 
control, which has been shown to substantially prevent or delay microvascular 
complications in adolescents and adults with type 1 diabetes.  Intensive 
therapy has not been systematically evaluated in children under 13 years with 
type 1 diabetes.  Younger children may be at increased risk for hypoglycemia 
in the setting of intensive therapy and the risk/benefit ratio of intensive 
glycemic control achieved with current therapeutic tools may be less 
favorable in this population.  This RFA will address that concern through 
creation of a Type 1 Diabetes in Children Research Consortium.  The 
Consortium will develop and implement a protocol using continuous monitoring 
devices in children with type 1 diabetes, in order to evaluate the utility of 
continuous monitoring devices and to determine if these devices are useful in 
improving glycemic control and preventing hypoglycemia in children with type 
1 diabetes.  This protocol might also evaluate and develop distinct, age-
appropriate treatment approaches to type 1 diabetes in children. 

The solicitation is part of a multi-faceted research program at the NICHD and 
the NIDDK intended to reduce morbidity and mortality from type 1 diabetes in 
the U.S. population.  Results of the Diabetes Control and Complications Trial  
(DCCT) demonstrated that near-normalization of blood glucose levels can be 
achieved through intensive therapy, and slows the progression and 
significantly reduces the risk of developing the microvascular complications 
of diabetes.  Although the same regimen and glycemic goals were imposed on 
both adults and adolescents, the latter group was distinctive in their 
response to the treatment regimen.  Intensive treatment in adolescents caused 
a three-fold greater risk for severe hypoglycemia and a two-fold risk for 
obesity compared to similarly treated adults with diabetes.  Additionally, 
the hemoglobin A1c levels remained significantly higher in the adolescent 
group compared to the adult subjects despite generally higher insulin 
dosages.  Notwithstanding the striking differences in the adolescents and 
adults, the conclusion of the DCCT was that intensive therapy was recommended 
for children over the age of 13, since the benefits appeared to outweigh the 
risks.

Insulin pumps and multiple daily injections, now the mainstays of strict 
glycemic control, are being prescribed more frequently in young children.  
This treatment approach may be associated with high rates of severe 
hypoglycemia, possibly leading to various adverse outcomes in some children.  
One problem inherent in the current system of blood glucose monitoring is 
that we do not know the true incidence, magnitude or duration of these 
hypoglycemic episodes.  New continuous monitoring systems for measuring 
interstitial glucose concentrations have the potential to revolutionize 
diabetes treatment.  These systems have been tested in adults but still 
require testing in children with type 1 diabetes to determine their value in 
improving metabolic control and reducing the risk of hypoglycemia.

This multi-center observational study, using the new continuous monitoring 
systems, should complement knowledge gained about the risks and benefits of 
intensive therapy in adolescents and adults during and after the DCCT.  While 
the benefits of intensive glycemic control in reducing complications are 
likely to accrue in younger children as well as in the DCCT population, the 
risks may be substantially different.  The incidence and severity of 
hypoglycemia may be increased the younger the age of the child.  Also, 
children with recurrent episodes of hypoglycemia may be at increased risk for 
learning disabilities and behavior problems. Although these issues cannot be 
fully addressed in an observational study of this length, they remain the 
driving force behind this RFA.  Data on the incidence, magnitude, and 
duration of hypoglycemia, as well as its sequelae, are needed to arrive at a 
clear consensus about the potential risks of contemporaneous treatment 
regimens of varying intensity in the pediatric population, especially in 
prepubertal children.  Data to inform decisions on treatment and monitoring 
options for young children and age cutoffs for such options will be developed 
through this observational study. 

Objectives and Scope

This RFA solicits applications 1) for support of Clinical Centers (CCs) to 
evaluate glycemic control in children with Type 1 Diabetes by the use of 
continuous glucose monitoring devices and 2) for support of a Data 
Coordinating Center (DCC) which will be responsible for providing 
administrative, analytical, and statistical support for this study.  

The CCs and the DCC will jointly comprise a Type 1 Diabetes in Children 
Research Consortium to achieve the following objectives:

o To determine the extent of hypoglycemia (frequency, duration and degree) in 
a contemporaneously treated population of children with type 1 diabetes; 

o To examine the relationship between intensity of therapy and risk of 
hypoglycemia; 

o To identify factors, including method of treatment, exercise, nutrition, 
other aspects of lifestyle and behavior, age, duration of diabetes, and other 
patient characteristics, that affect the risk for  hypoglycemia;

o To examine the value of current monitoring capabilities in management of 
children with type 1 diabetes;

o To measure the blood glucose levels of children without diabetes who are of 
comparable age and studied in the same manner as the study population using 
the continuous glucose monitoring devices. 

Study Protocol

This RFA solicits investigator-initiated clinical proposals to recruit, 
assess, and monitor subjects.  Each application for support as a Clinical 
Center should propose a protocol that can be carried out in a multi-center 
study of continuous glucose monitoring in children with and without diabetes 
to accomplish the objectives described above.  Investigators are invited to 
submit a detailed proposal containing the study design he/she believes best 
addresses these objectives. This longitudinal study should provide 
information on glucose levels throughout a 24-hour period in normal children 
and in children with type 1 diabetes treated by either conventional therapy 
or intensive therapy.  It should also address opportunities for ascertainment 
of the threshold for clinical recognition of hypoglycemia in children with 
type 1 diabetes using the continuous monitoring device. The application 
should present a rationale for the number of children of each age to be 
studied; describe how subjects will be selected to achieve appropriate 
representation of patient characteristics including methods of treatment; 
describe and justify the anticipated race, ethnic, and gender composition of 
the study population; describe and justify the proposed monitoring device to 
be used, and the setting, duration, and frequency of monitoring.  Emphasis 
should also be placed on inclusion of children across age, gender, 
socioeconomic, and racial-ethnic groups.  Incentives to enhance accrual and 
retention should be described in the application. 

A common protocol to be used by all CCs will be established by the Steering 
Committee during the planning phase (the first six months) of the project. 
Although the actual protocol to be implemented will ultimately be determined 
by the Steering Committee, the protocols proposed will provide the major 
basis for peer review of CC applications.  The Steering Committee, composed 
of the Principal Investigator of each Clinical Center, the Principal 
Investigator of the Data Coordinating Center, as well as the  NICHD and NIDDK 
Project Scientists, will meet during the planning phase of the cooperative 
agreement to design the actual study protocol. The Steering Committee will be 
the main governing board of this study and will have primary responsibility 
for developing common research designs, protocols, and manuals of operations, 
facilitating the conduct and monitoring of studies, and reporting study 
results.

Composition of Clinical Center Personnel

Applications for Clinical Centers will be strengthened by the participation 
of individuals with clinical expertise in pediatric endocrinology, behavioral 
research, nutrition, clinical research, and biostatistics. 

Approximate Timetable    
 
During the first six months, the Steering Committee and other personnel with 
appropriate expertise from the Clinical Centers and the Data Coordinating 
Center will work collaboratively to develop the study protocol, manual of 
operations, and analysis plan.  Enrollment and data collection efforts will 
occur in the latter half of the first year and in Years 02-04.5.  Data 
analysis will occur in the latter part of year five.  

SPECIAL REQUIREMENTS

Attendance at Meetings

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 six 
months, it is anticipated that at least three meetings will be 
required, to design the protocol and to 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. Application 
budget requests should include funds to support travel of the PI and one 
other investigator to attend scheduled Steering Committee meetings.

In addition, the chairperson of the Steering Committee and the Principal 
Investigator of the DCC will be expected to attend Data Safety and Quality 
Committee meetings, which will take place at least twice a year.

Terms and Conditions of Award

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. 
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, the NIH Grant Policy statement.

The administrative and funding instrument used for this program is a 
cooperative agreement (U10), 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 NICHD and NIDDK Project 
Scientists.

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 NICHD and NIDDK Project Scientists.  
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 (as determined by the Steering Committee), to 
transmit data in a timely manner to the DCC, 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 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 Data Coordinating Center (DCC) will have primary responsibility for 
Clinical Center coordination, the biostatistical analyses, and data 
management aspects of the clinical study.  The DCC will have both scientific 
and administrative functions. The DCC will review all proposed protocols and 
help develop the statistical design for the study, analyze study results and 
review all manuscripts for statistical considerations.  Based on input from 
the Steering Committee, the DCC will prepare and update protocols and manuals 
of operation, and will provide materials to aid in patient recruitment. The 
DCC will be responsible for establishing a database to accommodate data 
generated by the study, developing a data transmission system, and assessing 
data quality and completeness throughout the study.  The DCC will provide for 
central registration of all individuals enrolled in the study. The DCC will 
establish, via subcontracts, central laboratories and reading centers, if a 
need for such is determined by the Steering Committee. The DCC will provide 
statistical reports on the progress of study 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 DCC 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, children and minorities as 
subjects in clinical research, and the reporting of results in these 
subgroups. 

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 NICHD and 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 DCC will be expected to put all 
study materials and procedure manuals in the public domain and/or make them 
available to other investigators.

A study site and its institution may not be involved simultaneously in other 
studies involving the testing of glucose sensors in children with and without 
diabetes 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. NICHD and NIDDK Staff Responsibilities

The NICHD and NIDDK Project Scientists will provide scientific assistance 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 NICHD and NIDDK Project Scientists 
will be substantially involved as an active partner in those aspects of the 
scientific and technical management of the study stated in these Terms and 
Conditions.  This level of involvement will be above and beyond the level 
required for administration of traditional research grants.

The NICHD and NIDDK Project Scientists will have voting membership on the 
Steering Committee and, as appropriate, will participate in its 
subcommittees.

The NICHD and NIDDK reserve 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 NICHD and 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 
NICHD and 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 Clinical Center, the 
Principal Investigator of the DCC, and the NICHD and NIDDK Project Scientists 
(one vote combined).  The Steering Committee will have primary responsibility 
for developing common research designs, protocols and manuals, facilitating 
the conduct and monitoring of the study, and reporting study results. The 
Steering Committee will design the protocol, and develop standardized methods 
and measurements to be utilized in the study.  The Steering Committee will 
approve the protocol, changes to the protocol, and the manual of operation. 
Responsibility for the execution of the study 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 protocol 
and subsequently to discuss the progress of the study.  The NICHD and the 
NIDDK will select a chairperson from among the non-federal Steering Committee 
members or other experts in diabetes clinical research.  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 which will be appointed by the NICHD and the NIDDK.  It will be 
composed of pediatric and diabetes and clinical research experts not directly 
involved in the protocol.  Prior to the initiation of the study, 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, the NICHD and the NIDDK. 
The DSQ will monitor the study for safety and scientific validity, with 
authority to recommend protocol or procedural changes or early termination of 
the study.  The DSQ is advisory to the NICHD, the NIDDK, and the Steering 
Committee. The chairperson of the Steering Committee and the Principal 
Investigator of the DCC will attend DSQ meetings, which will take place at 
least twice a year.

4.  Arbitration Process

Any disagreement that may arise on scientific/programmatic matters (within 
the scope of the award) between award recipients and the NICHD and NIDDK may 
be brought to arbitration.  An arbitration panel (with appropriate expertise) 
will be formed to review the NICHD and NIDDK decision and recommend a course 
of action to the Directors, NICHD and NIDDK.  The arbitration panel will be 
composed of three members:  one selected by the Steering Committee (with the 
NICHD and the NIDDK not voting) or by the individual awardee in the event of 
an individual disagreement, a second member selected by the NICHD and the 
NIDDK, and the third member selected by the two prior selected members.

These special arbitration procedures in no way affects the awardee's right to 
appeal an adverse action that is otherwise appealable in accordance with PHS 
regulations 42 CFR Part 50, Subpart D, and DHHS regulations 45 CFR Part 16. 

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 is available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The 
revisions relate to NIH-defined Phase III clinical trials and require:  a) 
all applications or proposals and/or protocols to provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; 
and b) all investigators to report accrual, and to conduct and report 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences. 

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by 
the NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects,”  published in the NIH Guide for Grants 
and Contracts, March 6, 1998, and available on the Internet at:  
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 a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone 
number of the Principal Investigator, the identities of other key personnel 
and participating institutions, and the number and title of this RFA.  
Although a letter of intent is not required, is not binding, and does not 
enter into the review of a subsequent application, the information that it 
contains allows NICHD staff to estimate the potential review workload and 
plan the review.

The letter of intent is to be sent to Dr. Karen K. Winer at the address 
listed under INQUIRIES, below, by March 27, 2001.

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. 

APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants.  These forms are available at most institutional 
offices of sponsored research, on the Internet at 
http://grants.nih.gov/grants/funding/phs398/phs398.html, and from the 
Division of Extramural Outreach and Information Resources, National 
Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-
7910, telephone 301-435-0714, E-mail:  grantsinfo@nih.gov.   

Application Requirements

To promote the development of a collaborative program among the award 
recipients, a number of issues need to be addressed in the grant applications 
as discussed below.  Applicants should document their ability to recruit a 
sufficient number of participants, their ability to interact effectively with 
the coordinating center; and their willingness and capability to participate 
in monthly meetings during the planning phase (up to six months) and semi-
annual meetings over the duration of the five-year award.  It is anticipated 
that two investigators (including the PI), from each clinical site will 
attend these meetings. Also, applicants should state their willingness to 
follow the common protocol that will be agreed upon during the planning 
phase.

1.  Clinical Center Applications

All applicants should provide a detailed description of the design of the 
study and should demonstrate how the continuous monitoring will be 
implemented. Additionally, applicants should justify the proposed monitoring 
device to be used, along with the setting, duration, and frequency of 
monitoring. The application should contain a rationale for the number of 
children in each age to be studied and should describe how subjects will be 
selected to achieve appropriate representation of patient characteristics, 
including methods of treatment.  A crucial element of the study design is 
specification of the precise methods and timing for collecting data including 
the eligibility, baseline, and follow-up testing. Examples of proposed data 
forms and questionnaires should be given.  The process for 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, a 
justification for the chosen method should be included.  Also include the 
methods that would be used to ensure privacy and maintain confidentiality of 
data.  There must be a data and safety monitoring plan.
 
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 number of potential 
subjects 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.  Emphasis should also be placed on inclusion of children 
across age, gender, socioeconomic, and racial-ethnic groups.  Incentives to 
enhance accrual and retention should be described in the applications. 
Because the ultimate study carried out under this RFA will be a collaborative 
effort, an investigator may propose a study that requires more subjects than 
can be recruited from within his/her institution. The investigator should 
provide a detailed description of the total sample size needed as well as the 
number of subjects 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 section, “Inclusion of Women and 
Minorities in Research Involving Human Subjects”). The application must 
provide a detailed account of the local population pool from which subjects 
will be recruited, including the gender and racial/ethnic make-up of the 
population and the expected numbers of subjects from each group that could be 
recruited. A plan for recruitment and retention of participants must be 
provided.  Subcontracts may be used to recruit subjects from additional local 
sites not a part of the parent institution.  In this case, the Principal 
Investigator must include a detailed description of the subject 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 study, not all potential subcontractors will be needed. 

2. Data Coordinating Center (DCC) Applications

A separate complete application is required from institutions applying to be 
the DCC for the Type 1 Diabetes in Children Consortium.  Applicants for the 
DCC component are not required to be a clinical site within the Consortium, 
though applicants for clinical sites may also submit an application to be the 
DCC. 

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 protocol established 
cooperatively by the Steering Committee.  Applicants must address the 
following responsibilities of the DCC:  1) participation in the 
design of the final protocol and development of the manual 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 the protocol and of data quality; and 5) 
establishment of procedures that insure the safety and confidentiality of all 
records.

Data management and quality control procedures must be detailed.  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 the reporting of results that examine differences in treatment effects 
across these subgroups (see section, “Inclusion of Women and Minorities in 
Research Involving Human Subjects”).

Applications may not exceed 25 pages for sections a - d, excluding 
appendices, which may contain copies of pertinent forms or examples of 
correspondence useful for coordinating tasks.

3. Issues To Be Addressed By All Applicants

Qualifications and Experience:  Applicants must include a description of 
their experience and expertise to conduct a clinical study 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 subject 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.  

4. Budget Information

Detailed budget information should be provided for the proposed Clinical 
Center or Data Coordinating Center. The budget should be divided into three 
phases: 1) planning (first six months), 2) recruitment and study (three - 
four years), and 3) analysis (final six months).  The application should 
contain a detailed budget for each phase.

The planning phase will be for the development of the protocol and the manual 
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 subject care costs associated with the 
study. The application should detail these costs as dictated by the study 
that is proposed. The actual budget awarded after the initial project period 
will be determined once the Steering Committee finalizes the protocol. 
Therefore, the final awards may vary among sites. If any centralized 
laboratory assessments are required, costs for laboratory tests will be 
reimbursed using subcontracts through the DCC, at rates determined by the 
NICHD and the NIDDK.

Submission Instructions

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
stapled to the bottom of the face page of the application and must display 
the RFA number HD-01-009.  A sample RFA label is available at 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.  Please note this 
is in the pdf format.  Failure to use this label could result in delayed 
processing of the application such that it may not reach the review committee 
in time for review.  In addition, the RFA title and number must be typed on 
line 2 of the face page of the application form and the YES box must be 
marked.

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed photocopies, in one package, to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

At the time of submission, two additional copies of the application should be 
sent to:

L. R. Stanford, Ph.D.
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5E03, MSC 7510
Bethesda, MD  20892-7510
Rockville, MD 20852 (for express/courier service)

Applications must be received by May 11, 2001.  If an application is received 
after that date, it will be returned to the applicant without review.  

The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed.  This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must 
include an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and for 
responsiveness by the NICHD and 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 NICHD in accordance with the review criteria stated below.  
As part of the initial merit review, all applications will receive a written 
critique and may undergo a process in which only those applications deemed to 
have the highest scientific merit will be discussed, assigned a priority 
score, and receive a second level review by the National Child Health and 
Human Development Advisory Council and the National Diabetes and Digestive 
and Kidney Diseases Advisory Council.

Review Criteria

All applications will be reviewed according to the following criteria: 

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

o Significance:  The application should address the problem outlined in the 
RFA.  The application should demonstrate how the study will advance scientific 
and/or medical knowledge.

o Approach:  The adequacy of the proposed conceptual framework, design, 
methods, and analyses.  The  acknowledgement of  potential problem areas and the 
consideration of alternative tactics.

o Innovation:  The applicant should demonstrate how the project challenges 
existing paradigms or develops new methodologies or technologies.

o Investigator:  The investigator should be appropriately trained and well 
suited to carry out this work.  The proposed study should be appropriate to the 
experience level of the principal investigator and other researchers (if any).  
There should be evidence of prior experience in working collaboratively to carry 
out a clinical study or standard protocol as well as evidence of willingness to 
work cooperatively on the Steering Committee to develop and follow a 
unified protocol.

o Environment:  The environment in which the work will be done should 
contribute to the probability of success. The proposed protocol should take 
advantage of unique features of the scientific environment and employ useful 
collaborative arrangements. There should be evidence of institutional support.

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research. 

o The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project  
proposed in the application.

All applications for the Clinical Centers will also be reviewed with respect 
to the following:

o Approach:  Plans for the recruitment and retention of subjects will be 
evaluated.  Evidence of the ability to recruit, enroll and maintain subjects. 
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.

o The adequacy of plans to ensure accurate collection and timely transmission 
of study data to the DCC. 

o The appropriateness of plans to protect confidentiality of data. 

o The adequacy of the data and safety monitoring plan.

All applications for the Data Coordinating Center will be reviewed with 
respect to the following:

o Data  Management System

Demonstrated experience and ability to implement a data management system for 
collecting, checking, editing, and correcting data from Clinical Centers and 
entry of corrected data into a computer.  The system should include 
provisions to ensure the accuracy of data entry. 

o Quality Control System

Demonstrated ability to implement a quality control system for monitoring 
data collection procedures with timely feedback to the individual centers.

o Personnel

Evidence that the proposed Principal Investigator and other personnel have 
expertise in all aspects of study coordination including monitoring  and 
computerizing data, design and implementation of multicenter study protocols, 
and the design and execution of appropriate statistical analysis and 
reporting of data. 

o  Facilities

Adequacy of facilities and software for data management, monitoring and 
analysis. 

AWARD CRITERIA

Applications recommended by the NICHD and NDDK Advisory Council will be 
considered for award based on the scientific merit of the proposed project, 
as determined by peer review, and the ability of the investigators to meet 
the research objectives of this RFA.  In addition, program balance, defined 
as the scope and variety of research strengths to enable a successful 
collaborative program, the racial and ethnic composition of the populations 
being studied, and the geographical location of the trial will be considered.  
Awards are contingent upon the availability of funds.

SCHEDULE

Letter of Intent Receipt Date:    March 27, 2001
Application Receipt Date:         May 11, 2001
Peer Review Date:                 June 2001
Council Review:                   September 2001
Earliest Anticipated Award Date:  September 2001

INQUIRIES

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:

Karen K. Winer, M.D.
Endocrinology, Nutrition and Growth Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B11, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 435-6877
FAX:  (301) 480-9791
E-mail:  WinerK@mail.nih.gov 

Joan T. Harmon, Ph.D.  
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 697, MSC 5460
Bethesda, MD 20892-5460
Telephone:  (301) 301-594-8813
FAX:  (301) 480-3503
E-mail:  harmonj@extra.niddk.nih.gov 

Direct inquiries regarding fiscal matters to:

Mary Daley
Grants Management Branch 
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17E, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-1305
FAX:  (301) 402-0915
E-mail: md74u@nih.gov

Kim Law
Division of Extramural Activities 
National Institute of Diabetes Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 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 Nos. 
93.865 and 93.847.  Awards are made under authorization of Sections 301 and 
405 of the Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH grants policies and Federal Regulations 42 CFR 52 and 
45 CFR Parts 74 and 92.  This program is not subject to the intergovernmental 
review requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant 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 routing 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.

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