TYPE 1 DIABETES TRIALNET:  CLINICAL CENTERS

Release Date:  October 5, 2000

RFA:  DK-01-003

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

Letter of Intent Receipt Date:  February 28, 2001
Application Receipt Date:       March 29, 2001

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK), the National Institute of Allergy and Infectious Diseases 
(NIAID), and the National Institute of Child Health and Human Development 
(NICHD) are seeking applications for clinical centers (and associated 
networks of recruitment and follow-up sites) to perform intervention 
studies to preserve pancreatic beta cell function and prevent type 1 
diabetes.  The Clinical Centers will complete the ongoing Diabetes 
Prevention Trial for Type 1 Diabetes (DPT-1) and participate in the 
design and execution of pilot and expanded studies of new agents to 
prevent or ameliorate type 1 diabetes, and in natural history and 
genetics studies in populations screened for or enrolled in these 
studies.  

The Clinical Centers selected to complete the ongoing DPT-1 and to 
participate in new studies, as well as core support facilities, will 
constitute a national diabetes trial network (Type 1 Diabetes TrialNet or 
TrialNet) of clinical research groups whose aim is to recruit patients 
and to support studies that may eventually result in an improved 
understanding of type 1 diabetes and the prevention of the disease.  

A complementary Request for Application (RFA)(DK-01-004) is being 
published to establish the Type 1 Diabetes TrialNet Operations 
Coordinating Center, Data Monitoring Unit, core laboratories, compounding 
pharmacy, central distribution pharmacy, and clinical cost reimbursement 
system.  Institutions and investigators applying to become Clinical 
Centers may also apply for components of the TrialNet solicited under RFA 
DK-01-004.

This RFA responds to recommendations of the Congressionally-established 
Diabetes Research Working Group 
(http://www.niddk.nih.gov/federal/dwg/dwgsummary.htm), which developed a 
strategic plan for research in diabetes.  Among the extraordinary research 
opportunities mentioned in the plan were: the conduct of additional 
clinical trials of immunoprevention of type 1 diabetes using antigen-
specific, cytokine- or antibody-based immunotherapy; and the 
establishment of a national diabetes trial network of cooperative 
clinical research groups to create the stable, high-quality 
infrastructure necessary for the conduct of effective and efficient 
clinical trials in diabetes.

The actual studies to be performed, in addition to completion of DPT-1, 
will be determined by a steering committee (see Special Requirements, 
Study Organization below) composed of Principal Investigators of the 
Clinical Centers, Operations Coordinating Center, Data Monitoring Unit, 
Core Laboratories, and NIH Program Officers.  Nonetheless, applicants 
wishing to participate in these studies should propose one intervention 
study of a new agent to prevent or ameliorate type 1 diabetes.  Current 
DPT-1 Clinical Centers wishing only to complete DPT-1 and not to 
participate in future studies do not need to submit a proposal for a 
study of a new agent.

It is anticipated that many of the pilot and expanded intervention 
studies of new agents to prevent or ameliorate type 1 diabetes that 
eventually will be performed in the TrialNet will be proposed through 
this RFA.  However, after awards are made in response to this RFA, 
research proposals for pilot and expanded intervention studies requiring 
Type 1 Diabetes TrialNet resources may be submitted by non-members of the 
TrialNet (see Eligibility Requirements below).  The mechanism for 
receiving and evaluating future proposals, and prioritizing studies, will 
be determined by the TrialNet Steering Committee.

The Immune Tolerance Network (ITN), a program of the NIAID, NIDDK and 
Juvenile Diabetes Foundation International (JDF), also supports clinical 
trials to evaluate the safety and efficacy of tolerance induction 
strategies to prevent and ameliorate type 1 diabetes and other autoimmune 
diseases.  Information on this program can be found at 
http://www.immunetolerance.org.  The Type 1 Diabetes TrialNet and the ITN 
will provide an integrated approach to immunoprevention and amelioration 
of type 1 diabetes.  Promising pilot studies initiated in the ITN may 
lead to larger clinical trials that could be conducted using TrialNet.  
In addition, TrialNet may use assays provided through the ITN to generate 
information on mechanisms by which interventions exert their effect.

Investigators wishing to seek funding for ancillary studies, such as 
those identifying underlying mechanisms in immunoprevention, should 
consider other sources.  These include investigator-initiated grants and 
the ITN mentioned above.  Investigators interested in mechanistic studies 
involving patients and patient materials in the DPT-1 or Type 1 Diabetes 
TrialNet may also consider funding through the Hyperaccelerated 
Award/Mechanisms in Immunomodulation Trials (RFA AI-00-005).

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, Type 1 
Diabetes TrialNet, is related to the priority area of Diabetes.  
Potential applicants may view a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by investigators from institutions in North 
America.  This geographic constraint is necessary because of the need for 
close communication among members of the study group, the requirement for 
frequent Steering Committee meetings, and the anticipated need for site 
visits to ensure adequate recruitment, retention, and the use of 
standardized procedures across the studies.  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 may apply.  Applicants from 
racial/ethnic minority groups, women, and persons with disabilities are 
encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program 
will be the 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”, “Special Requirements”, 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 
2001.

Because the nature and scope of the research supported by the Type 1 
Diabetes TrialNet may vary over time and by site, it is anticipated that 
the sizes of awards may also vary.  After initiation of the TrialNet, 
awards in subsequent years will be determined by the requirements of the 
specific studies designed by the Steering Committee, the level of 
participation of individual sites, and the availability of funds.  Awards 
and level of support depend on receipt of a sufficient number of 
applications of high scientific merit.  Although this program is provided 
for in the financial plans of the NIDDK/NIAID/NICHD, awards pursuant to 
this RFA are contingent upon the availability of funds for this purpose.

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/NIAID/NICHD 
have not determined whether or how this solicitation will be continued 
beyond the present RFA.

FUNDS AVAILABLE  

Approximately $4.6 million in total costs per year will be committed to 
provide personnel and supplies to the Clinical Centers in order to 
complete DPT-1 and initiate planning for future studies conducted within 
the Type 1 Diabetes TrialNet, with a cap of approximately $228,000 per 
clinical center per year in total costs.  For Clinical Centers that 
previously participated in DPT-1, initial year funding will be allocated 
based on the success that Clinical Centers (and associated network sites) 
have had in recruitment and retention of DPT-1 participants and on 
numbers of network sites that Clinical Centers must administer.  These 
costs do not include expenses for patient care; additional funds in the 
amount of approximately $725,000 per year will be provided to TrialNet 
Clinical Centers for patient care costs related to the screening, 
treatment, and follow-up of patients in the DPT-1.  The funds allocated 
for patient care will be managed centrally by the clinical cost 
reimbursement system of the TrialNet’s core support facilities.  

Initial awards to the Clinical Centers will be in support of completion 
of DPT-1.  Subsequently, as additional studies are developed by the 
TrialNet Steering Committee (see Special Requirements, Study Organization 
below), additional funds will be provided.  

Proposed budgets should include costs for personnel and supplies to 
support completion of the DPT-1.  Proposed budgets should not include 
costs for patient care.  In addition, proposed budgets should not include 
anticipated costs to support pilot and expanded studies because final 
design of these studies and allocation of costs will need to be 
determined by the Type 1 Diabetes TrialNet Steering Committee and the 
NIDDK.

Ancillary studies will not be funded through this mechanism; however, 
interested investigators may seek funding through investigator-initiated 
grants and the ITN (www.immunetolerance.org).  Investigators interested 
in mechanistic studies involving patients and patient materials in the 
DPT-1 or Type 1 Diabetes TrialNet may also consider funding through the 
Hyperaccelerated Award/Mechanisms in Immunomodulation Trials (RFA AI-00-
005).

It is anticipated that up to 20 awards for Clinical Centers will be 
issued.  Past participation in the DPT-1 is not a prerequisite for 
participation in the Type 1 Diabetes TrialNet.  Nine clinical centers are 
currently supported for conduct of DPT-1 and are expected to compete for 
these awards.  Institutions that have participated in the DPT-1 as 
Affiliates or Satellites of these Clinical Centers, Regional Recruitment 
Coordinating Centers, Minority Recruitment Centers, and other sites not 
previously participating in the DPT-1, may apply for Clinical Center 
awards.  Institutions and investigators not participating in DPT-1 but 
with access to patient populations and with scientific expertise relevant 
to TrialNet are encouraged to apply in response to this solicitation.

RESEARCH OBJECTIVES

Background    

1)  Diabetes Prevention Trial for Type 1 Diabetes (DPT-1)

1.1) DPT-1 Objectives and Design

Type 1 diabetes arises in genetically predisposed individuals as a 
consequence of immune-mediated destruction of the pancreatic islet 
insulin secreting beta cells.  The onset of clinical symptoms of diabetes 
represents the endpoint of a chronic progressive decline in beta cell 
function, and occurs when the majority of beta cells have been lost.  
First-degree relatives of probands with type 1 diabetes have more than a 
tenfold risk of type 1 diabetes compared with the general population.  
Type 1 diabetes can be predicted with a high degree of accuracy in 
relatives of patients with type 1 diabetes by the presence of 
autoantibodies and evidence of pancreatic beta-cell dysfunction.  

The major objective of the ongoing DPT-1 is to determine whether early 
intervention using antigen-based therapies (parenteral or oral insulin) 
in nondiabetic relatives of persons with type 1 diabetes can delay the 
development of type 1 diabetes as a clinical disease.  The rationale for 
initiating the DPT-1 was based on several lines of evidence.  Parenteral 
insulin had been successfully used to prevent diabetes in animal models 
of spontaneous diabetes (e.g., BB rat, NOD mouse).  In humans, intensive 
insulin therapy in newly-diagnosed diabetic patients had preserved beta-
cell function, and small pilot studies of prediabetic patients suggested 
that insulin treatment may delay development of type 1 diabetes.  In 
these studies, it was thought that exogenous insulin may be serving as an 
immune modulator or may be decreasing the expression of secretory 
granule-associated antigens from the beta-cells, making them less 
susceptible to immune attack.  Oral insulin had been studied in the NOD 
mouse model of type 1 diabetes; these studies demonstrated that oral 
administration of islet cell autoantigens was effective in delaying the 
onset of type 1 diabetes.  In addition, ingestion of glutamic acid 
decarboxylase (GAD), a beta-cell antigen, by NOD mice also inhibited the 
development of diabetes.  These results suggested that tolerance provoked 
by presentation of oral insulin or GAD to the immune system via the 
intestinal mucosa could attenuate pancreatic islet autoimmunity, leading 
to a delay in the onset of type 1 diabetes.

Initial screening for DPT-1 is being conducted by determining the 
presence of islet cell autoantibodies (ICA) in nondiabetic relatives of 
individuals with type 1 diabetes.  Those individuals found to have ICA 
are then staged into different categories of risk for type 1 diabetes, 
depending on their point in the progression to clinical disease.  This 
further assessment of risk of type 1 diabetes in nondiabetic relatives is 
based on a number of factors, including:  genetic susceptibility, the 
presence of insulin autoantibodies (IAA), and the degree of loss of first 
phase plasma insulin response (FPIR) during an intravenous glucose 
tolerance test.  Individuals with a protective HLA haplotype are excluded 
from study.  “High risk” relatives are those who have been predicted to 
have a greater than 50% probability of developing type 1 diabetes within 
the next 5 years based on being positive for ICA and having a low FPIR.  
“Intermediate Risk” relatives are those who have been predicted to have a 
25-50% risk of type 1 diabetes during the next 5 years based on being 
positive for ICA and also for IAA, but not having a low FPIR.  Relatives 
at lower risk lack IAA and do not have a low FPIR.  Subjects were divided 
into predictive risk groups to permit different intervention strategies 
to be applied based on their stage in the progression of the disease.  
The more invasive therapeutic approach with parenteral administration was 
tested in the group with the higher estimated risk of type 1 diabetes.

In the “High Risk” group, the protocol is designed to determine whether 
parenteral insulin therapy, consisting of daily subcutaneous insulin 
injections with an accompanying annual course of continuous intravenous 
insulin, will delay the expected development of clinical type 1 diabetes.  
Subjects are being randomized to either the experimental treatment group 
or closely monitored (control) group who will be carefully assessed and 
offered treatment at the earliest sign of clinical diabetes.  The 
intervention protocol for the “Intermediate Risk” group is designed to 
determine whether orally-ingested insulin can induce immunological 
tolerance, thereby delaying the development of type 1 diabetes.  Subjects 
are being randomized to either the experimental treatment group or 
placebo-controlled group.  Randomized participants are followed at six-
month intervals.  Subjects who are ICA positive but who are at lower risk 
of type 1 diabetes are not being enrolled in the study but are being 
followed for progression to intermediate or high risk with the 
opportunity for enrollment at that stage.  

The design of DPT-1 requires the enrollment of 340 “High Risk” and 490 
“Intermediate Risk” subjects.  Screening for the trial began in September 
1993.  Subjects were first randomized to the “High Risk” protocol in 
December 1994 and to the “Intermediate Risk” protocol in September 1996.  
Participants are to be followed for at least two years and up to 
approximately 6 years.  As of July 2000, the recruitment for the “High 
Risk” protocol is approximately 95% complete and for the “Intermediate 
Risk” protocol is approximately 55% complete.  Recruitment is expected to 
be completed by the end of 2002.

1.2) DPT-1 Clinical Centers and Networks, Core Support Facilities

Nine parent Clinical Centers are participating in the DPT-1.  Parent 
Clinical Centers are involved in screening, staging, enrolling, and 
following study participants.  Each Clinical Center provides 
administrative support for its own network of Affiliates and Satellites.  
In total, there are approximately 350 Affiliates and Satellites 
participating in DPT-1 across the United States, Canada, and Puerto Rico.  
Affiliates screen, stage and follow participants, while Satellites are 
involved only in screening.  In addition, there are designated regional 
recruitment coordinating centers which provide local outreach to 
underserved geographic areas of the country to enhance recruitment, as 
well as minority recruitment centers which focus on increased recruitment 
of these population subgroups.

Current core support facilities of the DPT-1 include the Operations 
Coordinating Center (OCC), the Data Monitoring Unit (DMU), Core 
Laboratories, a Compounding Pharmacy, the Central Distribution Pharmacy, 
a consultant firm that provides the central telephone line and 
publicity/recruitment support, and the clinical cost reimbursement 
system.  The OCC coordinates all interactions between the core support 
facilities, Clinical Centers and associated networks of Affiliates and 
Satellites, sponsoring agencies, study committees, and consultants.  The 
OCC also develops and/or maintains financial management plans and all 
study protocols, manuals, agendas, and newsletters.  The DMU is 
responsible for all study data management and statistical considerations.  
In addition, the DMU tracks clinical tests performed within the DPT-1 and 
provides this information to two fiscal cluster facilities that 
distribute payments to the appropriate Clinical 
Centers/Affiliates/Satellites.  The core laboratories include the Islet 
Cell Antibody Laboratory, the Insulin Autoantibody Laboratory, the Class 
II Major Histocompatibility and DNA Extraction Laboratory, and the Beta 
Cell Function Laboratory.  The Central Distribution Pharmacy dispenses 
all therapeutic agents and placebos in DPT-1 studies.  It receives 
crystallized insulin and placebo in capsules from the separate 
compounding pharmacy.

DPT-1 is presently funded through August 2001.  The trial is jointly 
supported by the National Institute of Diabetes and Digestive and Kidney 
Diseases, the National Institute of Allergy and Infectious Diseases, 
National Institute of Child Health and Human Development, the National 
Center for Research Resources through funding of General Clinical 
Research Centers, the American Diabetes Association, the Juvenile 
Diabetes Foundation International, and industry.  

2.) Studies of New Immunologic Agents and Other Preventive and Treatment 
Strategies

In recognition of the seriousness of diabetes in terms of both human toll 
and economic costs, Congress directed the establishment of the Diabetes 
Research Working Group (DRWG) and charged it with developing a 
comprehensive plan for diabetes research.  During 1998, the DRWG and its 
subcommittees held a series of meetings, consulted with a wide range of 
experts in the field, and heard public commentary.  A comprehensive 
strategic research plan was submitted to Congress in 1999 
(http://www.niddk.nih.gov/federal/dwg/dwgsummary.htm).  As part of the plan, the 
DRWG identified areas of extraordinary opportunity for making genuine and 
significant progress toward understanding, more effectively treating, and 
ultimately preventing and curing diabetes.  Among these opportunities was 
the recommendation to “define the immunological basis of type 1 diabetes 
and develop methods for prevention of the disease.”  Specific 
recommendations included:  to intensify research to understand the 
immunological basis of type 1 diabetes; to complete mapping of T cell 
specificity of autoimmune responses to major pancreatic islet cell 
proteins and identify optimal strategies for immunotherapy; to expand the 
scope of efforts to identify immune response markers that reliably detect 
individuals predisposed to type 1 diabetes in the population at large; 
and to conduct additional clinical trials of immunoprevention of type 1 
diabetes using antigen-specific, cytokine- or antibody-based 
immunotherapy.  

In response to these recommendations, the NIDDK and DPT-1 investigators 
have convened meetings to consider future natural history, pilot and 
intervention studies.  A number of ideas were generated.  Potential 
cohorts for study include:  patients with type 1 diabetes who have 
evidence of residual pancreatic beta-cell function; individuals found to 
have biochemical antibodies in an ancillary study of the DPT-1 cohort, 
who do not meet eligibility criteria for the DPT-1; individuals found to 
be ICA positive in the DPT-1, who lack other beta-cell antibodies and 
have an intact first phase insulin response; individuals found during 
staging for the DPT-1 to be positive for protective HLA-haplotypes; 
individuals found to have diabetes during staging; and randomized DPT-1 
subjects who develop diabetes on follow-up.  Examples of potential agents 
to prevent or ameliorate type 1 diabetes include antigen-based therapies 
such as recombinant human GAD65 and the heat shock protein hsp60 p277 
peptide, monoclonal antibodies such as anti-CD3 and anti-CD25, and 
certain cytokine-based therapies.  Multiple pilot, feasibility, and 
efficacy studies could be done simultaneously to test promising agents in 
patients with type 1 diabetes who have evidence of residual beta cell 
function (including DPT-1 subjects who develop diabetes during follow-
up), or in patients identified in the screening process for DPT-1 who are 
not eligible for the trial.  Loss of C-peptide secretion would be a 
suitable design endpoint for such studies.  On the basis of these pilot 
studies, expanded intervention studies might be launched in new-onset 
type 1 diabetic individuals to assess beta-cell function over time and 
ultimately in at-risk pre-diabetic individuals to prevent development of 
diabetes.  

3.) Type 1 Diabetes TrialNet

The Diabetes Research Working Group also noted that clinical research and 
clinical trials in diabetes have been hampered by the lack of 
infrastructure to organize and support them.  The long-term natural 
history of the disease and its complications add to the complexity of 
clinical trials.  Needed are efficient systems for clinical research to 
provide the necessary numbers of patients and the stability of operations 
for long-term studies, and opportunities to include sufficient numbers of 
appropriate minority groups.  To that end it was recommended that there 
be established a national diabetes trial network of cooperative clinical 
research groups to create the stable, high-quality infrastructure 
necessary for the conduct of effective and efficient clinical trials in 
diabetes.

The established network in the DPT-1 of Clinical Centers, Affiliates and 
Satellites is an excellent platform on which to build an enhanced network 
that could comprise the Type 1 Diabetes TrialNet.  Currently there are 
nine parent Clinical Centers participating in screening, staging, 
randomization, and follow-up of volunteers in the DPT-1.  Each Clinical 
Center provides administrative management and training for an extended 
network of institutions and physicians, including Affiliates that also 
screen, stage, randomize, and follow volunteers, as well as Satellites 
that screen potential participants.  Expansion of the number of Clinical 
Centers and associated Affiliates and Satellites would enhance 
recruitment of subjects for the DPT-1 and future Type 1 Diabetes TrialNet 
studies. 

4.) Potential Genetics Studies using Type 1 Diabetes TrialNet

An additional extraordinary opportunity identified by the Diabetes 
Research Working Group was the study of the genetics of diabetes and its 
complications.  While it was recognized that most of the basic tools for 
genetic studies were in place and that much progress had been made, it 
was noted that current approaches were inadequate to tackle vital 
genetics questions in a reasonable time frame.  Impediments cited were 
inadequate resources, the lack of an appropriate mechanism to bring 
together groups of researchers and patient samples to conduct studies, 
and fragmented genetic repositories.

The DPT-1 study population and populations identified by the Type 1 
Diabetes TrialNet may be fruitful groups to study predisposing genes to 
type 1 diabetes and diabetic complications.  While it has not been 
determined whether or how such studies might be implemented, samples and 
associated data from participants of the DPT-1 and TrialNet may be 
entered into genetic repositories for use by investigators inside or 
outside the TrialNet.

Objectives and Scope    

The first objective of the Type 1 Diabetes TrialNet is to create an 
infrastructure that will enhance recruitment and follow-up of subjects in 
the DPT-1 and facilitate investigation of promising new approaches to 
prevent or ameliorate type 1 diabetes.  To accomplish this, each Clinical 
Center will have a Principal Investigator, a Trial Coordinator, and a 
Recruitment Coordinator, at a level of effort to be determined by the 
number and scope of trials underway.  

Initially, each Clinical Center will be responsible for implementation of 
the protocols of the DPT-1, including screening and staging of 
potentially eligible individuals, and randomization and follow-up of 
participants.  Screening of subjects involves identifying eligible 
subjects for screening (relatives of individuals with type 1 diabetes, 
either first-degree relatives age 3-45 years or second-degree relatives 
age 3-20 years), obtaining informed consent, obtaining blood to determine 
the presence of islet cell antibodies (ICAs), and collecting demographic 
and contact information.  Those individuals found to be ICA-positive are 
eligible for staging which involves obtaining informed consent, 
performing intravenous glucose tolerance (IVGTT) and oral glucose 
tolerance tests (OGTT), and drawing samples for insulin autoantibodies 
(IAA) and HLA-typing.  Confirmatory tests are also required.  For those 
individuals eligible for randomization, informed consent is again 
obtained and additional tests are performed, including the Wide Range 
Achievement Test (WRAT), an IVGTT and/or mixed meal tolerance test 
(MMTT), an OGTT, a 4-day insulin infusion (parenteral insulin arm), and 
blood draws for measuring blood glucose and HbA1c.  A physical 
examination is performed and medical and family history data are 
obtained.  Randomized subjects are followed every 6 months, at which time 
many of these same tests are performed and additional medical history is 
obtained.  Clinical Centers and their associated Affiliates/Satellites 
will be reimbursed for medical tests performed during screening, staging, 
randomization, and follow-up at rates determined by the NIDDK.

Each Clinical Center should have access to an NIH supported General 
Clinical Research Center (GCRC) or equivalent facility to support 
inpatient study costs occurring during staging and follow-up in the DPT-1 
and in future studies conducted in the TrialNet.  An “equivalent GCRC 
facility” is defined as dedicated inpatient beds staffed by personnel 
experienced in the conduct of research protocols and in performance of 
intravenous insulin infusions, with institutional commitment to provide 
such beds at no extra expense to the TrialNet.  GCRCs also provide 
support for outpatient testing.  

For the DPT-1, Clinical Centers will collaborate with the Operations 
Coordinating Center, the Data Monitoring Unit, the Core Laboratories 
(Islet Cell Antibody Laboratory, Insulin Autoantibody Laboratory, Class 
II MHC and DNA Extraction Laboratory, and Beta-Cell Laboratory), the 
Central Distribution Pharmacy, as well as the Affiliates and Satellites.  
The Principal Investigator, Trial Coordinator, and Recruitment 
Coordinator will work with the Operations Coordinating Center, the Chair 
of the Steering Committee, other Steering Committee members, NIH staff, 
and Study Committees to conduct the study in accordance with the DPT-1 
Protocol and Manual of Operations.  (The Steering Committee and Chair of 
the Steering Committee are defined under SPECIAL REQUIREMENTS, Study 
Organization.)  Clinical Centers and their network of Affiliates and 
Satellites are expected to meet patient recruitment goals as specified by 
the DPT-1 Study Group.  To accomplish this, Clinical Centers and their 
network of Affiliates and Satellites are expected to develop and maintain 
successful outreach activities that identify eligible participants and 
that result in randomization and retention of participants.  Clinical 
Centers will work with their Affiliates and Satellites, the Operations 
Coordinating Center, Data Monitoring Unit, and all Core Laboratories to 
achieve and maintain quality data that are obtained within expected 
timeframes.  Clinical Centers will provide administrative support, 
supervision, and training for their Affiliates and Satellites, and will 
be responsible for completion of certification requirements of their 
Affiliates and Satellites for certain study tests.

Affiliates of Clinical Centers should be medical centers with the 
capability to screen patients, perform tolerance tests (intravenous 
glucose, oral glucose and mixed meal) and conduct the two intervention 
protocols of the DPT-1.  Affiliates must have available a GCRC or 
equivalent facility, and must obtain certification to perform intravenous 
insulin infusions from the parent Clinical Center.  Affiliates must sign 
a Letter of Agreement that outlines the details of their participation in 
the study.  Clinical Centers will provide oversight of Affiliates and the 
activities of the Affiliates will be intertwined with those of the parent 
Clinical Center.  Affiliates will not receive core funding but will be 
reimbursed for patient tests performed during screening, staging, and 
randomization at rates set by the NIDDK.  Each Affiliate must be directed 
by a Principal Investigator who is a physician.  Affiliates are 
encouraged to participate on Study Committees.  Affiliates may have the 
opportunity to convert to a Clinical Center based on the ability to 
screen, enroll, and retain substantial numbers of subjects, having access 
to a GCRC or equivalent facility, and other criteria, if approved by the 
TrialNet Steering Committee, and as funds permit.

Satellites will be sites involved only in screening eligible volunteers.  
Clinical Centers will provide oversight of Satellites and the activities 
of the Satellites will be intertwined with those of the parent Clinical 
Center.  Satellites will not receive core funding but will be reimbursed 
for screening tests at rates set by the NIDDK.  Staging and randomization 
of subjects originally screened at a Satellite will take place at an 
Affiliate or Clinical Center closest to the subject geographically, or at 
the parent Clinical Center.  Satellites are encouraged to participate on 
Study Committees.

Clinical Centers, Affiliates, and Satellites must conform to the 
guidelines of the Office of Human Research Protections (OHRP) by 
obtaining an assurance, having an institutional review board (IRB) of 
record, and obtaining IRB approval annually.  They must also comply with 
NIH policies on inclusion of minorities, both genders, and children in 
clinical research.

A second objective of each parent Clinical Center and network of 
Affiliates and Satellites is to perform pilot and expanded intervention 
studies of new agents to prevent or ameliorate type 1 diabetes as well as 
natural history and genetics studies in populations identified by the 
DPT-1 and Type 1 Diabetes TrialNet.  Applicants should submit proposals 
for a clinical protocol to be carried out by the TrialNet.  Study 
procedures for future clinical trials will be determined as potential 
agents are selected and studies are designed.  Study procedures for these 
studies may be similar to those used in the DPT-1, although the 
population for study will likely differ; for example, future populations 
for study may be individuals with recent onset type 1 diabetes (See 
Research Objectives, Background, under Studies of New Immunologic Agents 
and Other Preventive and Treatment Strategies).  It is anticipated that 
multiple pilot studies would be performed simultaneously to test the 
feasibility of promising agents.  On the basis of these pilot studies, 
expanded intervention studies might be launched in new-onset type 1 
diabetic individuals to assess beta-cell function over time and in at-
risk pre-diabetic individuals to prevent the development of diabetes.  
The Type 1 Diabetes TrialNet may draw on positive findings from studies 
of agents tested in the Immune Tolerance Network 
(http://www.immunetolerance.org).

It is anticipated that many of the pilot and expanded intervention 
studies performed in the TrialNet will be proposed through this RFA.  The 
TrialNet Steering Committee will refine the design and implement these 
studies.  After awards are made in response to this RFA, research 
proposals for pilot and expanded intervention studies requiring TrialNet 
resources may be submitted by non-members of the TrialNet (see 
Eligibility Requirements above).  The mechanism for receiving and 
evaluating future proposals, and prioritizing studies, will be determined 
by the TrialNet Steering Committee.

The NIDDK expects that biologic samples and associated clinical data will 
be made available to the broader scientific community at an appropriate 
juncture to support further studies related to the prevention and 
etiology of type 1 diabetes, and in studies to identify genes 
predisposing to diabetes and its complications.

SPECIAL REQUIREMENTS

To promote the development of a collaborative program among the award 
recipients, Principal Investigators, trial coordinators, and recruitment 
coordinators are expected to attend DPT-1 and Diabetes TrialNet Steering 
Committee meetings where new studies will be designed, study progress 
will be monitored, issues related to study protocol and operations will 
be discussed, and ideas will be exchanged to enhance study progress.  For 
established clinical trials, twice a year meetings are anticipated but 
more frequent meetings may be required for development of new protocols.  
Trial coordinators and recruitment coordinators will meet on a regular 
basis by conference call, generally monthly, to discuss recruitment 
issues and study operations.  Clinical Center Principal Investigators 
will also meet on a regular basis by conference call to discuss emerging 
issues.  Clinical Center Principal Investigators, trial coordinators, and 
recruitment coordinators will be asked to serve as chairpersons or 
members of Study Committees as needed.   Affiliate and Satellite staff 
may also be invited to participate in Study Committees.  Site visits by 
members of the DPT-1 and Type 1 Diabetes TrialNet Study Group or the 
external Data Safety and Quality Monitoring Groups may be required to 
assess and improve methods used for recruitment/retention of participants 
and for data collection. 

Each Clinical Center applicant should have access to an NIH supported 
General Clinical Research Center (GCRC) or equivalent facility to support 
inpatient study costs occurring during staging and follow-up in the DPT-1 
and in future studies conducted in the TrialNet.  An “equivalent GCRC 
facility” is defined as dedicated inpatient beds staffed by personnel 
experienced in the conduct of research protocols and in performance of 
intravenous insulin infusions, with institutional commitment to provide 
such beds at no extra expense to the TrialNet.  GCRCs also provide 
support for outpatient testing.  

The design and implementation of new intervention, natural history, and 
genetics studies under the Type 1 Diabetes TrialNet will be determined by 
the Steering Committee and will occur after Clinical Centers are selected 
and awards are made.  Because the Principal Investigators will serve as 
voting members of the Steering Committee and will play a major role in 
the design of future studies, a significant aspect of review of 
applications will be the extent to which investigators can contribute to 
this process.  Therefore applicants are required to propose one 
intervention study that could be carried out under the TrialNet.  Natural 
history and genetics studies should not be proposed.  These proposals 
should include the scientific rationale for the study proposed, the 
population to be studied, eligibility and exclusion criteria for the 
study, patient recruitment and data collection methods, primary and 
secondary endpoints to be determined, and a discussion of the sample size 
required given associated assumptions.  The scientific rationale should 
include a discussion of what is the current “state-of-the-art”, future 
opportunities, and obstacles in the prevention of type 1 diabetes, and 
discuss how the field may best be moved forward.  

Study Organization

The Type 1 Diabetes TrialNet, or TrialNet, will be a national network of 
cooperative clinical research groups, consisting of a consortia of 
clinical centers and core support facilities, whose aim is to recruit 
patients and to support studies that may eventually result in an improved 
understanding of type 1 diabetes and the prevention of the disease.  

Each Clinical Center will receive funding through a separate U01 award 
mechanism.  Each Clinical Center will have responsibility for its 
associated network of Affiliates and Satellites as described above.  
Functions of the Clinical Centers have been described above under 
“Objectives and Scope”.  In addition to the Clinical Centers and their 
networks, the Type 1 Diabetes TrialNet will include the Operations 
Coordinating Center, Data Management Unit, Compounding Pharmacy, Central 
Distribution Pharmacy, and Core Laboratories.  A complementary RFA 
solicits proposals for these core support facilities (DK-01-004).  
Design, monitoring and analysis of the studies will be the responsibility 
of the Steering Committee (defined below) and will be accomplished 
through sub-committees.

The Operations Coordinating Center has both scientific and administrative 
functions.  Scientific functions include preparing and updating protocols 
and manuals of operations, developing meeting agendas, documenting 
minutes of meetings, overseeing the performance of quality control, and 
coordinating manuscript preparation and submission.  Administrative 
functions include coordinating interactions among the Clinical Centers, 
and between the Data Management Unit, Core Laboratories, consultant firm 
providing the central telephone line and publicity/recruitment support, 
and NIH Staff; assisting in financial management of the study; overseeing 
subcontracts to other core facilities, such as the Core Laboratories, the 
Compounding Pharmacy, and consultant firm; and providing a mechanism for 
communication among investigators by developing newsletters, scheduling 
meetings and conference calls, and maintaining membership rosters and 
committee lists.

The Data Management Unit (DMU) is responsible for all data management and 
statistical considerations for the DPT-1 and Type 1 Diabetes TrialNet.  
The DMU also has both administrative and scientific functions.  The 
administrative functions include providing for central registration and 
random assignment of all individuals enrolled in trials; preparing data 
management aids; receiving and maintaining participant data; serving on 
all DPT-1 and TrialNet administrative committees; and coordinating with 
the Central Distribution Pharmacy and patient care cost reimbursement 
system.  Scientific functions include the review of all proposed 
protocols and development of the statistical design for each study; 
analysis of study results; review of all manuscripts for statistical 
considerations; development and testing of predictive models for disease 
progression; providing statistical reports on progress of trials at all 
meetings; and conduct of statistical research concerning intervention 
trials in type 1 diabetes.

The Central Distribution Pharmacy dispenses all therapeutic agents and 
placebos to Clinical Centers in a masked manner as directed by the DMU.  
Currently for DPT-1, it receives crystallized insulin and placebo from a 
separate compounding pharmacy.

There are four Core Laboratories in the DPT-1.  The Islet Cell Antibody 
Laboratory serves as the central laboratory for measuring various 
autoantibodies to islet cell markers, and for measurement of anti-islet 
cellular immunity.  The Insulin Autoantibody Core Laboratory serves as 
the central laboratory for measurement of insulin autoantibodies.  The 
Class II MHC Laboratory extracts and preserves DNA from all subjects 
staged for eligibility for enrollment in intervention protocols, and 
determines the presence of HLA-DQA1*0102, DQB1*0602 which is being used 
to exclude individuals who have this protective haplotype.  The Class II 
MHC Laboratory may provide more complete class II HLA typing of all 
individuals entered into trials, as well as other genetic markers that 
influence susceptibility or progression of type 1 diabetes.  The Beta 
Cell Function Laboratory serves as the central laboratory for assessing 
beta cell function by measurement of immunoreactive insulin and C-
peptide, plasma glucose, and glycosylated hemoglobin HbA1c.  New studies 
performed within the TrialNet may require additional core laboratory 
measurements.  Core laboratory support may be consolidated under fewer 
laboratories if deemed possible and advantageous.  Assay cores of the 
Immune Tolerance Network may also be used for assessments in the 
TrialNet.

The Steering Committee has overall responsibility for the design, 
planning, execution, and publication of the research performed by the 
DPT-1 Study Group and Type 1 Diabetes TrialNet.  The Steering Committee 
will approve all protocols, changes to protocols, and manuals of 
operations.  It will define subcommittees, develop study policies, 
receive and act upon reports of subcommittees and review matters relevant 
to administrative, financial, medical, legal, and ethical considerations 
of studies.  The Steering Committee will maintain surveillance of DPT-1 
and Type 1 Diabetes TrialNet performance and, together with the 
NIDDK/NIAID/NICHD, is responsible for the addition or deletion of 
Clinical Centers.  At the present time, voting members of the DPT-1 
Steering Committee include each of the directors of the Clinical Centers, 
the director of the Operations Coordinating Center, the director of the 
Data Management Unit, each of the directors of the Core Laboratories, and 
the three representatives from the NIDDK, NIAID, and NICHD.  The chair of 
the Planning Committee is also a voting member; the Planning Committee is 
responsible for coordinating other Working Committees and integrating the 
Working Committees’ input into the DPT-1 Steering Committee agenda.  
(Examples of current Working Committees are the Eligibility and Events 
Committee, Treatment Committee, Ancillary Studies Committee, Clinical 
Center Directors Committee, and Trial Coordinators Committee.  Members of 
the Planning Committee consist of the Chair of the Steering Committee, 
Chairs of each Working Committee, and Operations Committee members.  The 
Operations Committee consists of the Chair of the Steering Committee, and 
a representative from the Operations Coordinating Center, the Data 
Monitoring Unit, and the NIDDK.  The Operations Committee selects the 
Chair of the Planning Committee.)  The NIDDK will select a chairperson 
for the DPT-1 and Type 1 Diabetes TrialNet Steering Committee from among 
Study Group members or other experts in clinical trials in type 1 
diabetes.  The NIDDK may appoint a new Chairperson of the TrialNet once 
the DPT-1 is completed.

The Chairperson of the Steering Committee is responsible for the overall 
administration and science of the DPT-1 and Type 1 Diabetes TrialNet 
activities by:  reviewing all concepts for science and feasibility; 
reviewing all protocols prior to implementation; reviewing all 
manuscripts, posters, and abstracts prior to publication; monitoring 
committee activities; assuring compliance with protocol requirements; 
observing and enforcing all DPT-1 and TrialNet policies and guidelines; 
and facilitating performance of institutions and centers participating in 
the DPT-1 and TrialNet.

It is anticipated that many of the pilot and expanded intervention 
studies performed in the TrialNet will be proposed through this RFA.  The 
TrialNet Steering Committee will refine the design and implement these 
studies.  After awards are made in response to this RFA, research 
proposals for pilot and expanded intervention studies requiring TrialNet 
resources may be submitted by non-members of the TrialNet (see 
Eligibility Requirements above).  The mechanism for receiving and 
evaluating future proposals, and prioritizing studies, will be determined 
by the TrialNet Steering Committee.  These competitions will be fair and 
open, and may involve external reviewers.

The Data Safety and Quality Monitoring Group (DSQ) is an external 
oversight committee of the DPT-1 appointed by the NIDDK and is composed 
of members not directly involved in the study. The DSQ monitors the 
conduct and results of the DPT-1 study for safety and efficacy, with 
authority to recommend protocol or procedural changes or early 
termination of the study.  The DSQ is advisory both to the NIDDK and to 
the DPT-1 Steering Committee.  The NIDDK may also appoint members to an 
external oversight committee for natural history, genetics, and 
intervention studies conducted in the Type 1 Diabetes TrialNet.  In 
addition to DSQ review, NIDDK may obtain review by external advisory 
groups to provide additional expertise pertaining to the design and 
implementation of natural history, genetics, and intervention studies to 
be conducted under TrialNet. 

The NIDDK expects that biologic samples and associated clinical data will 
be made available to the broader scientific community at an appropriate 
juncture to support further studies related to the prevention and 
etiology of type 1 diabetes, and in studies to identify genes 
predisposing to diabetes and its complications.

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

The Type 1 Diabetes TrialNet, or TrialNet, will be a national network of 
cooperative clinical research groups, consisting of a consortia of 
clinical centers and core support facilities, whose aim is to recruit 
patients and to support studies that may eventually result in an improved 
understanding of type 1 diabetes and the prevention of the disease.  

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, PHS, 
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(s) 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/NIAID/NICHD Program Officers.

1.  Awardee Rights and Responsibilities 

Awardees will have primary and lead responsibilities for the DPT-1 and 
future studies performed in the Type 1 Diabetes TrialNet, including 
research design and protocol development and modification, participant 
recruitment and follow-up, data collection and adherence to protocol, 
quality control, interim data and safety monitoring, final data analysis 
and interpretation, and preparation of publications, with assistance from 
the NIDDK/NIAID/NICHD Program Officers.  Awardees will collaborate with 
all individuals involved in conducting the DPT-1 and TrialNet studies, 
with investigators conducting ancillary studies, and with the 
NIDDK/NIAID/NICHD Program Officers.  Modifications to the protocols will 
be approved by the Steering Committee.

Clinical Centers and their networks of Affiliates and Satellites are 
expected to meet patient recruitment goals as specified by the DPT-1 and 
TrialNet Steering Committee.  Performance measures, such as patient 
recruitment, data acquisition and transmission, use of budget, and 
timeliness of progress reports are expected to be assessed by the DPT-1 
and Type 1 Diabetes TrialNet Steering Committee and subcommittees, and 
NIDDK/NIAID/NICHD, and may provide information needed to support future 
funding decisions.  The inability to meet performance requirements and 
responsibilities may result in an adjustment of funding, withholding of 
support, restriction of funds already awarded, or suspension or 
termination of the award.
 
The Operations Coordinating Center, Data Monitoring Unit, and Core 
Laboratories, together with the Clinical Centers and associated networks, 
must achieve and maintain quality data in accordance with the common 
protocols and manuals of operations specified by the DPT-1 and Type 1 
Diabetes TrialNet Steering Committee. 

Clinical Centers will work with their Affiliates and Satellites, the 
Operations Coordinating Center, the Data Monitoring Unit, and Core 
Laboratories to achieve and maintain quality data in accordance with the 
common protocols and manuals of operations specified by the DPT-1 and 
Type 1 Diabetes TrialNet Steering Committee.  The data must be obtained 
within expected timeframes as set by the DPT-1 and TrialNet Steering 
Committee.  In addition, all study data must be transmitted continuously 
to the Data Monitoring Unit according to the timeframes specified by the 
Steering Committee.

Clinical Centers will provide administrative support, supervision, and 
training for their Affiliates and Satellites.  Affiliates must sign a 
Letter of Agreement that outlines the details of their participation in 
the study.

All study investigators must agree to implement and adhere to an adverse 
event tracking system as designed by the DPT-1 Study Group and Type 1 
Diabetes TrialNet Steering Committee.

Awardees must provide periodic financial and administrative reports 
required by NIH for administration of cooperative agreements.  The 
Operations Coordinating Center must provide an overall summary of study 
progress on an annual basis.

As members of the DPT-1 and Type 1 Diabetes TrialNet Steering Committee, 
awardees will retain custody of and have primary rights to the data and 
biologic specimens developed and obtained under these awards, subject to 
Government rights of access consistent with current HHS, PHS, and NIH 
policies.  The NIDDK expects that biologic samples and associated 
clinical data will be made available to the broader scientific community 
at an appropriate juncture to support further studies related to the 
prevention and etiology of type 1 diabetes, and in studies to identify 
genes predisposing to diabetes and its complications.  The Operations 
Coordinating Center and Data Monitoring Unit will be expected to put all 
study intervention materials and procedures manuals in the public domain 
and/or make them available to other investigators.

Prompt and timely presentation and publication in the scientific 
literature of findings resulting from research undertaken by the DPT-1 
and Type 1 Diabetes TrialNet is required.  Awardees must agree to 
acknowledge NIH support in the publications and oral presentations 
resulting from research conducted under the cooperative agreements.  
Manuscripts and presentations will be written and reviewed according to 
the policies and procedures set forth by the DPT-1 and TrialNet 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 in the “NIH Guidelines for 
Inclusion of Women and Minorities as Subjects in Clinical Research.”

The NIDDK will select the Chairperson of the Steering Committee.  This 
individual must not have responsibility for recruitment or follow-up of 
study participants.  If a study investigator is selected as a 
Chairperson, he/she must designate a replacement investigator at his/her 
institution.  The Chairperson must have proven evidence of leadership 
ability and adequate time commitment for DPT-1 and/or Type 1 Diabetes 
TrialNet activities.

Core Laboratory Directors and the Director of the Data Monitoring Unit 
must not have responsibility for recruitment or follow-up of study 
participants.

A Clinical Center and its institution may not be involved simultaneously 
in the DPT-1, other TrialNet protocols, and in studies not affiliated 
with TrialNet if enrollment criteria overlap between studies and if the 
studies are actively recruiting participants.  Applicants should indicate 
their willingness to forego participating in studies that would compete 
for recruitment to the same study population.  This restriction does not 
apply to Affiliates and Satellites.  NIDDK may consider exemptions from 
this policy to allow institutions to participate in pilot studies of the 
ITN.

2.   NIDDK and Other NIH Staff Responsibilities

The NIDDK Program Officer and NIAID and NICHD Program Officers will 
provide scientific support to the awardees’ activities including protocol 
development and modification, quality control, interim data monitoring, 
final analysis, preparation of publications, and performance monitoring.  
Consistent with the cooperative agreement nature of this study, the 
Program Officers will be substantially involved as active partners in 
those aspects of the scientific and technical management of the trial as 
described in these Terms and Conditions.  This level of involvement will 
be above and beyond the levels required for administration of traditional 
research grants.

The NIDDK/NIAID/NICHD Program Officers each will have voting membership 
on the Steering Committee, and as appropriate, its subcommittees. 

The NIDDK will appoint the Chairperson of the DPT-1 and TrialNet Steering 
Committee from among investigators of the studies or other experts in 
clinical trials in type 1 diabetes.  The NIDDK may appoint a new 
Chairperson of the TrialNet once the DPT-1 is completed.  The NIDDK will 
maintain and appoint members of the Data Safety and Quality Monitoring 
Group and other external advisory groups as necessary for proper 
oversight of DPT-1 and TrialNet activities.  

The Data Safety and Quality Monitoring group, appointed by NIDDK, will 
provide overall monitoring of interim data and safety issues, and can 
advise the NIDDK/NIAID/NICHD on changes to protocol, elimination of 
Clinical Centers/Affiliates/Satellites, and study termination, if 
warranted.  These meetings will be held twice per year.

The NIDDK/NIAID/NICHD Program Officers, on behalf of their NIH 
Institutes, will have the same access, privileges and responsibilities 
regarding the collaborative data as the other members of the DPT-1 and 
Type 1 Diabetes TrialNet Steering Committee.

The NIDDK, in consultation with the NIAID and NICHD, 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 may terminate or curtail the study if a major study endpoint is 
reached substantially before schedule with persuasive statistical 
significance, if futility in reaching a significant difference between 
treatment groups is realized, if there is emergence of new information 
that diminishes the scientific importance of the study question, or if 
human subject safety or ethical issues dictate a premature termination.  
The NIDDK may also terminate the project in the event of a failure to 
develop or implement mutually agreeable collaborative protocols for the 
Type 1 Diabetes TrialNet or if there are substantial changes in the 
agreed-upon protocols with which the NIDDK cannot concur.

3. Collaborative Responsibilities 

The Steering Committee is composed of the Principal Investigator(s) of 
each Clinical Center, the director of the Operations Coordinating Center, 
the director of the Data Management Unit, each of the directors of the 
Core Laboratories, the Chair of the Planning Committee and the three 
representatives from the NIDDK, NIAID, and NICHD.  (The Planning 
Committee is responsible for coordinating other Working Committees and 
integrating the Working Committees’ input into the Steering Committee 
agenda.  Examples of current Working Committees are the Eligibility and 
Events Committee, Treatment Committee, Ancillary Studies Committee, 
Clinical Center Directors Committee, and Trial Coordinators Committee.  
Members of the Planning Committee consist of the Chair of the Steering 
Committee, chairs of each Working Committee, and Operations Committee 
members.  The Operations Committee consists of the Chair of the Steering 
Committee, and a representative from the Operations Coordinating Center, 
the Data Monitoring Unit, and the NIDDK.  The Chair of the Planning 
Committee is selected by the Operations Committee.)  The Steering 
Committee has overall responsibility for the design, planning, execution, 
and publication of the research performed as part of the DPT-1 and Type 1 
Diabetes TrialNet.  External reviewers may be included in the review and 
planning of new trials in the Type 1 Diabetes TrialNet to gain the 
necessary expertise required for evaluating and implementing new 
proposals.  The Steering Committee will approve all protocols, changes to 
protocols, and manuals of operations.  Each member of the Steering 
Committee will have one vote.  Subcommittees will be established by the 
Steering Committee, as it deems appropriate; the NIDDK/NIAID/NICHD 
Program Officers will serve on subcommittees as they deem appropriate.  

The Steering Committee will develop and maintain specific measures as 
outlined in the protocols and manuals of operations to assure the safety 
and protection of the rights of volunteers involved in the DPT-1 and 
Diabetes TrialNet.  The Principal Investigator for each awardee and 
investigators at Affiliates and Satellites 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 Clinical Centers, Affiliates 
and Satellites must be able to demonstrate that there is a current, 
approved Assurance on file with the HHS 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 as set forth in 
the Study protocols and manuals of operations.  The Principal 
Investigator agrees and assures that adequate records will be available, 
to enable outside monitors to assess compliance with applicable federal 
laws and regulations.

To promote the development of a collaborative program among the award 
recipients, Principal Investigators, trial coordinators, and recruitment 
coordinators are expected to attend DPT-1 and TrialNet Steering Committee 
meetings.  These are anticipated to meet twice a year for established 
trials but may meet more frequently for development of new protocols.  
Trial coordinators and recruitment coordinators will meet on a regular 
basis by conference call, perhaps monthly, to discuss recruitment issues 
and study operations.  Clinical Center Principal Investigators will also 
meet on a regular basis by conference call to discuss emerging issues.  
Clinical Center Principal Investigators, trial coordinators, and 
recruitment coordinators will be asked to serve as Chairpersons or as 
members of Study Committees as needed.  Members of Affiliates and 
Satellites are encouraged to participate in Committee meetings as well.

As members of the DPT-1 and Type 1 Diabetes TrialNet Steering Committee, 
awardees will retain custody of and have primary rights to the data and 
biologic specimens developed and obtained under these awards, subject to 
Government rights of access consistent with current HHS, PHS, and NIH 
policies.  The NIDDK expects that biologic samples and associated 
clinical data will be made available to the broader scientific community 
at an appropriate juncture to support further studies related to the 
prevention and etiology of type 1 diabetes, and in studies to identify 
genes predisposing to diabetes and its complications.  The Operations 
Coordinating Center and Data Monitoring Unit will be expected to put all 
study intervention materials and procedures manuals in the public domain 
and/or make them available to other investigators.

4. Arbitration 

Any disagreement that may arise on scientific/programmatic matters 
(within the scope of the award), between award recipients and the 
NIDDK/NIAID/NICHD may be brought to arbitration.  An arbitration panel 
will be composed of three members: one selected by the Steering Committee 
(with the NIDDK/NIAID/NICHD members not voting) or by the individual 
awardee in the event of an individual disagreement, a second member 
selected by NIDDK in consultation with NIAID and NICHD, 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.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and 
their sub-populations must be included in all NIH-supported biomedical 
and behavioral research projects involving human subjects, unless a clear 
and compelling rationale and justification are provided indicating that 
inclusion is inappropriate with respect to the health of the subjects or 
the purpose of the research. This policy results from the NIH 
Revitalization Act of 1993 (Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read 
the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as 
Subjects in Clinical Research," published in the NIH Guide for Grants and 
Contracts on August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a 
complete copy of the updated Guidelines are available at 
(http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm): 
The revisions relate to NIH defined Phase III clinical trials and 
require: a) all applications or proposals and/or protocols to provide a 
description of plans to conduct analyses, as appropriate, to address 
differences by sex/gender and/or racial/ethnic groups, including 
subgroups if applicable; and b) all investigators to report accrual, and 
to conduct and report analyses, as appropriate, by sex/gender and/or 
racial/ethnic group differences.

Under the statute, when an NIH defined Phase III clinical trial is 
proposed, evidence must be reviewed to show whether or not clinically 
important sex/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.

Cost is not an acceptable reason for exclusion of women and minorities 
from clinical trials.

When planning, conducting, and reporting an NIH defined Phase III 
clinical trial, it must be considered whether, based on prior studies, 
one of the following three situations apply:  that prior studies support 
the existence of significant differences, that prior studies support no 
significant differences, and that prior studies neither support nor 
negate significant differences.

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 sex/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.

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.

URL FOR INFORMATION ABOUT RFA FOR PROSPECTIVE APPLICANTS

Information about this RFA may be found at NIDDK’s website 
http://www.niddk.nih.gov/patient/trialnet.htm.  The website 
links to answers to frequently asked questions (FAQs) that prospective 
applicants have submitted.  Prospective applicants are encouraged to 
submit their questions to the email address:  
TrialNet@extra.niddk.nih.gov so that their questions and answers can be 
made available on the website.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 28, 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 plan the 
review.

The Letter of Intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 653, MSC 5452
Bethesda, MD  20892-5452
(for express/courier service:  Bethesda, MD  20817)
Telephone:  (301) 594-8885
FAX:   (301) 480-3505

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these awards.  These forms are available at most 
institutional offices of sponsored research; from the GrantsInfo, 
Division of Extramural Outreach and Information Resources, National 
Institutes of Health, 6701 Rockledge Drive, Suite 6095, Bethesda, MD 
20892-7910, telephone 301-435-0714, email: GrantsInfo@nih.gov.

Additional Materials to Include in the Application 

Applicants must describe plans to achieve the stated “Objectives and 
Scope”, “Special Requirements”, and “Terms and Conditions of Award” 
stated in this RFA.  In addition, applicants should address the following 
issues that are important to the successful development of a 
collaborative program to promote the DPT-1 and TrialNet.

Qualifications and experience.  Clinical Center applicants must include a 
description of investigators and staff with experience and expertise to 
collaborate in multicenter clinical trials and Phase II and Phase III 
studies to assess interventions for preventing or ameliorating type 1 
diabetes.  Applicants should describe their ability to lead clinical 
trials that could be performed using Type 1 Diabetes TrialNet resources.  
Applicants must give evidence of their ability to recruit and retain 
individuals in multicenter clinical trials, and describe their experience 
with prediabetic or diabetic subjects.  Applicants who have participated 
in the DPT-1 must document the number of subjects screened, staged, 
randomized and currently under follow-up.  Applications from DPT-1 
Clinical Centers should provide this information for their network as a 
whole and also separately for the parent Clinical Center site and the 
individual Affiliate and Satellite sites.  If applicants have particular 
expertise and accomplishments in recruiting individuals from minority 
groups, these should be described.  Documentation of institutional 
support for participating in a multicenter clinical trial to prevent type 
1 diabetes should be provided in the form of letters of support from the 
appropriate institution officials. 
 
It is important to establish the Principal Investigator’s ability to 
contribute to the scientific agenda and describe an adequate time 
commitment of the Principal Investigator (5-20%), Trial Coordinator 
(100%), and Recruitment Coordinator (50%).  Clinical Center applicants 
that are currently DPT-1 Clinical Centers should list sites capable of 
performing the responsibilities required of Affiliates and Satellites, as 
well as associated Principal Investigators, and describe their 
qualifications and experience in clinical trials and clinical studies in 
diabetes.  Affiliates and Satellites may include HMOs, clinics, or 
private practice physicians.  A Letter of Collaboration Agreement from 
each Affiliate and Satellite should be included in the appendix.  
Clinical Center applicants must demonstrate the ability to train and 
maintain the proficiency of Affiliate and Satellite staff in performing 
Study operations.  

Current DPT-1 Affiliates/Satellites or other institutions not currently 
participating in the DPT-1 that are applying to be a Clinical Center 
should not recruit current DPT-1 Affiliates or Satellites as network 
sites for their Clinical Center.  The DPT-1 and Type 1 Diabetes TrialNet 
are likely to redistribute Affiliates and Satellites once Clinical 
Centers are reviewed and selected.  In addition, there will be an effort 
to recruit new Affiliates and Satellites and these will be distributed 
among Clinical Centers.  For current DPT-1 Affiliates/Satellites applying 
to be a Clinical Center, a Letter of Collaboration Agreement should also 
be provided to their current parent Clinical Center, or another Clinical 
Center of choice, in case the applicant is unsuccessful in obtaining an 
award.  Current DPT-1 Clinical Centers applying to be a Clinical Center 
should consider providing a Letter of Collaboration Agreement to be an 
Affiliate to another DPT-1 Clinical Center in case they are unsuccessful 
in obtaining a Clinical Center award.  Affiliates and Satellites must not 
agree to be a network site to more than one Clinical Center applicant.

Study populations.  Clinical Center applications must discuss the number 
of type 1 diabetic patients to which the Center has access, so that they 
or their relatives may be approached about the DPT-1 and Type 1 Diabetes 
TrialNet.  Applicants should also describe the study populations of their 
proposed Affiliates and Satellites (if applicable).  A description of the 
pool of patients with type 1 diabetes, along with their demographic 
characteristics such as age range and ethnic/racial distribution should 
be provided.  In addition to describing the pool of diabetic subjects 
from which to draw potential study participants, applicants should 
describe other methods that might be used to recruit eligible subjects.  
Applicants who have participated in the DPT-1 must document the number of 
subjects screened, staged, randomized and currently under follow-up.  
Applications from DPT-1 Clinical Centers should provide this information 
for their network as a whole and also separately for the parent Clinical 
Center site and the individual Affiliate and Satellite sites (if 
applicable).  Current Affiliates/Satellites or other institutions not 
participating in DPT-1 who are applying to be a Clinical Center, and who 
are not proposing network sites, should describe the study population to 
which they have access at their own institution.  In addition, the 
methods that will be used to maintain privacy and confidentiality of 
participant data should be provided.

Willingness to participate in the DPT-1 and Type 1 Diabetes TrialNet.  
The Principal Investigator of the Clinical Center should state his/her 
general support of collaborative research and interaction with the 
NIDDK/NIAID/NICHD, their proposed Affiliates and Satellites (if 
applicable), the Operations Coordinating Center, the Data Monitoring 
Unit, the Central Distribution Pharmacy, and the Core Laboratories.  
Applicants should discuss the willingness of their proposed Affiliates 
and Satellites (if applicable), and the institutions involved, to pursue 
a per patient basis of operational costs.  Clinical Centers must be able 
to interact with the Data Monitoring Unit to transmit and edit data if 
necessary, and should discuss their capability to participate in such a 
system.

Willingness to forego participation in competing clinical trials and to 
collect biologic and genetic material as well as clinical data for the 
broader scientific community.  Applicants must also state their 
willingness for their Clinical Center and its institution not to be 
involved simultaneously in the DPT-1, other TrialNet protocols, and in 
studies not affiliated with TrialNet studies if enrollment criteria 
overlap between studies and if the studies are actively recruiting 
participants.  This restriction does not apply to Affiliates and 
Satellites. NIDDK may consider exemptions from this policy to allow 
institutions to participate in pilot studies of the ITN.  Applicants 
should state in their application their willingness to collect biologic 
and genetic samples as well as clinical data that may be used for future 
studies related to the prevention, etiology, and genetics of type 1 
diabetes by investigators both inside and outside the Type 1 Diabetes 
TrialNet.

Institutional resources. Clinical Center applicants should state whether 
they and their Affiliates (if applicable) have a General Clinical 
Research Center (GCRC) funded by the NIH National Center for Research 
Resources, or an equivalent clinical research center funded by the 
institution, which can be a resource for conducting the proposed 
research.  If so, a letter of agreement from either the GCRC (or GCRC 
equivalent) Program Director or Principal Investigator should be included 
with the application.  Resources for patient care and follow-up, 
including personnel, space, and facilities for insulin infusions, IVGTTs, 
OGTTs, and MMTTs should be described.  Letters from institutional 
officials should describe any other institutional support that will be 
available for the TrialNet. 

Clinical Protocols.  With one exception, applicants are required to 
propose one clinical trial protocol.  The exception is if a current DPT-1 
Clinical Center wishes only to complete DPT-1 and not to participate in 
future studies of the Type 1 Diabetes TrialNet.  Applicants proposing 
clinical protocols should include a discussion of the current “state-of-
the-art”, future opportunities, and obstacles in the prevention of type 1 
diabetes, and discuss how the field may best be moved forward.  For 
agents being proposed to prevent or ameliorate type 1 diabetes, 
scientific background must be provided about the agent, including results 
from animal and human studies, safety and any efficacy studies, and 
toxicity data.  Techniques to monitor adverse events and adjust dosage 
should be described, as well as methods for assessing patient compliance 
to treatment.  Any ethical concerns pertaining to use of the proposed 
agent must be addressed.  A thorough description of the population to be 
studied must be provided, with justification, including a definition of 
the cohort by age, sex, and race.  The ability to recruit this target 
population at the Clinical Center and network sites (if applicable) and 
the methods to be used should be described with an estimation of the 
current number of patients who fit the eligibility criteria and expected 
accrual rates.  (Since the NIH envisions that agents might be tested 
first in new-onset type 1 diabetes patients and then in at-risk 
prediabetic individuals, a careful description of access to these patient 
pools should be included.)  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 must be included.  
A description of the laboratory tests that are needed with appropriate 
methods for performing them should be provided, as well as other core 
facilities and interactions with core facilities that are needed.  Also 
included should be the methods that would be used to assure privacy and 
maintain confidentiality of data.  Sample size needs and the criteria and 
calculations used to estimate sample sizes should be detailed.  
Analytical methods to be used must be included.  Applicants must state 
their plans for reporting accrual by sex/gender and/or race/ethnicity and 
for the reporting of results that examine differences in treatment 
effects across these subgroups (see above under “INCLUSION OF WOMEN AND 
MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS”).  Plans for follow-up 
studies should be provided if results from smaller pilot, feasibility, 
and efficacy studies of the intervention are found to be positive.  A 
budget for the proposed clinical protocol should not be submitted because 
final design of these studies and allocation of costs will be determined 
by the TrialNet Steering Committee and NIDDK.

Applicants should not exceed 20 pages in describing their proposed 
Clinical Center and associated network sites (if applicable) and not 
exceed 20 pages in describing their proposed clinical protocol.  

Budget Information

Budget information should be provided only for the clinical center 
component of the application that would support completion of DPT-1 and 
not for future study components (see above under FUNDS AVAILABLE).  

For the Clinical Center component, applicants should request support for 
a Principal Investigator at 0.05-0.20 FTE, a trial coordinator at 1 FTE 
(preferably a nurse or certified diabetes educator), and a recruitment 
coordinator at 0.5 FTE.  These levels of effort are the maximum levels 
allowed; levels of effort that are awarded will vary depending on 
recruitment history, potential for recruitment, and expected intellectual 
contributions to DPT-1 and the Type 1 Diabetes TrialNet.  If additional 
FTE support is necessary, this will be determined by the 
NIDDK/NICHD/NIAID based on the requirements of the studies to be 
performed.  Reimbursement schedules for study tests performed by Clinical 
Centers and network sites will be determined by the NIDDK; it is 
estimated that approximately $725,000 per year will be provided for 
patient care costs related to the screening, treatment, and follow-up of 
participants in the DPT-1.  These reimbursement costs should not be 
included in budgets.  The NIDDK estimates the annual cost for supplies 
and patient retention items at $4000 and for travel of Clinical Center 
personnel to two Steering Committee meetings per year at $9000.  
Additional funds will be added to support the Study Chairperson if the 
Chairperson is selected from among the principal investigators of 
Clinical Centers; FTE support for the principal investigator chosen as 
the Steering Committee Chairperson would increase to approximately 0.50.

Affiliates and Satellites will also be reimbursed for clinical costs of 
tests performed for studies, but these costs also should not be included 
in submitted budgets.  Affiliate or Satellite members participating to a 
significant degree on committees, who are not otherwise provided core 
funding, may be remunerated as funds permit.  

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 March 29, 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 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 proposal.  Other considerations, such as access to 
patients, ability to recruit minority participants, and experience of key 
personnel, will be a part of the evaluation criteria.  

It will be necessary to review the applications from current DPT-1 
Clinical Centers differently than those from institutions applying for 
the first time.  While current Clinical Centers and their networks of 
Affiliates and Satellites will have a performance record of enrollment in 
the DPT-1, new institutions will be evaluated based on demonstration of 
their ability to recruit participants to other clinical trials.  Both 
current DPT-1 Clinical Centers and new centers will be evaluated on the 
basis experience of personnel, institutional commitment, and the 
scientific innovation and approach to their proposed clinical protocols.  
The different elements of the applications will be evaluated and scores 
will be summed to determine an overall score for the application; this 
overall score will be indicative of the potential of the Clinical Center 
to contribute to the completion of DPT-1 and attaining Type 1 Diabetes 
TrialNet goals.

Review Method

Applications will be reviewed for completeness by the CSR and 
responsiveness by the NIDDK.  Incomplete 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 in 
accordance with NIH peer review procedures.  As part of the initial merit 
review, all applications will receive a written critique.  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 review by the NDDK Advisory 
Council.

Clinical Centers responding to this RFA will be reviewed based on the 
following considerations: 

o Recruitment Capability.  Is there evidence of successful experience in 
recruitment and retention of research subjects in multicenter clinical 
trials?  Is there evidence of the ability to recruit, enroll, and 
maintain minority and non-minority subjects in a randomized trial or 
other clinical studies at the proposed Clinical Center and Affiliates and 
Satellites?  This includes documentation of access to an adequate patient 
population who may be approached in finding potentially eligible study 
participants.  Since it is likely that future trials will focus on new-
onset type 1 diabetes patients and prediabetic individuals, the ability 
to recruit these individuals will be evaluated carefully.

o Investigators.  Are the investigators appropriately trained and well-
suited to carry out this work?  Is the work proposed appropriate to the 
experience level of the investigators and staff?  Is there an appropriate 
amount of time planned for the effective coordination of the Clinical 
Center with Affiliates and Satellites, Operations Coordinating Center, 
Data Monitoring Unit, and Core Laboratories?  Is there evidence of prior 
experience in working collaboratively in carrying out a standard protocol 
in multicenter clinical trials or other clinical studies?  Is there 
evidence of willingness to work cooperatively in the DPT-1 and Type 1 
Diabetes TrialNet?  This will be assessed both for the Clinical Center 
and for associated Affiliates and Satellites.

o Environment.  Does the scientific clinical environment in which the 
work will be done contribute to the probability of success?  Is there 
evidence of institutional support and commitment for the proposed 
program?

o Data and Sample Management.  Are there adequate plans to ensure 
accurate collection and timely transmission of study data to the Data 
Monitoring Unit and patient samples to the Core Laboratories?  Is there 
documented experience in meticulous and expeditious handling of 
laboratory specimens and study data?

The clinical protocol which is required for all applications, except for 
those that propose only to complete DPT-1 and not to participate in 
subsequent activities of the Type 1 Diabetes TrialNet, will be reviewed 
based on the following criteria:

o Significance.  Is the proposed study relevant and will it contribute to 
the overall goals of the Type 1 Diabetes TrialNet?  If the aims of the 
application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

o Approach.  Is the conceptual framework, design, proposed population, 
methods, and analyses adequately developed, well-integrated, and 
appropriate to the aims of the proposed study?  Is the study feasible as 
proposed?  Does the applicant acknowledge potential problem areas and 
consider alternative tactics?  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 proposed study employ novel concepts, approaches, 
or methods?  Are the aims original and innovative?  Does the study 
challenge existing paradigms or develop new methodologies or 
technologies?

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 
documented ability of the investigators to meet the RESEARCH OBJECTIVES 
of the RFA.  Award decisions will be made based on the applicants’ 
potential contribution to subject enrollment and study design and 
execution as assessed by peer review, as well as program balance in terms 
of geographic locations of sites and ability to recruit minority 
participants.  Awards may be made to existing DPT-1 Clinical Centers only 
to complete DPT-1 and not to participate in other studies of the Type 1 
Diabetes TrialNet.  

Letter of Intent Receipt Date:    February 28, 2001
Application Receipt Date:         March 29, 2001
Peer Review Date:                 June-August, 2001
NDDK Council Review Date:         September, 2001
Earliest Anticipated Start Date:  September, 2001

INQUIRIES

Written and telephone inquiries concerning this RFA are strongly 
encouraged.  The opportunity to clarify any issues or questions from 
potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Catherine C. Cowie, PhD
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd, Rm 691, MSC 5460
Bethesda, MD  20892-5460
Telephone:  (301) 594-8804
FAX:  (301) 480-3503
Email:  cowiec@extra.niddk.nih.gov

Questions may also be submitted to the email address 
TrialNet@extra.niddk.nih.gov where they will be answered by email.  In 
addition, these questions and answers will be posted at the NIDDK website 
http://www.niddk.nih.gov/patient/trialnet.htm which links to 
frequently asked questions that prospective applicants have submitted.  
Applicants are strongly encouraged to visit this website on a regular 
basis in the course of preparing their applications.

For FEDEX, UPS, send to:

Catherine C. Cowie, PhD
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd, Rm 691
Bethesda, MD  20817

Inquiries may also be made to representatives of NIAID and NICHD:

Elaine Collier, MD
Chief, Autoimmunity Section
Division of Allergy, Immunology, and Transplantation
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, Room 5135, MSC 7640
Bethesda, MD  20892-7640
Telephone:  (301) 496-7104
FAX:  (301) 402-2571
Email:  ec5x@nih.gov

Gilman D. Grave, MD
Chief, Endocrinology, Nutrition, and Growth Branch
National Institute of Child Health and Human Development
6100 Executive Blvd, Room 4B-11, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5593
FAX:  (301) 480-9791
Email:  gg37v@nih.gov

Direct inquiries regarding fiscal matters to:

Cheryl Chick
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd, Rm 606, MSC 5456
Bethesda, MD  20892-5456
Telephone:  (301) 594-8825
FAX:  (301) 480-3504
Email:  chickC@extra.niddk.nih.gov

For FEDEX, UPS, send to :

Cheryl Chick
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd, Rm 606
Bethesda, MD  20817

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance 
No. 93.847, No. 93.855, and No. 93.113.  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.


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