TYPE 1 DIABETES TRIALNET:  CORE SUPPORT FACILITIES

Release Date:  October 5, 2000

RFA:  DK-01-004

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 an operations coordinating center 
which will provide for a data monitoring unit, central distribution 
pharmacy, and clinical cost reimbursement system to support intervention 
studies to preserve pancreatic beta cell function and prevent type 1 
diabetes.  The core facilities will support completion of the ongoing 
Diabetes Prevention Trial for Type 1 Diabetes (DPT-1), and support 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.

Additional core support facilities that are currently participating in 
the DPT-1, specifically the core laboratories, the compounding pharmacy, 
and the consultant firm for the central telephone line and 
publicity/recruitment support, will continue to operate during completion 
of the DPT-1 in order to ensure the integrity and continuity of the 
trial.  These facilities may change for the conduct of new pilot and 
expanded intervention studies, however, they are not being solicited in 
this Request for Application (RFA).

The core support facilities selected to complete the ongoing DPT-1 and to 
participate in new studies, as well as a consortia of clinical centers, 
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 RFA (DK-01-003) is being published to establish the Type 
1 Diabetes TrialNet Clinical Centers and for proposals for intervention 
studies of new agents to prevent and ameliorate type 1 diabetes.

The Operations Coordinating Center (OCC) will coordinate interactions 
between core support facilities, Clinical Centers and associated networks 
of recruitment/retention sites, sponsoring agencies, committees, and 
consultants, and will develop and/or maintain financial management plans 
and all study protocols, manuals, agendas, and newsletters.  The OCC will 
provide for the Data Monitoring Unit, existing and future Core 
Laboratories and compounding pharmacies, the Central Distribution 
Pharmacy, a clinical cost reimbursement system, and the consultant firm 
providing the central telephone line and publicity/recruitment expertise.  
If necessary, the OCC will provide for these core support facilities 
through subcontracts to one or more institutions.  The Data Monitoring 
Unit will be responsible for all study data management and statistical 
considerations and will coordinate with the Central Distribution Pharmacy 
and clinical cost reimbursement system.

This RFA responds to recommendations of the Congressionally-established 
Diabetes Research Working Group which developed a strategic plan for 
research in diabetes (http://www.niddk.nih.gov/federal/dwg/dwgsummary.htm).  
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 and core support facilities 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.  

The Immune Tolerance Network (ITN), a program of the NIAID, NIDDK, and 
Juvenile Diabetes Foundation International, 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.

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 domestic for-profit and non-profit 
organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and 
eligible agencies of the Federal Government.  This geographic constraint 
is necessary because of the need for close communication 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.  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 a cooperative agreement (U01), an assistance mechanism (rather 
than an acquisition mechanism) in which substantial NIH scientific and/or 
programmatic involvement with the awardee is anticipated during 
performance of the activity.  Under the cooperative agreement, the NIH 
purpose is to support and/or stimulate the recipient's activity by 
involvement in and otherwise working jointly with the award recipient in 
a partner role, but it is not to assume direction, prime responsibility, 
or a dominant role in the activity.  Details of the responsibilities, 
relationships and governance of the study to be funded under cooperative 
agreement(s) are discussed later in this document under the sections 
titled “Objectives and Scope”, “Special Requirements”, and "Terms and 
Conditions of Award."

It is anticipated that one award will be made to the Operations 
Coordinating Center which, if necessary, will support subcontracts to the 
other core support facilities.  The total project period for applications 
submitted in response to the present RFA should be 7 years.  The 
anticipated award date is September 2001.

At initiation of the Type 1 Diabetes TrialNet, support for the OCC and 
its subcontracts will be provided for completion of DPT-1 and planning of 
new studies to be conducted under TrialNet.  Level of support in 
subsequent years will be determined by the requirements of the specific 
studies designed and executed by the Steering Committee and by the 
availability of funds.  Awards and level of support depend on receipt of 
a sufficient number of applications of high scientific merit for the 
entire Type 1 Diabetes TrialNet.  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.

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 $4.7 million in total costs per year will be committed for 
the Operations Coordinating Center and all associated core support 
facilities for completion of the DPT-1 and for planning new studies in 
the Type 1 Diabetes TrialNet.  It is anticipated that one award will be 
made to the Operations Coordinating Center which, if necessary, will 
support subcontracts to one or more institutions to provide for the Data 
Monitoring Unit, the Core Laboratories, the compounding pharmacy(ies), 
the Central Distribution Pharmacy, clinical cost reimbursement system, 
and the consultant firm for the central telephone line and for 
media/recruitment support.  

The budget cannot exceed $2,060,000 in total costs annually for the 
Operations Coordinating Center (personnel, supplies, equipment and 
communications), Data Monitoring Unit (personnel, supplies, equipment, 
and communications), clinical cost reimbursement system, and Central 
Distribution Pharmacy Unit.  Additional details are provided below under 
BUDGET INFORMATION.  As indicated below under BUDGET INFORMATION, 
approximately $2.7 million in total costs annually will be provided for 
the Core Laboratories, the compounding pharmacy, the consultant firm for 
the central telephone line and publicity/recruitment support, patient 
care costs which will be reimbursed to recruitment/retention sites on a 
per subject basis, travel, and other expenses.  

Awards and level of support depend on receipt of a sufficient number of 
applications of high scientific merit for the entire Type 1 Diabetes 
TrialNet.  Funding after completion of DPT-1 will depend on the existence 
and status of studies of promising new agents, as well as the successful 
operation of the core support facilities and recruitment and retention 
sites of the TrialNet. 

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 might 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 five 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 insulin 
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, Compounding Pharmacy, Central Distribution Pharmacy, the 
clinical cost reimbursement system, and the consultant firm managing the 
central telephone line and providing publicity/recruitment support.  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 this 
information is provided 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 Compounding Pharmacy.

Currently, the OCC has subcontracts to the DMU, Central Distribution 
Pharmacy, the consultant firm providing the central telephone line and 
publicity/recruitment support, and two of the Core Laboratories.  The 
other two Core Laboratories are supported through subcontracts to other 
U01s currently being funded in DPT-1.  

DPT-1 is presently funded through August 2001.  The trial is jointly 
supported by the National Institute of Diabetes and Digestive and Kidney 
Disease, 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 
(http://www.niddk.nih.gov/federal/dwg/dwgsummary.htm).  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.  
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 
(http://www.niddk.nih.gov/federal/dwg/dwgsummary.htm).  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 existing structure in the DPT-1 of Clinical Centers and associated 
networks, as well as its core support facilities, is an excellent 
platform on which to build an enhanced infrastructure 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.  A complementary RFA 
(DK-01-003) is requesting applications to expand the number of Clinical 
Centers.  

As described above under Section 1.2, “DPT-1 Clinical Centers and 
Networks, Core Support Facilities,” core support facilities that 
currently exist in the DPT-1 are the Operations Coordinating Center 
(OCC), the Data Monitoring Unit (DMU), Core Laboratories, the Compounding 
Pharmacy, the Central Distribution Pharmacy, and a consultant firm 
managing the central telephone line and providing publicity and 
recruitment support.  Reimbursement for clinical tests performed within 
the DPT-1 is tracked by the DMU and this information is provided to two 
fiscal cluster facilities that distribute payments to the appropriate 
Clinical Centers/Affiliates/Satellites.  Modification of these facilities 
and of the structure will be necessary resulting from expansion of the 
number of Clinical Centers and performance of new studies.  New studies 
performed within the Type 1 Diabetes 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 (http://www.immunetolerance.org) 
may also be used for assessments in the TrialNet.

Currently, the OCC has subcontracts or purchase orders with the DMU, 
Compounding Pharmacy, Central Distribution Pharmacy, two of the Core 
Laboratories, and a consultant firm managing the central phone line and 
providing publicity/recruitment support.  The other two laboratories are 
supported through subcontracts to other U01s currently funded in DPT-1.  
The NIDDK/NIAID/NICHD are creating a new structure funded through one U01 
to the OCC which will provide support for all DPT-1 and TrialNet Core 
Laboratories.  Letters of Agreement with the OCC will be obtained from 
all Clinical Centers/Affiliates/Satellites to allow for the flow of 
reimbursement dollars for clinical care costs.

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 core facilities is to 
support completion of the DPT-1.  The second objective of the core 
facilities is to support expanded intervention studies of new agents to 
prevent or ameliorate type 1 diabetes.  In addition, the Type 1 Diabetes 
TrialNet may support natural history and genetics studies in populations 
screened for or enrolled in these studies.  

The Operations Coordinating Center (OCC) and associated Core 
Laboratories, consultant firm for the central telephone line and 
publicity/recruitment support, Data Monitoring Unit (DMU), Compounding 
Pharmacy, Central Distribution Pharmacy, and clinical cost reimbursement 
system will support the recruitment, randomization, and follow-up of 
participants in the DPT-1.  The core facilities will also provide this 
support for future natural history, genetics, pilot, feasibility, and 
efficacy studies, and for expanded intervention studies of the TrialNet.  
Interested applicants should review the complementary RFA for the Type 1 
Diabetes TrialNet:  Clinical Centers (DK-01-003) in order to appreciate 
the anticipated duties of the Clinical Centers and associated networks of 
recruitment and follow-up sites.

If necessary, the OCC will provide subcontracts or purchase orders for 
the Data Monitoring Unit, existing and future Core Laboratories and 
compounding pharmacies, the Central Distribution Pharmacy, the clinical 
cost reimbursement system, and the consultant firm providing the central 
telephone line and publicity/recruitment expertise.  

The OCC will coordinate interactions between the Clinical Centers and 
their associated networks of Affiliates and Satellites, the DMU (if 
separate from the OCC), Core Laboratories, study monitoring groups (e.g., 
laboratory, clinical centers/networks, safety), study committees and 
consultants, and sponsoring agencies.  In addition, the OCC will:  
facilitate the execution of study activities in the DPT-1 and Type 1 
Diabetes TrialNet as directed by the Steering Committee and Chairperson; 
develop and prepare study protocols and manuals of operations; provide 
financial management; communicate with DPT-1 and TrialNet membership, 
including circulation of newsletters, operations manuals, protocols, 
minutes of meetings, correspondence, publications, manuscripts, 
contracts, orders, materials necessary for progress reports and 
institutional reviews; prepare annual reports and subcontracts; develop 
publicity and other subject recruitment tools; interact with the media to 
facilitate recruitment and publicize the study; develop meeting agendas; 
convene, arrange, and conduct Steering Committee and subcommittee 
meetings; arrange and prepare materials for Data Safety and Quality 
Monitoring Group meetings; provide for shipment of samples between 
clinical sites and laboratories; oversee the performance of quality 
control audits; maintain membership rosters, study directories, and 
committee lists; provide updated slide sets for professional meetings on 
a semi-annual basis; maintain a reference reprint file of DPT-1 and Type 
1 Diabetes TrialNet publications; maintain files of conflict of interest 
forms and Institional Review Board (IRB) approval forms for all Clinical 
Centers/Affiliates/Satellites; obtain Letters of Agreement with all 
Affiliates and Satellites to provide for the flow of reimbursement 
dollars for patient care costs and to document a willingness to abide by 
study procedures; provide a central file for all ancillary studies and 
related documents; and oversee certification of personnel at sites for 
shipping of specimens and performing study tests.  A representative from 
the OCC will attend all study committee meetings, Steering Committee 
meetings, and Data Safety and Quality Monitoring Group meetings.

The OCC will be responsible for the coordination of the Core Laboratories 
participating in the DPT-1 and Type 1 Diabetes TrialNet.  Subcontracts 
will be provided to the laboratories from the OCC.  To ensure the 
integrity and continuity of the DPT-1, the current Core Laboratories will 
continue to be responsible for measurement of critical variables in the 
DPT-1 protocol.  The University of Florida will continue to measure 
cytoplasmic islet cell antibodies (ICA) as needed.  The measurement of 
insulin autoantibodies will be performed by the current laboratory at the 
Joslin Diabetes Center.  The University of Colorado will extract and 
preserve DNA from all participants staged in the DPT-1 for eligibility 
for enrollment in the intervention protocols; specifically HLA-DQA1*0102, 
DQB1*0602 will be determined.  In addition, the University of Washington 
VA Medical Center will continue to assess beta-cell function by 
measurement of immunoreactive insulin and C-peptide, plasma glucose, and 
glycosylated hemoglobin HbA1c.  

New studies performed within the Type 1 Diabetes 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 
(http://www.immunetolerance.org) may also be used for assessments in the 
TrialNet.  The OCC will be responsible for soliciting and reviewing 
submissions for additional Core Laboratories, and selecting optimal 
applications, as dictated by the TrialNet Steering Committee.

The current DPT-1 Core Laboratories and future Core Laboratories will 
communicate on a regular basis with Clinical 
Centers/Affiliates/Satellites regarding receipt of samples, sample 
integrity, and results of measurements as directed by DPT-1 and TrialNet 
protocols.  Future Core Laboratories will have had demonstrated expertise 
in performing the assays for research purposes, ideally in a clinical 
trial setting.  Laboratories will have on-line communication with the DMU 
and have equipment to read bar-coded samples; transmission of data must 
occur on a regular basis as dictated by the DPT-1 and Type 1 Diabetes 
TrialNet.  The laboratories will have appropriate quality control 
procedures that are documented and will participate in external quality 
assurance programs.  Laboratory directors should participate in all study 
Steering Committee meetings, and directors and other laboratory personnel 
are expected to participate in other committee meetings as needed.  The 
laboratories must abide by DPT-1 and Type 1 Diabetes TrialNet protocols 
and manuals of operations.

The OCC will also provide for a Compounding Pharmacy.  The current 
Compounding Pharmacy will continue to provide crystallized insulin and 
placebo in capsule for the DPT-1 oral insulin trial, to ensure the 
integrity and continuity of the trial.  Compounding Pharmacy requirements 
may change as new trials are designed using new agents.  The OCC will be 
responsible for soliciting and reviewing submissions for new compounding 
pharmacies, and selecting optimal applications, as dictated by the 
TrialNet Steering Committee.  Some drugs may be donated by pharmaceutical 
companies.

The consultant firm that currently manages the central telephone line for 
the DPT-1 (1-800-HALT-DM1) will continue in this capacity during 
completion of the DPT-1.  The consultant firm will respond to callers by 
describing the study and mailing brochures and study materials according 
to current protocol.  The firm will track telephone activity, and 
ascertain the source of hearing about the DPT-1 and other characteristics 
of the callers.  In addition, the firm will continue to produce the 
patient newsletter and provide necessary recruitment materials and 
publicity and outreach support.  Representatives from the consultant firm 
will attend Steering Committee and other Study Group meetings as needed.

If necessary, the OCC will provide support for the DMU through a 
subcontract.  The DMU will be responsible for all data management and 
statistical considerations for the DPT-1 and Type 1 Diabetes TrialNet.  
The DMU will receive data electronically from remote sites (i.e., Core 
Laboratories and Clinical Centers/Affiliates/Satellites) when 
appropriate.  When this is not appropriate, the DMU will receive data via 
hardcopy forms.  Data on hardcopy forms should be scannable for data 
entry when appropriate or double-entered to check for discrepancies.  
Data should be checked for logic and consistency.  Changes in participant 
status will be updated and reported to Clinical 
Centers/Affiliates/Satellites indicating the need for further tests and 
visits, or the need for randomization.  When appropriate and applicable, 
the DMU will generate letters describing test results to subjects.  
Errors on study forms and requests for correct information will be 
communicated back to Clinical Centers/Affiliates/Satellites.  A system of 
barcodes for use by the Core Laboratories will be generated by the DMU.  
The DMU will provide for central registration and random assignment of 
all subjects enrolled in trials.  Computer files will be maintained and 
backed up and hardcopy forms will be copied as necessary and filed.  The 
DMU will generate data quality reports such as for inconsistent/missing 
information, missing/damaged laboratory samples, subject status reports, 
center status reports, tests and forms past due, and reimbursement 
reports.  It is highly desirable that aggregate data be available online 
to individuals conducting DPT-1 and TrialNet studies at a website 
maintained by the DMU.  Information provided at the website might 
include, for example, recruitment data, recruitment data specific to 
individual Clinical Centers, monitoring group data (e.g., laboratory, 
clinical, and safety monitoring), up-to-date study forms, publications, 
DPT-1 and Type 1 Diabetes TrialNet site contact information, and 
information on ancillary studies.  These data should be accessible only 
by unique passwords.  

The DMU will provide statistical reports at all meetings on progress of 
the trials.   The DMU director or representative will serve on all DPT-1 
and Type 1 Diabetes TrialNet administrative committees, will attend all 
Steering Committee meetings and Data Safety and Quality Monitoring Group 
meetings, and will be asked to serve on other committees as needed.  The 
DMU will help develop and implement and will abide by DPT-1 and TrialNet 
protocols and manuals of operations.  The DMU will review all proposed 
protocols and develop statistical designs for studies, analyze study 
results, review all manuscripts for statistical considerations, develop 
and test predictive models for disease progression, and perform all other 
statistical needs for the DPT-1 and TrialNet.

There must be assurance that all study data transmitted electronically 
and stored data are secure and cannot be obtained by anyone other than 
those for whom it was intended.  For example, electronic data should be 
encrypted, methods should be in place to ensure that no modifications can 
be made during data transmission, and it should be possible to 
authenticate who sent and received the data and when the data were sent 
and received.  

The DMU will coordinate with the clinical cost reimbursement system by 
tracking all clinical tests performed in the DPT-1 and the TrialNet and 
maintaining necessary files.  Reimbursement reports will be generated for 
checking and approval by Clinical Centers.  The clinical cost 
reimbursement system will provide for the distribution of payments to 
appropriate Clinical Centers/Affiliates/Satellites as directed by the 
DMU.

The DMU will also coordinate with the Central Distribution Pharmacy.  For 
the DPT-1, the current Compounding Pharmacy will supply the Central 
Distribution Pharmacy with oral insulin and placebo.  The Central 
Distribution Pharmacy will dispense all therapeutic agents and placebos 
used in DPT-1 and Type 1 Diabetes TrialNet studies.  The Central 
Distribution Pharmacy will distribute these agents to Clinical Centers in 
a masked manner as directed by the DMU.

The OCC, DMU, Core Laboratories, Compounding Pharmacy, Central 
Distribution Pharmacy, and clinical cost reimbursement system must 
conform to the guidelines of the Office of Human Research Protections 
(OHRP) by obtaining an assurance, having an IRB of record, and obtaining 
IRB approval annually.

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

Collaboration of Investigators of DPT-1 and Type 1 Diabetes TrialNet

To promote the development of a collaborative program among the award 
recipients, principal investigators, trial coordinators, recruitment 
coordinators and representatives of the Operations Coordinating Center, 
Core Laboratories, and Data Monitoring Unit 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.  At these meetings, new studies will be 
designed, study progress will be monitored, issues related to study 
protocol operations will be discussed, and ideas will be exchanged to 
enhance study progress.  Representatives of the core support facilities 
will also be expected to serve on other study committees as needed.

Applicants must document their experience and capability to participate 
in a complex multicenter trial of this nature using a standard protocol.  
Evidence of institutional support for participating in a multicenter 
clinical trial to prevent type 1 diabetes should be provided.  Site 
visits by members of the DPT-1 and Type 1 Diabetes TrialNet Study Groups 
or the external Data Safety and Quality Monitoring Group may be required.

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. 

Up to 20 parent Clinical Centers are expected to complete the DPT-1 and 
participate in new studies within the TrialNet.  For the DPT-1, parent 
Clinical Centers are involved in screening, staging, 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.  

Current core support facilities of the DPT-1 include the Operations 
Coordinating Center (OCC), the Data Monitoring Unit (DMU), Core 
Laboratories, the Compounding Pharmacy, the Central Distribution 
Pharmacy, the clinical cost reimbursement system, and the consultant firm 
providing the central telephone line and publicity/recruitment support.  
Type 1 Diabetes TrialNet study structure is anticipated to be similar.  
The OCC will coordinate all interactions between the core support 
facilities, Clinical Centers and associated networks of 
Affiliates/Satellites, sponsoring agencies, study committees, and 
consultants.  The OCC will assist in financial management of the study, 
will develop and/or maintain all study protocols, manuals, agendas, and 
newsletters, and will provide subcontracts as needed to other core 
support facilities.  The functions of the DMU may be performed at the OCC 
or through a subcontract.  The DMU will be responsible for all study data 
management and statistical considerations.  In addition, the DMU will 
track clinical tests performed within the DPT-1 and Type 1 Diabetes 
TrialNet and will provide this information to the clinical cost 
reimbursement system for the distribution of payments to appropriate 
Clinical Centers/Affiliates/Satellites.  In the DPT-1, 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.  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 (http://www.immunetolerance.org) 
may also be used for assessments in the Type 1 Diabetes TrialNet.  The 
Central Distribution Pharmacy will dispense all therapeutic agents and 
placebos in DPT-1 and TrialNet studies as directed by the DMU.  The 
Central Distribution Pharmacy may receive agents from drug companies or 
other pharmacies, similar to the compounding pharmacy currently being 
used in DPT-1.  

The Steering Committee has overall responsibility for the design, 
planning, execution, and publication of the research performed by the 
DPT-1 Study Group and 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 core 
support facilities as well as 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 OCC, the DMU, and the NIDDK.  The Chair of the 
Planning Committee is selected by the Operations Committee.)  The NIDDK 
will select a Chairperson for the DPT-1 and Type 1 Diabetes TrialNet 
Steering Committee from among the Study Group members or other experts in 
clinical trials in type 1 diabetes.  The NIDDK may appoint a new 
Chairperson of the Type 1 Diabetes 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.

Research proposals for pilot and expanded intervention studies are being 
proposed in response to the DPT-1 and Type 1 Diabetes TrialNet Clinical 
Center RFA (DK-01-003).  It is anticipated that the majority of 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 the studies.  After awards are made in response to this 
RFA, research proposals for pilot, feasibility, and efficacy studies, and 
expanded clinical trials requiring TrialNet resources may be submitted by 
non-members of the TrialNet (see Eligibility Requirements in RFA DK-01-
003).  The mechanism for receiving and evaluating future proposals, and 
prioritizing studies, will be determined by the Type 1 Diabetes 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 regarding the design and 
implementation of clinical trials, natural history, and genetics 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. 

Core support facilities 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.

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.

In addition to periodic financial and administrative reports required by 
NIH for administration of cooperative agreements, Awardees must agree to 
furnish reports documenting recruitment and follow-up activity if 
requested by the Steering Committee and subcommittees.

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 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 or conducting 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 this 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.
Research conducted as a result of this RFA must include 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 to plan the 
review.

The Letter of Intent is to be sent to:

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

APPLICATION PROCEDURES

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

Additional Materials to Include in the Application 

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

A description of the activities of the Operations Coordinating Center 
must detail the plan for recruiting the remaining participants needed to 
complete the DPT-1, and to retain participants, since this effort will be 
coordinated and partially directed by the OCC.  The activities that would 
be performed by the consultant firm to aid the study recruitment and 
retention effort should be described.  These activities should be in 
addition to the consultant firm’s responsibilities of answering the 
central telephone line and responding to potential participants by 
mailing brochures and information, and producing the patient newsletter.  
Potential media strategies, important recruitment and retention 
materials, and outreach activities should be detailed.  Strategies for 
recruitment of minorities should be described, to enable accrual that 
would conform to NIH policy (see above under “INCLUSION OF WOMEN AND 
MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS”).  Potential problems 
likely to occur during recruitment and follow-up of minority or non-
minority participants should be described with a discussion of how to 
handle them.  Applicants must adequately describe plans for maintaining 
effective collaboration and communication between Clinical 
Center/Affiliate/Satellite Principal Investigators, Core Laboratories, 
the Data Monitoring Unit, and study participants.  They must describe 
their ability to provide fiscal management for large multicenter clinical 
trials.  A description of appropriate facilities, personnel, equipment, 
and evidence of institutional support must be provided.  Experience 
handling numerous subcontracts should be detailed.  Examples of forms and 
correspondence useful for coordinating tasks should be included.  

While the existing Core Laboratories will continue during completion of 
the DPT-1, the applicant should describe the approach that would be used 
for soliciting and evaluating proposals from new Core Laboratories that 
would support the conduct of pilot and expanded intervention studies of 
new agents.  [As mentioned previously, the utilization of laboratories of 
the Immune Tolerance Network by new trials may be appropriate 
(http://www.immunetolerance.org).]  

A solicitation and evaluation plan must also be provided for new 
compounding pharmacies that would support future intervention studies.  
Applicants should provide information on prior experience in 
participating in diabetes research and clinical trials. 

The Data Monitoring Unit should be described in terms of physical 
facilities, data management and computer resources, facilities for data 
retrieval and storage, and equipment for generating bar codes.  
Applications should describe proposed personnel and investigator/staff 
experience in large multicenter clinical trials, particularly in 
diabetes.  Specifically, a description of investigator/staff ability to 
design, support, conduct, and provide statistical expertise for clinical 
trials should be included.  Examples of data forms and questionnaires and 
software/computer programs appropriate for their use should be included 
and described.  Methods for sending and receiving data, electronically 
and by hardcopy, and maintaining data, should be provided.  Data 
management and quality control procedures must be detailed.  If 
applicable, a description of experience with voice-activated 
randomization should be given.  A description should be provided of 
experience and plans for multi-institutional study monitoring of data 
(e.g., center, laboratory, safety monitoring).  A simple description of 
methods for monitoring accrual by sex/gender and/or race/ethnicity and 
reporting differences in intervention effects in these subgroups should 
be provided (see above under “INCLUSION OF WOMEN AND MINORITIES IN 
RESEARCH INVOLVING HUMAN SUBJECTS”).  Any experience in website 
communication of specific study-wide data and information should be 
provided.  Methods for assuring privacy and maintaining confidentiality 
of data, including specific protections for internet-based data systems 
must be stated.  Evidence of institutional support must be provided.  If 
the Data Monitoring Unit will be at a different institution than the 
Operations Coordinating Center, and if the DMU will be handling 
subcontracts, the experience of the DMU in providing this function should 
be detailed.  Applicants must indicate their willingness to collaborate 
in multicenter trials of this nature using a common protocol.  

Applicants should describe the facilities of the Central Distribution 
Pharmacy, their experience in and usual procedures for distribution of 
drugs in multicentered trials in a masked manner, quality control 
procedures, and procedures for unmasking drug in the case of an adverse 
event.  

The clinical cost reimbursement system must be thoroughly described in 
terms of experience and the methods to be used for tracking patient care 
costs and reimbursing a large number of Clinical 
Centers/Affiliates/Satellites.  Facilities, computer hardware and 
computer software/programs, and turnaround time should be adequately 
detailed.

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.

Applications should not exceed 35 pages, excluding appendices.  

Budget Information

Approximately $4.7 million in total costs per year will be committed for 
core support facilities for completion of the DPT-1 and planning for new 
studies in TrialNet.  It is anticipated that one award will be made to 
the Operations Coordinating Center which, if necessary, will support 
subcontracts to one or more institutions to provide for the Data 
Monitoring Unit, the Core Laboratories, the compounding pharmacy(ies), 
the Central Distribution Pharmacy, clinical cost reimbursement system, 
and the consultant firm for the central telephone line and for 
media/recruitment support.

The budget should not exceed $2,060,000 in total costs annually for the 
OCC (personnel, supplies, equipment and communications), Data Monitoring 
Unit (personnel, supplies, equipment, and communications), clinical costs 
reimbursement system, and Central Distribution Pharmacy Unit.  Additional 
funds (in total costs) that are expected to be provided to the OCC 
annually and which should be included in submitted budgets are:  $200,000 
for the consultant firm to manage the central telephone line and provide 
publicity/recruitment support; $400,000 for the clinical centers’ use of 
laboratory supplies, and shipping tubes, vials, and boxes; $250,000 for 
overnight mail expenses and shipping of study specimens study-wide; 
$10,000 for the compounding pharmacy; $725,000 for patient care costs 
related to study tests that will be distributed to Clinical 
Centers/Affiliates/Satellites; and $48,000 for travel costs for 
representatives of the OCC, DMU, and core laboratories to attend 
necessary Steering Committee and DSQ meetings (estimated at $1500 per 
person per meeting); $105,000 for the Insulin Autoantibody Laboratory, 
$420,000 for the Islet Cell Antibody Laboratory, $120,000 for the Class 
II Major Histocompatibility and DNA Extraction Laboratory, and $405,000 
for the Beta Cell Function Laboratory.  Additional funds will be added to 
support the Study Chairperson if the Chairperson is selected from among 
members of the core support facilities.

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

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.

Applications will be reviewed for scientific and technical merit using 
the following criteria.  Applicants should note that the criteria 
incorporate consideration of the quality and feasibility of the proposed 
activities as well as consideration of past performance.

o Approach.  Is there an adequate understanding of the scientific agenda 
of the DPT-1 and Type 1 Diabetes TrialNet?  Can the core support facility 
and its staff contribute to the goals and enhance the capability of the 
Study Group as a whole?  Pertaining to Operations Coordinating Center 
activities, does the recruitment and retention plan outlined for the OCC 
and consultant firm appear reasonable for a large-scale clinical trial in 
type 1 diabetes and is it likely to succeed?  Does the approach conform 
to NIH guidelines for inclusion of women and minorities as human subjects 
in clinical research?  Does the applicant have a thorough understanding 
of the complexities of administering and monitoring a large-scale 
clinical trial and of maintaining effective collaboration and 
communication with members of the Study Group in large-scale clinical 
trials; is the plan likely to succeed?  Does the applicant show a good 
understanding of the requirements related to fiscal management and 
management of subcontracts?  Does the applicant provide a fair, open and 
reasonable plan for soliciting and evaluating future applications for 
laboratories and compounding pharmacies?  Pertaining to Data Monitoring 
Unit activities, is there a thorough understanding shown of the 
complexities of large-scale clinical trials, particularly in type 1 
diabetes, and does the applicant illustrate the ability to design, 
support, conduct, and provide statistical expertise in clinical trials?  
Does the applicant illustrate the ability to capture, monitor, transmit, 
store, ensure security, and otherwise manage clinical data in large-scale 
clinical trials?  Does the approach conform to NIH guidelines for 
inclusion of women and minorities as human subjects in clinical research?  
Does the applicant describe a reasonable plan for a Central Distribution 
Pharmacy for distributing drug in large-scale multi-centered clinical 
trials in a masked manner, and describe appropriate procedures for 
unmasking drug if necessary?  Are the quality control procedures of the 
Central Distribution Pharmacy adequate?  Is the plan for tracking patient 
tests that are performed at Clinical Centers/Affiliates/Satellites 
efficient and reliable and is there evidence of an efficient and fiscally 
responsible system to reimburse institutions with quick turnaround?

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 previous 
experience and competence with the design and administration of multi-
institutional clinical trials with extensive data collection requirements 
pertaining specifically to experimental design and statistical analysis, 
quality control and quality assurance, study monitoring, data collection 
and management, and compliance with regulatory requirements?  What are 
the qualifications and experience of the Project Coordinator(s) and key 
personnel, statisticians, computer programmers and data managers, 
pharmacists, and fiscal clerks?  Is there an appropriate amount of time 
planned for effective collaboration with Clinical 
Centers/Affiliates/Satellites and other core support facilities?  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?  

o Environment.  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Are the available 
facilities adequate for coordination of multicenter clinical trials 
tasks, data management and statistical support, drug distribution in a 
masked manner, and fiscal administration for distributing and managing 
funds involving multi-site studies?  Is there evidence of institutional 
support and commitment for the proposed program?

In addition to these criteria, in accordance with NIH policy, all 
applications will be reviewed with respect to the reasonableness of the 
proposed budget and the adequacy of the proposed protection for human 
subjects.

AWARD CRITERIA

Applications recommended by the NDDK Advisory Council will be considered 
for award based upon (a) scientific and technical merit; (b) programmatic 
and administrative considerations; and (c) availability of funds.

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
Grants Management Branch
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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