Full Text DK-93-008

NIDDM PRIMARY PREVENTION TRIAL: DATA COORDINATING CENTER

NIH Guide, Volume 22, Number 18, May 7, 1993

RFA:  DK-93-008 - (Reissued as RFA-DK-08-504)

P.T. 34

Keywords: 
  Clinical Trial 
  Disease Prevention+ 
  Data Management/Analysis+ 


National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  September 17, 1993
Application Receipt Date:  October 19, 1993

PURPOSE

The Division of Diabetes, Endocrinology and Metabolic Diseases (DDEMD),
National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), invites cooperative agreement applications for the Data
Coordinating Center in a multicenter, randomized clinical trial to
evaluate the efficacy of interventions designed to delay or prevent
onset of non-insulin dependent diabetes mellitus (NIDDM) in individuals
at increased risk for NIDDM.  The Data Coordinating Center will
participate with the NIDDK and fifteen to twenty Clinical Centers in
all phases of this trial.  A separate request for the Clinical Centers
has been issued (RFA DK-93-007).  The Data Coordinating Center and a
participating Clinical Center may be located in the same institution;
however, each must be administratively and fiscally distinct from the
other.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), NIDDM Primary Prevention Trial, is related to
the priority area of diabetes and chronic disabling conditions.
Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report:  Stock Number 017-001-00474-0 or Summary Report:  Stock Number
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325, telephone 202/783-3238.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by for-profit and non-profit domestic
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and
eligible agencies of the Federal government.  Minority individuals and
women are encouraged to submit as Principal Investigators.
Applications from minority institutions are especially encouraged.
Applications from foreign institutions will not be considered.

The expertise appropriate for this research program includes
statistical knowledge of the clinical and epidemiological aspects of
diabetes and expertise in data coordination for clinical trials.

MECHANISM OF SUPPORT

The administrative and funding mechanism to be used to undertake this
program will be a cooperative agreement (U01), which is an assistance
mechanism, rather than an acquisition mechanism.  Under the cooperative
agreement, the NIH purpose is to support and/or stimulate the
recipient's activity by collaborating 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 a
study funded under a cooperative agreement are discussed later in this
document under the section "Terms and Conditions of Award."

FUNDS AVAILABLE

It is anticipated that an award for one new Data Coordinating Center
will be made under this RFA.  Support during the planning phase (Phase
1) of this trial in FY 1994 is expected to be approximately $1,000,000
(direct and indirect costs).  The levels of effort are expected to
remain at this amount during the remainder of the study.  However,
funding will be provided by the NIDDK to support subcontracts for
centralized laboratory and clinical resources reflecting the start of
the full scale trial and described in greater detail under SPECIAL
REQUIREMENTS.  Funds for the subcontract(s) will be approximately five
million dollars (total costs) during Phase 2 to support adherence and
end point analyses.  Additional funds in the first year of Phase 2 will
be provided to cover the costs of screening.  The nature and extent of
the screening will be established by the outcome of the protocol
development.  Funds to support the subcontract aspects of the Trial
will largely cease during Phase 3 reflecting the final period of data
analysis and reporting.

Although this program is provided for in the financial plans of the
NIDDK, an award in response to the RFA is contingent on the
availability of funds for this purpose.

The total project period for applications submitted in response to the
present RFA will be seven years.  This is due, in part, to the
necessity to screen large numbers of potential participants to identify
individuals with sufficient risk to answer the study question discussed
under RESEARCH OBJECTIVES.  The anticipated award date is July 1994.

At this time the NIDDK anticipates that there will not be a renewed
competition after seven years.  If the NIDDK does not continue the
program, awardees may submit grant applications through the usual
investigator-initiated grants program.

RESEARCH OBJECTIVES

Background

A family history of diabetes, obesity, insulin resistance,
hyperinsulinemia, a history of gestational diabetes, and impaired
glucose tolerance (IGT) are risk factors for NIDDM (1).  Based on the
NHANES II survey data, IGT is present in 16 percent of adults aged 40
to 74 in the US and in 23 percent of this age group who have a family
history of diabetes and body weight greater than 120 percent of
desirable weight (2).  Minority populations have even higher rates of
IGT (3).  For high risk individuals the rate of progression to NIDDM is
5 to 10 percent per year (4).   Importantly, screening for IGT can
identify individuals at increased risk for development of NIDDM
(5,7,7).

In addition, obesity and gestational diabetes (GDM), an apparently
temporary condition of pregnancy, are important independent risk
factors for the subsequent development of NIDDM.  African, Hispanic and
Native American women have significantly increased prevalence of both
of these conditions.  It appears that excessive weight gain during
pregnancy may play a role in the appearance of GDM and the documented
lack of weight loss to pre-pregnancy levels following delivery may
conspire to magnify the risk of future NIDDM in these groups of
minority women.

There is currently no accepted standard of care for patients with IGT
or a history of GDM.  Screening for IGT, which is undiagnosed in most
affected individuals, is not widely recommended or practiced, nor are
there accepted interventions for patients with IGT.  No large scale,
randomized, prospective, controlled clinical trials have determined
whether or not progression of IGT to NIDDM can be prevented.

Insulin resistance is the earliest abnormality detected in individuals
who will develop NIDDM and appears to have a genetic component (8).
However, it is not known whether reversing insulin resistance will
prevent or delay onset of NIDDM.  Insulin resistance can be reduced
through weight reduction and exercise (9).  Corresponding to these
findings, epidemiological data indicate an association between exercise
frequency and significant lowering of risk for NIDDM (10,11).  Results
of another study performed in Sweden suggest that moderate weight
reduction of two to four percent of initial weight and increased
maximal oxygen uptake of 10 to 14 percent could be maintained for a
period of five  years.  This was associated with improvement in glucose
tolerance, blood pressure, lipids, and hyperinsulinemia, and reduced
mortality (12).  Sustained intervention appears to be necessary to
achieve these lifestyle changes (13) but importantly, such changes have
the potential to slow the deterioration of glucose tolerance in IGT,
thereby delaying the onset of diabetes.

Pharmacologic agents also can potentially prevent or delay onset of
NIDDM.  Biguanides are suggested to reduce insulin resistance and
improve glycemia and hyperinsulinemia, while sulfonylurea agents appear
to improve glycemia by increasing insulin secretion and through
extra-pancreatic effects.  Data in the literature are inconclusive with
respect to the ability of these agents to prevent or delay onset of
NIDDM.  One study using the biguanide metformin showed no effect on
prevention or delay of onset (14).  In contrast, studies with
sulfonylureas have shown decreased rates of diabetes and of mortality
in patients treated with modest doses for IGT (15,16) but are
inconclusive.  Nonetheless, these interventions could slow the
deterioration of glucose tolerance in patients with IGT.  In so doing,
diabetic complications, including atherosclerosis, may also be delayed
reducing morbidity and mortality due to diabetes.

Methods are available for potentially reducing insulin resistance and
improving glucose tolerance.  Based on this and the high rates of IGT
in the United States, the NIDDK has determined that a randomized
controlled clinical trial is necessary.  Such a trial would define the
effectiveness of interventions for delaying or preventing NIDDM in high
risk persons with glucose intolerance.  Since the estimated population
prevalence of undiagnosed NIDDM is six percent, screening for IGT will
detect individuals with previously undiagnosed NIDDM, most of whom do
not have fasting hyperglycemia (2).  The NIDDK also believes that those
with newly diagnosed NIDDM should be treated in a randomized,
prospective fashion to determine whether early detection and treatment
of NIDDM can reverse the disease process or have favorable effects on
the deterioration of glucose tolerance that is characteristic of NIDDM.

Goal of the Activity

The purpose of this RFA is to invite applications for the Data
Coordinating Center in a multicenter collaborative study of
interventions to prevent NIDDM in people with IGT or a history of GDM
and to prevent the worsening of glucose tolerance in people with newly
diagnosed NIDDM.  The study will determine whether onset of NIDDM can
be delayed and whether interventions in newly diagnosed NIDDM can
favorably influence glucose tolerance and progression to fasting
hyperglycemia.

The objectives of this RFA are to select a Data Coordinating Center to
participate in the following:

o  A full-scale trial with the Clinical Centers and the NIDDK

o  Design of the study protocol and writing of the manual of operations

o  Development of the operational plans for the trial in close
collaboration with the communities they serve.  These plans must
include racially and ethnically sensitive strategies for recruitment,
screening, enrollment and adherence to the study protocol.

o  The establishment of clinical and laboratory subcontracts to serve
as centrally supported resources for the Clinical Centers.

Additional clinical centers will be recruited through a follow-up RFA
if necessary to achieve adequate numbers of subjects.

The collaborative protocol will be developed by a Steering Committee
composed of the awardees, a Chairperson appointed by the voting members
of the Steering Committee from among the Committee members or from
experts in the field of diabetes and clinical trials not participating
directly in the study, the Principal Investigator of the Data
Coordinating Center, and the NIDDK Project Coordinator.  The protocol
and manual of operations will be subject to review by an uninvolved
expert group (Policy and Data Monitoring Committee), and the NIDDK.
The study will move into its operational phase only with the
concurrence of the awardees, the Policy and Data Monitoring Committee,
and the Institute.

Scope of the Activity

It is expected that the study will take place in fifteen to twenty
Clinical Centers over a period of seven years.  Each clinical center
will randomize an average of 200 study participants over a 12 month
period of recruitment.  The entire collaborative clinical trial will
consist of the following three phases:

Phase 1 (12 months):  Planning phase, collaborative development of the
protocol and manual of operations which includes procedures for data
collection and pretesting of these procedures.  There must also be
included in the manual well-defined procedures for the training and
certification of clinic personnel in study procedures.

Phase 2 (60 months):  Conduct of the full-scale collaborative clinical
trial including patient recruitment and followup.

Phase 3 (12 months):  Close out, analysis of data, and reporting of
results.

The Data Coordinating Center will participate during Phase 1 in the
planning phase of the Trial including protocol development, preparation
of the manuals of operations, sample size determination, estimates of
event rates and full statistical oversight.  Centralized laboratories
and centralized clinical support facilities will also be developed
during this period for use during Phase 2 supported through
subcontracts.  During Phases 2 and 3 the Data Coordinating Center will
analyze the cumulative data from the study with appropriate
participation of the Clinical Centers and the NIDDK.

Participation in Phase 1 will require staff of the Data Coordinating
Center to travel to meetings in a location such as Bethesda where the
protocols, manuals, and forms will be developed.  Phase 2 will require,
in addition to data processing and analysis, qualified personnel to
travel to the Clinical Centers to monitor quality control procedures,
to attend meetings with Clinical Center personnel and NIDDK staff, and
to conduct training programs for clinic staff.  Phase 3 will require
staff qualified to analyze data from large-scale clinical trials.
Additionally, the Data Coordinating Center will be required to assist
in managing the logistics of committee and sub-committee meetings
during the course of the trial and be responsible for taking minutes of
the various meetings.  It will also provide the support and guidance
necessary to maintain the scientific integrity of the trial through
Coordinating Center staff or procurement of consultants.

The Data Coordinating Center will be responsible for acquiring and
administering subcontracts for central laboratory and clinical
resources.  The applicant for the Coordinating Center must identify and
prepare budgets for the central laboratories and facilities proposed to
carry out the centralized activities dictated by the trial protocol.

The specific centralized facilities and the budgets to be supported
through subcontracts will depend on the final protocol developed
cooperatively by the Steering Committee.

The applicant should address the requirements of the Trial with a
description of the tasks to be performed and provide corresponding
budgets as presented later under "Budget Preparation by Study Phase."
It should, however, be understood that the final budgets will be
determined following the design of the study protocol and writing of
the manual of operations.

Examples of the types of centralized laboratory functions that may be
required include analyses such as blood glucose determinations, blood
lipid and lipoprotein subtypes, and determination of drug treatment
levels.  Endpoint analyses may include measures conducted at
centralized reading centers for electrocardiograms, reading of fundus
photography, non invasive vascular determinations and renal and
cardiovascular biochemistry.  For a central laboratory supported by a
subcontract from the Data Coordinating Center, all NIH policies and
procedures governing consortium grants must be adhered to.

The Data Coordinating Center will process and review all data
transmitted on standard forms and prepare periodic reports to
participating clinics on outstanding, incomplete, and delinquent forms
or other missing information.  The Coordinating Center will also
prepare reports to the NIDDK and the Steering and the Policy and Data
Monitoring Committees at regular intervals and as dictated by the study
needs.  The NIDDK Project Director will serve as a liaison between the
Data Coordinating Center and the Clinical Centers.

During Phase 3, the Data Coordinating Center will complete all analyses
of the data from the clinical trial.  Final reports will be submitted
to the Steering Committee and the Policy and Data Monitoring Committee.
The Coordinating Center, after final analyses, will collaborate with
the investigators and the NIDDK to prepare reports of the study for
publication.

SPECIAL REQUIREMENTS

The Data Coordinating Center will be closely involved with all facets
of the trial from the initiation of Phase 1 to Phase 3 final data
analysis and reporting.  The following minimum number of issues should
accordingly be addressed:

o  The participation of the Coordinating Center in the design and
refinement of all protocols and the Coordinating Center's function as
central point for assembling the Manuals of Operation and Forms
Manuals;

o  The Data Coordinating Center's primary responsibility in developing
and implementing systems necessary for intra-study communications.

o  The primary responsibility of the Data Coordinating Center for data
collection, editing, processing, analysis and reporting.

o  The responsibility for monitoring both the quality of the data and
the performance of each clinical center in the performance of the
protocols.

o  Documentation for experience in utilizing procedures that insure the
safety and confidentiality of all records.

Personnel

A Director and Deputy Director for the Data Coordinating Center must be
designated.  The Director of the Data Coordinating Center should be an
experienced biostatistician, epidemiologist, physician, or other
professional with experience in directing a coordinating center for a
large scale collaborative clinical trial or other large scale
epidemiological research project.  A physician with professional
interests in diabetes as part of the management team is highly
desirable.

Staff needs may be modified as the trial progresses; however,
statisticians, systems analysts, programmers, statistical assistants,
clerks, and administrative assistants must be available.  It is
appropriate that funds for adequate support staff to manage routine
tasks be requested.  It is expected that senior statistical staff
devote time to developing data analysis methods for use in the trial.

Budget Preparation by Study Phase

Applicants for the Data Coordinating Center should submit adequately
justified budgets for the entire anticipated project period of 84
months.  The budgets for each phase of the study should be clearly
delineated.  Final budgets, however, will be generated following the
design of the study protocol and writing the manual of operations
during Phase 1.

The Phase 1 budget period will be for establishment of the Data
Coordinating Center staff such as the PI, senior statistical advisor,
biostatistician, senior data controller, and others as required to
carry out the Coordinating Center's functions.  During this phase the
collaborating centralized laboratory functions and facilities and
individuals to perform clinical determinations of outcome measures will
be identified.  These centralized functions will be supported by
subcontracts provided through the Data Coordinating Center and are to
be included in the overall Coordinating Center budget for Phase 2.

The Phase 2 period will be for 60 months.  Separate budgets for each
12-month budget period in Phase 2 should be submitted.  Activities in
this second period will include all data handling costs, reporting
functions, meetings and the cost of the subcontracts necessary to carry
out laboratory and other central functions.

The Phase 3 budget period will be for 12 months.  This budget period
will be concerned with study close-out, analysis of study data, and
reporting of results in collaboration with the centers.

Budgets for both Phases 2 and 3 will be modified based on the final
protocol developed collaboratively during Phase 1.

Terms and Conditions of Award

1.  Cooperative Activities.  The administrative and funding mechanism
to be used to undertake this project will be cooperative agreements
(U01), which is an "assistance" mechanism, rather than and
"acquisition" mechanism.  Under the cooperative agreement, the NIDDK
purpose is to support and/or stimulate the recipient's activity by
collaborating 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 tasks and activities in carrying out the studies will
be shared among the awardees and the NIDDK Project Coordinator.

2.  Awardees Activities.  Awardees will have substantial and lead
responsibilities in all tasks and activities. These include protocol
development, patient recruitment and follow-up, data collection,
quality control, final data analysis and interpretation, preparation of
publications.  The awardee agrees to work cooperatively with the
Clinical Centers and agrees to follow the common protocol and manual of
operations developed in Phase 1 of the study by the Steering Committee.

Awardees will retain custody of and have primary rights to their data
developed under these awards, subject to Government, e.g., NIDDK, NIH,
or PHS, rights or access consistent with current HHS, PHS, and NIH
policies.

3.  NIDDK Activities.  It is the intention of the NIDDK that the
central resource units for the standardized assessment of key
laboratory and clinical parameters will be established and utilized by
all participating Clinical Centers.  These central resources will
function and be supported under the Data Coordinating Center award.

The NIDDK will name the Director, Special Programs from within the
Division of Diabetes, Endocrinology, and Metabolic Diseases to be the
Project Coordinator whose function will be to assist the Steering
Committee and Policy and Data Monitoring Committee in carrying out the
study.  The Project Coordinator will be a voting member of all key
study group committees.  The Project Coordinator will serve as
executive secretary of the independent Policy and Data Monitoring
Committee.  The NIDDK Project Coordinator will assist in quality
control, interim data and safety monitoring, final data analysis and
interpretation, preparation of publications, and coordination and
performance monitoring.

The NIDDK Project Coordinator will have voting membership on the
Steering Committee, and as  appropriate, its subcommittees.

The NIDDK reserves the right to terminate or curtail the study (or an
individual award) in the event of (a) a major breach in the protocol or
substantial changes in the agreed-upon protocol with which the
Institute does not agree or (b) human subject ethical issues that may
dictate a premature termination.

4.  Governance.  The primary governing body of the study will be the
Steering Committee comprised of each of the Principal Investigators of
the Clinical Centers and the Data Coordinating Center and the NIDDK
Project Coordinator.  The Steering Committee will have primary
responsibility for developing common clinical protocols, facilitating
the conduct and monitoring of the studies, and reporting the study
results.  Topics for the protocols will be proposed and prioritized by
the steering Committee.  Each member of the Steering Committee will
have one vote.  A chairperson will be appointed by the voting members
of the Steering Committee from among the Steering Committee members but
not including the Project Coordinator, or alternatively, from among
experts in the field of diabetes and clinical trials who are not
participating directly in the study.

It is anticipated that the Steering Committee will meet on a monthly
basis during protocol development (Phase 1), three times a year in
Phase 2, and two times in Phase 3.  Subcommittees of the Steering
Committee may be established as necessary and will meet as necessary.
The NIDDK Project Coordinator or designee and the Data Coordinating
Center will be represented on each subcommittee.

An independent Policy and Data Monitoring Committee supported by the
NIDDK and composed of experts in relevant medical, psychological,
statistical, operational, and bioethical fields who are not otherwise
involved in the study will be established to review periodically the
progress of the study.  The committee will oversee participant safety,
evaluate results, monitor data quality, and provide operational and
policy advice to the Steering Committee and the NIDDK regarding the
status of the study.  The Principal Investigator of the Data
Coordinating Center, the NIDDK Project Coordinator, and the Director of
the Division of Diabetes, Endocrinology and Metabolism may participate
as ex-officio, non-voting members of this Committee. Committee members
will be appointed by the Director, NIDDK in consultation with members
of the Steering Committee.  The NIDDK named Project Coordinator will
serve as executive secretary of the Policy and Data Monitoring
Committee.

5.  Arbitration.  Any disagreement that may arise in
scientific-programmatic matters between award recipients and NIDDK may
be brought to arbitration.  An arbitration panel will be composed of
three members - one selected by the Steering Committee (with NIDDK
member not voting) or by the individual awardees in the event of an
individual disagreement, a second member selected by NIDDK and the
third member selected by the preceding two members.  This special
arbitration procedure in no way affects the awardees' 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 regulations at 45
CFR part 16.

These special terms of award described above 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.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women in
study populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis must be placed on the need for inclusion of minorities
and women in studies of diseases, disorders and conditions which
disproportionately affect them. This policy is intended to apply to
males and females of all ages.  If women or minorities are excluded or
inadequately represented in clinical research, particularly in proposed
population-based studies, a clear compelling rationale must be
provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research design
and sample size appropriate for the scientific objectives of the study.
This information must be included in the form PHS 398 (rev. 9/91) in
Item 4 (Research Design and Methods) of the Research Plan AND
summarized in Item 5, Human Subjects.  Applicants are urged to assess
carefully the feasibility of including the broadest possible
representation of minority groups.  However, NIH recognizes that it may
not be feasible or appropriate in all research projects to include
representation of the full array of United States racial/ethnic
minority populations; i.e., Native Americans [including American
Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks,
Hispanics.

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology, prevention
[and preventive strategies], diagnosis, or treatment of diseases,
disorders or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

If the required information is not contained within the application,
the application will be returned without review.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and reflected in assigning
the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.

LETTER OF INTENT

Prospective applicants are asked, but not required, to submit a letter
of intent.  This letter is to include the name, telephone number and
mailing address of the Principal Investigator, the names of other key
personnel, the name of the applicant institution, and the number and
title of this RFA.  Such a letter of intent is not binding and it will
not enter into the review of any application subsequently submitted nor
is it a necessary requirement for application.  Letters of intent are
requested solely for planning purposes.  The information contained in
these letters is helpful in planning for the review of applications.
It allows NIDDK staff to estimate the potential review workload and to
avoid possible conflicts of interest in the review.  The NIDDK staff
will not provide responses to such letters.

Letters of intent are to be received no later than September 17, 1993,
and are to be addressed to:

Robert D. Hammond, Ph.D.

Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892
Telephone:  (301) 594-7515
FAX:  (301) 594-7503

APPLICATION PROCEDURES

Submit applications on form PHS 398 (rev. 9/91), the application form
for NIH research project grants.  This form is available in the
applicant institution's office of sponsored research and may be
obtained from the Office of Grants Inquiries, Division of Research
Grants, National Institutes of Health, Westwood Building, Room 449,
Bethesda, MD 20892, telephone (301) 594-7250.

Use the conventional format for research project grant applications and
ensure that the points identified in the SPECIAL REQUIREMENTS section
above and in the "Review Criteria" section below are fulfilled.  To
identify the application as a response to the RFA, Check "YES" on item
2a of page 1 of the application and enter the title "NIDDM Primary
Prevention Trial: Data Coordinating Center" and enter the RFA number
DK-93-008 in the space provided.

The RFA label found in the form PHS 398 application kit must be affixed
to the bottom of the face page of the original completed application
form.  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.

Send or deliver the completed, signed application and three complete
photocopies to the following office, making sure that the original
application with the RFA label attached is on top:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

Send two additional copies of the application to Dr. Hammond at the
address listed under LETTER OF INTENT. It is important to send these
two copies at the same time as the original and three copies are sent
to the Division of Research Grants, otherwise the NIDDK cannot
guarantee that the application will be reviewed in competition for the
RFA.

Applications must be received by October 19, 1993.  An application not
received by this date will be returned to the applicant.

REVIEW CONSIDERATIONS

Upon receipt, the Division of Research Grants (DRG) will review
applications for completeness.  Applications will be reviewed by NIDDK
staff for responsiveness to the objectives of this RFA.  If an
application is judged unresponsive or incomplete, the application will
be returned.

If the number of applications is large compared to the number of awards
to be made, the NIDDK will conduct a preliminary scientific peer review
and will withdraw from further competition those applications that are
not competitive for award.  The NIDDK will notify the applicant and
institutional official of this action.  Those applications judged to be
both competitive and responsive will be evaluated further according to
the review criteria stated below for scientific and technical merit by
an appropriate peer review group convened by the Division of Extramural
Activities, NIDDK.  Subsequently, they will be reviewed by the National
Advisory Diabetes and Digestive and Kidney Diseases Council.

Review Criteria

Specific criteria for review of applications will be as follows:

o  The scientific merit of the proposed approach to study design, data
collection and management for interventions as outlined in the RFA

o  Documentation of the specific competence and previous experience of
professional, technical, and administrative staff pertinent to the
operation of a Data Coordinating Center for a collaborative clinical
trial.  Prior experience in the collection of data from multiple
clinical sites, as well as experience in monitoring the quality of such
data must be demonstrated.

o  The approach to developing a cooperative relationship among the
participating clinical centers and exercising appropriate leadership in
matters of study design, data acquisition, data management, and data
analysis,

o  Suitability of the proposed data management and data analysis plans
as well as the specific plans for central laboratories and clinical
facilities,

o  Appropriateness of the proposed budget,

o  Ability to identify and enlist the cooperation of central
laboratories and clinical facilities to carry out centralized
biochemical and clinical support functions for the Clinical Centers.

o  The adequacy of the proposed facility, technical hardware, and
space;

o  The organizational and administrative structure of the proposed
Coordinating Center,

o  Evidence of the degree of commitment and support of the
organization/institution for the proposed Coordinating Center including
documentation of available space.

Seminar for Prospective Applicants

A special technical assistance workshop will be offered to assist
potential applicants.  The purpose of this seminar is to give
background information and respond to any questions about the
preparation of an application in response to this RFA.  The workshop
will be held in the Washington, DC metropolitan area approximately one
month after the publication of this announcement.  The NIH cannot
support individuals who wish to attend the conference, but the
conference will be open to any individual who wishes to attend.
Interested persons may contact Dr. Sanford A. Garfield, at the address
listed under INQUIRIES, for further information.

AWARD CRITERIA

The anticipated date of award is July 1994.  Applications will compete
for available funds with all other approved applications submitted in
response to this RFA.  The following will be considered in making
funding decisions:

o  Quality of the proposed work as determined by peer review,
o  Availability of funds.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Sanford Garfield, Ph.D.
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 626
Bethesda, MD  20892
Telephone:  (301) 594-7535
FAX:  (301) 594-9011

Inquiries regarding fiscal matters may be directed to:

Linda Stecklein
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649B
Bethesda, MD  20892
Telephone:  (301) 594-7543
FAX:  (301) 594-7594

Schedule

Letter of Intent Receipt Date:  September 17, 1993
Application Receipt Date:       October 19, 1993
Initial Review:                 February/March 1994
Review by the NIDDK Council:    May/June 1994
Anticipated Award Date:         July 1994

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No. 93.847.  Awards are made under the authority 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 PHS Grants
Policies and Federal Regulations 42 CFR Part 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.

References:

1.  National Diabetes Data Group:  Classification and diagnosis of
diabetes mellitus and other categories of glucose intolerance.
Diabetes 28:1039-57, 1979

2.  Harris MI, Hadden WC, Knowler WC, Bennett PH. Prevalence of
diabetes and impaired glucose tolerance and plasma glucose levels in
U.S. population aged 20-74 yr. Diabetes 36:523-534;1987

3.  Harris MI Epidemiological correlates of NIDDM in Hispanics, Whites,
and Blacks in the U.S. population. Diabetes Care 14:639-648:1991

4.  Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH.
The natural history of impaired glucose tolerance in the Pima Indians.
New Engl J Med 319:1500- 1506;1988

5.  Yudkin JS, Alberti KGMM, Mclarty DG, Swai ABM Impaired glucose
tolerance. Brit Med J 301:397-402;1990

6.  Eriksson KF, Lindgarde F, Impaired glucose tolerance in a
middle-aged male urban population: a new approach for identifying high
risk cases. Diabetologia 33:526- 531;1990

7.  Harris MI, Hadden WC, Knowler WC, Bennett PH: International
criteria for the diagnosis of diabetes and impaired glucose tolerance.
Diabetes Care 8:562-67, 1985

8.  Lillioja S, Mott DM, Zawadzki JK, Young AA, Abbott WGH, Knowler WC,
Bennett PH, Moll P, Bogardus C.  In vivo insulin action is a familial
characteristic in nondiabetic Pima Indians.  Diabetes 36:1329;1987

9.  Horton ES. Exercise and decreased risk of NIDDM. N Engl J Med
325:197;1991 (editorial)

10.  Helmrich SP, Ragland DR, Leung RW, Paffenbarger RS. Physical
activity and reduced occurrence of non-insulin- dependent diabetes
mellitus.  N Engl J Med 325:147;1991

11.  Manson JE, Nathan DM, Krowlewski AS, Stampfer MJ, Willett WC,
Hennekens CH. A prospective study of exercise and incidence of diabetes
among US male physicians.  JAMA 268:63;1992

12.  Eriksson KF, Lindgarde F.  Prevention of Type 2
(non-insulin-dependent) diabetes mellitus by diet and physical
exercise:  The 6-year Malmo feasibility study. Diabetologia
34:891-898;1991

13.  Page RCL, Harnden KE, Cook JTE, Turner RC.  Can life-styles of
subjects with impaired glucose tolerance be changed?  A feasibility
study.  Diabetic Medicine 9:562-566;1992

14.  Jarrett RJ, Keen H, Fuller H, McCartney M. Worsening to diabetes
in men with impaired glucose tolerance ("Borderline Diabetes").
Diabetologia 16:25- 30;1979

15.  Sartor G, Schersten B, Carlstrom S, Melander A, Norden A, Persson
G. Ten-year follow-up of subjects with impaired glucose tolerance.
Diabetes 29:41;1980

16.  Melander A, Bitzen P-O, Sartor G, Schersten B, Wahlin-Boll E.
Will sulfonylurea treatment of impaired glucose tolerance delay
development and complications of NIDDM?  Diabetes Care 13:53-58;1990

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