GLUCOSE SENSORS IN THE TREATMENT OF TYPE 1 DIABETES

NIH Guide, Volume 26, Number 38, November 21, 1997

RFA:  DK-98-008

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases
National Center for Research Resources

Letter of Intent Receipt Date:  February 19, 1998
Application Receipt Date:  March 19, 1998

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and
the National Center for Research Resources (NCRR) invite investigator-initiated
research grant applications to develop a glucose sensor or to create a closed-
loop system for regulating blood glucose.  Commercial development of needle-based
sensors and minimally invasive sensors is underway.  Several optical approaches
are appealing and are worthy of further development but are unlikely to yield a
functioning sensor in the near future.  This Request for Applications (RFA) is
intended to stimulate the application of advances in chemistry, engineering, cell
biology, biochemistry and endocrinology to the development of novel technologies
(which may include a combination of cellular and mechanical approaches) to
reliably and accurately measure glucose levels as part of a system to maintain
euglycemia.

This RFA allows for the submission of applications for two-year pilot and
feasibility grants, regular research project grants, and interactive research
project grants, which will support the efforts of several independent
investigators working in a collaborative manner.

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 RFA, Glucose Sensors in the Treatment
of Type 1 Diabetes, 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 No. 017-001-00474-0 or Summary Report: Stock No.
017-001-00473-1) through the Superintendent of Documents, Government Printing
Office, Washington, DC 20402-9325 (telephone: 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, 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. Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

Support of this program will be through the National Institutes of Health (NIH)
Research Project Grants (R01), Interactive Research Project Grants (IRPG), and
Exploratory/Developmental Research Grants (R21) award mechanisms. Guidelines for
preparing IRPG applications are available from the program official or from the
internet at: http://grants.nih.gov/grants/guide/pa-files/PA-96-001.html.

The R21 awards are to demonstrate feasibility of a concept and to generate
sufficient preliminary data to pursue it through other funding mechanisms.  These
grants are intended to (1) provide initial support for new investigators; (2)
allow exploration of possible innovative new leads or new directions for
established investigators; and (3) stimulate investigators from other areas to
lend their expertise to research within the scope of this solicitation. 
Applicants for the R21 must limit their requests to $100,000 direct costs per
year and are limited to two years.

Applicants from institutions which have a General Clinical Research Center (GCRC)
funded by the NIH National Center for Research Resources may wish to identify the
GCRC as a resource for conducting the proposed research.  In such a case, a
letter of agreement from either the GCRC program director or principal
investigator should be included with the application.

This RFA is a one-time solicitation.  Future unsolicited competing continuation
applications will compete with all investigator-initiated applications and be
reviewed according to the customary peer review procedures.

Applicants anticipating submitting IRPG applications or applicants requesting
more than $500,000 in direct costs per year for any year should consult with the
NIDDK Program Official listed under "INQUIRIES" at an early opportunity. 
Applicants for the R01 mechanism must receive permission from the NIDDK prior to
the submission of an application requesting more than $500,000 in direct costs
per year for any year of the proposed study.  NIDDK staff will coordinate
consideration and acceptance of such large applications by the staff of the
appropriate Institute.

The total requested project period for an application submitted in response to
this RFA may not exceed three years.  Budget escalations in future years are be
limited to 3% of recurring costs.  The anticipated award date is September 30,
1998.  Responsibility for the planning, direction, and execution of the proposed
project will be solely that of the applicant.  Awards will be administered under
Public Health Service (PHS) grants policy as stated in the PHS Grants Policy
Statement.

FUNDS AVAILABLE

For FY 1998, $4 million will be committed to fund applications submitted in
response to this RFA.  It is anticipated that 16 to 18 awards will be made. 
However, this funding level is dependent upon the receipt of a sufficient number
of applications of high scientific merit.  The award of grants pursuant to this
RFA is also contingent upon the availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

Diabetes mellitus affects approximately 16 million people in the United States. 
Individuals with type 1 diabetes mellitus have lost their ability to produce
insulin due to the immune destruction of their pancreatic beta cells, which
secrete insulin in response to a glucose challenge. Individuals with type 2
diabetes mellitus have lost their ability to over-produce insulin to maintain
euglycemia in the presence of insulin resistance.  Thus, both major forms of
diabetes mellitus demonstrate a loss of sufficient insulin production by the beta
cell.

On September 4 and 5, 1997, the NIH sponsored a workshop entitled "Diabetes
Mellitus: Challenges and Opportunities."  This workshop highlighted research
opportunities in several areas.  One of the most important areas identified was
the need to develop a glucose sensor to create a closed-loop system for
regulating blood glucose.  Intensive treatment of type 1 diabetes, although
effective in improving long-term outcome, is labor intensive and difficult to
implement for many patients with type 1 diabetes, and does not achieve
euglycemia.  Using currently available intensive treatment methods, the level of
glycemic control achieved, as measured by glycated hemoglobin (HbA1c), is at best
4-5 standard deviations above the mean value for the nondiabetic population.  The
implementation of intensive therapy is limited by the accompanying increased
frequency of severe hypoglycemia.  In addition, weight gain that accompanies
intensive therapy has resulted in an increasing prevalence of overweight patients
with type 1 diabetes.  Finally, currently available methods are particularly
problematic in children and adolescents, which is especially distressing since
our best clinical data support early intervention as being most effective.

Glucose sensors for the treatment of diabetes hold great promise for improving
metabolic control and quality of life for persons with diabetes.  The single
greatest change in the management of both type 1 and type 2 diabetes in the past
two decades has been the introduction and widespread implementation of reliable,
accurate, and relatively "user-friendly" self-glucose monitoring devices.  At
present, state-of-the-art technology cleanly divides mechanical delivery devices
and glucose sensing technology; however, the ultimate goal would be to develop
a "closed-loop" delivery system by combining the two technologies.

Scope and Objectives

Despite the enormous success of self-glucose monitoring, the technical challenges
of developing methods for continuous monitoring of blood glucose and several
highly publicized industry failures have overshadowed recent progress in the
field of glucose sensing.  Several approaches for continuous glucose measurement
are close to clinical applicability.

Various glucose sensor designs are in development. Designs that utilize an enzyme
electrode (such as glucose oxidase) and either a hydrogen peroxide or an oxygen
detection system appear to be the most successful to date.  These electrodes can
be placed subcutaneously or intravenously.  Other glucose sensor designs being
examined include acute microdialysis systems, transdermal extraction of tissue
fluids for glucose assay, and non- invasive technologies.  Future designs may
incorporate glucose sensing/alarm systems that are operational in vivo, such as
isolated islet electrical activity as a sensor.  These designs require more basic
research before demonstration of feasibility and subsequent development.

This RFA invites applications to improve or test sensors currently under
examination and to develop new approaches.  In this regard, understanding the
molecular mechanism by which ambient glucose concentrations elicit cellular
responses may yield new approaches to measuring glucose with potential
applications for glucose monitoring.  These can include the molecular events
leading to cellular recognition of hypo- or hyperglycemia.

The intended application of a specific sensor must be clearly defined, since it
specifies the required technology.  Also, the reproducibility of a sensor may be
related to its fabrication method especially whether each sensor is individually
made or mass-produced.  In fact, mass production methods may need to be developed
in hand with the clinical verification of a glucose sensor. Important functions
to be included in the design and verification of a sensor are hypoglycemic alarm,
continuous or frequent measurement of glucose levels, algorithms for converting
glucose data to insulin dose requirements, and finally, linking glucose
determinations to direct insulin delivery via a closed-loop system.

The movement of glucose sensors into the clinical arena requires ascertainment
of their longevity, the need for re-calibration, and the relationship between
blood and subcutaneous glucose concentrations especially during exercise and
hypoglycemia.  The latter issue includes the evaluation of the lag-time from
changes in blood glucose levels to changes in the subcutaneous tissue glucose
levels, which may be affected by local physiologic factors, such as tissue
architecture, microvascular perfusion, tissue oxygen distribution, movement,
implant biocompatibility and wound healing.  Assessment of this information
requires further animal studies for certain devices, but other devices are ready
to move into studies on normal volunteers and on volunteers with diabetes.

The scope of the present solicitation includes the further development of glucose
sensors to determine their clinical value and constraints; development and
verification of fabrication methods; establishment of miniaturization procedures
for the sensor and for control units; evaluation of the usefulness of the sensor
in individuals with type 1 diabetes; and development of a closed-loop system with
an accurate glucose sensing device, a controller, and an insulin delivery system.

Relevant topics listed below are examples and should not be construed as required
or limiting.

o  Development of glucose sensors

o  Investigation of relationship between blood glucose levels and dynamics in
different tissues, including relative concentrations, characteristics of lag-
times, determinants of partitioning

o  Innovative, speculative approaches which incorporate cellular and mechanical
technologies into the development of a glucose sensor

o  Development of fabrication and/or miniaturization methods applicable to
glucose sensors

o  Examination of noninvasive or optical approaches to ascertain proof of concept
and reliability especially related to variables affecting the path length and to
inter-individual variability conferred by different skin types

o  Independent assessment of clinical utility of a glucose sensor

o  Integration of sensor, control and delivery systems and creation of a true
artificial pancreas, which may include examination of appropriate parameters for
control of glycemia with insulin, delivered peripherally or intraperitoneally

o  Analysis of safety considerations of a closed-loop system with particular
emphasis on the risk of over- or under-treatment

o  Development of algorithms, telemetry, etc., to link the glucose sensor to the
insulin delivery system

o  Development of self-regulating implantable systems that are responsive to
blood glucose levels

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 is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research.  This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513), and in the NIH GUIDE FOR GRANTS AND CONTRACTS, Volume 23,
Number 11, March 18, 1994.

Investigators may also obtain copies from these sources or from the program staff
or contact person listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 19, 1998, a letter of
intent that includes a descriptive title of the proposed research; the name,
address, and telephone number of the Principal Investigator; the identities of
other key personnel and participating institutions; and the number and title of
this RFA.

Although a letter of intent is not required, is not binding, and does not enter
into the review of a subsequent application, the information that it contains
allows NIH staff to estimate the potential review workload and avoid conflict of
interest in the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Disease
45 CENTER DRIVE, Room 6AS-37F, MSC 6600
BETHESDA, MD 20892-6600
Telephone: (301) 594-8885
FAX: (301) 480-3505

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used in applying
for these grants.  These forms are available at most institutional offices of
sponsored research and may be obtained from the Division of Extramural Outreach
and Information Resources, National Institutes of Health, 6701 Rockledge Drive,
MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: 
ASKNIH@od.nih.gov.

The RFA label available in the PHS 398 (rev. 5/95) 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 2 of the face page of the application form and the
YES box must be marked.

As indicated under "Mechanism of Support," if a collaboration of individual
investigators is planned, it is necessary to identify one of the investigators
as the group coordinator and to cite this individual in all applications on page
2 of the form PHS 398 (rev. 5/95). Applicants who have entered into a
collaboration may submit the applications individually with a cover letter noting
their involvement and listing the other members of the collaboration.

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

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

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

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Disease
45 CENTER DRIVE, Room 6AS-37F, MSC 6600
BETHESDA, MD 20892-6600

Applications must be received by March 19, 1998.  If an application is received
after that date, it will be returned to the applicant without review.  The Center
for Scientific Review (CSR) will not accept any application in response to this
RFA that is essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application.  The CSR will not accept any
application that is essentially the same as one already reviewed.  This does not
preclude the submission of substantial revisions of applications previously
reviewed, but such applications must include an introduction addressing the
previous critique.

REVIEW CONSIDERATIONS

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 and undergo a process in which
only those applications deemed to have the highest scientific merit will be
discussed, assigned a priority score, and receive a second level review by the
National Advisory Council of the assigned Institute/Center.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In the
written review, comments on the following aspects of the application will be made
in order to judge the likelihood that the proposed research will have a
substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in the assignment of the overall score.

o  Significance: Does this study address an important problem?  If the aims of
the application are achieved, how will scientific knowledge be advanced?  What
will be the effect of these studies on the concepts or methods that drive this
field?

o  Approach: Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the aims of the
project? Does the applicant acknowledge potential problem areas and consider
alternative tactics?

o  Innovation: Does the project employ novel concepts, approaches or methods? 
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

o  Investigator: Is the investigator appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the principal investigator and other researchers (if any)?

o  Environment: Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements?  Is there evidence of institutional support?

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

o  Adequacy of plans to include both genders and minorities and their subgroups
as appropriate for the scientific goals of the research.  Plans for the
recruitment and retention of subjects will be evaluated.

The initial review group will also examine the provisions for the protection of
human and animal subjects, and the safety of the research environment.

o  Availability of special opportunities for furthering research programs through
the use of unusual talent resources, populations, or environmental conditions in
other countries which are not readily available in the United States or which
provide augmentation of existing U.S. resources.

o  For those applications that propose collaborative efforts between several
applicants, additional factors to be considered during the review would include
the efficacy of the collaboration, the commitment of the participants to the
collaboration, the design and responsibilities of the coordinating center and the
cost effectiveness of the collaborative effort.

R21 applications will have the additional review criteria:

o  Potential for novel and innovative approaches that clearly require additional
preliminary data for their value to be established.

IRPG applications will have these additional review criteria:

o  Each component R01 of the IRPG will be reviewed as above for its independent
scientific merit.

o  The reviewers will assess the intended IRPG interactions, including the
effectiveness and feasibility of the proposed IRPG group interactions, whether
or not they enhance the prospects for reaching the stated objectives of the
group, and the extent of synergy among the various projects.

AWARD CRITERIA

The anticipated date of award is September 30, 1998.

The factors that will be used to make award decisions include:

o  scientific and technical merit as determined by peer review,
o  availability of funds, and
o  programmatic priorities.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Joan T. Harmon, Ph.D.
Diabetes Research Section
National Institute of Diabetes and Digestive and Kidney Disease
45 CENTER DRIVE, Room 5AN-18G, MSC 6600
BETHESDA, MD 20892-6600
Telephone: (301) 594-8808
FAX: (301) 480-3503
E-mail: Joan_Harmon@nih.gov

Dov Jaron, Ph.D.
Biomedical Technology
National Center for Research Resources
6705 Rockledge Drive Room 6160  MSC 7965
Bethesda, MD 20892-7965
Telephone:(301) 435-0775
FAX: (301) 480-3659
Email: BTAdir@ep.ncrr.nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Nancy C. Dixon
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Disease
45 CENTER DRIVE MSC 6600
BETHESDA, MD 20892-6600
Telephone: (301) 594-8854
FAX: (301) 480-4237
E-mail: dixonn@extra.niddk.nih.gov

Louise Amburgey
Office of Grants Management
National Center for Research Resources
6705 Rockledge Drive Room 6086  MSC 7965
Bethesda, MD 20892-7965
Telephone: (301) 435-0844
Email: louisem@ep.ncrr.nih.gov

SCHEDULE

Letter of Intent Receipt Date:  February 19, 1998
Application Receipt Date:       March 19, 1998
Initial Review:                 June/July 1998
Second Level Review:            September 1998
Anticipated Date of Award:      September 30, 1998

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.847 (Diabetes, Endocrinology and Metabolism Research) and 93.371.  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 PHS grants policies and Federal Regulations 42 CFR 52 and 45
CFR Part 74.  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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