Release Date:  September 30, 1999

RFA:  DK-00-001 
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Allergy and Infectious Diseases
National Institute of Child Health and Human Development

Letter of Intent Receipt Date: March 14, 2000
Application Receipt Date: April 14, 2000.



The National Institute of Diabetes and Digestive and Kidney 
Diseases, the National Institute of Allergy and Infectious 
Diseases, and the National Institute of Child Health and Human 
Development invite investigator-initiated research grant 
applications for clinical studies of new approaches to therapy 
for type 1 diabetes.  The focus of this initiative includes 
studies of cell-based therapies, glucose sensing devices, pumps, 
biomechanical-artificial pancreas, gene therapy, 
immunomodulation to arrest or reverse type 1 diabetes mellitus, 
and methods to detect and prevent hypoglycemia.  These 
applications should propose clinical studies on individuals with 
type 1 diabetes.  For studies of immunomodulation to reverse 
diabetes, individuals recently diagnosed with type 1 diabetes 
might be the appropriate patient population.  Support for 
preclinical or clinical studies necessary to obtain approval for 
an investigational new drug or for an investigational device 
could be requested if the application also includes a clinical 
component.  Collaborative efforts linking expertise in molecular 
biology, cell biology, bioengineering, gene therapy, and 
immunology to expertise in type 1 diabetes are strongly 
encouraged.  While it is anticipated that improved glycemic 
control will prevent or delay complications, studies of 
therapies designed to address other aspects of prevention or 
therapy of complications are not responsive to this RFA.


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), NEW STRATEGIES FOR 
THE TREATMENT OF TYPE 1 DIABETES, is related to one or more of 
the priority areas. Potential applicants may obtain a copy of 
"Healthy People 2000" at


Applications may be submitted by domestic and foreign for-profit 
and nonprofit 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 


This RFA will use the National Institutes of Health (NIH) 
research project grant (R01) award mechanism, the Interactive 
Research Project Grant (IRPG) award mechanisms and the 
exploratory/developmental grant (R21) award mechanism.  R21 
awards are to demonstrate feasibility and obtain preliminary 
data testing innovative ideas that represent clear departure 
from ongoing research interests.  Guidelines for preparing IRPG 
applications are available from the program official or from the 
internet at:

Awards will be administered under NIH grants policy as stated in 
the NIH Grants Policy Statement.

The R21 exploratory/developmental studies are intended to:  (1) 
provide initial support for new investigators; (2) allow 
exploration of innovative new leads or new directions for 
established investigators in diabetes; and (3) stimulate 
investigators from other areas to lend their expertise to 
research in this area.  Pilot and feasibility grants are not 
intended to support or supplement ongoing funded research of an 
established investigator.  This program enables investigators to 
explore the feasibility of a novel concept related to 
development of new therapies for type 1 diabetes and generate 
sufficient data to pursue it through other funding mechanisms.  
These grants will not be renewable; continuation of projects 
developed under this program will be through the regular 
research project mechanism (R01).  R21 grants will be limited 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.  Responsibility for the 
planning, direction, and execution of the proposed project will 
be solely that of the applicant.  The total requested project 
period for applications submitted in response to this RFA may 
not exceed three (3) years. 

Specific application instructions have been modified to reflect 
"MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being 
examined by the NIH.  Complete and  detailed instructions and 
information on Modular Grant applications can be found at


For FY 2000, $3 million will be committed to fund applications 
submitted in response to this RFA.  It is anticipated that 8 to 
12 awards will be made.  However, this funding level is 
dependent upon the receipt of a sufficient number of 
applications of high scientific merit.  Although this program is 
provided for in the financial plans of the NIDDK, the award of 
grants pursuant to this RFA is also contingent upon the 
availability of funds for this purpose.



Type 1 diabetes results from immune destruction of the beta 
cells of the pancreas leading to loss of insulin secretion and 
resultant hyperglycemia.  Therapy with insulin prevents 
ketoacidosis but not the devastating long-term outcomes of 
diabetes.  The Diabetes Control and Complications Trial (DCCT) 
demonstrated that intensive treatment regimens to achieve tight 
control of blood glucose can significantly reduce the onset and 
progression of diabetic complications in individuals with type 1 
diabetes.  Intensive treatment of type 1 diabetes, although 
effective in improving long-term outcome, is difficult to 
implement for many patients and does not achieve euglycemia.  
The level of glycemic control achieved using currently available 
intensive treatment methods is at best 4-5 standard deviations 
above the mean value for the nondiabetic population, as measured 
by glycated hemoglobin (HbA1c).  Intensive therapy is also 
limited by the accompanying increased frequency of severe 
hypoglycemia and weight gain, resulting in an increasing 
prevalence of overweight patients with type 1 diabetes.  This 
RFA solicits applications for clinical studies of promising new 
therapeutic approaches for the treatment of individuals with 
type 1 diabetes.  The objectives are to develop better methods 
of optimizing glucose control in patients with type 1 diabetes, 
to test promising strategies for immunomodulation to reverse 
type 1 diabetes, and to develop approaches to prevent 
hypoglycemia and prevent or reverse hypoglycemia unawareness.

The needs and opportunities to develop better methods to achieve 
tight control of blood glucose were clearly stated in the 
recently published Report of the Congressionally-Established 
Diabetes Research Working Group entitled "Conquering Diabetes: A 
Strategic Plan for the 21st Century."  This report outlines a 
number of recommendations to improve therapy for type 1 
diabetes.  It calls for increased research in a number of areas.  
These include: evaluation of antigen-specific, cytokine or 
antibody-based immunotherapy; application of cell based 
therapies; prevention of transplant rejection or destruction by 
autoimmune mechanisms; evaluation of alternate strategies for 
insulin administration including mechanical approaches and 
alternate routes for insulin administration; and improved 
methods to prevent and detect hypoglycemia.

Scope and Objectives

The optimal treatment for individuals with type 1 diabetes would 
be to reverse the disease.  Towards this end, new clinical 
interventions in the autoimmune disease process that lead to 
type 1 diabetes are being developed.  Currently being considered 
for application to diabetes are strategies already being 
utilized to block the progression of other autoimmune diseases.  
T cell activation can be inhibited with an antibody that binds 
to a cell membrane component (CD40L or CTLA4) of an activating T 
cell and prevents further T cells from being activated (co-
stimulatory blockade).  A second strategy would be to induce 
tolerance to known islet cell antigens such as glutamic acid 
decarboxylase (GAD) or IA-2.  Another strategy involves 
suppression or modulation of lymphocyte function using 
appropriate cytokines such as IL-4 or IL-10.  Individuals 
recently diagnosed with type 1 diabetes might be a population in 
which these strategies could be successful in arresting or 
reversing the disease process.  Evaluation of the success of 
clinical protocols for immunomodulation/tolerance induction in 
individuals with newly diagnosed type 1 diabetes may be 
confounded by the occurrence of a spontaneous and transient 
resolution of diabetes (the "honeymoon" period).  Such proposals 
must address how efficacy will be established.

The present therapies for optimizing glucose control have 
inherent within them the risk of severe hypoglycemia which 
represents the single greatest barrier to tight control of blood 
glucose.  The risk is magnified as a result of both impaired 
recognition of an impending episode and compromised counter-
regulation to restore euglycemia.  Thus, efforts to detect and 
prevent hypoglycemia would be enhanced by the development of new 
techniques for self-monitoring the circulating glucose 
concentration.  Methods also need to be developed to facilitate 
recovery from hypoglycemia unawareness without the need for sub-
optimal glucose control.  Applications proposing development of 
methods to detect, prevent or limit hypoglycemia, to prevent 
hypoglycemia unawareness, and/or to facilitate recovery from 
hypoglycemia unawareness are encouraged.

Cell-based therapies are a promising approach to restore insulin 
production in response to glucose in individuals with type 1 
diabetes.  Human islet transplantation trials are presently 
ongoing.  However, it is clear that with present methods for 
harvesting and maintaining islets, there are insufficient human 
islets to treat all the individuals with type 1 diabetes.  
Therefore, several laboratories have been developing alternate 
sources of insulin producing cells.  These approaches have 
included genetic manipulation of non-beta cells and transformed 
beta cells to achieve regulated insulin secretion in response to 
physiological levels of glucose or other physiological cues.  
Other researchers have been investigating methods of expanding 
human beta cells or their progenitors in culture.  Studies of 
genetic manipulations and of immunomodulation to protect 
transplanted beta cells against rejection and autoimmunity are 
also underway.  Human studies of these cell-based therapies are 
within the scope of this RFA.

Improved mechanical approaches to insulin replacement and to 
assessment of blood glucose levels are a promising approach to 
optimizing glucose control.  Within the past ten years, external 
insulin pumps have been shown to aid in the successful delivery 
of insulin for individuals with type 1 diabetes.  There have 
also been several trials of implanted insulin pumps.  These 
pumps have been shown to have significant advantages over 
multiple daily insulin injections.  Development of non-invasive 
or minimally invasive glucose sensors is a very high priority 
area of research.  While a number of approaches and devices 
appear promising, additional research to optimize sensor 
development and validate these devices in patients is necessary.  
Linkage of the insulin pumps to these sensors and development 
and testing of a ‘closed-loop’ system are within the scope of 
this RFA.

R01 or R21 applications should focus on clinical studies to 
develop new approaches to the cure or improved treatment of type 
1 diabetes.  In addition, support for preclinical studies 
necessary to obtain approval for an investigational new drug or 
for an investigational device could be requested if the project 
also includes a clinical component.  

Studies directed at complications of type 1 diabetes other than 
hypoglycemia are not responsive to this RFA.  

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

o Evaluate immunomodulation regimens to reverse or arrest immune 
destruction of beta cells in patients with new onset diabetes

o Utilize cell based therapies to enhance or restore euglycemia

o Evaluate methods to detect hypoglycemia

o Evaluate methods to prevent or lessen the severity of 
hypoglycemia associated with intensive therapy

o Develop methods to identify people at increased risk for 

o Develop interventions to prevent or facilitate recovery from 
hypoglycemia unawareness

o Test promising glucose sensors

o Validate algorithms to relate blood glucose to glucose levels 
in the interstitial space

o Evaluate linkage of a glucose sensor with an insulin pump to 
form a closed-loop system

o Evaluate alternative methods of insulin administration, 
including mechanical devices offering substantial advantages 
over current pumps or alternate routes of insulin administration  

It is the policy of the NIH that women and members of minority 
groups and their subpopulations 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 new 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 was 
published in the Federal Register of March 28, 1994 (FR 59 
14508-14513) and in the NIH Guide For Grants and Contracts, Vol. 
23, No. 11, March 18, 1994, available on the web at:


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

All investigators proposing research involving human subjects 
should read the “NIH Policy and Guidelines on the Inclusion of 
Children as Participants in Research Involving Human Subjects” 
that was published in the NIH Guide for Grants and Contracts, 
March 6, 1998, and is available at the following URL address:

Investigators may also obtain copies of these policies from the 
program staff listed under INQUIRIES.  Program staff may also 
provide additional relevant information concerning the policy.


Prospective applicants are asked to submit, by March 14, 2000, 
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 the RFA in response to which the application may be 

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 NIDDK staff to estimate the 
potential review workload and avoid conflict of interest in the 

The letter of intent is to be sent to:

Chief, Review Branch 
Division of Extramural Activities, NIDDK
Natcher Building, Room 6AS-37F
45 Center Drive MSC 6600
Bethesda, MD 20892-6600 
Telephone:  (301) 594-8885
FAX:  (301) 480-3505


The research grant application form PHS 398 (rev. 4/98) is to be 
used in applying for these grants.  These forms are available at 
most institutional offices of sponsored research 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:

The modular grant concept establishes specific modules in which 
direct costs may be requested as well as a maximum level for 
requested budgets. Only limited budgetary information is 
required under this approach.  The just-in-time concept allows 
applicants to submit certain information only when there is a 
possibility for an award. It is anticipated that these changes 
will reduce the administrative burden for the applicants, 
reviewers and Institute staff.  The research grant application 
form PHS 398 (rev. 4/98) is to be used in applying for these 
grants, with the modifications noted below.


Modular Grant applications will request direct costs in $25,000 
modules, up to a total direct cost request of $250,000 per year. 
(Applications that request more than $250,000 direct costs in 
any year must follow the traditional PHS398 application 
instructions.)The total direct costs must be requested  in 
accordance with the  program guidelines and  the modifications 
made to the standard  PHS 398 application  instructions 
described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating 
Direct Costs (in $25,000 increments up to a maximum of $250,000) 
and Total Costs [Modular Total Direct plus Facilities and 
Administrative  (F&A) costs] for the initial budget period Items 
8a and 8b should be completed indicating the Direct and Total 
Costs for the entire proposed period of support.

complete Form Page 4 of the PHS 398. It is not required and will 
not be accepted with the application.

complete the categorical budget table on Form Page 5 of the PHS 
398. It is not required and will not be accepted with the 

Budget Narrative page. (See for 
sample pages.) At the top of the page, enter the total direct 
costs requested for each year.  This is not a Form page.

o Under Personnel, list key project personnel, including their 
names, percent of effort, and roles on the project. No 
individual salary information should be provided. However, the 
applicant should use the NIH appropriation language  salary cap 
and the NIH policy for graduate student compensation in 
developing the budget request.

For Consortium/Contractual costs, provide an estimate of total 
costs (direct plus facilities and administrative) for each year, 
each rounded to the nearest $1,000. List the 
individuals/organizations with whom consortium or contractual 
arrangements have been made, the percent effort of key 
personnel, and the role on the project. Indicate whether the 
collaborating institution is foreign or domestic. The total cost 
for a consortium/contractual arrangement is included in the 
overall requested modular direct cost amount.  Include the 
Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any 
variation in the number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides 
information used by  reviewers in the assessment of each 
individual's qualifications for a specific role in the proposed 
project, as well as to evaluate the overall qualifications of 
the research team. A biographical sketch is required for all key 
personnel, following the instructions below. No more than three 
pages may be used for each person. A sample biographical sketch 
may be viewed at:

- Complete the educational block at the top of the form 
- List position(s) and any honors;
- Provide information, including overall goals and 
responsibilities, on research projects ongoing or 
completed during the last three years.
- List selected peer-reviewed publications, with full 

o CHECKLIST - This page should be completed and submitted 
with the application. If the F&A rate agreement has been 
established, indicate the type of agreement and the date. 
All appropriate exclusions must be applied in the 
calculation of the F&A costs for the initial budget 
period and all future budget years.

o The applicant should provide the name and phone number 
of the individual to contact concerning fiscal and 
administrative issues if additional information is 
necessary following the initial review. 

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 your 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 on the RFA label and the YES box must be marked.  

The sample RFA label available at: 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 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, NIDDK
Natcher Building, Room 6AS-37F
45 Center Drive MSC 6600
Bethesda, MD 20892-6600

Applications must be received by April 14, 2000. 
If an application is received after that date, 
it will be returned to the applicant without review.  
Supplemental documents containing significant revision or 
additions will not be accepted, unless applicants are 
notified by the Scientific Review Administrator.  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.


Applications that are complete and responsive to the RFA 
will be evaluated for scientific and technical merit by 
an appropriate peer review group convened by the NIDDK in 
accordance with the review criteria stated below.  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, generally the top half of the 
applications under review, will be discussed, assigned a 
priority score, and receive a second level review by the 
National Diabetes and Digestive and Kidney Diseases 
Advisory Council or other appropriate National Advisory 

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

o Significance:  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 method? 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?

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

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

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

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

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.


The anticipated date of award is September 30, 2000.

Award criteria that will be used to make award decisions 

o Scientific merit as determined by peer review;

o Level of interaction between researchers in appropriate 

o Availability of funds;

o Programmatic priorities.


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. 
Division of Diabetes, Endocrinology and Metabolic 
45 Center Drive MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-8813
FAX:  301-480-3503

Elaine Collier, M.D.
Chief, Autoimmunity Section
Division of Allergy, Immunology, and Transplantation
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, Room 5135
Bethesda, MD 20892-7640
Tel (301) 496-7104
Fax (301) 402-2571

Gilman D. Grave, M.D.
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B11 - MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5593
FAX:  (301) 480-9791

Direct inquiries regarding fiscal and administrative 
matters to:

Florence Danshes
Division of Extramural Activities 
45 Center Drive MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-8861
FAX: (301)480-3504

Maryellen Connell
Grants Management Specialist
NIAID, Division of Extramural Activities
Room 2123
6700-B Rockledge Drive, MSC 7614
Bethesda, MD  20892-7614 (Regular Mail)
Bethesda, MD  20817 (Express Mail)
Phone: (301) 402-5576
FAX:  (301) 480-3780

E. Douglas Shawver
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17 - MSC 7510
Bethesda, MD  20892-7510
Telephone: (301) 496-1303
FAX: (301) 402-0915


This program is described in the Catalog of Federal 
Domestic Assistance No. 93.847 (Diabetes, Endocrinology 
and Metabolism Research), No. 93.855 (Immunology, 
Allergy, and Transplantation Research) and No. 93.865 
(Research for Mothers and Children).  Awards are 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 NIH 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 NIH mission to protect and 
advance the physical and mental health of the American 

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