BENCH TO BEDSIDE RESEARCH ON TYPE 1 DIABETES AND ITS COMPLICATIONS

RELEASE DATE:  August 30, 2002 (see reissuance RFA-DK-03-019)

RFA:  RFA-DK-03-001

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov)
National Institute of Allergy and Infectious Diseases (NIAID)
 (http://www.niaid.nih.gov)
National Eye Institute (NEI)
 (http://www.nei.nih.gov/)
National Heart, Lung, and Blood Institute (NHLBI)
 (http://www.nhlbi.nih.gov) 

LETTER OF INTENT RECEIPT DATE:  January 29, 2003
APPLICATION RECEIPT DATE: February 26, 2003

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanisms of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations:

PURPOSE OF THIS RFA

This is a reissuance of RFA DK-02-022.  The National Institute of Diabetes and 
Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and 
Infectious Diseases (NIAID), National Eye Institute (NEI), and the National 
Heart, Lung, and Blood Institute (NHLBI) invite applications involving 
partnerships between clinical and basic biomedical researchers with the goal of 
translating advances in our understanding of the molecular basis of type 1 
diabetes and its complications into new therapies for the prevention, treatment 
and cure of this disease.  In these "bench to bedside" research partnerships, a 
team of clinical and basic scientists will conduct collaborative research that, 
if successful, will bring basic research advances from the laboratory to a point 
where a potential new therapy can be tested in patients or in preclinical 
studies in animal models.  

RESEARCH OBJECTIVES

Background

Type 1 diabetes is an autoimmune disease characterized by the destruction of the 
insulin-secreting beta cells of the pancreas by cytotoxic T cells.  Diabetes is 
difficult to control with the current therapies available and as a result 
patients with type 1 diabetes may suffer devastating consequences including 
accelerated cardiovascular and peripheral vascular diseases, nephropathy, 
retinopathy, neuropathy, oral diseases and premature death.  The incidence of 
type 1 diabetes appears to be increasing worldwide.  Although the disease may 
occur at any age, the onset of type 1 diabetes peaks prior to twenty years of 
age.  In some populations, about one percent of all newborns will develop type 1 
diabetes during their lifetime.

Recent advances in fundamental science and in our understanding of the 
pathophysiology underlying type 1 diabetes and its complications offer 
tremendous promise for the development of new therapies.  Recently, a number of 
agents have shown promise for prevention or delay of type 1 diabetes in animals 
and limited human studies.  However, for such agents to reach their full 
therapeutic potential, a number of obstacles must be overcome.  These include 
access to existing animal models, as well as the development of improved models, 
in which to test new therapies and measures to predict or assess response to 
therapy in early trials of potential therapies.  Also needed are improved 
methods to monitor disease progression, such as methods to assess beta cell mass 
and inflammation.

Most recently the success of islet transplantation in freeing individuals with 
type 1 diabetes from the need for insulin therapy has yielded great excitement.  
However, this treatment is associated with significant side effects, and the 
long-term risks of the immunosuppressive agents used are not known.  Moreover, 
the protocol required two donor pancreata per recipient; therefore, current 
levels of organ donation provide insufficient organs for only a small fraction 
of the people who could potentially benefit from this therapy.  The recent 
success in islet transplantation provides additional impetus for research to 
develop methods to attain an unlimited supply of islets for transplantation; to 
improve methods for harvesting pancreata and isolating islets; to improve 
techniques for the administration of transplanted islets; and to develop 
approaches to minimize the toxicity of immunotherapy required for 
transplantation.

The complications of type 1 diabetes account for much of the burden of disease.  
Emerging information on the molecular mechanisms involved in pathogenesis of 
complications has identified multiple potential targets for therapeutic 
intervention.  In particular, inflammation is increasingly recognized as a 
contributing pathway to macrovascular disease.  The development of surrogate 
markers for the development of complications and of animal models that develop 
the complications of diabetes is critical for testing new therapies for 
complications of type 1 diabetes.  

Hypoglycemia is a devastating complication of type 1 diabetes that often limits 
the ability to rigorously control blood glucose.  Research is needed to foster 
translation of new understandings about the mechanisms of hypoglycemia 
unawareness and defective counter-regulation into new approaches to reduce the 
occurrence of hypoglycemia and pharmacologic approaches to restore counter-
regulation.  Improved devices for measuring and monitoring glycemia and/or 
development of closed loop systems linking glucose sensors and insulin delivery 
devices are also needed.

Multi-disciplinary teams of basic and clinical scientists will be required to 
overcome these obstacles and hasten our ability to bring new approaches to 
therapy forward to be tested in clinical trials.  Thus, the level of support 
that can be requested for pilot and feasibility studies is greater than is 
usually permitted under this mechanism.

Objectives and Scope

The overall objective of this RFA is to stimulate translational diabetes 
research by encouraging the formation of collaborative research teams composed 
of basic and clinical scientists focused on specific projects that have the 
potential to develop new therapies for type 1 diabetes or its complications.  
Applications must involve a team of clinical and basic scientists from a single 
or multiple institutions.  It is expected that the combined expertise of the 
investigators will foster the development of a basic research finding to the 
point where the underlying hypothesis can be tested in a clinical trial or an 
animal model to assess its value in the treatment and/or prevention of type 1 
diabetes or its complications.

Applications should focus on developing and testing methods for the prevention, 
cure or improved treatment of type 1 diabetes or its complications.  
Applications can also propose to develop new animal models or surrogate 
endpoints that will facilitate the testing of new therapeutic agents.  When 
compelling preliminary data suggests potential therapeutic value of a new 
pharmacologic agent, support may be requested for preclinical animal studies 
needed to move forward into clinical trials, including studies to determine 
optimal dosing and toxicity.   Research may include studies of etiology and 
pathogenesis of type 1 diabetes or its complications only in the context of a 
hypothesis that has clear potential to lead to a new target or strategy for 
prevention or therapy or to a new surrogate marker or animal model that will be 
useful for clinical trials.  
  
Relevant topics listed below are examples and should not be construed as 
required or limiting:

o Development and/or testing of strategies to retard or reverse the immune 
and/or inflammatory processes leading to the development of type 1 diabetes and 
its macro and microvascular complications

o Development and/or testing of measures to identify and quantify the risk of 
developing type 1 diabetes or to assess response to therapy to prevent or 
reverse  the autoimmune process and beta cell loss (i.e. pathogenic T-cell 
assays, imaging of beta cell mass or inflammation, etc.)

o Development of improved approaches to pancreas harvesting and/or islet 
isolation, evaluation, or administration

o Development and/or testing of strategies to develop new or improved sources of 
beta cells/islets or to enhance the regeneration or viability of beta 
cells/islets

o Development and/or testing of improved methods of immunoalteration of beta 
cells/islets or of the immune response in an attempt to prevent autoimmune and 
host-versus-graft destruction of beta cells/islets

o Development and/or testing of devices to measure glucose in blood, saliva or 
other body fluids and/or deliver insulin which offer advantages over current 
devices 

o Development of non-human primate or other animal models of type 1 diabetes or 
its complications which closely parallel the human disease; investigators should 
make clear that tissues and developed animal models will be made available to 
the research community and provide a plan for the dissemination of these models

o Identification and/or evaluation of surrogate endpoints which can be used in 
clinical trials to prevent, delay or reverse type 1 diabetes and its 
complications 

o Development or testing of innovative pharmacological agents and interventions 
to prevent or halt the progression of type 1 diabetes or its complications

MECHANISMS OF SUPPORT

Support for this program will be through the NIH Exploratory/Development 
Research Grant (R21), the Exploratory/Development Research Grant Phase 2 (R33), 
and the Phased Innovation Award (R21/R33 combined).  The R33 is a newly 
established NIH grant mechanism to provide a second phase for the support of 
innovative exploratory and development research initiated under the R21 
mechanism.  Under the Phased Innovation Award (R21/R33), transition of the R21 
to the R33 phase will be expedited and is dependent on completion of negotiated 
milestones.  

This RFA uses just-in-time concepts.  It also uses the modular budgeting format. 
(see http://grants.nih.gov/grants/funding/modular/modular.htm).   Specifically, 
if you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise, follow the instructions for non-
modular research grant applications.

Specific features of the Phased Innovation Award Mechanism (R21/33 Combined) 
include: 

o Single submission and evaluation of both a feasibility/pilot phase (R21) and 
an expanded development phase (R33) as one application. 
o Expedited transition of the R21 feasibility phase to an R33 development phase.
o Flexible budgets.
o Flexible staging of feasibility and development phases.

The use of the multiple mechanisms will allow projects to be submitted at 
various stages of development.  The R21 will provide support for projects in 
early stages of development where there is little or no preliminary data 
available and it is difficult to predict success sufficiently to develop an 
extended R33 phase.  The R33 will provide support for projects in which 
feasibility has been demonstrated and thus are ready for extended development.  
The combined R21/R33 will provide support for projects that require feasibility 
demonstration, and the aims and milestones of the R21 are sufficiently 
predictable to consider the extended R33 phase.

Responsibility for the planning, direction and execution of the proposed 
research project will be solely that of the applicant.  Except as otherwise 
stated in this RFA, awards will be administered under the NIH grants policy as 
stated in the NIH Grants Policy Statement, March 2001, available from the 
internet only at http://grants.nih.gov/grants/policy/nihgps_2001/.

Under this RFA, applicants may submit either an R21 application, a combined 
R21/R33 application (Phased Innovation Award application) or the R33 application 
alone, if feasibility can be documented, as described in the SUBMITTING AN 
APPLICATION section of this RFA.  The total project period for an application in 
response to this RFA may not exceed the following durations:  2 years for the 
R21 phase; 3 years for the R33 phase; 5 years for a combined R21/R33 proposal.  
In the combined application, the R21 phase may not extend beyond 2 years.  

For R21 and combined R21/R33 applications, the R21 phase may not exceed $250,000 
direct costs per year.  R21 budgets can exceed this cap to accommodate F&A costs 
to subcontracts to the project, in which case a non-modular budget format must 
be used.  The R33 application has a budgetary limit of $500,000 direct costs for 
each year.  It is strongly recommended that applicants contact institute staff 
at an early stage of application development to convey critical information, 
such as potentially large budget requests or to discuss programmatic 
responsiveness of the proposed project.  Early contact with institute staff is 
particularly critical relative to this RFA because it uses a new grant mechanism 
(R33) as well as an expedited review procedure.  Refer to the WHERE TO SEND 
INQUIRIES section of this RFA for institute staff contacts.

The combined R21/R33 application offers two advantages over the regular 
application process:

1.  Single submission and evaluation of both the R21 and the R33 phases as one 
application.

2.  Minimal or no funding gap between the R21 and R33.  The award of the R33 
funds will be based on program priorities, the availability of funds and the 
successful completion of negotiated scientific milestones as determined by 
program staff in the context of peer review recommendations.

To be eligible for the Phased Innovation Award, the R21 phase must include well-
defined quantifiable milestones that will be used to judge the progress and 
success of the proposed research, as well as a credible plan for the R33 phase.  
The Phased Innovation Award must have a section labeled Milestones at the end of 
the Research Plan of the R21 application.  This section must include well-
defined quantifiable milestones for the completion of the R21 portion of the 
application, a discussion of the suitability of the proposed milestones for 
assessing the success in the R21 phase, and a discussion of the implications of 
successful completion of the milestones for the proposed R33 study.

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 only solicitation.  At this time there are no definite 
plans to reissue this solicitation. Upon termination of these awards, 
investigators seeking continued funding may compete with all investigator-
initiated applications and be reviewed according to the customary peer review 
procedures.  The anticipated award date is September 30, 2003.

FUNDS AVAILABLE

The sponsoring ICs intend to commit approximately $2 million total costs in 
FY 2003 to fund 4 to 8 new grants in response to this RFA.  An applicant may 
request a project period of 2 (R21 phase alone), 3 (R33 phase alone) or 5 
(R21/R33 combined) years.  Because the nature and scope of the research proposed 
may vary, it is anticipated that the size of each award will also vary. Although 
the financial plans of the sponsoring ICs provide support for this program, 
awards pursuant to this RFA are contingent upon the availability of funds and 
the receipt of a sufficient number of applications of outstanding scientific and 
technical merit. 

ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) if your institution has any of the following 
characteristics: 
	
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, and 
laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to carry out 
the proposed research is invited to work with their institution to develop an 
application for support.  Individuals from underrepresented racial and ethnic 
groups as well as individuals with disabilities are always encouraged to apply 
for NIH programs.   
 
WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to answer 
questions from potential applicants.  Inquiries may fall into three areas:  
scientific/research, peer review, and financial or grants management issues:

o Direct your questions about scientific/research issues to:

James F. Hyde, Ph.D. 
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases 
6707 Democracy Boulevard, Rm. 609 MSC 5460
Bethesda, MD  20892-5460
Telephone:  (301) 594-7692
FAX:  (301) 435-6047
E-mail:  jh486z@nih.gov

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

Peter A. Dudley, Ph.D.
Division of Extramural Research
National Eye Institute
Executive Plaza South, Suite 350
Bethesda, MD  20892-7164
Telephone:  (301) 451-2020
FAX:  (301) 402-0528
Email:  pad@nei.nih.gov

Momtaz Wassef, Ph.D.
Leader, Atherosclerosis Research Group
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10186
Bethesda, MD  20892-7956
Telephone:  (301) 435-0550 
FAX:  (301) 480-2848
E-mail:  mw47d@nih.gov 

o Direct your questions about peer review issues to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 752 MSC 5452
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505
Email: CalvoF@extra.niddk.nih.gov

o Direct your questions about financial or grants management matters to:

Kathleen J. Shino, M.B.A.
Supervisory Grants Management Specialist
Division of Extramural Activities 
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 708 MSC 5456
Bethesda, MD  20892-5456
Telephone:  (301) 594-8869 
FAX:  (301) 480-3504
E-mail: ShinoK@extra.niddk.nih.gov

Pamela G. Fleming  
Grants Management Officer  
National Institute of Allergy and Infectious Diseases  
Division of Extramural Activities  
Room 2119  
6700-B Rockledge Drive, MSC 7614  
Bethesda, MD  20892-7614 (Regular Mail)  
Bethesda, MD  20817 (Express Mail)  
Phone:  (301) 402-6580  
FAX:  (301) 493-0597  
E-mail: pf49e@nih.gov

Chris Davis
Grants Management Specialist
National Eye Institute
6120 Executive Blvd
Suite 350, MSC 7164
Bethesda, MD  20892-7164
Telephone:  (301) 451-2020
FAX:  (301) 496-99977
E-mail:  cad@nei.nih.gov

David L. Reiter
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7044
Bethesda, MD  20892-7926
Telephone:  (301)435-0177
FAX:  (301)480-3310
E-mail:  dr36t@nih.gov 

LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that includes the 
following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o 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 IC staff to estimate the potential review workload and plan the review.
 
The letter of intent is to be sent by the date listed at the beginning of this 
document.  The letter of intent should be sent to:

Chief, Review Branch 
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 752 MSC 5452
Bethesda, MD  20892-5452
(For express/courier service: Bethesda, MD  20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505

SUBMITTING AN APPLICATION

Applications (R21, R21/R33, and R33) must be prepared using the PHS 398 research 
grant application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an 
interactive format.  For further assistance contact GrantsInfo, Telephone (301) 
435-0714, Email: GrantsInfo@nih.gov.
 
SUPPLEMENTAL INSTRUCTIONS:

I. SPECIFIC INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION 
AWARD APPLICATION:

The R21/R33 application must include the specific aims for each phase and clear 
measurable goals (milestones) that would demonstrate feasibility and justify 
transition to the R33 phase.  Applications must include a specific section 
labeled Milestones following the Research Plan of the R21 phase.  Milestones 
should be well described, quantifiable and scientifically justified and not 
simply a restatement of the specific aims. A discussion of the milestones 
relative to the progress of the R21 phase, as well as, the implications of 
successful completion of the milestones for the R33 phase should be included. 
This section should be indicated in the Table of Contents.  Applications lacking 
this information as determined by the NIH program staff, will be returned to the 
applicant without review.  For funded applications, completion of the R21 
milestones will elicit an NIH expedited review that will determine whether or 
not the R33 should be awarded. The release of R33 funds will be based on 
successful completion of negotiated scientific milestones, program priorities, 
and on the availability of funds. The expedited review may result in additional 
negotiations of award.

The R21/R33 combined applications must be submitted as a single application, 
with one face page.  Although it is submitted as a single application, it should 
be clearly organized into two phases.  To accomplish a clear distinction between 
the two phases, applicants are directed to complete Sections a-d of the Research 
Plan twice: one write-up of Sections a-d and milestones for the R21 phase and 
sections a-d again for the R33 phase.  The Form 398 Table of Contents should be 
modified to show sections a-d for each phase as well as the milestones.  There 
is a page limit of 25 pages for the composite a-d text of all applications 
(i.e., section a-d and milestones for the R21 phase plus sections a-d for the 
R33 phase must be contained within the 25 page limit for R21/R33 applications.)

In preparing the R21/R33 application, investigators should consider the fact 
that applications will be assigned a single priority score.  In addition, as 
discussed in the REVIEW CONSIDERATIONS section, the initial review panel has the 
option of recommending only the R21 phase for support.  However, an application 
with an R33 Phase that is so deficient in merit that it is not recommended for 
support will reflect upon the judgment of the applicant.  For these reasons, the 
clarity and completeness of the R21/R33 application with regard to specific 
goals and feasibility milestones for each phase are critical. The presentation 
of milestones that are not sufficiently scientifically rigorous to be valid for 
assessing progress in the R21 phase will reflect upon the scientific judgment of 
the applicant in this application.

1.  Face Page of the application:
Item 2.  Check the box marked "YES" and type the number and title of this 
RFA.  Also indicate that the application is submitted as an R21/R33.

Item 7a, DIRECT COSTS REQUESTED FOR INITIAL PERIOD OF SUPPORT:
For the R21 phase of the combined R21/R33 application, direct costs are limited 
to a maximum of $250,000 per year for a maximum of two years and the award may 
not be used to supplement an ongoing project.  The requested budgets can exceed 
this cap to accommodate for F&A costs to subcontracts to the project.  Insert 
the first year of R21 support in item 7a.

Item 8a, DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT:
For the R21 phase of the combined R21/R33 application, direct costs requested 
for the proposed period may not exceed $500,000 for two years of support.  The 
statement in item 7a above pertaining to subcontract costs also applies here.  
Insert sum of all years of requested support in item 8a

2.  Page 2 - Description:
As part of the description, identify concisely the research team ("bench to 
bedside partnership"), the fundamental research to be performed or the 
technology/tool to be developed, its innovative nature, its relationship to 
presently available knowledge or capabilities, and its expected impact on the 
diagnosis, treatment or prevention of type 1 diabetes or its complications.

3. Budget:
The application should provide a DETAILED BUDGET for Initial Budget Period (form 
page 4), for each of the initial years of the R21 and R33 phases as well as a 
budget for the entire proposed period of support (form page 5).  Form pages 
should indicate which years are R21 and R33.  All budgets should include a 
justification for each item requested.

4.  Research Plan:
Item a, Specific Aims:
The applicants must present specific aims that the applicant considers to be 
scientifically appropriate for the relevant phases of the project.  The 
instructions in the PHS 398 booklet for this section of research grant 
applications suggest that the applicant state the hypotheses to be tested.  
Furthermore for the R21 phase, preliminary data are not required, although they 
should be included when available. 

Item b, Background and Significance:
Elaborate on the innovative nature of the proposed research. Clarify how the 
fundamental research or tools/technologies to be developed as proposed in this 
project will result in a significant improvement over existing approaches.  
Explain the potential of the proposed studies for having a broad impact on a 
compelling area of type 1 diabetes research. Clearly identify how the project, 
if successful, would result in new capabilities for the treatment and prevention 
of type 1 diabetes and its complications.

Item c, Preliminary Studies/Progress Report:
While preliminary data are not required for the submission of the R21 phase, 
this section should provide current thinking or evidence in the field to 
substantiate the feasibility of the R33 phase.  While preliminary data are not 
required for submission of the R21 phase, easily understandable data that 
provide relevant information to aid the review should be included when 
available. The R33 phase need not repeat information already provided in the 
R21 phase.

Item d, Research Design and Methods:
Follow the instructions in the PHS 398 booklet.  In addition, for the R21 phase 
of combined R21/R33 applications only, the following information must be 
included as a final section of Item d:

Applications must include a specific section labeled Milestones following the 
Research Design and Methods of the R21 phase.  Milestones should be well 
described, quantifiable, and scientifically justified and not be simply a 
restatement of the specific aims. The milestones should not be a reiteration of 
the Specific Aims of the research project, but should be tangible 
accomplishments.  A discussion of the milestones relative to the success of the 
R21 phase, as well as the implications of successful completion of the 
milestones for the R33 phase and the page number of the milestones section 
should be listed. This section should be indicated in the Table of Contents. 

Applications lacking this information as determined by the Institute program 
staff, will be returned to the applicant without review.  For funded 
applications, completion of the R21 milestones will elicit an Institute 
expedited review that will determine whether or not the R33 should be awarded. 
The release of R33 funds will be based on successful completion of milestones, 
program priorities and on the availability of funds. The expedited review may 
result in additional negotiations of award.

II.  SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R21 APPLICATION WHEN SUBMITTED 
WITHOUT THE R33 PHASE.

MODULAR GRANT APPLICATION:
R21 only applications should be submitted in a modular grant format, unless 
exceeding the $250,000 budgetary cap in order to accommodate F&A costs to 
subcontracts to the project.  The total project period for an R21 application 
may not exceed two years.  The modular grant format simplifies the preparation 
of the budget in these applications by limiting the level of budgetary detail.  
Applicants request direct costs in $25,000 modules.  Section C of the research 
grant application instructions for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular grants 
is available at http://grants.nih.gov/grants/funding/modular/modular.htm.

1.  Face page of the application:
Item 2.  Check the box marked "YES" and type the number of this RFA.  Also 
indicate that the application is for an R21.

2.  Page 2, Description:
As part of the description, identify concisely the research team ("bench to 
bedside partnership"), the fundamental research to be performed or the 
technology/tool to be developed, its innovative nature, its relationship to 
presently available knowledge or capabilities, and its expected impact on the 
diagnosis, treatment or prevention of type 1 diabetes or its complications.

3.  Research Plan:
Item a, Specific Aims:
The applicants must present specific aims that the applicant considers to be 
scientifically appropriate for the relevant phases of the project.  The 
instructions in the PHS 398 booklet for this section of research grant 
applications suggest that the applicant state the hypotheses to be tested.  
Furthermore for the R21 phase, preliminary data are not required, although they 
should be included when available.

Item b, Background and Significance:
Elaborate on the innovative nature of the proposed research. Clarify how the 
fundamental research or tools/technologies to be developed as proposed in this 
project will result in a significant improvement over existing approaches.  
Explain the potential of the proposed studies for having a broad impact on a 
compelling area of type 1 diabetes research. Clearly identify how the project, 
if successful, would result in new capabilities for the treatment and prevention 
of type 1 diabetes and its complications.

Item c, Preliminary Studies/Progress Report:
R21 applications should provide current thinking or evidence in the field to 
support the project.  While preliminary data are not required, easily 
understandable data that provide relevant information to aid review could be 
included when available.

Item d, Research Design and Methods:
Instructions for PHS 398 should be followed.

III. SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R33 APPLICATION WHEN SUBMITTED 
WITHOUT THE R21 PHASE.

Applications for R33 grants are to be prepared according to the instructions 
provided in the PHS 398 booklet unless specified otherwise within items 1-4 
below.  

1.  Face Page of the application:
Item 2.  Check the box marked "YES" and type the number and title of this 
RFA.  Also, indicate that the application is for an R33.

2.  Page 2 - Description:
As part of the description, identify concisely the research team ("bench to 
bedside partnership"), the fundamental research to be performed or the 
technology/tool to be developed, its innovative nature, its relationship to 
presently available knowledge or capabilities, and its expected impact on the 
diagnosis, treatment or prevention of type 1 diabetes or its complications.

3. Budget:  
The application should provide a DETAILED BUDGET for the Initial Budget Period 
(form page 4) as well as a budget for the entire proposed period of support 
(form page 5).  Budget should include a justification of all items requested.

4.  Research Plan:
Item a, Specific Aims:

The instructions in the PHS 398 booklet for this section of research grant 
applications suggest that the applicant state the hypotheses to be tested. 

Item b, Background and Significance:
Elaborate on the innovative nature of the proposed research. Clarify how the 
fundamental research or tools/technologies to be developed as proposed in this 
project will result in a significant improvement over existing approaches.  
Explain the potential of the proposed studies for having a broad impact on a 
compelling area of type 1 diabetes research. Clearly identify how the project, 
if successful, would result in new capabilities for the treatment and prevention 
of type 1 diabetes and its complications.

Item c, Preliminary Studies/Progress Report:
This section must document that feasibility studies have been completed, and 
progress achieved, equivalent to that expected through the support of an R21 
project.  The application must clearly describe how the xploratory/developmental 
study is ready to scale up to an expanded development stage.  In the event that 
an applicant feels that some aspect of the approach or tools or technology to be 
developed is too proprietary to disclose, applicants at a minimum should provide 
a demonstration (results) of the capabilities of the proposed approach, tool or 
technology.

Item d, Research Design and Methods:
Follow the instructions in the PHS 398 booklet. 

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application.  Type the RFA number on the label.  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. The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: 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 the time of submission, two additional copies of the application must be sent 
to:

Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 752 MSC 5452
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD 20817)

APPLICATION PROCESSING: Applications must be received by the application receipt 
date listed in the heading of this RFA.  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 already reviewed, but such applications must include an 
Introduction addressing the previous critique

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIDDK.  Incomplete and/or non-responsive applications will 
be returned to the applicant without further consideration.

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the NIDDK in accordance with the review criteria stated below.  As part of the 
initial merit review, all applications will:

o Receive a written critique
o 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 and assigned a priority score
o Receive a second level review by the appropriate Institute National Advisory 
Council or Board.
 
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 
your application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these criteria in 
assigning your application's overall score, weighting them as appropriate for 
each application.  Your 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, you may propose to carry out important work that 
by its nature is not innovative but is essential to move a field forward.

(1) SIGNIFICANCE:  Does your study address an important problem?  If the aims of 
your application are achieved, how will scientific knowledge be advanced?  
What will be the effect of your studies on the concepts or methods that drive 
this field?  What may be the anticipated societal benefit of the proposed 
activity?  Is the research partnership likely to contribute to new and important 
discoveries about type 1 diabetes?

(2) APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Do you acknowledge potential problem areas and consider alternative 
tactics?  

(3) INNOVATION:  Does your project employ novel concepts, approaches or methods?  
Are the aims original and innovative?  Does your project challenge existing 
paradigms or develop new methodologies or technologies?   

(4) INVESTIGATORS: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of the other researchers?  Is the research 
partnership critical to the achievement of the milestones and the success of the 
research project?  Is the research team composed of both basic and clinical 
scientists who form a "bench to bedside partnership"? 

(5) 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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application 
will also be reviewed with respect to the following:

o PROTECTIONS:  The adequacy of the proposed protection for humans, animals, or 
the environment, to the extent they may be adversely affected by the project 
proposed in the application.

o INCLUSION:  The adequacy of plans to include subjects from both genders, all 
racial and ethnic groups (and subgroups), and children as appropriate for the 
scientific goals of the research.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria included in the section 
on Federal Citations, below)

o DATA SHARING:  The adequacy of the proposed plan to share data.

o BUDGET:  The reasonableness of the proposed budget and the requested period of 
support in relation to the proposed research.

o OTHER REVIEW CRITERIA:  For an R21/R33 application, the initial review group 
will evaluate the specific goals for each phase and the feasibility of the 
milestones that would justify expansion to the R33 phase.  The initial review 
group will evaluate how appropriate, realistic and quantifiable your proposed 
research milestones are, and whether the milestones are adequate for the 
demonstration and feasibility for transition to the R33 development phase.  They 
will also assess your timeframe for achieving the milestones and whether it is 
appropriate.  A single priority score will be assigned to each scored 
application.  As with any grant application, the initial review group has the 
option of recommending support for a shorter duration than that requested by the 
applicant, and basing the final merit rating on the recommended portion of the 
application.  For the R21/R33 application, this may result in a recommendation 
that only the R21 phase be supported, based upon concerns related to the 
application's specific goals and the feasibility milestones justifying expansion 
to the R33 phase.  Deletion of the R33 phase by the review panel or presentation 
of inadequate milestones in the application may affect the merit rating of the 
application.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date: January 29, 2003
Application Receipt Date: February 26, 2003
Peer Review Date:  June/July 2003
Council Review:  September 2003 
Earliest Anticipated Start Date: September 30, 2003

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
 
REQUIRED FEDERAL CITATIONS 

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components 
involving Phase I and II clinical trials must include provisions for assessment 
of patient eligibility and status, rigorous data management, quality assurance, 
and auditing procedures.  In addition, it is NIH policy that all clinical trials 
require data and safety monitoring, with the method and degree of monitoring 
being commensurate with the risks (NIH Policy for Data Safety and Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a clear and 
compelling justification is provided indicating that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research. This 
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public 
Law 103-43).

All investigators proposing clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete 
copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.   
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) all 
applications or proposals and/or protocols must provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) 
investigators must report annual accrual and progress in conducting analyses, 
as appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The 
NIH maintains a policy 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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  NIH policy 
requires education on the protection of human subject participants for all 
investigators submitting NIH proposals for research involving human subjects.  
You will find this policy announcement in the NIH Guide for Grants and Contracts 
Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on 
hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 
review. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to provide 
public access to research data through the Freedom of Information Act (FOIA) 
under some circumstances.  Data that are (1) first produced in a project that is 
supported in whole or in part with Federal funds and (2) cited publicly and 
officially by a Federal agency in support of an action that has the force and 
effect of law (i.e., a regulation) may be accessed through FOIA.  It is 
important for applicants to understand the basic scope of this amendment.  NIH 
has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public archive, 
which can provide protections for the data and manage the distribution for an 
indefinite period of time.  If so, the application should include a description 
of the archiving plan in the study design and include information about this in 
the budget justification section of the application. In addition, applicants 
should think about how to structure informed consent statements and other human 
subjects procedures given the potential for wider use of data collected under 
this award.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for 
NIH funding must be self-contained within specified page limitations. Unless 
otherwise specified in an NIH solicitation, Internet addresses (URLs) should not 
be used to provide information necessary to the review because reviewers are 
under no obligation to view the Internet sites.   Furthermore, we caution 
reviewers that their anonymity may be compromised when they directly access an 
Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving 
the health promotion and disease prevention objectives of "Healthy People 2010," 
a PHS-led national activity for setting priority areas. This RFA is related to 
one or more of the priority areas. Potential applicants may obtain a copy of 
"Healthy People 2010" at http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal 
Domestic Assistance No. 93.847 (NIDDK), 93.855, Immunology, Allergy and 
Transplantation Research (NIAID), 93.867 (NEI), and 93.837 (NHLBI)is not subject 
to the intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under authorization of Sections 301 and 
405 of the Public Health Service Act as amended (42 USC 241 and 284)  and 
administered under NIH grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 
CFR 52 and 45 CFR Parts 74 and 92. 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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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