BENCH TO BEDSIDE RESEARCH ON TYPE 1 DIABETES AND ITS COMPLICATIONS

Release Date:  October 11, 2001

RFA:  RFA-DK-02-022

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

Letter of Intent Receipt Date:  February 14, 2002
Application Receipt Date:       March 14, 2002

THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  MODULAR 
INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS 
THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED 
IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT 
http://grants.nih.gov/grants/funding/phs398/phs398.html.

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 
National Institute of Allergy and Infectious Disease (NIAID), National Eye 
Institute (NEI), and 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.  

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, Bench to Bedside 
Research on Type 1 Diabetes and Its Complications, 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/.

ELIGIBILITY REQUIREMENTS

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.  The clinical and basic biomedical 
researchers forming the partnership do not have to be from the same applicant 
institution.  Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as principal investigators.

MECHANISM 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.  Transition of the R21 to the R33 phase will be expedited 
and is dependent on completion of negotiated milestones.  

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the 
NIH. Complete and detailed instructions and information on Modular Grant 
applications have been incorporated into the PHS 398 (rev. 5/2001).  
Additional information on Modular Grants can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm

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 
APPLICATION PROCEDURES 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.  Although the R33 
application has no official budgetary limit, applicants requesting in excess 
of $500,000 direct costs in any single year of the grant period require prior 
approval before submission.  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 INQUIRIES sections 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 09/30/02.

FUNDS AVAILABLE

The sponsoring ICs intend to commit approximately $3 million total costs in 
FY 2002 to fund 8 to 12 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. 

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.  However, to reach 
this potential a number of obstacles must be overcome.  These include 
inadequate animal models in which to test new therapies and lack of measures 
to predict or assess response to therapy in early trials of potential 
therapies.  Most recently the success of islet transplantation in freeing 
individuals with type 1 diabetes from the need for insulin therapy has 
yielded great excitement and a new impetus for research to develop methods to 
attain an unlimited source of islets for transplantation and to minimize the 
toxicity of immunotherapy required for transplantation. 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.  

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 1diabetes or its 
complications.  Research may include studies of etiology and pathogenesis 
only in the context of a hypothesis that has clear potential to lead to a new 
target or strategy for prevention or therapy.  Applicants proposing research 
on certain topics which are relevant to this solicitation (e.g. surrogate 
markers for use in clinical trials for therapy of microvascular disease, 
pilot projects for prevention of nephropathy, new strategies to prevent 
hypoglycemia, new methods to image beta cells or the microcirculation, or 
gene therapy approaches is islet transplantation) may also wish to consider 
other solicitations that have been or may soon be issued; further information 
can be found at 
http://www.niddk.nih.gov/fund/crfo/may2002council/recently-cleared.htm   

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 
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 quantitate risk of 
developing type 1 diabetes or to assess response to therapy to prevent or 
reverse  the autoimmune process and beta cell loss

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 
long-term complications

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and 
their sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided indicating that inclusion 
is inappropriate with respect to the health of the subjects or the purpose of  
the research.  This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43). 

All investigators proposing research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS.

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: http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

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.
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.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specified page limitations. Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites. Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.
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 RFA 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.
LETTER OF INTENT 

Prospective applicants are asked to submit, by February 14, 2002, 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 submitted.

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 
plan the review.

The letter of intent is to 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

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 5/2001) 
at http://grants.nih.gov/grants/funding/phs398/phs398.html must be used in 
applying for these grants. This version of the PHS 398 is available in an 
interactive, searchable format.  For further assistance contact GrantsInfo, 
Telephone 301/435-0714, Email: GrantsInfo@nih.gov.

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

Applications are to be submitted on the grant application form PHS 398 (rev. 
05/01) and will be accepted at the application deadline indicated on the 
first page of this solicitation.  This version of the PHS 398 is available in 
an interactive, searchable PDF format at: 
http://grants.nih.gov/grants/forms.htm.  Applications should be prepared 
according to the instructions provided unless specified otherwise within this 
SECTION.  

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 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. 
5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be 
used in applying for these grants, with modular budget instructions provided 
in Section C of the application instructions. 

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 PHS 398 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:

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 nor 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.

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

Applications for R21 grants are to be submitted on the grant application form 
PHS 398 (rev. 05/01) and prepared according to instructions provided for R21 
applications in the previous section except that milestones and discussion of 
the implication of the milestones to an R33 phase are not required.  The 
grant application form PHS 398 is available in an interactive, searchable PDF 
format at: http://grants.nih.gov/grants/forms.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.

Maximum budget is $250,000 direct costs per year for two years.

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

Applications for R33 grants are to be submitted on the grant application form 
PHS 398 (rev. 05/01) and prepared according to the instructions provided 
unless specified otherwise within items 1-4 below.  The grant application 
form PHS 398 is available in an interactive, searchable PDF format at: 
http://grants.nih.gov/grants/forms.htm.  

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:  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 PHS 398 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 
above.

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 
exploratory/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. 

FOR ALL APPLICATIONS

Appendix:  All instructions in the Form 398 application kit apply.

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.

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
6707 Democracy Boulevard, Rm. 752 MSC 5452
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD 20817)

Applications must be received by the application receipt date listed in the 
heading of the RFA.  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 the 
Scientific Review Administrator notifies the applicants.  

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

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 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 appropriate NIH Institute Advisory Council.

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.

(1) 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?  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?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?  

(3) Milestones:  How appropriate, realistic and quantifiable are the proposed 
research milestones against which to evaluate the demonstration and 
feasibility for transition to the R33 development phase?  What is the 
timeframe for achieving the milestones and is it appropriate? 

(4) 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?  

(5) Investigators:  Are the investigators appropriately trained and well 
suited to carry out this work?  Is the work proposed appropriate to the 
experience level of the principal investigator and 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”?”
 
(6) 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 Criteria:

For the 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.  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 that 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.

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 evaluated.  

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 application.

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.

Schedule

Letter of Intent Receipt Date:    February 14, 2002
Application Receipt Date:         March 14, 2002
Peer Review Date:                 June/July, 2002
Council Review:                   September, 2002
Earliest Anticipated Start Date:  September 30, 2002

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.

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:

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. 603 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) 496-0484
FAX:  (301) 402-0528
Email:  pd8n@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

Direct inquiries regarding fiscal matters to:

Donald Ellis
Division of Extramural Activities 
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 709B MSC 5456
Bethesda, MD  20892-5456
Telephone:  (301) 594-8849 
FAX:  (301) 594-9523
E-mail:  de30z@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

Margie Baritz
Grants Management Specialist
National Eye Institute
6120 Executive Blvd
Suite 350, MSC 7164
Bethesda, MD  20892-7164
Telephone:  (301) 496-5884
FAX:  (301) 496-99977
E-mail:  mb41k@nih.gov

Ms. Jane Davis
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7156
Bethesda, MD  20892-7926
Telephone:  (301)435-0166
FAX:  (301)480-3310
E-mail:  jd53j@nih.gov

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).  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 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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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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