NEW THERAPIES FOR DIABETIC FOOT DISEASE

Release Date:  November 23, 1999

RFA:  DK-00-009

National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Nursing Research

Letter of Intent Receipt Date: March 24, 2000 
Application Receipt Date: April 25, 2000  

THIS REQUEST FOR APPLICATIONS (RFA) USES THE “MODULAR GRANT” AND 
“JUST-IN-TIME” CONCEPTS.  IT INCLUDES DETAILED MODIFICATIONS TO 
STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING 
APPLICATIONS IN RESPONSE TO THIS RFA.

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) and the National Institute of Nursing Research (NINR) invite 
investigator-initiated research grant applications to 1) study the 
etiology and pathogenesis of diabetic foot ulcers, and 2) develop 
effective prevention and treatment modalities. Diabetes is the 
leading cause of non-traumatic lower extremity amputations in the 
United States, and foot ulcers are a major predictor of future 
amputation in patients with diabetes.  Even without amputation, 
diabetic foot ulcers contribute a major economic burden to society 
and impair quality of life for the individual.  Despite advances in 
wound care, the incidence of diabetic foot ulcers, and of 
amputations, remains high.  New diagnostic, prognostic and 
therapeutic strategies need to be developed to reduce the burden of 
diabetic foot disease.  New insights into the etiology and 
pathogenesis of ulceration in the diabetic foot will help develop 
more effective measures for prevention as well as treatment.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 
2000," a PHS-led national activity for setting priority areas. This 
RFA, New Therapies for Diabetic Foot Disease, is related to the 
priority area of diabetes and chronic diseases. Potential applicants 
may obtain a copy of "Healthy People 2000" at 
http://odphp.osophs.dhhs.gov/pubs/hp2000

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. 
Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research 
project grant (R01) award mechanism.  Except as otherwise stated in 
this announcement, awards will be administered under Public Health 
Service (PHS) grants policy as stated in the PHS Grants Policy 
Statement.

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

This RFA is a one-time solicitation.  Future unsolicited competing 
continuation applications will compete with all investigator-
initiated applications and be reviewed according to the customary 
peer review procedures.  Responsibility for the planning, direction, 
and execution of the proposed project will be solely that of the 
applicant.  The anticipated award date is September 30, 2000.  

FUNDS AVAILABLE

NIDDK intends to commit approximately $1.5 million in FY 2000 to 
fund 5-8 new and/or competitive continuation grants in response to 
this RFA. An applicant may request a project period of up to 5 
years. NINR will commit $300,000 in FY2000 to fund one application 
relevant to the NINR mission.  Because the nature and scope of the 
research proposed may vary, the size of each award will also vary. 
It is anticipated that most applications will request less than 
$300,000 in direct costs during the first year. However, budgets may 
be larger if there is compelling justification. Applicants 
anticipating requesting more than $500,000 in direct costs in any 
year should consult with the NIDDK program official listed under 
INQUIRIES at an early opportunity. Although the financial plans of 
NIDDK and NINR 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

An estimated 16 million Americans are known to have diabetes, and 
millions more are considered to be at risk for developing the 
disease.  Diabetic foot lesions are responsible for more 
hospitalizations than any other complication of diabetes.  Among 
patients with diabetes, 15% will develop a foot ulcer, and 12-24% of 
individuals with a foot ulcer will require amputation.  Indeed, 
diabetes is the leading cause of non-traumatic lower extremity 
amputations in the United States.  Diabetic foot ulcers adversely 
affect the quality of life for the individual; in addition, the cost 
of caring for diabetic foot ulcers imposes a significant burden on 
society.

Much is known about the risk factors for developing foot ulcers in 
the diabetic patient.  Ulcers are most often caused by repetitive 
mechanical stress that is not recognized by the patient because of 
peripheral neuropathy and the loss of sensation.  A motor component 
to the peripheral neuropathy may lead to muscle atrophy, flexion 
deformity and/or abnormal gait, which, in turn, creates increased 
pressure points.  Autonomic neuropathy causes dyshidrosis and dry 
skin, which is more prone to cracking.  Finally, autonomic 
neuropathy may also be associated with arteriovenous shunting and 
altered skin perfusion.  Diabetologists generally agree that careful 
foot exams are a cornerstone to preventing foot ulceration.  Yet 
studies indicate that only 40 – 60 percent of patients with 
diagnosed diabetes have had a foot exam within the past year.  In 
addition, no guidelines exist for what constitutes a proper foot 
exam or what the optimal interval of such examinations should be. 

Although general medical progress has been made in improving wound 
care, the incidence of lower extremity amputations continues to 
rise.  Strategies for wound care that will lead to healing of ulcers 
and reduced amputation rates are critically needed.  Current 
treatment modalities include off-loading, debridement, dressings, 
antibiotics and vascular reconstruction.  Unfortunately, however, 
there are no widely accepted,  scientifically established guidelines 
for assessing and treating diabetic foot ulcers. 

Much recent progress has been made in learning about the biology of 
wound healing.  The acute response to injury involves the activation 
of the hemostatic cascade, which includes the release of growth 
factors and cytokines.  The second phase of wound healing involves 
the recruitment of neutrophils and establishes an inflammatory 
response.  Macrophages recruited as part of the inflammatory 
response release additional growth factors and cytokines, which 
attract fibroblasts and endothelial cells to the site of injury.  
This third phase is marked by the proliferation of these cells and 
the deposition of extracellular matrix.  The final, or remodeling, 
phase of wound healing is characterized by keratincyte  migration 
into the healing wound site.  The diabetic foot ulcer is a chronic 
wound and does not exhibit the orderly cascade of events which 
characterizes normal wound healing.  Instead, diabetic ulcers appear 
to be “stuck” in the proliferative phase and are characterized by 
ongoing inflammation.  The reasons for failure to heal are 
incompletely understood but are believed to include abnormalities in 
inflammatory cells in diabetics, peripheral neuropathy and repeated 
injury, and vascular disease.  A more precise understanding of the 
biology of wound healing, and its abnormalities in diabetes, should 
lead to new therapeutic modalities.

Scope and Objectives

The goal of this RFA is to stimulate the application of new 
molecular technologies to understanding the etiology and 
pathogenesis of diabetic foot ulcers, and to foster 
interdisciplinary approaches to the treatment and prevention of 
diabetic foot disease.  NINR is interested in clinical research to 
determine factors or interventions associated with improvement in 
foot care and skin ulcer prevention in diabetes.  Such studies may 
involve the development and testing of effective patient and health 
care provider education or other intervention strategies to prevent 
or treat skin ulcers. 

Appropriate topics for investigations responsive to this RFA  would 
include but are not limited to:

o Studies of how diabetes affects the expression and/or action of 
cytokines, growth factors or small molecules involved the process of 
wound healing.

o Studies of the effects of hyperglycemia on bacterial growth and on 
the function of white blood cells and macrophages, and of how such 
changes might predispose to infection or alter ulcer healing.

o Studies of how endothelial gene expression and/or function are 
affected by diabetes, including endothelial/matrix interactions.

o Studies of how diabetes-induced alterations in blood flow and/or 
endothelial function affect the wound healing process.

o Trials to establish optimal, cost-effective methods for assessing 
blood flow and determining which patients would benefit from 
perfusion studies and/or revascularization.

o Studies of how hyperglycemia affects keratinocyte biology.

o Studies to characterize ulcers and develop strategies for 
stratification that would be useful in the evaluation of treatment 
and prevention regimens in clinical trials. Such studies should also 
seek to establish criteria that would be helpful in predicting which 
ulcers are likely to heal and which patients should undergo 
amputation.

o Controlled, randomized trials to establish optimal therapeutic 
regimens to facilitate the healing of new ulcers. Such trials should 
evaluate the relative merits of currently used therapies, including 
(but not limited to) debridement, antibiotics, growth factors, off-
loading, and revascularization.  Such trials might include 
assessment not only of time to complete healing, but include 
analysis of cost-effectiveness, examining such issues as 
hospitalization and amputation rates, as well as productivity and 
quality of life issues for the patient.

o Studies to establish scientific principles for the design and use 
of footwear and other strategies to prevent the development and/or 
recurrence of foot ulcers. Studies to evaluate who would benefit 
from such interventions.

o Studies to develop and evaluate effective patient and/or health 
care provider education strategies, to facilitate compliance with 
prevention and treatment regimens.  

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 subpopulations must be included in all NIH 
supported biomedical and behavioral research projects involving 
human subjects, unless a clear and compelling rationale and 
justification is provided that inclusion is inappropriate with 
respect to the health of the subjects or the purpose of the 
research.  This policy results from the NIH Revitalization Act of 
1993 (Section 492B of Public Law 103-43).
 
All investigators proposing research involving human subjects should 
read the "NIH Guidelines For Inclusion of Women and Minorities as 
Subjects in Clinical Research," which was published in the Federal 
Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide 
For Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available 
on the web at: https://grants.nih.gov/grants/guide/notice-files/not94-100.html.

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: 
https://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.

LETTER OF INTENT 

Prospective applicants are asked to submit, by March 24, 2000, a 
letter of intent that includes a descriptive title of the proposed 
research; the name, address, and telephone number of the Principal 
Investigator; the identities of other key personnel and 
participating institutions; and the number and title of the RFA in 
response to which the application may be 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 avoid conflict of interest in the 
review.

The letter of intent is to be sent to:

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

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be 
used in applying for these grants.  These forms are available at 
most institutional offices of sponsored research and may be obtained 
from the Division of Extramural Outreach and Information Resources, 
National Institutes of Health, 6701 Rockledge Drive, MSC 7910, 
Bethesda, MD 20892-7910, telephone 301-710-0267, email: 
GrantsInfo@nih.gov.

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

BUDGET 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:

PHS 398

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

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD:  Do not complete 
Form Page 4 of the PHS 398. It is not required and will not be 
accepted with the application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT:  Do not complete 
the categorical budget table on Form Page 5 of the PHS 398.  It is 
not required and will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION:  Prepare a Modular Grant Budget 
Narrative page. (See 
https://grants.nih.gov/grants/funding/modular/modular.htm 
for sample pages.)  At the top of the page, enter the total direct 
costs requested for each year.  This is not a Form page.

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

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

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

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

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

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

o The applicant should provide the name and phone number of the 
individual to contact concerning fiscal and administrative issues if 
additional information is necessary following the initial review.  
The program announcement 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 available in the PHS 398 (rev. 4/98) application form 
must be affixed to the bottom of the face page of the application.  
Failure to use this label could result in delayed processing of 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 sample RFA label available at:  
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been 
modified to allow for this change.  Please note this is in pdf 
format.

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

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040 - MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/courier service)

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

Chief, Review Branch
Division of Extramural Activities, NIDDK
Natcher Building, Room 6AS-37F
45 Center Drive MSC 6600
Bethesda, MD 20892-6600

Applications must be received by 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 applicants are notified by the 
Scientific Review Administrator.  

The Center for Scientific Review (CSR) will not accept any 
application in response to this RFA that is essentially the same as 
one currently pending initial review, unless the applicant withdraws 
the pending application.  The CSR will not accept any application 
that is essentially the same as one already reviewed.  This does not 
preclude the submission of substantial revisions of applications 
previously reviewed, but such applications must include an 
introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR 
and responsiveness by NIDDK and NINR.  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 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 Advisory Councils of NIDDK and NINR.

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, reviewer 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?

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

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

(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?

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: March 24, 2000 
Application Receipt Date: April 25, 2000 
Peer Review Date: June-July 2000 
Council Review:  September 2000 
Earliest Anticipated Start Date: September 30, 2000  

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:

Barbara Linder, M.D., Ph.D. 
DDEMD
NIDDK 
Building 45, Room 5AN18A
Bethesda, MD 20892-6600
Telephone:  (301) 594-0021
FAX:  (301) 480-3503
E-mail:  linderb@extra.niddk.nih.gov

Nell Armstrong, Ph.D., R.N.
NINR, NIH
Building 45, Room 3AN12
Bethesda, MD 20892-6600
Telephone: (301) 594-5973
FAX: (301) 480-8260
E-mail: nell_armstrong@nih.gov

Direct inquiries regarding fiscal matters to:

Nancy Dixon
Division of Extramural Activities 
NIDDK
45 Center Drive MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-8854 
FAX:  (301) 480-4237
E-mail:  dixonn@extra.niddk.nih.gov

Jeff Carow
Grants and Contracts Management Office
NINR
Building 45, Room 3AN12
Bethesda, MD 20892-6600
Telephone: (301) 594-6869
FAX: (301) 480-8260
E-mail: jeff_carow@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic 
Assistance No. 93.847 and No. 93.361. 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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