Release Date:  August 30, 2001

RFA:  RFA-DK 02-016

National Institute of Diabetes and Digestive and Kidney Diseases
National Eye Institute
National Institute of Neurological Disorders and Stroke

Letter of Intent Receipt Date:  January 17, 2002
Application Receipt Date:       February 14, 2002



The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 
the National Eye Institute (NEI) and the National Institute of Neurological 
Disorders and Stroke (NINDS) seek applications to develop and validate 
biomarkers for the microvascular complications of diabetes. 

Prevention and treatment of long-term micro- and macrovascular complications 
remain a critical problem in the management of type 1 and type 2 diabetes 
mellitus. In the United States, diabetes is the leading cause of new 
blindness in working-age adults, of new cases of end stage renal disease and 
of non-traumatic lower leg amputations. Basic science advances in the coming 
years are expected to lead to new therapies to prevent or treat the 
development of nephropathy, retinopathy and neuropathy. Surrogate endpoints 
for complications can be utilized in clinical trials to assess the efficacy 
of these new therapies. In addition, such biomarkers may be useful for 
predicting those patients who are at high risk for the development of 
complications, and who may benefit from aggressive intervention.

This RFA invites basic and clinical research applications to develop 
biochemical, cellular, physiologic or genetic surrogate endpoints that can be 
used to predict risk, aid in early diagnosis and assess progression of the 
microvascular complications of diabetes.


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, Surrogate 
Markers for Diabetic Microvascular Complications, is related to the priority 
area of diabetes and chronic disabling conditions.  Potential applicants may 
obtain a copy of "Healthy People 2010" at


Applications may be submitted by domestic and foreign for-profit and 
nonprofit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal Government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as principal 


This RFA will use the National Institutes of Health (NIH) research project 
grant (R01) and the Exploratory/Development Research Grant (R21) award 
mechanisms.  Responsibility for the planning, direction, and execution of the 
proposed project will be solely that of the applicant.  The total project 
period for an R01 application submitted in response to this RFA may not 
exceed 5 years. Applications with requested budgets up to $250,000 direct 
costs in any year must use the modular grants format. Applications that 
request more than $250,000 direct costs in any year must follow the 
traditional PHS 398 application instructions.  

The R21 awards are to demonstrate feasibility and to obtain preliminary data 
testing innovative ideas that represent clear departure from ongoing research 
interests. These grants are intended to 1) provide initial support for new 
investigators; 2) allow exploration of possible innovative new directions for 
established investigators; and 3) stimulate investigators from other areas to 
lend their expertise to research within the scope of this solicitation. 
Applicants for the R21 must limit their requests to $125,000 direct costs per 
year and are limited to two years. These R21 grants will not be renewable; 
continuation of projects developed under this program will be through the 
regular research grant (R01) program.

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


For fiscal year 2002, the NIDDK, the NEI and the NINDS intend to commit 
approximately $2 million to fund 4 to 10 new and/or competing continuation 
grants in response to this RFA. An applicant may request a project period of 
up to 5 years for R01s and up to two years for R21s. 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 NIDDK, the 
NEI and the NINDS 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.  At this time, it is not known if this RFA will be reissued.



Prevention and treatment of long-term complications remain a critical problem 
in the management of type 1 and type 2 diabetes mellitus. In the United 
States, diabetes is the leading cause of new blindness in working-age adults, 
of new cases of end stage renal disease and of non-traumatic lower leg 
amputations. Diabetes has been estimated to cost the United States economy 
over $98 billion annually; much of this cost is related to the treatment of 
the long-term micro- and macrovascular complications of diabetes. 
Identification of patients at risk for the development of complications, with 
the hope of early intervention, is a public health priority. Early 
intervention is essential, because, by the time symptoms of disease are 
recognized, irreparable structural organ damage may have already occurred.

Diabetic nephropathy is the most common cause of end-stage renal disease 
(ESRD) in the U.S., accounting for approximately 45% of new cases. Major risk 
factors for the development of diabetic nephropathy include duration of 
diabetes and poor metabolic control. However, there is considerable 
ethnic/racial variability in the incidence of nephropathy, and not all 
patients with prolonged hyperglycemia develop ESRD, suggesting a strong 
genetic component to susceptibility. For renal disease, a valuable biomarker 
exists – microalbuminuria is the best available non-invasive predictor of 
diabetic nephropathy risk. Screening for microalbuminuria is considered 
“standard of care” and treatment of patients who have microalbuminuria with 
angiotensin converting enzyme inhibitors is partially effective in slowing 
progression to overt proteinuria and renal disease. However, the predictive 
value of microalbuminuria for the progression to overt nephropathy is not 
precise. More data are needed to delineate the extent to which increases in 
microalbuminuria predict either pathological progression, or ultimate 
progression  to end stage disease. In addition, some patients in whom 
microalbuminuria has not increased may nonetheless develop advanced renal 
lesions. Finally, prevention strategies might be most effective in patients 
with normal albumin excretion, if patients at high risk for the development 
of nephropathy could be identified before the development of 

Neuropathy is a frequent complication of diabetes. Symptoms include weakness, 
pain, and numbness, which may be serious enough to interfere with daily 
activities. To evaluate symptoms of diabetic neuropathy, standardized 
checklists have been developed and scoring systems devised that take into 
account symptom frequency and intensity. This approach is not very reliable, 
and is of little use for early intervention because symptoms may not occur 
until after neurological damage has occurred. Nerve conduction studies have 
been used to diagnose peripheral neuropathy for decades; however, results 
vary by age and sex, and the reliability of the tests can be affected by 
location of electrodes, distances measured, and temperature. Sural nerve 
biopsies can provide a great deal of information, but the procedure is highly 
invasive. Information on the status of nerves in the skin can also be 
obtained from skin punch biopsies or from a recently described skin blister 
method, but these diagnostic techniques are also relatively invasive. Reduced 
sensation can be detected with a monofilament; however, symptoms may not 
develop until after considerable nerve damage has occurred.

Diabetic peripheral neuropathy is often associated with peripheral vascular 
disease and impaired wound healing, resulting in more than 200,000 cases of 
foot ulcers and 80,000 amputations per year, with an annual medical cost of 
over $2 billion. In fact, diabetes is the leading cause of non-traumatic 
lower leg amputations in the United States. Thus, a top priority is the 
development of simple and reliable surrogate markers of early damage, to 
allow effective early intervention (i.e., before symptoms develop) to prevent 
ulcerations and disability. In addition, there are currently no widely 
accepted non-invasive surrogate markers that can be used to evaluate patient 
status, to measure therapeutic effectiveness and define end points for 
clinical trials. Surrogate markers for use in clinical trials are especially 
needed for diabetic neuropathy, as effective therapies for the prevention and 
treatment of diabetic neuropathy are not currently available.

Diabetes is the most common cause of new cases of blindness among working age 
adults. As with other microvascular complications, risk is related to 
duration of diabetes and glycemic control. After 15 years of diabetes, almost 
all patients with type 1 diabetes and two thirds of patients with type 2 
diabetes have background retinopathy. By the time visual acuity is affected, 
significant retinal damage has already occurred. Fluorescein angiography and 
fundus photography are effective methods for detecting retinopathy; however, 
these techniques can only be used to detect disease in its late stages, when 
some permanent visual loss has already occurred. Biomarkers are, therefore, 
needed to determine those at risk for developing retinopathy and for 
detecting disease at its earliest stages, so that more effective 
interventions can be used to prevent visual loss. In addition, because these 
techniques detect only late stages of retinopathy, trials of prevention or 
treatment regimens require long follow-up to detect clinically significant 
differences. Markers of early disease could potentially shorten the duration 
of clinical trials by allowing more sensitive detection of retinopathy 

Objectives and Scope

This RFA invites basic and clinical research applications to develop 
biochemical, cellular, physiologic or genetic surrogate endpoints that can be 
used to predict risk, aid in early diagnosis and assess progression of the 
microvascular complications of diabetes. The overall goal of this RFA is to 
develop biomarkers that could be used as diagnostic tools for the individual 
patient, or as outcome measures to be used in clinical trials testing new 
therapeutic agents. Ideally, such biomarkers will either predict 
susceptibility to retinopathy, nephropathy or neuropathy, detect early 
disease or correlate with pathological progression. Surrogate endpoints 
should be reliable, standardized and easy to use. Investigators responding to 
this RFA may wish to take advantage of existing epidemiological or long-term 
clinical studies that may have been established for investigation of diabetes 
or of other diseases. Studies in animal models will be considered responsive 
to this RFA if these applications have a clear-cut long-term goal of 
applicability to humans.

Recent studies of the pathogenesis of diabetic microvascular complications 
may provide clues for potential surrogate markers of disease. For example, 
several growth factors have been implicated in the development of 
nephropathy, and some studies indicate that urinary excretion of TGF-beta may 
be an early marker of nephropathy. Other urinary or circulating biomarkers 
may predict risk for microvascular complications. In addition, recent 
advances in molecular biology may open up new avenues of exploration for the 
development of surrogate endpoints. Thus, the use of gene or protein 
microarrays could provide powerful tools to screen for novel biochemical, 
cellular or genetic markers associated with disease susceptibility or 

New advances in imaging technologies also may provide opportunities to non-
invasively detect microvascular abnormalities and develop physiologic markers 
that are associated with diabetic complications. A related RFA (DK 02-001) 
solicits applications to develop imaging techniques to measure perfusion, 
tissue oxygenation, angiogenesis or inflammation in the peripheral 
microvasculature of skeletal muscle beds in individuals with diabetes. 

Appropriate topics for investigation under this RFA would include but are not 
limited to:

o Studies to identify and validate new biomarkers of early signs ( i.e., 
before the onset of symptoms) of retinopathy, nephropathy or neuropathy; 

o Studies to identify and validate new biomarkers that identify patients at 
risk for the development of  retinopathy, nephropathy or neuropathy;

o Studies to identify and validate new diagnostic tools that can be used to 
more sensitively monitor progression of retinopathy, nephropathy or 
neuropathy, including  studies to assess the correlation between non-invasive 
markers of disease and pathological progression;

o Studies to identify biomarkers that could be useful in predicting 
susceptibility to or development of multiple microvascular complications 
(e.g., retinopathy and nephropathy);

o Studies to develop non-invasive measures of oxygenation or blood flow in 
relevant tissues (e.g., retina);

o Studies, including ancillary studies to ongoing clinical trials, to clarify 
the predictive value of existing biomarkers or surrogate endpoints.


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 
a complete copy of the updated Guidelines are available at  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.


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 

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.
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.

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:


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:

Applicants may wish to place data collected under this RFA (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.


Prospective applicants are asked to submit, by January 17, 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) 594-8885
FAX:  (301) 480-3505


The PHS 398 research grant application instructions and forms (rev. 5/2001) 
at are to be used in 
applying for these grants. This version of the PHS 398 is available in an 
interactive, searchable PDF format.  For further assistance contact 
GrantsInfo, Telephone 301/710-0267, Email:

All application instructions outlined in the PHS 398 application kit are to 
be followed, with the following modifications for R21 applications:  

The Research Plan for R21 applications cannot exceed 15 pages and appendix  
material will not be accepted. Further details regarding the purpose and  
format of R21 applications can be found by reading the NINDS guidelines  
describing the R21 program (  
All R21 applications submitted in response to this Program Announcement should 
follow the NINDS  guidelines, regardless of Institute assignment. Applicants may 
also contact one of the Program Officials listed under “Inquiries” for further  
information.  If there is other important information it should be included 
in the PA. 


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 NIH staff.  The research grant application form PHS 398 (rev. 5/2001) at is to be used in 
applying for these grants, with modular budget instructions provided in 
Section C of the application instructions.

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:

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 

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 
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.


Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by program staff representing the participating NIH 
Institutes.  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 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 the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  Each 
of these criteria will be addressed and considered in assigning the overall 
score, weighting them as appropriate for each application.  Note that the 
application does not need to be strong in all categories to be judged likely 
to have major scientific impact and thus deserve a high priority score.  For 
example, an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.

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

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

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

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

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

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 

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.


Letter of Intent Receipt Date:    January 17, 2002
Application Receipt Date:         February 14, 2002
Peer Review Date:                 July 2002
Council Review:                   September 2002
Earliest Anticipated Start Date:  September 30, 2002


Applications will compete for available funds with all other approved 
applications. The following will be considered in making funding decisions:

o Quality of the proposed project as determined by peer review;
o Availability of funds;
o Program priority.


Inquiries 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. 
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 699 MSC 5460
Bethesda, MD 20892-5460
Telephone:  (301) 594-0021
FAX:  (301) 480-3503

Paul Kimmel, M.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Rm. 639
Bethesda MD 20892-5458
Telephone: 301-594-7717
FAX:  301-480-3510

Peter Dudley, Ph.D.
Vision Research Program 
National Eye Institute
Executive Plaza South, Rm. 350
Bethesda, MD 20892
Telephone: (301) 496-0484
FAX: (301) 402-0528

Paul Nichols, Ph.D.
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Rm. 2118
6001 Executive Blvd.
Bethesda, MD 20892
Telephone: (301) 496-9964
FAX: (301) 401-2060

Direct inquiries regarding fiscal matters to:

Charlette Kenley
Division of Extramural Activities
 National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 640 MSC 5456
Bethesda, MD 20892-5456
Telephone:  (301) 594-8847 
FAX:  (301) 480-3504

Margie Baritz
Division of Extramural Activities
National Eye Institute
Executive Plaza South, Rm. 350
Bethesda, MD 20892-6600
Telephone: (301) 496-5884
FAX: (301) 496-9997

Denise Chatman
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 3290
6001 Executive Blvd.
Bethesda, MD 20892
Telephone: (301) 496-9231
FAX: (301) 402-0219


This program is described in the Catalog of Federal Domestic Assistance No. 
93.847, 93.849, 93.867, and 93.853. Awards are made under authorization of 
sections 301 and 405 of the Public Health Service Act as amended (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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