RELEASE DATE:  July 12, 2004 (see addendum NOT-EB-04-004)

RFA Number:  RFA-EY-04-001 
EXPIRATION DATE:  February 15, 2005

Department of Health and Human Services (DHHS)

National Institutes of Health

National Eye Institute (NEI)


APPLICATION RECEIPT DATE:  February 14, 2005  


o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria


Diabetes is a prototypical chronic disease that imposes a large public health 
burden.  One of its many complications is diabetic retinopathy (DR).  Early 
detection of DR is an important problem because many Americans with diabetes 
do not get regular eye exams due mainly to distance, geography, and economic 
status.  Studies conducted in the 1980’s and 1990’s demonstrated that vision 
loss from DR could be prevented if treatment with laser photocoagulation 
therapy was initiated based upon regular screening and subsequent diagnosis 
of retinal disease.  In this Request for Applications (RFA) the NEI seeks to 
develop, apply, and evaluate noninvasive technology that is practical, 
affordable, and accessible so that patients with diabetes can benefit from 
remote site disease screening.


Nature of the Research Problem

Early detection is critical for the prevention and treatment of the blinding 
complications of retinopathy in persons with diabetes.  Evidence suggests 
that the retina begins to malfunction very early in diabetes, and that the 
sooner treatment is initiated the greater the chance for medical benefit.  
Ophthalmologists started treating diabetic retinopathy with lasers in the 
1960s in an attempt to seal leaking blood vessels and limit neovascular 
growth.  While laser treatment is effective, unfortunately about half of 
diabetic patients do not receive this treatment because they do not have the 
recommended regular dilated eye examination.  Currently, new retinal imaging 
technologies are being developed which have potential utility in remote-site 
clinics.  If interfaced with the internet, these technologies could allow 
primary health care providers to identify patients with retinopathy.  There 
are at least two barriers however to effective screening:  the cost of the 
noninvasive instrument and the ease and simplicity of its use.  Noninvasive 
technologies coupled with internet-based telemedicine communication platforms 
might facilitate remote expert clinical diagnosis and subsequent treatment 
recommendations, thus increasing access to medical care.

Background Information

Noninvasive assessment of retinal function in patents with diabetes has 
traditionally been done using fluorescein angiography, which is especially 
valuable in assessing advanced stages of retinal neovascularization.  This 
procedure allows an ophthalmologist to determine the course of further 
treatment.  Retinal fundus photography is another technique to assess retinal 
status so that the clinician can visualize the microvasculature features of 
DR.  However, complete examination with fluorescein angiography and/or fundus 
photography requires the patient, the photographer, and the retinal 
specialist to be physically present in the clinic.  Although this may be the 
best way to examine an individual, it may not be the best approach for mass 
screening for early detection of DR in diabetics.  Newer noninvasive 
technologies are currently being developed.  These include functional 
magnetic resonance imaging (fMRI), laser Doppler ultrasound, electron spin 
resonance spectroscopy (ESR), and fluorescence spectrometry.  These 
technologies are expensive, and diagnostic improvements are only one aspect 
of the problem of how to deliver the benefits of early detection to the 
widest possible range of Americans with diabetes.  The screening data needs 
to be interpreted, and treatment recommendations made.  With the increased 
ability to digitize images and transfer data over the internet it is possible 
for a retinal specialist at a major medical center to diagnose disease with 
the patient at a remote location.  This could allow screening of persons with 
diabetes by a qualified specialist, thus bringing the benefits of advanced 
surface feature and tissue imaging and high bandwidth Internet platforms to 
remote clinical settings.

Scientific Knowledge to be Achieved

Proliferative DR involves the formation of new blood vessels that develop 
from the retinal blood supply.  Much recent research points to the 
involvement of several factors in the etiology of DR, and several biological 
therapies are either in or close to entering clinical trials.  But no drug 
treatment for DR is currently available.  While laser photocoagulation and 
vitrectomy for proliferative retinal disease have been shown to be effective 
by large-scale, randomized, controlled clinical trials, these treatments 
require clinical observation of overt retinopathy.  Noninvasive techniques to 
enhance eye health care delivery at remote sites could add to the current 
knowledge base of clinical diagnosis and treatment and help increase our 
understanding of pathogenic mechanisms.  As therapies are developed, these 
could be made available to a larger number of patients if individuals with 
the disease were effectively screened and then diagnosed by an expert eye 
care professional.


The need to develop human biomedical imaging techniques has been identified at 
several recent workshops and conferences on diabetic complications.  For 
example, a March 30-31, 1999, workshop entitled "Biomedical Imaging Symposium: 
Visualizing the Future of Biology and Medicine" which was coordinated by the 
NIH Bioengineering Consortium (BECON), and addressed three scientific areas: 
(1) imaging at the cellular and molecular levels for early detection of 
disease; (2) imaging for the clinical diagnosis, staging and recurrence of 
disease; and (3) imaging applied to therapeutic applications and monitoring 
for various disease processes.  This symposium also emphasized the need to 
support fundamental methodological development of imaging techniques before 
disease-oriented and organ-specific applications are determined.

A conference entitled “JDRF-NASA Diabetic Retinopathy Research Workshop” in 
1999, sponsored in part by the NEI; the National Institute of Diabetes and 
Digestive and Kidney Diseases; and the National Institute of Neurological 
Disorders and Stroke, reviewed current technologies for assessing retinal 
function as well as new approaches to therapy.  A 2001 workshop on “Screening 
and Eye Exams for Diabetic Retinopathy” addressed the need for screening and 
eye exams for retinopathy and the way new technologies and telemedicine could 
enhance patient access to eye exams.

This RFA is designed to encourage submission of research grant applications 
that create, utilize, and evaluate noninvasive retinal imaging technologies 
that when joined with telemedicine provide retinopathy screening and eye exams 
at remote locations.  At present only about 50% of all diabetic patients are 
involved in an appropriate eye care program.  Telemedicine would allow eye 
imaging at the point of care, eliminating the need for a separate screening 
appointment.  Images can be captured and transmitted to a central resource for 
accurate medical assessment with diagnostic information and recommendations 
transferred back to the provider at the point of contact.  Telemedicine 
technology makes it possible to remove the barriers of distance, time, 
geography, and economics and bring services to the patients rather than the 
patients to the services.  Telemedicine is currently being tested and utilized 
in a number of state programs, including the California Indian health program.

Most current noninvasive technologies fall into several broad categories:  
retinal imaging, neurological function, and vascular function.  For retinal 
imaging, current technologies include the Retinal Thickness Analyzer (RTA) 
which produces three-dimensional maps of the retina.  A similar approach is 
used in optical coherence tomography (OCT) to obtain a high-resolution cross 
sectional map of the retina.  Spectral imaging of the retina can reveal 
tissue composition using chemical and spectroscopic signatures.  Spectroscopy 
can potentially map and/or classify clinical features such as perfusion, 
capillary dropout, hemorrhage, and retinal metabolism (by mapping cytochrome 
oxidative state).  Although potentially limited by spatial resolution, fMRI 
has the potential to be clinically powerful in measuring blood flow and 
oxygen content.  Sensitivity to inner retinal neuronal dysfunction is 
important for detection and study of early local changes in the retinas of 
diabetics and retinal neural circuitry can be assessed with the multifocal 
electroretinogram that tests the retina’s adaptive properties based on 
multifocal and geographically precise flashes.  Certain aspects of vascular 
structure and function can be studied noninvasively by fundus photography but 
the currently available cameras are bulky and require pharmacological 
dilation of the pupil for optimal image quality.  New advances in optical 
technology that could theoretically produce a sharper image include adaptive 
optics, ballistic imaging, and scanning laser ophthalmoscope.
These advancements can benefit diabetic patients by improving the technology 
needed to assess the functional status of the retina.  But they are currently 
expensive and have not been adapted for low cost use as screening 
technologies.  To be useful the application of the technology needs clinical 
and technological validation before it can be adopted for clinic application.

Project Organization

The NEI anticipates that applications will likely require the involvement of 
engineers, physicists, computer specialists, and bio-scientists knowledgeable 
in interfacing technology with disease applications.


This RFA will use the NIH Research Project (R01) award mechanism.  As an 
applicant you will be solely responsible for planning, directing, and 
executing the proposed project.  This RFA is a one-time solicitation.  Future 
unsolicited, competing-continuation applications based on this project will 
compete with all investigator-initiated applications and will be reviewed 
according to the customary peer review procedures.  The anticipated award 
date is December 1, 2005.

This RFA uses just-in-time concepts.  It also uses the modular budgeting as 
well as the non-modular budgeting formats (see  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular budget format.  Otherwise follow the instructions 
for non-modular budget research grant applications.  This program does not 
require cost sharing as defined in the current NIH Grants Policy Statement at


NEI intends to commit approximately $2M in FY 05 to fund 1 to 3 new grants in 
response to this RFA.  An applicant may request a project period of up to 5 
years and a budget for direct costs up to $500K per year.  Although the 
financial plans of the NEI 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 meritorious applications.


You may submit (an) application(s) if your institution has any of the 
following characteristics:

o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Foreign institutions are not eligible to apply


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


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

o Direct your questions about scientific/research issues to:

Peter A. Dudley, Ph.D.
Director, Retinal Diseases Program
Division of Extramural Research
National Eye Institute
Suite 1300
5635 Fishers Lane, MSC 9300
Bethesda, MD  20892
Telephone:  (301) 451-2020

o Direct your questions about peer review issues to:

Sam Rawlings, Ph.D.
Chief, Scientific Review Branch
Division of Extramural Research
National Eye Institute
Suite 1300
5635 Fishers Lane
Bethesda, MD 20892
Telephone: (301) 451-2020

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

William Darby
Grants Management Officer
Division of Extramural Research
National Eye Institute
Suite 1300
5635 Fishers Lane
Bethesda, MD 20892
Telephone: (301) 451-2020


Applications must be prepared using the Public Health Service (PHS) 398 
research grant application instructions and forms (rev. 5/2001).  
Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering 
System (DUNS) number as the Universal Identifier when applying for Federal 
grants or cooperative agreements.  The DUNS number can be obtained by calling 
(866) 705-5711 or through the web site at  
The DUNS number should be entered on line 11 of the face page of the PHS 398 
form. The PHS 398 document is available at in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 

up to $250,000 per year in direct costs must be submitted in a modular grant 
format.  The modular grant format simplifies the preparation of the budget in 
these applications by limiting the level of budgetary detail.  Applicants 
request direct costs in $25,000 modules.  Section C of the research grant 
application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at

USING THE RFA LABEL:  The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application.  Type the RFA number on the label.  Failure to use this label 
could result in delayed processing of the application such that it may not 
reach the review committee in time for review.  In addition, the RFA title 
and number must be typed on line 2 of the face page of the application form 
and the YES box must be marked.  The RFA label is also available at:

SENDING AN APPLICATION TO THE NIH:  Submit a signed, typewritten original of 
the application, including the Checklist, and three signed, photocopies, in 
one package to:

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

At the time of submission, two additional copies of the application and all 
copies of the appendix material must be sent to:

Sam Rawlings, Ph.D.
Chief, Scientific Review Branch
Division of Extramural Research
National Eye Institute
Suite 1300
5635 Fishers Lane
Bethesda, MD 20892
Telephone: (301) 451-2020

APPLICATION PROCESSING:  Applications must be received on or before the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the applicant 
without review.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within eight weeks.

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.  
However, when a previously unfunded application, originally submitted as an 
investigator-initiated application, is to be submitted in response to an RFA, 
it is to be prepared as a NEW application.  That is, the application for the 
RFA must not include an Introduction describing the changes and improvements 
made, and the text must not be marked to indicate the changes from the 
previous unfunded version of the application.


Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NEI. Incomplete and/or nonresponsive applications will 
not be reviewed.
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 NEI in accordance with the review criteria stated below.  As 
part of the initial merit review, all applications will:

o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications under 
review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the National Advisory Eye Council


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 evaluate the application in 
order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals.  The scientific review 
group will address and consider each of the following criteria in assigning 
the application’s overall score, weighting them as appropriate for each 

o Significance
o Approach
o Innovation
o Investigator
o Environment

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 

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?

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?

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?

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)?

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

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

subjects and protections from research risk relating to their participation 
in the proposed research will be assessed.  (See criteria included in the 
section on Federal Citations, below).

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

be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.


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


Application Receipt Date:  February 14, 2005
Peer Review Date:  June/July, 2005
Council Review:  September, 2005
Earliest Anticipated Start Date:  December 1, 2005


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


HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained. 

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

All investigators proposing clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October, 2001," published in the NIH Guide for Grants and Contracts 
on October 9, 2001 
A complete copy of the updated Guidelines is available at
The amended policy incorporates:  the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new 
Office of Management and Budget (OMB) standards; clarification of language 
governing NIH-defined Phase III clinical trials consistent with the new PHS 
Form 398; and updated roles and responsibilities of NIH staff and the 
extramural community.  The policy continues to require for all NIH-defined 
Phase III clinical trials that: a) all applications or proposals and/or 
protocols must provide a description of plans to conduct analyses, as 
appropriate, to address differences by sex/gender and/or racial/ethnic 
groups, including subgroups if applicable; and b) investigators must report 
annual accrual and progress in conducting analyses, as appropriate, by 
sex/gender and/or racial/ethnic group differences.

The NIH maintains a policy that children (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.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at

policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at

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 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.

DHHS issued final modification to the “Standards for Privacy of Individually 
Identifiable Health Information”, the “Privacy Rule,” on August 14, 2002.  
The Privacy Rule is a federal regulation under the Health Insurance 
Portability and Accountability Act (HIPAA) of 1996 that governs the 
protection of individually identifiable health information, and is 
administered and enforced by the DHHS Office for Civil Rights (OCR).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution.  The OCR website 
( provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on “Am I a covered 
entity?”  Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at

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

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

AUTHORITY AND REGULATIONS:  This program is described in the Catalog of 
Federal Domestic Assistance at and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the PHS Act as amended (42 USC 241 and 284) and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  All awards are subject to 
the terms and conditions, cost principles, and other considerations described 
in the NIH Grants Policy Statement.  The NIH Grants Policy Statement can be 
found at

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in 
certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care, or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.

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