NON-INVASIVE IMAGING FOR DIABETIC RETINOPATHY
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)
PARTICIPATING ORGANIZATION:
National Institutes of Health
(http://www.nih.gov)
COMPONENT OF PARTICIPATING ORGANIZATION:
National Eye Institute (NEI)
(http://www.nei.nih.gov)
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.867
APPLICATION RECEIPT DATE: February 14, 2005
THIS RFA CONTAINS THE FOLLOWING INFORMATION
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
PURPOSE OF THIS RFA
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.
RESEARCH OBJECTIVES
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.
Objectives
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.
MECHANISM OF SUPPORT
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
http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if
you are submitting an application with direct costs in each year of $250,000
or less, use the modular 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
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.
FUNDS AVAILABLE
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.
ELIGIBLE INSTITUTIONS
You may submit (an) application(s) if your institution has any of the
following characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, hospitals,
and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Foreign institutions are not eligible to apply
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to carry
out the proposed research is invited to work with their institution to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH programs.
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this RFA and welcome the opportunity to
answer questions from potential applicants. Inquiries may fall into three
areas: scientific/research, peer review, and financial or grants management
issues:
o Direct your questions about scientific/research issues to:
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
Email: pad@nei.nih.gov
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
Email: rawlings@nei.nih.gov
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
Email: wwd@nei.nih.gov
SUBMITTING AN APPLICATION
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 http://www.dunandbradstreet.com/.
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
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive
format. For further assistance contact GrantsInfo, Telephone (301) 710-0267,
Email: GrantsInfo@nih.gov.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting
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
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step
guidance for preparing modular grants. Additional information on modular
grants is available at
http://grants.nih.gov/grants/funding/modular/modular.htm.
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001)
application form must be affixed to the bottom of the face page of the
application. Type the RFA number on the label. Failure to use this label
could result in delayed processing of the application such that it may not
reach the review committee in time for review. In addition, the RFA title
and number must be typed on line 2 of the face page of the application form
and the YES box must be marked. The RFA label is also available at:
http://grants.nih.gov/grants/funding/phs398/labels.pdf.
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of
the application, including the Checklist, and three signed, photocopies, in
one package to:
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the application 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
Email: rawlings@nei.nih.gov
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.
PEER REVIEW PROCESS
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
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 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
application.
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
forward.
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:
PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human
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).
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of
plans to include subjects from both genders, all racial and ethnic groups
(and subgroups), and children as appropriate for the scientific goals of the
research. Plans for the recruitment and retention of subjects will also be
evaluated. (See Inclusion Criteria in the sections on Federal Citations,
below).
CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to
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.
ADDITIONAL REVIEW CONSIDERATIONS
BUDGET: The reasonableness of the proposed budget and the requested period
of support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
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
Award criteria that will be used to make award decisions include:
o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities
REQUIRED FEDERAL CITATIONS
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.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of
the NIH that women and members of minority groups and their sub-populations
must be included in all NIH-supported clinical research projects unless a
clear and compelling justification is provided indicating that inclusion is
inappropriate with respect to the health of the subjects or the purpose of the
research. This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).
All investigators proposing clinical research should read the "NIH Guidelines
for Inclusion of Women and Minorities as Subjects in Clinical Research -
Amended, October, 2001," published in the NIH Guide for Grants and Contracts
on October 9, 2001
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html).
A complete copy of the updated Guidelines is available at
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance with the new
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.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:
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
http://grants.nih.gov/grants/funding/children/children.htm
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH
policy requires education on the protection of human subject participants for
all investigators submitting NIH proposals for research involving human
subjects. You will find this policy announcement in the NIH Guide for Grants
and Contracts Announcement, dated June 5, 2000, at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The
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.
STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The
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
(http://www.hhs.gov/ocr/) 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
http://grants1.nih.gov/grants/guide/notice-files/NOT-OD-03-025.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. 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 http://www.healthypeople.gov/.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of
Federal Domestic Assistance at http://www.cfda.gov/ 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 http://grants.nih.gov/grants/policy/policy.htm.
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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