DIABETIC MACULAR EDEMA CLINICAL RESEARCH NETWORK

Release Date:  June 7, 2001

RFA:  RFA-EY-01-001

National Eye Institute
 (http://www.nei.nih.gov)

Application Receipt Date:  October 26, 2001

PURPOSE

The National Eye Institute (NEI) invites cooperative agreement applications 
to support three core centers to plan, implement, and conduct clinical trials 
of the treatment of diabetic macular edema.  These will include a Network 
Study Chair, a Coordinating Center (CC), and a Fundus Photograph Reading 
Center.  Clinical centers will be added to the network during the first year 
of operation as subcontracts to the Coordinating Center.  One clinical center 
will be established in the NEI Intramural Program, supported by NEI 
intramural funds.  Substantial involvement with the funded investigators by 
NEI staff is anticipated in the selection of hypotheses, trial and protocol 
design, monitoring of progress, and analysis and publication of data.

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010", a PHS-
led national activity for setting priority areas.  This Request for 
Applications (RFA), "DIABETIC MACULAR EDEMA CLINICAL RESEARCH NETWORK", is 
related to the priority areas of vision, diabetes, and chronic disabling 
conditions.  Potential applicants may obtain a copy of "Healthy People 2010" 
at http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit 
organizations, public and private, such as universities, colleges, hospitals, 
laboratories, units of State, tribal, 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.

The disciplines and expertise that will be sought for the core centers 
include but are not limited to the areas of biostatistics, clinical trials 
management, ophthalmology, and internal medicine.  The Network Study Chair 
should have prior experience in clinical diabetes and/or ophthalmic research 
and demonstrate an understanding of the ocular complications associated with 
diabetes.  The CC must have prior experience in developing and managing 
multicenter ophthalmic clinical trials.  The Fundus Photography Reading 
Center must be experienced in conducting research in diabetes and/or in the 
area of diabetic complications.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) cooperative 
agreement mechanism (U10), an assistance mechanism rather than an acquisition 
mechanism, in which substantial NEI scientific and programmatic involvement 
with the awardees is anticipated during performance of the research.  Under 
the cooperative agreement, there will be substantial NEI scientific and/or 
programmatic involvement with the awardees.  The NEI purpose is to assist, 
support and/or stimulate the recipient"s activities by facilitating 
performance of the effort as a partner.  The NEI will not assume direction, 
prime responsibility, or a dominant role in the activity.  Details of the 
responsibilities, relationships and governance of the network to be funded 
under cooperative agreements are described below.

The total project period for an application submitted in response to this RFA 
may not exceed seven years.  This RFA is a one-time solicitation.  At this 
time, the NEI has not determined whether or how this solicitation will be 
continued beyond the present RFA.  The anticipated award date is July 2002.

FUNDS AVAILABLE

The NEI intends to commit approximately $4.5 million total costs in FY 2002 
to support the core centers and approximately 25 clinical centers.  Funds to 
support the clinical centers will be included in the CC budget, except for 
the clinical center in the NEI Intramural Program.  The NEI is not requesting 
the submission of individual clinical center applications at this time.  Once 
the network core centers are operational and the protocol development phase 
begins, clinical center applications will be solicited.  The total project 
period for an application submitted in response to this RFA may not exceed 
seven years.  Awards in subsequent years will depend in part on the final 
design of the trials to be conducted.  Costs in the final year of the project 
period are expected to decrease since the primary focus will be on data 
analysis and reporting results.  Although the financial plans of the NEI 
provide support for this program, any awards 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 competing renewal applications will be accepted and/or if this RFA will be 
reissued.

There will be an administrative review organized by the NEI after 
approximately four years to determine if the network and each of its 
components have been performing as envisioned in terms of patient recruitment 
and implementation of protocols of importance to the field.  Based on this 
review, a decision will be made by the NEI whether to continue the research 
activities as planned, to refocus the activities, or to plan for an orderly 
closeout of the network.

RESEARCH OBJECTIVES

Background

Macular edema secondary to diabetic retinopathy is a major cause of visual 
loss in patients with diabetes.  For persons with diabetic macular edema, 
approximately 20% of those with Type 1 diabetes have visual acuity worse than 
20/40, and 50% of those with Type 2 diabetes have visual acuity worse than 
20/40.  This level of vision loss limits or prevents daily activities such as 
driving.  Data from the Wisconsin Epidemiologic Study of Diabetic Retinopathy 
suggest that the incidence of developing diabetic macular edema was 20% in 
patients with Type 1 diabetes, 25% for Type 2 diabetics using insulin, and 
14% for those not using insulin.  Current treatments for diabetic macular 
edema reduce the risk of vision loss by only 50%.

Intensive glucose control, as demonstrated by the Diabetes Control and 
Complications Trial, decreased the development of macular edema by 23% when 
compared to standard, conventional glucose control.  In the Early Treatment 
Diabetic Retinopathy Study (ETDRS), treatment of macular edema by focal laser 
photocoagulation was beneficial in reducing the rate of moderate visual loss 
by only 50%, defined as a loss of 15 or more letters on the ETDRS visual 
acuity charts compared to baseline.  However, the rate of visual improvement 
is low.  Furthermore, the laser burns that result from such focal laser 
treatment in patients treated in the ETDRS have been shown to increase the 
atrophy of the retinal pigment epithelium with the progressive enlargement of 
the initial focal scars of laser photocoagulation.  This potentially can lead 
to visual loss with central scotomas and a decrease in color vision.  A 
better technique for delivering focal laser photocoagulation is needed.

Medical treatment for diabetic macular edema is currently being evaluated in 
two clinical trials of a protein kinase-C (PKC) inhibitor and an anti-growth 
hormone (Octreotide).  Other medical treatments may have an effect on 
diabetic macular edema.  Studies have suggested the role of free radical 
production at the level of the retina in the pathogenesis of diabetic ocular 
disease.  Antioxidant vitamins may have a potential role in the treatment of 
diabetic retinopathy, including diabetic macular edema.  It is also known 
that laser photocoagulation may generate free radicals.  Treatment with 
antioxidants prior to and following laser photocoagulation may have 
beneficial effects on the retinal morbidity resulting from focal laser 
photocoagulation for diabetic macular edema.

Elevated levels of serum cholesterol have been shown in observational data to 
increase the presence and the development of retinal hard exudates in 
patients with diabetic macular edema.  There is also a two-fold increase in 
the risk of moderate vision loss in five years in patients with elevated 
serum cholesterol (total cholesterol, low density lipoprotein cholesterol, 
and triglycerides).  These observational data appear to indicate that 
lowering serum lipid levels may have a beneficial effect on diabetic macular 
edema.

There is a need to evaluate promising new approaches to treating diabetic 
macular edema and to investigate other approaches as they become available.  
The existence of a network would accelerate clinical research and evaluation 
of new treatment approaches.  A network could carry out multicenter trials, 
as opposed to single-center trials, thus reducing the number of patients 
needed at each clinical center and allowing accrual to be completed more 
rapidly.  Further, a common treatment protocol would reduce variables that 
contribute to patient outcome and allow valid comparisons between treatments.  
Finally, the network approach would provide a framework for rapid initiation 
of important studies, efficient use of pooled clinical expertise in idea 
generation and protocol development, and efficient use of central resources 
for data management, quality control, and endpoint evaluation.

Research Scope

The overall objective of this RFA is to develop an infrastructure to 
accelerate the development and conduct of clinical trials of the treatment of 
diabetic macular edema.  The proposed network would assist collaborating 
investigators, working in partnership with NEI staff, in developing and 
implementing specific, detailed protocols for multicenter clinical trials in 
the treatment of diabetic macular edema.

Some examples of research topics that could be addressed in well-designed 
clinical trials and would be appropriate for this RFA include, but are not 
limited to, the following:

o Modification of current photocoagulation techniques
o Lowering of serum lipid levels
o Inhibition of PKC/Vascular Endothelial Growth Factor
o Inhibition of other growth factors
o Inhibition of inflammation
o Vitrectomy

Organization of the Network

The cooperative network will be composed of three core centers (the Network 
Study Chair, the CC, and the Fundus Photograph Reading Center) and 
approximately 25 clinical centers, including one in the NEI Intramural 
Research Program.  Investigators from these units will be responsible for 
proposing research topics to be adopted by the network, guiding development 
of protocols approved for inclusion in the network, enrolling and following 
patients, assisting in the analysis of data and preparation of manuscripts, 
and disseminating research findings.

The Network Study Chair, in collaboration with NEI, will provide overall 
scientific leadership for the network.  The Chair will take the lead in 
selection of ideas for clinical trials.  The Chair will be responsible for 
the following activities:  development of trial protocols, operational 
management of the network, arranging meetings and conference calls of the 
Executive Committee and the Protocol Review and Oversight Committee, and, 
with assistance from the Coordinating Center, informing network participants 
of progress in protocol development, trial-related issues, and administrative 
issues related to the network.  The Network Chair will serve as chair of the 
Executive Committee (EC).

The CC will have both scientific and administrative functions.  The CC will 
arrange for meetings and conference calls of the Data and Safety Monitoring 
Board (DSMB).  The functions of DSMB will be supported by funds provided to 
the CC specifically for the DSMB, including member honoraria and expenses.  
CC staff will assist with preparation of trial protocols, including the 
statistical design of each study, update protocols, data collection forms, 
and materials to aid in patient recruitment, analyze study results, and 
review all manuscripts for statistical considerations.  The Principal 
Investigator of the CC will be a member of the EC.

The Fundus Photograph Reading Center staff will develop and implement a 
fundus photograph classification/grading system, assist in the development of 
ideas for network clinical trials, and assist in the development of 
protocols.  The Principal Investigator of the Fundus Photograph Reading 
Center will be a member of the EC.

The DSMB will be composed of individuals not directly involved in patient 
care or data collection in the network.  The DMSB will be responsible for 
periodically reviewing accumulated data for evidence of adverse or beneficial 
treatment effects, for initiating recommendations for modification of study 
protocols, including termination of the treatment when appropriate, and for 
assessing data quality and clinic performance.  The DSMB will operate in a 
manner consistent with the Guidelines of the National Eye Institute for Data 
and Safety Monitoring of Clinical Trials 
(http://www.nei.nih.gov/funding/policy/policy6.htm).

The EC will be composed of the Network Study Chair, who serves as Chair, 
Principal Investigators of the other core centers, an NEI representative, and 
five Clinical Center Principal Investigators who will serve for a fixed term 
of two years upon election by the full group of Clinical Center Principal 
Investigators.  The EC will act as the administrative and executive arm of 
the trial and serve as the main governing body of the network.  The EC will 
prioritize research topics for protocol development and will review protocols 
prior to submission to the Protocol Review and Oversight Committee.  The EC 
will make decisions on operational issues, consider and adopt changes in 
study procedures as necessary, review and implement recommendations from the 
DSMB, review the progress of trials in achieving their main goals and take 
steps required to enhance likelihood of success, and review data collection 
practices and procedures as summarized in performance monitoring reports for 
Clinical Centers to identify and correct remediable deficiencies.  The EC 
will meet two or three times during the first year of network operation and 
two times each year thereafter.

A Protocol Review and Oversight Committee, composed of approximately eight 
individuals with expertise in diabetes, ophthalmic complications of diabetes, 
and clinical trials design and methodology will be organized by the NEI, with 
input from the Network Study Chair and Principal Investigator of the 
Coordinating Center.  It will include NEI intramural Clinical Directors and 
extramural Program Directors as well as extramural scientists independent 
from the network.  This Committee will give final approval to the therapeutic 
agents and procedures to be tested, approve study protocols prior to 
submission to the DSMB, and evaluate and approve all major protocol changes 
during the course of a trial prior to review and approval by the DSMB.  The 
Network Study Chair, or designee, will serve as the Executive Secretary.  
Protocols will be open in the network for patient accrual only after approval 
by the Protocol Review and Oversight Committee, the DSMB, and the NEI.  The 
Protocol Review and Oversight Committee will have an initial orientation 
meeting in the Washington, D.C., area during the first year.  Thereafter, 
annual meetings will be held.  Conference calls to review protocols and 
proposed protocol changes and to discuss inclusion of new agents and/or 
procedures in the network will be held as needed.

SPECIAL REQUIREMENTS

Terms and Conditions of a Cooperative Agreement Award

These special Terms and Conditions of Award are in addition to and not in 
lieu of otherwise applicable Office of Management and Budget administrative 
guidelines, Department of Health and Human Services (DHHS) grant 
administration regulations at CFR Parts 74 and 92, as applicable, and other 
DHHS, PHS, and NIH Grant Administration policy statements.

1. Awardee Rights and Responsibilities

o  Awardees have primary authorities and responsibilities to define 
objectives and approaches, and to plan, conduct, analyze, and publish 
results, interpretations, and conclusions of their studies.  The design, 
methods, and procedures of the clinical trial will be detailed in an awardee-
prepared and maintained, study-adopted Manual of Procedures.  The awardees 
will have the responsibility of following the protocol.

o  Awardees will retain custody of and have primary rights to the data 
developed under these awards, subject to Government rights of access 
consistent with DHHS, PHS, and NIH policies.

o  The Network Study Chair is responsible for the overall conduct of the 
clinical trial and for providing scientific, technical, and administrative 
leadership to the study.  The PI will have lead responsibility for planning 
and directing all phases of the study and for using the study"s resources.  
In carrying out these responsibilities, the PI will actively seek advice from 
all of the study"s components, including the representative of the NEI.

o  Resource Core Centers (e.g., Data Coordinating Center) may be involved in 
performing specified support functions such as training and certification of 
clinical center staff, designing and maintaining quality assurance programs, 
managing data, analyzing data, and preparing publications.  The director of 
each resource core center is responsible for all aspects of the operations of 
his/her resource center and for the local implementation of the study 
protocol.

o  One Clinical Center will be established in the NEI Intramural Program, 
supported by NEI intramural funds.  The PI of the NEI Clinical Center will 
have the same responsibilities as the PI of any other participating Clinical 
Center as described in these terms of award.  The director of any 
participating Clinical Center has the primary responsibility of identifying 
and recruiting eligible patients at that center.  The director will be 
responsible for the follow up, as specified in the study protocol, of each 
patient enrolled in the clinical trial and for submitting required data to 
the Resource Core Center(s).  The director is also responsible for ensuring 
that clinic personnel are trained and certified to carry out study 
procedures.

o  The PI agrees to the governance of the study through an EC when 
appropriate.  EC voting membership shall consist of the PI, directors of any 
resource core centers or participating clinical centers, and the NEI Program 
Director.

2. NEI Staff Responsibilities

The appropriate NEI extramural Program Director from the Division of 
Extramural Research whose name appears on the Notice of Grant Award will 
participate with and assist, but not direct:

o  the PI in the nomination and selection of an independent DSMB,

o  the PI and the EC, in assuring that patient information handbooks, 
recruitment information, press releases, and publicity exhibits are properly 
prepared and disseminated,

o  the PI in identifying additional participating clinics, when needed to 
enhance patient recruitment,

o  the EC in routine performance monitoring of the entire study including 
matters of quality control within and among various components, and in the 
determination of inadequate patient recruitment or failure to comply with the 
protocol on the part of individual clinics,

o  an Editorial Committee in the preparation and review of study results for 
publication,

o  the DSMB as an ex officio member and will participate in all decisions of 
the DSMB, such as to proceed from one phase of the study to the next, 
implement protocol changes, evaluate patient recruitment issues, approve any 
ancillary studies, plan data analysis, announce study findings, and determine 
the timing of release of any reports.

The NEI reserves the right to curtail, withhold, or terminate support for the 
study, for an individual award, or for support of a participating consortium 
in situations involving:  inadequate patient recruitment, follow up, data 
reporting or quality control, a major breach of the study protocol, a 
substantive change in the set protocol to which the NEI does not agree, 
statistical evidence that the major study endpoint has been reached ahead of 
schedule, or human subject ethical issues that dictate a premature 
termination.  Prior to taking such actions, NEI will consult with and receive 
recommendations from the DSMB.

3. Collaborative Responsibilities

DSMB:  A group composed of individuals not directly involved in patient care 
or data collection in the trial, who are responsible for periodically 
reviewing accumulated data for evidence of adverse or beneficial treatment 
effects, for initiating recommendations for modification of the study 
protocol, including termination of the treatment when appropriate, and for 
assessing data quality and clinic performance.

EC:  A group composed of the PI, who serves as Chair, directors of any 
Resource Core Centers, the NEI representative, and a small group of Clinical 
Center directors who are elected for a set term by the full group of Clinical 
Center directors.  This committee acts as the administrative and executive 
arm of the trial.  It makes decisions on day-to-day operational issues, 
considers and adopts changes in study procedures as necessary, reviews and 
implements recommendations from the DSMB, reviews progress of the trial in 
achieving its main goal and takes steps required to enhance likelihood of 
success, and reviews data collection practices and procedures as summarized 
in performance monitoring reports for Clinical Centers to identify and 
correct remediable deficiencies.

Editorial Committee:  A group composed of the Study Chair, CC Principal 
Investigator, the NEI extramural Program Director, and several Clinical 
Center directors elected by the full group of participating Clinical Center 
directors.

4.  Outside Participation

Support or other involvement of industry or any other third party in the 
study--e.g., participation by the third party, involvement of study resources 
or citing the name of the study or NEI support, or special access to study 
results, data, findings, or resources--may be advantageous and appropriate.  
However, except for licensing of patents or copyrights, support or 
involvement of any third party will occur only following notification of and 
concurrence by NEI.

5.  Arbitration

Any disagreement that may arise on scientific/technical matters within the 
scope of the award between award recipients and the NEI may be brought to 
arbitration.  An arbitration panel will be composed of three members, one 
member selected by the Study Chairperson, a second member selected by the 
NEI, and a third member selected by the two prior selected members.  This 
special arbitration procedure in no way affects the awardee"s rights to 
appeal an adverse action that is otherwise appealable in accordance with PHS 
regulations at 42 CFR Part 50, subpart D, and DHHS regulations at 45 CFR Part 
16.

Investigator and Coordinator Meetings

During the first year of network operations, there will be three meetings of 
all network investigators to select research topics and begin protocol 
development.  At the third meeting, the coordinators from each clinical 
center will attend for protocol orientation and training.  For budget 
purposes, each meeting will be two days with one being held in an East Coast 
location, one in a Midwest location, and one in a West Coast location.  In 
subsequent years, there will be two meetings per year of investigators and 
coordinators.

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 are provided indicating that inclusion 
is inappropriate with respect to the health of the subjects or the purpose of 
the research.  This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).

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

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by 
the NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects" that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies from the officials 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

DATA AND SAFETY MONITORING IN CLINICAL TRIALS

Applicants are directed to the full text of the NIH Policies regarding Data 
and Safety Monitoring and Reporting of Adverse Events that are found in the 
NIH Guide for Grants and Contracts Announcements at the following web 
sites:http://grants.nih.gov/grants/guide/notice-files/not98-084.html, 
http://grants.nih.gov/grants/guide/notice-files/not99-107.html,
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html

All applicants receiving an award under this RFA must comply with the NIH 
policy cited in these NIH Announcements and any other data safety and 
monitoring requirements found elsewhere in this RFA.

The following is a brief summary of the Data and Safety Monitoring and 
Adverse Event Reporting Requirements:

Data and Safety Monitoring is required for every clinical trial.  Monitoring 
must be performed on a regular basis and the conclusions of the monitoring 
reported to the extramural Program Director.

The type of data safety and monitoring required will vary based on the type 
of clinical trial and the potential risks, complexity and nature of the 
trial.  A plan for data and safety monitoring is required for all clinical 
trials.  Phase III clinical trials generally require the establishment of a 
DSMB.  The establishment of a DSMB is optional for Phase I and Phase II 
clinical trials.

The DSMB/Plan is established at the time the protocol is developed and must 
be approved by both the Institutional Review Board (IRB) and the Government 
and be in place before the trial begins.  If the protocol will be developed 
during the research funded under this RFA, a general description of the data 
and safety monitoring plan must be submitted as part of the proposal and will 
be reviewed by the initial review group.  If the protocol has been developed 
and is included as part of the submitted proposal, the complete and specific 
data and safety monitoring plan must be submitted as part of the proposal.

Monitoring plans, at a minimum, must include the prompt reporting of adverse 
events to the IRB, Food and Drug Administration and NIH.  The frequency of 
reporting of the conclusions of the monitoring activities should also be 
described in the plan.  The overall elements of each plan may vary depending 
on the size and complexity of the trial.  Examples of monitoring activities 
to be considered are described in the NIH Policy for Data and Safety 
Monitoring at http://grants.nih.gov/grants/guide/notice-files/not98-084.html.

For multi-site Phase I and Phase II trials, a central reporting entity that 
will be responsible for preparing timely summary reports of adverse events 
for distribution among sites and IRBs should be considered.  Organizations 
with a large number of clinical trials may develop standard monitoring plans 
for Phase I and Phase II trials.  In this case, such organizations may 
include the IRB-approved monitoring plan as part of the proposal submission.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS

NIH policy requires education on the protection of human subject participants 
for all investigators submitting NIH proposals for research involving human 
subjects.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website:  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, Internet addresses (URLs) should not be used to provide 
information necessary for 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.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev. 
4/98) for a single application receipt date of October 26, 2001.  Application 
kits are available at most institutional offices of sponsored research and 
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, e-mail:  [email protected].

Material to Include in Applications

All applications submitted in response to this RFA must conform to the page 
limitations specified in the PHS 398 (rev. 4/98) grant application kit.

Applications for the Network Study Chair should describe a clinical trial 
that could potentially be included in the network.  A description of the 
rationale, research aims, outcome measures, overall study design, sample size 
estimation, and the potential patient population should be included.  This 
should not exceed four pages.

Applications for the Coordinating Center should provide a description of the 
systems they would use for patient randomization, quality assurance, data 
management, and statistical analysis.

Applications for the Fundus Photograph Reading Center should provide a 
description of the type of systems that would be used to judge eligibility, 
and to classify and assess changes in the retina due to diabetic macular 
edema.

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 2a of the face page of the application 
form and the YES box must be marked.  The sample RFA label available at 
http://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 20827 (for express/courier service only)

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

Chief, Scientific Review Branch
National Eye Institute
Executive Plaza South, Suite 350
6120 Executive Blvd., MSC 7164
Bethesda, MD 20892-7164
Rockville, MD 20852 (for express/courier service only)

Applications must be received by the application receipt date listed in the 
heading of this RFA.  If an application is received after this date, it will 
be returned to the applicant without review.

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 a substantial 
revision of an application already reviewed, but such an application must 
including an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
for responsiveness by the National Eye Institute.  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 NEI in accordance with the review criteria stated below.  All 
applications will 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 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  The 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 in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project  
proposed in the application.

Additional scientific/technical merit criteria specific to the objectives of 
this RFA for the Network Study Chair include:

o  The experience, qualifications, and administrative experience of the 
principal investigator and staff in conducting clinical trials in diabetes 
and/or ophthalmic complications related to diabetes.  Experience of the 
principal investigator in the effective management and coordination of a 
multicenter clinical trial and/or a network.

o  Adequacy of the rationale and plans for design of a treatment clinical 
trial investigating diabetic macular edema.

o  Adequacy of proposed overall administrative organizational structure and 
procedures for managing and coordinating the network activities, committees, 
and collaborative arrangements.

Specific criteria to be used for the initial scientific merit review of 
applications for the CC include:

o  The experience and qualifications of the Principal Investigator and key 
staff in conducting ophthalmic clinical trials.

o  Previous experience of the Principal Investigator and key staff in 
developing clinical trial protocols and effectively managing and coordinating 
multicenter clinical trials.

o  Adequacy of proposed systems to be used for randomization, data 
management, quality control, data analysis, clinic monitoring, and 
preparation of scientific publications.

Specific criteria to be used for the initial scientific merit review of 
applications for the Fundus Photograph Reading Center include:

o  Qualifications and experience of the Principal Investigator in managing a 
fundus photograph reading center involved in multicenter clinical trials.

o  Experience of the Principal Investigator and key staff in developing and 
using grading/classification systems for ocular diseases, especially retinal 
diseases.

o  Adequacy of the proposed system to be used to classify and assess changes 
in the development of diabetic macular edema.

Schedule

Application Receipt Date:         October 26, 2001
Peer Review Date:                 February/March 2002
Council Review:                   June 13-14, 2002
Earliest Anticipated Start Date:  July 2002

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and technical merit 
as determined by peer review, program balance, and the availability of funds.

INQUIRIES

Written and telephone 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:

Donald F. Everett, M.A.
Program Director, Collaborative Clinical Research
National Eye Institute
Executive Plaza South, Suite 350
6120 Executive Blvd., MSC 7164
Bethesda, MD 20892-7164
Telephone:  301-496-5983
FAX:  301-402-0528
e-mail:  [email protected]

Direct inquiries regarding fiscal matters to:

Mr. William Darby
Grants Management Officer
National Eye Institute
Executive Plaza South, Suite 350
6120 Executive Blvd., MSC 7164
Bethesda, MD 20892-7164
Telephone:  301-496-5884
FAX:  301-496-9997
e-mail:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.867.  Awards are made 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 recipients to provide a smoke-free 
workplace and promote the one-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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