Full Text EY-93-01

CLINICAL CENTERS FOR OCULAR HYPERTENSION TREATMENT STUDY

NIH GUIDE, Volume 22, Number 1, January 8, 1993

RFA:  EY-93-01

P.T. 34

Keywords: 
  Hypertension 
  Vision 
  Clinical Trial 


National Eye Institute

Application Receipt Date:  March 12, 1993

PURPOSE

The National Eye Institute (NEI) invites applications for cooperative
agreements to support participating clinics in the Ocular
Hypertension Treatment Study (OHTS).  The OHTS is an investigator-
initiated, randomized, multicenter, clinical trial to determine
whether medical reduction of intraocular pressure prevents or delays
the onset of glaucomatous optic nerve and/or visual field damage in
ocular hypertensive subjects.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Clinical Center for OHTS, is related to the
priority area of reducing significant visual impairment due to
glaucoma.  Potential applicants may obtain a copy of "Healthy People
2000" (Full Report:  Stock No. 017-001-00474-0) or "Healthy People
2000" (Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, private practice clinicians, health maintenance
organizations or managed health care organizations, units of State
and local governments, and eligible agencies of the Federal
Government.  Applications from minority individuals and from women
are encouraged.

MECHANISM OF SUPPORT

Awards will be made as cooperative agreements (U10). This is an
assistance mechanism of support in which there will be substantial,
ongoing involvement by NEI staff during the performance of the
clinical trial and interaction between the awardee and NEI staff
during performance of the project.  This RFA is a one-time
solicitation.

FUNDS AVAILABLE

It is expected that approximately 30 to 40 awards will be made as a
result of this RFA.  The total funds available for the first year of
support are expected to be approximately $1.9 million; however, this
support level is conditional upon the receipt of applications of
substantial and significant scientific merit.  Awards are expected to
be made in November 1993.  Although the financial plans of the NEI
provide for these projects, awards pursuant to this RFA are also
contingent upon the availability of funds.

RESEARCH OBJECTIVES

Background

Glaucoma is one of the leading causes of blindness in the United
States and other industrialized countries, and is the number one
cause of blindness in African Americans.  Moreover, glaucoma is one
of the most common causes of blindness in individuals above age 60,
one of the fastest growing groups in the U.S.  Elevated intraocular
pressure (IOP) is a key risk factor for the development of open-
angle glaucoma.  However, there is no consensus on whether early
treatment of elevated IOP prevents or delays the onset of open-angle
glaucoma.

The OHTS is an investigator-initiated activity funded by cooperative
agreements from the NEI.  Applications were received in October 1991
from Dr. Michael Kass, professor of ophthalmology at Washington
University, as the Study Chairman and Dr. Mae Gordon, assistant
professor of ophthalmology at Washington University, for the
Coordinating Center.  Initial review for scientific merit was held in
March 1992; secondary review by the National Advisory Eye Council
(NAEC) was in May 1992.  Cooperative agreements were made in
September 1992 to support these central OHTS activities.

Although the OHTS is designed to study the efficacy and safety of
early medical treatment in ocular hypertension, there will be other
benefits as well.  This study will allow one to refine and validate
estimates of risk for individual patients with ocular hypertension in
a large national sample.

African Americans have a much higher prevalence of open- angle
glaucoma than do whites.  However, there are no prospectively
obtained data on the conversion rate of African Americans with ocular
hypertension to open-angle glaucoma.  This study will include a
minimum of 400 African American ocular hypertensives, and will
provide data to determine the conversion rate of African American
ocular hypertensive subjects to open-angle glaucoma.

At the conclusion of this study, practitioners should be able to
provide reasonable estimates of risk for individual ocular
hypertensive patients and know which ocular hypertensive individuals
are most likely to benefit from early prophylactic medical treatment.

Other

The OHTS is a randomized, multicenter clinical trial to determine
whether medical reduction of intraocular pressure (IOP) prevents or
delays the onset of glaucomatous optic nerve and/or visual field
damage in ocular hypertensive subjects.  One thousand five hundred
subjects with IOP greater than or equal to 26 mm Hg in at least one
eye (IOP greater than or equal to 21 mm Hg in the fellow eye) and
normal visual fields and optic discs in both eyes will be assigned
randomly to receive stepped medical treatment to both eyes or no
treatment to both eyes.  These subjects are considered to be at
moderate risk for the development of open-angle glaucoma.  The
subjects will be followed twice yearly with automated, threshold,
central, static Humphrey 30-2 perimetry, and yearly optic disc
photographs will be taken.  The study endpoints are progressive optic
disc cupping and/or reproducible glaucomatous visual field loss in
either eye of a patient.  All visual fields and optic disc
photographs will be read in masked fashion by central reading
centers.  It is projected that the time required to recruit the
required patients will be two years, and each patient will be
followed for a minimum of five years.  During the course of the
study, data will also be collected for an analysis of the cost
effectiveness of preventative treatment in ocular hypertension.  This
will include ascertainment of both direct costs of treatment as well
as indirect nonmonetary costs.  In addition, data will be collected
on the impact of medical treatment on the patients' quality of life.

An organization applying as a clinical center in the OHTS must
document its capability to recruit 25 or more fully eligible patients
per year (for two years) for the clinical trial.

SPECIAL REQUIREMENTS

The Principal Investigator and Clinical Coordinator will be asked to
attend a two-day training meeting to be held in St. Louis during the
first project year. Applicants are advised to include plans for this
training meeting in their budget requests.  The Principal
Investigator and Clinic Coordinator of each participating clinic will
be requested to attend an annual one-day meeting of study
investigators to be held in conjunction with the annual meeting of
the American Academy of Ophthalmology.  Applicants are advised to
include plans for meeting travel expenses in their budget requests
using the following as guidance:  The NEI will provide support for
the cost of one night's lodging and one day of per diem for the
Principal Investigator; roundtrip air fare, one night's lodging, and
one day of per diem will be provided for the Coordinator to attend
this annual meeting.

Applicants are advised to describe plans to accommodate the stated
program requirements, criteria, and NEI staff involvement (explained
below).

Terms and Conditions.  The Principal Investigator will be responsible
for all aspects of the day-to-day operations of his/her clinical
center and the local implementation of the study protocol.  He/She
will have the primary responsibility to identify and recruit eligible
patients. He/She will be responsible for the follow up of each
patient enrolled in the clinical trial and submitting the required
data to the Coordinating Center.

The Principal Investigator will retain custody of and have primary
rights to the data developed under the cooperative agreement, subject
to Government rights of access, consistent with current DHHS, PHS,
and NIH policies.

The Chief of the NEIs Collaborative Clinical Research Branch (CCRB)
will participate with and assist, but not direct:

1.  The Study Chairperson and Coordinating Center Director in the
nomination and selection of the independent Data and Safety
Monitoring Committee.

2.  The Study Chairperson and, when appropriate, the Executive
Committee, in ensuring that standardized patient information
handbooks, recruitment information, press releases, and publicity
exhibits are properly prepared and implemented.

3.  The Study Chairperson in the identification of additional
clinics, if necessary, in order to enhance patient recruitment.

4.  The Executive Committee in routine performance monitoring of the
entire study including matters of quality control among various
components and in the determination of inadequate patient recruitment
or failure to comply with the protocol on the part of individual
clinics.  Clinic support can be withheld or terminated based on these
determinations.

5.  The Data and Safety Monitoring Committee as an ex officio member
and will participate in all decisions of the Committee, e.g., to
proceed from one phase of the study to the next, to implement
protocol changes, to evaluate patient recruitment issues, to approve
any ancillary studies, to plan data analysis, and to announce study
findings and the timing of release of any interim or final reports.

The independent Data and Safety Monitoring Committee will serve as an
arbitrator for resolution of potential differences of opinion among
the investigators and NEI staff concerning the scientific conduct of
the study. This arbitration process in no way affects the rights of a
recipient to appeal selected grants administration decisions in
accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS
regulations at 45 CFR Part 16.

These special terms of award are in addition to, and not in lieu of,
otherwise applicable OMB administrative guidelines, DHHS grant
administration regulations at 45 CFR Parts 74 and 92, as applicable,
and other DHHS, PHS, and NIH grant administration policies.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that all applications for NIH research grants and
cooperative agreements will be required to include minorities and
women in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale
for its choice.  In addition, gender and racial/ethnic issues should
be addressed in developing a research design and sample size
appropriate for the scientific objectives of the study.  This
information should be included in the form PHS 398 in Sections 1-4 of
the Research Plan AND summarized in Section 5, Human Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However,
NIH recognizes that it may not be feasible or appropriate in all
research projects to include representation of the full array of
United States racial/ethnic minority populations (i.e., Native
Americans (including American Indians or Alaskan Natives),
Asian/Pacific Islanders, Blacks, Hispanics). The rationale for
studies on single minority population groups should be provided.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.

All applications involving human subjects submitted to NIH are
required to address these policies.  NIH funding components will not
award grants or cooperative agreements that do not comply with these
policies.

APPLICATION PROCEDURES

The application form PHS 398 (rev.10/91) is to be used in applying
for these cooperative agreements.  These forms are available at
institutional offices of sponsored research and from the Office of
Grants Inquiries, Division of Research Grants, National Institutes of
Health, 5333 Westbard Avenue, Room 449 Bethesda, MD 20892, telephone
301/496-7441.

The RFA label available in the PHS 398 must be affixed to the bottom
of the face page. 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 title of the
application and the RFA number must be typed on line 2a of the face
page of the application.

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

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

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

Janet M. Cuca, Ph.D.
Review and Special Projects Officer
National Eye Institute
Building 31, Room 6A06
Bethesda, MD  20892

Applications must be received by March 12, 1993.  If an application
is received after that date, it will be returned to the applicant
without review.

REVIEW CONSIDERATIONS

Applications will be evaluated in accordance with the criteria stated
below by an initial review group that will be convened by the Review
and Special Projects Office, NEI.  Applications will then undergo
second-level review by the National Advisory Eye Council.

In the event of a large response to this RFA, applications may be
subject to triage by a peer review group to determine their
scientific merit relative to other applications.  The NEI will remove
from further consideration those applications judged by the triage
process to be noncompetitive for award and notify the applicant and
institutional official.  Those applications judged to be competitive
will undergo further review.

The factors considered in evaluating responses to this RFA will be:

1.  Experimental Design:  adequacy of the participating clinic's
procedures for patient recruitment and patient retention and
followup, data collection and data management, quality control of
clinical examinations, training and certification of personnel, and
testing and monitoring of study procedures;

2.  Personnel:  qualifications of all key personnel (whether
compensated from the grant or not), including their experience and
track record in clinical trials (NEI-supported and other);

3.  Resources and Facilities:  sources and numbers of fully-eligible
patients, of patients with related disorders, and of eligible
patients likely to have participated in the study who were seen over
a recent one-year period; documentation of intended collaborations;
the clinic's recruitment and retention track record in clinical
trials; and, the physical facilities and equipment available for the
study; and,

4.  Budget:  appropriateness and reasonableness of all items
requested relative to the overall scope of the study, the potential
for patient recruitment, and the budget justifications provided in
the application.

These competitive applications will undergo initial review by the
Vision Research Review Committee on June 21-22, 1993, and receive
second-level review by the National Advisory Eye Council at its
September 9-10, 1993, meeting.

AWARD CRITERIA

The anticipated date of award is November 1993.

Funding decisions will be made on the basis of scientific and
technical merit as determined by peer review, program needs, and the
availability of funds.  The total cost of each application will also
be taken into consideration.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.  Potential applicants are requested to write
or telephone Dr. Richard L. Mowery to receive copies of selected
chapters from the OHTS Manual of Procedures that will be helpful in
preparing an application for submission.

Direct inquiries regarding programmatic issues to:

Dr. Richard L. Mowery
Chief, Collaborative Clinical Research Branch
National Eye Institute
Building 31, Room 6A49
Bethesda, MD  20892
Telephone:  (301) 496-5983
FAX:  (301) 402-0528

Direct inquiries regarding administrative matters to:

Gaye Lynch
Chief, Grants Management Section
National Eye Institute
Building 31, Room 6A48
Bethesda, MD  20892
Telephone:  (301) 496-5884

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.868.  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 PHS grants policies and Federal Regulations 42 CFR 52 and 45
CFR Parts 74 and 92, as applicable.  This program is not subject to
the intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

.

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