SUPPORT OF CLINICAL TRIALS IN VISION RESEARCH

NIH GUIDE, Volume 22, Number 37, October 15, 1993



PAR NUMBER:  PAR-94-003



P.T.





Keywords:



National Eye Institute



PURPOSE



The National Eye Institute (NEI) is reannouncing its intention to use

the cooperative agreement mechanism (U10) to support future

investigator-initiated clinical trials in vision research.  This is

not an announcement of a new program or initiative.



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 program

announcement, Support of Clinical Trials in Vision Research, is

related to the priority area of chronic disabling conditions.

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 and foreign for-profit and

non-profit organizations, public and private, such as universities,

colleges, hospitals, laboratories, units of State and Local

governments, and eligible agencies of the Federal government.

Applications from minority and women investigators are encouraged.



MECHANISM OF SUPPORT



The administrative and funding instrument to be used for this program

will be a cooperative agreement (U10), an assistance mechanism

(rather than an acquisition mechanism) in which substantial NIH

scientific and/or programmatic involvement with the awardee is

anticipated during performance of the activity.  Under the

cooperative agreement, the NIH purpose is to support and/or stimulate

the recipient's activity by involvement in and otherwise working

jointly with the award recipient in a partner role, but it is not to

assume direction, prime responsibility, or a dominant role in the

activity.  Because the nature and scope of the research proposed in

response to this Program Announcement may vary, it is anticipated

that the number and sizes of awards will vary also.  Details of the

responsibilities, relationships, and governance of the study to be

funded under cooperative agreement(s) are discussed later in this

document under the section "Terms and Conditions of Award."



SPECIAL REQUIREMENTS



The following terms and conditions will be incorporated into the

award statement and provided to the Principal Investigator(s) as well

as the institutional official(s) at the time of award.



Terms and Conditions of Cooperative Agreement Award



These special Terms and Conditions of Award are in addition to and

not in lieu of otherwise applicable OMB administrative guidelines,

HHS grant administration regulations at 45 CFR Parts 74 and 92, as

applicable, and other HHS, PHS, and NIH Grant Administration policy

statements.



1.  Awardee Rights and Responsibilities



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(s) of Operations, and the awardees will have the

responsibility of following the protocol.



Awardees will retain custody of and have primary rights to the data

developed under these awards, subject to Government rights of access,

consistent with current HHS, PHS, and NIH policies.



The Study Chairperson is responsible for the overall conduct of the

clinical trial and for providing scientific, technical, and

administrative leadership to the study.  He/She 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 Study Chairperson will actively seek advice

from all of the study's components, including the representative of

the NEI.  The Study Chairperson is usually the individual who

developed the idea for the clinical trial and was the leader in

preparing the Manual of Operations and organizing the study

components.



The Principal Investigator of each resource core center (e.g., Data

Coordinating Center) will play an important role in the design,

implementation, and execution of the clinical trial.  Each Principal

Investigator is responsible for all aspects of the operations of

his/her resource center and for the local implementation of the study

protocol.  The resource core centers are involved in performing

specified support functions such as training and certification of

clinical center staff, designing and maintaining quality assurance

programs, data management, data analysis, and preparing publications.



The Principal Investigator of each participating clinical center has

the primary responsibility of identifying and recruiting eligible

patients at his/her center.  He/She 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 center(s).  The Principal Investigator is also

responsible for ensuring that his/her clinic personnel are trained

and certified to carry out study procedures.



2.  NEI Staff Responsibilities



The appropriate NEI extramural program director from the Division of

Collaborative Clinical Research whose name appears on the Notice of

Grant Award will participate with and assist, but not direct:



a.  The Study Chairperson and Coordinating Center Director in the

nomination and selection of an independent Data and Safety Monitoring

Committee.



b.  The Study Chairperson and, when appropriate, the Executive

Committee, in assuring that patient information handbooks,

recruitment information, press releases, and publicity exhibits are

properly prepared and disseminated.



c.  The Study Chairperson in the identification of additional

participating clinics, if necessary, in order to enhance patient

recruitment.



d.  The Executive Committee 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.



e.  The Editorial Committee in the preparation and review of study

results for publication.



f.  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, to announce study

findings, and to determine the timing of release of any interim or

final reports.



The NEI reserves the right to curtail, withhold, or terminate support

for the study (or an individual award) in situations involving:

inadequate patient recruitment, follow-up, data reporting, or quality

control; a major breech of the study protocol; a substantive change

in the agreed-upon 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 Data and Safety

Monitoring Committee.



3.  Collaborative Responsibilities



Data and Safety Monitoring Committee:  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.



Executive Committee:  Composed of the Study Chairperson, who serves

as Chair, directors of the resource core centers, the NEI

representative, and a small group of clinical center Principal

Investigators who are elected by the full group of participating

clinical center principal investigators for a set term.  This

committee acts as the administrative and executive arm of the

clinical 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 Data and Safety

Monitoring Committee; 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:  This committee has the responsibility for

reviewing manuscripts produced by the study investigators and for

assisting in the preparation of the main trial results.  Its members

are the Study Chairperson, coordinating center director, the NEI

representative, and several clinical center investigators elected by

the full group of participating clinical center Principal

Investigators.



4.  Arbitration



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/technical

conduct of the study.  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 HHS regulation at 45 CFR Part 16.



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 applicants for NIH clinical research grants and

cooperative agreements are 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 must 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 must be provided.



The composition of the proposed study population must be described in

terms of gender and racial/ethnic group.  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 must 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 must be provided.



For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, epidemiology,

prevention (and preventive strategies), diagnosis, or treatment of

diseases, disorders or conditions including but not limited to

clinical trials.



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.



For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including

minorities.



If the required information is not contained within the application,

the review will be deferred until the information is provided.



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 for clinical research 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



Potential applicants are strongly encouraged to contact NEI staff

prior to the preparation and submission of an application to discuss

NEI's possible interest in supporting the clinical trial and to

request additional information that will be helpful in preparing

applications.



Applications are to be submitted on the grant application form PHS

398 (rev. 9/91) and will be accepted at the standard application

deadlines as indicated in the application kit.  Application kits are

available at most institutional offices of sponsored research and may

be obtained from the Office of Grant Information, Division of

Research Grants, National Institutes of Health, Westwood Building,

Room 449, Bethesda, MD 20892, telephone 301/435-0714.



For item 2a on the Face Page, enter "NEI Clinical Trial Cooperative

Agreement."  For item 2b on the Face Page, enter the code "U10."



The applicant should provide a statement acknowledging and agreeing

to NEI staff post-award involvement in conducting the clinical trial,

and should describe plans to accommodate this involvement.



The complete, typewritten, signed original of the application,

including the Checklist, and three exact copies, in one package with

any appendices, must be mailed or delivered 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:



Review and Special Projects Officer

National Eye Institute

Executive Plaza South, Room 350

6120 Executive Boulevard

Bethesda, MD  20892



REVIEW CONSIDERATIONS



Applications will be assigned by the Division of Research Grants on

the basis of established Public Health Service referral guidelines

and reviewed in accordance with standard NIH peer review procedures.

Applications assigned to the NEI will be reviewed for scientific

merit by an initial review group convened by the NEI Review and

Special Projects Officer.  Second level program and policy review for

applications assigned to NEI will be conducted by the National

Advisory Eye Council.  All applications will be reviewed using the

following standard review criteria:



o  scientific, technical, or medical significance and originality of

proposed research;



o  appropriateness and adequacy of the experimental approach and

methodology proposed to carry out the research;



o  qualifications and research experience of the Principal

Investigator and staff, particularly but not exclusively in the area

of the proposed research;



o  availability of resources necessary to perform the research; and,



o  appropriateness of the proposed budget and duration in relation to

the proposed research.



In addition, the following criteria will also be considered by

NEI-convened review groups when assessing the scientific merit of

applications:



Study Chairperson's Application



o  the rationale for the clinical trial and the reasonableness of the

specific objectives in addressing a major problem in vision research;



o  the appropriateness of the experimental design for testing the

problem/hypothesis and the measures chosen to assess the effect of

the intervention, the plans for minimizing bias, and the criteria for

the study endpoints;



o  the study procedures and administrative arrangements for

implementing the experimental design/protocol;



o  the justification for the sample size, the availability of the

patient pool, the likelihood of achieving the target sample size in a

reasonable time, the reasonableness of the general statistical

approach, and the procedures for technical monitoring of the study

centers for adherence to protocol and for data monitoring to

determine whether protocol changes are needed; and,



o  the scientific, clinical, and administrative qualifications of the

Study Chairperson and other key personnel.



Coordinating Center/Other Resource Center Applications



o  the reliability and accuracy of the center's past performance and

the potential of the center's future performance in a clinical trial;



o  the experience of the Principal Investigator and other key

personnel in clinical trials;



o  the ability of the center to manage and to analyze data for the

clinical trial; and,



o  the appropriateness of the proposed procedures for data

management, data storage, and analytical activities.



Participating Clinical Center Applications



o  adequacy of the participating clinical center's procedures for:

patient recruitment, patient retention, patient followup, data

collection and management, quality control of clinical examinations,

and training and certification of personnel;



o  the qualifications of all key personnel including their experience

and track record in clinical trials; and



o  the sources and numbers of fully-eligible patients, the number of

eligible patients likely to have participated in the clinical trial

who were seen over a specific period of time, and the clinic's

patient recruitment and retention track record in clinical trials.



AWARD CRITERIA



The following will be considered in making funding decisions for

applications assigned to the NEI and recommended by the National

Advisory Eye Council:



o  scientific and technical merit of the proposed clinical trial as

determined by peer review;

o  relevance to NEI program goals and key research questions

identified in "Vision Research - A National Plan:  1994-1998;" and

o  availability of funds.



INQUIRIES



Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.

For information regarding this notice and referral to the appropriate

NEI program or grants

management staff, contact:



Dr. Richard L. Mowery

Division of Collaborative Clinical Research

National Eye Institute

Executive Plaza South, Room 350

Telephone:  (301) 496-5983



The NEI publication, "Vision Research - A National Plan:  1994-1998,"

is available from:



Office of Science Policy and Legislation

National Eye Institute

Building 31, Room 6A25

Bethesda, MD  20892

Telephone:  (301) 496-4308



AUTHORITY AND REGULATIONS



This program is described in the Catalogue of Federal Domestic

Assistance No. 93.867, Vision Research.  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 Part 74.  This program is not

subject to the intergovernmental review requirements of Executive

Order 12372 or Health Systems Agency review.



.


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