Support of Clinical Trials in Vision Research

Policy

The National Eye Institute (NEI) wishes to alert potential applicants that it uses cooperative agreement awards to support investigator-initiated clinical trials in vision research.

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, DHHS grant administration regulations at 45 CFR Parts 74 and 92, as applicable, and other DHHS, 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 DHHS, 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 Extramural 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, for an individual award, or support for 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 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

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 regulation at 45 CFR Part 16.

Inclusion of Children and of Women and Minorities in Study Populations

NIH-funded projects that involve human subjects are required to include children, minorities and both genders 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 children, women and minorities in studies of the diseases, disorders, and conditions that affect them disproportionately. Further information on this policy appears in the PHS 398 application kit. Peer reviewers will address specifically whether the research plan conforms to these policies. If the representation of children or of women and minorities 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 the recommendation to further consider the application and in the priority score assigned to the application. NIH funding components will not award grants or cooperative agreements that do not comply with this policy.

Human Subjects

As part of the peer review process, the peer review group carefully considers protections from research risk. The reviewers will assess the adequacy of safeguards of the rights and welfare of research participants based on the information in the application. NIH no longer requires Institutional Review Board (IRB) approval and certification of the proposed research prior to NIH peer review. But all applications to the NIH involving human subjects must document approval by the IRB before they are eligible for funding. The NEI also requires that trial-specific informed consent documents must be submitted prior to the initial review. Please refer to the PHS 398 application kit for further information and guidance on human subject issues.

Application Procedures

Potential applicants are strongly encouraged to contact NEI staff prior to the preparation and submission of an application.

Applicants should submit applications using form PHS 398 (Rev. 5/2001), and follow the instructions supplied with this form. These forms are available in an interactive electronic format at http://grants.nih.gov/grants/funding/phs398/phs398.html

Enter the code U10 in item 2 on the face page of the application.

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 original application and FOUR exact copies should be sent to:

Center for Scientific Review
National Institutes of Health
Suite 1040
6701 ROCKLEDGE DRIVE MSC 7710
BETHESDA MD 20892-7710
BETHESDA MD 20817-7710 (for express mail or courier service)

In order to expedite the review of the application, at the same time, please mail or deliver ONE additional complete copy of the application to:

Samuel C. Rawlings, Ph.D.
Chief, Scientific Review Branch
National Eye Institute
Division of Extramural Research
Suite 1300
5635 Fishers Lane, MSC 9300
Bethesda, MD 20892-9300

Review Considerations

Applications will be assigned by the Center for Scientific Review 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 staff of the Scientific Review Branch, NEI. 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:

• scientific, technical, or medical significance and originality of proposed research;
• appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research;
• qualifications and research experience of the Principal Investigator and staff, particularly but not exclusively in the area of the proposed research;
• availability of resources necessary to perform the research; and,
• 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

• the rationale for the clinical trial and the reasonableness of the specific objectives in addressing a major problem in vision research;
• 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;
• the study procedures and administrative arrangements for implementing the experimental design/protocol;
• 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,
• the scientific, clinical, and administrative qualifications of the Study Chairperson and other key personnel.

Coordinating Center / Other Resource Center Applications

• the reliability and accuracy of the center's past performance and the potential of the center's future performance in a clinical trial;
• the experience of the Principal Investigator and other key personnel in clinical trials;
• the ability of the center to manage and to analyze data for the clinical trial; and,
• the appropriateness of the proposed procedures for data management, data storage, and analytical activities.

Participating Clinical Center Applications

• adequacy of the participating clinic's procedures for: patient recruitment and patient retention and follow-up, data collection and data management, quality control of clinical examinations, training and certification of personnel, testing and monitoring of study procedures;
• qualifications of all key personnel (whether compensated or not), including their experience and track record in clinical trials (NEI-supported and other);
• adequacy of the potential sources and numbers of fully-eligible patients and the documentation of any proposed collaborations; the clinic's recruitment and retention track record in clinical trials; the physical facilities and equipment available for the study; and,
• appropriateness and reasonableness of all items requested relative to the clinic's potential for patient recruitment, and to the overall scope of the clinic's proposed activities.

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:

• scientific and technical merit of the proposed clinical trial as determined by peer review;
• relevance to NEI program goals and key research questions identified in National Plan for Eye and Vision Research; and,
• availability of funds.

Inquiries

Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcomed.

For further information regarding the initial scientific review, prospective applicants should contact Dr. Rawlings at (301) 451-2020.

For inquiries about the programmatic aspects of this announcement, applicants should contact: Eleanor Schron, Ph.D., Maryann Redford, D.D.S., M.P.H., Natalie Kurinij, Ph.D., or Donald Everett, M.A., Collaborative Clinical Research, NEI, at:

National Eye Institute
Division of Extramural Research
Suite 1300
5635 Fishers Lane, MSC 9300
Bethesda, MD 20892-9300
Telephone: (301) 451-2020

For grants administration information, applicants should contact:

William W. Darby
National Eye Institute
Division of Extramural Research
Suite 1300
5635 Fishers Lane, MSC 9300
Bethesda, MD 20892-9300
Telephone: (301) 451-2020
Fax: (301) 496-9997
E-mail: wwd@nei.nih.gov

The NEI publication, National Plan for Eye and Vision Research, is available from:

Office of Science Policy and Legislation
National Eye Institute
Building 31, Room 6A25
31 CENTER DR MSC 2510
BETHESDA MD 20892-2510
Telephone: (301) 496-4308.

Or on the web at http://www.nei.nih.gov/strategicplanning

Authority and Regulations

This program is described in the Catalogue of Federal Domestic Assistance No. 93.867, Vision Research. Awards 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.