Clinical Study Oversight Committee Guidelines

I. Roles and Responsibilities

The Clinical Study Oversight Committee (CSOC) is an independent group of experts that advises NIDCR and study investigators on clinical studies not involving an intervention. Such clinical research studies may be complex, involve risk or vulnerable populations, and may be observational, specimen collection, epidemiology or surveillance studies. The responsibilities of the CSOC are to 1) monitor human subject safety by reviewing and evaluating the accumulated study data, 2) review study conduct and progress, and 3) make recommendations to NIDCR concerning the continuation, modification, or termination of the study. The CSOC considers study-specific data as well as relevant background information about the disease, procedures and progress of the study.

Prior to the first data review and preferably prior to study initiation, the CSOC should define its deliberative processes. These may include event triggers or a process that would call for an ad hoc review, milestones expectations, endpoint analysis, and voting procedures. The CSOC is also responsible for maintaining the confidentiality of its internal discussions and activities as well as the contents of reports provided to it.

The CSOC should review the protocol, including the oversight and risk monitoring plan, and identify any major concerns prior to implementation. During the study the CSOC should review:

• Real-time and cumulative safety data for evidence of procedure-related adverse events
• Unanticipated problems involving risks to subjects or others (for additional information, see Office for Human Research Protections)
• Adherence to the protocol; and
• Factors that might affect the study outcome or compromise the study data, such as protocol violations, losses to follow-up, breach of subject confidentiality)
• Unexpected barriers, if any, to study progress or completion, such as slow enrollment new data or findings, other milestones, change in resources, and futility of endpoints, etc.)

The CSOC should conclude each review with each member’s recommendation to NIDCR as to whether the study should continue, be modified, or be terminated. Recommendations regarding modification of the design and conduct of the study may include corrective actions when performance is unsatisfactory, recommendations to suspend or terminate enrollment, or recommendations to modify consent documents.

Confidentiality must always be maintained during all phases of CSOC review and deliberations.

II. Membership

The membership of the CSOC should reflect the disciplines and clinical specialties such as dental, medical, nursing or behavioral sciences, necessary to interpret the data from the clinical study and to fully evaluate subject safety. The CSOC generally consists of at least three voting members. Membership usually includes an Independent Safety Monitor (ISM) from one or more participating sites, expertise in the clinical aspects of the disease/subject population being studied or procedure being performed, and expertise in current clinical research conduct and methodology.

Consideration should be given to including other voting or ad hoc members such as a biostatistician or a bioethicist if the study design or subject population would benefit from their expertise. CSOC and ad hoc members may be from the principal investigator’s institution or from other participating sites but should not be directly involved with the trial or under the supervision of the study investigator. Furthermore, the CSOC members should generally be in a different organizational group than the Principal Investigator (PI).

NIDCR and other NIH staff who are not involved in the study may also participate as voting members. However, members of the sponsoring NIDCR Branch are discouraged from having voting privileges. Program Officials (PO) or other NIH staff involved in the study may participate as ex officio, non-voting members. Representatives of the manufacturer (industrial collaborator) of the test substance(s) or any other individual with vested interests in the outcome of the study are not eligible to serve on the CSOC as ex officio or voting members.

Conflict of Interest

No member of the CSOC should have direct involvement in the conduct of the study. Furthermore, no member should have or appear to have financial, proprietary, professional, or other interests that may affect impartial, independent decision-making by the CSOC. Letters of invitation to prospective CSOC and ad hoc members should include the following: "Acceptance of this invitation to serve on the xxx CSOC confirms that I do not have any financial or other interest with any of the organizations involved in the study that constitute a potential conflict of interest." In addition, all CSOC and ad hoc members will sign a Conflict of Interest certification to that effect at the time they are asked to participate (see CSOC Conflict of Interest). At the beginning of every CSOC meeting, NIDCR program staff or the CSOC Chair will reconfirm that no conflict of interest exists for CSOC members. Interests that may create a potential conflict of interest should be disclosed to the CSOC prior to any discussion. The CSOC will determine how to handle such potential conflict. The CSOC can require that a member with a potential conflict not vote or take other means deemed appropriate. NIDCR may dismiss a member of the CSOC in the event of unmanageable potential conflict or appearance of conflict.

Selection and Invitation to Participate

The NIDCR PO holds primary responsibility for the formation of the CSOC, unless the Clinical Terms of Award for a grant specifically identifies this as the responsibility of the grantee. The PO (or grantee as specified) is responsible for developing the roster of potential CSOC members. Recommendations for proposed members may be solicited from many sources. The proposed roster of members must be submitted to the Chief, Office of Clinical Trials Operations and Management (OCTOM) and the NIDCR Medical Monitor for review and approval before invitations are issued.

The PO (or grantee as specified) is responsible for identifying the CSOC Chair. He/she may either select the Chair directly or ask CSOC voting members to select the Chair.

III. Meetings

The structure and operating procedures for a CSOC are usually less formal than that of a DSMB. The initial CSOC meeting should occur before the start of the trial or as soon thereafter as possible. NIDCR staff may discuss NIDCR's perspective on and expectations for the study at this initial meeting. At this meeting the CSOC should discuss the protocol, set triggers for data review, define a quorum, and establish guidelines for monitoring the study. The CSOC should decide which member(s) should receive reports of serious adverse events in real time and determine if on-site review of clinical records might be needed. Guidelines for stopping the study for concerns of risk or other factors should be established. At this meeting, the CSOC should also develop procedures for conducting business (e.g., data required for review, voting rules, attendance, etc.). Teleconference calls may often be an appropriate means for conducting meetings.

Based on initial discussions, the CSOC should decide whether to meet on a regular basis or only with the occurrence of adverse events or unanticipated problems involving risks to subjects. In many cases, it may be appropriate for meetings to be convened on an ad hoc basis based on the occurrence of adverse events or unanticipated problems involving risks to subjects. Scheduling of meetings should be based on the magnitude of the perceived risks, rate of subject enrollment, or problems that occur during the progress of the study.

The PO or designee is responsible for convening meetings or conference calls as needed unless the Clinical Terms of Award for a grant specifically identifies this as the responsibility of the grantee. However, meetings may be requested for cause by any member of the CSOC, the investigator, IRB, or NIDCR. The investigator will be responsible for ensuring the distribution of materials for review to CSOC members and other meeting participants.

CSOC meeting format

The recommended meeting format may consist of the following sessions: Open Session, and Closed Executive Session.

A. Open Session: Occurrences of adverse events, unanticipated problems involving risks to subjects, enrollment and endpoints are reviewed. Issues relating to the general conduct and progress of the study will also be considered. CSOC members, voting and ex officio members, NIDCR staff members, and ad hoc experts attend and participate in this session. The lead investigator and study statistician, if applicable, should attend and participate to present results and respond to questions. This session is open to study investigators, coordinating center staff, and NIDCR staff.

B. Closed Executive Session: This final session involves only voting members to ensure complete independence for making decisions and formulating independent recommendations.

Voting

A quorum, as defined by the CSOC in the initial meeting, must be present either in person or by conference call. After a thorough discussion of CSOC members' opinions and rationale and a joint attempt to reach clarity regarding individual recommendations, the final recommendations of each CSOC member should be solicited in Closed Executive Session (ex officio members shall not vote and shall not be present at this voting session). A consensus opinion or recommendation among members is not required; each member may have individual opinions. The final recommendations are recorded and either identified as majority or minority positions or accompanied by actual vote tallies for each divergent recommendation, i.e., as number of votes for or against a particular action, e.g., continue study, terminate study, etc.

IV. Study Reports for CSOC Review

It is the responsibility of the PI to ensure that the CSOC is apprised of all new safety and risk information relevant to the study. Summary safety, enrollment data, and other progress reports (e. g.: protocol deviations, site monitoring summaries) should be forwarded periodically to the CSOC. The CSOC should receive all protocol revisions and may receive other documents relating to the study.

Reports are prepared by the study statistician or the investigator. The general content for reports to the CSOC is as determined by the CSOC at the initial meeting. The CSOC and NIDCR must also review and approve the actual data elements to be presented. At each meeting, additions or modifications to these reports may be directed by the CSOC on a one-time or continuing basis. Distribution of written reports should allow sufficient time for review.

Reports for meetings of the CSOC will consist of the Open Session Report. Open Session reports are distributed to CSOC members, selected NIDCR staff, and other appropriate persons as directed by the CSOC.

V. Other Reports of Study Progress

Safety and enrollment data should be forwarded periodically to all CSOC members. The CSOC should also receive all protocol revisions and may receive other documents relating to the study, such as annual reports, protocol deviations, manuscripts, and newsletters.

VI. Reports from the CSOC

A. Verbal Report: At the conclusion of a CSOC meeting, the CSOC should discuss its findings and recommendations with NIDCR representatives and the study investigators. If NIDCR is not represented at the meeting, the CSOC Chair should contact NIDCR immediately after the meeting to debrief the PO.

B. Summary Report: The CSOC will periodically issue a written summary report that identifies topics discussed by the CSOC and describes their individual findings, overall safety assessment, and recommendations. This would generally occur after each meeting but CSOCs that meet on a more frequent basis may summarize more than one meeting in each report. The rationale for recommendations will be included when appropriate. This report will not include confidential information. The CSOC Chair or designee is responsible for preparing and distributing the report. Unless otherwise specified, the summary report will be forwarded through the NIDCR PO to a designated study team representative (usually the Principal Investigator) and to other appropriate NIDCR staff. The study team representative is responsible for disseminating the CSOC summary report to site investigators. Site investigators must, in turn, submit the reports to their respective Institutional Review Boards (IRB) in accordance with local IRB policy.

C. Immediate Action Report: The CSOC Chair will notify the PO of any findings of a serious and immediate nature, such as if the CSOC recommends that all or part of the study be discontinued. The PO will immediately inform appropriate NIDCR staff, including the Director of OCTOM and the NIDCR Medical Monitor. In addition to verbal communications, recommendations to discontinue or substantially modify the design or conduct of a study must be conveyed to NIDCR in writing on the day of the CSOC meeting. This written, confidential briefing may contain supporting data and should include the CSOC members’ rationale for its recommendations. The written briefing should be submitted to OCTOM.