Guidelines for NCCIH-Appointed Data and Safety Monitoring Boards

Background

It is the National Institutes of Health (NIH) policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Guide, June 12, 1998, Notice 98-084: NIH POLICY FOR DATA AND SAFETY MONITORING). In addition to the NIH requirements, the National Center for Complementary and Integrative Health (NCCIH) also requires an IRB-approved data and safety monitoring plan prior to study initiation for all human subjects research that involves greater-than-minimal risk to participants (as determined by the IRB). The principal investigator (PI) should confer with the NCCIH Program Director prior to funding of an award to discuss whether a Data and Safety Monitoring Board (DSMB) will be required.

For larger multicenter trials, and other trials conducted under a grant, contract or cooperative agreement, NCCIH frequently requires that a DSMB perform monitoring functions. For most trials that require a DSMB, NCCIH will appoint the DSMB and identify a DSMB Executive Secretary (ES) for its operations. This document summarizes NCCIH guidelines concerning the establishment, responsibilities, and operating procedures of an NCCIH-appointed DSMB.

Board Activities

The DSMB plays a crucial role in ensuring the safety and welfare of patients enrolled in clinical trials, and operates without undue influence from any interested party, including study investigators or NCCIH staff.

Responsibilities

DSMB responsibilities are to:

1. Protect the safety of the study participants
2. Review and approve the research protocol, informed consent documents, and plans for data safety and monitoring
3. Evaluate the progress of intervention trial(s), including periodic assessments of data quality and timeliness, participant recruitment, accrual and retention, participant risk versus benefit, performance of the trial site(s), and other factors that can affect study outcome
4. Consider factors external to the study when relevant, such as scientific or therapeutic developments that may have an impact on the safety of the participants or the ethics of the trial
5. Report on the safety and scientific progress of the trial
6. Make recommendations to the NCCIH concerning continuation, termination, or other modifications of the trial based on the observed beneficial or adverse effects of the treatment under study
7. If appropriate, conduct interim analysis of efficacy in accordance with stopping rules that are clearly defined in advance of data analysis. In some cases, these stopping rules are proposed by the PI and approved by the DSMB with modification as necessary to ensure patient safety
8. Ensure the confidentiality of the trial data and the results of monitoring
9. Assist NCCIH by commenting on any problems with study conduct, enrollment, sample size, and/or data collection.

Membership

Each DSMB must have a Chair and members who are independent of the study and generally have expertise in biostatistics, epidemiology, clinical trials, bioethics, and key subject areas involved in the research. Members are nominated by the DSMB ES in consultation with the NCCIH Program Director, and appointed by the NCCIH Director. Every DSMB must have an NCCIH-appointed DSMB ES who is not involved in the study or with the study team, and is impartial in DSMB interactions. The DSMB ES is typically a member of the NCCIH Office of Clinical and Regulatory Affairs (OCRA), with clinical trials expertise.

The DSMB Chair will be identified by NCCIH prior to the first meeting of the board. While the Chair will lead all meetings of the DSMB, the Chair and the DSMB ES will cooperate on development and execution of all logistic activities associated with the DSMB, including 1) oversight and coordination of all meetings and communications; 2) development of the agenda; 3) identification and review of substantive materials; and 4) production of meeting minutes and reports. In addition, the DSMB ES ensures that the DSMB complies with all NIH and PHS policies and procedures concerning DSMB activities, and objectively communicates DSMB comments and recommendations to relevant NCCIH staff.

Conflicts of Interest

Conflicts of Interest (COI) for DSMB members must be reviewed and managed appropriately. COIs are reviewed by the DSMB ES and NCCIH/OCRA staff. Written documentation attesting to absence of COI is required; potential conflicts that develop during a member's tenure on a DSMB must be disclosed to NCCIH in a timely fashion.

Board Process

The first meeting will take place before initiation of the trial to discuss the protocol and to establish guidelines to monitor the study. The DSMB will also review and approve a Charter document that will be submitted to NCCIH/OCRA. The Charter is a living document and can be amended throughout the course of the trial. The DSMB Chair, with input from the PI and NCCIH staff, will prepare the initial agenda, which should address issues concerning commencement of the trial. The initial tasks of the DSMB are to review the entire protocol and informed consent forms (or any other study document deemed relevant by the DSMB) with regard to subject safety; identify needs for protocol modification; and, after receipt of a satisfactory protocol, recommend to NCCIH initiation of expenditure of project funds. The DSMB will also identify the relevant data parameters to be reported by the study team to the DSMB and the format of these data. At the first DSMB meeting, the DSMB will also be informed by the DSMB ES that study data included in closed reports during the trial can be presented by masked intervention groups (e.g., Group A vs. Group B) or in an unmasked fashion.

Following the initial meeting, the DSMB should convene at least annually to review accumulated data on safety and, if appropriate, review planned interim analysis. Meetings may be convened as conference calls, as well as in person, although the initial meeting and meetings to discuss interim analysis will be face-to-face. An emergency meeting of the board may be called at any time by the Chair or by NCCIH should a question of patient safety arise. The DSMB may modify procedures during the conduct of a trial, as needed, with approval of the Chair and in consultation with the DSMB ES.

The format for DSMB meetings consists of an open session, a closed session, and an executive session.

Open Session

The briefing open sessions are attended by the DSMB, the DSMB ES, study PI(s), study team members, including the study biostatistician, and NCCIH staff. The DSMB may limit the number of non-board members in attendance. The number of non-DSMB members (study team and NCCIH representatives) in attendance should be limited, as they are observers to the proceedings, and not overwhelm free and open exchange among DSMB members. Non-DSMB members are expected to interact objectively in DSMB proceedings. Typically, NCCIH Program Official(s) for the study will attend open sessions. Issues discussed in open sessions usually include conduct and progress of the study, including patient accrual, compliance with protocol, general safety issues, and any other problems encountered. Patient-specific data and treatment group data are not presented in the open session.

Closed Session

Closed sessions are attended by the DSMB. NCCIH staff participation in closed sessions in which unmasked data will be discussed is restricted to the DSMB ES and unmasked Coordinating Center staff. Additional NCCIH representatives must be approved by the DSMB ES, in consultation with the DSMB Chair.

All study progress and safety data, as well as planned interim analyses are presented at this session. The DSMB may choose to review masked group data, or may request review of unmasked data during the trial. Access to unmasked data must be limited to DSMB members and a small group of additional individuals who are to be determined at the onset of the study. Generally, these data are prepared by and presented to the DSMB by the unmasked trial biostatistician. The discussion at the closed session is completely confidential.

Executive Session

Executive sessions are attended by the DSMB members. NCCIH staff is not required to attend the executive session; however, the DSMB Chair may request the DSMB ES to remain in the executive session at their discretion. On occasion, the DSMB Chair may request other NCCIH staff to participate in the executive session. NCCIH staff members who are requested to participate in closed or executive sessions will remain objective in their interactions with the DSMB and not attempt to influence recommendations of the DSMB. The DSMB Chair will record minutes/recommendations during the executive session, when the DSMB ES is not present. In the executive session, the DSMB will discuss the general conduct of the trial and all outcome results, including adverse events. DSMB recommendations are developed and finalized in the executive session.

Reports

Interim Reports: Interim reports are generally prepared by the study biostatistician(s) and distributed to the DSMB, at least 1 week prior to a scheduled meeting. The contents of the report are determined by the DSMB. Additions and other modifications to these reports may be directed by the DSMB on a one-time or continuing basis. Interim data reports generally consist of two parts: Part 1 (Open Session Report) provides information on study aspects such as accrual, baseline characteristics, and other general information on study status. Part 2 (Closed Session Report) may contain data on study outcomes, including safety data and pre-planned interim analyses, if any. Interim reports are confidential.

Reports From the DSMB: A formal report from the Chair and approved by the DSMB should be supplied to NCCIH, which will be communicated to the PI and the grantee institution. Each report should conclude with a recommendation to either 1) continue the study without changes; 2) continue the study with changes; or 3) terminate the study. This recommendation should be made by formal majority vote and fully justified by the preceding report.

Confidentiality

All materials, discussions, and proceedings of the DSMB are completely confidential. Members and other participants in DSMB meetings are expected to maintain confidentiality. Each member of the DSMB, including nonvoting members, must sign a statement of confidentiality.