Data safety monitoring board (DSMB)

Data safety monitoring board (DSMB) Slide set: File:DSMB.pdf

Overview

The DSMB charter describes the roles and responsibilities of the DSMB and identifies its members. In addition, the role of the sponsor is defined. The charter also outlines the plan for implementing the roles of the DSMB members and conducting early safety data review. The DSMB may recommend at any time during the conduct of the study, modification of the protocol or discontinuation of the studies for safety reasons. In addition, should outstanding benefit of the investigational drug compared with placebo be demonstrated during the study, the DSMB may recommend that consideration be given to stopping the studies while taking into account the need to accumulate further safety data to allow adequate assessment of risk.

Confidentiality

• All DSMB members must treat patient data, analysis reports and meeting discussions, including the meeting minutes as strictly confidential. Breaches of this confidentiality by any DSMB member may seriously undermine the successful conduct and overall integrity of the study as well as its ultimate interpretation. It is understood that no DSMB member will disclose this information to others without prior written authorization from the Sponsor.
• Until the studies are officially terminated, DSMB members will not discuss information regarding results of analyses or DSMB concerns and deliberations outside the membership of the DSMB unless otherwise noted in the charter. Each member of the DSMB signs a confidentiality agreement by which he/she agrees to keep all information, deliberations, recommendations and conclusions confidential until the studies are officially terminated.

Members

DSMB may consist of the following independent members:

• Five qualified clinicians with expertise in relevant clinical specialties
• One biostatistician with experience in the monitoring and the analysis of the clinical trial data
• Chairman

Responsibilities

The DSMB will:

• Adhere to the DSMB charter requirements.
• Approve any changes to the DSMB charter (summarized in a history of changes document), with sign-off by the DSMB Chairman.
• Provide recommendations to the Executive Committee and sponsor surrounding study conduct matters that affect safety.
• Review the safety data at the planned safety reviews and identify if significant safety concerns arise during the study.
• Request an ad hoc analysis for safety whenever it feels one is warranted.
• Review any other data that may affect subject continuation.
• Make recommendations regarding study progression.
• Make a recommendation to allow or not allow dosing between 12 and 48 hours in study
• Make a recommendation regarding dose escalation in study
• Review available data if one or more of the study level stopping rules is met as determined by the DSMB chair
• Review PK data and any other data that may affect subject or study continuation

Consultant Responsibilities

• Be utilized when requested by the DSMB chairman or Executive Committee to contribute their expertise related to field specialty issues.
• Adhere to the DSMB charter requirements.
• Provide recommendations to the DSMB chairman or Executive Committee surrounding study conduct matters that affect safety in the related field specialty.
• If requested, review the safety data at the planned safety reviews and identify if significant safety concerns arise during the study.

Sponsor/Designee Responsibilities

The Sponsor is responsible for notifying regulatory authorities and investigators if necessary. Specific responsibilities include the following:

• The Sponsor will inform the DSMB of any potential safety concern(s) that were previously unreported.
• The Sponsor will review the DSMB recommendations when notified by the Executive Committee.
• The Sponsor will remain responsible for expedited regulatory reporting of unanticipated adverse effects according to regulations.
• Quintiles will maintain the clinical database for the trial. The unblinded statistician will be responsible for the creation of the DMSB safety and efficacy reports.

Meetings

Regular DSMB meetings will be conducted face-to-face or by teleconferences (utilizing a secure teleconference line). However, a face-to-face meeting is planned to be held at least once annually. The DSMB Chairman or C5R Project Manager will write minutes to summarize the discussion that takes place during the meeting. The draft meeting minutes will be reviewed by the DSMB and final approval will be provided by the DSMB chairman.

Initial Organization

An initial organization meeting will occur in order to formally establish the DSMB and thoroughly acquaint the DSMB with the study protocol and the DSMB charter. This meeting will provide the DSMB with an opportunity to recommend revisions to both the charter and the communication plan between the DSMB and the Sponsor. Initial Organizational Meeting Objectives may include:

• DSMB charter finalization
• Outline the logistics of the interaction between the DSMB, statistician and the sponsor
• Establish future meeting timelines
• Review the list of tables, figures and listings

Attendees

The following attendees will attend:

• DSMB members
• Sponsor representatives: Lead medical monitor or clinical science lead, statistician and other representatives as needed
• Independent statistician
• Executive committee chairman
• Research project manager

Documents

The following documents should be provided, if available, by the Sponsor prior to the initial organizational meeting:

• Study protocols
• Current investigator brochure
• Clinical study reports for completed studies
• SAE reporting plan
• Informed consent forms

Open and Closed Sessions

The DSMB will also be convened to review all available data if one or more of the study level stopping rules is met. Each formal DSMB meeting will be separated into two sessions: an open session during which open reports will be presented and discussed, followed by a closed session during which closed reports will be presented and discussed.

Open Sessions:

The DSMB members, the independent statistician, the project manager, and representatives of the executive committee and the sponsor will attend open sessions. Open sessions will consist of a general study update and will provide a forum for DSMB members to discuss any issues pertinent to the overall conduct of the study and seek additional information.

Closed Sessions:

Only DSMB members and the independent statistician will attend the closed session. During closed sessions, the DSMB will review and discuss the unblinded data summaries and formulate a recommendation. The DSMB may choose to hold an executive session to be attended only by the voting members of the DSMB.

Unscheduled Meetings

The DSMB, the executive committee, or the sponsor may request an ad hoc DSMB review of the data based on a perceived concern for patient safety. The DSMB will be convened to review all available data if one or more of the study level stopping rules is met. In addition, the DSMB may decide to meet and review all available safety data based on other safety signals not designated as a stopping rule.

Quorum

A quorum (minimum of 4 members) of the DSMB is required for all conference calls and meetings. A quorum must be present on the call to make a decision about the continuation of the trial and is required for any proposal, motion, or recommendation to be made to Sponsor. In the event of a tie, the chairman will make the final decision.

Voting

The DSMB members vote on all recommendations which will be submitted to the sponsor via the executive committee. To vote, a DSMB member must participate on a conference call. No member may delegate his/her vote in case of absence.

Data Review

• Four to six weeks prior to each DSMB meeting, representatives of the sponsor will forward the relevant blinded safety data to the independent statistician. This will ensure that the DSMB report (as prepared and distributed by the independent statistician) is available to the DSMB members at least one week prior to the meeting and that the sponsor report is available to the open session meeting attendees at least three days prior to the meeting. Upon request from the DSMB, updated safety presentations may also be provided at each DSMB meeting based on a snapshot of the database taken approximately two weeks prior to each meeting.
• Cardiovascular events will be adjudicated by a Clinical Events Committee (CEC).
• The DSMB will review best available data which includes summaries of adjudicated cardiovascular events as well as those reported on the eCRFs by the investigators. Investigator-reported Major Adverse Cardiovascular Events (MACE) will be analyzed for unexpected between-treatment-group trends, in addition to analysis of adjudicated MACE, in order to better assure timely detection of unexpected adverse trends in MACE.
• Reporting to DSMB will be as follows:
  • 7 calendar days for death/life-threatening and 15 calendar days for all other SAEs.
• Independent statistician will forward unblinded reports for AEs and SAEs to the DSMB chairman and DSMB statistician for review. The DSMB chairman may, in turn forward the report(s) to the full DSMB and/or convene an ad hoc meeting to discuss these reports as needed.
• The DSMB may review data at any time based on their request or at the request of the executive committee or the sponsor, if necessary, to ensure the safety of the subjects. Upon such a request, safety presentations will be provided to the DSMB between the regularly scheduled meetings.

Sponsor Reports

• Representative of the sponsor will forward the relevant blinded safety data to the independent statistician in a timely manner. This will ensure that the DSMB report (as prepared and distributed by the independent Statistician) is available to the DSMB members approximately one week prior to a full DSMB meeting.
• For limited data reviews by the DSMB chairman and statistician, the independent statistician will provide the DSMB report within 5 working days from receipt of the data.
• The Sponsor report for a full DSMB meeting will be available to the open session meeting attendees approximately three days prior to the meeting. Upon request from the DSMB, updated safety presentations may also be provided at each DSMB meeting based on a snapshot of the database taken approximately one week prior to each meeting.

Decision Guidelines

• The objectives of the a priori scheduled DSMB meetings are to review the data and make recommendations on the conduct of the studies. In case of disagreement, the DSMB members will vote and in case of equal votes, the DSMB Chairman will make a final recommendation.
• Upon reviewing the available study data and the FDA-suggested guidelines and analyses for early dosing of investigational product, the DSMB assessed the safety of the investigational product. This recommendation harmonizes the US with all other sites and allowed the study to be conducted under a single global harmonized protocol.
• A recommendation to terminate study would have been based primarily on the overall assessment of safety in the active treatment group compared to the placebo group. As many voting DSMB members as possible, but not less than four, must have participated in any vote to consider a recommendation for early termination of the study.
• The DSMB may recommend a change to the protocol to ameliorate any safety concerns or provide recommendations regarding subsequent dosing and/or study progression/stopping