Data safety monitoring board (DSMB)

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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.

  • 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

Operational Guidelines

Safety Review Reports

  • The independent statistician will be responsible for producing and distributing the DSMB open and closed reports and other materials required by the DSMB.
  • The sponsor will be responsible for providing the required data to the independent statistician. No member of the sponsor’s study team, except for translational scientist, will have knowledge of or access to the results of any analyses by treatment group until after the final database lock.
  • No trial action will result from the sponsor review. The request by the sponsor must be approved by the executive Committee chair and DSMB chair. The request will include details of the aggregate data tables to be reviewed, procedure for maintenance of the blind within the sponsor organization, as well as the maintenance of the trial’s scientific integrity.
  • The independent statistician will provide the DSMB with the closed reports at least one week prior to each meeting and will provide the sponsor with the open reports at least three days prior to each meeting. The independent statistician will verify the shipping address for each DSMB member prior to each upcoming meeting in case of change of address or to accommodate travel or extended time away from the office.
  • The Sponsor study statistician will be the liaison with the independent statistician and will attend the open sessions. The independent statistician will attend both the open and closed sessions.
  • At the request of the DSMB, the independent statistician will produce ad hoc presentations to address potential safety issues as they emerge. The DSMB will also be able to seek additional expert advice as appropriate.

DSMB Recommendations

  • Within 24 hours of each DSMB meeting, the DSMB Chairman will provide via electronic mail the DSMB's recommendation(s) based on its review of the data to the executive committee and to the sponsor.
  • The DSMB Chairman may discuss the DSMB's recommendation(s) with the executive committee chairman and the sponsor prior to the submission of the written recommendation(s), as appropriate.
  • The DSMB may provide justification to recommendation(s); however, no unblinded data should be revealed.
  • The DSMB Chairman will prepare a separate written document that contains only the DSMB's recommendation(s) to continue, modify, or stop the studies.
  • The Executive Committee chair will forward a letter describing the DSMB recommendation via the sponsor to the Investigators for archiving and submission to the local IRBs/ERBs as required.
  • If the DSMB recommends stopping study, the sponsor will make the final decision to stop the study after discussion with the DSMB and the executive committee, and as appropriate, any regulatory authorities.
  • If the DSMB recommends in study that the first administration of investigational product may occur at a specific time, the closed report to FDA will be submitted in addition to informing the sponsor of the recommendation as per the process outlined above.
  • If the DSMB recommends stopping study, the sponsor will make the final decision to stop the study after discussion with the DSMB and the executive committee and as appropriate, any regulatory authorities.

Archiving of DSMB Activities and Related Documents

  • After each closed session meeting, the DSMB Chairman, or designee, will circulate minutes of the closed session, including the DSMB's recommendation(s) to all closed session attendees for review. Final minutes of the closed sessions will be approved and archived by the DSMB Chairman and distributed only to the members of the DSMB and the independent statistician.
  • The Executive Committee for the studies and the sponsor will not have access to any materials reviewed during the closed session (e.g., reports and minutes). Minutes of the open sessions will be circulated by the DSMB Chairman, or designee, to all open session attendees for review. Final minutes of the open sessions will be approved by the DSMB Chairman and distributed to all open session attendees.
  • Open session minutes and DSMB recommendations for the studies to the study chairman will be archived by an independent body during the study. Closed session minutes will be archived by an independent body during the study. At the end of the study all meeting minutes (open and closed sessions, DSMB recommendations) will be provided to the sponsor by the independent body to be filed in the TMF.

Reports for DSMB Review

  • The report shell for tables/figures/listings will be prepared by the independent statistician. This information will be the most current data available at the time of the analysis. Therefore, the report will contain both clean and unclean data. In addition, the report will contain endpoint data adjudicated by the Clinical Events Committee, as they become available.
  • Adjudicated and non- adjudicated data will also be identified in the report from the independent statistician.
  • The DSMB members will review and approve the predefined format for the report addressing the safety issues of the trial before the first review meeting.
  • Reports for open and closed sessions will be prepared and distributed by the independent statistician.
  • At subsequent meetings, additions or modifications to these reports may be directed by the DSMB on a one-time or continuing basis.

General Content of Reports

  • Data to be reviewed by the DSMB will include, but are not limited to:
    • Subjects enrolled
    • Patient disposition
    • Selected demographic/baseline factors to include gender, race and age
    • Selected laboratory results
    • Deaths
    • Serious Adverse Events
    • Non-serious adverse events of interest
    • Co-primary safety endpoints
    • Secondary safety endpoints
    • Secondary efficacy endpoints (e.g. MACE and MACE-related components)
    • Any additional ad-hoc reports as requested by the DSMB
    • Pharmacometrician’s report (if applicable)
  • Data that will be reviewed for the safety lead-in period may be substantially fewer than those listed above as less data are collected during this phase.
  • The Sponsor may ask the DSMB to review other data at its discretion. This list may be revised at any time by mutual agreement of the DSMB and the Sponsor.
  • The DSMB may require additional data in order to place certain safety findings into context, to make an assessment of benefit/risk and arrive at one general recommendation regarding the study.
  • The Sponsor may ask the DSMB to review other data at its discretion. This list may be revised at any time by mutual agreement of the DSMB and the Sponsor. The DSMB may require additional data in order to place certain safety findings into context, to make an assessment of benefit/risk and arrive at one of three general recommendations regarding study conduct (continue without changes, continue with changes, terminate).

Additional Reports

  • The DSMB will continue to review on an ongoing basis the unblinded safety data regarding the AEs and laboratory data for study.














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