The Role of Data and Safety Monitoring Boards
Outline:‐
Fraser Health 5th Annual Research Week - DAY5
Ruth Milner
Research Consultant at large
Background
Sponsors of studies evaluating new drugs, natural products, and devices using either patients or healthy volunteers are required to monitor these studies Various individuals and groups play different roles in clinical trial monitoring. One such group is a DSMB, appointed to oversee and evaluate the progress of a trial particularly the safety and efficacy data .
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What is a DSMB?
Does every clinical trial require one?
What is the structure?
How are members selected?
What are their roles and responsibilities?
How does the board function?
What is a DSMB Charter?
Test!!
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
Center for Drug Evaluation and Research (CDER)
Center for Devices and Radiological Health (CDRH)
March 2006
The Role of Data and Safety Monitoring Boards
Clinical Trial Interactions
The Role of Data and Safety Monitoring Boards
Sponsor
Sponsor
Steering
Committee
Regulatory
Authority
Data and Safety
Monitoring Board
y A Data and Safety Monitoring Board (DSMB) — is an independent group of experts who monitor patient safety and treatment efficacy data while a clinical trial is ongoing.
Coordinating Centre
CRO
Event
Adjudication
What is a DSMB?
SITES
y The Board provides an “arms length” review to act on behalf of patients (or subjects) to ensure their safety.
LABS
Does every trial require a formal DSMB?
All clinical trials require safety monitoring, but not all trials require monitoring by a formal committee that is external to the trial organizers, sponsors, and investigators.
For many “low risk” interventions, such as physiotherapy trials, the choice can be made to have only internal monitoring
Note: FDA does NOT required a DSMB for every study
Criteria for judging whether formal board is necessary.
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What is the Risk to Trial Participants?
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Is DSMB Practical?
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Will a DSMB help to ensure that trial is scientifically valid
Official Vision of a DSMB in action
What is the structure?
“Establishment and Operation of
Clinical Trial Data Monitoring
Committees”
Note: some agencies refer to DSMBs as DMCs
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126578.
pdf
Who?
How selected ‐ What expertise?
The Board should comprise clinicians with expertise in the area of medicine which is the focus of the trial, and at least one methodologist and one biostatistician
All members should have prior experience on a DSMB (or at least the majority)
For trials with high risks or with broad public (read political)
health implications, the DSMB may include a medical ethicist.
The methodologist should be a trial expert (could be a physician) The minimum number on the Board is 3, but there is no upper limit.
Prior experience is particularly important for
the statistician who should be expert in trial design and analysis with particular expertise in interim analyses and sequential designs.
Clinicians should be expert in the field of the trial. Real DSMB – morning start
Conflicts of interest should be considered in choosing individuals to serve on a DSMB. The most obvious conflict is financial interest that could be substantially affected by the outcome of the trial
Some trials may require participation of other types of scientists. Toxicologists, and/or geneticists, psychologists, epidemiologists, and clinical pharmacologists, could be included in particular trials where such expertise is important to assist with the interpretation of interim results.
What are their roles and responsibilities?
‐ At start‐up
• Reviews the study protocol and any protocol amendments, makes recommendations to the Steering Committee and Sponsors ‐ During study
• The DSMB reviews data generated by the study particularly adverse and serious adverse events on a periodic basis and recommends one of the following actions to the study Steering Committee :
‐ continue as is
• Reviews overall data collection methods and safety monitoring procedures and makes recommendations for additions or adjustments
‐ continue with modification
‐ discontinue part of study (one arm or testing regimen)
• Defines safety and related parameters to be monitored, frequency of committee monitoring reviews, methods for review, and establishes criteria for making recommendations to the Steering Committee. ‐ discontinue completely
Real DSMB – Lunchtime
How does the board function?
Decisions must be voted on
Scheduled Meetings The DSMB physically convenes prior to initiation of the study. Thereafter, the frequency of scheduled meetings depends on patient enrollment and safety event rates. However, a scheduled meeting convenes in a single location at a minimum of once yearly. If necessary, additional meetings may be held by
conference calls if the DSMB so decides. Quorum:
Three quarters of the Board members must be present for voting on recommendations to the Steering Committee. If a member is likely to be absent, the committee may choose to appoint an alternate – (usually just add a member to the Board).
Duly voted and passed DSMB recommendations to the Steering Committee are transmitted in writing to the Steering Committee chairman within seven working days of the meeting
Meeting Format Confidentiality is paramount
Meetings consist of open and closed portions. During the initial open portion of a meeting, the Sponsor and Study Chair may be invited to make brief presentations and be available for questions from the DSMB members. The open session only discusses aggregate data.
The closed session will be restricted to the DSMB and the staff from the Statistical Data Analysis Center. The closed session discusses data by assigned treatment group. Real DSMB – Evening
What is a DSMB Charter?
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Introduction
Responsibilities of the DSMB Organization and Interactions
DSMB Members Scheduling, Timing, and Organization of Meetings
Discussion of Confidential Material
Reports of DSMB Deliberations
Reports to the DSMB Statistical Monitoring Guidelines •DSMB yes/no
•Who? expertise
•How many?
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Pharmacokinetics of oral morphine ‐ Phase 1
Trial of two airways clearance techniques – multicentre
Evaluation of training residents using simulation or standard learning material
RCT of MMF to reduce dependence on steroids in lupus patients
Trial of chinese herbs against placebo for reduction of nausea during chemotherapy
•Rates of recruitment, ineligibility, noncompliance, protocol violations and dropouts, overall and by study site;
• Completeness , error rate and timeliness of data;
• Degree of concordance between site evaluation of events and
centralized review;
• Balance between study arms on important prognostic variables;
• Accrual within important subsets.
• Adverse events and whether these are likely as a result of the study
• Safety data (including lab results)