By Matt Downs, MPH, Statistical Scientist, WCG Statistics Collaborative
For a DMC, that first organizational meeting sets the stage for the DMC’s future data reviews. It should occur prior to recruitment and have a robust agenda.
I like to use the analogy of a boat in a port. Before you set sail, you want to make sure you’re headed in the right direction. You’re going to plot your course and check the navigational devices before heading out to the ocean.
That’s why the organizational meeting needs to take place before recruitment begins. This meeting is the last chance for the DMC to identify potential trial obstacles and offer feedback while its members are still naïve to the study data. Any requests after the DMC begins to review data will make sponsors wonder, “What’s really going on? What’s behind that question?” So, it's much cleaner to be able to have those discussions before the DMC has seen interim data.
There’s another reason to meet before recruitment begins: Some potential DMC members will refuse to serve because holding the organizational meeting post-recruitment suggests that the sponsor doesn’t have its safety monitoring process fully established.
To get started, you’ll need an agenda that includes a review of past trials, the study design, and the template for the interim reports the DMC will review. And, although it may change because of enrollment, you want to give thought to scheduling the date of the first data-review meeting.
Ideally, this first meeting should be in person. Yes, that makes scheduling difficult, but keep in mind most DMCs will be working together for years. It’s useful to meet the other committee members and sponsor representatives—and the independent statistical team that will be preparing interim reports.
Get to Know the SDAC
The Statistical Data Analysis Center (SDAC) goes by various names, but the task is the same: It prepares and presents the safety and efficacy reports for the DMC’s reviews at their interim meetings. An SDAC statistician—that would be my role—will attend the DMC meetings and have access to unmasked data. As an independent organization, it has no vested interest in the outcome of the trial. Usually, at least two other statisticians will be participating: The DMC statistician, who is a member of the DMC and typically sees unmasked data, and the trial statistician, who typically has access only to masked data that are pooled over treatment group.
Review the Documents
Conduct a thorough review of the protocol. DMC members will often freely give you their opinions on your study design. It is also a time to review prior studies for this and other indications. What do you know about the existing safety profile of the drug? This gives committee members a sense of what to expect and the ability to recognize if there is a new safety issue that wasn’t uncovered from prior studies.
Review the informed consent. If a safety issue emerges, committee members need to know if the participants were warned about possible side effects.
Hammer Out the Charter
The charter will be the DMC’s operations manual for the next few years. Among the items to include:
- The DMC’s charge and responsibilities
- Responsibilities of other study players
- The communications process, including steps to ensure confidentiality
- Disclosure of potential conflicts of interest
- Decision guidelines and statistical boundaries
- Data flow and content of the report
- Meeting logistics (governance, frequency of meeting, logistics of report distribution, etc.)
Address Tough Questions Early
- Will the DMC have access to efficacy data? This is one of the stickiest issues that comes up. It’s best to address it at the organizational meeting. The DMC members must have the ability to access efficacy data, even when reviewing only safety, because they need the ability to assess risk vs. potential benefit.
- How current will the data be? Too often, this topic gets overlooked, but DMCs need to know–if for no other reason, to control expectations.
- What’s the level of masking? Determine the level of masking the DMC expects in its closed reports. Interim DMC reports often semi-mask the treatment groups with labels such as ‘Group A’ and ‘Group B’. Sometimes, committee members will feel that the DMC should only know the true identity of the treatment upon request if needed given the emerging data. However, we generally recommend that DMC members should be aware of the treatment group identities corresponding to the semi-masked labels at the DMC’s very first report.
- How will the DMC handle futility/overwhelming efficacy? State in the charter whether one of the DMC’s charges is to consider a recommendation for trial termination due to futility or overwhelming efficacy. If this isn’t part of the DMC’s charge, the sponsor should explain why during this first meeting.
- Can the DMC hold unscheduled meetings? The charter should give the DMC the authority to conduct unscheduled meetings without notifying the sponsor. For instance, if the DMC sees a potential emerging safety signal, it may choose to meet sooner than the next planned meeting.
Clarify Communications and Confidentiality
Set the ground rules during the organizational meeting for the flow of information and be crystal clear about what’s at stake. The interim data that the DMC is reviewing must be held in confidence. We encourage all study communication between the DMC and sponsor to go through the SDAC, which can make sure all messages are appropriately routed. Think of us as a firewall.
This bit of advice will have more of an impact on future studies, but I think it’s worth mentioning. DMC members should have past experience in serving on DMCs—the more the better. But where do new DMC members get experience? Some sponsors have been opening attendance at the DMC meeting, even the closed sessions, to trainee members. Usually these trainee members do not officially take part in formulating the DMC’s recommendations, but they gain experience by having access to interim data and observing the deliberations of the other DMC members.
More to Know
What I’ve talked about here just skims the surface, but it’s a solid start. If you want to learn more about how to improve DMCs, download the Clinical Trials Transformation Initiative’s “Recommendations: Data Monitoring Committees
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About the Author
Matt Downs is a Statistical Scientist at WCG Statistics Collaborative and has worked at WCG Statistics Collaborative for over 25 years. Mr. Downs has served as the Independent Reporting Statistician for over 100 industry-sponsored Data Monitoring Committees. His work with industry sponsors has ranged from preparation of DMC charters and interim analysis plans to managing the statistical programming and interim report writing. In addition to reporting to DMCs, he has also served on industry- and government-sponsored committees as the voting DMC statistician.