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Clinical trials can be complex. Multiple treatment arms, various dosing schedules and regimens, placebo controls, multifaceted endpoints, blinded study staff, pragmatic design elements, and multinational sites all fuel the complexity. Not surprisingly, clinical trials receive a lot of oversight from regulatory agencies as well as independent committees, who oversee different aspects of the trial. Institutional review boards (IRB), also known outside the US as research ethics boards (REB), ethics committees (EC), or independent ethics committees (IEC), are likely the most well-known of the independent oversight committee functions. (For the sake of simplicity, in this article we’ll refer to this committee as an IRB.) However, depending on the nature of the trial, other independent committees may be involved in oversight, including institutional biosafety committees (IBC), scientific review committees (SRC), endpoint adjudication committees (EAC), and data monitoring committees (DMC), just to name a few. All play an important role in providing trial oversight, keeping participants and research staff safe, and helping the IRB make its determination that a trial has an adequate safety monitoring plan as required by FDA regulation 21 CFR 56.111(a)(6). In this blog we will take a look at the specific role DMCs play in overseeing research, and how IRBs rely on the independent DMC’s oversight of interim trial data to ensure an adequate safety monitoring plan is in place. What Is an Independent Data Monitoring Committee (DMC)?A DMC is an independent group of experts that conduct a periodic review of accumulated interim data during a clinical trial. DMCs are strenuously recommended for certain clinical trials by both US FDA and EU EMA guidelines. Particularly in trials with a blind or placebo control, the purpose of the DMC is to review unblinded trial data as it is collected to detect and report safety concerns, early evidence of benefit or harm, and futility of the treatment, using criteria outlined in the clinical trial protocol. DMCs are typically comprised of 5-6 members, including biostatisticians and clinicians, who all must be independent of the trial sponsor. Sponsors are responsible for creating the DMC for the trial or engaging an independent firm to create and administer the DMC on the sponsor’s behalf. Many sponsors use independent administrators to support separation and independence of the DMC as an independent oversight committee. The DMC will typically operate under a detailed charter outlining what data the committee will review, how members are selected and vetted for conflicts, and other operational considerations governing how the committee will be run, including the format for reporting and providing recommendations back to the sponsor. Understanding When Data Monitoring Committees Are NeededFDA guidance outlines when the agency expects a DMC to be created. However, sponsors may engage independent DMCs for other types of studies, and on occasion, the IRB may determine there is a need for a DMC as part of the clinical protocol’s overall data safety monitoring plan. In brief, the FDA recommends that sponsors consider using a DMC when:
Most commonly DMCs are created for later phase, randomized, drug and device studies where there is a need for an independent committee to evaluate interim study data for emerging participant safety issues and to determine if stopping rules have been met. The DMC is advisory to the sponsor and provides an opinion, based on interim analysis, as to whether the trial should continue as it has been, receive changes to the trial design, or be stopped early. Most DMC charters give the committee the power to make recommendations only. Unlike the IRB, which under the FDA regulations has authority to disapprove or terminate approval for research (21 CFR 56.113) the DMC only plays an advisory role to the sponsor. What’s the Difference Between a Data Monitoring Committee (DMC) and a Data Safety Monitoring Board (DSMB)?FDA guidelines use the terminology of “independent clinical trial data monitoring committees” – quite a mouthful. For short, both FDA and EMA simplify to “data monitoring committee” as the term describing the group, independent of the sponsor, who is charged with looking at the data to determine when trial endpoints, and other milestones, are met. In North America, these groups are also referred to as data safety monitoring boards (DSMBs). In other parts of the world, they are also known as data and safety monitoring committees (DSMCs), independent data monitoring committees (IDMCs), and other similar titles. Regardless of the name, the concept and purpose of these committees are the same – providing independent oversight of certain aspects of the study, and in blinded research evaluating unblinded study results to determine if endpoints and other milestones have been met. Where Do DMCs Fit With IRB Review?US FDA regulations stipulate IRBs must determine that “where appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.” (21 CFR 56.111(a)(6)) The IRB must determine if an adequate “plan” is in place to adequately monitor data to “ensure” the safety of the participants (emphasis added). This is typically referred to in the clinical protocol document as the “data safety monitoring plan” (DSMP). One of the primary ways a sponsor satisfies this regulatory requirement is to utilize an independent DMC as part of the plan. The IRB will typically view a monitoring plan which incorporates an independent DMC as “adequate provision” to ensure data is being monitored for safety. During the trial, as part of the required continuing review process, IRBs typically request copies of the DMC’s recommendations to the sponsor. In this way, the IRB can leverage the work of an independent DMC and its recommendations to determine if there is any new information which may impact the IRB’s decision to approve the research to continue, require alterations to the research, inform participants of potential new risk information, or not approve the research to continue (21 CFR 56.109(f)). ConclusionIRBs do not see unblinded study data and are not in a position to know unilaterally if trials have met stopping rules. They must rely on review by the independent DMC, and other oversight committees, to work collaboratively to protect clinical trial participants. At Advarra, our IRB diligently reviews each trial’s data safety monitoring plan to ensure it is adequate to satisfy the FDA regulatory criteria. Many times, the safety monitoring “plan” will include an independent DMC, and in these circumstances, the IRB routinely verifies if the DMC recommends stopping the trial early or making any changes to reduce participant risk. The DMC and IRB are two committees, with different roles and focuses, both working together to independently oversee a clinical trial and the safety of the participants More insights on Advarra’s requirements for DMC can be found in our IRB Handbook for Investigators, Institutions, Sponsor, and Sponsor Representatives in CIRBI (login required). Have questions about how IRBs review plans for data monitoring? Get free answers to your most pressing research questions in 1 business day when you Ask the Experts-Ask Advarra.– ASK THE EXPERTS! Back to Resources
Data Monitoring Committees (DMCs) also known as Data Safety Monitoring Boards (DSMBs) and Data Monitoring and Ethics Committee (DMEC) play a vital role in the safety of clinical trials and also enhance the validity and integrity of the results collected from trials. While trial Investigators and Sponsors run the day-to-day management of clinical trials, DMCs make suggestions concerning the overall conduct of the trial. According to the International Conference on Harmonisation’s (ICH) guidelines on Good Clinical Practice (GCP) and Statistical Principles for Clinical Trials, Data Monitoring Committees (DMCs) are “an independent data monitoring committee that may be established by the sponsor to access at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, or modify or stop a trial.” Data Monitoring Committees (DMCs) are selected by trial Sponsors and are put in place to protect the interests of clinical trial participants and to provide integrity and credibility to the trials themselves. They have an advisory role and should be entirely independent from trial Sponsors and Investigators. DMCs should be the only individuals performing the interim analysis with access to data on the efficacy and safety of the investigational product and the clinical trials. Their independence from trial Sponsors and Investigators and the confidentiality of the interim data ensures that unreliable results won’t be spread around and taken as fact. It also reduces any prejudgements that can have a detrimental effect on enrolment and the flexibility to implement any modifications to the trial. DMCs can be objective in their recommendations and the trial Sponsors can make decisions without any bias or prior knowledge of the interim study results. Whether the DMCs advice is accepted, is entirely up to the trial Sponsors. The members of a DMC should include clinicians and at least one biostatistician with prior experience in dealing with clinical trial conduct, methodology and interim data analysis. DMCs are typically made up of at least 3 members, although larger groups can exist for bigger studies. Members of a DMC should be recruited under ‘independent scientist agreements’ which removes the risk of any conflicts of interest and emphasises that the DMC are independent from the trial Sponsor who use their scientific expertise to interpret the trial data without any bias. A DMC Charter is a document which defines the responsibilities of the DMC, their relationship with other trial components and the agenda for each meeting they hold. They also set the guidelines for statistical monitoring, ensuring confidentiality and communication, and an outline for the Open and Closed Reports that will be provided to the DMC. The guidelines set by the Charter should be discussed and approved by both the DMC and the trial Sponsors at the DMC Organisational Meeting which is held before the clinical trial takes place. |
Data monitoring committees (dmcs) are required for:
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