DMC vs EAC: What’s the Difference?
Clinical trials can be complex. Multiple treatments arms, various dosing schedules and regimens, placebo controls, multifaceted endpoints, blinded study staff, pragmatic design elements, and multinational sites all fuel the complexity. In its March 2006 guidance Establishment and Operations of Clinical Trial Data Monitoring Committees, the U.S. Food and Drug Administration (FDA) solidified the need for sponsors to consider establishing independent committees to oversee certain aspects of clinical trials.
Around the same time, the terminology of data monitoring committee (DMC) and endpoint adjudication committee (EAC) started to infiltrate the clinical trial world. These committees had been around prior to guidance, but the March 2006 FDA guidance and similar guidance in July 2005 from the European Medicines Agency (EMA) solidified the need for these two groups. Over fifteen years later, most involved in clinical research have at least heard of EACs and DMCs, also known as clinical event committees (CECs) and data safety monitoring boards (DSMBs), respectively.
So what’s the difference between an EAC and a DMC? This blog outlines the requirements for each committee, what they do, and the critical roles each plays in keeping research participants safe and in advancing clinical research.
DMCs: The Macro View
It’s important to look at the aggregate, big picture during a clinical trial to understand how things are going overall. As the study goes on, researchers may be wondering:
- How do we know if the investigational product is working better than the placebo or comparator arm?
- Is the investigational product not working well, and the trial should stop early?
- Are more adverse events coming up than expected, causing us to change the protocol design or take a pause while we evaluate why this is occurring?
In many studies, researchers and sponsors do not have access to unmasked study information and so have no way to begin answering questions like these. As the trial continues, someone independent from those conducting the trial needs to monitor the unmasked data in a thoughtful, pre-planned, and unbiased way. This is usually the job of a DMC or DSMB.
The DMC is an independent group of experts conducting periodic review of the accumulated interim data during a clinical trial. Particularly in trials with a blind or placebo control, a DMC’s purpose is to review the unmasked, aggregate, worldwide trial data as it is collected. From there, members can detect and report safety concerns, early evidence of benefit or harm, and/or treatment futility using criteria outlined in the clinical trial protocol and DMC charter. Usually made up of five or six members, DMCs include biostatisticians and clinicians who all must be independent of those sponsoring, organizing, or conducting the trial.
In short, DMCs use statistical models to oversee research safety at a macro level. All the data is unmasked, aggregated, and analyzed per the protocol’s data safety monitoring plan and the DMC charter. If the DMC detects safety issues, futility, or other pre-defined criteria, they may recommend the sponsor halt the trial early or make safety changes in the protocol.
EAC: The Micro View
Converse to DMCs, EACs focus on the opposite end of the spectrum at the micro level. Today’s modern drug, biologic, and device treatments are highly complex with multiple and complicated modes of interaction within the body. The human body is also complex, each of us living with unique physical environments, various comorbidities, and different concomitant medications and medical histories.
Just as the practice of medicine is far from simple, in many clinical trials it can also be difficult and require a fair bit of medical judgment to determine if a certain medical event was related to the investigational drug or device – or some other confounding factor. Specific endpoints in the trial may also require expert medical judgment to determine if the participant’s event met the protocol’s pre-defined criteria.
The event evaluation and the subsequent determination of relatedness or endpoint completion can profoundly impact the statistical calculations regarding the investigational product’s safety and efficacy. Especially in rare disease or similar small population studies, a few adjudication decisions made one way or the other can mean the difference between potential product approval or denial.
Given the importance of these individual judgments, both FDA and EMA guidance on monitoring committees strongly encourage sponsors to have an independent group of experts conducting this important adjudication activity, to remove any perception of bias. This is where the independent EAC comes in.
EACs evaluate individual medical events to determine if the event characteristics meet the protocol’s defined endpoints or adverse event criteria. The committees are comprised of multiple medical experts who evaluate events occurring in the trial through a pre-defined adjudication process outlined in the protocol or EAC charter to render an option on the event. Depending on trial requirements, EACs may look at medical histories, various scans and images, and other participant information available from the sponsor or research site. Adjudication determinations about the individual events are then incorporated into the overall trial data, ultimately impacting the DMC’s analysis of aggregate trial-wide data.
A Note About the Regulatory Basis for DMC and EAC
U.S. FDA and the International Conference on Harmonisation Good Clinical Practice (ICH GCP) E6 (R2) require sponsors to monitor the safety of their trials. In the March 2006 guidance, FDA strongly suggests DMCs and DSMBs are an appropriate way for sponsors to fulfil this requirement. Additionally, EMA guidance from July 2005 has similar recommendations. Both regulatory agencies cover the importance of appropriate independent assessment and adjudication of certain outcome events in the trial and intimate independent endpoint adjudication committees as an appropriate framework.
Both FDA and EMA guidance do not prescribe operational specifics for the committees other than to strongly suggest the DMC and EAC oversight committees must be independent from those who sponsoring, organizing, or conducting the trial. In other words, the sponsor or contract research organization (CRO) is not in the best position to administer and control the DMC or EAC. As such, Advarra’s independent DMCs and EACs play an important role in providing independent oversight and both operate in accordance with both U.S. FDA and EU EMA guidance.
Completing the Research Oversight Environment
Both DMCs and EACs play an integral role in clinical research oversight and evaluation. DMCs take the worldwide, high-level perspective using advanced analytical methods to evaluate aggregate data. EACs dive deep into the micro level evaluation of specific events to make critical assessments, contributing to the broader trial data and ultimately determinations on safety and efficacy used by the regulatory agencies to determine approval.