Clinical Endpoint Adjudication Committees: Not Just for “Endpoints”
As the name implies, endpoint adjudication committees adjudicate, or pass judgment, on endpoints in a clinical trial. But what else do these important committees look at? This blog outlines some of the critical events where endpoint adjudication committees (EACs) – also known as clinical event committees (CECs) – can be used to look at more than just “endpoints” in clinical research.
EAC Versus CEC
If you are not familiar with what an EAC does and the value they bring to clinical research, read our blog DMC vs EAC: What’s the Difference? to learn more.
In its March 2006 guidance, Establishment and Operations of Clinical Trial Data Monitoring Committees, the U.S. Food and Drug Administration (FDA) solidified and reinforced the need for clinical trial sponsors to consider establishing certain independent committees to provide independent oversight and insights for clinical trials.
Thus, EACs were introduced to industry, highlighted as a way for sponsors to ensure their research plans incorporate appropriate independent medical assessments and adjudication processes. However, some sponsors already had individuals or committees formulated to look at clinical events during research, and the CEC terminology stuck around.
At Advarra, we primarily use the terminology of EAC, as that is what’s used in the regulatory guidance. In practice, EAC and CEC are synonymous.
Adjudicating Certain Research Events Requires Medical Judgment
Many clinical events result in clear determinations, are easily discernible, and are measurable with defined thresholds by calibrated instrumentation and lab test. Defined thresholds may answer questions such as:
- Did the blood pressure exceed a certain amount?
- Was the creatinine level in the blood under a certain number?
- Did the person test positive via a polymerase chain reaction (PCR) test for the virus on or over day 15?
- Has the person taken a certain drug in the last 90 days prior to enrollment?
None of these examples would require medical judgment to discern; they are all binary yes/no, easy to document, and are definite questions.
Undoubtedly though, not all events occurring in clinical trial conduct are this clear cut. Just as the practice of medicine is multifaceted, many times in research, substantial medical judgement needs to be applied.
In medical practice, there is room for practice, opinion, or judgment. When you are talking about clinical research, regulatory guidance makes clear that those decisions in the trial requiring medical judgement to adjudicate should be independent.
Unlike in medical practice, where a physician may make their own judgment and then proceed to treat based on that opinion, these research decisions should be adjudicated or reviewed by someone besides those sponsoring, organizing, or conducting a trial.
Common areas where EAC or CECs would get involved as an independent adjudicator of events to provide expert assessment back to the sponsor include:
Eligibility and Randomization
Inclusion and exclusion criteria often contain determinations on ranges of disease progression, comorbidity severity, and other judgments requiring medical expertise. There are occasions where potential participants are on the cusp of the inclusion and exclusion criteria – in these cases, judgment helps determine if the protocol is safe for them.
Increasingly, sponsors are turning to trusted independent EAC/CECs to make these determinations, rather than the local principal investigator (PI) or the sponsor’s medical director. The PI and medical director aren’t unqualified; rather, by using an EAC/CEC, the sponsor can eliminate the perception of bias in the evaluations.
Because the EAC/CEC is comprised of therapeutic experts, the level of expertise is increased for these decisions. Not only can eligibility and randomization decisions profoundly impact a participant’s safety, they can also skew the overall trial data if judgments are not consistent or are influenced by the bias to include more participants.
Adverse Event Causality
Was an adverse event (AE) or some other event caused by the study drug or device? A lot goes into those assessments. A participant’s overall medical history, comorbidities, concomitant medications, and environmental factors will potentially influence the event’s causality evaluation and relatedness to the investigational product (IP).
These evaluations, to the extent medical judgment is needed, should be done by an independent committee, looking at the clinical event and adjudicating a determination. Side effects and unexpected events play a critical role (along with efficacy) when regulators are considering approval. Using an independent committee to reach consensus and eliminate the perception of bias in the evaluation may influence how regulators view the data.
Safety and Continuation
EACs and CECs can also evaluate overall participant safety and ongoing participation in a research trial. These types of assessments are more common in oncology and other conditions where participants are dealing with severe illness. An EAC/CEC is primarily responsible for evaluation of defined clinical endpoints. These endpoints help the sponsor evaluate continuation for a participant in the study.
The PI has the primary authority and responsibility to monitor participants and pull them from the study if there are safety concerns. However, having a periodic independent assessment regarding a participant’s safety as they continue in research can add value to the study, aiding in eliminating the perception of bias.
Having a trusted independent group of experts involved in the study can add expertise, reassure investigators they are making the right calls, and eliminate the perception of bias. All are good and necessary activities to support public trust in research and provide appropriate safety oversight for participants.
Sponsors should plan early for how they can leverage an independent EAC or CEC and work with that partner to develop and define a charter that complements the protocol design.