Why Device, Diagnostic, and Digital Therapeutic Research Needs Endpoint Adjudication
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 sponsors to consider establishing certain independent committees to provide independent oversight and insights for clinical trials. The term “endpoint adjudication committee” (EAC) (also known as a “clinical event committee” or CEC) started to infiltrate the device research world, and FDA began encouraging device developers to ensure their research plans incorporated appropriate independent medical assessments and adjudication.
So why would a device clinical trial need an EAC or CEC? This blog explains how device developers utilize EACs and CECs to enhance their development team’s expertise, protect participants, and move research along through regulatory approval safer, smarter, and faster.
What is an EAC/CEC?
In a nutshell, endpoint adjudication committees and clinical event committees provide expert medical judgment to determine if a research participant has met a protocol-defined endpoint. Complex clinical trials often require a professional assessment to determine if an event truly meets the protocol endpoint criteria, or if it was caused by underlying medical conditions, comorbidities, or other factors.
This oversight may also be necessary when specific therapeutic expertise is needed beyond what the principal investigator or sponsor’s medical monitor can offer. The number of participants meeting an endpoint is essential to evaluating the safety and/or efficacy of an investigational compound or device. To learn more, check out our blog DMC vs EAC: What’s the Difference?
A Quick Note on the Regulatory Term “Devices”
This blog specifically refers to “devices” in research. Keep in mind that in the regulatory worldview of the U.S. FDA and EU European Medicines Agency (EMA), the term “devices” covers a lot of different items. According to section 201(h) of the Food, Drug, and Cosmetics (FD&C) Act, a “device” can be “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part” which meets certain criteria regarding the device’s intended purposes and how primary intended purposes are achieved (namely that the device “does not achieve its primary intended purposes through chemical action with or on the body…and which is not dependent upon being metabolized for the achievement of its primary intended purposes”).
What specifically does the FDA regulate as a device? We know it covers instruments and contrivances, but let’s talk specific examples. Some common items include, but aren’t limited to:
- Digital therapeutics (e.g., mobile health [mHealth] apps)
- Diagnostic assays
- Laboratory developed tests (LDTs) (e.g., advanced genomic analysis)
- Traditional devices, including:
- Cranial stimulation
- Laser surgery tools
- Electronic toothbrushes
So when we talk about “devices,” it can sometimes be challenging to apply the regulations to a specific device, because we’re describing a pretty diverse landscape.
Enhance Device Developer’s Medical Expertise
Most device developers likely do not have a worldwide team of medical experts on staff with experience in all possible therapeutic disciplines. However, it is critically important for developers to have access to such diverse therapeutic expertise.
For instance, say you need to determine if your digital therapeutic device caused a participant’s seizure, or if it occurred because of some underlying medical condition. You would likely need an experienced neurologist to evaluate the event. Or, for example, you may need an experienced neuropsychologist to determine if your mHealth app was responsible for a participant’s improved cognitive function, or if it was the result of concomitant medications they were on or other environmental factors.
Many device developers are skilled in application development, design, and manufacturing. But they may not necessarily have all the requisite medical expertise to evaluate adverse event causality, or to adjudicate complex endpoints where medical judgment is needed. Yet, in order to secure regulatory approval from the agencies to conduct research – and in some cases ethics approval from the institutional review board (IRB), research ethics board (REB), or ethics committee (EC) – device developers must have access to this deep and broad medical expertise.
Independent EACs and CECs provide device developers with the necessary expertise to augment the research team for a given protocol or broader development program. CECs and EACs are specifically and carefully designed with the appropriate experts who work with the sponsor according to the committee’s charter in the evaluation of research events. They can make determinations regarding adverse event causality, relatedness, and seriousness, as well as provide an evaluation of complex endpoints requiring medical judgment.
And importantly, independent EACs provide a mechanism for device developers to demonstrate to regulators that appropriate safety oversight is in place for the device research.
Independent Assessment Eliminates Perception of Bias
Today’s devices can be highly complex with unique modes of interaction within the body. The human body is a complicated place; each of us has unique physical environments we live in, various comorbidities, and different concomitant medications and medical histories – all of which affect how devices may impact us.
Determining if a device is working as intended, or if some other confounding medical issue is driving the outcome, can be difficult. Medical judgment is often needed to determine if a certain medical event was related to the device or some other confounding factor. Specific endpoints in the trial may also require expert medical judgment to determine if the participant’s results meet the protocol’s pre-defined endpoint.
The evaluation of events and the subsequent determination of relatedness or endpoint completion can profoundly impact the statistical calculations regarding the investigational device’s safety and efficacy. A few adjudication decisions one way or the other by the medical experts can mean the difference between potential product approval, or not.
Given the importance of these individual endpoint judgments in demonstrating safety and efficacy, both FDA and EMA have guidance strongly encouraging sponsors to have an independent group of experts separate from those sponsoring, organizing, or conducting the trial to conduct this important adjudication activity. By engaging an independent EAC, sponsors can eliminate the perception of bias and confidently reassure regulators regarding the medical evaluations and judgments incorporated into the research results.
Whether you are developing a digital therapeutic for ADHD, precision genomic assays, the next life-altering medical device, and any type of device in between, someone needs to provide an independent assessment if your investigational device is working as anticipated.
CECs and EACs provide device developers with an independent mechanism to both expand the therapeutic expertise of their own research team and eliminate the perception of bias when interpreting endpoints. With the help of a qualified EAC/CEC and access to a worldwide network of clinicians in all therapeutic areas, sponsors can move device research forward more quickly and with greater confidence.