What PRAC's Flagging of Cenobamate Means for Drug Regulation

A new regulatory safety communication from the European Medicines Agency's Pharmacovigilance Risk Assessment Committee is prompting labelling updates and risk characterization changes for cenobamate (Ontozry), with direct implications for regulatory affairs professionals and those overseeing post-authorization compliance.1 Following a case review, the committee agreed to issue a direct healthcare professional communication after reports of severe liver injury, including hepatic failure, in patients taking the anti-seizure medicine. Most cases occurred in patients using cenobamate alongside other anti-seizure agents. This development signals a practical reminder of how post-market surveillance data can trigger cascading documentation obligations that extend well beyond medical affairs. These changes will touch quality management systems, batch release documentation, patient information leaflets, and any materials subject to regulatory review across multiple markets. The case also illustrates that post-authorization safety data can reframe a product's risk profile in ways not fully anticipated at initial approval, making robust pharmacovigilance infrastructure and responsive documentation workflows an operational necessity rather than a compliance formality.

How Are the Recommended Monitoring Requirements Changing?

Prescribers are now advised to perform liver function tests before initiating treatment and to continue monitoring throughout its duration.1 When a patient presents with symptoms such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice, prompt clinical evaluation and liver function testing are recommended. Patients should be counseled to seek medical attention immediately if such symptoms arise.

When liver injury is suspected or confirmed, dose reduction or discontinuation should be considered.1 The guidance aligns with the existing summary of product characteristics, which already cautions against abrupt discontinuation due to the risk of rebound seizures. Elevated liver enzyme levels have been listed in the product's prescribing information as a common side effect, occurring in up to 1 in 10 patients. Following the case review, the committee recommended that liver injury be added as a rare side effect, occurring in up to 1 in 1,000 patients, along with updated warnings directed at both patients and healthcare professionals.

The direct healthcare professional communication will be forwarded to the human medicines committee for adoption.1 Once approved, it will be distributed to healthcare professionals by the marketing authorization holder according to an agreed communication plan and published in national registers across EU member states.

How Else Is the EMA Developing Drug Processes and Regulations?

A separate but equally consequential development from recent regulatory activity concerns preclinical research methodology.2 On March 31, 2026, the human medicines committee issued a draft qualification opinion for a new approach that replaces standard animal control groups in dose-range finding studies with virtual control groups. The statistically derived comparators built this methodology with characterized historical control data validated through expert judgment. This signals a tangible shift in what regulators will accept as scientifically valid evidence in future medicine applications.

The immediate application is specific: dose-range finding studies in rats.2 This is just the initial step, as the committee has indicated that this qualification creates a blueprint for broader use, with potential future iterations applicable to toxicological studies for which control groups are routinely required. The cumulative reduction in animal use could be substantial.

The practical implication is that study designs incorporating virtual control groups, applied within the defined context of use, may now be submitted with a clearer path to regulatory acceptance.2 Human safety remains a non-negotiable threshold; any implementation must demonstrably avoid compromising study outcomes or downstream clinical trial safety.

Public consultation on the draft opinion runs until May 12, 2026.2 Organizations with relevant scientific expertise are encouraged to submit comments, making this an active window for industry input into a methodology that could meaningfully influence how non-clinical development is conducted across the sector.

References

1. European Medicines Agency. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 7-10 April 2026. Published April 10, 2026. Accessed April 10, 2026. https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-7-10-april-2026
2. European Medicines Agency. EMA consults on virtual control groups to help reduce animal use in medicines development. Published March 31, 2026. Accessed April 10, 2026. https://www.ema.europa.eu/en/news/ema-consults-virtual-control-groups-help-reduce-animal-use-medicines-development