Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
Cenobamate shows comparable efficacy to existing options, as it has not been directly compared with other antiseizure medicines. The evidence indicates that cenobamate reduces seizure frequency and increases the number of patients achieving seizure freedom, but the uncertainty in indirect comparisons and the lack of Phase 3 evidence limit the strength of the claim. The committee noted that the short-term clinical evidence is promising but does not demonstrate a clear edge over existing treatments.
Cost effectiveness
Cenobamate is considered cost-effective within the Healthcare framework, with an ICER of £20,522 per QALY gained, which is within acceptable thresholds. The committee acknowledged uncertainties in the economic model but concluded that cenobamate represents a good use of Healthcare resources compared to other treatments.
Quality of life
The evidence suggests that cenobamate may lead to improvements in quality of life by reducing seizure frequency, which is a significant concern for patients. However, the data on HRQoL improvements are not robust and primarily derived from indirect measures, indicating moderate benefits rather than substantial improvements.
Supporting Domains
Safety and Adverse Effects
Cenobamate has a generally acceptable safety profile, with adverse events similar to other add-on therapies. However, there are concerns regarding the long-term adverse effects and the potential for higher rates of treatment discontinuation due to adverse events, which necessitates careful monitoring.
Comparator Selection
The comparators used in the analysis were primarily third-generation antiseizure medications, which may not fully represent the range of available treatments. The committee noted that older medications, which are still in use, were not adequately considered, leading to potential gaps in the comparative effectiveness evidence.
Patient Population and Subgroups
The trials included a representative population of adults with drug-resistant focal seizures, which aligns well with the intended use of cenobamate. However, the exclusion of patients with psychiatric comorbidities may limit generalizability.
Care Pathway Integration
Cenobamate can be integrated into existing treatment pathways with minor adjustments, primarily due to its once-daily dosing regimen, which enhances adherence. The committee noted that it would be initiated in specialist epilepsy centers, which aligns with current practices.
Resource Use and Cost Implications
The resource use estimates were based on clinical expert opinion, which may overestimate costs. The committee expressed concerns about the accuracy of these estimates, indicating a moderate risk in the economic implications of adopting cenobamate.
Evidence Quality and Robustness
The evidence base includes two registrational trials and additional observational studies, but there are significant methodological limitations and potential biases. The reliance on indirect comparisons and the absence of long-term comparative data contribute to concerns about the robustness of the evidence.
Uncertainty, Sensitivity, and Broader Impacts
There are notable uncertainties regarding the long-term effectiveness and safety of cenobamate, particularly due to the lack of direct comparative evidence and potential biases in the economic model. The committee highlighted the need for further data to address these uncertainties.
