The main evidence for cenobamate came from 2 registrational trials, C013 and C017. These are multinational, multicentre, double-blind trials that compared cenobamate with placebo in a total of 659 adults (aged 18 to 70) with drug-resistant focal seizures despite treatment with at least 1 antiseizure medicine in the last 1 or 2 years, who had 1 to 3 concomitant medicines at baseline that continued during the trial (background therapy). People with progressive central nervous system disease or 'psychiatric illness, psychological, or behavioural problems' were excluded from the trials. Short-term clinical evidence shows that cenobamate reduces the number of seizures. Longer-term effectiveness and safety evidence of cenobamate comes from 2 open-label single-arm observational studies (C017-OLE and C021). The results showed that 23.2% of people were seizure free for at least 1 year during the C017 OLE study. It is uncertain how this compares with other antiseizure medicines because cenobamate has not been directly compared with them. The results of an indirect comparison are uncertain because the clinical trials included are short and have different designs. Because it is unclear how the benefit of cenobamate compares with its risks, it should only be started in a tertiary epilepsy service. The committee considered the cost effectiveness of cenobamate compared with other third generation medicines (brivaracetam acetate, eslicarbazepine acetate, lacosamide and perampanel). It recognised the limited amount of long-term evidence available, the uncertainty about cenobamate's adverse effect profile and the omission of relevant comparators. In the company's base case, cenobamate dominates all other comparator treatments (that is, it is more effective and less costly than comparators). In the scenario using the Jacoby study for resource use assumptions, cenobamate was more effective and more costly than all other comparator treatments. This resulted in an incremental cost-effectiveness ratio (ICER) of £20,522 per quality adjusted life year (QALY) gained. The committee considered that the Jacoby resource use estimates were likely to be an underestimate of costs and therefore considered this to be the highest value in the range of probable ICERs. In addition, there were potential uncaptured benefits that were not included in the ICER, such as improvement in carer utility. Considering this, the committee concluded that cenobamate is a cost-effective use of NHS resources for treating drug-resistant epilepsy despite significant uncertainty in the clinical data and comparisons with other treatments. It recalled the clinical experts' comments that cenobamate may be used earlier in the pathway if shown to be effective and safe in clinical practice. The committee considered that it had not seen any evidence to support its use earlier in the pathway. It agreed that it should only be used as an add-on treatment after at least 1 add-on treatment had not controlled seizures and that treatment should be started in specialist epilepsy centres.