Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
Fenfluramine demonstrated a clear clinical advantage in reducing convulsive seizures compared to placebo in two Phase 3 trials, with significant reductions in seizure frequency. Additionally, it may be more effective than the comparator, cannabidiol plus clobazam, although direct comparisons are limited. The evidence supports a strong therapeutic impact, particularly in patients who have not responded to standard treatments.
Cost effectiveness
The cost-effectiveness estimates for fenfluramine fall within the range considered acceptable by NICE, suggesting it provides good value for money. The committee noted that the ICER was within the range of £20,000 to £30,000 per QALY gained, which is typically acceptable for Healthcare resources.
Quality of life
The evidence indicates that fenfluramine may improve quality of life for patients with Dravet syndrome and their carers, as shown by improvements in PedsQL scores in one of the trials. However, the results were not statistically significant in the second trial, indicating moderate but not overwhelming evidence of benefit.
Supporting Domains
Safety and Adverse Effects
Fenfluramine has a manageable safety profile, with adverse events reported at similar rates to placebo. While some patients discontinued treatment due to adverse events, the overall incidence was low, indicating acceptable safety and tolerability.
Comparator Selection
The trials compared fenfluramine against appropriate standard care options, including placebo and the established treatment of cannabidiol plus clobazam. The committee agreed that these comparators were relevant and reflective of current clinical practice.
Patient Population and Subgroups
The trials included a representative population of children and young adults with Dravet syndrome, and the evidence considered various subgroups. However, there were some limitations in subgroup analyses, which slightly affect the generalizability.
Care Pathway Integration
Fenfluramine can be integrated into existing treatment pathways as an add-on therapy without requiring significant changes to current practices. The committee noted that it fits well within the standard care framework for Dravet syndrome.
Resource Use and Cost Implications
The budget impact of fenfluramine is manageable, and the committee noted that it is likely to provide net savings in the long term due to its effectiveness in reducing seizure frequency and associated healthcare costs.
Evidence Quality and Robustness
The evidence base is strong, supported by multiple Phase 3 trials with low bias risk. The committee found the overall quality of evidence to be robust, although some uncertainties remain regarding long-term effects.
Uncertainty, Sensitivity, and Broader Impacts
While there are some uncertainties regarding the long-term effects and the relationship between seizure frequency and mortality, the overall context supports the use of fenfluramine, particularly given the high unmet need in this patient population.
