Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
Fenfluramine demonstrated a moderate benefit in reducing drop seizures compared to standard care, with a median percentage reduction of 26.5% in the primary clinical trial. However, the evidence is limited by the lack of direct head-to-head comparisons with cannabidiol plus clobazam, leading to uncertainty about its relative effectiveness.
Cost effectiveness
The cost-effectiveness estimates for fenfluramine are uncertain, with the economic model suggesting similar or lower costs compared to cannabidiol plus clobazam. However, the high level of uncertainty in the model parameters and assumptions raises concerns about its overall cost-effectiveness.
Quality of life
The evidence on HRQoL improvements is minimal and largely based on indirect measures. While there are indications of some quality of life benefits, the data lacks robustness and does not show significant improvements across validated instruments.
Supporting Domains
Safety and Adverse Effects
Fenfluramine has an acceptable safety profile, with most adverse events being mild to moderate, such as decreased appetite and drowsiness. Serious adverse events were rare, indicating a good tolerability compared to existing therapies.
Comparator Selection
The primary comparator, cannabidiol plus clobazam, is appropriate; however, the inclusion of standard care as a comparator is less robust due to its heterogeneous nature and the uncertainty surrounding its efficacy.
Patient Population and Subgroups
The trial population is broadly representative of the intended patient population with Lennox-Gastaut syndrome, including a range of ages and treatment histories, which supports generalizability.
Care Pathway Integration
Fenfluramine can be integrated into existing care pathways with minor adjustments, as it is recommended as an add-on therapy to current antiseizure medications without requiring significant changes to clinical practice.
Resource Use and Cost Implications
While the initial budget impact appears manageable, the potential for high resource use due to ongoing monitoring and the uncertainty in cost-effectiveness estimates raises concerns about long-term sustainability.
Evidence Quality and Robustness
The evidence base includes a Phase 3 RCT, but there are significant limitations in the data quality, including reliance on indirect comparisons and potential biases in the economic model.
Uncertainty, Sensitivity, and Broader Impacts
There are notable uncertainties regarding the clinical effectiveness and cost-effectiveness of fenfluramine, particularly due to the heterogeneity of the comparator treatments and the assumptions made in the economic model.
