Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The clinical effectiveness of ganaxolone is uncertain, as the evidence from the Marigold trial indicates a mean decrease of 14% in seizure frequency compared to a 65% increase in the placebo group. While there is some evidence of a reduction in seizure frequency, the committee expressed concerns about the reliability of these results due to potential biases and the natural variability of seizure frequency. The lack of robust long-term data further undermines the strength of the evidence.
Cost effectiveness
The cost-effectiveness estimates for ganaxolone are deemed unreliable due to structural uncertainties in the economic model. The committee noted that the ICERs presented were not reflective of the uncertainties in the modelling, and there was insufficient evidence to establish that ganaxolone is cost-effective compared to usual care.
Quality of life
The evidence regarding HRQoL is derived from utility values based on proxy conditions, which introduces significant uncertainty. The Marigold trial did not collect direct HRQoL data, and the estimates used may not accurately reflect the impact of ganaxolone on quality of life for patients with CDD. The committee acknowledged the limitations of the utility data and the potential for overestimation of benefits.
Supporting Domains
Safety and Adverse Effects
Ganaxolone has an acceptable safety profile, with adverse effects primarily being mild to moderate. The committee noted that while there are concerns regarding polypharmacy and potential adverse effects, the overall safety profile is comparable to existing treatments.
Comparator Selection
The trial compared ganaxolone to placebo plus usual care, which is acceptable but does not include head-to-head comparisons with other standard treatments for CDD. This limits the ability to fully assess its relative effectiveness against existing options.
Patient Population and Subgroups
The trial population is representative of the intended patient population, including children aged 2 years and older with CDD. However, there are limitations regarding the generalizability of the findings to all patients with CDD due to the rarity of the condition.
Care Pathway Integration
Ganaxolone is positioned as an add-on treatment to existing antiseizure medications, which aligns well with current clinical practice. The integration into care pathways is feasible with minor adjustments required for monitoring and administration.
Resource Use and Cost Implications
The economic model indicates a notable cost burden associated with ganaxolone, but the exact implications are uncertain due to the lack of reliable cost-effectiveness estimates. The committee noted that the model may not fully capture the resource implications of treatment.
Evidence Quality and Robustness
The evidence base is limited, with concerns regarding the robustness of the clinical trial data and the economic model. The committee highlighted significant uncertainties and biases that affect the overall credibility of the evidence.
Uncertainty, Sensitivity, and Broader Impacts
There are high levels of uncertainty surrounding the treatment effects and cost-effectiveness of ganaxolone. The committee noted that the rarity of CDD complicates evidence generation and increases the uncertainty in the decision-making process.
