Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The clinical evidence for exa-cel is primarily based on the CLIMB SCD-121 trial, which was a single-arm study with a small sample size of 43 participants. While the trial showed promising results, with 96.6% of participants free from severe vaso-occlusive crises (VOCs) for at least 12 months, the lack of a comparator group and uncertainties regarding long-term efficacy limit the strength of the evidence. The committee noted that the treatment effect duration is unknown, and the trial’s follow-up period was relatively short, leading to concerns about the robustness of the findings.
Cost effectiveness
The cost-effectiveness estimates for exa-cel are highly uncertain, with the ICER exceeding the range typically considered acceptable by NICE. The committee recognized that while exa-cel has the potential to be cost-effective, the current evidence does not robustly support this conclusion due to uncertainties in the economic model and the assumptions made regarding treatment effects and complications.
Quality of life
The evidence suggests that exa-cel may lead to improvements in health-related quality of life, particularly for those experiencing recurrent VOCs. The committee acknowledged the significant negative impact of sickle cell disease on patients’ daily lives and noted that exa-cel could potentially alleviate some of these burdens. However, the exact impact on HRQoL remains uncertain due to the limited data available.
Supporting Domains
Safety and Adverse Effects
The safety profile of exa-cel appears acceptable, with adverse events primarily related to the HSCT procedure. The committee noted that while there are risks associated with the treatment, they are manageable and comparable to existing therapies. The absence of serious adverse events in the trial supports a favorable safety assessment.
Comparator Selection
The clinical trial for exa-cel was a single-arm study without a direct comparator, which raises concerns about the validity of the efficacy claims. The committee acknowledged that while standard care was referenced, the lack of head-to-head comparisons limits the ability to draw definitive conclusions about the relative effectiveness of exa-cel compared to existing treatments.
Patient Population and Subgroups
The trial population included patients aged 12 years and older with severe sickle cell disease, which aligns well with the intended use of exa-cel. The committee noted that the population is representative of those who would benefit from the treatment, although there are concerns about the generalizability of the results due to the small sample size and limited geographic diversity.
Care Pathway Integration
Exa-cel is designed to be integrated into existing care pathways for sickle cell disease, with no significant new infrastructure or training required. The committee noted that the treatment process aligns with current practices for stem cell collection and infusion, facilitating its adoption within the healthcare system.
Resource Use and Cost Implications
The introduction of exa-cel is expected to have a significant budget impact, particularly given its high list price of £1,651,000 per treatment. While the potential for reduced healthcare resource use due to fewer VOCs is acknowledged, the overall cost implications raise concerns about affordability and sustainability within the Healthcare.
Evidence Quality and Robustness
The evidence base for exa-cel is primarily derived from a single clinical trial with a small sample size and limited follow-up. While the trial design was appropriate for assessing initial safety and efficacy, the lack of robust long-term data and potential biases in the evidence limit its overall reliability. The committee emphasized the need for further data collection to strengthen the evidence base.
Uncertainty, Sensitivity, and Broader Impacts
There are significant uncertainties surrounding the long-term effectiveness of exa-cel, particularly regarding the durability of treatment effects and the potential for complications. The committee recognized that while exa-cel addresses a significant unmet need, the uncertainties in the evidence and economic modeling may restrict its use and acceptance within the healthcare system.
