Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The clinical effectiveness of ivosidenib was demonstrated in the ClarIDHy trial, a Phase 3 study that showed significant improvements in progression-free survival (PFS) and overall survival (OS) compared to placebo. The hazard ratios for PFS and OS were 0.37 and 0.49, respectively, with p-values indicating strong statistical significance. However, the lack of direct comparison with mFOLFOX limits the rating to A+.
Cost effectiveness
The cost-effectiveness analysis indicates that the ICER for ivosidenib is within the acceptable range of £20,000 to £30,000 per QALY gained, particularly when considering the severity weight applied to QALYs. This suggests that the treatment is marginally cost-effective, justifying a rating of A.
Quality of life
The evidence suggests that ivosidenib is well tolerated and offers a more convenient oral administration compared to mFOLFOX, which has significant side effects. While specific HRQoL data were not detailed, the qualitative feedback from patient experts indicates a positive impact on quality of life, justifying a rating of A.
Supporting Domains
Safety and Adverse Effects
Ivosidenib has a favorable safety profile with mostly mild to moderate adverse events reported. The patient expert noted that it is generally well tolerated compared to traditional chemotherapy, which has significant side effects. This supports a rating of A+.
Comparator Selection
While the committee acknowledged that mFOLFOX and best supportive care were appropriate comparators, the lack of direct head-to-head trials with mFOLFOX raises concerns about the robustness of the evidence. Thus, a rating of B++ is appropriate.
Patient Population and Subgroups
The trial population included adults with unresectable or metastatic cholangiocarcinoma with an IDH1 mutation, which is representative of the intended patient population. The committee noted that the subgroup used for the indirect comparison reflected Healthcare clinical practice, supporting a rating of A.
Care Pathway Integration
Ivosidenib can be integrated into existing treatment pathways with minimal disruption, as it is an oral treatment that does not require new infrastructure or extensive training. This ease of integration supports a rating of A+.
Resource Use and Cost Implications
The economic model indicates that the budget impact is manageable, and the treatment is expected to be resource-efficient. The committee’s conclusions about the ICER being within acceptable limits further support a rating of A.
Evidence Quality and Robustness
The evidence base is primarily derived from a well-conducted Phase 3 RCT, with additional supportive data from indirect comparisons. While there are some concerns regarding the indirect treatment comparison, the overall quality of evidence remains strong, justifying a rating of A.
Uncertainty, Sensitivity, and Broader Impacts
There are notable uncertainties regarding the indirect treatment comparison and the selection of subgroups, which could impact the robustness of the conclusions. While the unmet need is significant, these uncertainties warrant a rating of B++.
