Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The clinical trial evidence from two Phase 3 randomized controlled trials (SIOPEL 6 and COG ACCL0431) demonstrates a clear clinical advantage of anhydrous sodium thiosulfate in reducing the incidence of hearing loss caused by cisplatin chemotherapy. In SIOPEL 6, the incidence of hearing loss was 63.0% in the cisplatin-only group compared to 32.7% in the group receiving both cisplatin and anhydrous sodium thiosulfate (relative risk 0.52, p=0.002). Similarly, COG ACCL0431 showed a reduction from 56.4% to 28.6% (odds ratio 0.27, p=0.0039). These results indicate significant improvement in primary outcomes, although overall survival data was not statistically significant, which introduces some uncertainty.
Cost effectiveness
The cost-effectiveness estimates for anhydrous sodium thiosulfate fall within the acceptable range for Healthcare resources, particularly after the company revised its base-case model and increased the patient access scheme discount. The committee concluded that the ICER was acceptable, considering the significant unmet need for preventing cisplatin-induced hearing loss, which supports its cost-effective use.
Quality of life
The evidence suggests that anhydrous sodium thiosulfate may improve quality of life by preventing hearing loss, which is crucial for speech and language development in children. The model incorporates health utility values that reflect the benefits of reduced hearing loss severity, indicating moderate improvements in HRQoL. However, specific validated tools measuring HRQoL outcomes were not extensively detailed in the trials.
Supporting Domains
Safety and Adverse Effects
The safety profile of anhydrous sodium thiosulfate appears acceptable, with adverse events primarily being mild or moderate. The trials did not report significant severe adverse events, indicating a good tolerability compared to existing therapies. However, the committee noted that the evidence on adverse effects was not exhaustive.
Comparator Selection
The treatment was compared against standard cisplatin chemotherapy in both trials, which is appropriate given the context of preventing hearing loss. The use of relevant comparators strengthens the evidence base, although the committee acknowledged some limitations in the generalizability of the results due to differences in trial populations.
Patient Population and Subgroups
The trials included a representative population of children aged 1 month to 18 years with localized solid tumors, which aligns with the intended use of the therapy. However, there were concerns regarding the generalizability of results from mixed populations in COG ACCL0431, which included both localized and metastatic cases.
Care Pathway Integration
Anhydrous sodium thiosulfate can be integrated into existing care pathways with manageable adjustments, such as timing of administration relative to cisplatin. The committee noted that protocols are being revised to minimize delays in administration, indicating a good fit within current clinical practices.
Resource Use and Cost Implications
The economic model suggests that the adoption of anhydrous sodium thiosulfate will not impose an unsustainable budget impact on the Healthcare, especially with the negotiated discount. The potential for reduced costs associated with managing hearing loss further supports its economic viability.
Evidence Quality and Robustness
The evidence is derived from two Phase 3 trials, which are robust in design. However, there are some uncertainties regarding the small sample sizes and the use of different grading scales for hearing loss, which could affect the reliability of the findings. Overall, the evidence is credible but has some limitations.
Uncertainty, Sensitivity, and Broader Impacts
While there are uncertainties regarding the overall survival impact and the applicability of trial results to the Healthcare, the committee acknowledged the significant unmet need for preventing hearing loss in children undergoing cisplatin treatment. This context mitigates some of the uncertainties.
