Authors' objectives: To assess the effectiveness and cost-effectiveness of seven new drugs used for inoperable or metastatic malignant melanoma patients relative to each other in the Norwegian setting.

Authors' results and conclusions: RESULTS: Our results are based upon 17 randomized controlled trials. Our conclusions for the relative effectiveness of the included drugs or combinations of drugs are based upon network meta-analyses using both direct and indirect evidence with dacarbazine as a common comparator. We ranked the different treatments in terms of their likelihood of leading to the best results for each endpoint. The rankings were interpreted cautiously taking into account the quality of the evidence. The cost-utility analysis was based on a probabilistic discrete-time Markov cohort model. Our findings: For overall survival: Nivolumab and pembrolizumab in monotherapy, as well as nivolumab combined with ipilimumab, vemurafenib combined with cobimetinib, and dabrafenib combined with trametinib seemed to have a higher probability of good performance than the other available treatment strategies. For progression free survival: Dabrafenibin combination withtrametinib and vemurafenib combined with cobimetinib seemed to have a higher probability of good performance than the other available treatment strategies. For health related quality of life:Evidence from pairwise comparisons for four interventions reported better health related quality of life in the intervention groups. For serious adverse events: We could not establish any differences between the treatment strategies. However, pembrolizumab and nivolumab seemed to have a higher probability of fewer serious adverse events than the other treatment strategies. We assessed the quality of the evidence for overall survival and progression free survival from the network meta-analyses to be moderate or high for the majority of our comparisons. For serious adverse events, we assessed the quality to be low or very low in most of our assessments. The analysis of cost-effectiveness was conducted using the maximum pharmacy retail prices, due to the fact that negotiated discounts are hidden from the general public as per contract between the Drug Procurement Cooperation system and the manufacturers. None of the interventions are cost-effective at the maximum pharmacy retail prices, and the budget impact if the interventions are accepted in clinical practice are substantial. Drug price reductions in the region of 63 to 84 percent would be necessary to improve the cost-effectiveness and reduce the budget impact. CONCLUSION: All conclusions are given with respect to the current state of the evidence and with the reservation that new evidence from randomized controlled trials can change the ranking of the interventions both with regards to effectiveness and cost-effectiveness (one of the interventions still do not have marketing authorization). None of the interventions are cost-effective at the maximum pharmacy retail prices. The budgetary impact of accepting some or all of the new interventions in clinical practice can be substantial, potentially diverting resources away from other interventions or treatment areas with better cost-effectiveness. The budgetary impact and incremental cost-effectiveness ratios can however be reduced through price reductions. We believe that drug price reductions in the region of 63 to 84 percent, depending on drug, would be necessary for the interventions to represent cost-effective use of resources in the Norwegian setting. We find it difficult to separate the new PD-1 immunotherapies nivolumab and pembrolizumab with respect to cost-effectiveness. If the new immunotheraphies in monotherapy are accepted in clinical practice, we expect increased effectiveness compared to ipilimumab in monotherapy, but at an increased cost. The potential budgetary savings with price reductions from the maximum pharmacy retail price may be as high as NOK 131 million per year across the immunotherapies, if a cost-effectiveness level of NOK 500,000 per gained quality adjusted life year is assumed. Based on the cost-effectiveness results, we cannot argue that any of the BRAF or MEK inhibitor monotherapies (dabrafenib, vemurafenib, trametinib), should be preferred over another, or that any BRAF/MEK combination (dabrafenib and trametinib or vemurafenib and cobimetinib), should be preferred over another. However, the combination therapies are more likely to give the highest quality adjusted life year gains in the long run, at an increased cost. For the BRAF/MEK inhibitors, the potential budgetary savings with price reductions may be as high as NOK 147 million per year.

Authors' methods: In this health technology assessment, clinical effectiveness was measured in terms of overall survival, progression free survival, health-related quality of life and serious adverse events. In the economic evaluation the primary endpoint was the incremental cost-effectiveness ratio with effectiveness measured in quality-adjusted life-years. Results were also presented in life years gained, in net health benefits, scatterplots, probability of being cost-effective and value of information analysis. We performed a systematic search for randomized controlled trials in February 2015 in relevant bibliographic databases, Google Scholar and websites of selected health technology assessment agencies. We updated the search in September 2015. We contacted relevant pharmaceutical companies to obtain additional information. Two reviewers worked independently to identify relevant publications. One review author extracted data from the included references and another review author verified the data. We performed network meta-analyses where appropriate according to population, intervention, control and outcome. We ranked the different treatments in terms of their likelihood of leading to the best results for each endpoint. This we did by help of the surface under the cumulative ranking curve (SUCRA). The quality of the direct evidence, indirect evidence, and the combined evidence from the network meta-analyses were evaluated by two review authors using the GRADE working group approach for network meta-analysis. Our cost-utility analysis were based on a probabilistic discrete-time Markov cohort model with three health states, progression free survival, progressed disease and death. We adjusted the baseline transition probabilities with the hazard ratios from the network meta-analysis. Clinicians in the field provided information relevant for the estimation of costs as well as modelling assumptions. Due to the fact that negotiated discounts are hidden from the general public, as per contract between the Drug Procurement Cooperation system and the manufacturers, the analysis of cost-effectiveness was conducted using the official maximum pharmacy retail prices.

Project Status: Completed

Year Published: 2015

URL for published report: https://www.fhi.no/en/publ/2015/a-health-technology-assessment-of-the-new-drugs-for-inoperable-or-metastati/

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Norway

Pubmed ID: 28510382

Organisation Name: Norwegian Institute of Public Health

Contact Address: P.O. Box 222 Skoyen, N-0123, Oslo