Authors' results and conclusions: Results clinical literature review: Three RCTs compared Trikafta with standard of care (placebo) in patients aged 6 and older with cystic fibrosis who have one F508del mutation and one minimal function mutation in the CFTR gene (F/MF). In addition, for patients aged 6 and older with cystic fibrosis who are homozygous for F508del mutation (F/F), a network meta-analysis is available comparing Trikafta with standard of care (placebo). These RCTs and the network meta-analysis provide consistent high-quality evidence for the efficacy of Trikafta in comparison with standard of care up to 24 weeks for the outcomes reported in the trials. Beyond 24 weeks, an open-label extension of two RCTs provides non-randomized follow-up data up to 48 weeks, and appears to confirm the effectiveness of Trikafta. Trikafta also has been shown to be a safe intervention (with follow-up up to 96 weeks), with most of the reported adverse events being related with the underlying disease (i.e. cystic fibrosis). Adverse events that warrant attention are psychiatric disorders, headache and gastrointestinal symptoms because of frequency, and rash, hepatic adverse events and distal intestinal obstruction syndrome because of severity. No studies were identified for the following populations and/or outcomes: RCTs that compare Trikafta with standard of care (placebo) in patients aged 6 and older with cystic fibrosis who are homozygous for F508del mutation (F/F), who have one F508del mutation and one residual function mutation in the CFTR gene (F/RF), or who have one F508del mutation and one gating mutation in the CFTR gene (F/G); data on mortality as an efficacy outcome; data on quality of life measured with a generic utility instrument; effectiveness data based on RCTs beyond 24 (- 48) weeks; safety data beyond 96 weeks. Exploratory economic evaluation For the economic part, we note that there are a lot of large uncertainties for calculating the cost-effectiveness of Trikafta. The presence of uncertainty is common in economic evaluations. However, in this case, there is high uncertainty for all key variables: the magnitude of the impact on mortality, the (longer-term) impact on ppFEV1 and the associated impact on quality of life and disease management costs. These major uncertainties were also highlighted in previous HTA reports. To deal with these uncertainties, several scenarios were developed modelling hypothetical mortality hazard ratios. Based on information from previous HTA reports, assumptions were also modelled regarding the impact on the decline in ppFEV1, QoL, disease management costs and lung transplants. Results were also calculated for different time horizons, discount rates for costs and effects and Trikafta price discounts. Given the high uncertainty for the different input variables, it was not possible to indicate one specific base case analysis. The results for the different scenarios were presented side by side with the intention of displaying the possible ICERs and identifying the most determining variables. Across all scenarios (excluding two discount rate scenarios), when applying the official list price for Trikafta, there was no average ICER that was lower than CHF1 million per quality-adjusted life year (QALY) gained. This result was in line with the results of three of the four identified HTA reports. The main reason is the annual cost of about CHF228 000 per patient and the chronic use of this intervention. Only when combining a number of 'optimal' scenarios (a mortality hazard ratio of 0.1, an optimistic evolution in ppFEV1 and a lower disease management cost when using Trikafta) and a price discount of 90%, an ICER of about CHF100 000 per QALY gained was obtained. Given the large uncertainties regarding several determining variables, future research on the (longer-term) impact of Trikafta on mortality, ppFEV1, quality of life and disease management costs may shed more light on the cost-effectiveness of this intervention. Notwithstanding, the exploratory scenario analyses performed show that the cost-effectiveness is mainly determined by the annual recurrent cost for Trikafta. Swiss-specific data are available describing the number of homozygous and heterozygous patients. At the official list price, the total budget impact over 5 years for treating 69 F508d homozygous patients aged 6-11 years would be about CHF78 million. This would become about CHF55 million if substitution costs for other CFTR modulators (Kalydeco, Orkambi and Symdeko) are taken into account. For treating another 70 F508del heterozygous patients aged 6-11 years, the total budget impact over 5 years would be about CHF79 million or CHF78 million, without and with inclusion of substitution costs, respectively. This budget impact should not be separated from the potential budget impact to treat patients over 12 years old (305 homozygous and 266 heterozygous patients). Under full market penetration, treating all homozygous patients (n = 374) with Trikafta would result in a 5-year budget impact of about CHF426 million (or CHF397 million after subtraction of substitution costs). This would be CHF383 million or CHF368 million, respectively, for treating 336 heterozygous patients. Conclusion The evidence on short-term outcomes provides consistent high-quality evidence for the efficacy of Trikafta. However, evidence on important outcomes such as mortality, the (longer-term) impact on ppFEV1 and the associated impact on quality of life and disease management costs is lacking. Notwithstanding, the exploratory economic evaluation shows that ICERs exceed CHF1 million per QALY gained in just about all scenarios. Only in an 'optimal' scenario in combination with a 90% price discount, the ICER potentially approaches about CHF100 000 per QALY gained. The budget impact depends, among other things, on the target population to be taken into account. Both cost-effectiveness and budget impact are mainly determined by the annual cost of Trikafta and its chronic use.

Authors' methods: To provide relevant input for the economic analysis of this report, a pragmatic systematic literature review was done to evaluate the efficacy and safety of Trikafta. A systematic literature review for economic evaluations is also performed. Targeted searches were performed for specific input variables, such as quality of life. The information from this literature review and the critical assessment performed by other health technology assessment (HTA) assessors provide information to set up an (exploratory) economic evaluation for the Swiss setting.

Project Status: Completed

URL for project: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-projekte/trikafta.html

Year Published: 2024

URL for published report: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/e0002tkcf-health-economic-evaluation.pdf.download.pdf/e0002tkcf-health-economic-evaluation.pdf

English language abstract: An English language summary is available

Publication Type: Other

Country: Switzerland

Organisation Name: Swiss Federal Office of Public Health (FOPH)

Contact Address: Federal Office of Public Health, Schwarzenburgstrasse 157, CH-3003 Berne, Switzerland

Contact Name: Stephanie Vollenweider

Contact Email: hta@bag.admin.ch

Copyright: Swiss Federal Office of Public Health