The committee concluded that a discount rate of 3.5% was appropriate for this technology appraisal. Found inside – Page 793A recent phase II clinical trial has investigated the effects of combining lumacaftor with ivacaftor in the treatment of patients with the ΔF508 mutation ... 1136/16 Lumacaftor with ivacaftor film-coated tablet (Orkambi®) for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who are homozygous for the F508del mutation in the CF transmembrane conductance regulator (CFTR) gene (May 2016) The appraisal committee reviewed the data available on the clinical and cost effectiveness of lumacaftor–ivacaftor, having considered evidence on the nature of cystic fibrosis in people who are homozygous for the F508del mutation and the value placed on the benefits of lumacaftor–ivacaftor by people with the condition, those who represent them, and clinical experts. It noted that the ERG's sensitivity analysis showed that the incremental cost-effectiveness ratio (ICER) for lumacaftor–ivacaftor plus standard of care compared with standard of care alone ranged from £135,500 to £459,000 per quality-adjusted life year (QALY) gained. Ivacaftor 125 mg; Lumacaftor 200 mg; 112: tablet (POM) £8000.00 (Hospital only) — — Granules All products. (2015) showed differences in health-related quality of life measured by the EQ‑5D for 3 levels of cystic fibrosis severity as measured by ppFEV1, and when these utility data were included in the company's economic model, the base-case ICER increased by £65,000 per QALY gained. 27 July 2016. The patient experts highlighted that managing cystic fibrosis is relentless and can take up 2 or more hours of the person's time each day. The committee concluded that the rate of ppFEV1 decline was age dependent for all people with cystic fibrosis, irrespective of treatment. The committee heard from the clinical experts that up to 20% of people in the Cystic Fibrosis Registry have mild disease, and that cystic fibrosis in people homozygous for the F508del mutation was classified as severe. It understood from the clinical experts that there were key differences in the severity of the condition between cystic fibrosis mutations (for example, some mutations result in little or no cystic fibrosis transmembrane conductance regulator [CFTR] protein function and in others, there is some residual function), but the trial populations were generalisable to the clinical population in England (see section 4.4). Therefore, the committee concluded that it could not recommend the use of lumacaftor–ivacaftor with data collection for this appraisal. It noted that the company's pooled analysis of TRAFFIC and TRANSPORT suggested that lumacaftor–ivacaftor as an add-on therapy to standard of care reduced: the total number of pulmonary exacerbations by 39%, pulmonary exacerbations needing hospitalisation by 61% and. ORKAMBI is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients age years and older who are homozygous for the 2. 4.14 The committee discussed the company's methods for estimating the treatment effect of lumacaftor–ivacaftor on pulmonary exacerbations. LONDON--(BUSINESS WIRE)--Jun. It acknowledged that NHS England has published a clinical commissioning policy for ivacaftor monotherapy, which is for people of 6 years and older who have 1 of 9 mutations. The committee acknowledged that most predictors of mortality in people with cystic fibrosis were captured by the Cox proportional hazards model published by Liou et al. The ERG considered that the company's approach may have led to the double counting of quality-of-life gains and mortality reductions in the modelling. Therefore, the ERG considered that the company may have overestimated the survival benefit for lumacaftor–ivacaftor by including only pulmonary exacerbations needing hospitalisation or intravenous antibiotics. -CF patients in England will be among the first in Europe to benefit from access to KAFTRIO ®, if the medicine is approved by the European Commission- It noted that in the trials, the adherence rate was 96.5%, but the company had assumed an adherence rate of 90% in its economic model. The reductions in pulmonary exacerbations seen with lumacaftor–ivacaftor treatment were clinically significant and important for managing cystic fibrosis. Oral Granules. However, the clinical experts stated that in general, an increase in ppFEV1 would be associated with a lower risk of exacerbation. 4.3 The committee discussed how lumacaftor–ivacaftor would be used in clinical practice. The committee noted the comments from a consultee on the appraisal consultation document indicating that although the acute improvement in ppFEV1 was modest, when combined with the improvement in rates of exacerbations, the clinical trials provide evidence that lumacaftor–ivacaftor may significantly improve the long-term outcome for patients. However, it heard from the clinical experts that the average rate of decline in ppFEV1 was generally 1–2% per year for all people with cystic fibrosis, and that a decline in ppFEV1 of 2% or more per year reflected rapidly declining lung function. It agreed that direct health effects for carers had not been taken into account in the company's economic model as considered appropriate in NICE's guide to the methods of technology appraisal (2013). 2016 Apr;52(4):229-37. doi: 10.1358/dot.2016.52.4.2467205. However, the committee concluded that even if the company's economic model had taken into account these uncaptured direct health effects, its recommendation would remain unchanged. The committee stated that it would have expected to see a difference in health-related quality of life between the 2 treatment groups in the company's trial because of the differences in the rate of pulmonary exacerbations. It was not certain how independent the effects of lumacaftor–ivacaftor on ppFEV1 and on pulmonary exacerbations were. Last updated on Jan 1, 2021. NICE's methods guide states that 'a discount rate of 1.5% for costs and benefits may be considered by the committee if it is highly likely that, on the basis of the evidence presented, the long-term health benefits are likely to be achieved. It also concluded that the reductions in pulmonary exacerbations seen with lumacaftor–ivacaftor treatment were clinically significant and important for managing cystic fibrosis. Uncertainties around and plausibility of assumptions and inputs in the economic model. The committee was aware that the European public assessment report stated that the company's primary analysis method (that is, a mixed-effects model for repeated measures) takes into account the variability, and therefore it was not considered appropriate to reduce it by time point averaging. The committee heard from the clinical experts that a substantial number of people with pulmonary exacerbations who need supportive treatment cannot be admitted to hospital in a timely manner because specialist cystic fibrosis centres in England have limited capacity and cannot cope with demand. It was aware that in TRAFFIC, TRANSPORT and PROGRESS, approximately 13% of people discontinued lumacaftor–ivacaftor by week 48, but in the company's base-case analysis people could only stop treatment in the first 24 weeks. Therefore, it concluded that there was uncertainty associated with the treatment effect on BMI in the company's model, but was satisfied this would only have a small impact on the ICER. a 3.5% discount rate for both costs and effects.The committee also agreed that there was considerable uncertainty around: the estimates of relative effectiveness for ppFEV1 decline, the rapid rate of ppFEV1 decline in the standard of care group, how the treatment effect was modelled when people came off treatment and over the longer term (that is, no waning effect of treatment over time), how independent the effects of lumacaftor–ivacaftor on ppFEV1 and on pulmonary exacerbations were, the effect of using data for pulmonary exacerbations needing hospitalisation or intravenous antibiotics in the modelling rather than for all pulmonary exacerbations, potential overestimation of cost savings associated with hospitalisation and. It was also aware that only small changes in health-related quality of life were seen when using the disease-specific CFQ‑R in the company's trials, and therefore the lack of sensitivity to showing changes in health-related quality of life in people treated with lumacaftor–ivacaftor was not limited to the generic EQ‑5D‑3L. Treatment is determined according to each person's needs, because current options manage the symptoms and complications associated with cystic fibrosis rather than the cause of the condition. It also concluded that the consequences on the treatment effect of discontinuing treatment were inappropriately modelled in the company's base-case analysis, which potentially biased the ICER in favour of lumacaftor–ivacaftor. The committee therefore acknowledged that lumacaftor–ivacaftor was a valuable new therapy for managing cystic fibrosis. Our registration can be found here on Farmatec's website. It noted that the mean absolute change in ppFEV1 from baseline to week 24 ranged from approximately 2.45% to 2.8%, depending on whether the outcome was based on 24‑week data alone or an average of 16‑week and 24‑week data respectively. October 2017. Found inside – Page 959Benefit from ivacaftor *P < demonstrated .001. ... of ivacaftor in combination with lumacaftor, a potentiator molecule to “chaperone” the misfolded protein ... The committee agreed that lumacaftor–ivacaftor offers people an oral treatment option that has the potential to ease the treatment burden by reducing the number of pulmonary exacerbations needing intravenous antibiotics and hospitalisation. The committee heard from the clinical experts that the costs of managing these types of cystic fibrosis were broadly similar. pulmonary exacerbations needing intravenous antibiotics by 56%.The committee heard from the clinical experts that pulmonary exacerbations are associated with long-term decline in ppFEV1, and a treatment that reduces the need for hospitalisation by 61% would be clinically significant. The committee considered the company's economic model, the evidence review group's (ERG) critique and the ERG's exploratory analyses. Talk to your doctor about other fatty foods to eat with lumacaftor and ivacaftor. Together, lumacaftor and ivacaftor may help more chloride ions to pass into and out of the cells—helping keep a balance of salt and water in certain organs, such as the lungs. A patient expert stated that an absolute increase of 2.8% in ppFEV1 may not be viewed as clinically significant, but from a patient perspective any improvement in lung function is welcomed. 4.8 The committee discussed the health-related quality-of-life data collected in TRAFFIC and TRANSPORT. It explained that this was a result of the company applying a rate ratio to the number of pulmonary exacerbations (treatment effect), and another reduction to the cost of hospitalisation by 61%, for people having lumacaftor–ivacaftor plus standard of care. Found insideIn both studies, patients were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor ... The committee heard from the clinical experts that only a small number of people are treated with mannitol dry powder in clinical practice and the standard of care treatments in the trials were generally appropriate. It noted that the consequences of this reduction were accounted for in the company's cost-effectiveness analysis. Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible. It commented that using a Weibull function to model the age-specific background mortality seemed reasonable. TRAFFIC AND TRANSPORT were international multicentre (including 5 UK centres) double-blind, phase III placebo-controlled trials in people 12 years and over with cystic fibrosis who are homozygous for the F508del mutation. However, it understood from the clinical experts that Liou excluded a major predictor of lung function and mortality in people with cystic fibrosis, that is, chronic Pseudomonas infection. This is most common CF-causing mutation worldwide and approximately half of all Canadian patients with CF are homozygous for the F508del mutation. Educational Resources. A patient expert highlighted that people appreciate that lumacaftor–ivacaftor is taken orally, and any treatment that can reduce the burden and unpleasant side effects of intravenous antibiotics would be welcomed. The committee was aware from the company's scenario analyses that choosing the rate ratio for pulmonary exacerbations needing intravenous antibiotics or hospitalisation, rather than the overall rate ratio, resulted in a more favourable ICER for lumacaftor–ivacaftor. The committee recognised the difficulty of valuing health states in chronic conditions of an unpredictable nature because a person's health-related quality of life is generally their current health on the day of assessment rather than at the time of an event (for example, pulmonary exacerbation), and it was not always assessed over the longer term. In its submission, the company stated that lumacaftor–ivacaftor addresses an unmet need because it is the first treatment to specifically target the F508del mutation. NHS England has an interim access agreement with Vertex Pharmaceuticals, which includes collecting further data through an interim data collection agreement. However, the committee was aware that the company had used the number of pulmonary exacerbations needing hospitalisation or intravenous antibiotics in the Liou et al. The committee noted that the company's utility model showed an association between EQ‑5D score and ppFEV1, which suggests that differences between utility and cystic fibrosis severity as measured by ppFEV1 existed. 4.20 The committee discussed whether it was plausible that people would discontinue lumacaftor–ivacaftor treatment after 24 weeks. The committee also understood from the clinical experts that the trial populations broadly represent people who would be offered lumacaftor–ivacaftor in England. Data was collected from patient charts, laboratory and radiology records. CT Thorax images were reviewed for evidence of air trapping using the Brody score. It identified 2 phase III randomised controlled trials, TRAFFIC and TRANSPORT, and 1 ongoing extension study, PROGRESS. It understood from the clinical experts that there was no single standard of care. 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