How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? 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. It noted that the primary outcome of TRAFFIC and TRANSPORT, the change from baseline to week 24 in ppFEV1, was calculated as an average of week 16 and week 24 results to reduce variability. The clinical experts stated that the health-related quality of life of people in hospital is often low, not only because of physical symptoms, but also because hospital treatment can be isolating, which can have a psychological impact. 4.19 The committee discussed the rates of adherence included in the company's economic model and ERG's exploratory analysis. 1 Recommendations November 2019: Although NICE does not recommend lumacaftor–ivacaftor, NHS England has said that it is now available on … 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. Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) protein potentiator that increases chloride transport in the abnormal CFTR protein. 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. The application of the recommendations in this guidance is at the discretion of health professionals and their individual patients and do not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian. Appraisal title: Lumacaftor–ivacaftor for treating cystic fibrosis homozygous for the F508del mutation. 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 understood from the clinical experts that in clinical practice, people would only discontinue lumacaftor–ivacaftor because of adverse events or because they did not adhere to treatment, and not because of a change in ppFEV1. Found inside – Page 297Table 2 Treatment options for patients with cystic fibrosis Pharmacological therapies CFTR modulators Potentiator: Ivacaftor Corrector: Lumacaftor, ... recommend lumacaftor-ivacaftor therapy (Orkambi®) for routine use in the NHS in England. Lumacaftor increases the amount of this channel on cell surfaces, while -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-. Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The average length of a pulmonary exacerbation in clinical practice should be used (12–14 days). The committee highlighted that data sources such as the Cystic Fibrosis Registry were not limited to the population homozygous for the F508del mutation. It understood from the clinical experts that in clinical practice, people would only discontinue lumacaftor–ivacaftor because of adverse events or because they did not adhere to treatment, and not because of a change in ppFEV1. It also heard from the clinical experts that most people who stopped lumacaftor–ivacaftor in clinical practice had felt worse soon after coming off treatment. The committee concluded that lumacaftor–ivacaftor would be considered as an adjunct to standard of care for treating cystic fibrosis in people homozygous for the F508del mutation. 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. 5 Appraisal committee members and NICE project team. The committee concluded that cystic fibrosis has a major impact on the quality of life of patients and their carers. The committee agreed that in clinical practice, people would discontinue treatment after 24 weeks because of adverse events or because they did not adhere to treatment, and that it was reasonable to assume that the rate at which people discontinued treatment would reduce after the initial treatment period of 24 weeks. A patient expert highlighted that because of the unpredictable nature of the condition, it was difficult to make plans for the future and this has a substantial impact on psychological wellbeing (for example, causing symptoms of stress, anxiety and depression). Found inside – Page 268Lumacaftor has been reported to cause strong cytochrome P450-3A induction both preclinically and clinically [96], limiting the use of lumacaftor–ivacaftor ... 4.21 The committee discussed the company's costs for managing cystic fibrosis. Technology appraisal guidance [TA398] Methods: 39 subjects from the PROSPECT Part B study who had been prescribed lumacaftor/ivacaftor by their CF care team at a CF Foundation's Therapeutic Development Network center were recruited. 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. the ICER for lumacaftor/ivacaftor compared with placebo was $95,016 per FEV 1% predicted. There was a rapid rate of ppFEV1 decline in the standard of care group. The committee highlighted that the company had been inconsistent in its approach to selecting pulmonary exacerbation data for its model. Ivacaftor 125 mg; Lumacaftor 200 mg; 112: tablet (POM) £8000.00 (Hospital only) — — Granules All products. Lumacaftor–ivacaftor offers people an oral treatment option that has potential to ease the treatment burden by reducing the number of pulmonary exacerbations needing intravenous antibiotics and hospitalisation. It heard from the patient experts that cystic fibrosis can impair a person's social life and ability to work, and significantly affects the lives of their families and carers. Evidence-based recommendations on lumacaftor–ivacaftor (Orkambi) for treating cystic fibrosis in people 12 years and older who are homozygous for the F508del mutation. Lumacaftor and Ivacaftor Tablets. 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. NHS indicative price. This was because they considered that these patients would have substantial capacity to benefit from treatment. The committee stated that the lack of clear selection criteria for choosing this study increased the uncertainty around the company's results because the relative rate of decline in ppFEV1 for lumacaftor–ivacaftor plus standard of care compared with standard of care alone had a considerable impact on the ICER. The committee acknowledged that the company's scenario analysis and ERG's exploratory analysis had arbitrarily assumed that 1.9% of people having lumacaftor–ivacaftor discontinued treatment per year after 24 weeks until the end of year 15 in the economic model. The committee concluded that longitudinal changes rather than acute changes in ppFEV1 were more clinically relevant for assessing long-term outcomes of cystic fibrosis, and both the observed and extrapolated benefits of lumacaftor–ivacaftor on ppFEV1 were taken into account in the company's cost-effectiveness analysis. They should do so in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. The person may have to take up to 50 tablets every day and may need frequent hospital admission. This is a distressing announcement for the thousands of families who could benefit from the therapy that NICE’s Appraisal Consultation Document (ACD) concludes is a valuable new therapy for The committee concluded that, overall, the company's methods for estimating survival seemed valid but there was uncertainty about how the differences in outcomes between the whole cystic fibrosis population and the population with the F508del mutation would affect the cost-effectiveness results. The committee concluded that the treatment costs associated with lumacaftor–ivacaftor treatment in the economic modelling had been substantially underestimated by the company. The committee was aware that NHS England commissioning policy decisions should not be taken as setting precedent for future policy decisions. The committee highlighted that in the company's economic model, the decline in ppFEV1 was approximately 2% or more per year for people younger than 24 years in the standard of care alone group. November 2019: Although NICE does not recommend lumacaftor–ivacaftor, NHS England has said that it is now available on the NHS for treating cystic fibrosis. Lumacaftor–ivacaftor would be considered as an adjunct to standard of care for treating cystic fibrosis in people homozygous for the F508del mutation. 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. In both TRAFFIC and TRANSPORT, people had treatment for 24 weeks and were then enrolled into the 96‑week PROGRESS extension study if they completed treatment. There was considerable uncertainty around the selection and estimates of relative effectiveness for ppFEV1 decline. The committee stated that the standard method of using the general population's valuation of descriptions of health-related quality of life to generate utility values was appropriate. The committee agreed that it was plausible that the decline in ppFEV1 was age dependent for people having lumacaftor–ivacaftor plus standard of care or standard of care alone. 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. Estimate of the size of the clinical effectiveness including strength of supporting evidence. The committee concluded that, even without including any of its preferred assumptions, the estimated ICERs were considerably higher than what is normally considered a cost-effective use of NHS resources. 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