Mannitol dry powder for inhalation for treating cystic fibrosis

Clinical practice

4.2 The Committee discussed the clinical needs of people with cystic fibrosis. It heard from clinical specialists that cystic fibrosis leads to considerable morbidity and early mortality, and that there is no single standard care pathway in the UK. Clinicians and patients working with cystic fibrosis centres decide on treatment according to each patient's needs. The clinical specialists added that the aim of treatment in adults is to maintain lung function (as measured primarily by the absolute volume of FEV₁ in millilitres), particularly after the age of 30 years. In response to the consultation, the clinical specialists added that it is particularly important to manage cystic fibrosis to prevent a further decline in lung function in patients with rapidly declining lung function (that is, more than 2% per year decline in FEV₁% predicted). Clinicians and patients manage lung function primarily through efforts to reduce airway infections, increase airway clearance, aid sputum clearance and maintain body weight through good nutrition. The Committee heard from the clinical specialists that approximately 98% of people with cystic fibrosis are registered with cystic fibrosis centres, and that clinicians use the Cystic Fibrosis Trust guidelines as the basis for best standard of care. The Committee heard from the clinical specialists that, as with hypertonic saline, rhDNase is inhaled as a nebulised solution and is an adjunct to physiotherapy, along with inhaled, oral or intravenous antibiotics for Pseudomonas aeruginosa, and that use of rhDNase varies widely across the UK. The Committee concluded that best standard of care for cystic fibrosis was complex and tailored to patient needs, and that rhDNase treatment was considered a component of best standard of care.

4.3 The Committee considered the place of mannitol within the cystic fibrosis treatment pathway, particularly in relation to the use of hypertonic saline. It noted the therapeutic indication of mannitol as an add-on therapy to best standard of care. The Committee heard from the clinical specialists that, after treatment with rhDNase, a patient would be offered either mannitol or hypertonic saline. The clinical specialists stated that approximately 40% of patients in the UK are treated with hypertonic saline. However, the patient expert highlighted that the unpleasant taste and experience of hypertonic saline can lead to poor adherence and this was confirmed by the clinical specialists. The Committee considered whether mannitol could replace nebulised hypertonic saline, but noted that the decision problem and the marketing authorisation clearly defined mannitol as an add-on therapy, and it would not be expected to replace any component of current treatment. The Committee was aware that both of the trials presented by the manufacturer excluded patients taking hypertonic saline, and therefore that the manufacturer had not provided the Committee with any evidence of effectiveness of mannitol added on to hypertonic saline. At the second meeting, the manufacturer noted that, because mannitol and hypertonic saline have a similar mechanism of action (both are osmotic agents), the manufacturer did not expect that mannitol would be added on to a treatment regime containing hypertonic saline. Also, taking into consideration the treatment pathway survey provided by the manufacturer in response to the ACD, the Committee acknowledged that mannitol was unlikely to be used in most patients, and that mannitol would be used as an add-on therapy to best standard of care, but not as a replacement for hypertonic saline use in people with stable cystic fibrosis. The Committee also noted that the manufacturer in its response to the ACD proposed that mannitol should only be considered in people with cystic fibrosis for whom hypertonic saline is not appropriate.

4.4 The Committee considered a patient's experience of cystic fibrosis, which involves several treatments, and how patients would use mannitol. The patient expert explained the difficulties in adhering to treatments, and stated that using mannitol with an inhaler would be much easier than using hypertonic saline with a nebuliser and would likely encourage adherence. Again, the Committee was aware that the marketing authorisation for mannitol stipulates that it would add on to, rather than replace, existing therapies. The Committee heard from the patient expert and clinical specialists that the treatment time for mannitol could be cut to 2–3 minutes twice a day with training and practice, whereas nebulised treatments take much longer. The patient expert also described the issues faced by carers, with increased burdens from both assisting with treatment and helping patients to maintain normal lives. The patient expert and clinical specialists stated that current therapies (particularly therapies delivered by nebulisers) are complex to set up and to deliver, and equipment needs careful cleaning, which adds to the treatment burden, as do the difficulties in travelling with nebuliser equipment. The patient expert also highlighted the cost to patients of treatments, which are not fully funded by the NHS. The Committee agreed that there were potential advantages to patients of having a wider choice of treatment options. The Committee concluded that cystic fibrosis and its management had a major impact on the quality of life of patients and their carers, and that mannitol could ease some of this burden because it is a dry powder for inhalation, is associated with fewer unpleasant effects, needs less costly equipment and needs less time to administer than nebulised treatments.

Clinical effectiveness

4.5 The Committee noted that the manufacturer's original submission was in line with the anticipated marketing authorisation (treatment of cystic fibrosis in adults aged 18 years and over as an add-on therapy to rhDNase, and in patients ineligible for, intolerant of, or whose condition inadequately responded to, rhDNase), and did not reflect the current approved marketing authorisation (treatment of cystic fibrosis in adults as an add-on therapy to best standard of care). The Committee also noted that the population specified in the scope included children, and included rhDNase and hypertonic saline as comparators. The Committee noted that the group of all people not using rhDNase was a clinically heterogeneous group, and included patients who cannot use rhDNase, and patients who can but do not use rhDNase for reasons not recorded. The Committee heard from the clinical specialists that the use of rhDNase varies geographically within the NHS. The Committee concluded that the analyses carried out for the populations described as people using rhDNase and all people not using rhDNase would reflect the population in the final marketing authorisation.

4.6 The Committee considered the evidence submitted by the manufacturer on the clinical effectiveness of mannitol. The Committee was concerned that the statistical power of the presented analyses was reduced by having to limit the population to adults, which reduced the population to almost half of the original trial population, as well as by differentiating according to rhDNase use, and then further according to the reasons for not using rhDNase. The Committee was also concerned that a considerable number of initial study participants did not proceed to randomisation. The Committee further noted that the analysis of the subgroups using and not using rhDNase was part of the trial protocol, but that the trials were powered for statistical significance only for the group using rhDNase, and not for the group not using rhDNase. The Committee concluded there were some concerns about the design of the trials and the resulting analyses, particularly with the post-hoc analyses and low statistical power, and that these factors increased the uncertainty in the results, including the possibility that real differences existed that the study did not demonstrate statistically.

4.7 The Committee heard from the manufacturer that 50 mg mannitol twice daily was used as the placebo in the trials after a request from regulatory authorities. The Committee heard from the manufacturer that it chose this dose from a dose-ranging study. Both the manufacturer and clinical specialists acknowledged that there was likely to be a small therapeutic effect at this dose, as also suggested by the FEV₁ increasing from baseline by 52.4 ml in the DPM-CF-302 trial in the control group. The Committee concluded that mannitol would be more effective than reported in the trials, if the placebo had had a clinical effect.

4.8 The Committee considered the outcomes used in the trials, and how these differed from the outcomes used in clinical practice in adults with cystic fibrosis. The Committee discussed the manufacturer's selection of absolute change in FEV₁ in millilitres in the trial and FEV₁% predicted in the economic model, and the manufacturer's definition of 'responders' as people whose absolute FEV₁ improved by 100 ml or 5% or more, or whose FEV₁% predicted improved by 5% points. The Committee heard from clinical specialists that both absolute FEV₁ and FEV₁% predicted measurements are used in clinical practice, that a change in absolute FEV₁ between 75 and 100 ml is clinically meaningful, and that FEV₁% predicted is used for children and to compare across different adult patient populations. The clinical specialists explained that the manufacturer's definition of a response did not accurately reflect clinical practice in the UK. If a patient felt better, but did not reach the threshold defining response (for example, their absolute FEV₁ increased by only 80 ml), the clinician would be unlikely to recommend stopping treatment. The patient expert concurred, stating that lung function can vary from day to day, and that small changes could make a difference to daily life and activity. The Committee concluded that the FEV₁ response outcomes were clinically relevant, but that the definition of 'responders' in the original manufacturer's submission differed from UK practice.

4.9 The Committee considered whether the 2 trials presented were equivalent, as the eligibility criteria at the lower end of FEV₁% differed between the 2 studies. The clinical specialists explained this was because DPM-CF-301 was conducted largely in the UK, and DPM-CF-302 largely in the US, where prophylactic antibiotics and rhDNase are used more frequently than in the UK, and because there are differences in the regulations of the Food and Drug Administration and European Medicines Agency pertaining to the lower limit of FEV₁% predicted for inhaled substances. The Committee was concerned about the way in which the 2 trials were blinded, and whether functional unblinding existed. It was also concerned that mannitol may cause rebound bronchoconstriction, but acknowledged that patients had undergone a mannitol tolerance test before entering the trials, and also heard from the clinical specialists that rebound bronchoconstriction did not occur in the trials. Overall, the Committee concluded that the 2 trials presented were equivalent and that it was reasonable to pool the results, but that there were methodological concerns about the analysis of clinical outcomes in the studies, and that there may have been functional unblinding, which would increase uncertainty about the clinical effectiveness of mannitol.

4.10 The Committee discussed the issue that hypertonic saline was not included as a comparator in the manufacturer's submission, although it was included in the scope and the ERG's indirect comparison (see section 3.37). Being aware that the use of nebulised hypertonic saline was an exclusion criterion in both the DPM-CF-301 and DPM-CF-302 trials, the Committee noted that there was no clinical-effectiveness data for mannitol in people who used hypertonic saline. The Committee heard from the manufacturer and the ERG that there were difficulties in comparing the 2 osmotic agents, in particular because of the heterogeneity in the outcome measures in the clinical trials of the 2 osmotic agents and the lack of definition of the concentration of hypertonic saline solution used in clinical practice in the UK. The Committee noted the Cochrane review of hypertonic saline for cystic fibrosis, and the apparent improvement in pulmonary exacerbations and quality of life compared with isotonic saline, and heard that the clinical specialists considered the review to have been well-performed and valid. The Committee noted that, despite the final marketing authorisation permitting the addition of mannitol to best standard of care, mannitol would be unlikely to be used as an add-on to hypertonic saline because mannitol and hypertonic saline have similar mechanisms of action (see section 4.3). However, because the lack of clinical evidence precluded the use of hypertonic saline as a comparator in the analysis, and because the Committee was not presented with any evidence demonstrating the effectiveness of mannitol in people using hypertonic saline, the Committee concluded that the only possible recommendation is for people for whom other osmotic agents are not considered appropriate. The Committee concluded that adults with cystic fibrosis who cannot take hypertonic saline, for example for reasons of intolerability, represent a population with unmet need who would be able to benefit from the use of mannitol. The Committee further concluded that a clinical trial would be needed to establish the relative effectiveness of mannitol compared with hypertonic saline.

4.11 The Committee considered the incidence of adverse reactions during the trials, and their effects on people with cystic fibrosis. The Committee heard from the clinical specialists that productive cough is seen as a positive effect whereas irritating cough is seen as negative, but noted that learning to control cough is an important part of managing cystic fibrosis. The patient expert discussed the experience of using current therapies, and how the negative effects (such as unpleasant taste and sensations) affect a person's daily life and increase the burden of treatment. The Committee considered the manufacturer's response to the ACD and noted that mannitol was not more likely to cause haemoptysis than best supportive care. In the Committee's view, adverse reactions were not sufficiently captured by effects on quality of life through the HUI2 measurement in DPM-CF-302, given that a week could elapse between the adverse reaction and reporting, and the bias towards a higher chance of filling in the questionnaire when feeling well, rather than feeling ill. The Committee concluded that the treatment of cystic fibrosis can cause several moderate and severe adverse reactions, and that it can be difficult to establish the effect of adverse reactions on health-related quality of life in a disease as complex as cystic fibrosis.

4.12 The Committee noted that each trial collected quality-of-life data but that the manufacturer had not submitted EQ-5D data as preferred by NICE. The Committee heard from the clinical specialists and the patient expert that assessing quality of life in people with cystic fibrosis is very difficult because they often describe their quality of life as being equivalent to people without cystic fibrosis or without other chronic conditions. The patient expert explained that she perceived her life as 'normal', and had never known any other health state. The Committee recognised the difficulty in valuing health states in chronic conditions, but 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 concluded that current measures of quality of life may not accurately capture the consequences of having cystic fibrosis and of its treatments.

4.13 The Committee considered the relationship between absolute change in FEV₁ and pulmonary exacerbations. The Committee heard from the clinical specialists that FEV₁ and pulmonary exacerbations have not previously been shown to be directly related. The Committee noted that the average rate of pulmonary exacerbations was lower in people considered 'responders' than in 'non-responders' in DPM-CF-301. The Committee questioned that incidence of pulmonary exacerbations in people not using rhDNase was lower than in people using rhDNase in DPM-CF-301, but it was the other way around in DPM-CF-302, and the manufacturer could not explain this difference. The Committee was aware that the 36.5% relative risk reduction in the rate of exacerbations with mannitol compared with control in people not using rhDNase was not statistically significant, but acknowledged that this could be a result of the post-hoc subgrouping (see section 3.10). On balance, however, the Committee acknowledged that it was plausible that absolute change in FEV₁ and pulmonary exacerbations could be related. The Committee concluded that mannitol is clinically effective in improving both lung function (FEV₁) and pulmonary exacerbations in people with cystic fibrosis. The Committee further concluded that there are subgroups of people who may experience greater benefit from mannitol, such as people who cannot use rhDNase, but that there is a degree of uncertainty about the magnitude of any increased clinical effectiveness.

Cost effectiveness

4.14 The Committee considered the manufacturer's cost-effectiveness analysis, and the ERG's critique and exploratory analyses. It noted that the manufacturer originally used a patient-level simulation model to evaluate the cost-effectiveness of mannitol compared with best standard of care in people using rhDNase and people ineligible for or intolerant of, or whose condition inadequately responded to, rhDNase. The Committee also noted that clinical-effectiveness data presented in the submission were not used directly in the model, instead the manufacturer derived transition parameters from the 2 mannitol trials and from the literature, and incorporated them into the model through regression analysis. In a response to the ACD, the manufacturer provided a revised cost-effectiveness model, addressing some of the Committee's concerns. The Committee noted that the structure of the original model was not a health-state model, but rather was a model of the cystic fibrosis treatment pathway. The Committee was aware of the ERG's concerns about the manufacturer's original assumptions that any improvement in FEV₁% predicted would be maintained throughout the lifetime of the patient, and that it would be directly translated into lowered morbidity and mortality rates. The Committee considered that not all relevant UK data were identified by the manufacturer's search strategy in the original submission, and that the manufacturer's response to the ACD addressed these concerns in part. The Committee acknowledged the changes to the model made by the manufacturer in their response to the ACD, but that substantial uncertainty remained about the long-term benefits of using mannitol. The Committee noted that the ICER would increase if the effects of mannitol were only maintained in the short term. The Committee concluded that the cost-effectiveness model was complex and may not adequately reflect the clinical trial data.

4.15 The Committee considered the way in which the manufacturer had incorporated the clinical-effectiveness data in the model, and was concerned by the limited number of variables incorporated from the trials. It noted that the modelling of treatment effect used FEV₁% predicted, and not the trials' primary outcomes of absolute FEV₁. The Committee considered the assumptions and variables incorporated into the manufacturer's model, one of which being that mortality depended only on FEV₁% predicted, the presence or absence of Burkholderia cepacia infection, age and sex. The Committee was aware that other studies, including one using UK data, demonstrated a wider range of variables associated with mortality in cystic fibrosis than the variables in the BioGrid data used by the manufacturer. The Committee particularly noted that BMI was not included in the manufacturer's mortality calculations, whereas it was a parameter for other variables in the model, and had been identified in registry studies as an independent risk factor for death in cystic fibrosis. In addition, the Committee noted that the hazard ratio associated with Burkholderia cepacia infection was greater in the manufacturer's analysis than in multivariate survival analyses of UK and US registry data. The Committee noted that the manufacturer stated that mannitol did not affect the risk of infection with Burkholderia cepacia complex in the model. The Committee acknowledged that there was little evidence that mannitol would alter other factors associated with mortality, but concluded that the mortality rate in the manufacturer's model may not accurately reflect mortality in cystic fibrosis. The Committee considered that other validated models of cystic fibrosis mortality exist, and that the manufacturer's model was unlikely to accurately represent the cystic fibrosis population in the UK. The Committee concluded that the model underestimated the mortality rate, and that a higher mortality rate would increase the ICER.

4.16 The Committee expressed concerns about the assumption used in the model related to how change in FEV₁% predicted is modelled over time derived from the BioGrid study, but was satisfied with the manufacturer's clarification at the second meeting that FEV₁% predicted declined over time in the model, as expected in a cohort of patients with cystic fibrosis. Given that there is a rise in the rate of pulmonary exacerbations with age, the Committee considered it was difficult to interpret with any certainty the evidence provided by the regression model. The Committee was also concerned that the manufacturer did not consider the effect of treatment with mannitol on BMI, even though BMI was a parameter in the model used to estimate FEV₁% predicted. The Committee concluded that there was substantial uncertainty in the assumptions surrounding the changes in FEV₁% predicted with age and that this led to uncertainty about the applicability of the model to the UK population with cystic fibrosis.

4.17 The Committee considered the assumption that the difference in FEV₁% predicted from treatment with mannitol observed at week 26 would be maintained over the patient's lifetime, and whether this was likely to be seen in clinical practice. The Committee noted that this delay in FEV₁ decline would prolong the time before, but possibly not prevent, future lung transplants. The Committee noted that the assumption of a maintained long-term benefit of mannitol would affect the ICER favourably, but that there was substantial uncertainty around this assumption. The Committee noted the sensitivity analyses carried out by the manufacturer and the ERG in which the time horizon was shortened to 5 and 10 years, which could be used as a proxy for a shorter duration of benefit, and that the ICERs were considerably increased with these shorter time horizons. However, it noted the ERG's opinion that a longer time horizon of 50 years may reflect the expected benefit of patients who entered the clinical studies with a mean age around 30 years. The Committee concluded that although there was evidence on the short-term effectiveness of mannitol on FEV₁, the long-term effect of mannitol on FEV₁ was unknown and that this increased the uncertainty in the ICER.

4.18 The Committee considered the effect of varying adherence to treatment and of stopping rules on the ICERs, and discussed the ERG's sensitivity analysis and the manufacturer's revised analysis of reduced adherence. The Committee noted that, in the trial, the adherence was 87% based on the date of the last treatment, but the manufacturer had assumed costs reflecting 100% adherence in the model. The Committee therefore concluded that the costs of mannitol were overestimated in the original submission. However, the Committee noted that the sensitivity analyses reported in the manufacturer's response to the ACD lacked face validity because the analyses included reduced costs for mannitol, but no changes to the benefits. The Committee concluded that there is uncertainty around the validity of the assumptions around adherence and whether stopping rules reflect clinical practice, but that an adherence rate as seen in the trial might reduce the base-case ICER.

4.19 The Committee noted from the manufacturer's comments that the original definition of PDPE, as used in the trials, was different from the definition used in clinical practice, and therefore more clinical exacerbations would be seen in clinical practice. The Committee considered that this could imply that mannitol may be more effective in preventing exacerbations and hospital admissions than assumed in the cost-effectiveness model, which used the trial definition of PDPE. The Committee concluded that, in clinical practice, mannitol could prevent more exacerbations than those within the PDPE definition, which would decrease the ICER.

4.20 The Committee considered that adverse reactions were not incorporated into the manufacturer's model. The Committee heard from the patient expert and clinical specialists that quality-of-life measurements did not accurately capture the effect of adverse reactions on the quality of life of people with cystic fibrosis. The Committee noted that treatments for cystic fibrosis can increase the incidence of haemoptysis, but that haemoptysis was also associated with exacerbations, which occurred less frequently in people taking mannitol compared with people not taking mannitol. The Committee concluded that the economic model had not incorporated the specific impact of adverse reactions on the health-related quality of life in people with cystic fibrosis and that there was uncertainty about how this would affect the ICER.

4.21 The Committee considered the generalisability and internal validity of the model. The Committee considered that the relationship between FEV₁% predicted and lung transplantation in the model could not be fully explained by the manufacturer or the ERG. The Committee heard from the ERG that the proportion of people with cystic fibrosis alive at 55 years predicted by the model (15%) was greater than that found in the UK cystic fibrosis population. The Committee heard from the ERG that approximately 2% of people with cystic fibrosis are still alive at 50 years, but the clinical specialists questioned the validity of this number from the cystic fibrosis registry data. The Committee noted the comparison of the Australian data with UK registry data provided by the manufacturer in response to the ACD, and the manufacturer's interpretation that this indicated a similar trend in mortality. The Committee noted that there was a difference between the mean FEV₁% predicted values in the BioGrid and UK population datasets (see section 3.54). The Committee considered the clinical specialists' and ERG's comments that any improvement in FEV₁% predicted would reduce the mortality rate. Based on this, the Committee was not persuaded by the manufacturer's interpretation, and remained concerned that mortality was not modelled in a way that accurately reflected the mortality rate in people with cystic fibrosis in the UK. The Committee noted that, when the relative risk of death for the individual subgroups was used in the model, more QALYs were gained with mannitol in people not using rhDNase than in people using rhDNase. The Committee heard from the manufacturer that this was possibly a chance finding because of the small sample size in the subgroup of people who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The Committee concluded that there were substantial issues with generalisability and internal validity of the model, and that this would increase the uncertainty around the ICERs.

4.22 The Committee considered the quality-of-life measurements collected in the 2 trials and those used in the model. The Committee noted that the manufacturer had used the HUI2 utility measure, rather than the EQ-5D measure preferred by NICE. The Committee noted that the multiple comorbidities associated with cystic fibrosis and their large impact on daily life suggested that the baseline utility value of 0.899 was high, and that the revised figure of 0.896 for people not using rhDNase was not substantially different. The Committee was also aware that the model was sensitive to the baseline utility with the ICER increasing as the baseline utility decreased. In the original model, the utility increase in patients with improved respiratory symptoms was greater in the mannitol group than in the control group, whereas the utility decrease in patients without improved symptoms was greater in the control group than in the mannitol group. In response to the ACD, the manufacturer submitted a model where the utility values for the health states were the same, irrespective of treatment. However, the Committee concluded that it was not convinced that the health-related quality of life of the health states in the model had been valued with any certainty, and that this led to increased uncertainty around the calculated ICERs for mannitol compared with best standard of care.

4.23 The Committee considered the relationship between the outcomes, mortality, and quality of life within the model. The Committee noted the uncertainty around the effect of mannitol on life expectancy given the assumption of lifetime efficacy in the model. The Committee noted that virtually all of the benefit of mannitol was from its modelled extension of life-years gained, with very little benefit resulting from improved health-related quality of life, and that the ERG suggested that a more direct link between lung function and quality-of-life utilities could have produced lower ICERs. The Committee considered whether this was likely to be an accurate reflection of real life, and heard from the patient expert that there were substantial quality-of-life improvements in taking an inhaled treatment such as mannitol. The Committee concluded that there was uncertainty about the accuracy of the quality-of-life data and the projected benefits of mannitol on life expectancy, and as a consequence there was further uncertainty as to the robustness of the modelled ICERs.

4.24 The Committee noted that the costs presented initially by the manufacturer were treatment specific rather than health-state specific. The Committee agreed that the use of health-state specific costs was more appropriate and acknowledged that the manufacturer had incorporated health-state specific costs in the model provided as part of the manufacturer's response to the ACD. The Committee concluded that the modelling incorporating health-state specific costs was more appropriate than that based on treatment specific costs, but that a model based on lung-function specific costs and utilities would be even more appropriate.

4.25 The Committee considered the ICERs produced by the manufacturer and the ERG. The Committee noted that the manufacturer's original base-case ICERs were above £40,000 per QALY gained in both people using and people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. Furthermore, the Committee noted that the ERG's base-case ICERs were £82,500 per QALY gained in people using rhDNase and £29,900 per QALY gained in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, when subgroup specific model inputs were used. The Committee noted that, in response to a request for clarification, the manufacturer's probabilistic ICERs were £27,700 per QALY gained for people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and £54,300 per QALY gained in people using rhDNase, and the respective ERG's estimates were £30,100 per QALY gained for those who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and £53,800 per QALY gained for the rhDNase group. The Committee had not been provided with an ICER for the whole population for which mannitol is licensed, but could conclude from the subgroup data by rhDNase use that mannitol would not represent a cost-effective treatment for the whole population for which it is licensed. Noting that the ICERs for the subgroup of people using rhDNase were between £50,000 and £80,000 per QALY gained, the Committee concluded that mannitol was not cost effective for people using rhDNase, and could not be recommended for this subgroup. The Committee concluded that the ICERs for mannitol in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase were underestimates because mortality in the model was underestimated, and also associated with several uncertainties because of the lack of validity in the model (for example, the duration of the effect long term). Therefore, the Committee concluded that the ICERs for mannitol were likely to be above £30,000 per QALY gained in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, and that mannitol could not be recommended for this subgroup.

4.26 The Committee was aware of the ICERs provided in the manufacturer's response to the ACD in the subgroup of people not using rhDNase (irrespective of the reason for not using rhDNase). The Committee understood from the ERG's critique that this new ICER in people not using rhDNase was lower than the ICER in the original subgroup of people who cannot use rhDNase. According to the ERG there were several factors that could have led to the lower new ICER for adults not using rhDNase, including the manufacturer having used a bigger difference in cost between mannitol and control, having used exacerbation rates suggested by the ERG, and having included drop-out rates derived from the trials, rather than having assumed that all people whose condition responded to mannitol remained on treatment for their lifetime. However the Committee was also aware that mannitol improved lung function less in the people not using rhDNase than in people who cannot use rhDNase, and therefore found the new ICERs counterintuitive. Importantly, the Committee noted that the subgroup of people not using rhDNase (for unspecified reasons) is clinically not clearly identifiable, and therefore it could not make recommendations for this subgroup.

4.27 The Committee further explored whether there was a group of adults with cystic fibrosis in whom treatment with mannitol would provide a cost-effective use of NHS resources, taking into consideration the responses received on the ACD. The Committee was aware that the manufacturer had, in its response to the ACD, made a proposition for increased cost effectiveness for mannitol treatment in patients with rapidly declining lung function irrespective of rhDNase use. Furthermore, the Committee noted a statement from the clinical specialists in response to ACD consultation, which identified patients with rapidly declining lung function, despite best standard of care, because those patients would particularly benefit from mannitol, a suggestion that the Committee considered was biologically plausible. The Committee noted that any increase in lung function would be proportionally greater for patients with rapidly declining lung function because they would have more to gain than patients with more stable lung function. The Committee was therefore aware that a group with rapidly declining lung function has higher capacity to benefit from mannitol treatment. The Committee further noted that mannitol appeared to be more clinically effective in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase (see section 4.13). The Committee concluded that there is an unmet clinical need in patients with rapidly declining lung function, particularly if there are no other therapies appropriate to offer the patient.

4.28 The Committee discussed the cost effectiveness of mannitol in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, and whose lung function declines rapidly (yearly FEV₁% predicted decline of more than 2%). The Committee used, as a starting point for these discussions, the manufacturer's original probabilistic ICER of £27,700 per QALY gained in people who cannot use rhDNase and the ERG's ICER of £30,100 per QALY gained. There were factors that the Committee agreed would increase uncertainty around the ICERs; those that may increase the ICERs include assumptions about mortality and the long-term effect of mannitol on lung function. Factors that may decrease the ICERs include the possibility of higher rates of pulmonary exacerbations in clinical practice, a rate of adherence reflecting clinical practice, establishing if there is a link between lung function and quality-of-life utilities, and estimating more realistic utility values associated with mannitol use. The Committee agreed that, if mannitol treatment was offered only to patients with a rapid decline in lung function, the ICER would most likely be lower because of this group's lower quality-of-life and lung function, and a greater potential to improve. The Committee concluded that the ICER for mannitol in patients for whom hypertonic saline is not considered appropriate (see section 4.10), who cannot use rhDNase, and whose lung function is rapidly declining would be under £30,000 per QALY gained. It also took into account the severity of the disease and the importance of treatment options for people with cystic fibrosis who have few alternative options. The Committee concluded that mannitol should be recommended as an acceptable use of NHS resources as a treatment option for people with cystic fibrosis who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, whose lung function is rapidly declining, and for whom other osmotic agents are considered inappropriate.

4.29 The Committee discussed whether mannitol should be considered an innovative technology, or if there were any significant and substantial health benefits that were not included in the economic model. It heard from the clinical specialists and the patient expert that the treatment burden is substantially less for an inhaler than for a nebuliser and that mannitol, being a dry powder, represents a step-change in the way cystic fibrosis is managed in the UK. When questioned, the manufacturer stated that the model accurately reflected the utility gain to patients. The Committee concluded that treatment with an inhaler provided practical advantages over treatment with nebulisers, but mannitol as an add-on therapy would not replace the use of nebulisers, and so could not be considered a step-change in treatment.

4.30 The Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations. The only potential equality issue identified was whether the inhaler used for mannitol inhalation would present a disproportionate burden on patients with physical disabilities. However, the Committee noted the clinical specialists' and patient expert's view that all available treatments are difficult to administer, and that the use mannitol as an add-on therapy to best standard of care would not increase the treatment burden.

Summary of Appraisal Committee's key conclusions