1 Appraisal Committee's preliminary recommendations

1.1 Mannitol is not recommended for the treatment of cystic fibrosis in adults as an add-on therapy to best standard of care.

1.2 People currently receiving mannitol for the treatment of cystic fibrosis should have the option to continue treatment until they and their clinician consider it appropriate to stop.

2 The technology

2.1 Mannitol (Bronchitol, Pharmaxis) is a mucoactive agent that causes water to enter the airway lumen and hydrate airway secretions. This increases the clearance of secretions and pathogenic bacteria by reducing the viscosity of secretions and stimulating cough. Mannitol dry powder is inhaled from a hand-held, breath-activated device. Mannitol has marketing authorisation as an add-on therapy to best standard of care in adults with cystic fibrosis. The dose used in clinical trials was ten 40-mg capsules, that is 400 mg, inhaled twice daily.

2.2 The most common adverse reactions associated with mannitol as stated in the manufacturer’s submission are cough, exacerbation of cystic fibrosis, headache and pharyngolaryngeal pain. The most clinically significant adverse event associated with mannitol use is haemoptysis. The manufacturer's submission lists the following adverse reactions: condition aggravated, cough, bacteria sputum, headache, nasophayngitis, lower respiratory tract infection, pharyngolaryngeal pain, haemoptysis, upper respiratory tract infection, abdominal pain, arthralgia, vomiting, pyrexia, sinusitis, bronchitis, fatigue, influenza, influenza-like illness, malaise, nasal congestion, pain in extremity, toothache, dizziness, gastrooesophageal reflux disease, procedural pain and stomach discomfort.

2.3 Mannitol is available as a 5, 10, 20 or 40mg powder capsule for inhalation. The manufacturer stated that the list price is £0.84 per 40-mg capsule, or an average cost of £16.88 per day, including the cost of the inhaler. The manufacturer's submission quoted a cost for a 14-day pack of 280 capsules and two inhalers of £236.25. These prices do not include VAT. Costs may vary in different settings because of negotiated procurement discounts.

3 The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of mannitol and a review of this submission by the Evidence Review Group (ERG; appendix B). The decision problem addressed the clinical and cost effectiveness of inhaled mannitol compared with best supportive care in adults with cystic fibrosis who do or do not use rhDNase; the scope also included a comparison with inhaled hypertonic saline.

Clinical effectiveness

3.1 The manufacturer presented clinical effectiveness data from two randomised multi-national double-blinded control trials (DPM-CF-301 and DPM-CF-302). The trials were designed to assess the effectiveness of twice-daily mannitol at a dose of 400 mg compared with mannitol at a sub-therapeutic dose of 50 mg in addition to best supportive care with or without rhDNase. Best supportive care included inhaled antibiotics, anti-inflammatory agents, bronchodilators, vitamin supplements, pancreatic enzymes, and antidiabetic agents for people with diabetes. The trials had 26-week double-blind phases, followed by an unblinded phase of 26–52 weeks. The inclusion and exclusion criteria for the two trials were similar but not identical; the lower cut-off for FEV₁% predicted was 30% in DPM-CF-301 and 40% in DPM-CF-302.

3.2 DPM-CF-301 had 295 participants (190 adults) and took place at 40 centres in Australia, New Zealand, the UK and Ireland. The manufacturer presented results for adults only. There were 114 adults in the mannitol arm and 76 adults in the control arm. There were 58 adults using rhDNase in the mannitol arm and 44 adults using rhDNase in the control arm. There was a group not taking rhDNase, of which there were 30 adults who were ineligible, intolerant or inadequately responsive to rhDNase in the mannitol arm and 13 adults ineligible, intolerant or inadequately responsive to rhDNase in the control arm.

3.3 DPM-CF-302 had 305 participants (151 adults) and took place at 53 centres in the USA, Canada, Argentina, Germany, Belgium, France and The Netherlands. The manufacturer presented results for adults only. There were 93 adults in the mannitol arm and 58 adults in the control arm. There were 64 adults using rhDNase in the mannitol arm and 41 in the control arm. There were 15 adults who were ineligible, intolerant or inadequately responsive to rhDNase in the mannitol arm and 7 in the control arm. Following a request by the ERG for clarification, the manufacturer submitted information on two groups defined by their use of rhDNase: rhDNase users and those who were ineligible for, intolerant of, or who had responded inadequately to rhDNase.

3.4 The trial protocols for DPM-CF-301 and DPM-CF-302 were similar but not identical. Potential participants were screened for bronchial hyper-responsiveness to mannitol, and those with hyper-responsiveness were excludedprior to randomisation. Patients taking nebulised hypertonic saline were also excluded. Eligible patients were then randomised to receive either 400 mg mannitol twice daily, or a sub-therapeutic dose of 50 mg mannitol twice daily. Randomisation was stratified by region and rhDNase use. There were four follow-up visits after the screening visit, at week 0 (to start treatment with mannitol or control) and at weeks 6, 14, and 26. In both trials, participants were offered the opportunity to continue or start mannitol treatment in an open-label phase for a further 26 weeks in order to gain further information on adverse reactions; in DPM-CF-302, there was an additional open-label extension phase of 26 weeks, giving a total of 78 weeks.

3.5 The primary outcome in both trials was the absolute forced expiratory volume at 1 second (FEV₁) as measured in millilitres. Both trials reported changes in FEV₁ from baseline in the mannitol group compared with the control. The manufacturer’s submission noted that the primary outcome was the change in absolute FEV₁ over 26 weeks, but at the Committee meeting the manufacturer stated that the a priori protocol-defined primary outcome was a change in absolute FEV₁ from week 6 to 26.

3.6 Secondary outcomes included the proportion of people who responded by FEV₁ criteria defined as achieving an increase of at least 100 ml in FEV₁ from baseline (that is, from week 6 as defined by the manufacturer at the Committee meeting), at least 5% relative increase in FEV₁ from baseline, or at least a 5 percentage point increase in ‘FEV₁% predicted’. Protocol-defined pulmonary exacerbations (PDPE) were defined as pulmonary events with four or more pre-defined symptoms or signs needing intravenous antibiotics. Reductions in the frequency of both PDPE and hospital care were measured in both trials.

3.7 Both trials measured quality of life using the Cystic Fibrosis Questionnaire – Revised (CFQ-R); DPM-CF-302 also used the Health Utility Index 2 (HUI2). The CFQ-R was administered to participants at week 0 and then at weeks 14 and 26. Antibiotic use and adverse events were also measured in both trials.

3.8 In the manufacturer’s original submission, lung function was reported only for one of the subgroups relevant to the appraisal, adults who used rhDNase. Following a request by the ERG for clarification, the manufacturer submitted data on change in FEV₁ and exacerbation for the adult rhDNase group and also for adults who were ineligible, intolerant or inadequately responsive to rhDNase.

3.9 In the DPM-CF-301 trial, mannitol plus rhDNase statistically significantly improved lung function between 6 and 26 weeks compared with control, as measured by change in FEV₁ from baseline (week 6 to 26) of 109.3 ml (95% confidence interval [CI] 52.77 to 165.77; p < 0.001) (figures rounded). This difference was evident at 6 weeks (although this was defined by the manufacturer at the Committee meeting as baseline) and was maintained over the 26-week double-blind phase. For the other measures of lung function, the mean difference from baseline in changes between adults randomised to receive mannitol plus rhDNase compared with controls were: mean percentage change in FEV₁ from baseline of 4.2% (95% CI 0.31 to 8.07); change in ‘predicted FEV₁%’ of 2.7% (95% CI 0.59 to 4.73) and change in forced vital capacity (FVC) of 117.4 ml (95% CI 1.00 to 233.85). Following a request for clarification, the manufacturer provided the change in FEV₁ between 6 and 26 weeks for the 43 adults who were ineligible, intolerant or inadequately responsive to rhDNase; this was 147.0 ml, which was statistically significantly different from control (p = 0.02, no numerical absolute values provided).

3.10 In the DPM-CF-301 trial, for rhDNase users, the incidence of PDPE (time period unspecified) was 27.6% for adults randomised to mannitol compared with 36.4% in controls. For adults who were ineligible, intolerant or inadequately responsive to rhDNase, the incidence of PDPE (time period unspecified) was 16.7% for those receiving mannitol compared with 30.8% in controls. The rate of PDPE per year was 1.41 (±2.69 standard deviation [SD]) for adults receiving mannitol plus rhDNase compared with 1.58 (±2.70 SD) in controls, and 0.41(±1.11 SD) for adults who were ineligible, intolerant or inadequately responsive to rhDNase compared with 0.64 (±1.00 SD) in controls . The trials were not powered to demonstrate statistically significant  differences for PDPE outcomes in these subgroups.

3.11 In the DPM-CF-301 trial, the manufacturer did not report the proportion of adults considered to be responders using FEV₁ criteria for the two subpopulations according to rhDNase use.

3.12 In the DPM-CF-302 trial, the mean change in FEV₁ between 6 and 26 weeks for adults randomised to receive mannitol plus rhDNase was not significantly different from controls (88.5 ml, 95% CI –8.46 to 185.36). For the other measures of lung function in adults randomised to receive mannitol plus rhDNase compared with controls, the mean difference in the changes from baseline were 5.4% (95% CI –0.44 to 11.31) for FEV₁, 3.0% (95% CI –0.61 to 6.50) for change in FEV₁% predicted and 96.9 ml (95% CI –7.68 to 201.55) for changes in FVC. Following clarification, the manufacturer provided the difference in the change in FEV₁ between 6 and 26 weeks for mannitol in 22 adults who were ineligible, intolerant or inadequately responsive to rhDNase compared with controls; this was 208.6 ml (p = 0.061, no absolute numerical values provided).

3.13 In the DPM-CF-302 trial, the incidence of PDPE (time period unspecified) was 18.8% in adults receiving rhDNase alone compared with 9.8% for adults receiving mannitol plus rhDNase. For adults who were ineligible, intolerant or inadequately responsive to rhDNase, the PDPE incidence (time period unspecified) was 13.3% for those receiving mannitol compared with 42.9% in controls. The estimated PDPE rate per year was 0.83 (±2.51 SD) for adults receiving mannitol plus rhDNase compared with 0.19 (±0.58 SD) in controls, and 0.26 (±0.68 SD) for adults who were ineligible, intolerant or inadequately responsive to rhDNase compared with an estimated 0.86 (±1.08 SD) in controls . However, the trials were not powered to demonstrate statistically significant differences for these outcomes in these subgroups.

3.14 In the DPM-CF-302 trial, the manufacturer did not report the FEV₁ responder status for the two subpopulations according to rhDNase use.

3.15 The manufacturer presented pooled analyses of the DPM-CF-301 and DPM-CF-302 trials. The outcomes in the pooled analysis did not include the primary outcome, absolute FEV₁, but instead were ‘FEV₁% predicted’, the proportion responding according to FEV₁ criteria, and the rate of PDPE per patient per year. However, ‘FEV₁% predicted’ was reported for only one of the relevant populations, adults using rhDNase. Following a request for clarification from the ERG, the manufacturer submitted results for change in FEV₁ and pulmonary exacerbation for adults using rhDNase and adults who were ineligible, intolerant or inadequately responsive to rhDNase. For the pooled adult population of rhDNase users, the mean change in FEV₁ between 6 and 26 weeks for patients receiving mannitol plus rhDNase was 94.1 ml (no 95% CI given). The change was 166.7 ml (95% CI not given) for adults receiving mannitol who were ineligible, intolerant or inadequately responsive to rhDNase.

3.16 In the pooled analyses of FEV₁ response the manufacturer did not differentiate by rhDNase status, and did not submit a statistical analysis of the difference between the two groups. The proportion of adultsin the two studies combined who experienced an FEV₁ response was 48.3% in the mannitol group and 34.3% in the control group.

3.17 Adverse events were not reported for the rhDNase subgroups, but instead for the whole adult population. Overall, the manufacturer reported that approximately 89% of all adults experienced at least one adverse event, the most common adverse reaction being cough (the only adverse reaction that occurred in more than 10% of adults). However, the manufacturer considered productive cough a desired effect of treatment with mannitol. Other adverse reactions with a prevalence between 1% and 10% were decreased appetite, headache, haemoptysis, bronchospasm, wheezing, asthma, condition aggravated, pharyngolaryngeal pain, and chest discomfort.

3.18 Haemoptysis was the most clinically significant adverse reaction in both studies and  was observed in 11.9% of adults on treatment with mannitol and 8.5% in the control group in the DPM-CF-301 trial, and in 7.1% and 2.5% respectively in the DPM-CF-302 trial.

3.19 Health-related quality of life was not reported according to rhDNase subgroup, but for the whole adult population. There were no statistically significant changes in the CFQ-R domains in either trial for adults randomised to receive mannitol relative to control group. The results suggested some improvement in the respiratory, physical and vitality domains of CFQ-R, but these did not achieve statistical significance. In DPM-CF-302, there was no statistically significant difference in HUI2measurements between adults randomised to receive mannitol and controls.

Cost effectiveness

3.20 The manufacturer developed a Markov health-state transition model, implemented as a patient level simulation model evolving over the lifetime of the patient, and modelling two treatment options: treatment with inhaled mannitol and treatment without inhaled mannitol. The manufacturer did not model inhaled hypertonic saline as a treatment option. The model assumed lifetime treatment with mannitol. The analysis had a time horizon of 100 years, at which point all patients will have died. The timescale of the initial cycle lengths were taken from the time between visits in the DPM-CF-301 and DPM-CF-302 trials, and were 6 weeks for the first cycle, 8 weeks for the second cycle and 12 weeks for each subsequent cycle. The transition parameters between the health states depended on characteristics derived from the clinical trial such as age, history of pulmonary exacerbations and use of mannitol.

3.21 The health states in the model include cystic fibrosis, cystic fibrosis with improved respiratory symptoms, lung transplantation, death from cystic fibrosis, and death from an unrelated cause. At baseline, all patients enter in the cystic fibrosis health state. As patients progress, if at any point their FEV₁% predicted falls below 30%, they enter the lung transplantation state in which they had a probability of receiving a transplant in subsequent cycles. The model includes a discontinuation rule under which patients who do not respond to mannitol treatment within 6 weeks stop mannitol and switch to best standard of care. Modelled to mirror the clinical trial, the definition of a response is either a relative increase of ≥ 5% in absolute FEV₁ or an absolute increase of ≥100 ml in FEV₁ at week 6 from baseline. In subsequent cycles, a patient may switch between the health states of cystic fibrosis and cystic fibrosis with improved respiratory symptoms and back again, and patients in either state may experience a pulmonary exacerbation. Patient characteristics such as body mass index (BMI), age and FEV₁% predicted are updated from submodels reflecting the natural history of cystic fibrosis during each cycle of the model.

3.22 The manufacturer did not use clinical effectiveness data from the DPM-CF-301 and DPM-CF-302 trials other than to obtain baseline values and some transition parameters; instead, the manufacturer derived transition parameters from the literature and from the commissioned BioGrid study, using regression analysis. The baseline characteristics age, sex, BMI and FEV₁% predicted were taken from the pooled adult population from the DPM-CF-301 and DPM-CF-302 trials. The manufacturer also used data from the trials to estimate the probability of response to mannitol, FEV₁% predicted after 26 weeks of treatment, effect of treatment on pulmonary exacerbations and in the probability ofimprovement in respiratory symptoms. The manufacturer estimated changes in FEV₁% predicted and the risk of an exacerbation after baseline from the BioGrid retrospective observational study of the disease progression of cystic fibrosis, which used data from Australia and was commissioned by the manufacturer. The decline over time in FEV₁% predicted was modelled dependent on age, age above 30 years, pulmonary exacerbations (using hospital admissions as a proxy), and FEV₁% predicted for patients. The manufacturer estimated the relationship between FEV₁% predicted and mortality rate from the BioGrid data using survival analyses. In the model, mortality also depended on concurrent infection with Burkholderia cepacia and lung transplantation. After a request for clarification from the ERG, data on these variables were provided for those who were ineligible, intolerant or who had an inadequate response to rhDNase.

3.23 Utility values were largely drawn from HUI2 data collected during the DPM-CF-302 trial; the manufacturer also included values from the literature for lung transplantation and pulmonary exacerbations. The manufacturer did not map the HUI2 data to EQ-5D data. The baseline utility was taken as the mean overall HUI2 global utility score at baseline (0.899). The manufacturer calculated the change in utility between baseline and either the visit 3/week 14 or the last visit in the case of early withdrawal. The manufacturer calculated the HUI2 global utility scores for each health state by adding the average change to the baseline utility. Utilities for parallel health states (for example, patients with improved respiratory symptoms and patients without improved respiratory symptoms) differed between treatment arms. The increase in utility for patients with improved symptoms was 0.009 in the control group and 0.019 in the mannitol group. The decrease in utility for patients without improved symptoms was 0.046 in the control group and 0.022 in the mannitol group. The HUI2questionnaire was administered at weeks 0, 12 and 26, but has a recall period of 1 week, and so did not capture the effect of PDPEs on health-related quality of life. Therefore, the manufacturer took utility data for PDPEs and post-lung transplantation from the literature. Adverse events had a negative impact on CFQ-R data in both trials.

3.24 Costs were calculated for each treatment option at 26 weeks, but the manufacturer made no distinction according to patients whose lung function improved and those whose did not. The model included costs related to pulmonary exacerbation and for the time periods before and after lung transplantation. Prices were taken from national reference costs. The manufacturer included costs for concomitant medications (mostly antibiotics) for both groups, and used a mean cost of £3253 in the mannitol group and £2972 in the control group. Nearly all patients were admitted to hospital at least once, and approximately 40% had a community visit during the 26-week randomised phase of the trial. Costs of pulmonary exacerbation were taken from the trial data. For patients receiving mannitol, the mean total cost of medications, community visits and hospitalisations without a PDPE in the 26-week trial period was £4391, and with a PDPE the cost was £12,852. For patients in the control group, the mean total costs without and with a PDPE were £4664 and £10,354 respectively. The manufacturer used peri-transplant costsfrom the UK literature and resource use from the trial and patient records. The manufacturer applied a standard discount rate of 3.5% to both costs and benefits.

3.25 The manufacturer’s base-case results indicated an incremental cost-effectiveness ratio (ICER) for mannitol compared with control (best supportive care) of £47,095 per quality-adjusted life year (QALY) gained for the adult rhDNase users and £41,074 per QALY gained for adults ineligible, intolerant or inadequately responsive to rhDNase and.

3.26 The manufacturer undertook extensive scenario analyses and deterministic sensitivity analyses. However, these did not consider populations defined by rhDNase use as in the originally proposed  therapeutic indication (the manufacturer performed analyses on rhDNase users and non-users, rather than on the rhDNase non-user subgroup for whom rhDNase was unsuitable). The parameters that changed the ICER by more than 10% were: FEV₁% predicted at baseline, the regression parameter estimate for mannitol treatment used to predict the FEV₁% predicted after 26 weeks of treatment (that is, the effect of treatment), the relative risk of an exacerbation with mannitol relative to control for people considered to be treatment responders, the relative risk of a subsequent exacerbation if there had been an exacerbation in the previous year, hazard rate of death for the FEV₁% predicted, the utility decrement associated with an exacerbation, the utility associated with no improvement in respiratory symptoms among patients using or not using mannitol, and the cost of an exacerbation.

3.27 The manufacturer also performed sensitivity analyses showing the effect of treatment failure after 1, 5, 10 and 20 years. The original model assumed that patients using mannitol maintained the gains in FEV₁% predicted over their lifetime. Not maintaining the improvements in FEV₁% predicted over the long term had a large effect on the ICER. If the improvement in FEV₁% predicted were maintained for1 year the ICER was £149,587 per QALY gained; if improvements were maintained for 5, 10 and 20 years, the ICERs were £86,981, £63,539 and £49,907 per QALY gainedrespectively. Factors from sensitivity analyses which had an impact on the ICER were the rate ratio of pulmonary exacerbations between those receiving and those not receiving mannitol, whether the discontinuation rule was applied, the relative risk of a PDPE if the patient experienced an exacerbation in the previous year, costs and utilities. Rather than providing separate analyses for rhDNAse users and rhDNAse non-users, eachcompared with best standard of care, the manufacturer provided incremental analyses that included control and the rhDNase non-user group(rather than the rhDNase unsuitable non-user group). The manufacturer concluded that the main factors affecting the ICER were the cost of mannitol, the relative risk of pulmonary exacerbations in the mannitol group, the impact of pulmonary exacerbations on quality of life, the FEV₁% predicted when starting mannitol, the improvement in FEV₁% predicted on mannitol treatment, the hazard rate of death for FEV₁% predicted and utility for patients whose symptoms do not improve.

3.28 Following a request from the ERG the manufacturer provided scenario analyses taking into account reduced adherence to treatments, which reduced the costs in the mannitol group. Using a lower mean adherence rate gave an ICER of £37,387 per QALY gained for mannitol compared with control in the rhDNase group, and £33,934 per QALY gained for mannitol compared with control in rhDNase non-users.

3.29 There was uncertainty around the relative risk of PDPE, and the model was sensitive to any fluctuation in this parameter. Using the relative risk of exacerbation associated with treatment with mannitol for the total adult population provided by the manufacturer in response to a request for clarification from the ERG, the ICER for mannitol compared with control was £54,329 per QALY gained in the rhDNase user group and £27,673 per QALY gained in the rhDNase non-user group. In the control group of rhDNAse users, 9.62 QALYs were gained using either the relative risk associated with treatment based on the total adult population or the rhDNase user population. In the mannitol group of rhDNase users, 10.42 QALYs were gained in the analysis for the relative risk based on the total adult population, and 10.27 QALYs for the relative risk based on the rhDNase user population. Using the relative risk associated with exacerbations for the rhDNase user and non-user group, the ICERs were £19,828 and £74,140 per QALY gained respectively. The QALYs gained that were presented for the mannitol rhDNase users were: 10.96 QALYs in the analysis for the relative risk based on the total adult population, and 11.14 QALYs for the relative risk based on the rhDNase unsuitable non-user population.    The QALYs gained for the control group rhDNase unsuitable non-users using either the relative risk based on the total adult population or the rhDNase unsuitable non-user population were 9.53.

3.30 In the manufacturer’s probabilistic sensitivity analyses, as an add-on therapy to best standard of care, mannitol had a 16.4% probability of being cost effective at an ICER of £30,000 per QALY gained and a 7.4% probability at an ICER of £20,000 per QALY gained. For rhDNase non-users, mannitol had a 25.8% probability of being cost effective at an ICER of £30,000 per QALY gained and a 10.9% probability at an ICER of £20,000 per QALY gained.

3.31 The manufacturer conducted two further subgroup analyses, one by baseline FEV₁% predicted and the other among patients who respond to treatment with mannitol by 6 weeks. The analyses showed that as baseline FEV₁% predicted declines, the ICER decreases. For FEV₁% predicted ≥ 80%, the ICERs were £56,228 and £50,688 per QALY gained for rhDNase users and non-users respectively. For FEV₁% predicted of 60–79%, the ICERs were £51,049 and £45,247 per QALY gained for rhDNase users and non-users respectively. For FEV₁% predicted 40-59%, the ICERs were £45,630 and £39,511 per QALY gained for rhDNaser users and non-users, respectively. For FEV₁% predicted < 40%, corresponding ICERs were £30,746 and£23,704 per QALY gained respectively.

3.32 In response to a request from the ERG for clarification to estimate the cost effectiveness separately for rhDNase users and ineligible non-users, the manufacturer re-ran the probabilistic sensitivity analysis. This resulted in mean ICERs of £53,796 per QALY gained for the rhDNase group and £30,080 per QALY gained for the group ineligible for rhDNase.

Evidence Review Group comments

3.33 The ERG regarded DPM-CF-301 and DPM-CF-302 as well designed, high-quality trials, with a large combined study population. The ERG noted that the change in therapeutic indication of mannitol limiting it to adults, which reduced the combined study population to a total of 341, and consequently reduced the statistical power of all the analyses.

3.34 The ERG conducted pooled analyses on the results of the DPM-CF-301 and DPM-CF-302 trials. These showed statistically significant differences between mannitol and control with all outcomes related to lung function. Among rhDNase users the differences between mannitol and control in the period 6 to 26 weeks were as follows: 91.8 ml (95% CI 30.85 to 152.69) for change in FEV₁, 4.6 (95% CI 1.33 to 7.80) for % change in FEV₁, 2.7 (95% CI 0.94 to 4.52) for FEV₁% predicted and 106.1 ml (95% CI 28.27 to 183.91) for FVC. For the group for whom rhDNase was unsuitable, the change in FEV₁ from week 6 to 26 was 162.3 ml (95% CI 51.77 to 272.87) (figures rounded).

3.35 The ERG’s pooled analyses showed that for the adult rhDNase users, there were no differences between mannitol and control groups in the incidence PDPE over the week 6 to 26 trial period (RR = 1.00, 95% CI 0.61 to 1.66), and no significant difference in the estimated rate of PDPE per year (RR = 1.14, 95% CI 0.75 to 1.73). In the group for whom rhDNase was unsuitable, there were also no significant differences between mannitol and control in the incidence of PDPE (RR = 0.44, 95% CI 0.18 to 1.10) over the course of the trial, but there was a significant change in absolute FEV₁. For FEV₁ non-responders, the rate of pulmonary exacerbations was 1.11 for the mannitol group and 1.08 for controls; for FEV₁ responders, the rate of pulmonary exacerbations was 0.38 for the mannitol group and 0.97 for the control group. The ERG stated that restriction of the therapeutic indication to adults meant that the analysis was under-powered, a problem compounded by the post-hoc subgroup analyses of the pooled trial data, and contributed to the uncertainty around the results.

3.36 The ERG conducted an indirect comparison of mannitol with hypertonic saline, in line with the scope. The two measures common to the identified study of hypertonic saline (0.9% saline) (Elkins et al. 2006) and the DPM-CF-301 and DPM-CF-302 trials were measurements of FEV₁ and pulmonary exacerbations. The ERG found that mannitol improved FEV₁ compared with hypertonic saline, although this was only statistically significant for the subgroup ineligible for rhDNase. The estimated difference in FEV₁ between mannitol and hypertonic saline was 94.3 ml (95% CI 29.02 to 159.62), and for the subgroup receiving rhDNase 23.8 ml (95% CI –64.95 to 112.49) (figures rounded). The ERG indicated that hypertonic saline seemed superior to mannitol in reducing pulmonary exacerbations, but the ERG did not attempt a comparison because the specific outcome measures for pulmonary exacerbations in the studies were different. The pulmonary exacerbationrates in the two trials were defined as the number of exacerbations divided by the number of participant-years of follow-up, whereas Elkins et al. reported the mean number of exacerbations per patient.

3.37 In the ERG’s view, the basic structure of the manufacturer’s Markov model was appropriate for the research question. The ERG deemed the structure of the model sufficiently inclusive and diverse to model the complexities of cystic fibrosis, but the ERG expressed some concerns about the cost-effectiveness model.

3.38 The ERG questioned the assumption by the manufacturer in the model that mannitol use was completely independent of rhDNase use (that is, that any benefit of mannitol did not depend on whether a patient used, or did not use, rhDNase). This led the ERG to reanalyse  the data according to suitability of rhDNase and to divide the group not receiving rhDNase into those who were eligible to take rhDNase and those who were ineligible to take rhDNase, in line with the proposed licence.

3.39 The ERG noted that the manufacturer had chosen not to use the results of the trials in the model, but instead had developed regression equations to estimate lung function. The ERG felt that the use of regression was appropriate for this Markov patient-level model, and noted that the manufacturer had consulted with experts on cystic fibrosis and modelling. The manufacturer also ran a microsimulation (100,000 trials) to compare the model output with the pooled results of the DPM-CF-301 and DPM-CF-302 trials. The ERG found small mistakes in the model, but noted that the validation checks matched the results of the clinical studies at a time horizon of 26 weeks.

3.40 The ERG noted that one of the most important assumptions made by the manufacturer was that any improvement in FEV₁% predicted would be maintained throughout the lifetime of the patient, and would directly translate into lower rates of morbidity and mortality. The ERG was concerned that there were no long-term data to support this assumption. The ERG questioned the manufacturer’s use of Australian BioGrid data for transition parameters and hospitalisation costs, which may not be generalisable to the UK.

3.41 The ERG was concerned about the several assumptions made by the manufacturer about pulmonary exacerbations, namely the narrow confidence intervals around the baseline rate based on the BioGrid data used in the deterministic sensitivity analysis, and questioned whether it applied to a UK population.

3.42 The ERG was concerned about the assumption made by the manufacturer that HUI2 utility and cost parameters depended on treatment, but not on health state.

3.43 The ERG conducted exploratory analyses to examine the effect on the ICER of varying the model assumptions and the input parameters, including the difference in costs and utilities associated withrespiratory symptoms and exacerbations, and the mortality rate of cystic fibrosis by varying the FEV₁% predicted. However, because of a lack of data, the ERG could not investigate the manufacturer’s assumption that the probability of moving between health states remained the same over the lifetime of the patient.

3.44 The ERG amended the model to include treatment-independent and improvement-specific values for costs and utilities; using rhDNAse subgroup-specific relative risks associating treatment with exacerbations, changing the cost of rhDNase from £16.88 to the most recentprice of £16.55 (‘British national formulary’ [BNF] 61); and adjusting model parameters, probabilities and distributions.

3.45 The ERG’s exploratory cost-effectiveness analysis included the treatment options of best standard of care, rhDNase and mannitol, but not hypertonic saline. In rhDNase users, the ERG compared mannitol plus best standard of care (including rhDNase) with best standard of care (including rhDNase). In patients ineligible, intolerant or inadequately responsive to rhDNase, the ERG compared mannitol plus best standard of care with best standard of care. These amendments resulted in the ERG’s base-case ICER for mannitol plus best standard of care compared with best supportive care of £80,098 per QALY gained for the adult rhDNase group and£29,883 per QALY gained for adults ineligible, intolerant or inadequately responsive to rhDNase. The main reasons for the changes to the ICERs were the use of health state-specific costs and utilities by the ERG rather than treatment specific costs and utilities used by the manufacturer, and the population specific relative risks for exacerbations.

3.46 The ERG investigated the relationship between improvements in FEV₁% predicted and survival, and found evidence to support the assumption that a 1 percentage pointimprovement in FEV₁% predicted was related to an approximate 5% reduction in mortality.

3.47 The ERG examined the assumption that the FEV₁%predicted improvement caused by mannitol would be maintained over the lifetime of the patient  by reducing the time horizon of the model as a proxy for a shorter duration of effectiveness. This was similar to the scenario analysis conducted by the manufacturer. The ERG’s analyses resulted in ICERs for a time horizon of 5 years of £188,551 per QALY gained for rhDNase users, and £90,126 per QALY gained for those ineligible for rhDNase. For a time horizon of 10 years, the corresponding ICERs were £127,625 and £49,854 per QALY gained respectively.   

3.48 The ERG pointed out that the manufacturer had generated cost data based on whether a patient received mannitol or not, rather than whether the patient was in a given health state. The manufacturer divided costs according to respiratory symptoms or according to rhDNase use, but did not stratify costs by both factors simultaneously. The ERG used the information available to calculate the ratio of the improvement-specific costs to the overall mean costs as an estimate of the difference in costs by health state. The ERG calculated that patients with improved respiratory symptoms have 93% of the overall costs, whereas those without improved symptoms have 105% of the overall costs. The ERG assumed these percentages also applied to rhDNase mean costs. The ERG did not provide separate ICERs using these differential costs, but derived estimated 6-month treatment costs for improved and not improved respiratory symptoms in rhDNase users and ineligible non-users. The ERG concluded that health state-specific costs should be used rather than treatment-specific costs.

3.49 The ERG re-ran the probabilistic sensitivity analyses with assumptions based on its exploratory analyses and calculated that there was a zero probability that the ICER for mannitol would lie below £30,000 per QALY gained for rhDNase users. For those for whom rhDNase was unsuitable, the probability that the ICER would be below £20,000 per QALY gained was 5%, and the probability it would be below £30,000 was 50%.

3.50 The ERG considered the health-related quality of life data provided by manufacturer in the form of HUI2 data collected in the DPM-CF-302 trial, and questioned the use of treatment-dependent values for utility. For its own sensitivity analyses, the ERG used values for utilities received from the manufacturer in response to a request for clarification and assumed that these values were independent of treatment. The manufacturer and the ERG did not identify any other substantial health-related benefits not included in the QALY, apart from the possible reduction in burden of treatment related to inhaling a dry powder rather than a nebulised solution.

3.51 The factors identified by the ERG as causing significant differences in the ICERs generated by the ERG and the manufacturer were the post-hoc stratification of rhDNase groups, the assumption that any improvement in FEV₁% predicted caused by mannitol would be sustained over the patient’s lifetime, the assumption that patients whose condition did not respond to mannitol would discontinue therapy, and the effect of pulmonary exacerbations on utility. There was also theuncertainty engendered by the lack of hypertonic saline as a comparator.

3.52 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/guidance/TAXXX

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of mannitol, having considered evidence on the nature of cystic fibrosis and the value placed on the benefits of mannitol by people with cystic fibrosis, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

Clinical practice

4.2 Committee discussed the clinical need of people with cystic fibrosis. It heard from clinical specialists that cystic fibrosis is a multifaceted condition that leads to considerable morbidity and early mortality. The clinical specialist stated that there is no one standard care pathway in the UK, with clinicians working with CF Centres to decide on treatment according to the individual patient’s needs. She 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 age 30 years. Clinicians and patients achieve this 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 specialist that best standard of care for cystic fibrosis has a complex treatment pathway, 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 antibiotics for Pseudomonas, 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 as an add-on therapy to best standard of care. Clinical experts agreed with the Committee, noting that following treatment with rhDNase, a patient would be offered either mannitol or hypertonic saline, but stated that they could also imagine a further scenario in which patients were offered both mannitol and 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 experts. The Committee concluded that mannitol would be used currently as an add-on therapy to best standard of care, but that there was uncertainty whether patients would use it as an alternative to nebulised therapies (in particular hypertonic saline). 

4.4 The Committee considered a patient’s experience of cystic fibrosis, which involves a number of 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. The Committee heard from the patient expert and clinical specialist 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 those 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 provided by the NHS without prescription charges.  The Committee considered that there were potential advantages to patients of having a wider choice of treatment options. The Committee concluded that cystic fibrosis 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 less time to administer.  

Clinical effectiveness

4.5 The Committee considered the manufacturer’s and the ERG’s interpretations of the original decision problem (set out in the scope) based on the original proposed therapeutic indication andthe impact of the change in the approved marketing authorisation on the decision problem currently under consideration. The Committee noted that the manufacturer’s submission was in line with the original anticipated marketing authorisation, and did not reflect the current approved marketing authorisation. Specifically, the submission was for the treatment of cystic fibrosis in adults aged 18 years and over as an add-on therapy to rhDNase, and in patients ineligible, intolerant, or inadequately responsive to rhDNase, whereas the final positive Committee for Medicinal Products for Human Use (CHMP) opinion is for mannitol for the 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 manufacturer did not explain for whom rhDNase was unsuitable, specifically thosewho were ineligible, intolerant, or inadequately responsive to rhDNase. The clinical specialist explained that those ineligible to take rhDNase were those not fulfilling the eligibility criteria for treatment with mannitol within the trials. The Committee heard from the clinical expert that the use of rhDNase varies geographically within the NHS. The Committee heard that approximately 40% of patients with cystic fibrosis use nebulised hypertonic saline. The Committee also 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. The Committee concluded that the analyses carried out for the populations described as rhDNase users and those ineligible, intolerant, or inadequately responsive to rhDNase would reflect the population in the marketing authorisation.

4.6 The Committee considered the evidence submitted by the manufacturer on the clinical effectiveness of mannitol. The Committee noted that limiting the analysis to adults reduced the population to almost half of the original population of the two trials, and that differentiating according to rhDNase use, and then further according torhDNase suitability, further reduced the statistical power of these post-hoc analyses. The Committee was concerned about the absence of the trial protocols from the manufacturer’s submission, and therefore could not fully understand the design of the trials and their analyses. The Committee concluded there were significant concerns about the post-hoc stratification and the resulting small number of patients included in the analyses, particularly given the lack of access to the trial protocols. Furthermore, the Committee considered the trial design and whether the initial study protocol was designed to assess the primary outcome as absolute FEV₁ from weeks 6 to 26, as confirmed by the manufacturer during the Committee meeting, or from weeks 0 to 26, as presented in the manufacturer’s submission, and the influence that this would have on the validity of the results. The Committee noted that a considerable number of study participants did not proceed to randomisation. The Committee concluded there were significant concerns about the design of the trials and the resulting analyses, and that these factors  increased the uncertainty in the results.

4.7 The Committee heard from the manufacturer that 50 mg mannitol twice daily was used as placebo in the trials  following 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 week 6 to week 26 by 52.4 ml in the DPM-CF-302 trial. 

4.8 The Committee considered the outcomes used in the trials, and how these differed from those used in clinical practice in adults with cystic fibrosis. The Committee questioned the selection of FEV₁ measurements in the trial and in the economic model. It noted that the primary outcome in the two trials was absolute FEV₁, but that the measurement of lung function used in the model was FEV₁% predicted.  The Committee also noted that the manufacturer’s submission created a definition of responders as those whose (absolute) FEV₁ improved by 100 ml or ≥5%, or whose FEV₁% predicted improved by 5 percentage points.The Committee heard from clinical specialists that both absolute FEV₁ and FEV₁% predicted measurements are used in clinical practice, that between 75 and 100 ml absolute FEV₁ change is clinically meaningful, and that FEV₁% predicted is used for children and to compare adult patients with their peers. The Committee noted that in the trials patients who did not meet the definition of response stopped treatment at 6 weeks. The clinical specialist explained that this differed from 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 FEV₁% predicted 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 was not convinced that clinicians and patients would adhere to the stopping criteria assumed within the manufacturer’s submission. 

4.9 The Committee considered whether the two trials presented were equivalent, as the lower end of the FEV₁% predicted eligibility criteria differed between the two studies. The clinical specialist explained that 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 the difference in the regulations of the Food and Drug Administration (FDA) and European Medicines Agency (EMA) pertaining to the lower limit of FEV₁% predicted for inhaled substances. The Committee discussed the use of imputed height calculations for the FEV₁% predicted data, but the manufacturer was unable to provide information on how many individual measurements were adjusted in this way, thereby increasing uncertainty about the robustness of the manufacturer’s clinical outcomes. The Committee was concerned about the way in which the two trials were blinded, and whether there was likely to have been functional unblinding. It was also concerned that mannitol might cause rebound bronchoconstriction, but acknowledged that patients had undergone a mannitol tolerance test before entering the trials. The Committee heard from the clinical specialist that rebound bronchoconstriction did not occur in the trials. Overall, the Committee concluded that the two 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.   

4.10 The Committee considered the analysis of the trials. In particular, the Committee was concerned that the manufacturer used the FEV₁ value established at the screening stage prior to baseline as a covariate when analysing the randomised control trials. When questioned, the manufacturer did not explain why it had done this. The Committee further noted that the manufacturer had not provided the unadjusted figures for the absolute FEV₁ at week 0. The Committee considered that there may have been differences in patients entering the trial, but concluded that any differences would have been compensated by randomisation rather than being adjusted for as a covariate. The Committee was concerned that the manufacturer chose to omit data from weeks 0 to 6 and use data from weeks 6 to 26 only. The manufacturer and clinical specialist explained that this was a common way of designing trials for drugs for cystic fibrosis, that there is often an ‘overemphasised’ lead-in period, and that using data from week 6 rather than week 0 was a way to mitigate this effect. However, the Committee was not persuaded that the analyses of the trials represented the data accurately and completely. 

4.11 The Committee discussed the lack of hypertonic saline as a comparator in the manufacturer’s submission, despite being included in the scope and the ERG’s indirect comparison. The Committee heard from the manufacturer and the ERG that there were difficulties in comparing the two, in particular because of the heterogeneity in the outcome measures 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 relative to the use of isotonic saline, and heard that the clinical specialists considered the review to be well-performed and valid. The Committee considered the heterogeneity of the studies available for hypertonic saline and the model presented by the manufacturer. It noted that the outcome measures for pulmonary exacerbations used in the review of hypertonic saline treatment were different from those used in the mannitol trials. The Committee acknowledged that there was little evidence to compare hypertonic saline with mannitol, but recognised that, although not within the context of the marketing authorisation, mannitol may replace hypertonic saline in clinical practice in the UK. 

4.12 The Committee considered the relationship between absolute 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 clinical specialists noted that rhDNase improves pulmonary exacerbations, but not FEV₁, in some trials, although the trials for mannitol seemed to indicate that in DPM-CF-301 and DPM-CF-302 the improvement in FEV₁ was linked to a decrease in the number of pulmonary exacerbations. The Committee noted that the average rate of pulmonary exacerbations was lower in patients considered responders than in non-responders in DPM-CF-301. The Committee questioned the lower incidence of pulmonary exacerbations in the rhDNase non-users compared with rhDNase users in DPM-CF-301, and the reverse in DPM-CF-302, but the manufacturer could not explain this difference. The Committee concluded that improvements in FEV₁ and pulmonary exacerbations with mannitol would be clinically significant, but there was uncertainty about the magnitude of the effect of mannitol on these outcomes.

4.13 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 specialist that productive cough was seen as a positive effect whereas irritating cough was seen as negative, but noted that learning to control cough was an important part of managing cystic fibrosis. The patient expert discussed the experience of using current therapies, and how the negative events (such as unpleasant taste and sensations) affect her daily life and increase the burden of treatment. 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 the week-long recall period, 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 a number of 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.

4.14 The Committee considered how each trial had collected quality of life data. Both trials collected CFQ-R data, and DPM-CF-302 also collected HUI2, but none of these results showed statistically significant differences between the mannitol and control groups. The Committee noted that the manufacturer had not submitted EQ-5D quality of life 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 patients often rate 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 concluded that current measures of quality of life may not accurately capture the consequences of having cystic fibrosis on perceived and actual health-related quality of life.

4.15 In summary, the Committee concluded that there was evidence from the trial data to show that mannitol has a positive clinical effect on lung function in the short term but there was uncertainty about the magnitude of the effect of mannitol.

Cost effectiveness

4.16 The Committee considered the manufacturer’s cost-effectiveness analysis and the ERG’s critique and exploratory analyses. It noted that the manufacturer used a patient-level simulation model to evaluate the cost-effectiveness of mannitol compared with best standard care for rhDNase users and those ineligible, intolerant, or inadequately responsive 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 two mannitol trials and from the literature, and incorporated them into the model through regression analysis. The Committee noted that the structure of the 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 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, as well as the assumption that HUI2 utility and cost parameters depended on treatment, and not on health state. The Committee concluded that the cost-effectiveness model was complex and may not adequately reflect the clinical trial data. 

4.17 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, despite the trials’ primary outcomes being absolute FEV_1, and that the FEV₁ measure had not been incorporated within the structure of the model. The manufacturer stated that the FEV₁% predicted was used because it was considered the most appropriate outcome for the children in the trials, and the Committee understood that the manufacturer did not change the model when the population changed to adults only.  

4.18 The Committee considered the assumptions and variables incorporated into the manufacturer’s model. The manufacturer had assumed that mortality was a function only of FEV₁% predicted and the presence or absence of Burkholderia cepacia infection, as well as 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, and particularly noted that body mass index was not included in the manufacturer’s mortality calculations, whereas it was a parameter for other variables within the model. In addition, the Committee noted that the hazard ratio associated with Burkholderia cepacia infection was significantly greater in the manufacturer’s analysis than than in multivariate survival analyses of UK and US registry data. 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 within the manufacturer’s model may not accurately reflect mortality in cystic fibrosis. The Committee concluded that the model underestimated the mortality rate, and that a higher mortality rate would increase the ICER.

4.19 The Committee considered the assumption used in the model derived from the Australian BioGrid study that, for a patient without exacerbations, FEV₁% predicted declines with time until age 30 years, and then begins to rise, an assumption which the clinical specialists noted to be unrealistic. Given that there is a rise in the rate of pulmonary exacerbations with age, the Committee considered it was difficult to interpret the evidence provided by the regression model. The Committee also noted that the manufacturer did not consider the effect of treatment with mannitol on body mass index, even though body mass index was a parameter in the model used to estimate FEV₁% predicted. The Committee was concerned that the search strategy employed by the manufacturer in constructing the model may have excluded relevant UK data which would have more accurately informed estimates of pulmonary function and mortality. The Committee concluded that there was significant uncertainty surrounding the assumption that FEV₁% predicted changed with age and that the use of UK data would have been more appropriate. 

4.20 The Committee considered the lack of hypertonic saline as a comparator in the cost-effectiveness analyses. The Committee concluded that the available evidence on hypertonic saline could not currently be incorporated into the manufacturer’s model, and that the cost effectiveness of mannitol compared with hypertonic saline could not be established.

4.21 The Committee considered the assumption that the benefits in FEV₁% predicted from treatment with mannitol observed at week 26 would be maintained over the patient’s lifetime, and whether this was likely in clinical practice. The Committee noted that this would delay, but possibly not prevent, future lung transplants. The Committee was concerned that the improvement in FEV₁% predicted with mannitol over time in the model meant that the mortality risk would decline over time which the Committee considered to be implausible. 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. The Committee noted that the assumption of a maintained long term benefit of mannitol would affect  the ICER favourably, but that there was significant uncertainty around this assumption and the manufacturer had not explored the effect of tapering of benefit through sensitivity analyses. The Committee noted the sensitivity analyses carried out by the manufacturer and the ERG in which the time horizon was shortened, which could be used as a proxy for a shorter duration of benefit, and that the ICERs were considerably increased. The Committee was not convinced that the clinical benefits on FEV₁ of mannitol would be maintained long term as modelled by the manufacturer and that this was likely to underestimate the ICER.      

4.22 The Committee considered the effect on the ICERs of varying adherence to treatment and of stopping rules, and noted that the model did not incorporate the effect of varying these factors. The Committee considered the ERG’s sensitivity analysis of reduced adherence, but noted that the manufacturer had not incorporated the possibility of declining adherence over time. The Committee also considered the effect of the stopping rule, having heard from the clinical specialist that clinicians and patients would be unlikely to follow the trials’ stopping rule in clinical practice. The Committee concluded that the model did not adequately reflect adherence to treatment and to stopping rules, and that the ICERs were likely to be higher if the model reflected clinical practice.   

4.23 The Committee considered that adverse events 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 sometimes haemoptysis was a symptom of cystic fibrosis, but that severe haemoptysis was a significant adverse reaction. The Committee concluded that the economic model had not incorporated the specific impact of adverse reactions on the health-related quality of life of people with cystic fibrosis and that their inclusion could increase the ICER. 

4.24 The Committee considered the internal validity of the model. The Committee considered the relationship between FEV₁% predicted and lung transplantation in the model, however, the relationship could not be fully explained by the manufacturer or the ERG. The Committee heard from the ERG that the proportion of patients alive at age 55 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 patients with cystic fibrosis are still alive at age 50, but the clinical specialist questioned the validity of this number from Cystic Fibrosisregistry data. The Committee questioned the assumption that the total QALYs gained were higher for those taking mannitol alone than for those taking mannitol as an add-on treatment. The Committee was concerned that when the relative risk for the individual subgroups was used in the model, more QALYs were gained with mannitol in the rhDNase non-user group than in the rhDNase user group. The Committee heard from the manufacturer that this was possibly because of the small sample size in the rhDNase ineligible non-user group. The utility increase in patients with improved respiratory symptoms was greater in the mannitol group than in the control group, whereas the utility decrement for patients without improved symptoms was greater in the control group than in the mannitol group. The Committee concluded that utility values for specific health states would either not differ between treatment arms or would possibly favour the control group, who would be experiencing fewer adverse reactions. The Committee concluded that there were significant issues with the internal validity of the model, and that this would increase the uncertainty around the ICERs.

4.25 The Committee considered the quality of life measurements collected in the two mannitol trials and used in the model. 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. The Committee was also aware that the model was sensitive to the baseline utility with the ICER increasing as the baseline utility decreased. The Committee was concerned about the use of HUI2 data rather than the EQ-5D preferred by NICE, noting that there are 8000 health states defined by the HUI2 questionnaire, as opposed to 243 defined by the EQ-5D. The Committee noted that this may account for small changes in quality of life observed in the trial and result in increased uncertainty about valuing quality of life with cystic fibrosis in the long term. The Committee concluded that it was not convinced that the health-related quality of life of the health states had been appropriately valued and incorporated into the model, and that this led to increased uncertainty around the calculated ICERs for mannitol compared with best standard of care.

4.26 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 within 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. The Committee considered whether this was likely to be an accurate reflection of real life, as the Committee heard from the patient expert that there were significant quality of life improvements in taking an inhaled treatment, such as mannitol. The Committee concluded that there was uncertainty about the accuracy of quality of life data and the projected benefits of mannitol on life expectancy, and as a consequence there was further uncertainty in both directions as to the robustness of the modelled ICERs.

4.27 The Committee considered the costs used in the model. The Committee noted that the costs presented by the manufacturer were treatment specific rather than health state specific, as highlighted by the ERG. The Committee considered that the use of health state-specific costs was more appropriate. The Committee concluded that the ERG modelling incorporating health state-specific costs was more appropriate.

4.28 The Committee considered the ICERs produced by the manufacturer and the ERG. The Committee noted that original ICERs presented in the manufacturer’s submission were not presented according to the population specified in the scope, but were adjusted in the clarification phase of the appraisal. The Committee noted that the base-case ICERs presented by the manufacturer and the ERG were above £30,000 for both the rhDNase user and ineligible non-users. The Committee noted that the manufacturer’s probabilistic ICERs were £27,673 per QALY gained in the rhDNase non-user group and £54,329 per QALY gained in the rhDNase user group and the ERG’s estimates were £30,080 per QALY gained for those ineligible for rhDNase and £53,796 per QALY gained for the rhDNase group. However, the Committee considered there was considerable uncertainty regarding the robustness of the model and concluded that incorporating the uncertainty around the parameter estimates increased the ICERs. The Committee concluded that the ICERs for mannitol were unlikely to fall below £30,000 per QALY gained. 

4.29 The Committee considered the sensitivity analyses undertaken by both the manufacturer and the ERG. It noted that these analyses did not provide sufficient or specific details of the influence of key parameters and assumptions for it to understand which of these key factors had the greatest influence on the ICERs. The Committee considered that the factors likely to have the most effect in the model were the duration of the effect of mannitol, the relationship between measured outcomes, health-related quality of life and mortality, and the baseline FEV₁, but it concluded that only more extensive sensitivity analyses would allow a better understanding of the uncertainty around the ICERs. 

4.30 The Committee considered the subgroup defined by baseline FEV₁% predicted of <40 in the rhDNase ineligible subgroup. The ICER for this subgroup was the only one presented by the manufacturer which was less than £30,000 per QALY. However, the Committee considered that there was insufficient evidence to model the resources specifically for this subgroup, and that the manufacturer had identified this subgroup post-hoc, generating considerable uncertainty regarding the effectiveness of treatment in this subgroup, the proportion of patients within this subgroup who were specifically ineligible, unresponsive, or intolerant to rhDNase, and the subgroup-specific impact of treatment on health-related quality of life. Consequently the Committee concluded that it was unable to assess the clinical and cost effectiveness of mannitol treatment in this subgroup, and that the evidence was not sufficiently robust to support a separate recommendation.    

4.31 The Committee discussed whether mannitol should be considered an innovative technology, or if there were any significant and substantial health benefits which were not included in the economic model. It heard from clinical specialists and patient expert that the treatment burden is significantly 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 included all potential benefits associated with mannitol treatment. The Committee concluded that treatment with an inhaler provided practical advantages over treatment with nebulisers, but because mannitol as an add on therapy would not replace the use of nebulisers, and so could not be considered a step change in treatment. The Committee agreed  that no additional health-related benefits had been identified which had not been adequately captured by the economic model.

4.32 The Committee considered whether NICE’s duties under the equalities legislation required it to alter or to add to its recommendations. The Committee noted that the manufacturer did not raiseany equality issues in its submission. The only equalities issue raised by the consultees was whether the inhaler used for mannitol inhalation would present a disproportionate burden on patients with physical disabilities, but the Committee noted the clinical specialists’ and patient expert’s view that current treatments would present more difficulties. The Committee concluded that its preliminary recommendations did not differentiate between any groups of people and did not limit access compared with other groups and that there was no need to alter or add to its recommendations.

4.33 The Committee concluded that the ICERs based on using subgroup specific effectiveness values would be the starting point for its decision and noted that the ERG’s analyses led to ICERs above £30,000 per QALY gained. However, the Committee agreed that these ICERs were associated with considerable uncertainty, because of the small numbers resulting from post-hoc stratification of the trial data, the uncertainty generated by the use of data from week 6 rather than baseline, and the questions surrounding the structure of the model. Additionally, there were factors that the Committee agreed would increase the ICERs, including the use of utility values by health state rather treatment arm, alternative assumptionssurrounding the long-term effect of mannitol on lung function and pulmonary exacerbations, the consequent unreliability in the efficacy estimates, and the use of UK specific data on natural history of the disease. Therefore, the Committee concluded that mannitol could not be considered a cost-effective use of NHS resourcesfor the treatment of cystic fibrosis.   

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title:		Section
Key conclusion
Mannitol is not recommended for the treatment of cystic fibrosis in adults as an add-on therapy to best standard of care. The Committee concluded that the ICERs based on using subgroup specific effectiveness values would be the starting point for its decision and noted that the ERG’s analyses led to ICERs above £30,000 per QALY gained. However, the Committee agreed that these ICERs were associated with considerable uncertainty, because of the small numbers resulting from post-hoc stratification of the trial data, the uncertainty generated by the use of data from week 6 rather than baseline, and the questions surrounding the structure of the model. Additionally, there were factors that the Committee agreed would increase the ICERs, including the use of utility values by health state rather treatment arm, alternative assumptions surrounding the long-term effect of mannitol on lung function and pulmonary exacerbations, the consequent unreliability in the efficacy estimates, and the use of UK specific data on natural history of the disease. Therefore, the Committee concluded that mannitol could not be considered a cost-effective use of NHS resources for the treatment of cystic fibrosis.			1.1 4.33
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee heard from the patient expert and clinical specialist that current treatments are difficult to use and do not encourage adherence. The Committee concluded that cystic fibrosis had a major impact on the quality of life of patients and their carers.	4.4
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The patient expert explained the difficulties in adhering to treatments, and felt that using mannitol with an inhaler would be easier than using hypertonic saline with a nebuliser and would likely encourage adherence. The Committee heard from clinical and patient experts that the treatment burden is significantly less for an inhaler than for a nebuliser. However, the Committee concluded that mannitol could not be considered innovation step change as it would not replace nebulisers.	4.4 4.31
What is the position of the treatment in the pathway of care for the condition?		The Committee noted the new proposed licence as an add-on therapy to best standard of care. Clinical experts agreed, noting that following treatment with rhDNase, a patient would be offered either mannitol or hypertonic saline, but stated that they could also imagine a further scenario in which patients were offered both mannitol and hypertonic saline. The Committee concluded that mannitol would be used currently as an add-on therapy to best standard care, but that there was uncertainty whether it would be likely to be used as a replacement for nebulised therapies in clinical practice.	4.3
Adverse reactions		The Committee considered the possible adverse reactions associated with mannitol, notably cough and haemoptysis.  The Committee noted that there are different types of cough, and some are considered beneficial. The Committee noted that haemoptysis was the most clinically significant adverse event associated with mannitol use, and that it would require monitoring. The Committee concluded that the treatment of cystic fibrosis can cause a number of moderate and severe adverse reactions, and that it can be difficult to establish the effect of adverse reactions on health-related quality of life.	4.13, 4.23
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The evidence of clinical effectiveness was derived from two randomised multi-national double-blinded control trials (DPM-CF-301 and DPM-CF-302). The trials were designed to assess the effectiveness of twice-daily mannitol at a dose of 400 mg compared with mannitol at a dose of 50 mg in addition to best supportive care with or without rhDNase. The trials had 26-week double-blind phases, followed by an unblinded phase of 26–52 weeks. The inclusion and exclusion criteria for the two trials were similar. The adult-only intention-to-treat population was 341. Differentiating this population into rhDNase users and non-users, and then into different populations of rhDNase non-users (those ineligible, intolerant, or inadequately responsive to rhDNase) further reduced the statistical power of the analyses.  The Committee noted the omission of the trial protocol from the manufacturer’s submission.	3.1 4.6
Relevance to general clinical practice in the NHS		The Committee heard from the clinical specialist that best standard of care in the UK varies from patient to patient, that best standard of care for cystic fibrosis has one of the most complex treatment pathways within the NHS, that approximately 98% of patients 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 discussed the variability of access to rhDNase across the UK, and whether patients who were ineligible for rhDNase would be eligible for mannitol under the marketing authorisation.	4.2
Uncertainties generated by the evidence		The Committee noted that there were significant concerns about the post-hoc stratification into rhDNase and lung function subgroups.  The small numbers in these analyses increased uncertainty and reduced the statistical power of the trial results. The Committee noted that hypertonic saline was not presented as a comparator, and consequently there were difficulties in establishing the role of mannitol in the treatment pathway, because although not within the context of the marketing authorisation, mannitol may replace hypertonic saline in clinical practice in the UK.	4.5, 4.6, 4.11
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		The Committee noted that the manufacturer did not provide a clear explanation defining who was unsuitable to use rhDNase, specifically those ineligible, intolerant, or inadequately responsive to rhDNase. The clinical expert explained that rhDNase ineligibility was defined as not fulfilling the eligibility criteria for treatment with mannitol within the trials, and that the criteria for deciding who can and cannot take rhDNase varies geographically within the NHS. The Committee concluded that that appropriate populations for consideration were rhDNase users and those ineligible, intolerant, or inadequately responsive to rhDNase. The Committee also considered subgroups defined by lung function, notably baseline FEV1% predicted of <40 in the rhDNase unsuitable subgroup.  However, the Committee considered that the manufacturer identified this subgroup post-hoc, generating considerable uncertainty regarding the effectiveness of treatment in this group, the proportion of patients within this subgroup who are specifically ineligible, unresponsive, or intolerant to rhDNase,.  Consequently the Committee concluded that it was unable to address the effectiveness of mannitol therapy in this subgroup, and that the evidence was not sufficiently robust to support a separate recommendation.	4.5, 4.30
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee considered the relationship between absolute FEV1 and pulmonary exacerbations. The Committee heard from the clinical specialists that the relationship between FEV1 and pulmonary exacerbations has not historically been found to be linear. The clinical specialists noted that rhDNase improves pulmonary exacerbations but not FEV1 in some trials, although the trials for mannitol seemed to indicate that the improvement in FEV1 was linked to a decrease in the number of pulmonary exacerbations. The Committee concluded that improvements in FEV1 and pulmonary exacerbations with mannitol would be clinically significant, but there was uncertainty about the magnitude of the effect of mannitol on these outcomes.	4.12
Evidence for cost effectiveness
Availability and nature of evidence		The manufacturer developed a Markov health-state transition model, taking into account individual patient pathways over a life time horizon, and modelling two treatment options: treatment with inhaled mannitol and treatment without inhaled mannitol. The manufacturer did not model inhaled hypertonic saline as a treatment option. The manufacturer did not use clinical effectiveness data from the trials presented in the submission other than to obtain baseline values and some transition parameters; instead, the manufacturer derived transition parameters from the literature and from its own commissioned studies, and incorporating them into the model through regression analysis. The Committee noted that the structure of the model was not a health state model, but rather was a model of the cystic fibrosis treatment pathway.	3.20, 3.21 3.22 4.16
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee was aware of the ERG’s concerns about the manufacturer’s assumptions that any improvement in FEV1 would be maintained throughout the lifetime of the patient, and that it would be directly translated into lowered morbidity and mortality rates, as well as the assumption that HUI2 utility and cost parameters depended on treatment, and not on health state. The Committee concluded that the cost-effectiveness model was complex and may not adequately reflect the clinical trial data.  It was concerned about the limited number of variables incorporated into the model, and that there were other models of cystic fibrosis that had incorporated a greater variety of variables.  The Committee also noted the implausibility of the assumption made based on the BioGrid data that FEV1 increases after age 30.	4.16, 4.17, 4.18, 4.19
Incorporation of health-related quality-of-life benefits and utility values 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 Committee noted that the complexity and number of comorbidities associated with cystic fibrosis and the treatment burden were not adequately reflected in quality of life measurements. The Committee was also aware that the model was sensitive to the baseline utility with the ICER increasing as the baseline utility decreased. The Committee was concerned by the use of HUI2 data rather than EQ-5D. The Committee concluded that it was not convinced that health-related quality of life of patients with cystic fibrosis had been appropriated valued and incorporated into 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.  The Committee agreed with the manufacturers statement at the meeting that the model included all potential benefits associated with mannitol treatment, and that no additional health-related benefits had been identified which had not been adequately captured by the economic model.	4.23, 4.25, 4.26, 4.31
Are there specific groups of people for whom the technology is particularly cost effective?		The Committee considered the subgroup defined by baseline FEV1% predicted of <40 in the rhDNase unsuitable subgroup. The ICER presented for this subgroup was the only one presented by the manufacturer with an estimated ICER of less than £30,000 per QALY gained. However, the Committee considered that there was insufficient evidence to model the resources specific to this subgroup, and that the manufacturer identified this subgroup post-hoc, generating considerable uncertainty regarding the effectiveness of treatment in this group, the proportion of patients within this subgroup who are specifically ineligible, unresponsive, or intolerant to rhDNase, and the subgroup-specific impact of treatment on health-related quality of life. Consequently the Committee concluded that it was unable to assess the clinical and cost effectiveness of mannitol treatment in this subgroup, and that the evidence was not sufficiently robust to support a separate recommendation.	4.30
What are the key drivers of cost effectiveness?		The Committee considered the sensitivity analyses undertaken by both the manufacturer and the ERG. It noted that these analyses did not provide sufficient or specific details of the influence of key parameters and assumptions for it to understand which of these key factors had the greatest influence on the ICERs.  The Committee considered that the most probable factors driving the model were the duration of the effect of mannitol, the relationship between measured outcomes, HRQoL and mortality, and the baseline FEV1.	4.29
Most likely cost-effectiveness estimate (given as an ICER)		The Committee agreed that the ERGs base case ICER of more than £30,000 per QALY gained would be the starting point for its decision. However, the Committee considered there was considerable uncertainty regarding the robustness of the model and concluded that incorporating the uncertainty around the parameter estimates increased the ICERs.	4.28, 4.29
Additional factors taken into account
Patient access schemes (PPRS)		Not applicable
End-of-life considerations		Not applicable
Equalities considerations and social value judgements		The only equalities issue raised was whether the inhaler used for mannitol inhalation would present a disproportionate burden on patients with physical disabilities, but the Committee noted the clinic and patient experts’ view that current treatments would present more difficulties than would mannitol. Given that the preliminary recommendations did not differentiate between any groups of people, the Committee concluded that its recommendations did not limit access to the technology for any specific group compared with other groups and that there was no need to alter or add to its recommendations.	4.32

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Related NICE guidance

There is no related guidance for this technology.

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in November 2015. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Amanda Adler
Chair, Appraisal Committee
May 2012

Appendix A: Appraisal Committee members and NICE project team

A Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Amanda Adler (Chair)
Consultant Physician, Addenbrooke's Hospital

Professor Ken Stein (Vice Chair)
Professor of Public Health, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Professor Keith Abrams
Professor of Medical Statistics, University of Leicester

Dr Ray Armstrong
Consultant Rheumatologist, Southampton General Hospital

Dr Jeff Aronson
Reader in Clinical Pharmacology, University Department of Primary Health Care, University of Oxford

Dr Peter Barry
Consultant in Paediatric Intensive Care, Leicester Royal Infirmary

Professor John Cairns
Professor of Health Economics Public Health and Policy, London School of Hygiene and Tropical Medicine

Mark Chapman
Health Economics and Market Access Manager, Medtronic UK

Eleanor Grey
Lay member

Dr Neil Iosson
General Practitioner

Terence Lewis
Lay Member

Professor Ruairidh Milne
Director of Strategy and Development and Director for Public Health Research at the National Institute for Health Research (NIHR) Evaluation, Trials and Studies Coordinating Centre at the University of Southampton

Dr Rubin Minhas
General Practitioner and Clinical Director, BMJ Evidence Centre

Dr Elizabeth Murray
Reader in Primary Care, University College London

Dr Peter Norrie
Principal Lecturer in Nursing, DeMontfort University

Professor Stephen Palmer
Professor of Health Economics, Centre for Health Economics, University of York

Dr Sanjeev Patel
Consultant Physician & Senior Lecturer in Rheumatology, St Helier University Hospital

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Dr John Rodriguez
Assistant Director of Public Health, NHS Eastern and Coastal Kent

Alun Roebuck
Consultant Nurse in Critical and Acute Care, United Lincolnshire NHS Trust

Navin Sewak
Primary Care Pharmacist, NHS Hammersmith and Fulham

Roderick Smith
Finance Director, West Kent Primary Care Trust

Cliff Snelling
Lay Member

Marta Soares
Research Fellow, Centre for Health Economics, University of York

Professor Rod Taylor
Professor in Health Services Research, Peninsula Medical School, Universities of Exeter and Plymouth

Tom Wilson
Director of Contracting & Performance, NHS Tameside & Glossop

Dr Nerys Woolacott
Senior Research Fellow, Centre for Health Economics, University of York

B NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Dr Grace Jennings
Technical Lead(s)

Dr Bhash Naidoo
Technical Adviser

Jeremy Powell
Project Manager

Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by Kleijnen Systematic Reviews:

• Riemsma R, Maiwenn J et al. Mannitol dry powder for inhalation for the treatment of cystic fibrosis, Kleijnen Systematic Reviews (April 2011)

B The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

• Pharmaxis

II Professional/specialist and patient/carer groups:

• Association of Respiratory Nurse Specialists
• British Thoracic Society
• Cystic Fibrosis Trust
• Royal College of Nursing
• Royal College of Paediatrics & Child Health
• Royal College of Physicians
• United Kingdom Clinical Pharmacy Association

III Other consultees:

• Department of Health
• Sandwell PCT
• Welsh Assembly Government

IV Commentator organisations (did not provide written evidence and without the right of appeal):

• British National Formulary
• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• NHS Quality Improvement Scotland
• Roche Products

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on mannitol by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Mrs Penny Agent, Deputy Director of Rehabilitation & Therapies, Royal Brompton & Harefield HS Foundation Trust, nominated by Pharmaxis – clinical specialist
• Dr Diana Bilton, Consultant Physician, Royal Brompton Hospital, nominated by Pharmaxis – clinical specialist
• Mrs Emma Lake, Senior Clinical Care Patient Advisor, the Cystic Fibrosis Trust, nominated by the Cystic Fibrosis Trust – patient expert

D The following individuals were nominated as NHS Commissioning experts by the selected PCT allocated to this appraisal. They gave their expert/NHS commissioning personal view on mannitol by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Alexis Macherianakis, Consultant in Public Health Medicine, Sandwell PCT, selected by Sandwell PCT – NHS Commissioning expert

E Representatives from the following manufacturer/sponsor attended Committee Meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Pharmaxis