glycopyrronium in a Swedish healthcare setting

Respiratory Medicine (2014) 108, 1786e1793

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.elsevier.com/locate/rmed

Cost-effectiveness of the LABA/LAMA dual bronchodilator indacaterol/glycopyrronium in a Swedish healthcare setting David Price a, Dorothy Keininger b, Madlaina Costa-Scharplatz c,*, Karen Mezzi b, Maria Dimova d,1, ¨rn Sta ¨llberg e Yumi Asukai d, Bjo a Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Polwarth Building, Aberdeen AB25 2ZD, UK b Primary Care Franchise, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland c Novartis Pharma AB, Box 1150, TA¨BY, Stockholm S-183 79, Sweden d IMS Health Economics and Outcomes Research, 210 Pentonville Road, London N1 9JY, UK e Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden

Received 2 July 2014; accepted 23 September 2014

Available online 2 October 2014

KEYWORDS COPD; Costs; Cost-minimisation; Cost-effectiveness; Economic evaluation

Summary Background: Indacaterol/glycopyrronium (IND/GLY) is a once-daily inhaled fixed-dose combination of indacaterol (IND), a long-acting b2-adrenergic agonist (LABA), and glycopyrronium (GLY), a long-acting muscarinic antagonist (LAMA) for use as maintenance treatment to relieve symptoms of chronic obstructive pulmonary disease (COPD) in adults. Objective: To determine the economic benefits of IND/GLY compared with the free combination of indacaterol and glycopyrronium (IND þ GLY), and with the fixed-dose combination of salmeterol/fluticasone (SFC), in a moderate-to-severe COPD population with lowexacerbation risk. The model-based analysis extrapolated results up to lifetime time horizon and calculated costs per quality-adjusted life year. Methods: Assuming equal efficacy, a cost-minimisation analysis compared IND/GLY vs IND þ GLY using model inputs from the double-blind, randomised SHINE trial. The doubleblind, randomised ILLUMINATE and TORCH trials were used to analyse cost-effectiveness versus SFC. To consider ICS-related pneumonia events, published odds ratio comparing an ICSexposed group to a control group of COPD patients was used. Direct and indirect drug costs as well as drug acquisition costs (in Swedish Krona [SEK]) were derived from published Swedish

* Corresponding author. Tel.: þ46 87323200. E-mail address: [email protected] (M. Costa-Scharplatz). 1

Present affiliation: Mapi Group, 73 Collier Street, London N1 9BE, UK.

http://dx.doi.org/10.1016/j.rmed.2014.09.015 0954-6111/ª 2014 Elsevier Ltd. All rights reserved.

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sources. Cost and effects were discounted with 3%. Uncertainty was assessed by one-way and probabilistic sensitivity analyses (PSA). Results: IND/GLY was cost-saving vs IND þ GLY with incremental savings of SEK (EUR) 768 (85), and 3309 (368) per patient over one and five years. IND/GLY was found to be less costly and more effective compared to SFC with cost savings of SEK (EUR) 2744 (303), 8854 (976), 13,938 (1536), 27,495 (3031) and 43,033 (4744) over one, three, five, ten years and lifetime. The PSA indicated that all iterations produced dominant results for IND/GLY. Conclusion: IND/GLY is cost-minimising vs IND þ GLY and dominates SFC in the maintenance treatment of COPD patients in Sweden. Encouraging dual bronchodilator therapy over an ICS-containing combination results in lower total costs and better outcomes compared to combination therapy including fluticasone in moderate-to-severe COPD patients with low exacerbation risk. ª 2014 Elsevier Ltd. All rights reserved.

Introduction Chronic obstructive pulmonary disease (COPD) is a progressive and treatable but incurable disease, found to be a major cause of chronic morbidity and mortality worldwide [1]. Studies consistently report COPD to be a leading cause of death [2,3]. In Sweden the prevalence of COPD, defined according to the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) guidelines, was estimated to be 14.1% of the adult population aged 20e69 [4]. Population studies have shown that COPD is largely underdiagnosed [4] or misdiagnosed as asthma [5,6], and of those diagnosed many remain undertreated [7]. The economic burden of COPD in Sweden was estimated at SEK 13.9 billion (EUR 1.46 billion) in 2010 with the majority of costs found to be attributable to indirect costs due to loss of productivity. Main drivers of the direct costs were hospitalisations (for the very severe patients), and drug costs (for the patients with severe, mild or moderate disease) [8]. Improving the management of COPD patients will allow for greater symptom control and thus likely reduce loss of productivity as a result of the disease. Additionally, improved disease management and effectiveness of treatments is likely to reduce COPD related hospitalisations resulting in cost-savings to the health care system [9]. There are a number of pharmacologic therapy options for COPD. Long-acting bronchodilators, in the form of longacting b2-agonists (LABAs) or long-acting muscarinic antagonist (LAMAs), are central to the management of COPD. When symptoms are not adequately controlled by a single LABA or LAMA, international guidelines recommend combining bronchodilators from different classes [1]. The current Swedish guidelines (released in 2009) recommend LAMA as first-line treatment and LABA as alternative or addon treatment for inadequately controlled COPD patients. For more severe patients with frequent exacerbations, inhaled corticosteroids (ICS) in combination with LABA are recommended [10]. However, in 2013 approximately 55% of the total number of COPD patients over 45 years have been treated with an ICS/LABA combination, 29% with LAMA and 17% with LABA [11]. The high usage of ICS/LABA has also been published in a regional assessment report based on data from the PRAXIS study which showed that 40% of patients in GOLD states 1 and 2 in Sweden are treated with ICS/LABA combination [12]. Prescribing of ICS/LABA outside

of the GOLD guidelines has also been reported from realworld data in other countries [13e18]. However, patients receiving an inhaled corticosteroid with LABA or in addition to dual bronchodilator therapy, are at risk for additional adverse events such as pneumonia and influenza [19]. Non-adherence to the recommendations from clinical guidelines was found to increase the burden of COPD in subjects with moderate-to-severe disease [20,21]. The long-term bronchodilator strategy for COPD patients is therefore of clinical and economic interest and especially relevant from a policy and payer perspective. Indacaterol/glycopyrronium bromide (IND/GLY) (Ultibro Breezhaler) is a fixed-dose LABA/LAMA combination which received reimbursement in Sweden in February 2014 providing a new alternative for patients remaining symptomatic with long-acting monotherapy [22]. It is a once-daily inhaled fixed-dose combination of indacaterol (IND), a LABA, and glycopyrronium bromide (GLY), a LAMA, and it is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD [23]. This fixed-dose LAMA/LABA combination provides a new alternative for patients remaining symptomatic with long-acting monotherapy. The objectives of this study were to compare IND/GLY with the free combination of indacaterol plus glycopyrronium (IND þ GLY) in terms of costs and to evaluate its cost-effectiveness versus the fixed-dose combination of salmeterol/fluticasone (SFC), in moderate to severe COPD population with a low-exacerbation risk from a Swedish societal perspective. Although SFC is not recommended for use in COPD patients with low exacerbation risk [1] it was included as a comparator as it is often used in such patients in clinical practice [18]. This cost-effectiveness analysis aims therefore to provide the longer-term evidence in terms of quality-adjusted life years (QALYs) and costs of using IND/GLY combination over SFC in a moderate-tosevere COPD population with low-exacerbation risk.

Methods Model structure This was a patient-level simulation model in which Monte Carlo simulation methods [24] were used to follow individual

1788 Table 1

D. Price et al. Population and efficacy inputs for comparison of IND/GLY and the free combination. IND þ GLYb

IND/GLY

COPD severity at baseline, % patients Moderate Severe Age at baseline, years Males at baseline, % FEV1 improvement vs. placebo at 26 weeks, L Exacerbation rate versus placebo a b

Mean

Range (SD/95% CIa)

Source

Mean

Range (SD/95% CIa)

63.6% 36.4% 63.9 75.4 0.2

e e SD  8.83 e 95% CI: 0.17, 0.24

[37] [37] [37] [37] [37]

63.6% 36.3% 63.9 75.4 0.2

e e SD  8.83 e 95% CI: 0.17, 0.24

0.57

95% CI: 0.41, 0.79

[38]

0.57

95% CI: 0.41, 0.79

For the calculation of 95%, a standard error was assumed to be 10% of the mean. SD Z standard deviation, CI Z confidence interval. Assumption of efficacy and safety equivalence between IND/GLY and IND þ GLY applied.

patients over various time horizons (Fig. 1). The generated patients were moved through the model one at a time, progressing and experiencing clinical events according to preset probabilities. Disease severity was determined at each cycle based on the patient’s lung function. In the event of discontinuation, patients had their FEV1 levels fall back to what it would have been, had they never been treated. Probabilities of exacerbation (severe or non-severe) were determined by severity of disease and treatment choice. Exacerbations were defined in annual rates which in turn were adjusted to the specified cycle length. Cycle lengths were 6 months, with outcomes reported over time horizons of one, three, five and 10 years and over a lifetime. Discounting of 3.0% for costs and outcomes was applied. The structure of the model was previously described in detail and validated [25]. The predictability of the model was tested by populating it with data from natural history of disease studies as well as with clinical trial data. The validation with these studies found the model to have good predictive ability, yielding in this way a good degree of external validity.

Figure 1

The model produced three categories of outputs e clinical, cost and cost-effectiveness. This allowed costminimisation and cost-effectiveness analyses to be conducted. In addition, number needed to treat (NNT) to avoid one exacerbation and cost per exacerbation avoided can be calculated on the basis of the clinical and costeffectiveness sets of outputs.

Clinical data Comparison of indacaterol/glycopyrronium with the free combination The BEACON study was a phase III study comparing the safety and efficacy of IND/GLY versus concurrent administration of IND þ GLY for a blinded treatment period of 28 days [26]. The primary objective of the study was to evaluate the non-inferiority of IND/GLY as compared to the concurrent administration of IND þ GLY in terms of its effect on trough FEV1 after 28 days of treatment. A total of 193 patients were randomised, of which 59.6% and 40.4%

Model schematic.

Swedish cost-effectiveness analysis of indacaterol/glycopyrronium Table 2

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Population and efficacy inputs for comparison of IND/GLY and SFC. IND/GLY Mean

COPD severity at baseline, % patients Moderate 80.3% Severe 19.7% Age at baseline, years 63.3 Males at baseline, % 70.9 FEV1 improvement vs. 0.259 placebo at 26 weeks, L Exacerbation rate versus placebo 0.61 ICS-related pneumonia risk versus 1.0 control group (odds ratio) a

SFC a

Range (SD/95% CI )

Source

Mean

Range (SD/95% CIa)

Source

e e SD  7.93 e 95% CI: 0.209, 0.311

[27] [27] [27] [27] [27] [28]

80.3% 19.7% 63.3 70.9 0.159

e e SD  7.93 e 95% CI: 0.129, 0.191

Assumed Assumed Assumed Assumed [28]

95% CI: 0.37, 0.85 95% CI: 0.9, 1.1

Calculated Assumed

95% CI: 0.48, 1.03 95% CI: 2.62, 3.70

Calculated [19]

0.75 1.78

For the calculation of 95%, a standard error was assumed to be 10% of the mean. SD Z standard deviation, CI Z confidence interval.

had moderate and severe disease, respectively. The BEACON study demonstrated that once-daily IND/GLY provides an efficacy and safety profile similar to the concurrent administration of its monocomponents [26]. Given the evidence of non-inferiority between IND/GLY and the free combination of the components, the first analysis was run as a cost-minimisation analysis. The population and efficacy inputs used for the comparison of IND/GLY with the free combination of IND þ GLY are summarised in Table 1. Comparison of indacaterol/glycopyrronium with salmeterol/fluticasone Model inputs for the comparison of IND/GLY versus SFC were derived on the basis of data from the ILLUMINATE trial [27]. Since the model described treatment effects versus a placebo baseline the study of Mahler et al. [25] and the TORCH trial [24] have been used to estimate input values compared to placebo. ILLUMINATE was a 26-week treatment, randomised, double-blind, multicentre study, with parallel-group and double dummy design to assess the efficacy, safety and tolerability of IND/GLY compared to SFC in patients with moderate (80.3%) and severe (19.7%) COPD. The primary endpoint was to demonstrate the superiority of IND/GLY compared with SFC for the standardised area under the curve from 0 to 12 h post dose for FEV1 after 26 weeks of treatment [27]. IND/GLY improvement from baseline in FEV1 (L) at 26 weeks was based on data from ILLUMINATE [27] and SFC’s improvement from Mahler et al. [28]. The model design required the FEV1 improvement of the therapies to be estimated compared to a placebo baseline. Such data was, however, not available from the ILLUMINATE trial [27] due to the lack of a placebo arm in the study. Thus, data from Mahler et al. [28] for FEV1 improvement of SFC versus placebo was used. Reflecting the mean treatment difference of 0.1 L for IND/GLY versus SFC, the IND/GLY FEV1 improvement was calculated as the treatment effect of SFC versus placebo plus 0.1 L. Thus, input values for the model were 0.259 L for IND/GLY and 0.159 L for SFC versus placebo, as all FEV1 values were benchmarked versus placebo. Similarly, for the calculation of the exacerbation rates versus placebo, a placebo arm was needed. The

TORCH trial (which was once again selected in the absence of a pooled and adjusted source to provide a placebo anchor) reported a rate ratio of 0.75 (95%CI: 0.69e0.81) for SFC versus placebo [29]. This rate ratio of 0.75 was applied to the annual rate of exacerbations for SFC from ILLUMINATE, 1.05 [30], to derive a hypothetical placebo rate of 1.40; this placebo rate was used with the IND/GLY annual exacerbation rate (0.847(30)) to derive a rate ratio of IND/ GLY versus placebo. For the consideration of the ICSrelated pneumonia events, published odds ratio comparing an ICS-exposed group to a control group of COPD patients was used [19]. A summary of the population and efficacy inputs used for the comparison of IND/GLY with SFC are summarised in Table 2.

Costs The analysis was conducted from the societal perspective and accounted for direct and indirect costs. Direct costs comprised COPD drugs, maintenance, exacerbation event and pneumonia event costs. Daily drug costs (in Swedish Krona [SEK]) were derived from the Swedish National Formulary of Drugs [31]. Maintenance cost was defined as nonexacerbation-related cost, after the exclusion of COPD drug costs, and was based on two subsequently published analyses from the OLIN study [8,32]. The published maintenance costs from 2010 [8] were adjusted by the relative proportion of costs for exacerbations from the earlier publication using the same data source [8,32]. Costs of exacerbation were calculated based on data from a cost-of-illness study in the Swedish setting [33]. Exacerbations were classified as non-severe or severe depending on the associated resource utilisation. A patient with a non-severe exacerbation was assumed to visit a physician and requiring temporary additional therapy. An exacerbation was considered severe if the patient needed to be admitted to the hospital. The costs per non-severe and severe exacerbations were SEK 1,239 and SEK 26,590, respectively. Pneumonia costs were based on three diagnosis-related group (DRG) codes (D47A, D47C, D47E) describing lung inflammation with three varying levels of complication [34]. As no information on case-mix of these three different DRGs was available, a straight average of

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D. Price et al.

these three has been used. Costs included in the analysis are presented in Table 3.

Mortality Probability of death was determined by a COPD-specific mortality hazard ratio [34] and general all-cause mortality. The Obstructive Lung Disease in Northern Sweden (OLIN) study was used to describe the risk of death per unit increase in FEV1%. OLIN was a Swedish longitudinal study that followed COPD patients (64% male) over a period of 20 years, having mortality as a primary endpoint [4]. Swedish life tables from the Official Statistics of Sweden [35] for 2013 were used to describe the background all-cause mortality.

Baseline utilities were applied at each cycle depending on the disease severity state of the patient and a number of other characteristics. These were calculated based on a regression model published by Rutten van Molken et al. [36]. This regression function allows utilities to be assigned to patients based on a multi-factorial consideration, rather than based solely on the 2008 GOLD disease severity classification. The co-efficient values used in the regression model included gender, post-bronchodilator FEV1% predicted, number of hospital admissions and emergency visits in the previous year, body mass index (BMI) and comorbidities. Utility at each cycle is calculated by the regression equation as below: Utility value Z 0.688 þ Gender*0.057 þ FEV1 percent predicted* 0.003 þ ER visits in the last year þ 0.029 þ Hospital admission in the last year * 0.02 þ Number of concomitant diseases*-0.01 þ BMI*-0.003.

Results

IND/GLY resulted in incremental cost savings versus the free combination, ranging from SEK -768 and SEK -8703 depending on the time horizon. The results of the costminimisation analysis are presented in Table 4.

Comparison of indacaterol/glycopyrronium with salmeterol/fluticasone IND/GLY was dominant for all time horizons versus SFC, meaning the total estimated costs were lower and resulted in better outcomes. Cost savings occurred for drug, maintenance, exacerbation, pneumonia event and indirect costs. Most of the savings were due to reduction in the indirect and maintenance costs. Patients receiving IND/GLY had no pneumonia events, less severe and non-severe exacerbations and better outcomes in terms of number of life years (LYs) and QALYs. Numbers needed to treat to avoid one exacerbation ranged from seven over one year to one over five and ten years and 0.42 over a lifetime (Table 5).

Cost inputs (in SEK).

Direct costs Daily drug cost IND/GLY IND þ GLY SFC Annual cost of maintenancea GOLD 1 GOLD 2 GOLD 3 GOLD 4 Cost per exacerbationa Non-severe Severe Cost per pneumonia episode Annual indirect costsa GOLD 1 GOLD 2 GOLD 3 GOLD 4 a

One-way sensitivity analysis (OWSA) and probabilistic sensitivity analysis (PSA) were performed for the costeffectiveness comparison to account for uncertainty in the model. The effects of individual variables were estimated in the OWSA, by testing an upper and lower limit. Key model inputs varied were FEV1 improvement, exacerbation rate versus placebo, and severity of population at baseline. To account for second order uncertainty, a PSA was conducted for 1000 cohorts with 10,000 patients per cohort.

Comparison of indacaterol/glycopyrronium with the free combination

Utilities

Table 3

Uncertainty

Costs (SEK)

Source

Uncertainty

19.31 21.46 19.69

[31] [31] [31]

Results from the OWSA suggested that the FEV1 improvement and the disease severity of the patients included in the analysis would have the highest impact on the estimates. The PSA found IND/GLY to be dominant in all

e e 12,995 43,469

[8,32] [8,32]

1239 26,590 42,169

[8,32] [8,32] [39]

3133 21,877 34,407 118,517

[8] [8] [8] [8]

Inflated with consumer price index to 2013.

Table 4 Results of the base case cost-minimisation analysis (IND/GLY vs IND þ GLY). Time horizon (years)

Total costsa (SEK) IND/GLY

IND þ GLY

Incremental total costs (SEK)

1 3 5 10 Lifetime

27,635 91,788 149,464 273,053 500,248

28,403 93,906 152,772 278,685 508,951

768 2118 3309 5632 8703

a Total costs Z direct costs (drug, maintenance [additional therapy], exacerbation, pneumonia-related costs) and indirect costs.

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1791

iterations. The cost-effectiveness plane derived on the basis of the PSA is presented in Fig. 2 below.

Discussion To the authors knowledge this analysis is the first to explore the comparisons of a fixed combination of LABA/LAMA with a free LABA þ LAMA combination or SFC. The results of the cost-minimisation analysis versus the free combination of IND þ GLY suggested that IND/GLY was associated with incremental cost savings over one, three, five and 10 years as well as over the lifetime at a daily cost of SEK 19.31. IND/ GLY was found to dominate SFC at all time horizons. IND/ GLY was associated with cost savings, and efficacy and safety benefits when compared with SFC. The conducted analyses had several limitations. The cost-minimisation comparison of IND/GLY versus the free combination was based on the assumption of noninferiority. This implied that compliance and effectiveness were assumed to be equivalent between the two comparators. The main limitation of the cost-effectiveness analysis was the lack of direct evidence that can be used for the comparison versus SFC in terms of therapy FEV1 improvement against placebo and therapy exacerbation benefit versus placebo. The current analysis is based on the assumption that the baseline rates for placebo from one trial can be used in another. A further limitation of the analyses is that formoterol/ budesonide (FBD) could not be included in this analysis. FBD is the more widely used LABA/ICS product in Sweden, and there is also differential evidence for ICS-related adverse events when using fluticasone or budesonide. The comparison of IND/GLY versus SFC may therefore not be generalisable to a comparison versus FBD. However, no head-tohead clinical data was available to support this comparison. The analyses were conducted according to the 2008 GOLD Guidelines Update COPD disease severity classification based on FEV1 to reflect the approach followed in the clinical trials used as the source for the clinical inputs. One area of new research could be to explore the impact of the GOLD 2011 guidelines classification which has been redefined using exacerbation history and symptoms in addition to spirometry. This would result in different classifications of disease severity and potentially allow evaluation of drug therapies tailored to more specific groups of patients. In the current COPD treatment paradigm, dual bronchodilator therapy is recommended; however, as no fixedTable 5

Figure 2 Results of probabilistic sensitivity analysis: incremental cost-effectiveness scatter plot of IND/GLY versus SFC.

dose dual bronchodilator was previously available, this provides a new treatment option for moderate-to-severe COPD patients without the potential risks of ICS. This analysis explores the potential consequences of encouraging a dual bronchodilator therapy over a combination with ICS and showed that non-ICS therapy results in less pneumonia events, severe and non-severe exacerbations and better outcomes compared to combination therapy including fluticasone in moderate-to-severe COPD patients. Payers and policy-makers should be encouraged to ensure that guidelines are followed and tested before resorting to the addition of an ICS. Compliance with clinical guidelines will result in both cost-savings for the system as well as improved health outcomes in patients with moderate-tosevere COPD and low exacerbation risk. Sweden is currently reviewing the price of respiratory drugs that may impact on the results of the analysis conducted here by lowering the price of SFC. While the magnitude of the exact price reduction is unknown, the current parameters indicate that an approximately 20% reduction in SFC would still result in IND/GLY dominating SFC. However, in that scenario cost-savings are smaller especially in the shorter time horizons. While these differences are small on a per patient basis, they may provide significant savings for health care systems managing large populations. When the price reduction reaches 25%, oneyear time horizon results are no longer dominant, and when larger price reductions are applied the ICERS has to be evaluated based on Swedish cost-effectiveness thresholds. In conclusion, the conducted analyses found IND/GLY to be costesaving when compared with the free combination of IND þ GLY and cost-effective when compared with SFC, in patients with moderate or severe COPD and low

Incremental results of the base case cost-effectiveness analysis for IND/GLY versus SFC. Time horizon

Incremental costs (SEK) Direct costs Indirect costs Incremental life-years Incremental QALYs Incremental pneumonia events Exacerbations avoided

1 year

3 years

5 years

10 years

Lifetime

2744 1156 1588 0 0.001 0.02 0.06

8854 3709 5145 0.005 0.006 0.06 0.22

13,938 5883 8055 0.015 0.015 0.10 0.37

27,495 11,495 15,999 0.063 0.047 0.18 0.68

43,033 18,157 24,876 0.310 0.200 0.31 1.07

1792 exacerbation risk. The results imply that the use of IND/GLY is likely to reduce the economic burden of the disease to the Swedish healthcare system. Results are likely to be true in other markets in terms of cost-savings generated by avoidance of clinical events; the overall cost-effectiveness results will be dependent on drug prices, but the results from Sweden indicate that an approximately 20% price differential between IND/GLY and SFC would still result in overall cost-savings.

Conflict of interest This study and manuscript were sponsored by Novartis which manufacturers Ultibro Breezhaler. DK, MCS, and KM are employees of Novartis. YA and MD are employees of IMS Health who are paid consultants to Novartis. BS has received honoraria for educational activities from AstraZeneca, GlaxoSmithKline, Meda, Merck Sharp and Dohme, and has served on an advisory board arranged by AstraZeneca, Novartis, and Boehringer Ingelheim. DP has consultant arrangements and/or has received research grants and/or has spoken for the following companies: Activaero, Aerocrine, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Merck, Mundipharma, Medapharma, Novartis, Napp, Nycomed, Orion, .Pfizer, Sandoz, Teva and UK National Health Service.

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[30]

[31]

[32]

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