REVIEW URRENT C OPINION
Dry powder inhalers in cystic fibrosis: same old drugs but different benefits? Lesley Uttley and Paul Tappenden
Purpose of review Newer ‘innovative’ formulations of antibiotics for Pseudomonas aeruginosa lung infection in patients with cystic fibrosis include colistimethate sodium and tobramycin in the form of dry powders for inhalation (DPIs). Whilst these DPIs are anticipated to improve patient adherence because of increased convenience and ease of administration, questions remain concerning whether they are as clinically effective, safe and cost-effective as nebulized antibiotics. Recent findings This review describes the recent findings of a health technology assessment of the clinical effectiveness and cost-effectiveness of colistimethate sodium and tobramycin DPIs with regard to how innovative treatments may be judged to be incrementally better than existing treatments. The original assessment was undertaken to inform the National Institute for Health and Care Excellence’s Technology Appraisal Programme to inform national clinical guidance on the use of these new treatments in the National Health Service. Summary Three trials were included in the systematic review. Issues surrounding the clinical effectiveness and costeffectiveness of colistimethate sodium DPI and tobramycin DPI are discussed in light of the considerable uncertainties associated with the available evidence. Keywords antipseudomonal antibiotics, dry powder, health technology assessment, Pseudomonas aeruginosa, systematic review
INTRODUCTION Cystic fibrosis (CF) is an inherited condition which is characterized by the abnormal transport of Cl across transporting epithelia, leading to the production of thick sticky mucus in the lungs, pancreas, liver, intestine, and reproductive tract, as well as an increase in the salt content in sweat. People with CF experience many problems, including recurrent respiratory infections and difficulties digesting food. People with CF are susceptible to lung infections; this is because the thick mucus makes it difficult for the body to clear inhaled bacteria, and because people with CF have an increased airway inflammatory response to pathogens. CF significantly impairs health-related quality-of-life (HRQoL) and limits life expectancy. Amongst the most common infections in CF, including Staphylococcus aureus, Haemophilus influenzae, and Burkholderia cepacia complex, Pseudomonas aeruginosa is the most prevalent, with between 55 and 65% of CF patients between age 20 and 49 years in the United Kingdom infected with chronic P. aeruginosa in 2010 [1].
CURRENT TREATMENT FOR PSEUDOMONAS AERUGINOSA In clinical practice, nebulized antipseudomonal antibiotics represent the mainstay of treatment for patients with chronic P. aeruginosa, although patients may also receive a number of other treatments, including bronchodilators, macrolides, mucolytics, and other forms of airway clearance (e.g., physiotherapy) [2]. Treatment is time-consuming and burdensome for patients, with administration of nebulized antibiotics taking up to an hour per day whilst patients are in good health and longer during periods of ill health. Consequently, the adherence of patients to nebulized antibiotics tends to be limited; this may The University of Sheffield, Sheffield, South Yorkshire, UK Correspondence to Dr Lesley Uttley, School of Health and Related Research (ScHARR) University of Sheffield Regent Court, 30 Regent Street Sheffield, S1 4DA, UK. Tel: +44 114 2220782; fax: +44 114 2724095; e-mail: [email protected] Curr Opin Pulm Med 2014, 20:607–612 DOI:10.1097/MCP.0000000000000109
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-pulmonarymedicine.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cystic fibrosis
KEY POINTS The evidence that dry powder formulations of antipseudomonal antibiotics work as well as their nebulized counterparts is currently weak. Considerable uncertainty surrounds whether dry powder antibiotics colistimethate sodium and tobramycin represent good value for money for the NHS. Future research should aim to demonstrate long-term non-inferiority of dry powder inhalers to nebulized antibiotics using clinically meaningful primary endpoints, such as acute exacerbations as well as FEV1% predicted.
lead to a loss of control of disease symptoms. In recent years, quicker and more convenient formulations of antipseudomonal antibiotics have been developed in the form of dry powder inhalers (DPIs) [3]. Two antibiotics are available in dry powder form: colistimethate sodium (colistin) and tobramycin [4,5]. DPIs are more portable than nebulizers and are simpler and quicker to prepare and administer; these therefore represent a welcome innovation to patients with CF and their carers who spend hours per week preparing, using and cleaning nebulizers for inhaled antibiotics.
another. Non-inferiority trials should not however be confused with ‘equivalence trials’ which aim to determine whether a given (typically new) intervention is therapeutically similar to another [6]. This approach to establishing non-inferiority may be criticized for regarding the existing standard of care as a worthwhile clinical goal. However, incremental innovation, whereby the new drug does not represent a novel or ‘ground-breaking’ molecular formulation but rather a variation on an existing drug, does have merit in the development of new treatments. Formulations of drugs which expand existing drug classes add to the prescribing clinician’s arsenal of therapeutic alternatives, increases competition between products and creates stimulus for further innovation. Moreover, an original ‘breakthrough’ drug does not necessarily remain the most effective or the best in the group indefinitely [7]. Most importantly, trials which aim to establish whether a new treatment is not statistically significantly worse than the existing treatment should have suitable rationale for the non-inferiority margin and how such a margin has been determined.
REVIEW OF CLINICAL EVIDENCE CONCERNING COLISTIMETHATE SODIUM DRY POWDER INHALER AND TOBRAMYCIN DRY POWDER INHALER In 2011, NICE undertook a technology appraisal [8,9 ,10,11] of the antipseudomonal antibiotic DPIs (and corresponding inhaler devices): colistimethate sodium (Colobreathe and Turbospin device), and tobramycin (TOBI and Podhaler) for the treatment of chronic P. aeruginosa lung infection in patients with CF. Three randomized controlled trials were included in the review [12–14]. Two trials evaluated colistimethate sodium DPI [15 ,16] versus nebulized tobramycin or nebulized colistin and one trial compared tobramycin DPI [17–20] versus nebulized tobramycin. Both colistimethate sodium DPI and tobramycin DPI were reported to be non-inferior to nebulized tobramycin in the two phase III non-inferiority trials, for the outcome of forced expiratory volume in the first second (FEV1% predicted), based on information from two of the trials. However, there were problems with the design of the included trials, indicating that their results should be judged with caution. None of the trials included in the review met the time horizon of 12-months’ follow-up recommended by the European Medicines Agency for efficacy trials, [21] with both of the phase III trials following patients for durations of only 24 weeks [22]. As such, the existing evidence base does not include information about the long-term efficacy &&
EVALUATING NEW FORMULATIONS OF OLD DRUGS Within health technology assessment, newer ‘innovative’ treatments are usually required to possess an additional advantage, such as greater availability, reduced cost, less invasiveness, fewer adverse effects, or greater ease of administration [2]. Despite these apparent benefits, there remain two pertinent questions with respect to the new DPIs: first, are they as safe and effective as conventional nebulized antibiotics (‘do they work?’), and; second, is their comparative cost-effectiveness profile acceptable to decision-makers (‘are they worth paying for?’). These questions of clinical effectiveness and cost-effectiveness are central to health technology assessment and form the basis of recommendations on the use of particular health technologies from the National Institute for Health and Care Excellence (NICE) and other similar health technology assessment bodies elsewhere. Equivalent benefits of new drugs cannot merely be claimed on the basis of nonsignificant statistical tests from traditional superiority trials. Non-inferiority trials aim to determine whether a given treatment is not statistically significantly worse than 608
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Volume 20 Number 6 November 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Dry powder inhalers in cystic fibrosis Uttley and Tappenden
and safety of these treatments [23]. Both of the large trials could also be criticized for the way that the results had been analysed, with the trial of colistimethate sodium DPI (COLO/DPI/02/06) only reaching non-inferiority when analysed nonparametrically, and the trial of tobramycin DPI [the ‘Establish A new Gold standard Efficacy and safety with tobramycin in cystic fibrosis’ (EAGER) trial] only presenting results without imputation for missing data. The smaller trial of colistimethate sodium DPI (COLO/DPI/02/05) was not powered to detect an effect in FEV1% predicted as it was only 4 weeks in duration prior to crossover; this study reported no significant differences in FEV1% predicted between arms and from baseline. It was not possible to draw any firm conclusions from the review with respect to the relative efficacy, measured by FEV1% predicted, of any intervention compared with any other intervention except nebulized tobramycin due to: missing data, uncertain comparability of patient characteristics, and incompatible methods of analysing the data. Further, as FEV1% predicted is a surrogate outcome, the European Medicines Agency recommends that it should be considered alongside ‘harder’ outcomes, such as exacerbations [21,24]. Both tobramycin DPI and colistimethate sodium DPI appeared to be less effective in reducing the frequency of exacerbations, but patients treated with DPIs spent less time on antibiotics. Adverse events were mostly similar between arms within trials, except for cough, which was higher in both DPI intervention arms. In both trials, more patients in the DPI intervention arms withdrew due to adverse events. The statistical and clinical significance of differences in sputum density, resistance data, exacerbations, and adverse event data are not known. None of the trials measured HRQoL using a preference-based measure (e.g., the Euroqol EQ-5D or the SF-6D) and the duration of study follow-up was insufficient to draw any conclusions regarding the effect of DPI formulations on mortality in comparison with nebulized tobramycin. Overall, there remains considerable uncertainty with respect to the net clinical benefit of the DPI products and nebulized antibiotics for the treatment of chronic P. aeruginosa.
ECONOMIC ISSUES SURROUNDING THE USE OF COLISTIMETHATE SODIUM DRY POWDER INHALER AND TOBRAMYCIN DRY POWDER INHALER Demonstrating relative clinical efficacy alone is not sufficient to judge whether DPIs are equivalent, or even superior, to nebulized antibiotics. There is also
a need to assess whether the DPIs represent good value for money for the National Health Service (NHS), that is, whether they should be considered to be cost-effective or not. At the time of writing, the list prices for tobramycin DPI and colistimethate DPI were £1790 and £968 per 28 treatment days, respectively, whilst the cost of nebulized tobramycin is approximately £1187 per 28 treatment days [25]. Preparations of nebulized colistin vary in cost, but may be notably less expensive than these products. If a new technology incurs greater costs than the current standard treatment for a given indication, funding that new product means that something else which produces health for other patients will be displaced elsewhere in the health service [26]. As such, there is a need to consider whether any additional value afforded by the new technology outweighs the health forgone associated with curtailing existing treatments and services elsewhere in the health service. In England and Wales, NICE uses information on the cost-utility of new treatments versus existing therapies, defined in terms of the incremental cost-effectiveness ratio (ICER), to inform such judgements about the balance of additional value and opportunity cost. Within this cost-utility framework, the ‘value’ of health technologies is measured in terms of quality adjusted life years (QALYs); this metric is intended to reflect both the duration and quality-of-life (morbidity, psychological, functional, social, and other factors) of patients receiving particular treatments. Judgements about the acceptability of an ICER for a particular therapy is made through reference to a cost-effectiveness threshold; NICE typically operates a cost-effectiveness threshold in the range 20 000 to £30 000 per QALY gained [27]. This threshold is intended to represent the monetary cost of each QALY which is displaced as a result of funding a new more expensive treatment. At present, research concerning the cost-effectiveness of treatments for CF remains worryingly under-researched. To date, there have been very few full economic evaluations of treatments for CF [28–30]. None of the existing published economic analyses relate to the cost-effectiveness of DPI antibiotics versus nebulized antibiotics for the treatment of chronic P. aeruginosa. Given the lack of existing economic analyses, the authors of this article undertook a de-novo economic evaluation to assess the cost-effectiveness of the DPI products versus nebulized antibiotics [11]. Within this economic analysis, Tappenden et al. used patient-level data from the two pivotal trials of colistimethate sodium DPI and tobramycin DPI to inform a health economic model to assess the costeffectiveness of DPIs versus nebulized treatments.
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Cystic fibrosis
The economic analysis was undertaken from the perspective of the United Kingdom NHS and evaluates costs and health outcomes associated with competing DPI and nebulized antibiotics over a lifetime horizon. The authors developed a state transition model [31] based on transitions between three strata of lung function, measured in terms of FEV1% predicted (FEV1>70%, FEV1 40–70%, and FEV1
Dry powder inhalers in cystic fibrosis: same old drugs but different benefits? Lesley Uttley and Paul Tappenden
Purpose of review Newer ‘innovative’ formulations of antibiotics for Pseudomonas aeruginosa lung infection in patients with cystic fibrosis include colistimethate sodium and tobramycin in the form of dry powders for inhalation (DPIs). Whilst these DPIs are anticipated to improve patient adherence because of increased convenience and ease of administration, questions remain concerning whether they are as clinically effective, safe and cost-effective as nebulized antibiotics. Recent findings This review describes the recent findings of a health technology assessment of the clinical effectiveness and cost-effectiveness of colistimethate sodium and tobramycin DPIs with regard to how innovative treatments may be judged to be incrementally better than existing treatments. The original assessment was undertaken to inform the National Institute for Health and Care Excellence’s Technology Appraisal Programme to inform national clinical guidance on the use of these new treatments in the National Health Service. Summary Three trials were included in the systematic review. Issues surrounding the clinical effectiveness and costeffectiveness of colistimethate sodium DPI and tobramycin DPI are discussed in light of the considerable uncertainties associated with the available evidence. Keywords antipseudomonal antibiotics, dry powder, health technology assessment, Pseudomonas aeruginosa, systematic review
INTRODUCTION Cystic fibrosis (CF) is an inherited condition which is characterized by the abnormal transport of Cl across transporting epithelia, leading to the production of thick sticky mucus in the lungs, pancreas, liver, intestine, and reproductive tract, as well as an increase in the salt content in sweat. People with CF experience many problems, including recurrent respiratory infections and difficulties digesting food. People with CF are susceptible to lung infections; this is because the thick mucus makes it difficult for the body to clear inhaled bacteria, and because people with CF have an increased airway inflammatory response to pathogens. CF significantly impairs health-related quality-of-life (HRQoL) and limits life expectancy. Amongst the most common infections in CF, including Staphylococcus aureus, Haemophilus influenzae, and Burkholderia cepacia complex, Pseudomonas aeruginosa is the most prevalent, with between 55 and 65% of CF patients between age 20 and 49 years in the United Kingdom infected with chronic P. aeruginosa in 2010 [1].
CURRENT TREATMENT FOR PSEUDOMONAS AERUGINOSA In clinical practice, nebulized antipseudomonal antibiotics represent the mainstay of treatment for patients with chronic P. aeruginosa, although patients may also receive a number of other treatments, including bronchodilators, macrolides, mucolytics, and other forms of airway clearance (e.g., physiotherapy) [2]. Treatment is time-consuming and burdensome for patients, with administration of nebulized antibiotics taking up to an hour per day whilst patients are in good health and longer during periods of ill health. Consequently, the adherence of patients to nebulized antibiotics tends to be limited; this may The University of Sheffield, Sheffield, South Yorkshire, UK Correspondence to Dr Lesley Uttley, School of Health and Related Research (ScHARR) University of Sheffield Regent Court, 30 Regent Street Sheffield, S1 4DA, UK. Tel: +44 114 2220782; fax: +44 114 2724095; e-mail: [email protected] Curr Opin Pulm Med 2014, 20:607–612 DOI:10.1097/MCP.0000000000000109
1070-5287 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-pulmonarymedicine.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cystic fibrosis
KEY POINTS The evidence that dry powder formulations of antipseudomonal antibiotics work as well as their nebulized counterparts is currently weak. Considerable uncertainty surrounds whether dry powder antibiotics colistimethate sodium and tobramycin represent good value for money for the NHS. Future research should aim to demonstrate long-term non-inferiority of dry powder inhalers to nebulized antibiotics using clinically meaningful primary endpoints, such as acute exacerbations as well as FEV1% predicted.
lead to a loss of control of disease symptoms. In recent years, quicker and more convenient formulations of antipseudomonal antibiotics have been developed in the form of dry powder inhalers (DPIs) [3]. Two antibiotics are available in dry powder form: colistimethate sodium (colistin) and tobramycin [4,5]. DPIs are more portable than nebulizers and are simpler and quicker to prepare and administer; these therefore represent a welcome innovation to patients with CF and their carers who spend hours per week preparing, using and cleaning nebulizers for inhaled antibiotics.
another. Non-inferiority trials should not however be confused with ‘equivalence trials’ which aim to determine whether a given (typically new) intervention is therapeutically similar to another [6]. This approach to establishing non-inferiority may be criticized for regarding the existing standard of care as a worthwhile clinical goal. However, incremental innovation, whereby the new drug does not represent a novel or ‘ground-breaking’ molecular formulation but rather a variation on an existing drug, does have merit in the development of new treatments. Formulations of drugs which expand existing drug classes add to the prescribing clinician’s arsenal of therapeutic alternatives, increases competition between products and creates stimulus for further innovation. Moreover, an original ‘breakthrough’ drug does not necessarily remain the most effective or the best in the group indefinitely [7]. Most importantly, trials which aim to establish whether a new treatment is not statistically significantly worse than the existing treatment should have suitable rationale for the non-inferiority margin and how such a margin has been determined.
REVIEW OF CLINICAL EVIDENCE CONCERNING COLISTIMETHATE SODIUM DRY POWDER INHALER AND TOBRAMYCIN DRY POWDER INHALER In 2011, NICE undertook a technology appraisal [8,9 ,10,11] of the antipseudomonal antibiotic DPIs (and corresponding inhaler devices): colistimethate sodium (Colobreathe and Turbospin device), and tobramycin (TOBI and Podhaler) for the treatment of chronic P. aeruginosa lung infection in patients with CF. Three randomized controlled trials were included in the review [12–14]. Two trials evaluated colistimethate sodium DPI [15 ,16] versus nebulized tobramycin or nebulized colistin and one trial compared tobramycin DPI [17–20] versus nebulized tobramycin. Both colistimethate sodium DPI and tobramycin DPI were reported to be non-inferior to nebulized tobramycin in the two phase III non-inferiority trials, for the outcome of forced expiratory volume in the first second (FEV1% predicted), based on information from two of the trials. However, there were problems with the design of the included trials, indicating that their results should be judged with caution. None of the trials included in the review met the time horizon of 12-months’ follow-up recommended by the European Medicines Agency for efficacy trials, [21] with both of the phase III trials following patients for durations of only 24 weeks [22]. As such, the existing evidence base does not include information about the long-term efficacy &&
EVALUATING NEW FORMULATIONS OF OLD DRUGS Within health technology assessment, newer ‘innovative’ treatments are usually required to possess an additional advantage, such as greater availability, reduced cost, less invasiveness, fewer adverse effects, or greater ease of administration [2]. Despite these apparent benefits, there remain two pertinent questions with respect to the new DPIs: first, are they as safe and effective as conventional nebulized antibiotics (‘do they work?’), and; second, is their comparative cost-effectiveness profile acceptable to decision-makers (‘are they worth paying for?’). These questions of clinical effectiveness and cost-effectiveness are central to health technology assessment and form the basis of recommendations on the use of particular health technologies from the National Institute for Health and Care Excellence (NICE) and other similar health technology assessment bodies elsewhere. Equivalent benefits of new drugs cannot merely be claimed on the basis of nonsignificant statistical tests from traditional superiority trials. Non-inferiority trials aim to determine whether a given treatment is not statistically significantly worse than 608
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&&
Volume 20 Number 6 November 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Dry powder inhalers in cystic fibrosis Uttley and Tappenden
and safety of these treatments [23]. Both of the large trials could also be criticized for the way that the results had been analysed, with the trial of colistimethate sodium DPI (COLO/DPI/02/06) only reaching non-inferiority when analysed nonparametrically, and the trial of tobramycin DPI [the ‘Establish A new Gold standard Efficacy and safety with tobramycin in cystic fibrosis’ (EAGER) trial] only presenting results without imputation for missing data. The smaller trial of colistimethate sodium DPI (COLO/DPI/02/05) was not powered to detect an effect in FEV1% predicted as it was only 4 weeks in duration prior to crossover; this study reported no significant differences in FEV1% predicted between arms and from baseline. It was not possible to draw any firm conclusions from the review with respect to the relative efficacy, measured by FEV1% predicted, of any intervention compared with any other intervention except nebulized tobramycin due to: missing data, uncertain comparability of patient characteristics, and incompatible methods of analysing the data. Further, as FEV1% predicted is a surrogate outcome, the European Medicines Agency recommends that it should be considered alongside ‘harder’ outcomes, such as exacerbations [21,24]. Both tobramycin DPI and colistimethate sodium DPI appeared to be less effective in reducing the frequency of exacerbations, but patients treated with DPIs spent less time on antibiotics. Adverse events were mostly similar between arms within trials, except for cough, which was higher in both DPI intervention arms. In both trials, more patients in the DPI intervention arms withdrew due to adverse events. The statistical and clinical significance of differences in sputum density, resistance data, exacerbations, and adverse event data are not known. None of the trials measured HRQoL using a preference-based measure (e.g., the Euroqol EQ-5D or the SF-6D) and the duration of study follow-up was insufficient to draw any conclusions regarding the effect of DPI formulations on mortality in comparison with nebulized tobramycin. Overall, there remains considerable uncertainty with respect to the net clinical benefit of the DPI products and nebulized antibiotics for the treatment of chronic P. aeruginosa.
ECONOMIC ISSUES SURROUNDING THE USE OF COLISTIMETHATE SODIUM DRY POWDER INHALER AND TOBRAMYCIN DRY POWDER INHALER Demonstrating relative clinical efficacy alone is not sufficient to judge whether DPIs are equivalent, or even superior, to nebulized antibiotics. There is also
a need to assess whether the DPIs represent good value for money for the National Health Service (NHS), that is, whether they should be considered to be cost-effective or not. At the time of writing, the list prices for tobramycin DPI and colistimethate DPI were £1790 and £968 per 28 treatment days, respectively, whilst the cost of nebulized tobramycin is approximately £1187 per 28 treatment days [25]. Preparations of nebulized colistin vary in cost, but may be notably less expensive than these products. If a new technology incurs greater costs than the current standard treatment for a given indication, funding that new product means that something else which produces health for other patients will be displaced elsewhere in the health service [26]. As such, there is a need to consider whether any additional value afforded by the new technology outweighs the health forgone associated with curtailing existing treatments and services elsewhere in the health service. In England and Wales, NICE uses information on the cost-utility of new treatments versus existing therapies, defined in terms of the incremental cost-effectiveness ratio (ICER), to inform such judgements about the balance of additional value and opportunity cost. Within this cost-utility framework, the ‘value’ of health technologies is measured in terms of quality adjusted life years (QALYs); this metric is intended to reflect both the duration and quality-of-life (morbidity, psychological, functional, social, and other factors) of patients receiving particular treatments. Judgements about the acceptability of an ICER for a particular therapy is made through reference to a cost-effectiveness threshold; NICE typically operates a cost-effectiveness threshold in the range 20 000 to £30 000 per QALY gained [27]. This threshold is intended to represent the monetary cost of each QALY which is displaced as a result of funding a new more expensive treatment. At present, research concerning the cost-effectiveness of treatments for CF remains worryingly under-researched. To date, there have been very few full economic evaluations of treatments for CF [28–30]. None of the existing published economic analyses relate to the cost-effectiveness of DPI antibiotics versus nebulized antibiotics for the treatment of chronic P. aeruginosa. Given the lack of existing economic analyses, the authors of this article undertook a de-novo economic evaluation to assess the cost-effectiveness of the DPI products versus nebulized antibiotics [11]. Within this economic analysis, Tappenden et al. used patient-level data from the two pivotal trials of colistimethate sodium DPI and tobramycin DPI to inform a health economic model to assess the costeffectiveness of DPIs versus nebulized treatments.
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cystic fibrosis
The economic analysis was undertaken from the perspective of the United Kingdom NHS and evaluates costs and health outcomes associated with competing DPI and nebulized antibiotics over a lifetime horizon. The authors developed a state transition model [31] based on transitions between three strata of lung function, measured in terms of FEV1% predicted (FEV1>70%, FEV1 40–70%, and FEV1
![[Dry powder inhalers in cystic fibrosis].](/assets/img/hold.png)
