The clinical effectiveness and cost-effectiveness of inhaler devices used in the routine management of chronic asthma in older children: a systematic review and economic evaluation

Background: This review examines the clinical effectiveness and cost-effectiveness of hand-held inhalers to deliver medication for the routine management of chronic asthma in children aged between 5 and 15 years. Asthma is a common disease of the airways, with a prevalence of treated asthma in 5–15-year-olds of around 12% and an actual prevalence in the community as high as 23%. Treatment for the condition is predominantly by inhalation of medication. There are three main types of inhaler device, pressurised metered dose, breath actuated, and dry powder, with the option of the attachment of a spacer to the first two devices under some prescribed circumstances. Two recent reviews have examined the clinical and cost-effectiveness evidence on inhaler devices, but one was for children aged under 5 years and the comparison in the second was made between pressurised metered dose inhalers and other types only. Objectives: This review examines the clinical effectiveness and cost-effectiveness of manual pressurised metered dose inhalers, breath-actuated metered dose inhalers, and breath-actuated dry powder inhalers, with and without spacers as appropriate, to deliver medication for the routine management of chronic asthma in children aged between 5 and 15 years. Methods: Two previous HTA reviews have compared the effectiveness of inhaler devices, one focusing on asthma in children aged under 5 years and the other on asthma and chronic obstructive airways disease in all age groups. For the current review, a literature search was carried out to identify all evidence relating to the use of inhalers in older children with chronic asthma. A search of in-vitro studies undertaken for one of the previous reviews was also updated. The data sources used were: 15 electronic bibliographic databases; the reference lists of one of the previous HTA reports and other relevant articles; health services research-related internet resources; and all sponsor submissions. Studies were selected according to strict inclusion and exclusion criteria, and relevant information concerning effectiveness and patient compliance and preference was extracted directly on to an extraction/evidence table. Quality assurance was monitored. Economic evaluation was undertaken by reviewing existing cost-effective evidence. Further economic modelling was carried out, and tables constructed to determine device cost-minimisation and incremental quality-adjusted life-year (QALY) thresholds between devices. Results: Number and quality of studies, and direction of evidence: Fourteen randomised controlled studies were identified relating to the clinical effectiveness of inhaler devices for delivering β2-agonists. A further five were on devices delivering corticosteroids and one concerned the delivery of cromoglicate. Overall, there were no differences in clinical efficacy between inhaler devices, but a pressurised metered dose inhaler with a spacer would appear to be more effective than one without. These findings endorse those of a previous HTA review but extend them to other inhaler devices. Seven randomised controlled trials examined the impact on clinical effectiveness of using a nonchlorofluorocarbon (CFC) propellant in place of a CFC propellant in metered dose inhalers, both pressurised and breath activated, although only one study considered the latter type. No differences were found between inhalers containing either propellant. A further 30 studies of varying quality, from 12 randomised controlled trials to non-controlled studies, were identified that concerned the impact of use by, and preference for, inhaler type, and treatment adherence in children. Differences between the studies, and limitations in comparative data between various inhaler device types, make it difficult to draw any firm conclusions from this evidence. Summary of benefits: No obvious benefits for one inhaler device type over another for use in children aged 5–15 years were identified. Costs and cost per quality-adjusted life-year: Two approaches have been taken: cost-minimisation and QALY threshold. In the QALY threshold approach, additional QALYs that each device must produce compared with a cheaper device to achieve an acceptable cost per QALY were calculated. Using the cheapest and most expensive devices for delivering 200 μg of beclometasone per day, assuming no cost offset for any device, and a threshold of £5000, the largest QALY needed was 0.00807. With such a small QALY increase, no intervention can be categorically rejected as not cost-effective. Conclusions: Generalisability of findings: On the available evidence there are no obvious benefits for one inhaler device over another when used by children aged 5–15 years with chronic asthma. However, the evidence, in the majority of cases, was compiled on children with mild to moderate asthma and restricted to a limited number of drugs. Therefore the findings may not be generalisable to those at the more severe end of the spectrum of the disease or to inhaler devices delivering some of the drugs used in the management of asthma. Need for further research: Many of the previous studies are likely to have been underpowered. Further clinical trials with a robust methodology, sufficient power and qualitative components are needed to demonstrate any differences in clinical resource use and patients’ asthma symptoms. Further studies should also include the behavioural aspects of patients towards their medication and its delivery mechanisms. It is acknowledged that sufficient power may prove impractical owing to the large numbers of patients required

Improved inhalation therapies of brittle powders

textAdvancements in pulmonary drug delivery technologies have improved the use of dry powder inhalation therapy to treat respiratory and systemic diseases. Despite remarkable improvements in the development of dry powder inhaler devices (DPIs) and formulations in the last few years, an optimized DPI system has yet to be developed. In this work, we hypothesize that Thin Film Freezing (TFF) is a suitable technology to improve inhalation therapies to treat lung and systemic malignancies due to its ability to produce brittle powder with optimal aerodynamic properties. Also, we developed a performance verification test (PVT) for the Next Generation Cascade Impactor (NGI), which is one of the most important in vitro characterization methods to test inhalation. In the first study, we used TFF technology to produce amorphous and brittle particles of rapamycin, and compared the in vivo behavior by the pharmacokinetic profiles, to its crystalline counterpart when delivered to the lungs of rats via inhalation. It was found that TFF rapamycin presented higher in vivo systemic bioavailability than the crystalline formulation. Subsequently, we investigated the use of TFF technology to produce triple fixed dose therapy using formoterol fumarate, tiotropium bromide and budesonide as therapeutic drugs. We investigated applications of this technology to powder properties and in vitro aerosol performance with respect to single and combination therapy. As a result, the brittle TFF powders presented superior properties than the physical mixture of micronized crystalline powders, such as excellent particle distribution homogeneity after in vitro aerosolization. Lastly, we developed a PVT for the NGI that may be applicable to other cascade impactors, by investigating the use of a standardized pressurized metered dose inhaler (pMDI) with the NGI. Two standardized formulations were developed. Formulations were analyzed for repeatability and robustness, and found not to demonstrate significant differences in plate deposition using a single NGI apparatus. Variable conditions were introduced to the NGI to mimic operator and equipment failure. Introduction of the variable conditions to the NGI was found to significantly adjust the deposition patterns of the standardized formulations, suggesting that their use as a PVT could be useful and that further investigation is warranted.Pharmaceutical Science

An Inhaler Tracking System Based on Acoustic Analysis:Hardware and Software

In treating asthma and chronic obstructive pulmonary disorder (COPD), acquisition of authentic and effective feedback from patients on regimen adherence is difficult. Face-to-face and oral reporting methods do not satisfy current intelligent medication best practices. This paper presents a system to track and analyze daily inhaler usage. A portable electronic device that attaches to the inhaler uses an accelerometer and capacitive sensors to detect users’ motion and an embedded digital microphone to capture sounds while the inhaler is in use. In terms of analysis, sound features are extracted, and breath phases are identified by employing a hidden Markov model with a Gaussian mixture model. A feature template is also constructed and used to search for and identify “canister pressed” events. The system provides objective feedback, quantifying asthma, and COPD patients’ adherence to medication regimens. Although interest in asthma adherence to medication regimens is growing, there is still a relative paucity of research and, indeed, compliance devices in this area; the tracking system can help doctors better understand the patient’s condition and choose an appropriated treatment plan. At the same time, patients can also improve their self-management by system feedback

Formulation and Characterization of Pulmonary Drug Delivery Systems

The inhalation therapy is one of the oldest drug delivery methods known. The significance of inhalation can be understood notably through its remarkable history. The goals of this review are to explore the pulmonary drug delivery, its significant relevance and various advantageous properties, particularly due to the physiology of the lungs. The drug delivery into the lungs can be provided by several inhalation instruments presently accessible on the market such as nebulizers, MDIs, and DPIs. Supplementary devices suchlike spacers for instance are also available in order to optimize the therapy results. The efficiency of these devices depends on several parameters of the formulation used, as well as its deposition in the lungs. Therefore, this review focuses on the meticulous testing performed on both the formulation and the device carrying it in the interest of insuring safety, quality, and efficacy of the final product. Ultimately, the pulmonary drug delivery represents a substantially advantageous alternative route of administration to obtain a systemic effect as well. This review aims to the better understanding of the development of pulmonary dosage forms and its complex process which requires extensive considerations and thorough optimization

Health care's response to climate change: a carbon footprint assessment of the NHS in England

Background: Climate change threatens to undermine the past 50 years of gains in public health. In response, the National Health Service (NHS) in England has been working since 2008 to quantify and reduce its carbon footprint. This Article presents the latest update to its greenhouse gas accounting, identifying interventions for mitigation efforts and describing an approach applicable to other health systems across the world. Methods: A hybrid model was used to quantify emissions within Scopes 1, 2, and 3 of the Greenhouse Gas Protocol, as well as patient and visitor travel emissions, from 1990 to 2019. This approach complements the broad coverage of top-down economic modelling with the high accuracy of bottom-up data wherever available. Available data were backcasted or forecasted to cover all years. To enable the identification of measures to reduce carbon emissions, results were disaggregated by organisation type. Findings: In 2019, the health service's emissions totalled 25 megatonnes of carbon dioxide equivalent, a reduction of 26% since 1990, and a decrease of 64% in the emissions per inpatient finished admission episode. Of the 2019 footprint, 62% came from the supply chain, 24% from the direct delivery of care, 10% from staff commute and patient and visitor travel, and 4% from private health and care services commissioned by the NHS. Interpretation: This work represents the longest and most comprehensive accounting of national health-care emissions globally, and underscores the importance of incorporating bottom-up data to improve the accuracy of top-down modelling and enabling detailed monitoring of progress as health systems act to reduce emissions. Funding: Wellcome Trust

The Impact Of An Educational Program On Asthma Symptoms And Knowledge In The Late Adolescent

Despite advances in medical technology, statistical evidence indicates that asthma related morbidity and mortality rates continue to rise, especially in the late adolescent population. Current research literature suggests that patient education may be beneficial in obtaining and maintaining asthma control in the pediatric and adult populations. Currently, however, there is little research available regarding the impact of education in the late adolescent population. This study, therefore, sought to determine the impact of an educational program on asthma symptoms and knowledge among late adolescents. Becker\u27s Health Belief Model was used as the theoretical framework. A quantitative, quasi-experimental design was utilized to test the two research null hypotheses. The first null hypothesis was there will be no difference in asthma symptoms of late adolescents before and after an asthma educational program. The second null hypothesis was there will be no difference in knowledge of asthma of the 111 late adolescent before and after an asthma educational program. Subjects included male and female adolescents between the ages of 18 and 2 5 years who had been referred by their primary care health provider as candidates for enrollment in the asthma education study and who met all study criteria. Data were obtained from participant questionnaires and lung function studies. Asthma symptoms were measured and assessed by utilization of the American College of Allergy, Asthma & Immunology Life Quality (LQ) Test and by objective peak flow measurements. Asthma knowledge was measured and assessed by utilization of the National Heart, Lung and Blood Institute questionnaire Check Your Asthma IQ. Baseline data were obtained prior to a 40- to 6 0-minute educational intervention; post intervention data were then obtained at 2 weeks following the intervention. Telephone follow-up data were obtained at approximately 6 to 8 weeks following the intervention. The data were collected at the student health center of a large university in Northeast Mississippi. Data were analyzed using descriptive statistics and the two-tailed t t e s t

Investigation of bipolar charge distribution of pharmaceutical dry powder aerosols using the phase doppler anemometry system

This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University London.Electrostatic properties of formulation component materials and blends play an important role in dry powder inhalation (DPI) products, and that valid measurement of charge distribution will lead to more precise control of powder behavior in DPI manufacturing processes. Ultra-fine powders are known to be bipolarly charged, have non-spherical shapes and tend to be highly cohesive. Real time, non-invasive techniques need to be developed to obtain a precise and accurate time-history characteristic of electrically charged powders as they aerosolize from a DPI product, and how this measure relates to materials behavior throughout the various steps of a manufacturing process i.e. from drug micronisation, blending with lactose, through to filling dose units. A novel non-invasive technique for simultaneous measurement of size and charge of pharmaceutical powders is considered which employs the Phase Doppler Anemometry (PDA) system. Previous research demonstrated the advantages of this technique in measuring the bipolar charge distribution on a population of particles. These findings led to significant improvements in understanding performance of dry powder formulations, manufacturing processes and development of new platforms for inhaled drug delivery. The main aim of this research is to perform an investigation of electrostatic propertiesof pharmaceutical dry aerosols using the PDA system. The PDA technique was used to track the motion of charged particles in the presence of an electric field. The magnitude as well as the polarity of the particle charge can be obtained by solving the equation of particle motion in DC and AC fields combined with the simultaneous measurement of its size and velocity. The results show the capability of the technique to allow real-time size and charge distribution in the control of dry powder attributes that are critical to fully understanding manufacturing design space. The data obtained from initial investigations of electrical properties of pharmaceutical powders and bipolar charge measurements was used to perform an in-depth study of electrostatic properties of pharmaceutical aerosols dispensed by dry powder inhaler (DPI) devices. The delivery of a drug to the lungs can only be achieved by a combination of inhaler device and drug formulation which is capable of producing an aerosol of an aerodynamic diameter smaller than 5 μm and of appropriate charge. The aerosols generated by these devices are often bipolarly charged and can influence specific site deposition in human lung. By controlling the electrostatic charge generated by tribielectrification, it may be possible to achieve the desired drug deposition in the airways. Bipolary charged dispensed ultrafine particles are inhaled through the extrathoracic and tracheobronchial airways down into the alveolar region. Anatomically realistic respiratory airways and computation fluid dynamics (CFD) models have been created to study airflow structures and predict aerosol deposition within the human respiratory system using visible human data sets, human casts and morphometric data. Many theoretical studies of charged aerosol deposition in human respiratory systems have been developed, however getting real time, non-intrusive data of bipolar charge levels on aerosols dispensed from DPI’s within the human respiratory system represents a challenging issue. This research project presents a simplified human upper airway model which combined with the modified Phase Doppler Anemometry (PDA) system is able to provide real time bipolar charge distributions of aerosols delivered from several commercially available DPI devices. A three dimensional (3D) reconstruction of the upper respiratory system was performed from two dimensional (2D) images obtained from computerized tomography (CT), magnetic resonance imaging (MRI) and cryosectioned images available from Visible Human Server data set (Ecole Polytechnique Fédérale de Lausanne). The resulting dimensions of the model were consistent with morphometric data from the literature from which the simplified upper airway model consisting of two connected segments, i.e., the oral airways from the mouth to trachea (Generation G0), was created. The findings of this study provided a better understanding of the interaction between specific active ingredients and DPI devices. These results may be used in designing future generation DPI devices and a better understanding of aerosol transport and deposition efficiency within the human airways.Engineering and Physical Sciences Research Council. Pfizer team, U

The Development of A New Dry Powder Inhaler

A new dry powder inhaler (DPI) for respiratory drug delivery was developed. This novel device is characterized by a micro-dose, passive delivery and multiple doses individually sealed in one replaceable disk. The micro-dose delivery system uses only a small amount of excipient, such as 2-3mg lactose, thereby improving the drug delivery efficiency. The passive delivery method eliminates the need for coordination between breath and device actuation such as the pressure metered dose inhaler (pMDI). Finally, 14 doses on a disk reduce the need to frequently change dosage disks. In addition, each dose is effectively protected by a blister package to minimize damage from moisture and oxygen. A comprehensive evaluation on key parameters, including dosage emittion, air flow resistance and fine particle fraction, has been conducted. The air resistance of our device is about 0.06 kPa0.5·min/liter, slightly higher than several marketed products but close to Inhalator®. The in vtiro performance results show that this new dry powder inhaler is able to achieve a high efficiency for drug delivery, with 10% of drug remaining in the device. This device can also effectively disperse drug particles to acquire a high fine particle fraction (FPF) as 50%. A primary stability research demonstrates that the FPF of a formulation containing 5%-fine additive would stay at 40% when being accelerated for 3 months. Furthermore, comparative studies between this novel inhaler and typical marketed products –such as Diskus®, Turbuhaler® and Aerolizer®, show that when combined with suitable formulations, the FPF of our device could be about 25% as Diskus® and Aerolizer®, or above 40% as Turbuhaler® and Clickhaler®. When using the same powder, our device shows a FPF of 50%, similar as Clickhaler® and Aerolizer® and higher than Twister®, indicating similar or better performance of our inhaler device to disperse drug particles. Because no existing powder filling system could satisfy the filling requirements of this new inhaler, a new powder dispensing and packaging system was developed. The new powder filling system designed and implemented in our lab was evaluated and optimized to improve the uniformity of filling weight and drug content among disks/blisters. The relative standard deviation (RSD) of filling weight among disks and blisters is 1~3% and 6~8% respectively. The uniformity of drug content among disks, with a RSD from 2~5%, demonstrate the filling system could completely meet the requirements of the inhaler development. Suitable drug formulations for this new DPI were also developed, including research and optimization of powder composition and processing. The preparation of a uniform drug-lactose blend was investigated, including the mixing method, mixing time & speed, and mixing sequence. The composition studies are conducted to better understand the effect of the drug particle and excipient on the drug delivery. Experiments show that the powder composition and processing have a significant influence on the in vitro performance, which can be controlled and adjusted to obtain the desired results. For example, when increasing the ratio of fine additive from 0% to 20%, the FPF is increased from 20% to 45%. Meanwhile, if the mixing time is extended from 2min to 10min, the FPF experiences a drop from 35% to 22%. With the optimization of powder composition and processing, development of the powder filling system and implement of the new inhaler device, this novel inhaler can deliver 2-3mg powder per dose with an adjustable fine particle fraction from 25%-50%