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Consequently, development of long-acting, nebulized β-agonists and anti-muscarinics represent a significant unmet therapeutic need, 38 a gap one author described as a "compelling opportunity." 11 Nevertheless, this opportunity has been largely over- looked to date. It has been suggested that this is due to unfavorable commercial considerations. 38 Once proof- of-principle is achieved, the nebulized formulation is normally dropped in favor of continued development of the drug in a pMDI or DPI form to serve the majority of patients. After the pMDI or DPI product is marketed, a nebulized product may be considered as a lifecycle opportunity, but since this is a completely different delivery system and formulation requiring its own dose- ranging and pivotal Phase III studies, introduction to the market can take five years or more. By that time, little of the original drug patent life may remain, so unless for- mulation patents can be obtained, there is insufficient time to recover the investment before generic copies enter the market. One potential way around this would be to develop the product in a nebulizer with character- istics that are hard to copy, thereby effectively creating a co-labelled or combination product. Such features can include medication volume and breath-actuation men- tioned above, patient management systems discussed below, or a bespoke interface between the drug packag- ing and device. 39, 40 However, this would then potentially preclude the device from being used with other, general- purpose nebulized products. Therefore, leaving nebulized product development until late in the drug's lifecycle can make a new drug in nebu- lized form commercially unattractive. In order to over- come this problem, one company, Mylan, has decided to go straight to market with a new long-acting mus- carinic (LAMA) drug in nebulized form, despite having previously licensed a different LAMA for use in inhalers. 41, 42 An alternative novel approach is to focus first on bringing the nebulized formulation to market, and only to start development of a pMDI or DPI once the new drug candidate has successfully demonstrated safety and efficacy. Not only does this mitigate the costs associated with drug failure during development, it also allows outcomes to be evaluated in the most severe group of patients (already requiring nebulized treat- ments), in whom a positive effect should be easiest to demonstrate. This has been modelled from a financial perspective, and shown to be likely to give a much better financial return on research and development invest- ments, even when drug sales are modest. 43 Furthermore, it is generally easier and quicker to develop a formulation which is physically and chemically stable for a nebulizer than for an inhaler, even if this means developing a lyophilized product for reconstitution. A greater range of excipients is available to the formulator, resulting in fewer challenges to making formulations that are easily dispersible back to respirable form. Consequently, there is more time for the inhaler formulation to be developed while the nebulized variant is already in the clinic. A new drug may also benefit from a new device. The increasing linkage between drug and delivery device dur- ing clinical trials also has added significance beyond the development stage. The microelectronic platform upon which mesh nebulizers are built can easily be supple- mented with sensors, logic circuits, antennas and micro- processors during development. These additional fea- tures could then be used to provide sophisticated collec- tion, analysis and transmission of data for incorporation into an e-health system for patient management. Data pertaining to nebulizer operation, usage characteristics and a range of measures relevant to monitoring disease progression could then be leveraged to aid the success of the new drug product during clinical studies and approval. The assessment of adherence to drug usage in clinical trials is required by the principles of good clinical practice, and the collection of data such as adherence and compliance is currently incorporated into a range of devices. 44 The expansion into parameters providing information on disease progression is in its infancy. 45 But if the data can be shown to help the patient improve self- management of his or her condition, it can be expected to be seen as an advantage that outweighs concerns around privacy. Beyond launch, these same features could be used to ensure the continued commercial suc- cess of the drug, with better disease control promoting continued use of drug and device. Patients enrolled in clinical studies are not typical of the wider population in terms of their amount of interaction with healthcare providers. One of the fundamental issues affecting the treatment of respiratory diseases remains the issue of poor adherence to prescribed regi- men, which can be subdivided into three phases: initia- tion, implementation and persistence. 46 The prescrip- tion of a new drug with a user friendly "aspirational" technology device package could contribute to success- ful initiation of treatment while an easy-to-use design with feedback features to aid correct use of the device could aid implementation. But aiding persistence may require extended logging, memory and communication modules that are already proving to be advantageous in the treatment of respiratory disease. One example of this technology in use is in the treatment of cystic fibrosis. An e-health system that consists of a mesh nebulizer fitted with a logging function can be used in conjunction with communication hardware and software to allow upload- ing of adherence information to a secure central server, compliant with all data privacy and security regulations. Patients, clinicians and support personnel such as rela- tives can log into the server to examine data concerning treatment and adherence. This type of approach has been shown to facilitate: an increase in the number of doses taken correctly, 47 high levels of adherence that can be sustained over 12 months, 48 a reduction in treatment times 49 and a correlation of better lung function with optimum adherence. 50 14 JUNE2017 Inhalation