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three-dimensional structure and biological activity of the molecule. The ability to select meshes during the manu- facturing process that produce specific mass median aerodynamic diameters (MMADs) for the aerosol distri- butions may also allow greater targeting of aerosols to specific regions of the airways and lungs from mesh neb- ulizers. 21 Along with delivery of aerosol boluses and con- trolled flow, 22 this may be useful in the development of drugs that have a narrow therapeutic window between efficacy and the onset of side effects. As a result, nebulizers are often used in Phase I and IIa trials, where there is still high clinical risk associated with the investigational drug, so the expense of developing a more complicated and costly DPI or pMDI inhaler for- mulation can be avoided. Dosimetric, breath-activated, mesh nebulizers can be used to deliver reproducible doses with little waste and so are ideally suited for dose- ranging studies and instances when the quantity of drug manufactured for early studies is low. More recently, breath-actuated mesh nebulizers, including those incor- porating data logging capability, have been used in clin- ical trials and have provided useful data to explain anom- alous patient results, for example, a lack of exposure explainable by failure to adhere to the treatment regi- men. 23 Furthermore, if remote monitoring is used while the trial is underway, adaptive trial designs can be used to exclude non-adherent patients. 24 Evidence for the increasing adoption of mesh technol- ogy can be found in an examination of clinical trial reg- isters, 25, 26 established in the US in 2000 and the EU in 2004. A search of US and EU clinical trial registers undertaken in January 2015, showed that between 2005 and 2012, mesh nebulizers were used in 53% of valid studies, while the use of jet (44%) and ultrasonic (3%) nebulizers was lower. (Studies were considered valid if they were clinical trials involving nebulizers with the fol- lowing excluded from the analysis: nebulizer not speci- fied, study withdrawn, study not a drug trial or for non- inhaled drugs, study investigated hypertonic saline or heliox, scintigraphy, provocation tests, used spinning- top aerosol generators or nasal delivery.) Examination of the clinical trials in terms of sponsorship showed that mesh nebulizers were favored over jet nebulizers in clin- ical trials sponsored by pharmaceutical companies as opposed to clinician-sponsored studies (Figure 2). The three most popular models of mesh nebulizer were the I-neb AAD System (Respironics Respiratory Drug Delivery [UK] Ltd, Chichester, UK), Aeroneb Go (Respironics Respiratory Drug Delivery [UK] Ltd, Chichester, UK), and eFlow (Pari GmBH, Starnberg, Germany), and all were available on the market by 2004. 27-29 Demonstrating nebulizer performance Historically, there has been a substantial difference in performance between some of the best and worst nebu- lizer systems on the market. 30, 31 However, as drug discov- ery and development becomes more targeted and new Clinical trials sponsored by pharmaceutical companies registered by year between 1999 and 2014 that used mesh (blue), jet (purple) or ultrasonic (orange) nebulizers Figure 2 16 18 20 14 12 10 8 6 4 2 0 1999-2000 2001-2002 2003-2004 2005-2006 2007-2008 Year Number of clinical trials 2009-2010 2011-2012 2013-2014 12 JUNE2017 Inhalation