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20 February 2019 Inhalation only be reliably established largely through human clinical development. Once approved, quality con- trol of the product should be based on that empirical body of evidence, which may (and often will) vary from product to product. It is not just the mean tar- get values but also the margins of variability in prod- uct specifications that should depend on the prod- uct's preclinical and clinical performance. A drug that is administered at doses well to the right of the plateau of the dose-response curve, and is safe and tolerable at those doses, would not need to have the same narrow in vitro specifications as a drug with a narrow therapeutic index with significant side effects at higher doses, which could outweigh the drug's benefits. In the case of delivery to the lungs for topical or systemic effect, accurate targeting to the desired regions of the respiratory tract would assist in achieving the required therapeutic benefit(s) for nar- row therapeutic index drugs. At the same time, it is highly desirable to minimize deposition elsewhere. ere is no absolute regional selectivity, even for the delivery of monodisperse aerosols, but substantial shifts in the proportion of dose depositing in central or peripheral airway regions can be achieved with particle size control. 23 e control of breathing (inspiratory flow rate) and placement of a drug-containing-aerosol "bolus" in different parts of inspired volume may have equally dramatic impact. 19, 23, 24 Incorporation of these find- ings, based on good scientific principles, into modern inhalation systems tailored at specific patient popula- tions is certainly a goal that is within our reach. Closing thoughts Before you pursue any of these exciting research opportunities, please conduct a thorough literature review. You do not want to spend your precious time and talent to later learn that you were "reinventing the wheel." No matter which of these exciting opportunities (or others) in inhalation you pursue, using your talent to help enhance the lives of patients through your research can be one of the most inspiring and reward- ing career journeys you can make. References 1. Prevost DR et al, (2010) Nontuberculous myco- bacterial lung disease prevalence at four integrated health care delivery systems. Am. J. Respir. Crit. Care Med. 182:970-976. 2. Strollo SE et al, (2015) e burden of pulmonary nontuberculous mycobacterial disease in the United States. Annals ATS 12:1458-1464. 3. Cipolla D and Gonda I, (2011) Formulation tech- nology to repurpose drugs for inhalation delivery. Drug Disc. Today: erap. Strat. 8:123-130. imize oropharyngeal deposition. is could elimi- nate much of inter- and intra-individual variability in delivery of drugs to the thorax and, as a conse- quence, improve delivery efficiency and reproduc- ibility to the lung. This outcome was, indeed, demonstrated in humans some time ago. 19 In this context, I believe we need more than just out- standing R&D—we also need evidence-based regula- tory incentives that motivate companies to remove this wasteful and potentially toxic portion of the aero- sol cloud, which can lead to unnecessary systemic exposure. e European developments in this respect are somewhat encouraging, in that the sponsors of generic versions of inhaled corticosteroids are at least not penalized for reduction of the systemic exposure to the drugs compared to the reference product. In the US, the requirements for "sameness" between the original reference product and the generic substitute have certainly not resulted in a rapid introduction of generic inhaled products. Research that would sub- stantiate changes in the regulatory paradigm and result in incentives to improve the safety and efficacy of approved inhaled drugs would be very valuable for the global community at large, as it would provide easier access to better medicines. Improving nasal delivery is article would be incomplete if I did not com- ment on airborne particle deposition in the naso- pharynx. In contrast to the oropharynx, the nose is a frequent target organ for locally acting drugs and vaccines, and more recently as the portal for sys- temic delivery of drugs or delivery of drugs to the brain. Modeling and understanding regional depo- sition in the nose is at least as challenging as with oropharyngeal deposition. So we need better under- standing, as well as delivery devices and formula- tions that maximize "productive" regional delivery and disposition based on the desired location in the nose, while minimizing escape of drug beyond the nasopharynx, which is not only wasteful but a safety concern as well. 20 Nasal delivery is arguably less well-developed and therefore has at least as much potential for exciting innovations as do orally inhaled drugs. e FDA is encouraging and sponsoring efforts in basic under- standing of nasal delivery. 21 And when you see head- lines like, "Nasal drug delivery technology market is expected to exceed US $64 billion by 2023," 22 you young scientists should pay some attention! I can smell a lot of exciting opportunities in this area! Targeting orally inhaled products with narrow therapeutic indices Goals are universal for the delivery of any therapeutic dosage form: minimize toxicity and maximize effi- cacy and tolerability. At present, these attributes can