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22 June 2020 Inhalation We applaud the process of harmonization of com- pendial standards in the form of drug product mono- graphs. 12-14 However, such standards could be used more extensively than that which appears to be currently con- templated, in order to be much more impactful for the public good. The foundations of the post-approval quality of inhaled products, whose clinical performance is assumed to resemble the results of the pivotal clinical trials that justified their approval, are in the adherence to good manufacturing principles and quality control systems that focus on the critical attributes of these medicines. ese systems ultimately reflect the Chem- istry, Manufacturing and Controls (CMC) aspects of the product used in the pivotal trials. In principle, it can be reasoned that if an innovator is able to release their batches of commercial product based on in vitro assessment methods and specifications derived from a thorough understanding of the product, then a generic version of the product from another manufacturer that is made under GMP conditions, tested with the same methods and compli- ant with the same specifications as the innovator's product should be as safe and efficacious as the original product and therefore approved without any additional clinical studies. Yet in the US, generic versions of OIPs—specifically pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs)—cannot be approved on the basis of in vitro studies only. is contrasts with EU regulations where this is possible in principle and an algo- rithm for the decision process starting with in vitro "bioequivalence" is avail- able, which allows a generic product to be approved without conducting "bioequivalence" clinical trials. 15-17 is difference has enabled the approval in the EU of at least four generic versions of the Advair Diskus. However, even in the EU, there are both practical challenges and logical inconsistencies in these reg- ulations: there is no universal reference standard to which the generic company can compare their prod- ucts. e generic company must pass bioequivalence studies against "randomly" selected reference batches, with no certainty that these are either "representa- tive" of the batches on the market, or, indeed, of the properties of the batches that were used in the pivotal approval trials. Running complicated pharmacoki- netic trials with multiple batches to provide evidence of bioequivalence seems even less meaningful in light of the findings that samples of the marketed reference product may fail bioequivalence tests against "itself " due to inter-batch variations. 18-20 e barriers to entry of generic products are not just in the form of patent infringement and regulatory exclu- sivity. ey also include regulatory hurdles associated with the nature and quantity of the evidence required to prove their equivalence to innovator reference products to have such generics approved. For example, Wixela ® Inhub ® (Mylan, Canonsburg, PA, US), the only generic version to date of GSK's Advair Diskus® (Brentford, UK) approved in the United States, took "10 years of rigorous develop- ment." 6 Mylan reported 7 that their R&D expenditure for this generic development was more than $700 mil- lion US. No doubt, a significant portion of the length and cost was the preparation for and conduct of the 28-day "bioequivalence" trial that enrolled more than 1,000 patients. 8 The Novartis/Oriel program with their generic version of Advair has not yet succeeded in obtaining approval, despite extensive pharmacokinetic and efficacy trials to provide evidence of "bioequiva- lence" 9, 10 and has subsequently been suspended with a write-off of $442 million US. 11 Clearly, innovators have an interest in obtaining the maximum protection through patents and regulatory exclu- sivity, while generic companies and the public have an interest in the earliest approval of "generic" products. The purpose of this article is to initiate a dis- cussion among all key stakeholders to find ways to provide the general public with the best-possible inhaled drugs at an affordable cost while rewarding the industry for taking the risk of investing in the development of more efficacious and safer medicines. For illustration, we propose some examples of what might be done. As many companies would not develop new inhaled products without including the US in their potential mar- ket, we will focus on the US. Improving accessibility while protecting innovation The question is: Can we improve accessibility and affordability of orally inhaled therapies while protecting incentives for the development of innovative products? We believe the answer is "Yes" and want to provide the important assurance that this goal should, and can be, achieved without any adverse impact on the quality, safety and efficacy of the products reaching patients. As we will outline in detail here, a combination of reg- ulatory incentives for innovators, in return for their assistance preparing the necessary monographs, should enable sufficient risk reduction to allow generic prod- ucts to be approved on the basis of compliance with the monographs, without the need for human clinical trials to prove equivalence. Can we improve accessibility and affordability of orally inhaled therapies while protecting incentives for the development of innovative products?

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