Abstract/Summary

Generic alternatives to orally inhaled products (OIPs) to treat respiratory diseases are challenging to develop clinically, due to uncertainty of what methodology could be used to demonstrate bioequivalence (BE) and the relevance of traditional methods of demonstrating BE. OIPs assert their pharmacological effect directly in the lung and have minimal systemic absorption, thus it is necessary to test the effect of these drugs in the lung to demonstrate that a generic product is BE to the reference product; this is termed local therapeutic equivalence (LTE). This thesis describes the identification and testing of a clinical development pathway to demonstrate BE for a generic form (Wixela™ Inhub™) of Advair® Diskus® to provide a more affordable inhaled corticosteroid/ long-acting β2-receptor agonist (ICS/LABA) to patients with respiratory diseases in the USA. Two methodologies (FeNO and methacholine challenge) were assessed to determine whether they could be used to prove LTE; however, upon completion of these studies it was ascertained that neither were suitable. Therefore, there was no suitable pharmacodynamic method available to demonstrate LTE. The method utilised to provide LTE was a large study in asthma patients using lung function as the endpoint, i.e., if FEV1 was the same between the test and reference products, the LTE would be proven. The lung function measures were bioequivalent and therefore, LTE for Wixela™ Inhub™ when compared to Advair® Diskus® was demonstrated. Additionally, pharmacokinetic (PK) BE was demonstrated, measuring fluticasone propionate (FP) and salmeterol concentrations in plasma at each available dose strength following dosing of Wixela™ Inhub™ or Advair® Diskus®. The successful completion of the clinical development program means that the development of a generic ICS/LABA is viable clinically, because of the demonstration of BE in both plasma and the lung. Therefore, this should increase the availability of affordable, quality medicines for patients with respiratory diseases.