In addition to calls for better understanding of patient inhaler use through the use of electronic sensors, RDD 2016 included numerous discussions of how to achieve a more nuanced understanding of API and/or formulation behavior, both in vitro and in vivo, including the need to take into account real-world use conditions such as pressure, temperature, and relative humidity; patient factors such as age, gender, and muscle strength; more realistic inhalation profiles and more realistic endpoints than FEV1.
In a talk titled, “Knowledge Gaps and Challenges Facing Development of Orally Inhaled Drug Products,” the FDA’s Sau (Larry) Lee acknowledged the difficulty of following the agency’s guidance on bioequivalence for DPIs, which was published in 2013, saying, “We recognize that the clinical studies proposed in the bioequivalence guidance puts a lot of burdens on the company, so we are still exploring more efficient methodologies to establish bioequivalence for these locally acting inhalation products.” He also acknowledged problems related to intellectual property around DPI device design when the agency requires a generic product to have a similar device to the innovator, which leads to “a quite limited design space.”
Lee then described some of the agency’s scientific initiatives to meet the challenges of DPI development, initiated in 2009, with a goal of better understanding DPI performance for both innovators and generics. One study, he said, compared the Flovent Diskus to the Cipla Multihaler, using CFD simulations to match local pressure drop and air flow velocity of the two devices and to get as similar aerodynamic particle size distribution.
He also addressed the question, as did several other speakers, of the relationship between PK and regional lung deposition, noting that for poorly soluble drugs such as fluticasone propionate, dissolution is the rate limiting step. Lee then described an upcoming PK study designed to evaluate the characteristics of different DPI formulations with the same emitted dose but different MMADs and presumably different deposition patterns, as well as a CFD modeling initiative to better understand the effects of formulation characteristics and physiological parameters on deposition.
