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The article discusses the challenges and potential solutions in the regulatory pathway for generic orally inhaled drug products (OINDPs). The current pathway is challenging due to the cost and time associated with meeting the clinical end-points and the low success rate. However, the FDA has been actively funding the development of technologies to enable in vitro-in silico approaches and have even updated some Product Specific Guidance (PSG), introducing the “alternative approach to the comparative clinical end-point Bioequivalence study (CCEP BE)”.
The main challenge associated with evaluating these factors in CCEP BE is that patient-to-patient variability has such a significant impact on outcomes. This typically means that cohorts of 1-2,000 patients, over a number of weeks, are needed to build enough power for the statistical analysis, which quickly becomes very costly. Furthermore, it is difficult to replicate and discriminate patient variability in a way that determines whether similarities or differences are the result of the patients’ (in)ability to use the product as intended, the difference in the patients’ diseased lung physiology, or whether it is a fundamental difference between products themselves.
The article proposes an in-vitro-in silico approach that can cover the complete range of patient-to-patient variation in a fraction of the cohort size, and produce a more robust result. Any difference can be clearly attributed to a certain factor and the relative influence and interconnection between multiple differences on the outcome can be modeled. This not only allows for a credible prediction of bioequivalence, but can also help to determine which critical quality attributes (CQA) are most clinically significant for each drug product within the context of efficacy.
The article concludes that this approach not only provides regulators with the confidence they need, but also provides a robust tool to help with the development and optimization of a product from the outset. The outcome offers an opportunity to go beyond the current expectations of the industry and regulatory bodies, and proposes an incontrovertible approach that may arguably be proven to be less risky than performing the existing clinical end-point studies and, in time, become the recommended approach rather than only the alternative.
