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19 January 2023

EMA perspective on using mechanistic models to support development of complex generic drug products


Several European regulators provide perspective on the use of mechanistic models and specifically physiological based pharmacokinetic modelling in a complex generic drug development.


Model-informed drug development approaches receive wide regulatory acceptance in the European Medicines Agency to support new drug development. For generic drugs, the European regulators have not reached a common position on how to use these methods. This article expands on the existing EMA regulatory framework for bioequivalence and physiological based pharmacokinetic (PBPK) modelling to propose conditions where mechanistic models could support or potentially waive clinical bioequivalence (BE)/bioavailability (BA) studies.


The article focuses on a complex generic drug development (products that have complex active ingredients, formulations, dosage forms, or routes of administration or are complex drug–device combination products). Complex generics are submitted to the EMA as generic (e.g., systemically acting products such as long-acting injectables) or hybrid (e.g., locally acting products such as orally inhaled products or semisolid cutaneous products) applications under Article 10(1) or 10(3) of Directive 2001/83/EC as amended, respectively.


The EMA’s experience in assessing PBPK approaches to support or even waive BE is limited, but there is a willingness to engage in a discussion regarding the utility and qualification of these models. As a first step, it is recommended to focus on a clinical setting where regulators would likely be more open in accepting model-based BE (MBBE), that is, where clinical PK BE studies are hindered by feasibility constrains or are not fully informative. The EMA qualification procedure11 represents a suitable forum to drive regulatory requirements and acceptance forward. The topic of MBBE is already on the radar of European regulators and of the newly formed methodology working party in particular. The EMA, with the aim to build expertise and achieve consensus on the use of PBPK absorption models, joined an IQ Consortium collaboration initiative on PBBM with other regulatory agencies. Where there is a will, there is a way!


The full article is available at [Open Access]:

Manolis E, García-Arieta A, Lindahl A, et al. Using mechanistic models to support development of complex generic drug products: European Medicines Agency perspective [published online ahead of print, 2023 Jan 11]. CPT Pharmacometrics Syst Pharmacol. 2023;10.1002/psp4.12906. doi:10.1002/psp4.12906