Review on organ-on-chips for medicines safety assessment: A European regulatory perspective.

This review examines a decade (2010-2020) of organ-on-chip (OoC) development, focusing on their application in the non-clinical safety assessment of medicinal products. It includes a detailed description of the types of OoCs, the organs, tissues and interactions mimicked, as well as their various applications. A broad range of organs and combinations of organs were modelled in the reviewed OoCs, with the liver, kidney and heart being the most frequently mimicked. Consistent with this, hepatoxicity and metabolism-induced toxicity were the primary focus of the safety assessment, highlighting the interest in improving safety testing in this organ. Furthermore, a list of the reported biological safety endpoints and medicinal compounds tested in all OoCs is detailed. The majority of OoCs reviewed measured toxicity using only one endpoint, which were often related to viability or cell death. In the context of the data collected, this review also includes a regulatory discussion, highlighting challenges and opportunities for increased regulatory acceptance of OoCs for safety assessment. Key considerations for OoC qualification are discussed, including the importance of defining a clear context of use, selecting relevant endpoints and reference compounds. The ongoing activities of the European Medicines Agency to promote the integration of new approach methodologies (NAMs), including OoCs, into regulatory submissions are also outlined.