Review on organ-on-chips for medicines safety assessment: A European regulatory perspective_suppl1

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. Plain language summary Organ-on-chips (OoCs) are innovative microdevices that replicate human or animal organs in laboratory settings, aiming to increase the predictability of physiological responses to medicinal products and potentially reducing reliance on animal testing. This review examines the development of OoCs from 2010 to 2020, focusing on their use in safety testing of medicines. The review describes the different types of OoCs developed, the organs they mimic (such as the liver, kidney, and heart) and their use in medicines safety testing. In addition, the types of medicinal compounds tested are reported. Finally, the review also highlights the challenges and opportunities for OoCs to be accepted by medicines regulators, such as the European Medicines Agency.