The value of organs-on-chip for regulatory safety assessment

Abstract

complete replacement of animal tests is not yet possible. Especially in case of the more complex systemic endpoints (e.g., carcinogenicity and reproductive toxicity), adequate animal-free methods are not yet available. Similarly, sufficiently predictive animal-free models to obtain information on toxicokinetics (absorption, metabolism and excretion), which is indispensable to calculate safe exposure limits for humans from in vitro assays, are still lacking. In short, from a regulatory point of view, the transition to a more predictive safety assessment of chemical and pharmaceutical substances requires the development of novel models and methods that reflect complex human physiology and biology in vitro.In this respect, one of the fastest-growing, most promising innovative technologies is the organ-on-chip (OC) technology (Marx et al., 2016). However, its value for regulatory safety assessment of chemical substances and pharmaceuticals is still unclear. Its role is in part dependent on the future development of regulatory safety assessment, which is widely recognized to be in need of a transition to accommodate the increased level of toxicological knowledge and animal welfare considerations (Piersma et al., 2018b).

Microphysiological systems: What it takes for community adoption

“…8,24 It is now becoming increasingly clear that MPS can serve as in vitro tools within many areas of drug development, 25,26 including serving as physiologically-relevant platforms for early lead compound target validation and therapeutic safety and toxicity assessment during the preclinical phase. 12,[27][28][29] In addition, MPS can be used for modeling of both common and rare diseases, 7 with successful modeling of a number of rare disorders, such as Progeria, 30,31 Barth syndrome, 32 and hereditary hemorrhagic telangiectasia. 33 MPS have also been employed to better understand drug response pathophysiology, stratification of patient subpopulations, 7 and patient-specific chips for personalized medicine.…”

Applicability of organ-on-chip systems in toxicology and pharmacology

“…To fully capitalize on the value of OoC for toxicology and pharmacology and to define the next steps for actual application of OoC in safety testing of chemicals and efficacy and safety testing of pharmaceuticals, multiple stakeholders need to be involved. Implementation of OoC requires effective partnerships between academia, biotech companies, regulatory agencies, chemical and pharmaceutical companies, patient groups, and other governmental agencies (Beilmann et al 2019;Tagle 2019;Heringa et al 2020;Tetsuka et al 2020).…”

“…Two major scenarios that allow the transition to more predictive and 3 R-compliant drug development and regulatory safety assessment can be identified, an evolutionary and a revolutionary one (Scialli et al 2018;Burgdorf et al 2019). The evolutionary approach represents the current practice of replacing one animal test at a time by a set of non-animal methods that together predict the endpoint for which the animal test was designed (Heringa et al 2020). The evolutionary approach is carried out in a stepwise fashion as standardized and validated non-animal methods become available and the relevance or predictivity of an alternative approach is still defined by comparison to (reference) animal data.…”

“…Opportunities and limitations of OoCs in the context of the transition to a more predictive, non-animal regulatory safety assessment have been discussed (Heringa et al 2020). OoC can play a role in both the evolutionary and the revolutionary transition of regulatory safety assessment.…”

“…However, full validation relies on a more comprehensive reference set which, again, can hardly be defined (Mastrangeli et al 2019). Regarding the current validation process, a practical barrier would be that different components from the complex OoC systems are marketed by different laboratories which together would have to organize the validation process (Heringa et al 2020). It is agreed, however, that regulatory acceptance will require confidence that only strict quality control can create (Smirnova et al 2018).…”