Biology-inspired microphysiological systems to advance patient benefit and animal welfare in drug development

Abstract

The first microfluidic microphysiological systems (MPS) entered the academic scene more than 15 years ago and were considered an enabling technology to human (patho)biology in vitro and, therefore, provide alternative approaches to laboratory animals in pharmaceutical drug development and academic research. Nowadays, the field generates more than a thousand scientific publications per year. Despite the MPS hype in academia and by platform providers, which says this technology is about to reshape the entire in vitro culture landscape in basic and applied research, MPS approaches have neither been widely adopted by the pharmaceutical industry yet nor reached regulated drug authorization processes at all. Here, 46 leading experts from all stakeholders - academia, MPS supplier industry, pharmaceutical and consumer products industries, and leading regulatory agencies - worldwide have analyzed existing challenges and hurdles along the MPS-based assay life cycle in a second workshop of this kind in June 2019. They identified that the level of qualification of MPS-based assays for a given context of use and a communication gap between stakeholders are the major challenges for industrial adoption by end-users. Finally, a regulatory acceptance dilemma exists against that background. This t4 report elaborates on these findings in detail and summarizes solutions how to overcome the roadblocks. It provides recommendations and a roadmap towards regulatory accepted MPS-based models and assays for patients' benefit and further laboratory animal reduction in drug development. Finally, experts highlighted the potential of MPS-based human disease models to feedback into laboratory animal replacement in basic life science research.

Keywords: assay qualification; drug testing; iPSC-derived organoids; industrial adoption; microphysiological systems; multi-organ-chip; organ-on-chip; organoids; regulatory acceptance.

Fig. 1:. Historical sketch of the establishment of the MPS stakeholder community

Grey and green arrows - impact of academia and MPS suppliers on other stakeholders in the process of development, transfer and use of MPS-based models and assays.

Fig. 2:. Life cycle of an MPS-based assay

Academia-driven MPS inventions are translated into qualified MPS equipment and chips by the supplier industry. Developers of all four stakeholders create MPS-based models, methods and tests. The pharmaceutical industry subsequently selects a model for a specific purpose and validates the respective MPS-based context of use assay to test safety and efficacy of novel drug candidates or advanced therapies. These data support clinical trial authorization and, consequently, final approval for use in patients.

Fig. 3:. The US tissue chip program at a glance

This FDA-DARPA-NIH MPS-based program aimed at developing in vitro platforms that use human tissues to evaluate the efficacy, safety and toxicity of promising therapies (adopted from Smirnova et al., 2018).

Fig. 4:. Established stakeholder interaction channels

MPS devices, chips, models and methods are provided to end users and academia for data generation by the supplier industry. End users (pharmaceutical industry and CROs) are translating the methods into qualified assays for internal decision-making and use the data for clinical trial submissions, eventually resulting in authorization by regulators. Academia develops new MPS solutions that are absorbed by MPS suppliers. All four stakeholders consist of developers of MPS technologies.

Fig. 5:. The Japanese AMED-MPS program at a glance

The interdisciplinary research teams are developing four human organ models and the Central Research Center is uniting researchers and end users to accomplish the program.

Fig. 6:

MPS-based assay application aligned to the drug discovery and development life cycle

Fig. 7:

Steps towards MPS-based assay qualification which will define the performance standards

Fig. 8:

Smart stakeholder communication scheme

Fig. 9:. A roadmap toward patient benefit and animal welfare

Brown, blue, green and grey arrows – influence of academia, MPS suppliers, end users and regulators, respectively, on other stakeholders in the process of development, transfer, use and data assessment of MPS-based models and assays.

Fig. 10:

Schematic of a minimal set of human organs, their physiological connection through blood vessels and nerves, and the systemic physiological in- and output of a human to be downscaled to an MPS-based organismal model in order to create a universal physiological template (UPT)

Fig. 11:

Schematic illustration of the creation of MPS-based disease modeling by treating a universal physiological template (UPT) with respective agents

Fig. 12:

Schematic illustration of merging technologies of MPS and machine learning to continuously improve in vitro and in silico models towards the systemic organismal emulation of human (patho)biology Adopted from Smirnova et al. (2018).