The drug development world has seen a recent surge in enthusiasm around development of better human in vitro drug testing tools. This is due in part to the passage of the FDA Modernization Act 2.0 in 2022, which has ushered in a new era. Traditionally, animal models have been necessary for assessing drug safety and efficacy; however, the limitations and ethical concerns associated with animal testing have driven the exploration of alternative methods. The FDA Modernization Act 2.0 paves the way for the widespread adoption of alternatives to animal testing for the purposes of drug and biological product applications. Specifically, this bill allows preclinical tests to be replaced with nonclinical in vitro tests conducted outside a living organism, such as cell-based assays and microphysiological systems.

A new frontier for drug development

This legislative change has huge implications for innovation in in vitro testing technology and could propel us towards a future of drug testing that is more successful and does not require the use of animal test subjects. A priority of drug developers is the creation of new in vitro models which are more predictive of clinical success of putative therapies. The problem that has long plagued pharmaceutical developers and the medical community is the low success rate of therapies in clinical trials, despite success in earlier animal testing. This is especially true for central nervous system (CNS) diseases and many cancers. For more on this subject, see our upcoming blog post, “3D Neural Cell Relevance.” This monumental change in critical path drug discovery methodology is expected to lead to increased drug testing using cell-based assays and will likely change the drug discovery paradigm leading to better selection of drug candidates and improved clinical trial outcomes.

Tumor spheroids and beyond – human models for preclinical drug testing

Next generation in vitro tools for drug testing come in many varieties. Traditional 2-dimensional adherent cell culture is still widely used for early drug screening and efficacy studies, but scientists have been hard at work building on these simple models to develop advanced methods of growing cells in vitro that can better recapitulate important aspects of the organ or disease system they wish to study. Growing cells as 3-dimensional aggregates known as “spheroids” is an excellent way to model solid tumors, and can more accurately reflect growth dynamics, extracellular matrix structure, and penetration of potential therapeutics than in 2D. “Organoids” are similarly grown in 3D aggregates, but typically start from stem or progenitor cells and utilize growth factors to drive development of a particular organ structure in miniature. Organoids therefore can recapitulate developmental processes and include greater complexity and multiple cell types. Spheroids and organoids generally rely on simple support scaffolds or no scaffolds at all, whereas “organs on a chip” involve growing cells in customized culture-ware or microfluidic chips. Organ-on-a-chip models can allow more control of spatial location of different cell types incorporated into the culture and allow modeling of fluid perfusion and/or tissue barriers. Each of these types of tools for preclinical testing offer unique advantages and limitations, but this growing toolbox of in vitro models for preclinical drug testing provides a variety of approaches which can be selected based on the disease or research question of interest.

In vitro models for drug testing offer several new opportunities that animal models do not. Despite the undeniable usefulness of animal models in preclinical drug development, it is appreciated now more than ever that drug responses are species-specific. Therefore, the greatest strength of in vitro models is that they utilize human cells with a more relevant genetic background. The ability to generate particular cell types from induced pluripotent stem cells means it is possible to use patient-derived cells to create in vitro models of drug testing, enabling these models to be used for precision patient-specific medicine applications. Disease-related drug targets can also be investigated in vitro using gene editing, which is much more straightforward in vitro than in in vivo models. Advanced in vitro models combined with genetic editing are a powerful approach for validating potential targets and optimizing lead drug candidates. Finally, in vitro models are much more accessible for most mechanistic and functional experiments than animal models, such as evaluating cell migration or neurotransmission in the case of the CNS.

Further innovation is required before in vitro models for preclinical drug testing can recapitulate all questions to be addressed in the drug development process. Although in vitro models are increasingly becoming more structurally complex and can even model interactions between multiple organ systems, they are not yet able to model drug effects across all organ systems, and structural validity of organoid or organ-on-a-chip models is still somewhat limited. Because of this, it is still not possible to characterize a drug’s pharmacokinetic profile or toxicological profile in vitro.

Ultimately, animal models will remain an integral part of the drug development process for the foreseeable future. However, the FDA Modernization Act incentivizes researchers to explore innovative new approaches to preclinical drug characterization. Biotect Services specializes in cutting-edge in vitro models for preclinical drug testing, including tumor spheroid models and 3D co-culture models of the central nervous system including neurons, astrocytes, and microglia. We are always striving to develop more predictive and clinically relevant models, so get in touch today to discuss your drug development needs with us and to learn more about our customized approach to in vitro drug testing!

Referenced in this article: “FDA Modernization Act 2.0”

Article written by Kendra Lechtenberg, Ph.D.