As regulatory agencies encourage the adoption of new approach methodologies, pharmaceutical developers are increasingly exploring human induced pluripotent stem cell-derived models to improve translational predictivity. Successfully integrating these systems into drug development pipelines requires robust validation, a strong quality infrastructure and clear context-of-use frameworks

Xuan Xu and Amr Othman at FUJIFILM Cellular Dynamics

Although recent regulatory and scientific developments have rapidly accelerated momentum in the past year, the pharmaceutical industry had already been undergoing a gradual shift in how early-stage drug discovery and safety testing are conducted. For decades, preclinical testing relied heavily on animal models to evaluate efficacy, pharmacology and toxicity. While these systems have contributed significantly to drug development, their limitations in predicting human biology have been long recognised, reflected amongst other indicators in the high rate of drug clinical failure despite promising animal data.

In response, drug developers over the past decade have increasingly relied on human-relevant test systems and computational approaches. New approach methodologies (NAMs) aim to provide more predictive, human-relevant models for evaluating drug candidates. NAMs include advanced in vitro models, organ-on-chip systems and computational approaches. Among these technologies, induced pluripotent stem cell (iPSC)-derived platforms have emerged as one of the most versatile approaches for modelling human disease and drug responses, given their ability to develop into nearly any type of human cell.

However, while the scientific promise of iPSC models is widely recognised, the practical challenges now facing the pharmaceutical sector is how to move these systems beyond exploratory research tools and integrate them into robust, decision-making frameworks within drug development. Thankfully, there is already significant research as well as established models to help move the field towards more rigorous non-clinical standards.

Regulatory policy is increasingly encouraging the adoption of alternative testing approaches with the goals of improving the predictivity of non-clinical testing while reducing reliance on animal studies. Today’s shifts reflect growing recognition that differences in physiology, genetics and disease mechanisms often limit the translational relevance of animal studies, particularly for biologics or therapies targeting human-specific pathways. However, regulatory leadership has already driven progress in the field.

The US Food and Drug Administration (FDA) helped launch a public-private initiative in 2013 to build an assay for testing the pro-arrhythmic potential of new drugs.1 The resulting comprehensive in vitro pro-arrhythmia assay, which integrated iPSC-derived cardiomyocytes along with ion channel assays and in silico modelling, has since become the global standard for cardiac safety assessments.

Starting in the early 2000s, the European Pharmacopoeia and European Commission began supporting the ‘3Rs’: replacement, reduction and refinement of animal testing.2,3 One early adoption has been potency testing for biologics like botulinum neurotoxin, approved in Europe for multiple neurological uses including certain movement disorders. What used to require ten or more mice to run LD50 assays now typically requires a few vials of neuronal NAMs.

In the US, the actions taken by legislators, the FDA and the National Institutes of Health have set the stage for regulatory acceptance of NAMs, opening the door for even faster uptake. The 2022 FDA Modernization Act 2.0 formally removed the legal requirement for animal testing in new drug development and authorised the use of non-animal non-clinical tests when evaluating the safety and efficacy of investigational new drugs. This and more recent legislation enables developers to use scientifically validated alternatives including iPSC-based NAMs and other cell-based assays, when appropriate. Meanwhile, the FDA has launched initiatives like Safety Studies to accelerate the development as well as the regulatory acceptance and formal alignment of such methods.4-6

In parallel, the National Institutes of Health (NIH) has shifted funding priorities and launched several initiatives to promote the development and use of NAMs. The NIH launched a dedicated hub for developing highly reproducible, standardised organoid-based NAM platforms to bridge the gap in regulatory acceptance.7 It also established the Tissue Chip Consortium with a key focus on integration of iPSC-derived cells into new human organ-on-a-chip models.8

iPSCs are generated by reprogramming adult somatic cells into a pluripotent state, enabling them to differentiate into virtually any cell type in the human body.9 This capability allows researchers to generate human cell types that would otherwise be difficult or impossible to obtain in sufficient quantities for laboratory research.

Enhanced multicellular iPSC models are extending use cases beyond single-cell readouts. Co-culture and 3D tissue models (ie, cardiac microtissues or ‘heart-on-chips’) incorporating iPSC-derived cardiomyocytes plus fibroblasts or endothelial cells are being used to evaluate structural cardiotoxicity and contractile dysfunction under chronic dosing.12

Similarly, iPSC-derived neurons are increasingly being deployed to support studies of neurodegenerative disease mechanisms or neurotoxicity. As monocultures often fail to capture the complexity and multifaceted cellular interactions of disease relevant phenotypes, the neurons are increasingly being co-cultured with iPSC-derived astrocytes and microglia in both 2D and 3D.

Since their introduction in the mid-2000s, iPSCs have transformed biomedical research. The technology has been used for disease modelling, drug discovery and toxicity testing since at least 2011. Over the past decade, it has become increasingly leveraged in NAMs, supporting the development of complex, multicellular systems that recreate tissue- and organ-level functions. By combining multiple cell types, researchers can create physiologically relevant models that recreate key biological phenotypes and support.10 iPSC-derived renal and intestinal models are also being explored to support applications in absorption, distribution, metabolism, and excretion profiling with transporter function and barrier integrity assessments. In parallel, blood-brain barrier models incorporating iPSC-derived brain microvascular endothelial cells, pericytes and astrocytes are being utilised to evaluate both small and large molecules, for brain penetration, brain shuttling and assessing drug distribution in disease states where the blood-brain barrier is disrupted.

In drug discovery, the human origin of iPSC-derived cells allows them to capture biological pathways that may not exist in animal models, while their capability for indefinite expansion and industrialised manufacturing provides a consistent source of cells for reproducible assays. iPSC-derived systems can also be engineered much more easily and quickly than animal models to represent specific genetic backgrounds, enabling disease-specific modelling and precision medicine research. These characteristics make iPSC models particularly well suited for integration into NAM frameworks aimed at improving the predictive value of preclinical testing – so long as the iPSC building blocks are developed and qualified with rigorous attention to reproducibility, biological relevance and context of use.

Translating iPSC models into routine tools within drug development requires addressing several practical challenges. Early applications of iPSC technology were often limited to exploratory research settings, where variability between cell lines, differentiation protocols and assay conditions could be tolerated.

In a development environment, however, the standards are much higher. Assays used to support drug development decisions must demonstrate reproducibility, scalability and defined performance characteristics. This requires a clear understanding of the context of use for a given model, including the specific biological questions it is intended to address. For example, iPSC-derived cardiomyocytes may be used to assess cardiac toxicity or electrophysiological effects.11

Each application requires appropriate validation and benchmarking to demonstrate that the system provides reliable and interpretable results. Another important consideration is the maturation state and functional relevance of iPSC-derived cells. While advances in differentiation protocols have improved cellular maturity and physiological relevance, ensuring consistency across experiments remains a critical requirement for drug development workflows.

One of the most significant steps in integrating iPSC models into drug development pipelines is establishing robust quality systems around cell production and assay execution. Cell line authentication, batch-to-batch consistency and standardised differentiation protocols are essential for maintaining reproducibility. Quality control metrics like genomic stability, cell identity markers and functional readouts must be defined and monitored throughout the manufacturing process.

In addition, scalable production methods are required to support the high-throughput screening and safety testing workflows typical in pharmaceutical development. Advances in automated cell culture, cryopreservation and assay miniaturisation are helping to address these challenges, enabling more reliable deployment of iPSC-derived models in industrial settings. Standardisation across laboratories also plays a crucial role in enabling broader adoption. As NAM technologies gain traction, collaborative initiatives between industry, academia and regulators are increasingly focused on defining validation frameworks and best practices for advanced human-cell-based assays.13

Importantly, the adoption of NAMs does not necessarily mean the (immediate) elimination of animal studies – that moment could be a decade or more away. In many cases, these systems are initially implemented as complementary tools that provide additional mechanistic insights or early safety signals. As confidence builds in iPSC-based NAMs, and data sets continue to grow, there will be an interdigitation of non-clinical methods that depends on the stage of development and therapeutic area.

For example, iPSC-derived models can be used to screen candidate compounds for potential toxicity or disease-specific effects earlier in the development process, helping prioritise the most promising candidates for further study.

In the short term, there could be areas where iPSC-based NAMs support smarter or more focused animal studies. Over time, as validation data accumulates and regulatory confidence increases, these systems may take on a larger role in supporting decision-making. In this way, NAMs can be integrated stepwise into existing development frameworks rather than replacing established methodologies overnight. This incremental approach allows organisations to build experience with new technologies while maintaining regulatory alignment and scientific rigour.

The pharmaceutical industry is entering a period in which human-relevant model systems are becoming central to drug discovery and development strategies. Advances in stem cell biology, tissue engineering and microphysiological systems are enabling increasingly sophisticated representations of human biology in the laboratory. Within this evolving landscape, iPSC-derived models occupy a unique position. Their ability to generate diverse human cell types from renewable sources makes them a powerful platform for studying disease mechanisms, evaluating drug responses and supporting the transition towards more predictive preclinical testing.

Successfully implementing these systems, however, requires more than technological innovation. It demands careful attention to assay validation, manufacturing consistency and regulatory context. Pharmaceutical developers will need to build robust infrastructure around iPSC-based models and clearly define their context of use to improve translational success in drug development while making sure to align model qualification with regulatory expectations. And while elimination remains a long-term goal, success will be defined stepwise, as new opportunities to leverage NAMs lead to progressive decreases in the use of animal models.

1. Visit: cipaproject.org/

2. Visit: usp.org/sites/default/files/usp/document/events-and- training/04-edqum-pharmacopeia-europe-activities-in-thefield-of-ngs-hts.pdf

3. Visit: eur-lex.europa.eu/eli/dir/2010/63/oj/eng

4. Visit: fda.gov/about-fda/domestic-mous/mou-225-25-012.

5. Visit: fda.gov/files/newsroom/published/roadmap_to_ reducing_animal_testing_in_preclinical_safety_studies.pdf

6. Visit: fda.gov/files/newsroom/published/roadmap_to_ reducing_animal_testing_in_preclinical_safety_studies.pdf

7. Visit: nih.gov/news-events/news-releases/nih-establishesnations-first-dedicated-organoid-development-centerreduce-reliance-animal-modeling

8. Visit: ncats.nih.gov/research/research-activities/tissue-chip

9. Visit: pubmed.ncbi.nlm.nih.gov/38670977/

10. Visit: pubmed.ncbi.nlm.nih.gov/30737492/

11. Visit: pubmed.ncbi.nlm.nih.gov/36099065/

12. Visit: biorxiv.org/content/10.1101/2025.10.29.684362v1

13. Visit: pubmed.ncbi.nlm.nih.gov/40639680/

Xuan Xu is senior field application scientist at FUJIFILM Cellular Dynamics. Her work with global customers includes the implementation of iPSC models for drug discovery, toxicology and disease modelling. She has collaborated with more than 500 organisations to integrate advanced cellular models into research and development workflows. Xu earned her PhD in Molecular Medicine from UT Health Science Center San Antonio, TX, US.

Amr Othman is field application scientist at FUJIFILM Cellular Dynamics, where he provides technical and scientific support for customers in advancing the adoption of human iPSC-based technologies in pharmaceutical and biotech for translational research, with a particular focus on complex in vitro and organ-on-chip systems. With a background training as a licensed clinical pharmacist and over ten years of experience in organ-on-chip models, Amr specialises in bridging biological complexity with practical applications – translating customer insights into optimised workflows, assay strategies and product development direction. He holds a Master’s degree in Pharmaceutical Sciences from Utrecht University, the Netherlands.