The development of new drugs is a complex, multi-stage process that traditionally relies heavily on animal testing. This practice, while crucial for ensuring the safety and efficacy of new treatments in humans, raises significant ethical concerns and scientific limitations. 

Many toxicological tests using animals have remained relatively unchanged over the decades, but as our scientific capabilities advance, so too must our methodologies. Innovative approaches such as organoids, organ-on-a-chip technology, and advanced in vitro models present promising alternatives. The challenge lies in transitioning from established practices to these new methodologies, necessitating collaboration between drug developers, contract laboratories and regulatory bodies to establish new standards for preclinical testing.

The Necessity of Animal Testing
Animal testing has long been a cornerstone of biomedical research. Before a new drug reaches human trials, it must undergo rigorous testing to evaluate its safety and effectiveness. Animal models provide critical insights into the complex interactions of drugs within a living organism, often predicting human responses. This step is essential to identify potential side effects and toxicities that might not be evident through in vitro tests alone.

Despite its importance, animal testing is fraught with ethical issues and scientific limitations. The physiological differences between animals and humans can lead to inaccurate predictions of human reactions. Furthermore, the ethical concerns surrounding the use of animals in research have led to increasing public and scientific calls for alternative methods.

Innovative Alternatives: A Glimpse into the Future
The future of drug testing lies in innovative technologies that can replicate human biology more accurately and ethically. Three promising methodologies are organoids, organ-on-a-chip, and advanced in vitro models.

Organoids - These are three-dimensional structures grown from stem cells that mimic the complexity of human organs. Organoids can replicate many aspects of an organ's functionality, providing a more accurate model for studying drug responses and disease mechanisms. For instance, liver organoids can be used to study drug metabolism and toxicity, potentially reducing the need for animal testing in these areas.


Recognising the vital role that early preclinical toxicology studies play in the success of a clinical candidate, organoids help overcome the many challenges drug developers face at this early stage. One emerging methodology is the generation of patient-derived organoid biobanks, comprising human organs as well as dogs, guinea pigs, rats and other species commonly used in toxicology studies. The ability to bridge the gap between animal and human data in toxicology studies, provides a critical advantage for pharmaceutical companies to assess the human translatability of their animal studies before enrolling in expensive clinical trials. Additionally, if drug developers encounter toxicity issues in a specific animal species, this technology lets them investigate if these effects occur in other species as well helping them make informed decisions regarding species selection for further testing and reduce and refine animal studies.

Organ-on-a-Chip - This technology involves creating miniature, bioengineered devices that simulate the functions of human organs. These chips contain living cells arranged to mimic tissue interfaces, providing a highly controlled environment for studying drug interactions. Organs-on-chips can be interconnected to form a "human-on-a-chip," allowing researchers to observe how drugs affect multiple organ systems simultaneously, thus providing a more holistic understanding of drug effects
.

A unique application of organ-on-a-chip technology in preclinical toxicology testing is the liver-on-a-chip model. This device mimics the complex microarchitecture and functionality of the human liver, allowing researchers to assess drug metabolism and hepatotoxicity with high accuracy. It enables the study of drug-induced liver injury, a major cause of drug failure, by replicating liver responses to pharmaceuticals, chemicals, and toxins in a controlled environment. This model provides insights into dose-dependent toxicity, chronic exposure effects, and interactions between different compounds, offering a more predictive and ethical alternative to traditional animal testing.

Advanced In Vitro Models - Utilising human cells and tissues in culture, these models offer insights into cellular responses to drugs. Advances in tissue engineering and microfluidics have improved the complexity and functionality of these systems, making them more representative of human physiology.


A unique application of advanced in vitro methodologies that can reduce animal testing in preclinical toxicology is high-content screening (HCS) using human cell lines. HCS integrates automated microscopy and image analysis to evaluate cellular responses to drug compounds in a high-throughput manner. This technique allows for detailed examination of multiple toxicity endpoints, such as cell viability, morphology, and intracellular processes, using human-relevant models. By providing comprehensive toxicity profiles quickly and efficiently, HCS minimizes the need for animal studies, enabling earlier identification of toxic compounds and more ethical drug development practices. This approach accelerates screening while reducing reliance on animal testing.

The Transition: From Old to New
Transitioning from traditional animal testing to these innovative methodologies is not a straightforward process. It requires a concerted effort from contract laboratories, regulatory bodies, and the scientific community. Key steps in this transition include:

Validation and Standardisation - New methods must be rigorously validated to ensure they provide reliable and reproducible results. Standard protocols need to be developed, and their efficacy compared against established animal models. Regulatory agencies must be involved in this process to facilitate acceptance and integration into the drug development pipeline.

Collaboration and Education - Contract laboratories play a crucial role in this transition. By collaborating with academic institutions, biotech companies, and regulatory agencies, they can help develop and refine these new technologies. Additionally, educating researchers and stakeholders about the benefits and limitations of these methods is essential for widespread adoption.

Regulatory Frameworks - Regulatory bodies need to update guidelines and frameworks to accommodate new testing methodologies. This involves not only recognizing the validity of alternative models but also providing clear pathways for their use in preclinical testing. Initiatives such as the FDA’s Predictive Toxicology Roadmap of 2017 and the FDA Modernization Act 2.) of 2022  are steps in the right direction. In the UK the MHRTA remains characteristically slow off the mark.

Investment in Research - Continued investment in research and development of alternative testing methods is crucial. Funding from both public and private sectors can accelerate the advancement and validation of these technologies.

Conclusion
Just as the drug development lifecycle is long and arduous, the journey from traditional animal testing to innovative methodologies like organoids, organ-on-a-chip, and advanced in vitro models is complex, but necessary.  As a toxicology testing laboratory we continually strive for more ethical and accurate drug testing methods, working collaboratively with contract laboratories, regulatory bodies, and the broader scientific community. 

Hoeford Research is exploring these new technologies to begin its next chapter. We believe that by working together to establish new standards, we can ensure the continued safety and efficacy of new drugs while reducing our reliance on animal models. The future of drug testing is not just about replacing one method with another; it's about evolving our approaches to better serve humanity and uphold ethical standards.