The search for adequate alternatives to animal testing and models dates back over sixty years when the 3R principle to replace, reduce, and refine animal use in research and testing was first defined. Since 1938, the U.S. government mandated that new drug development protocols include testing on animals before human clinical trials could begin. On December 29, 2022, President Biden signed the FDA Modernization Act 2.0, which allows drug developers to use non-animal methods. Non-animal model alternatives include miniature tissue models, organs-on-a-chip, computational and mathematical models, stem cell research, and non-invasive diagnostic imaging. While significant advancements have been made, these alternatives are not without limitations and require further development. Organs-on-a-chip, for example, could be better for testing certain drugs and compounds, and organoids lack all the cell types or characteristics of actual human organs.
In this article, we will cover the significant advancements in technology that are reducing the reliance on animal testing for drug approval. We’ll explore various non-animal model alternatives, such as organs-on-a-chip, organoids, in silico methods, and integrated approaches, and their potential to transform the pharmaceutical industry towards more ethical and efficient practices.
Policy Direction for Animal Testing
In 2015, the National Institutes of Health (NIH) announced it would terminate research on chimps and retire them to sanctuaries. According to the FDA Modernization Act 2.0, drug developers can submit safety and efficacy data from sources other than animals for drug approval. In Europe, the European Union Parliament voted in 2021 to phase out animal testing, while the OECD has invested in developing new integrated approaches to testing and assessment (IATA) strategies to reduce animal testing.
How Technology Reduces Animal Testing
The development of alternative methods to animal tests for drug approval is directed by an ethical point of view and scientific, economic, and legal points of view. New alternative methods incorporate the 3R principle:
- Replacing: Substituting animal models with non-animal systems or with less developed animals.
- Reducing: Decreasing the number of animals required while still achieving testing objectives.
- Refining: An alternative testing method enhances animal well-being.
Non-animal Model Alternatives: Examples
1. Organs-on-a-Chip
Organ-on-a-chip (OoC) platforms are clear, bioengineered microfluidic devices roughly the size of a memory stick. Cultured with different kinds of human living cells, the device replicates human organ-body level pathophysiology. According to Sunildutt et al. (2023), the OoC platform can be an alternative for animal models with various purposes in drug testing and precision medicine. Due to their small-scaled culture environment, the highly controlled dynamic experimental conditions, and their likeness to the in vivo structure, OoCs are advantageous in clinical research.
OoC systems that simulate aspects of the brain allow researchers to investigate neuroinflammation mechanisms and evaluate the efficacy of drug candidates. Applications of multi-organ on-chip platforms include the study of type 2 diabetes, cancer metastasis, and the reproductive function of women. OoCs are also used in dental, oral, and craniofacial (DOC) research. Kreutzer et al. (2022) reviewed alternative strategies in cardiac preclinical research, which included OoCs, organoids, and in silico trials.
2. Organoids
Organoids are 3D cellular structures grown in a lab that mimic the architecture and function of native tissues, e.g., organoids may have the characteristics of full-size hearts and brains. Generated in vitro from stem cells or differentiated cells, e.g., epithelial cells, organoids are used to study organ development, disease modeling, and drug discovery. According to Silva-Pedrosa et al. (2023), organoids have provided insights on the pathogenesis of cancer, metabolic diseases, and brain disorders. Organoids have also demonstrated the ability to predict patient response to drugs, including cystic fibrosis medications and chemotherapy.
3. Organoid Models for Precision Cancer Immunotherapy
Sun et al. (2022) highlight the limitations of conventional in vivo animal and 2D in vitro models in precision cancer immunotherapy research, in contrast with alternative tumor organoid models. The authors discuss the application of complex tumor organoids in testing cancer immunotherapeutics and personalized cancer immunotherapy.
4. Organoid Models for Infectious Disease
The study by Blutt & Estes (2022) found that organoid models for infectious disease recapitulate many characteristics of in vivo disease. These models provide new insights into human respiratory, gastrointestinal, and neuronal host-microbe interactions.
5. In Silico Alternatives
Novel computational models that use artificial intelligence (AI) and machine learning (ML) can predict the toxicity of a chemical, thereby reducing reliance on animal testing in some circumstances.
6. Ocular Surface Toxicity
The Draize eye irritation test is performed in rabbits to test for ocular surface toxicity. Rauchman et al. (2023) studied the toxic external exposure that leads to ocular surface injury and found that new in vitro and computer-based, in silico models surpass the gold standard Draize test.
7. Acute Toxicity Assessment
The most common animal assays for acute toxicity assessment of chemicals is known as a “6-pack” battery of tests. The tests include three topical (skin sensitization, skin irritation and corrosion, and eye irritation and corrosion) and three systemic (acute oral toxicity, acute inhalation toxicity, and acute dermal toxicity) endpoints. Borba et al. (2022) developed and tested quantitative structure-activity relationship (QSAR) models for all six endpoints. They found the models to have high internal accuracy and demonstrated an external correct classification rate of 70 – 77%. The study found that the comprehensive collection of computational models can be an alternative to in vivo 6-pack tests.
8. Microtissue-Based In Vitro Models
Stengelin et al. (2022) find that microtissue-based in vitro models can address the issue of finding an adequate alternative to animal testing. To this end, they recommend further research to continuously improve the fundamentals and increase the functionality of these models.
9. Integrated Approaches for Testing and Assessment (IATA)
In line with its goal of reducing animal testing, the OECD developed the Integrated Approaches for Testing and Assessment (IATA) and describes it as, “pragmatic, science-based approaches for chemical hazard characterization that rely on an integrated analysis of existing information coupled with the generation of new information using testing strategies. IATA follows an iterative approach to answer a defined question in a specific regulatory context, taking into account the acceptable level of uncertainty associated with the decision context.“
10. IATA and Toxicology
To solve complex toxicological endpoints that require more than stand-alone alternative methods, Caloni et al. (2022) highlight the role of IATA. They recommend leveraging synergies of integrated approaches and evidence generation from in vivo, in vitro, and in silico studies.
Conclusion: Advancing Towards Ethical and Efficient Drug Approval
The rapid progress in technology is leading the way in reducing animal testing required for drug approval. While challenges and limitations still exist, the global direction is clear: a shift towards ethical, scientific, and efficient drug approval processes that prioritize animal welfare without compromising on safety and efficacy standards.
Though the FDA Modernization Act 2.0 is a huge step in the right direction, Marty et al. (2022) highlight the need to track the contributions of new approach methods to continue to reduce animal use in clinical research. They recommend that organizations first define the scope, e.g., the definition of “animal” and applicable studies, followed by establishing baseline animal use and the metrics for animal savings. As the industry diligently monitors and assesses the impact of these novel and innovative approaches, it is evident that the drug development industry, alongside other fields reliant on animal testing, will significantly curtail the use of animal testing.
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