Guest Blog|Reducing the use of animals in drug development whilst ensuring human safety
Guest blog by NC3Rs
The use of animals in research continues to rank highly in the public consciousness, with a 2018 Ipsos MORI poll showing that three-fifths of people are interested in the methods used by scientists to replace, reduce and refine the use of animals in research (the 3Rs). The UK’s National Centre for the Replacement, Refinement and Reduction of Animals in Research (the NC3Rs) is committed to furthering this goal. Its programme includes a long-standing collaboration with the pharmaceutical industry that has led to changes in company practice and regulatory guidelines.
A new paper describes the findings of a project, led by the NC3Rs and the Association of the British Pharmaceutical Industry, which has explored whether toxicological data from a single animal species only could be used to develop a drug without compromising human safety – a major shift in practice that would see a reduction in the use of at least 150 animals per test compound.
According to international guidelines most conventional drugs (typically ‘small molecule’ drugs) must be studied in two mammalian species, a rodent (usually rat or mouse) and a non-rodent (usually dog, minipig or non-human primate), to assess their potential toxicity before human trials begin. The same principles apply for biological products (‘biologics’) such as monoclonal antibody therapies, with the exception that the guidelines allow one pharmacologically relevant species to be used for long-term toxicity studies if comparable toxicities had been identified in studies using two species in short-term studies carried out earlier in the drug development pipeline.
The project was overseen by an expert working group which included representatives from 25 global pharmaceutical and biotechnology companies, six contract research organisations (CROs) or consultants, two academic institutions and four regulatory bodies. Using the NC3Rs’ strong track record of acting as an honest broker for the cross-company sharing of data, 18 pharmaceutical and biotechnology companies provided detailed information on 172 compounds at various stages of development. The data included molecule types, the animals used in short and long-term studies and the toxicities observed. When two species had been used, the working group compared the toxicities to see how often similar effects were observed and if it might have been possible to reduce to one species for the long-term studies.
Overall the analysis showed that there are wider opportunities, than are currently being adopted by companies, to use one rather than two species for the toxicity testing of biologics, not just for monoclonal antibodies but also for peptides and protein therapies. Despite the guidelines already allowing for this where there are similarities in toxicities in early studies, ambiguity in defining what comparable toxicities are between two species means that some companies continue to conduct studies in rodents and non-rodents to avoid questions from regulators and delays, for example if further studies are subsequently requested. Providing greater clarity is essential and the NC3Rs is now working with industry to establish a framework for defining comparable toxicities.
For small molecule drugs the data analysis illustrates that with hindsight the use of a single animal species would have been applicable for some long-term studies. This is the first study to have identified this potential. However, achieving regulatory flexibility to support the use of a single species only requires the analysis of a bigger dataset to build confidence and understanding of when this would (and would not) be appropriate, and which species to choose. Nevertheless, the project has already led to companies reviewing opportunities to use one species for compounds in development.
If you are interested in learning more about this project, or other work of the NC3Rs to reduce the reliance of animals within toxicity testing, sign up for the Tox News e-newsletter for regular updates. You can also find more information via the NC3Rs Toxicology and Regulatory Sciences website hub.