A paper recently published in Regulatory Toxicology and Pharmacology has highlighted opportunities to use one rather than two species for long-term toxicity testing. In this article, FRAME explains the history behind toxicity testing regulation and how better availability of toxicity data across academia and industry may help to reduce or negate the need for two species altogether.
Toxicity testing and research
Animals have been used in research for hundreds of years. The practice of mandatory animal tests for product safety first appeared in the US in 1938, with the introduction of the Food, Drug and Cosmetic Act by the FDA (U.S Food and Drug Administration). The regulations were introduced in response to cases of cosmetic products causing life changing injuries and chemicals used in medicines poisoning people.
The regulations for proving drug safety, tolerability and efficacy were tightened up in many countries during the 1960s, following the Thalidomide tragedy. This led to the creation of the Committee on Safety of Drugs, which reviews new drug applications, in 1963 and the introduction of the Medicines Act in 1968.
Current guidance from medicines regulatory bodies require safety and tolerability data from two species, a rodent (rat or mouse) and a non-rodent (dog, minipig or non-human primate) to assess the safety of pharmaceutical drugs prior to human clinical trials. This has been common practice for the past 40 years and is still the advised approach for regulatory toxicology testing for small molecule drugs.
Today’s regulations are based on international guidelines for the toxicity testing of pharmaceuticals which were established in the late 1980s by the Organisation for Economic Co-operation and Development (OECD) and the International Conference on Harmonization for Registration of Pharmaceuticals for Human Use (ICH). These guidelines have been reviewed over the years, resulting in changes that have reduced the number of animals or species required in certain toxicology studies. The guidelines advise use of the most ‘relevant species’ in terms of its similarity to humans in how it responds to a particular drug.
The standard reasoning is that a drug may react differently in one species compared to another, and so using two provides more information about the potential safety of a drug. Data studies looking at the validity of animal models in preclinical safety testing have already concluded that the lack of toxicity in an animal model provides little insight into a lack of similar toxicity in humans and also therefore the chances of an adverse drug reaction. Where a second species adds no more information or value in a preclinical study, it is not necessary.
Opportunities for use of one species
A recent study led by the National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs) and co-funded by an industry consortium led by the Association of the British Pharmaceutical Industry (ABPI) has provided further evidence to support the reduction of animal use in toxicity testing. An international working group representing 37 organisations collaborated in a data sharing exercise to evaluate the use of two species within regulatory general toxicity studies. The aim of the project was to see whether data from a single species could be used without compromising human safety. This has the potential to reduce the total numbers of animals used worldwide for drug toxicity testing without increased risk to humans.
The project analysed data from the toxicity testing of 172 compounds at various stages of development, including small molecule drugs, which are chemically synthesised and taken orally and biological drugs, which are extracted from or manufactured in living organisms and administered by injection, for example antibodies or vaccines. The analysis highlighted that there are opportunities to use one species, particularly in studies of 13 to 39 weeks duration, for a wider range of drug modalities than is currently permitted, according to international and national guidelines, without being detrimental to human safety.
The results indicate opportunities for single species use in late stage testing of biological drugs within existing regulations. Whilst the preliminary findings for small molecule testing show there are possibilities for using a single species, more research is needed to define when this may be appropriate.
Better availability of toxicity data
FRAME welcomes the finding of this study and continues to question the current scale of animal use in toxicology testing, the value of using two species in some situations and the relevance of the species being used.
Commenting on the paper, Director of the FRAME Alternatives Laboratory, Dr Andrew Bennett says:
“The study represents an achievable attempt to reduce the number of tests requiring two species, whilst acknowledgingthat two species will still be needed at some stages of the drug testing and development process. The findings of the project show that better availability of data across academia and industry may help to reduce or negate the need for two species altogether.
“We know that the value of animal testing for human adverse drug reactions is limited due to physiological and metabolic differences between the species. The outcomes of this study highlight a growing need for alternative toxicity tests, such as 3D in vitro models.”
The FRAME Alternatives Laboratory has been developing a cell-based liver model which should have applications in assessing the toxicity of drugs and ultimately provide more relevant information about human drug responses. You can read more about the project here.
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