Review of the use of two species in regulatory toxicology studies

Current regulatory guidelines usually require safety and tolerability data from two species, a rodent (rat or mouse) and a non-rodent (dog, minipig or non-human primate), before administration of potential new medicines to humans in the first clinical trials. In the UK in 2018, animals used for repeat dose toxicity testing purposes (just one of the safety tests conducted) amounted to 7,606 experimental procedures using mice, 26,163 experimental procedures using rats, 2,188 experimental procedures using dogs and 1,709 experimental procedures using non-human primates (data from 2018 Home Office statistics). Obviously the UK is only one of the countries performing these tests and it is impossible to estimate how many animals are used by the industry as a whole worldwide. Many of these regulatory toxicology tests were introduced 30 or 40 years ago - the pharmaceutical industry has changed considerably in the intervening years with new drug targets, new types of compounds and new in vitro and in silico technologies available to evaluate safety. Where appropriate, regulatory requirements have evolved and been updated to adopt in vitro tests, refine in vivo tests and reduce the numbers of animals used. This ABPI-funded project is a further opportunity to review whether the standard testing paradigm can be modified, to provide an evidence base to propose updates with regards to the need for two species.

An international expert working group was formed in 2016, consisting of 37 organisations (pharmaceutical/biotechnology companies, contract research organisations, academic institutions and regulatory bodies).  We have reviewed how and when two species are used within pharmaceutical regulatory toxicology studies, and whether a rodent and a non-rodent species are still required in the current industry landscape. The initial focus for the project has been on whether existing opportunities to use a single species are being fully exploited and/or could be expanded, without detrimental effect on human safety.  Within the current paradigm for the development of biologicals, reduction to a single species for longer-term studies (the 13, 26 or 39 week toxicity studies to support long-term dosing in humans) may be possible if similar target organ toxicity profiles are identified in two species within the short-term studies (the 4 week toxicity studies to support first administration in humans), as outlined within the ICHS6(R1) guideline.  We have collected preliminary evidence that supports this, and for expansion of the opportunities to other modalities (e.g. small molecules).  However, applying these opportunities to the current nonclinical toxicology strategies for other molecule types and change/incorporate into the regulatory guidelines would need more robust evidence to demonstrate minimal risk/impact for human risk assessment.   

This work has been published in Regulatory Toxicology and Pharmacology – we have also produced a summary of the findings.

Total number of drug candidates per molecule type within the dataset (where the number of organisations submitting data for the specific molecule type is shown in parenthesis).  In total, unpublished data on 172 drug candidates were shared by 18 different companies.

Number of species used for different molecule types.  The dataset included examples where a single species was used for small molecule development, as well as highlighting that a high number of biological molecules do use two species and that there were opportunities for these molecules to reduce to a single species for long-term dosing studies.

Related Content

News: Opportunities for use of a single species in drug development
Q&A: Opportunities for use of one species for longer-term toxicology testing during drug development: a cross-industry evaluation
News: Launch of a new NC3Rs-ABPI collaboration
Additional data: Reducing the use of recovery animals

Prior H, Haworth R, Labram B, Roberts R, Sewell F and Wolfreys A (2020). Justification for species selection for pharmaceutical toxicity studies. Toxicology Research 9: 758-770. doi: 10.1093/toxres/tfaa081

Prior H et al. (2020).  Opportunities for use of one species for longer-term toxicology testing during drug development: a cross-industry evaluation. Regulatory Toxicology and Pharmacology 113: e104624.  doi: 10.1016/j.yrtph.2020.104624

Prior H et al. (2019). Integration of Consortia Recommendations for Justification of Animal Use within Current and Future Drug Development Paradigms. International Journal of Toxicology. 38: 319-325. doi: 10.1177/1091581819852922

Prior H et al. (2018). Reviewing the Utility of Two Species in General Toxicology Related to Drug Development. International Journal of Toxicology 37(2): 121-124. doi: 10.1177/1091581818760564

Prior H, Labram B and Sewell F (2020).  Incidence of new toxicities in biologics and small molecules upon long-term dosing.  The Toxicologist 174(1): #3404. Late-breaking poster presented at SOT, March 2020.

Prior H and Sewell F (2019).  Are We Fully Exploiting the Use of a Single Species for Post-”First-in-Human” (FIH) Studies Allowed within ICHS6? The Toxicologist 168(1): #2117. Poster presented at SOT, March 2019.

Prior H, Gellatly N and Sewell F (2018).  Can we expand the use of one species for post-First-in-Human (FIH) studies, within and beyond ICHS6?  Poster presented at ACT, November 2018.

Prior, H Gellatly N, Sewell F, and Kimber I (2018).  Reviewing the use of two species in toxicology studies supporting drug development. Toxicology Letters 295 (S1): S222-S223. Poster presented at EuroTox, September 2018.

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