Why isn’t this large animal model being used more in toxicology studies?

How do minipig models rank in the research world? It’s a good question.

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals, otherwise known as the ICH, accepts the use of a rodent and non-rodent species in pre-clinical toxicology studies, and recognizes minipigs as one of those non-rodent species.

The reason for using two different animal species is simple: multiple studies conducted in different animal models builds confidence that the experimental compounds being tested are safe and effective enough to undergo clinical trials.

Traditionally, non-rodent species have been conventional large animal models. We have decades of data demonstrating the utility of these models in many different disease areas, from cancer and heart disease to AIDS. But alternative models, such as the minipig, which despite its name is not so mini, are also acceptable as there are numerous anatomical, physiological, genetic and biochemical similarities to humans.

Conversation percolating around the use of minipig models intensified five years ago after RETHINK, a project funded by the European Commission FP6 Framework Programme, published eight seminal papers in the Journal of Pharmacological and Toxicological Methods. The objective of RETHINK was to evaluate the potential impact of toxicity testing in the minipig as an alternative approach in regulatory toxicity testing, and some in the field of toxicology thought that the papers might stimulate discussion and perhaps propel the use of minipigs forward.

That does not appear to have happened to a large extent. Outside of preclinical dermal studies, where minipigs had long been a popular choice anyway, these models have not gained as much ground in biomedical research as one might have thought. Here at Charles River we do use various minipig models for a wide range of safety studies. These studies include pharmacokinetic, safety pharmacology, and toxicity studies using various dose routes including oral, dermal, parenteral, intranasal, dermal, ocular, and wound healing studies. Still, there is no evidence to suggest that minipigs are replacing large animals in any of these kinds of safety assessment studies.

For instance, at our North American facilities minipigs constitute just 3 and 4 percent of the large animals used in preclinical studies. At our European site it is between 4 and 6 percent, suggesting geography has little to do with efforts to replace conventional large animal species with minipigs.

These internal data appear to mirror what is happening elsewhere in the US. Statistics compiled by the US Department of Agriculture, which tracks the number of pigs, including minipigs, in research settings, finds little has changed since the RETHINK papers appeared five years ago. In fact, the number of pigs used in biomedical research dropped from 58,763 in 2008 to 55,729 in 2013, though what proportion of that number constitutes minipigs is unclear as the USDA does not track this group separately.

Just why the minipig has not replaced other animal models is undoubtedly due to multiple factors and subject to interpretation. One reason could be that the industry is simply too reluctant to replace their conventional large models, which they have relied on for years to advance drug products. One also needs specialized knowledge and skills to work with minipigs in order to use them effectively in research.

With that said, the benefits that minipigs provide cannot be discounted either. For instance cost and supply factors are a potential advantage over some large animal species. Indeed, the RETHINK papers point out a number of advantages. The minipig model has utility in reproductive toxicology studies, though the lack of placental transfer of antibodies may limit its role in reproductive testing of some biotechnology products. For safety pharmacology studies, minipigs are considered an advantageous model in particular for cardiovascular safety pharmacology tests. The immune system of the pig is better characterized than some of the other conventional large animal models, however consideration toward potential limitations of availability of appropriate reagents/assays for this species exist. Moreover, as time goes on we are learning more and more about how these models perform in safety assessment. There is now a sufficient body of historical data that enables unequivocal data interpretation, and continued consideration should be given to use of the minipig as an alternate model of choice.

I have worked with minipigs for 35 years. To me it makes sense to use them over conventional large animal models. But I would be curious to hear what others think about the minipig model, what their experiences have been and their take on what has or rather has not happened since RETHINK.

How to cite:

Mansell, P. Rethinking the Minipig. Eureka blog. Sep 2, 2015. Available:  http://eureka.criver.com/rethinking-the-minipig/