Amid pressure to limit discovery losses and be more ethically responsible, the pharma industry is slowly bowing to the growing weight of evidence to find alternatives to testing on animals
Many years can be spent developing a prototype drug only for the whole exhaustive discovery process to end in inconclusive failure. It can be a bitter pill for many pharma companies to swallow. Individual drug development costs can reach $2.6bn, according to the Tufts Center for the Study of Drug Development.
Animal testing on species including rodents, dogs and primates has long played a key role in the development of drugs and the understanding of how diseases work. However, animal models also have critical translation issues when results are compared to human trials.
In regards to preventing late stage failure, Dr David Hay, principal investigator at the University of Edinburgh’s MRC Centre for Regenerative Medicine argues that generating accurate data from animal models and extrapolating these findings so that they are relevant to human biology remains an area fraught with challenges.
On the top of longstanding concerns about the ethics of inflicting suffering on animals – and pressure on pharma companies to behave in a more responsible manner – a movement is building to encourage researchers to develop drug testing models that do not involve animals.
A raft of organisations are conducting research into in-vitro and in-silico technologies – which seek to significantly minimize the use of animals in drug testing. A future in which drug discovery is far less reliant on animal testing may be on the horizon.
Organ-on-a chip technology
The use of computer modelling in the field of pharmatoxicology is rising; allowing ‘organ-on-a-chip’ technology to mimic the behavior of a live organ. The chips are preloaded with cell types designed to reflect human biology and provide a number of different readouts regarding the safety and efficacy of a compound. Chip equivalents of the liver, lung and kidney have been created and research is underway to connect multiple chips so they can act as a network – with the aim to achieve the prospect of a ‘human-on-a-chip’. Compounds could be tested on this digital human and then results could observe how the candidate interacts with various organs and the reactions that occur simultaneously.
3D bioprinting
Three-dimensional bioprinting uses cultured cellss or other biocompatible materials to build tissues and organs. These three-dimensional biofabrication strategies mimic the features of tissues and organs and can potentially replace the damaged parts of a patient’s body. In the near future these engineered tissues could replace animal models and provide a more predicative model for drug metabolism and toxicity in humans.
Researchers are in the process of trying to construct man-made tissues and organs to create heart models and MedPrin’s 3D printed dura mater product for brain surgeries.
US-based early-stage medical laboratory Organovo, meanwhile, is involved in testing liver tissue for preclinical toxicity testing and drug screening using its NovoGen 3D bioprinting process. The company’s exVive3D human liver tissue for preclinical drug discovery testing was launched in 2014, which looks for potential liver toxicity and checks ADME – adsorption, distribution, metabolism and excretion – outcomes.
IPS Cell models
The use of induced pluripotent stem cells – a type of pluripotent stem cell generated directly from adult cells – allows the creation of organ systems for toxicology testing from just one cell source. The chief advantage is that there is no need to rely on freshly available cells or cryopreserved cells. However, Phillip Hewitt, head of early investigative toxicology at Merck,warns it remains a challenge to ensure these cells are of adult phenotype and fully differentiated so they are actually predicative of toxicological end points in human cells.
Minimizing animal requirements
The National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3rs) – which issues guidelines on animal testing – argues that if animal testing has to be conducted it should follow a series of rigorous methodological controls and suffering should be minimized.
In a study published earlier this year, researchers Kelly Gouveia and Jane Hurst found that the often-used practice of picking up mice up by the tail, although ostensibly painless, can cause stress and anxiety in rodents, which can affect cognitive functioning. As a result, the study concluded that more considerate handling of the mice would improve the overall effectiveness of testing during the drug discovery process.
In another study, Durham University’s Dr Kamar Ammen-Ali designed experimental apparatus for neurodegeneration testing on rodents. In 2012, the continual trial design significantly reduced the amount of rats used with good results being achieved at an earlier stage. In the five years prior to the paper being published around 43,000 animals were used in similar memory tasks for drug screening, this new trial design could have reduced this down to 26,000. The NC3rs notes that the application of this could lower the amount of animals used in studies of this kind around the world by 3,000 on an annual basis.
The University of Portsmouth’s institute of Biomedical and Biomolecular science, meanwhile, has found that the amount of male Xenopus frogs used in animal testing could be cut significantly in the industry. Its study found that it is possible to create 32 embryos from one sperm sample, rather than the normal four to eight.
In collaboration with AstraZeneca and the University of Plymouth, the NC3rs examined the welfare levels of zebrafish used in the industry. Results identified an opportunity to reduce over production and wastage – 32 of the 76 laboratories involved could not identify how many zebrafish were more than five days old and were unused.
As the pharmaceutical industry looks to limit the huge financial loses it can incur during the drug discovery process – as well as presenting a more ethical face to the world – these techniques and findings look set to become increasingly widespread in the coming years and are poised to shake-up the industry’s reliance on using animal subjects and put advocates in a stronger position in the competitive race to land-grab blockbuster therapies.