English summary

Summary: Replacing primates

Advances in science and technology provide non-animal techniques that are faster, more accurate and of direct relevance to people.

Animal research on the other hand, is outdated and suffers from the flaw that all species respond differently to substances. Studies have shown differences between humans and laboratory monkeys, on average, a third of the time.

This was illustrated when the UK test drug TGN1412 caused terrible, almost fatal, and permanent side effects in human volunteers. Yet the drug had been given to laboratory monkeys in doses 500 times that given to the volunteers, without side effects. Now many agree that this disaster could have been avoided by using advanced technology – microdosing.

Replacing primates in commercial testing

Microdosing involves giving tiny, safe, doses of new compounds to human volunteers and samples of blood or urine can then be analysed by Accelerator Mass Spectrometry (AMS). AMS counts individual atoms – it can detect a liquid compound even if just one litre of it has been diluted in the ocean.

AMS can show how compounds have been absorbed, distributed, metabolised and excreted by the human body. The EU Microdose AMS Partnership Programme recently compared microdosing data to animal tests. It proved to be 80% predictive of human drug absorption and distribution – significantly more accurate than primate, dog and rodent models.

Adoption of high-level advanced techniques such as microdosing/AMS would allow drug development to be accelerated, accuracy to be improved, and costs cut.

Whilst regulatory testing is the largest area of primate use in labortories, it is one section of the overall testing strategy for new drugs. Therefore primates could be replaced more easily than was the case for the EU cosmetics testing ban, which was more complex because it needed a ‘start to finish’ replacement strategy.

Primates come at the end of the regulatory testing strategy, along with dogs. They fulfil the requirement for tests on a second mammal, apart from a rodent.

This means that by the time the monkeys were being strapped into restraint chairs for the experiments we have described overleaf, hundreds even thousands, of smaller animals would already have died to test the same product.

If the EU and Member States are to take serious steps to replace animal tests with advanced technology, then it is vital that the animal tests be ended earlier in the programme – to be replaced by advanced methods based upon human data, such as microdosing. Industry and regulators, and indeed much of academia, are inherently resistant to change, but the reality is that primates are a poor predictor of human responses.

There are now a range of multi-disciplinary, sophisticated techniques that allow the safe and accurate examination of potential effects on humans (see list). We have seen how implementation of the Cosmetics Directive has ensured the validation and implementation of replacements for a range of tests, and as a result, how it has dramatically cut animal use.

Implementation of replacements for primates could signal the start of an evolution throughout regulatory testing, towards modern methods. Such advanced techniques are good for European science and industry, good for animals, good for people.

Replacing primates in academia

Academic experiments in universities, particulalrly neurological research, is another large area of primate use. These studies cause extreme suffering and can include implanting electrodes and other equipment into the animals’ heads. Often this so-called ‘fundamental’ research does not describe any potential application for human benefit.

Yet, advances in modern scanning techniques such as fMRI and MEG are enabling non-invasive neuroimaging of the human brain, providing unprecedented understanding of mental illness, neurodegenerative diseases, vision, hearing, speech, pain and more. This provides data of direct relevance to patients, who can be asked to describe how they feel.

In 2008, a meeting at the European Parliament was presented with a comparison of data from scanning studies of human patients and electrodes implanted in the heads of monkeys. The same level of data was obtained – yet importantly one set of data was of direct relevance to people.

There are no regulatory requirements for these academic experiments, so this is a field where replacement could be very rapid. A different approach would be needed for different fields of research, but this could be achieved through expert consultation and a focussed, technical review, managed by the Commission, under the new Directive.

Alternatives

The benefits of some of these new techniques is that they can build on and advance existing knowledge, rather than simply starting from scratch in a different species. Here are some examples of modern techniques that can save primates, advance human health, and put Europe at the forefront of science.

Microdosing and Accelerator Mass Spectrometry (AMS): Giving safe ultra low doses to volunteers combined with precision analysis (see Replacing Primates).

Computer analysis, simulation, modelling and more: For example QSARs (Quantitative Structure Activity Relationships) – a computer modelling system, which correlates a compounds’ structure and properties with its activity; Derek for windows (DfW) is an expert knowledge base computer programme that applies rules; it predicts a chemical’s toxicity from its molecular structure; and High throughput screening: This involves robotics and sophisticated control software which rapidly analyses compounds for drug discovery.

Human cell cultures: growing human cells in the laboratory, so that they reflect how they work in the body, and how they respond to test compounds. Specialised cell cultures, such as liver, kidney and brain cells are being used.

Human tissue cultures: Pharmaceutical companies already use liver tissue to provide biological data and safety test compounds, because this avoids the problem that animal test data is not a reliable indicator of likely effects in humans. (It is only government regulations that require use of animals in order for a product to be approved for sale).

3-dimensional (3D) human tissue engineering can be used for drug testing. The scaffold can be made from synthetic or natural materials, with differing scientific advantages. Tissue can be constructed to recreate whole body systems, such as the artificial immune system.

Biochips: These show the effect on different cells in the body and how toxicity is altered when the compound is broken down (metabolized) in the human body. They provide data quickly and cheaply, including data for different human organs.

Toxicogenomics: This seeks to translate data about genetic variation and gene expression into an understanding of the biological systems in organisms, including humans, and the effects of changes in the systems on health.

Post mortem analysis of tissues donated by patients to allow cellular examination of human disease.

Advanced scanning techniques such as MEG and fMRI for detailed study of patients (see Replacing primates).