Major steps have been taken in the process towards reducing and replacing the use of laboratory animals in medicinal research. Jan Willem van der Laan and Peter Theunissen, senior assessor and assessor in the MEB's Pharmacology, Toxicology and Kinetics (FTK) unit each published two articles in peer-reviewed journals in 2016. The results of their studies are major building blocks in the pursuit of medicine development without animal testing.
These publications also reflect the MEB’s ambition to reduce animal experimentation. Recent insights will ensure that, in the long term, when developing new medicines, it will no longer be necessary to test their efficacy in two animal species. It may be possible to carry out full or partial testing using in vitro techniques, e.g. using cultured cells.
The studies by Van der Laan and Theunissen concern the prediction of possible carcinogenic effects of a medicines, and damaging effects of a medicine during gestation/pregnancy. The studies are based on data on hundreds of medicines in two databases created by the MEB and the RIVM for this purpose.
"We looked at whether rats and rabbits have the same predictive value for medicines during pregnancy. This turned out to be true in 70 to 80% of cases; for many substances it does not matter whether we use a rat or a rabbit," explains Peter Theunissen about his research. "In the long term, we may be able to replace testing with an animal species with an in vitro study. In this way I want to find out more about mechanisms and hope we can also test in human models, for example human stem cells. This would give us more insight into the situation involving humans. It may be that we’re being over-cautious now, and that we will find out in the future that more medicines can be used safely during pregnancy. That would mean a lot to me."
Adjustment of guidelines
The research results have led to the updating of a new international guideline on toxicity during reproduction. A public version will be presented for consultation before the summer of 2017. This is a great breakthrough according to Van der Laan: "It will be extraordinary if medicine regulatory authorities are ultimately satisfied with testing on one species instead of two, with us favouring a cell culture approach. We are going to gain experience in this area. We hope that all countries will renounce the test in multiple animal species as we transition towards research that does not involve testing on animals. If the need for animal testing can be reduced or eliminated, new medicines may become available more quickly."
The two studies by Van der Laan address the predictive value of carcinogenicity of pharmacological data from the database. "We are working internationally on a regulatory experiment. We are currently asking for predictions by the manufacturers for 50 substances, and will later determine whether these predictions have come true. If these predictions do turn out to be true, we will be able to update the guideline on carcinogenic effects. That is a great process to be involved in. One realises how important it is to do this together with other authorities, the industry and scientists. Without this experiment, we would not have been able to convince the United States Food and Drug Administration (FDA)."
Van der Laan and Theunissen note that this scientific research does not involve any conflict of interest between countries, authorities or the industry. "There is enthusiasm among those involved. You are a scientist, and you want to minimise the unnecessary use of laboratory animals, but ultimately you are also responsible for the effect of medicinal products on humans. The hesitation is about whether the material in the database provides a good impression of reality and whether the conclusion is not unduly positive. Missing a certain category of substances could pose a threat to public health. We have succeeded in getting this issue onto the agenda by building and using a personal, international network. Knowing each other and trusting each other will take you further," explains Van der Laan.
Peter Theunissen: "You work with people who want to do more, who look further and wonder why things work the way they do." FTK colleague Peter van Meer is also involved in reducing the use of laboratory animals: "And that you consider what the data tell you as a scientist. What can you do with the data? That you don’t view the guideline as dogma, and that there might also be a different way." Van der Laan adds to this: "Animal experimentation is not the gold standard, but unfortunately we cannot yet do without this approach at this time."
"You do have the ambition to achieve something. The piece about carcinogenicity has been prepared for a very long time. I started the analysis in 2011, to be followed by an ICH initiative*, and ultimately this leads to a publication in which you make a strong case for it. Then you hope you’ve written something that will attract a lot of attention," says Van der Laan. "These papers reinforce the fact that we want to evaluate our guidelines in a scientific manner and are prepared to transform them into other guidelines. This is something we are very good at in the Netherlands. There is a lot of interest for this from Japan, Europe and the United States."
Theunissen stresses that the great amount of interest is also thanks to the large dataset. Van der Laan: "Scientific evidence is extremely important. Not only do you have to have the statements, but you have to support them with the data you have collected."
The scientists are happy with the recognition they have received from their academic colleagues and from the industry, even though the process of moving towards medicine development that does not involve animal testing is very slow going. Van der Laan: “The MEB is a driving force in this process. I have always received support from the MEB to invest time in this type of work alongside my assessment work. That is essential in developments such as these.”
* International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)
- Comparison of rat and rabbit embryo–fetal developmental toxicity data for 379 pharmaceuticals: on the nature and severity of developmental effects. Critical Reviews in Toxicology Volume 46, Issue 10, 2016
- Comparing rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on systemic dose and developmental effects. Critical Reviews in Toxicology, published online: 21 Oct 2016
- Prediction of carcinogenic potential of chemicals using repeated-dose (13-week) toxicity data. Regulatory Toxicology and Pharmacology Volume 81, Pages 242–249, November 2016
- Prediction of the Carcinogenic Potential of Human Pharmaceuticals Using Repeated Dose Toxicity Data and Their Pharmacological Properties. Frontiers in Medicine Volume 3, Article 45, October 2016