Non-clinical research plays a crucial role in the development of new medicinal products and treatments. Although clinical trials on humans receive the most attention, non-clinical research is enormously important as it enables us to gain an understanding of the safety and efficacy of potential treatments. Non-clinical research includes animal experiments (in vivo research), testing on cell cultures (in vitro research) and computer simulations (in silico research). Identifying potential problems early in the development process helps streamline clinical trials, leads to better outcomes for trial participants and ultimately improves medicinal products.
The FAMHP has a dedicated team of non-clinical assessors who are the first to assess potentially new medicinal products. Before clinical trials on humans are allowed to begin, the assessors investigate the safety and efficacy of a potential new medicinal product. To do so, the team assesses whether tests on cell cultures, animals and computer simulations have been properly designed and conducted, what the results are and how the results can be translated into decisions that have an impact regarding the administration of the test product to healthy volunteers and patients. The assessors do not work in a bubble. They must take social issues into account, such as the ethics of animal testing, as well as scientific and technological advances in which, for example, computer simulations may replace certain tests on animals or artificial intelligence will be used in the future. They work in an international context, where their expertise and experience are highly valued.
The 3R concept has been around since the 1950s and stands for Replacement, Reduction and Refinement. It was developed as a response to growing public concern about animal testing. Replacement or substitution involves seeking methods that do not make use of laboratory animals, such as alternatives that use human cells, physicochemical testing and computer simulations. Reduction looks at ways to reduce the number of experiments and the number of animals per experiment, while Refinement seeks to make the conditions for the animals as optimal as possible, to reduce their pain and improve their living environment.
Europe embedded this concept in legislation in the 1980s and since then, all animal experiments must comply with 3R. Although legislation has become stricter, there is still debate concerning the ethics of animal testing. More recent initiatives, such as the European Citizens Initiative, have resulted in 1.4 million Europeans calling on the European Commission to further tighten legislation on animal testing and put an action plan on the table to phase out the use of animals for testing purposes. The use of higher mammals, such as non-human primates, dogs and pigs, remains a specific concern.
By continuing to follow the 3R concept, researchers and the government can ensure a responsible and respectful approach to animal testing. New methods, such as organs on a chip and computer models, are the subject of a great deal of research and may benefit medicinal product development. Several 3R methods have already been accepted by the regulatory authorities of the European Union in the context of specific medicinal product dossiers, and some methods are included in international guidelines or monographs of the European Pharmacopoeia (the official manual of requirements for the preparation of medicinal products for human and animal use).
While the European Medicines Agency (EMA) has always supported the application of 3R, in 2022, following the reorganisation of the EMA working groups, a new working group was established in collaboration with the Scientific Committees for Human (CHMP) and Veterinary (CVMP) use. The Joint CVMP/CHMP 3Rs Working Party (J3RsWP, which is chaired by Sonja Beken) aims to provide visible leadership on 3R in Europe by means of enhanced cooperation between all stakeholders. In collaboration with the EMA’s Innovation Task Force, the qualification of new 3R methods is being encouraged.
Each year, approximately 1.1 million animals are used in Europe while carrying out regulated research into new medicinal products (for human and veterinary use). The majority of those animals are rodents. Higher mammals such as pigs, dogs and non-human primates are used in smaller numbers (about 2 %). Higher mammals are also used in translational research that provides the link between fundamental research and specific research on potential medicinal products, especially to investigate the possible effects of medicinal products on the whole body, organs and immune system. This is essential for complex disease states such as cancer and immune diseases, in which it is necessary to understand the interactions between different systems in the body in order to develop effective treatments. It remains important to weigh up the benefits of using these animals in scientific research against the ethical objections.
Sonja Beken, the head of department responsible for the team of non-clinical assessors and chair of the J3RsWP gives her perspective:
“The bottom line is that 3R is about better science. I believe we are currently at a tipping point. When designing studies, we need to think differently and supplement the knowledge accumulated from in chemico, in silico and in vitro testing methods to the point where ideally only one targeted animal test is needed.
Abolishing animal testing completely will be difficult, but I am convinced that by making incremental improvements, which will of course be evidence-based, we will bring about positive change. As the competent government, the will is there and it also exists within the pharmaceutical industry, which is investing heavily in it. In fact, the competent authorities, including European, American and Japanese partners, are working together in this regard and international guidelines already exist for the approval of certain 3R methods.”
The FAMHP’s non-clinical assessors work in a European partnership with the EMA as the hub. In May 2022, the operation of the existing EMA working groups of non-clinical assessors was reformed. From that point onwards, the Non-clinical Working Party (NcWP) was established as a central working group, with two Belgian members, Sonja Beken and Karen Van Malderen. This in itself serves as confirmation of the expertise at the FAMHP because the members of that working group are no longer delegated by each Member State but are chosen purely on the basis of their experience and knowledge. Karen Van Malderen was elected vice chair of the working group.
The NcWP provides product-related support at the request of various EMA committees. The working group also prepares, reviews and updates guidelines and concept papers, participates in European and international cooperation, liaises with stakeholders, such as pharmaceutical industry representatives, and conducts training and workshops for assessors.
As Karen Van Malderen, a non-clinical assessors at the FAMHP and vice chair of the NcWP explains:
“We got off to a flying start with the NcWP in 2022. The case files already on the table were taken forward by the newly formed working group, and we quickly saw the many benefits now that the most relevant non-clinical expertise had been centralised. In addition to the product-related advice we provide, two areas are worth mentioning.
Karen Van Malderen
The first is the lessons learned from the coronavirus pandemic. We want to incorporate the efficiency and pragmatism underlying the work we did back then into our processes, while at the same time continuing to be aware of the pitfalls we identified at the time. The things we need to watch out for applies both to vaccines, other new medicinal products and the use of existing medicinal products to treat new conditions or repurposing. The second is the presence of nitrosamines in medicinal products. Nitrosamines are chemical impurities that occur in the production of a large number of medicinal products and for which analysis has been ongoing since 2018 to seek solutions. For both areas, we have the necessary expertise at the FAMHP and are playing an active part in the discussions.”
The impact of new technologies, a constantly changing society and intense multidisciplinary collaboration (scientific and regulatory) are clearly part of the work of non-clinical assessors at the FAMHP. Though the work carried out by these officials is not in the limelight, they have a huge impact on medicinal product development.
Karen Van Malderen is a pharmacist and toxicologist. She works as a non-clinical evaluator with a focus on paediatric applications. She chaired the EMA’s Paediatric Committee (PDCO) Working Group of Non-Clinical Assessors for five years. Today, she is vice chair of the renewed Non-Clinical Working Group (NWCP) and sits as an FAMHP delegate on the PDCO of the EMA.
Sonja Beken is a biologist, toxicologist and doctor of pharmaceutical sciences. She was instrumental in establishing the team of non-clinical assessors at the FAMHP and still leads the team. She was a member of the Safety Working Party (SWP) from 2001 onwards and vice chair from 2013-2016. She chaired the initial 3R working groups at the EMA (2010-2016) and currently chairs the new 3R working group (J3RsWP) at the EMA.