Sonja Beken: ‘My motto is always: communication and cooperation!’

How can regulatory bodies speed up the transition to animal-free innovation? If you ask Sonja Beken, the key is integration of available knowledge. She is the coordinator for a team of non-clinical assessors at Belgium's Federal Agency for Medicines and Health Products (FAMHP). The team relies on the results obtained in a combination of in vitro and in vivo tests to evaluate the non-clinical properties of medicines - from vaccines to nanomedicines - on efficacy, bioavailability and safety for volunteers and patients. They also work on behalf of the European Medicines Agency (EMA) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

‘We look at the guidelines for testing on a toxicological basis (whether a medicine poisons an organ), pharmacological basis (how a medicine works) and pharmacokinetic basis (how the body responds to a medicine). And we examine where we can refine, reduce and replace animal testing in the international arena’.

Room for interpretation

Part of the work involves giving scientific advice because the guidelines do not constitute a strict law. ‘If you provide sufficient scientific evidence that an animal model does not provide significant information, you may deviate from it. In the process of medicine development, there is a continuous dialogue between assessors, pharmacists and startups about whether and when such a deviation is sufficiently substantiated. You can request scientific advice in every Member State and from the EMA at the European level. Sometimes, however, there are differences between regions in terms of approach. ‘In very specific cases, you can use in vitro tests to replace animal studies that would otherwise be necessary. However, in the international arena you sometimes see animal studies that Europe does not consider necessary. In other words, as a country you lead the way in an international context. To ensure harmonisation between the different regions in the world, regular international consultations within the ICH context take place.’

Recent news indicates that the transition to animal-free research is in progress in the United States, too. The Environmental Protection Agency (EPA) wants to reduce their funding for animal studies by 30% in 2025 and 100% in 2035 and is investing in the development of alternative tests. Sonja sees their investment in alternatives as very positive. ‘Various large-scale projects to advance technologies have been carried out or are currently under way’. Sonja notes that this is why you need to avoid creating a bubble. ‘Do not say “this one new method will replace everything.” The new organ-on-a-chip technologies, for example, are very promising, but you have to integrate them into a larger whole. You need to stay focused on the final demand and use all available knowledge to solve it’.

‘The integrated use of all the tools that we now have, all of the clinical data and our joint scientific thinking will enable us to reach solutions’.

Integrated

The integrated approach already exists for new methods to treat diseases, such as ATMPs, cell and gene therapy products. The non-clinical development is determined on the basis of questions about the product on the one hand and the human indication on the other. ‘What is the product: cell or gene therapy? What is the indication: cancer or an eye disease? Where do the cells end up with cell therapy? Can the stem cells cause tumours? Is this a medicine for children or for adults? Which safety conditions apply to them? The non-clinical development for other ways to treat diseases such as biological medicines is more or less customised, too: ‘tailor-made’, as it is called. This concept could – where possible – be extended to the development of chemical medicines.

‘With regard to a new medicine, its safety for and efficacy in humans is the main focus. That is why it is very important to first check whether, for example, a rat or a monkey is actually suitable for the animal study that you must perform. Are the pharmacology and pharmacokinetics when you administer the medicine to an animal comparable to when you administer it to a human?’ Selecting the right animal species is not always self-evident. This aspect is thoroughly examined in advance for animal testing involving biological medicines. For the 3Rs (replacing, reducing and refining), however, it is very important to further expand that debate.

Companies' medicine development departments are modernising and medicine research and development is being done with highly progressive new in vitro methods. Yet when it comes to mandatory non-clinical tests they often simply follow the guidelines to get a good assessment for a new drug - and the corresponding market access. ‘A revolution is required within companies and regulatory authorities to collaborate in an innovative way on alternatives and to use results from new, qualified testing methods to design and support the mandatory non-clinical programme. “Tailor-made,” in other words.’

Targeted searching

‘Communication between test developers, assessors and end users is vitally important’. They each have their own approach: the developing academics want to continuously improve technological research methods; assessors want to better predict the safety, bioavailability and efficacy of new medicines for humans using data; and end users want to find the best medicine for certain diseases. The trick is to connect these different standpoints. You bring together the knowledge and experience that eventually may allow you to either replace or greatly reduce animal testing in stages of the development process.

‘For example, you could study general toxicity using a “liver-on-a-chip” instead of an animal. The question is when you can present the results obtained on the basis of those new technologies to assessors.’ Sonja thinks that developers, assessors and end users should be sitting down at the table with each other at an early stage, even if it is not yet known exactly what is on the table. Everyone at that table has a different approach. This can drive and potentially speed up the development and possible qualification of a new technology such as organ-on-a-chip.

As the development of new methods is global and most of the guidelines on testing medicine are international in nature, a global dialogue is vital. Qualification studies are needed for each method within the 3R principle (replace, reduce and refine). Only then can a method be adopted in a guideline or be suitable for taking decisions about the safety, bioavailability and / or efficacy of medicines. Qualification studies must follow certain procedures that are clearly described in the EMA guidelines.

The object of the studies is to see whether a test method is useful and reliable within a predetermined context. The qualification of new methods determines whether or not evaluators accept results obtained using a new technology. The point is that you know what a certain method does within acceptable limits for a predefined object. ‘This model measures this endpoint for these substances to predict that object, within the current requirements for efficacy and safety (“context-of-use”). The type of qualification study you use and the parameters you examine depends on the method or technology to be investigated.

Organ-on-a-chip

Organ-on-a-chip is a very promising technology. You could potentially use it to demonstrate the safety and bioavailability as well as the efficacy of new medicines. The organ-on-a-chip technology represents a significant advance compared to earlier in vitro systems. After all, organ-on-a-chip is closer to the in vivo situation. Using cells of human origin also facilitates extrapolation to humans. Moreover, integrating different organs on a chip can, in the longer term, enable us to greatly reduce and possibly even replace certain animal tests. The EMA organised a workshop in this context with all of the parties involved in early October 2017. The purpose of this workshop was to determine the state of this technology in Europe and what role it can occupy in non-clinical medicine development.

Consultation between the parties involved is the key to progress

Consortia such as ORCHID bring relevant parties such as cell biologists, engineers, end users and regulatory bodies (national, European and the EMA) to the table. Together they steer the development of organ-on-a-chip in the desired direction. Based on potential applications of this technology, they examine which further development is needed and how they can obtain the qualification. Due to a lack of experience and results using these methods, there is still uncertainty about their usability.

Nevertheless, this technology can lead to a more accurate selection of candidate medicines. After all, if the pharmaceutical industry can apply organ-on-a-chip in an early stage in medicine development, then they can identify candidate medicines with a favourable safety profile and optimum efficacy earlier. That can reduce the use of laboratory animals in the short term. If the pharmaceutical industry can acquire experience with organs on a chip, regulatory bodies could potentially incorporate these methods more easily in a subsequent phase. After all, there will be more results that can substantiate the qualification of these methods.

Momentum

Given the present advances in biotechnology, the opportunities for data sharing and the current political will, Sonja believes that the time has come to continue the concept of dialogue, not only at the European level but also at the global level. Sonja firmly believes that all parties involved must contribute out-of-the-box ideas. ‘We are all scientists! Being rigid is not what brings about change. In the process, we must take care to avoid throwing everything overboard. Through integrated use of all available tools – including the knowledge from previous tests with animals – you will achieve better science and you can replace animal testing at the same time.’