This is our discussion with Lydia Ainsworth which was recorded for the Solutions OP Clinical Trials podcast. You can listen to the original recording here. Please note that the interview below is adapted and not a transcript. This was done to improve readability.
Interviewer: Welcome to today’s episode of the podcast. I am joined by Lydia Ainsworth, our Senior Clinical Data Quality Manager, to discuss animal testing and more specifically the purpose of it, the ethical issues and the future of animal testing. It’s a very popular topic at the moment. Among many regulators, everyone’s trying to reduce the amount of animals used in clinical research, so I think it will be a very interesting topic for everyone.
Animal testing has existed throughout the centuries. It was used not only to study anatomy and physiology but also to help the progress of medicine. Animals were used as models of humans to study diseases. However, dissection of animals is not always the best approach to study diseases. Why? Because death changes the tissues in the body in a way that it may not necessarily provide correct information about the development of the disease or the physiological process.
While animals were widely used in the past, during the Renaissance, they started using human cadavers to study human anatomy and physiology. But still, animals are used even today for studying, modelling different diseases, and learning about the development of new drugs. Lydia will discuss more later about the ethical issues of using animals in testing and the alternatives to animal testing, and I will cover some other aspects.
Another thing I wanted to mention here is that it’s not only the ethical problem of using animals, but also the cost and the extensive testing period required to obtain all the necessary clinical data for the study. And as I mentioned, animals are not always the best or most reliable models for studying human diseases.
So I’ll start with the first part: why do we need any more testing in clinical research, and what are the most frequently used animals? I think it’s very important to recognise the contribution animals have made to the development of human medicine and how we study human diseases.
The most common animals used in clinical research are mice and rats, and they’re approximately 95% of the animals used in clinical research. They are preferred because they are small and easy to house. And they have a short reproductive cycle and their lifespan is 1 to 3 years, so they’re kind of easier to maintain. They are relatively easy to genetically manipulate, which could allow for studying mutations.
Their organs are smaller in shape and structure, and similar to human organs, so mice were used as models for many diseases like hypertension, seizures, cancer, obesity, heart disease, respiratory disease, deafness, and many other conditions. Mice are also used for nutrition, behavioural, aging, sensory and genetic studies.
The other type of animals that are quite often used are rabbits. It’s very interesting that the world’s first vaccine for rabies was actually developed using rabbits as test animals, and rabies causes acute encephalitis. It’s a very serious disease, and the vaccine that was developed is very important.
There are some genetically inbred rabbits which are developed specifically for clinical research on specific diseases. They’re used normally to study myocardial infarction and atherosclerosis. Rabbits are also used as model of human pregnancy and for production of polyclonal antibodies for use in immunology research.
The other animals, which are probably the second most commonly used in clinical research, are dogs. After mice, they typically use dog models, especially in oncology studies. Dogs are also frequently used as a second animal species for toxicology testing. The reason is that data obtained from dogs could be extrapolated to humans; that’s why they’re preferred. And dogs are very common model when studying liver toxicity.
The last group of animals which are used in animal testing are monkeys. They are used to develop new drugs and medical devices, specifically for the treatment and prevention of infectious diseases. However, sometimes they’re also used to study eye diseases and transplantation research. Monkeys are used only as a backup if there are no other reliable models available. Normally, they’re used to study drugs that cause birth defects or drugs that affect the central nervous system, for testing monoclonal antibodies, or also to test drugs which cause vomiting or any other conditions. Because testing on monkeys could predict hazards to humans, they are often used for drug testing for paediatric patients.
As I said, apart from the ethical reasons for not using animals, there are other reasons, and cost is one of them. My research showed me that the cost of mice per animal is between $20 and $300 US dollars, and that depends. So genetically modified mice, they tend to be more expensive. For rabbits, the cost is between $125 to up to $270 US dollars, depending on whether there are special-bred rabbits for a particular disease. For dogs, the cost is between $300 US dollars up to $1,000 US dollars, it depends if you have any special breed. For monkeys, that cost goes even higher, it’s $6,000 US dollars per monkey, and for some special monkeys which are bred for research, the cost can go above $50,000 US dollars per animal.
That’s only for the animal costs. Otherwise, for housing smaller animals, it’s between $1,500 US dollars per year for housing and caring, and that cost can go up to $10,000 US dollars per year for monkeys.
Apart from ethical reasons, it is very expensive, and creating these special breeds is also costly. That is why we need to find alternative solutions, even though we acknowledge all the benefits of using animal models for medicine. We must consider the ethical issues involved in the use of animals in research.
Lydia will now cover the other part, which is what the ethical issues are with animal testing in clinical research.
Lydia Ainsworth: As Olga mentioned, I will discuss some ethical issues related to animal testing and clinical research. The ethical concerns surrounding animal testing primarily relate to how we see the moral value of animals, their intrinsic worth, and how humans perceive their pain and life experiences.
Obviously, animals can’t give consent in the way humans require for participation in research. Because of this, numerous ethical regulations must be in place to minimise the suffering inflicted on animals. However, looking back at earlier research practices, the use of animal testing was not regulated because it was believed that animals did not experience pain in the same way humans do.
However, it is now well documented in animal behaviour research that animals do experience pain and distress, and the procedures used in animal testing might subject them to this. This includes physical distress from the experimental procedures themselves, but also psychological distress from lab conditions, which might result in social deprivation and an inability to display natural behaviours as they would in the wild.
So, the use of animal testing in research creates a conflict of moral interest, because if one were to argue that animals have the same intrinsic value as humans, then their use in clinical research would be unjustifiable.
However, in clinical research, ethical decisions about the use of animals are made from a utilitarian perspective, which means that the use of animals in research is justified if the benefits to human beings outweigh the harm caused to the animals. And weighing up the harm against the potential benefit can be difficult.
As I said before, there are quite a lot of regulations on making these kinds of decisions. For example, the European Medicines Agency recommends the 3Rs as guidelines for assessing ethical decisions for research involving animals. This includes reduction, reducing the number of animals involved in experimentation to the minimum required to have reliable data.
Then there’s refinement, the procedures have to minimise the harmful effects on animals. For example, this can include ensuring our staff are properly trained and using specific methods that reduce suffering, such as anaesthesia.
The third R is replacement. So, where possible, researchers have to use alternative techniques that don’t involve animals at all. And some researchers, and within regulation, are also talking about the fourth R, which is responsibility. Researchers have a responsibility to promote animal welfare and commit themselves to understanding and researching animal suffering, to further improve the conduct of research that involves animal testing.
These guidelines emphasise that the use of animals in research requires careful consideration and calculating many different factors to make sure that harm is kept to a minimum, while the potential benefit is maximised.
But obviously, this approach raises some issues. One concern is that during the early stages of animal testing and drug development, there is often no proven benefit to humans at that point, so animal models can only offer limited information. Drugs or interventions may succeed in animal experiments but fail in humans, which means animals might suffer without any guaranteed benefit to humans.
On the other hand, some drugs might have been withheld from humans because they weren’t effective in animals, but they were later proven to be safe and effective in humans. One example of this is aspirin. In early animal testing, it wasn’t shown to be effective, but now it’s obviously approved as a really safe and effective drug in humans. This goes to show that animal testing isn’t always reliable or ethical, despite following procedures to maximise benefit to humans while minimising harm to the animals involved.
Therefore, all research involving animal testing must undergo thorough ethical reviews. This is the case for regulatory authorities worldwide, such as UK Research and Innovation, the European Medicines Agency, and the FDA, all of which have a review process for any research involving animal testing. Additionally, researchers conducting these tests must adhere to very strict regulations and measures.
Interviewer: That’s brilliant, and it’s a very good point about the ethical issues, particularly regarding pain, how it was accepted that there was no pain. Sometimes, in early research, we don’t know if it will actually help humans, so these are very good points.
It’s a very good transition to my next part, which is about when it’s acceptable to use animals in clinical research, because there are some cases where we need that, and it’s a proven benefit for humans. For example, diseases observed in animals are also observed in humans; it could be acceptable to use animals to develop new treatments. The best example for this is the simian immunodeficiency virus (SIV), which is naturally observed in animals, and it’s a similar development to the HIV virus. SIV is observed in gorillas, chimpanzees, and mangabeys. It was critical that scientists were able to work with these monkeys and study SIV and learn about the natural history of SIV, which helped a lot in the development of HIV therapies and treatments later on.
For example, monkeys were used to study the transmission of the virus from the mother to the baby by taking blood from them to see how the virus is transmitted. As I also said, we wouldn’t have the initial anti-HIV therapies without the monkey researcher back in the day, so they were really critical for this.
Another part where animals have played a crucial role is in achieving transplant tolerance, which involves training the immune system not to recognise the new organ as foreign and attack it.
Transplant tolerance could be different between the different species. So, what works in mice may not be effective in pigs. Therefore, researchers developed a method that was initially used in the past for kidney transplants to achieve transplant tolerance. They started with mice, then moved to pigs, followed by monkeys, and finally humans.
The tolerance is built when you transferring donor stem cells along with the kidney. This process trains the immune system to accept these cells as its own, and over time, using stem cells from different animals helps to create a transplant that could be acceptable for humans.
Another important part where monkeys are used is in developing and studying psychiatric conditions and neurological diseases like Parkinson’s and dementia. They do a lot of observational studies to see how this affects monkeys and do extrapolations for humans.
Another important part where monkeys are used is in vaccine studies to observe immune responses to antibodies or viruses because many viruses affect monkeys, which are similar to those that affect humans. If they have blood samples that they can test and learn from, it could help understand how the virus develops in humans as well.
There are cases where it has been essential to use animals, and currently, there is probably no alternative. However, this does not mean that there will not be an alternative in the future.
Here we come to the next section where Lydia will tell us about what alternatives are available, and maybe we won’t need to use animals in the future. We’ll learn more from her.
Lydia Ainsworth: It definitely seems like there is more of a push recently to move away from animal testing to other methods, and obviously that’s partly due to a lot of advances in technology and research techniques. And there is significant investment in these methods because animal testing can be very costly. Companies can reduce the use of animal testing, they seem to be eager to do that.
Some of the alternatives include chemical methods. Researchers can perform lab experiments on proteins and DNA outside of human cells. This can be used to look at drug interactions at a molecular level and give some indication of how this might affect the human body without the need to test on live animals.
You also have in vitro methods, such as tissue culture and 3D printing techniques, which allow researchers to grow human cells outside the body and, in some cases, produce mini organs that can replicate human organs and their physiological functions.
So again, these can be used to test how human cells might respond to a drug and may be able to replace animal models to give indications of how a drug behaves, providing accurate information on drug toxicology without the need for animal testing.
There’s also a lot of advancement in what’s known as in silico methods, including AI and computer simulations. Some advanced AI modelling can simulate how compounds might interact with the human body. It uses existing information of the investigational drug or compound information about biological processes, and uses mathematical predictions to model how that might work. This can be faster and often cheaper than animal testing. So, as I said before, it can be appealing to drug development companies.
However, as Olga was saying, obviously sometimes animal testing is still necessary, so these alternatives aren’t without limitations, and it’s unlikely that they will be able to replace all animal testing procedures. Animal testing might still be required in some areas of clinical research. But I’d say that overall, it seems like within the field of clinical research, there is a lot of focus on the reduction and replacement guidelines in the 3Rs, as I mentioned earlier.
Moving away from the use of animal experimentation where possible to minimise unnecessary suffering, while still promoting medical advancements and the improvement of human lives.
Last year, the UK government released a press statement, I believe in November, outlining some strategies it plans to implement to phase out animal testing in favour of alternative methods. So it just seemed like we are moving away from animal testing and taking advantage of these alternatives, which are becoming much more available.
Interviewer: That’s very true, and it’s not just the UK MHRA; the FDA is also very keen on moving away from animal testing. They’re strongly in support of this, especially in the UK, where we’ve seen that in silico models are very effective.
I actually attended a few calls where they discussed how you can use in silico models to predict and extrapolate data, forecast disease progression, and determine your endpoints and so on. It’s a very interesting method.
Maybe you can’t use it completely to eliminate any more animal research, but again, we don’t know how that will progress with the AI, if we’ll be able to have any AI models that we can use that could actually provide us with more accurate and better data in the future. So, I think it’s still open to many new opportunities for everyone who wants to contribute to research and reduce the reliance on animals, which I think is a very good thing. If we can remove the need to use animals, that would be fantastic, but at the moment, we are not there yet.
