Choosing Wisely: The Ethics, Science, and Emotion Behind Species Selection

Sarah Gould:
So a lot of psychological research has been done on decision making, and one of the things that has come out of that is that all decisions are based on emotions. Now scientists try and be objective as possible. But actually if you go down to there are a lot of emotions that are involved. For example, the biggest one is fear of rejection from a regulatory authority. Nobody wants to be rejected that your dossier isn't good enough that you've selected the wrong species, because what would happen if that happens, then you can't get into a clinic as quickly as you would like to get into the clinic and help the patient. So that has a real impact.

Mary Parker:
I’m Mary Parker, and welcome to Sounds of Science. Today, we’re joined by Charles River’s Sarah Gould to explore one of the most critical and often misunderstood decisions in preclinical research, species selection and justification. Choosing the right species for a study isn’t just a checkbox; it’s a decision rooted in science, ethics, experience, and sometimes even emotion. It’s about understanding the disease, predicting human responses, aligning with regulatory expectations, and upholding our responsibility to animal welfare. In short, it’s where science meets wisdom. Let’s get started. Welcome to Sounds of Science. Sarah, we’re really happy to have you on the show.

Sarah:
Thank you very much, Mary, and thanks for inviting me along.

Mary:
I’m actually really excited for this discussion. So, can you tell us a little bit about yourself and your role at Charles River?

Sarah:
. My role here in Charles River is as a Scientific Advisor, I work in a group where we have six scientists, and we help support people developing drugs or vaccines to give strategic regulatory advice. The group has a huge amount of experience in drug development and vaccine development, and so we’re able to offer that advice, working from discovery right up to license as is required.

Mary:
So basically, you're helping clients navigate the regulatory process and kind of telling them which assays are good and even which species they might want to use.

Sarah:
That would be part of it. Yep. It's navigating the regulatory, but it’s also navigating discovery and de-risking as well, which can also be an important part of drug development.

Mary:
Before any new drug reaches patients, it has to undergo rigorous in vivo and in vitro testing to ensure safety and efficacy. But this isn’t just about convenience, it’s about scientific relevance, regulatory expectations, and, of course, ethical responsibility. Let’s start with the big question. Why is species selection such a critical factor in preclinical research and drug development?

Sarah:
Okay, so what are we trying to do? We are really trying to ensure as much safety as possible. Obviously, safety can never be a hundred percent guaranteed, but the idea of any of the testing that we’re doing non clinically is to try and ensure as much safety as possible. And there we’re having to use in vitro or in vivo as it makes sense that we can try and translate into clinic. And so often at the moment, it has to be in vivo. That's our kind of gold standard. And so then you're looking at when we’re looking at in vivo, well, which is the best species? Because at the end of the day, humans are human. Is any other species really like a human? Well, the answer is going to be fundamentally no, but what will be most like what do we think we can predict? So that’s the sort of basis that we’re coming from. And then we’re trying to make, there are other aspects to practicality even comes into it in selecting species, ethics comes into it, all sorts of aspects comes into then selecting a species. But you want to be trying to get a species that you can predict as best as possible for going into humans.

Mary:
From what I understand, during COVID, it turned out that one of the best species for testing things on turned out to be hamsters because they would actually develop respiratory symptoms when exposed to COVID and mice didn't. It made it more obvious when they got sick, which of course makes it a better species for us to use because the less invasive you have to do testing to see if the animal has gotten sick, the better for you and the better for the animal. Is that an example of where a species might unexpectedly turn out to be the right species to use, and you have to do a little bit more thinking to get to that conclusion?

Sarah:
At the time we were looking at the research that we had been doing on SARS-1, which had used larger animal models. And as we moved into SARS-2, actually we started off maybe with some larger animal models, but everybody was very keen to try and use smaller animal models. And yes, in this particular case with SARS-2 hamster turned out to be more predictive for human clinical signs. And the mouse, no, not so predictive unless you used a transgenic mouse and that was implicated on receptors and binding, which can be different across the species. But that actually highlights why it's important to understand the molecule you are developing. Its biology, its function, its pharmacology, homology, binding, all these aspects. And then with your animal species or your in vivo that you need to consider both in pharmacology and in toxicology need to be considered so that you can get the best predictive model possible. And often, again, if you take COVID as an example, you'll see that different species were used and that maybe some were more predictive than others. But that's difficult to say at the beginning. You then have to look back retrospectively to understand your animal models and continually evolve.

Mary:
Yeah, I mean that makes sense. We were basically starting from scratch with a new viral variant. So what are some common misconceptions about species selection in preclinical research?

Sarah:
So there is a little bit of misconception that we tick box and we just select a small species and a large species and it's X species and Y species. And it depends on the molecule, it depends on the pharmacology, what might be the species that you select. But there's also a practicality to it because we need to have a certain historical understanding of the species. And obviously you're only going to get that with doing those studies in that same species. So, we have built up historical databases in certain species that can also influence species selection because if you start to do a study in a species that you less understand even from a handling point of view, then that could be problematic both in translation but also in terms of handling and managing the data, et cetera. So there's lots of different aspects, there's practical aspects, there's scientific aspects that have to all sort of come together.

Mary:
Selecting the right species kind of sounds like not a one size fits all decision. So it's carefully considered; researchers must weigh multiple factors to ensure model accurately predicts how a drug will behave in humans. So like you said, it depends on what data we have on that species and what we have historically done in the past, plus whatever we've learned since then. So what factors go into selecting the right species for a study?

Sarah:
Yeah, absolutely, that's what it should be. Ideally, we should be looking at case by case selection of our in vivo models. So, what factors need to be considered? Well, the modality is important in species selection. Is it a small molecule? Is it a biological, what type of biologic is it? a vaccine? So that's one of the base questions we should be looking at. And there's slightly different criteria, and that criteria can really depends on the types of potential safety risks. For example, with a small molecule, and you will see this in the guidelines, it talks about selecting a rodent and a non-rodent. It doesn’t tell you which rodent, it doesn’t tell you which non-rodent specifically, but it says that’s what you need to, so you've got to select two species. We also know with small molecules, you’re going to be, you need to understand the metabolites for the species as compared with humans, and at least one of the species should be pharmacologically relevant.

Now actually, that wasn’t necessarily the case pre 2017 and the guidelines were updated. Well, particularly the European guidelines were updated to say at least one of the species needed to be pharmacologically active. Now that might be quite a surprise, why wasn’t that there before? But there you go. There is an evolution in the way we develop drugs and to understanding. So that’s the selection for a small molecule. For a biologic, it’s slightly different. We’re looking at relevancy, very much so on the pharmacological side, we’re not necessarily looking at metabolites because that's not necessarily relevant for a biologic. And sometimes we can, with a biologic, if there's only one relevant species or we see that in terms of comparability with species, we could select just one relevant species rather than the two. So that's something that you need to consider and really understand that relevance of species is important.

Mary:
Well, it's funny that you mentioned that regulations have been updated recently because I think there are maybe some people who think that rules regarding the use of animals and drug development were kind of written long ago and then just left stagnant, which is absolutely not the case. So that's always good to note.

Sarah:
They are updated, but however, they are not maybe updated as much as we would like to see because it can take some resource and some challenging to get them updated because we've also got to understand the science. So the science is usually ahead of the regulators. So again, you a drug developer can consider you've got a particular case, a particular molecule, you can write your strategy with scientific rationale as to what you should be doing to consider the safety. And at the end of the day, it's safety that's important. And the scientific understanding of how to achieve that safety assessment as best as possible before going into human and putting humans at risk.

Mary:
How can species selection influence the outcome of a drug candidate's development? If you choose the wrong species, will that affect how your drug progresses through the pipeline?

Sarah:
Absolutely. Well, if you choose the wrong species, but if you don't know that you've chosen the wrong species.

Then you are potentially putting patients humans at risk because you will not have got a translatable model. So that it's absolutely critical to try and understand as best as you can how to select species. I'm sure many of you will know the story of te Janeiro, which was tested in larger species, but at that time for various reasons and anybody can look up the history, did not predict the outcome that happened in the clinical trial. So that's a good example of selection of species. But did we always understand the science at that point? Again, if you're developing a new modality or a new molecule target, we might not always understand the science. So we always have to be very cautious of that to try and understand as much as possible. But again, science safety cannot be guaranteed that makes it challenging. But yes, I'd always encourage that you do the scientific exercise of going through and understanding how you've selected species. And I think we need to make sure we are doing that correctly as best as possible.

Mary:
Science alone doesn't guide every decision in the lab. So beyond science, what role does ethical responsibility play in choosing the right species for research?

Sarah:
So ethics plays an important role, but the challenge with ethics is it's subjective. So culturally there are going to be differences in the ethics of how you use animals or your consideration to those factors of using an animal. And I'm sure many of you will be aware of those ethical differences across cultures. But we do consider, and certainly in Europe and North America, are considering the use of the larger animals as compared to the smaller animals and where you can use a smaller animal instead of a larger animal. I think we'd all prefer to see the use of a smaller animal compared with the larger animals. And just to add on that ethics point, I mean if you can use an in vitro, if there's not a necessity to go into in vivo, I think we'd also be looking at in vitro. So I think it's constantly on, well, it's certainly constantly on my mind as to how we can consider the use.

Mary:
And of course, like you mentioned, it depends on the regulatory body of whatever country the drug is being developed in, because countries have different laws. But even across the board, I would say most regulatory bodies are pretty conservative because patient safety is their number one priority. So they don't want to make change just for the sake of making change. They want it to have an abundance of data backing up any change.

Sarah:
Absolutely. And I think again, the challenge, isn’t it? Because again, it comes back to safety. So you want to ensure the safety of the patients and you therefore, if the gold standard test and our understanding is a certain species and a certain model, and that can be pharmacologically driven as well, then you may have to use large species in some cases. And then it's a case of looking at how you do the studies, trying to refine them as much as possible, limit numbers as much as possible. Those sorts of aspects comes into the study design.

Mary:
And then of course there's the scientists themselves. So how do psychological and emotional factors influence species selection?

Sarah:
Yeah, that's an interesting question. So a lot of psychological research has been done on decision making, and one of the things that has come out of that is that all decisions, some scientists may argue against this, but all decisions are based on emotions. Now scientists try and be objective as possible. So how could it possibly be? We're making decisions and it's our emotions and running it. So that's an interesting one. But actually if you go down to there are a lot of emotions that are involved. For example, the biggest one is fear of rejection from a regulatory authority. Nobody wants to be rejected that your dossier isn't good enough that you've selected the wrong species, because what would happen if that happens, then you can't get into a clinic as quickly as you would like to get into the clinic and help the patient. So that has a real impact. So making the wrong decision. So sometimes scientists may think, well, I'll err on the side of caution, therefore, what's most similar to humans? That may be the species I might select, for example. So that just gives you some idea. There's other fear factors that come to the selection, but I think getting it wrong is one of the key ones that can drive decisions.

Mary:
The 3Rs of replacement, reduction and refinement are obviously integral to ethical animal research. So how do they shape decision making in species selection?

Sarah:
Well, again, I think one of the biggest things to think about, and this may be to do with relevance of species, is don't use an irrelevant species. And also where you don't need to use a species and use in vitro, you could use in vitro. So I think again, and that's about the reduction. I don't know that it actually comes into refinement, but I think it could definitely come into reduction.

Mary:
So to truly understand the landscape of species selection, we should probably examine global regulatory agencies and how they weigh in. So how do global regulatory agencies view species selection?

Sarah:
Absolutely. I think actually regulators are the key in this because at the end of the day, anybody doing drug development, you are putting your dossier into the regulatory, and it's for the regulatory body to accept or not accept your evaluation and what models you've used, et cetera. So they play a big part in this and they're looking that the sponsors or the clients are selecting the appropriate species. They want to ensure that the science is correct. But if they push back at a certain, they raise a certain criticism that something hasn't been done for XY reason, they're are going to end up redoing studies, et cetera. Or you didn't select the right species. . And sometimes the regulators themselves are going to be conservative again, that may depend on which country they are sitting in. So some countries are more conservative than others. And again, your ethics will come into it also for a regulator with the differences in ethics considerations between the different countries across the world.

Mary:
what challenges do researchers face when justifying their species choice to regulatory bodies, and how do they navigate those discussions?

Sarah:
I think sometimes I think it will depend on the background of the person developing the drug or the company developing the drug. I think for some in biotech, they may have less knowledge or understanding. So it's a case of ensuring that they have that understanding coming to talk to people like myself or the group I work in, scientific advisory services that can help give that advice. We have so much knowledge in that to help them navigate the challenges. I don't even think myself, I have a lot of experience in it, but even myself, you have to consider, it's a challenging question, what species do I select? Because at the end of the day, if you get it wrong, it can impact on the safety.

Mary:
So Charles River obviously supports the FDA's recent focus on alternatives and it's aligned with our company's vision, and we view this as a long-term opportunity for our business. Charles River has a long commitment to the replacement reduction and refinement of animal use for biomedical research and has supported the FDA's efforts to advance the validation and adoption of new approach methodologies or nams. And I think it wasn't it last year where the FDA passed the modernization act, which is basically taking away the requirement to use animals. But although you still have to prove safety, and they haven't offered their best pick for alternatives yet. So we're in a very transitional place right now. So what role does Charles River play in accelerating the adoption of alternative methods?

Sarah:
I think by one, really looking and understanding what we're trying. We've got a lot of experience with developing drugs, so we can look at what's happening, we can learn from what's happening. We can encourage sponsors to really look at the 3Rs to understand that there could be other options. I mean, let's give an example. Therapeutic vaccines are quite an example when sometimes there isn't a relevant animal model or definitely not for using a large animal model. And so we can help support that by helping provide those scientific arguments to then support and have discussions with the regulators. So that's something else to consider that you have those early discussions with regulators, but you are giving the scientific understanding of what model could be used or, so to go back to that example with a therapeutic vaccine where often there might not be a relevant model.

So we say, okay, we're going to look at what we call off-target toxicology, and we're just going to put it through a very small animal model, and that will assure safety because there isn't another animal model. And then we can use some in vitro information, et cetera, and build up sort of building up the package with points to understand in terms of risks of safety, if you see what I mean. So we can help support that. And by also, we have a very broad knowledge and we see a lot of drugs coming through. We're looking at the science we are keeping on top of where regulators are, et cetera. We can also push boundaries and look at technologies to say, oh, well, we could bring this in or have a look at that. I'm not giving specifics here.

Mary:
That's okay. I mean, basically what you're saying is Charles River has over 75 years of experience doing exactly this, and all of that experience is all data points that we can use to guide our decisions going forward and know what might work and what is probably not worth pursuing.

Sarah:
We can certainly, absolutely, and we've got a lot of experience and knowledge in that and trying to understand. And we're also keen to look at ways to move forward, which don't use animals, and I think that's important, but at the same time, you've got to guarantee safety. So again, that's the challenge we're at from a scientific community and a regulatory community. And if you go back to that modernization act, and even before the FDA was always happy to take just in vitro data. So it's about understanding when you're looking at replacements as well. For in vitro it's like, well, how do I translate? Now? Some people argue sometimes we struggle with translation of animals as well, because at the end of the day, a humans are human and we are different, but we've got a lot of understanding of that. So it's bringing in all that understanding, looking at that, understanding products. That's what Charles River's good at because it sees such a breadth and depth of products that we can help to pull that together and really think about what can we do in the future? How can we push this forward? We're not there yet, but we're working on it.

Mary:
Yeah, it's funny to think how those minute differences between species can affect the basic drug development process because we're always told at the Children's Science Museum that we share 98% of our DNA with a banana, but we certainly don't test on bananas. And it's just that 2% that's different. So when you think about it, it's like they're very minute little differences, but they make a big change when you're studying a disease.

Sarah:
And it's complicated. It's complicated because there's all sorts of factors that come in to understand in the physiology of a drug and how it works in a body.

Whereas in vitro often is it's a simplification of a system, but the body is not a simplified system. So how we completely replicate that is going to be a challenge. And as you say, animals are similar. We share, as you say, a high percentage with even bananas, even higher as we go up the ladder, but we're still not the same. And even human to human is not the same. Again, quite interestingly with certain products, you can have quite different reactions from different humans because of genetics or age or gender. So nothing is like, it's all about really, it's a question of risk management and trying to de-risk as much as possible.

Mary:
So speaking of non-animal models, from a scientific standpoint, what kinds of non-animal models like organoids or micro physiological systems do you think hold the most promise in replacing animal testing and drug development? And maybe not replacing all animal testing, but what are some of the ones that you think are the most promising?

Sarah:
I actually think probably the future needs to be what I would call holistic

You're not going to have one model that's going to be the all-singing, all dancing answer. You're going to have to build up a holistic package of data coming in from different aspects, testing different endpoints that will then give you an overall risk assessment. And if I just think of two at the moment that we are very good at predicting from an in vitro perspective, we're already there. And that is genotox, in vitro mutagenicity tests quite good, even in silica, quite predictivity. And for QT prolongation, we have the, what's called the hERG assay quite good in terms of predictivity. It's not perfect, absolutely, but hopefully you can see where my vision's going is you're looking at the endpoints and you go, okay, we'll have this in vitro test to test that endpoint this to test that endpoint, and we'll identify some really key endpoints to really focus in on. I think that might be the future. The other aspect that's the biggest challenge probably is when we are developing the drugs and looking at the safety, you are actually looking at the exposure of the drugs in the body. So it's the exposure of the drug and how the body handles the drug that also needs to be understood, and that is different between species. So can you imagine trying to do that in vitro? I think that's a big challenge.

Mary:
Yeah, a hundred percent agree. I think that you're spot on when you say that the holistic approach is going to be the way forward. So this question kind of answers itself, but do you think species selection will evolve significantly over the next decade?

Sarah:
I hope so. I have been supporting this species selection for some time in trying to improve how we do that to get people to really think about it. So if anybody's listening, please think about it, or please come and have a discussion. I would like to see us move forward on this and really get better at it. If we don't have a relevant species, that's important to understand. What do we do when we don't have a relevant species? Is that the time when we can be using an opportunity for in vitro, or maybe in some cases, going back to sort of the 3Rs, we could just use one relevant species and that would be good enough. So reducing the numbers of animals, et cetera. So yeah. I hope we are going to evolve further. We have been, and I hope we continue.

Mary:
So finally, if you could change one thing about the way the industry approaches species selection, what would it be?

Sarah:
Really justify your species selection with not just saying, this is a species that is accepted by the regulatory authorities. Really consider that you've thought about the pharmacology. It depends on your modality, but your understanding how and why you've selected this species. That's what I'd really like to see. And I'd like to see it in scientific papers as well. So often when you read a scientific paper and they say, we've used this, we've used that. It doesn't actually often give the rationale as to why really they selected that species.

Mary:
Thank you, Sarah, for being part of sounds of science. It's been a pleasure having you on the show.

Sarah:
Thank you.

Mary:
Sarah Gould is Director Scientific Advisory Services at Charles River. Stay tuned for the next episode of Sounds of Science. Until then, you can subscribe to Sounds of Science on Apple Podcasts, Spotify, Stitcher, or wherever you get your podcasts. Thanks for listening.