S4, E10: Modernizing Drug Development

Michael Templin (00:02):
If you look at history, the in vivo studies have been considered the central pillar, the gold standard of drug development. The good part about the act, and in some ways, the way it's written, and how it does highlight that there are other options, and it brings them up to a more similar level.

So again, when you have early conversations, or when you're planning, how are you going to bridge from the discovery phase into the non-clinical phase? What are all my options?

And now, the in vitro, the micro physiological systems, and the in silico, by bringing them up, and giving them more prominence, they bring them more to mind, and more to focus to say, how do we balance all of these tools?

Todd Poley (01:02):
Since the passing of the Federal Food, Drug, and Cosmetic Act of 1938, animal testing has been required for every new drug development protocol introduced the United States.

Over the last century, the industry has seen several scientific advancements in preclinical research. And at the end of 2022, president Biden signed the FDA Modernization Act 2.0 into law. The act enables clinical trial leaders to use alternatives to animal studies, before entering clinical trials. Which models could replace animal testing as the gold standard of preclinical research, and how might these methods bring drugs to market faster?

I'm Todd Poley, and in this episode of Vital Science, we speak with Michael Templin from Charles River Scientific Advisory Services team about the benefits, and challenges of this new legislation, ways in which animal research has evolved in recent years, and how drug developers, and patients might benefit from the industry's new trajectory.

Gina Mullane (02:04):
Hi Mike, and welcome to Vital Science. We're honored to have you here today.

Michael Templin (02:08):
Thank you so much for the opportunity to talk today.

Gina Mullane (02:12):
Would you start off by telling us a little bit about yourself, and your role at Charles River, please?

Michael Templin (02:17):
I'll start a little bit with my role in Charles River. So the group I'm in is called Scientific Advisory Services. And just as the name implies, one of our primary goals is to get involved early in the drug development process, and outline what a program could look like, some of the key points, what's been done in discovery, what are the program goals in the clinic, and then, primarily design a nonclinical program that provides the bridge between those two.

As my background, I've been in drug development since the mid-nineties, so more years than I care to admit sometimes, but it's true, so I have to. And that's really been my focus, and goal over the years, just as I mentioned, to get compounds moved from what are interesting research candidates into clinical drug development candidates. Of course, with the ultimate goal of trying to get better therapies, or sometimes new and novel therapies to patients.

Gina Mullane (03:17):
This must be a very rewarding role. You're on the front lines, I should say, of those drug developers, and hearing about their dreams, and what they hope to accomplish, and you have the ability to influence that.

Is there an aspect of your work that you're most passionate about?

Michael Templin (03:40):
Probably the most passionate aspect of what I do, is again, trying to figure out that puzzle, for lack of a better term, of how to move a compound forward. In science, you work from unknowns, and knowns, and how do you link the knowns together, fill them in, and address the unknowns, again, to make that story as a compound moves forward.

I actually started, my undergraduate was in pharmacy, worked as a pharmacist, so I saw the end of drugs being used in the patient setting, or in the public setting, and there was always the questions about how do they get there, what makes a drug that is successful, versus one that is not successful? And it's a privilege to be able to work in that early process to be able to move compounds forward.

Gina Mullane (04:30):
Wow. What a interesting perspective. So we understand, and know that animals are essential to really understand the progression of diseases, and the biological mechanisms, and equally as important to understand the safety and efficacy, and there's been quite an evolution over time, and understanding, and how animals are used.

Could you share a little bit about your view, your experiences, as far as the evolution, and just how you see this journey being important?

Michael Templin (05:03):
The two strongest places I've seen, or the most advancements are the first in, of course, animal husbandry. Our colleagues within the veterinary sciences, and the animal husbandry have done a phenomenal job over the last years of being able to provide environments, they're really are research environments, but to make them as positive, from a health benefit, from a socialization interaction, so that we can conduct the best science.

Of course, you need a healthy animal that is in an environment that is most positive to them, and they've done phenomenal jobs of being able to determine how you do that in a regulated controlled setting, but give the animals plenty of feedback.

The other greatest advancement has been, as we all know, technology is moving at an amazing pace, and it's been true for the aspects of drug development as well. And that's where I've seen a major change in the types of assays, the type of endpoints we can evaluate to make those that are most meaningful to be able to predict, it's never an absolute, but have the best ability to predict potential effects, both positive, or negative in the clinic.

So there's been an amazing expansion of the questions we can ask, as well as an expansion of how we ask them.

Gina Mullane (06:32):
Wow. Lots to cover on that. I'm excited to hear more.

As we know, the FDA Modernization Act 2.0 was signed into law earlier this year, and part of that was amendments to wording around animal testing.

What's your understanding of this legislation, and how do you expect it to impact drug discovery and development?

Michael Templin (06:53):
Yeah, probably like many people who read it first, when you first read the animal parts of this, there are the concerns, "Where do we gain, where do we lose? What are the real impact?" But we've all had a few more months to read it over many times, have discussions about it, and in the end, there are definitely some positive things that will come out of this.

It will change how drug development is done, which is always needed. We need to improve on the technologies. What we learned yesterday is fantastic, but we need to apply those for tomorrow.

And that's been my biggest aspect of, again, reading through it, and considering how it impacts my day-to-day job, those that I work with, their day to day job, and then, eventually how we're going to apply this for improvements in the long run.

Todd Poley (07:52):
The FDA Modernization Act 2.0, allows previously underutilized alternatives to animal testing to be used to their maximum potential. This includes three popular alternatives in vitro models, micro psychophysiological systems, and in silico models.

In vitro assays are lab tests conducted on cells, tissues, or organs outside of a living organism. In vitro assays can mimic complex biological processes, and testing the safety, and efficacy of a therapy, often leading to faster, more cost-effective results.

Micros Psychophysiological systems, also known as organs on chips, are miniature devices that mimic the functions, and responses of human organs, and tissues, in a controlled environment. Organs on chips can be used to study the effects of therapies on human physiology, and are especially useful in personalized medicine development.

In silico models, are computer-based simulations that use mathematical, and computational algorithms to assess safety, and efficacy, by predicting the behavior, and outcomes of therapies in the human body. These models provide insights into complex biological processes, which can be helpful in guiding drug discovery, and development, and identifying potential side effects.

Let's hear more from Michael on the insights being gained through these alternative models.

Gina Mullane (09:19):
There is certainly a lot we can learn from these preclinical approaches, particularly in vitro. How do you see this newfound data being used moving forward?

Michael Templin (09:29):
Being primarily an in vivo scientist, I will have to admit, in the past I've looked at in vitro systems, a little hate to say it, but it's true, more as supportive data that we could use here and there to answer some key questions. But again, there's been phenomenal advancements over the last few years on those in vitro systems.

So now, they have the ability, in gaining more ground every day, to be able to move up from more a supporting role to a primary role. We're able to look at individual cells, we're able to look at systems where they combine cell types. In vitro does in some ways include the so-called organs on a chip, where we can combine liver with another organ, or as we all know, the gut and the brain have a lot of communication, and you can set up the in vitro, ex vivo systems, in order to try to understand what are those more subtle communications between organs, and where are their positives, and where are their potential concerns.

So they really, now, have the ability to ask and answer very specific questions, but also give us greater dynamics that, maybe, weren't available 10, or so years ago in vitro systems.

And in some ways, that was wasn't really a criticism, but in some ways, they were too limited, but we're losing those limitations very, very quickly, and in the future we'll be able to ask highly dynamic questions in a more controlled, well-established system.

Again, they move up to a higher level, and take a greater prominence in how a drug candidate moves forward, and it can include where we may need to answer some questions with in vivo studies, but if the question canon is fully answered by an in vitro system, then there is no need to repeat that in the animals, so it's one of the places we can replace, reduce, refine.

Todd Poley (11:40):
A key component of the FDA modernization 2.0 Act, is removing the animal testing requirement for biosimilars. Drug development, typically, involves three key areas of assessment, analytical, nonclinical, and clinical.

With novel drugs, much of the work in these three areas must be built from the ground up, but this is not the case with biosimilars. Unlike novel drugs, the characteristics needed for biosimilar candidates are already known, so drug developers are tasked with establishing analytical similarity, and determining clinically meaningful differences between the biosimilar, and innovator product.

From a scientific perspective, this means nonclinical testing is less essential than a novel drug research. By removing animal testing from the equation, the act allows biosimilars to move more efficiently through the drug development process, and into the clinical setting.

Now, let's hear more from Michael on how animal testing studies may evolve moving forward.

Gina Mullane (12:43):
So we did speak a little bit about the three Rs, replacement, reduction, and refinement, and we're very familiar with this framework as a foundational, and important element of animal research.

At Charles River, we've been thinking more about this fourth R of responsibility. It's a way for all of us in the company to think about what the three Rs mean to us, and how we can uphold them, and elevate them.

From your point of view, what does the role of responsibility mean, when it comes to animal research, under the umbrella of the three Rs?

Michael Templin (13:15):
Yeah, that's probably one of those that means something a little bit different to everyone, and has a different role depending upon the context. We said the traditional three Rs were replacement, refinement, and reduce.

And in the case of this act, we see that to come through. Where can we have places that we can replace? We touched on in vitro, and the great invest advancements that have been made in there. Are there places that you can, the term is, replace our alternative, but it's really where can you answer the questions from an in vitro perspective, therefore you don't need to ask and answer them in an in vivo setting.

The other would be refinement, and that is, it's our responsibility to consider what is the best means to generate data. In some cases that may be an in vivo study. There will be other cases where in vitro, the micro physiological systems, or things I do look forward to are some of the computer AI-based systems, that will be able to capture massive amounts of information, and distill it down into usable ranges.

But we have the responsibility, not only to know that they exist, we have the responsibility to determine where can they be applied, where should they be applied, and how do we use them?

Gina Mullane (14:48):
Yeah, and as you're saying that, I'm thinking about your role as a scientific advisor. You're you working with clients every day, researchers every day, talking about ways that they can, and should conduct their research so that it reaches approval.

Do you find yourself leaning into this concept a little bit more now? Is there anything changing in your sphere, that you see, is influenced by this?

Michael Templin (15:16):
It is definitely changing, and it's always a good case when, this is where the publicity around the FDA 2.0 Act has had the positive aspects of it, because it's on people's mind. It's often a conversation that we have with a potential sponsor, or those that are trying to develop a drug candidate. They will often bring it up, "I've heard about this. What does it mean for my drug development pathway? Where is it appropriate to use animals? Where would it be appropriate to use other systems?"

And this is where publicity works in your favor, because it opens an easy pathway to discuss, let's talk about the entire program. Sometimes in calls there can be a very focused agenda, "What do we need to do next?" But it's just as important, and it's our responsibility, if we can bring that back in again, to say, "Okay, what does the entire program look like?"

Yes, we need to focus on the next month, the next three months, the next six months, but drug development is a very dynamic process. It can be a very long process, as in some cases, but if we look at what we need to look overall, it also makes it easier to say, "Okay, where can these pieces fit in? Where do they best provide the data?"

People are more open to it, but they're also more open to saying, "Okay, here's where we refine. Here's where we replace." Here may be a hole that we're going to have to figure out how we fix when we have more data to know what questions remain.

Gina Mullane (16:53):
That's really helpful to hear it that way. I think it's exciting for people to hear that this is becoming part of real life. It really is changing the scope of research.

I think, my takeaway is that perhaps you're saying there's you always going to be a need, or for the foreseeable future, a need for animals as part of the scope, but we're looking every day to find other options were available.

Is that a fair summary?

Michael Templin (17:23):
Absolutely. If you look at history, the in vivo studies have been considered the central pillar, the gold standard of drug development. The good part about the act, and in some ways the way it's written, and how it does highlight that there are other options, and it brings them up to a more similar level.

So again, when you have early conversations, or when you're planning, how are you going to bridge from the discovery phase into the nonclinical phase, what are all my options? And now, in vitro, the electrophysiological systems, and the in silico, by bringing them up, and giving them more prominence, they bring them more to mind, and more to focus to say, "How do we balance all of these tools?"

Because again, it can be a long, and challenging process to move things forward, and the more tools we have in order to ask those questions is an absolute positive. It's never a case where you know, have too many tools in order to solve this problem. It's going to be just our responsibility to figure out what is the best tool to use for the question at hand. How do we refine it? How do we determine what are the key questions, and what data set is needed to answer those questions?

Where they come from is important, but less important than determining what is the key question.

Gina Mullane (18:57):
So in what ways can partnering with a CRO early in the study design phase, really maximize the efficacy of the vitro studies of a therapeutic and the discovery of a new therapy?

Michael Templin (19:11):
Yeah, we often go with the phrase, it's never too early to start interacting with your CRO, or your development partners, and that is truly accurate. It loses its meaning sometimes when you think of the overall program, and project, but it is definitely true.

As I went through a little bit, when you look at moving forward, there are going to be places where there's unexpected results, there will be places where result, it does work out as expected, but you have to set that plan, and you want to know what are, again, what are my best approaches in order to ask the questions, and then, develop answers, and it may change over time. It will change over time more often than not as you collect data, but the only way to get there is to start as early as possible, and say, "Okay, here is my intended plan."

Todd Poley (20:12):
The act has open new doors for drug developers to mix and match approaches, and optimizing the unique development process for the therapy at hand. This involves considering the use of in vitro, and in vivo assays, as well as micro psychophysiological systems, to address key questions early.

For example, these methods can be used to create a target product profile in order to outline what the drugs should achieve, the diseases it will be used for, the dose, and frequency.

Being proactive, and thinking big picture from the first phase of study, can help researchers anticipate the problems that inevitably arise during drug development, and be more equipped to respond.

Gina Mullane (20:54):
It's great that drug developers will have flexibility in designing their preclinical research, and whether they select an alternative model, or stick with animal testing as their standard.

Here at Charles River, we recently introduced an office of responsible animal use, to give greater attention, and focus resources around these principles.

From your point of view, in what ways will driving improvements to animal welfare shape the future of the industry?

Michael Templin (21:21):
The interesting thing was in drug development, it's always the timelines, and the potential financial risks, or investments that need to be made. Again, by going through, and thinking about this early, by being responsible in the way we approach this, by having a CRO that thinks about these things, or provides you options as early as possible, there will always be financial risks. There will always be the data's not going to turn out the way that you expect it.

But it gives us the opportunity, as a CRO, it gives the sponsors of a drug development candidate the opportunity to think about, how can they best maximize their efforts, their dollars, to minimize those risks to the extent in which you can minimize those risks?

Gina Mullane (22:18):
I'm wondering, from your point of view, what is the impact on patient safety, as we think about these changes, and the evolution, and the approaches that we're taking? Do you have any concerns there, or do you have any kind of philosophies around that?

Michael Templin (22:38):
No concerns when it comes to patient safety. It is always first and foremost. Like I mentioned, one of our roles in the Scientific Advisory Services Group, is often early in the process to talk with a drug developer, again, about what they know, from a research perspective, and what they want to accomplish in the clinic, what types of patients, what are their ages? Are there secondary diseases that may also be involved with this? Do drugs have to be taken for a short time, or will they be taken for a long time?

And think about all those things as you're moving, and designing a non-clinical program. Patient safety is always the absolute requirement for whatever happens.

But safety in some ways can be a little bit of a relative term. There is the risk benefit of not treating a disease, versus using a pharmaceutical, or a drug in order to treat that. No drug is perfect. We all know that there are some unfortunate things that can happen in individual patients.

So you have to take the what's the most sensitive patients, what risks are associated with that, where are the average patients, what risks, and benefits are associated with that, and how do we, in the best means possible, establish a non-clinical program that will identify potential risks?

It is, as toxicologists, we do look at those, and sometimes what are the potential negatives, because that's part of our job, as non-clinical drug development professionals, in order to identify what could be some of the risks, because if you can identify the risk, you have a better chance of going into patients with a reasonable expectation of safety, but you can never take the patient out of the equation. It always has to be first, and foremost in your thought process.

How does this piece of information correlate, or how is it associated, eventually, with a patient, a person that will have to take this drug, or needs to take this drug?

Gina Mullane (25:03):
Helpful. Sounds like we are in good hands with someone like you at the helm. It's been an enlightening conversation. Thanks so much for sharing today.

Michael Templin (25:12):
Thank you so much for the opportunity.

Todd Poley (25:15):
Michael Templin, is a senior principal scientific advisor at Charles River. Vital Science will be on hiatus in August, and we look forward to kicking off our fifth season with a new episode in September.

Did you know that Charles River has a sister podcast, Eureka's Sounds of Science? This monthly podcast shares scientific, patient, and advocacy perspectives, on trending issues in the drug development industry.

You can subscribe to Vital Science, and Sounds of Science, on Apple Podcasts, Spotify, Stitcher, or wherever you get your podcasts.

Until then, thanks for listening.