Beyond Animal Testing: The FDA Modernization Act and the Future of Drug Discovery

Hi, everyone, and welcome to CrownCast, the podcast from Crown Bioscience exploring emerging trends, perspectives, and breakthroughs in oncology, drug discovery, and development. I'm your host for today, Michelle Dawn Mooney, and I am delighted to be joined by Professor Thomas Hartung, a member of Crown Bioscience's Scientific Advisory Board and Chair of Evidence Based Toxicology at the Johns Hopkins Bloomberg School of Public Health. Thomas is also Director of the Johns Hopkins Center for Alternatives to Animal Testing and Professor of Pharmacology and Toxicology at the University of Konstanz in Germany. Thomas, welcome to CrownCast. It is a pleasure to have you here today. How are you? Good. Wonderful. This time from Sweden. Thank you for making time to speak with us. I want to start off here. Can you tell our listeners a little bit about your background and the roles and initiatives you're currently involved in? Yeah, I mean, I'm an academic and out of medicine and biochemistry and some studies of mathematics, informatics, I developed as my quest trying to find better ways to develop drugs and establish the safety of chemicals by using modern technologies, not these outdated animal experiments which were typically or many of them were introduced when I was not yet born or in kindergarten. I'm really interested to bring in the most modern technologies, which I actually, from my point of view, outperform in many cases the traditional methods. You have a remarkably broad range of affiliations and experience across research, regulation and policy. Can you tell us more about the different organizations and initiatives you work with and how those roles connect? You know, I became first a Professor of Pharmacology and Toxicology in Konstanz, Germany, and then joined the European Commission for seven years, where I was heading the validation body for alternative methods. This was then the starting point that Johns Hopkins offered me this Chair for evidence based toxicology and the directorship for the Center for Alternatives to Animal Testing. But in the meantime, I have additional affiliations for molecular microbiology and immunology, for cellular and molecular medicine in the school of medicine, or in the Whiting School of Engineering, and most recently added also Georgetown University, where I'm more or less in the policy field. So you see it's broad, which means also not necessarily in no field as deep as some others are, I'm the guy for the connections, for bringing people together across disciplines and also bridging into policy. Because if you once have worked in the scientific support to policy, as I did for the European Commission, you understand it's not only about the next scientific paper, but a lot is about enabling legislation, opening the minds for change. You mentioned policy, which brings us to one of the central topics of today's discussion: the FDA Modernization Act. For listeners who may be less familiar with it, can you explain what the FDA Modernization Act is and what it is intended to achieve? I mean, we observed that on both sides of the Atlantic, the number of citizens being critical about animal experiments is growing. In the US it's pretty much split half if we talk about medical animal experiments. But it's interesting not the typical gridlock between the two parties along partisan lines it is actually across these. About fifty percent in the US and Europe it's even sixty percent who are skeptical about this. This leads increasingly to activities by policymakers who simply want to represent what citizens want. In the US this led quite remarkably to unanimous legislation both in Congress and in Senate in 2022 already, which was called the FDA Modernization Act. This legislation which was signed into law by Biden on the 23rd December 2022 said essentially we want the FDA to consider more non animal methods. They're listing a number of these methodologies which include computational methods but also complex in vitro systems like organ on chip systems. So a very important signal to the entire community that policymakers said we want you to do differently. This was a signal to the FDA, it was a signal to the regulated industry and it was signal to biotech companies that this is a market which is evolving. It is clearly a fascinating and potentially transformative time for the industry. So looking at the development of new approach methodologies, including organoids, computational models, and other in vitro and in silico approaches, what do you expect the short and medium term effects of these regulatory changes to be? I mean, it does not change everything from one day to the other. And it's also not something which is just now taking place, but it is a transformative movement which is taking place here. So the Environmental Protection Agency in the US, for example, already in 2019 under Andrew Wheeler said we want to move out of animal testing as a standard requirement by 2035. A very strong signal. This was just renewed last month also here in the US and EPA and FDA were joined in April also by the NIH, saying they want to emphasize now the human relevant methodologies. So we have here really a synergy of the most important regulatory agencies in the US and the NIH, the biggest funding body in the world. The FDA is arguably the most important regulatory body in the world, because all the pharmaceutical companies only look for the FDA. Because we are just four percent of the world population, but we are fifty three percent of the drug market and sixty seven percent of the drug market under patent. So it is really a very important signal to drug makers that something is going to happen and that this type of information are not only welcome but are going increasingly to be mandated. And how do you expect these developments to affect the contract research industry, particularly providers that have traditionally focused heavily on in vivo research, but are now expanding into new approach methodologies? The CROs are very often the translators between the two, especially for the smaller companies. They need the advice. They don't have the in house capacity to follow trends. The CROs are the ones to pick up what is possible, what can be done, what can be reasonably offered. Also even the larger companies are increasingly interested in outsourcing certain things. You know these complex methods require quite a bit of stuff to maintain. And if you don't run a model permanently, it is often wise to outsource this to somebody who is just doing the job for a number of different companies in a continuous and high quality fashion. You typically need two people to maintain one technology in the industry. So you can imagine what the maintenance costs are for even relatively simple test systems. It seems increasingly likely that drug developers will need to combine several different approaches, bringing traditional methods together with newer technologies and models. From a CRO perspective, that may make it more important than ever to act not simply as a service provider, but as a collaborative scientific partner that can help clients develop and then integrate novel approaches? Absolutely. I mean, I've coined the term "invivitrosi" which is the combination of in vivo, in vitro, and in silico to describe that we need to combine these. There are very few places who are capable of maintaining the different methodologies for such an integrated approach at the same time. Also, when I was heading the validation body for Europe, I have to say, I learned the hard way how difficult it is to work with academic groups. Yeah? They were always toying around. When we had a protocol, they would always come, oh, we found something better here. Yeah? And we had to tell them, no. You have to stick to the protocol as it is. We don't want something better, we just want something standardized. This type of thinking is there in the contact research organizations. This is why our validation studies very often included these. Also then again, as the translators of these technologies and the ambassadors for these methods towards the various clients. Validation and standardization will clearly be critical as regulators become more familiar with these methods and expectations continue to evolve. Drawing on your experience, which new methodologies and innovative in vitro technologies are already making an impact, and which do you believe have the greatest future potential? There's a number of disruptive technologies. Disruptive means really changing the game. I would focus on two in particular, which is the complex in vitro systems or how the FDA calls them Microphysiological Systems (MPS) and AI, the artificial intelligence facilitated methodologies. You could make a similar argument for the various omics technologies and sensor technologies and so on. The cell culture part, for example, has not been really a competitive technology before the 80s. In the 80s we started to see the first methods and they were based on cell lines often tumor cell lines or very simple primary cell lines for fibroblasts and similar, but not really reflecting anything of the functionality of these cells in an organ. This has changed, especially for the human ones, which are the most relevant ones obviously, especially since now more than fifty percent of the new drugs are so called biologicals, which means they are either human proteins or antibodies against human structures, where animal testing is completely useless. These type of test systems have become available only in the last twenty years. This is simply because if you want to use something more than skin or blood cells, you don't get primary cells. Not regularly at least. I'm working on the brain and if I want to pick your brain, you will kindly refuse, I think. It is a problem to get to good materials. The problem in an ethically clean way was only solved in 2006 when Yamanaka developed the technology of induced pluripotent stem cells (iPS cells). We had some human embryonic stem cells seven years earlier, but there was a lot of fight is this ethically acceptable or not because they came from in vitro fertilization surplus embryos or fertilized eggs, you have to say. Shinya Yamanaka, who received the Nobel Prize already six years later, which shows how quickly this was recognized as a breakthrough technology, we have over the last twenty years seen a mushrooming of protocols to produce essentially any human tissue architecture and functionality. This is what I think is the best description of a microphysiological system something which is reproducing architecture and functionality of one or more organs, which can also interplay if you put them on a chip with microfluidics. This is a new technology which really has given rise to test opportunities, in particular for these biological drugs, which are second to none. There's no other technology which allows this type of testing. Accurately modelling complex biological systems and gaining access to tissues and materials that are truly representative of patients remains a significant translational challenge. Are there particular stages of drug discovery and development or particular organs and biological systems for which developing alternative approaches is especially difficult? The more complex the organ and the more specific architecture has to be reached, the more difficult this is. We have a pretty good overview because over the last four years we did the Microphysical Model Systems World Summit, the fourth one coming now to Brussels in June. These MPS World Summits we have accompanied by creating an international MPS society which is now taking over from my team, the organization of these conferences. But I can say, organs where architecture plays a big role, like the brain, like the kidneys, they are still challenging to create functionality. But we're making enormous progress. So my group is focusing on the brain. There's more and more models also for the different zones of the brain and bringing them together in assembloids. And we have coined the term of 'Organic Intelligence', O. I., of really developing cognitive functions for the brain. So we let it talk through electrophysiological sensors with an AI system. We let our brain organoids play computer games. And what sounds very futuristic and science fiction is taking place and is getting more and more standardized that we can start benchmarking for drug development. The progress being made in areas such as brain organoids and organoid intelligence sounds remarkable. So looking ahead, what further developments do you anticipate in this field over the coming months and years? And where do you think the science is heading? I mean, these MPS are critical for producing new data and giving us actual human relevant test data. But what we see as in every field, AI is at the moment starting to enter the game, also in pharmacology and toxicology. AI has been good enough to design drugs since about 2019. You have to imagine, of these projects started around this time, eighteen AI first drugs entered human trials in 2023 already. Eighteen. This is a record for the development and one by Insilico Medicine which was started in 2019 as the others already successfully passed in 2024 phase 2a in patients and entered into a phase 2b study for lung fibrosis. Not a simple indication and I think this is only showing us what we're going to have to expect. One day earlier to the market means for a company on average one million dollars. It's really an enormous value proposition to design drugs with AI. My group is mainly working on the safety side of using AI, so predicting toxic properties. Here we see similar groundbreaking advances that AI is actually already now outperforming the predictive capacity of animal tests. For many of the simple toxicities we are already now better than the reproducibility of the respective animal tests. For the more complex endpoints a lot of validation has to be done but the general theme is it is now more about building trust into these methods than it is about actually technological further development. You have described significant progress in the use of artificial intelligence for both drug design and safety assessment. Do you think it will still be several years before AI is adopted more broadly across drug discovery and development, or are there applications where it can already provide meaningful value today? Depends on where. AI is already now extremely good to help you in an emergency case. You need information quick. There's a spill of a substance you don't have really information. Better AI than nothing. It already now can be a plausibility check. Do these data make sense? It can help you to prioritize, to focus on lead substances with a better predicted profile of toxicity effects. In extreme, a chemist can already now enter a formula and see whether there is likely liabilities and say, is it worth synthesizing this now for the next year or so? And then perhaps just put the energy into a molecule which is more likely going also to make it into humans. Thomas, we've covered a lot of landscape here, and I want to be conscious of your time. So to close, what advice would you give to people working in drug discovery and development as they respond to the FDA Modernization Act and consider how best to adopt new approach methodologies? Yeah, I think we have a unique situation and time where, we don't need to move as we have always been doing it. The doors are opening up for something new. That's a synergy of different moments. One is the regulators have started to see that there's limitations in the traditional approach. They are opening up at the moment dramatically in the US, but also something similar is happening in Europe with the European agencies. The second thing is the technologies are there. The biotech companies are producing microphysiological systems and AIs and they are open. The third component we have been seeing through Covid that we can actually do remarkable things with much less animal testing. Normally the development of a vaccine is ten point six years and the success probability is six percent. But in one year essentially without animal testing nine COVID-19 vaccines have been making it as all reasonably successful drugs. And in one and a half years we had two antivirals, again largely without animal testing, because there is still no good model for COVID-19 in animals. So we have really seen here that we might be able to rely much less in our development processes on these animal models. This is what is now the moment in time to open up in a transparent and probably also jointly between industry in a pre competitive field, trying to develop these technologies, setting industry standards and finding out with the regulators what is acceptable information, which is then going to help this development and registration processes. An excellent message to end on. Thomas, thank you so much for joining us at CrownCast. It's been a fascinating conversation. We greatly appreciate you sharing your expertise and your perspective with us today. Thank you for being here. And I want to thank all of you for tuning in and listening to this episode of CrownCast. We hope you found the discussion valuable. To hear more conversations with scientific experts from around the world, you can subscribe to CrownCast on YouTube or Spotify, or you can visit the Crown Bioscience website at crownbio.com. I've been your host today, Michele Dawn Mooney. Thanks again for listening. We hope to connect with you on another podcast soon.