 We need to move to our next speaker, so it's gonna be Clarissa Franca Diaz-Carnero, talking about towards best practice in decision-enabling preclinical trials. Yeah, thanks. Okay, so today I'll be talking on behalf of the decide project team. All past and present members are listed here. And the starting point for our project and for this talk is this idea of this translational gap and how promising interventions in preclinical settings fail to show same results in clinical settings. And there are many reasons for this. Yeah, human conditions can be very complex. Even when we do understand them, experimental models can be very limited in modeling this. When they, even when we do have good models research, when it's done at the frontiers of knowledge, it's very risky and we don't expect this to be right all the time. Even when it is right, preclinical researchers are not always prepared for all the regulatory requirements that will come later before something reaching humans. But yeah, on the basis of all of this, there's a point that results may not be trustworthy to begin with. And this is the central focus of our project and our initiatives and efforts. There are many reasons for why results may not be trustworthy. And especially when we're talking about limitations in statistical inference, it is important to make a distinction between exploratory and confirmatory preclinical trials. In this context, exploratory research is dealing with an unlimited potential of dirts and targets. And it's focused on developing theories, primarily doing this by larger packages of small experiments. In contrast, confirmatory research, more focused on bringing one intervention to test in humans. And they do this through small packages of large experiments, usually with higher methodological rigor. It was in this context in 2019 that the German Ministry for Research and Education published a call for funding projects on confirmatory preclinical studies and systematic reviews with the goal of strengthening this preclinical evidence base to promote more translation of results. Applicants needed to have early evidence from exploratory studies and they need to partner with other laboratories to conduct a multi-center studies. 12 projects were funded across different areas of medicine. And the decide project was funded as an accompanying project to this call. So decide meaning decision-enabling confirmation of innovative discoveries and exploratory evidence. And there are two primary goals for the site. In one hand, we provide support measures for this preclinical confirmatory trials in supporting the planning analysis and interpretation of the studies, how to deal with animal, obtaining animal permits and evaluating pre-registration options. Most importantly, we focus on how to specify key decision criteria that will be useful for informing the drug development process. There are also two key meta-research goals, meaning to identify challenges in boundary conditions and confirmatory multi-center preclinical studies and to develop a framework on how these studies can be planned, conducted, analyzed and evaluated in a way that they are decision-enabling as the project calls for. We started the project by establishing the basis for how we provide the support and how we can then analyze the changes that these confirmatory trials made. What I wanted to highlight here is that we find it useful to make a distinction, for example, between external validity and translation of validity that may be a little bit different from other fields, meaning that external validity we're talking about general visibility to other preclinical settings. And then we move on to translation of validity as the general ability to clinical settings because the requirements to achieving both of these general disabilities are going to be very different. And then we established this scheme here that how replications can play a role in improving each of these validities and how other measures besides just simply doing an exact replication can improve, for example, including additional controls or alternative hypotheses that can be concomitantly tested. We do this guidance and the research mostly based on individual consultations with the funded groups, but then we also combine them, gather them in a workshop to see, to get them to talk to each other and identify the key challenges and boundaries for how to conduct these types of studies and beyond the experimental design, a topic that really came up very prominently was how to deal with creation of standards of protocols and procedures where we're doing preclinical research in multiple laboratories and how to deal with quality control across these laboratories and how to deal with the variation that emerges either naturally or that can be introduced through experimental design choices. We came up with a list. This is just an example here of some topics that were the minimum requirement, the best practice guidance that we come to are not necessarily new, but what we find very useful is to acknowledge the restrictions that the preclinical setting can have in implementing some of these good research practices in experimental design. This helps to bring the researchers more open to a conversation rather than just saying, no, I cannot do that. This is not relevant to me and just saying bye. We move on to further develop a framework for how to deal with external validity. In the preclinical settings, we identified several strategies that have been published and we just tried to organize them in terms of low barrier, like the yellow strategies highlighted there, the use of heterogeneous models or multi-batch designs and then other more resource intensive strategies that add variation to the experiments through different ways. So for example, genitalizability tests can add variation between experiments, systematic heterogenization strategies that in variation within an experiment and of course, multi-center designs just add variation naturally that emerge from different centers. There were several limitations and challenges in conducting this project. For one, what we expected from the exploratory studies were not very frequently met, meaning also reliability and reliability criteria but also bioavailability and those findings, studies that could inform and help the confirmatory stage to be more straightforward. Registration in vitro studies was very, very challenging into how we do this and how we talk to the groups about this. We are also working on obtaining some sort of national harmonization in Germany for animal authority permits to also facilitate and make these multi-center studies more common and more easy to conduct. Two other points that we are now currently trying to investigate is how the choices of sample sizes can have an impact on the rates of replication success depending on the replication success criteria that's used and also that these studies are usually not focused on a single primary outcome on a single model but they usually include evidence from multiple types including in vitro and various in vivo models and there is very little evidence to guide this best practice we try to establish this framework based on theoretical considerations but we believe that developing this unified framework can help do more meta research on the evidence on gathering evidence for each of these practices and then after the framework is well established and developed we need evaluation of how this had an impact to what extent and what the limitations of this framework. And yeah, thank you. Thank you so much, that was great. We have three and a half minutes for questions. So please use the microphones. Yes. We can wait for the questions from the audience. In the meantime, I think I missed how many years you've got the funding for? Four years. Four years, so you are just starting, yes? Or you've been already going for a while? Yeah, no, it started in 2020. 2020, so you are? Almost at the end. Yes. So do you think this sort of work will continue and you will get like more funding and... This is the big question. We of course applied for more funding. The project was funded for four years to try to get these proclinical projects from their conception to also after getting the results. During these past four years we had major disruptions in laboratory activities that were not so possible. So we are working on trying to get some more extension because the idea of the project was that at this point we do have some data to analyze, but we don't. So, yeah. How about the feedback? Yes, yes. The feedback has been very, very positive that they see like, oh, I've always heard about these things and we didn't really understand how we could do this or we didn't think that this was applicable to us and how we do exploratory research and how it is important to take this next step to more confirmatory frame of mind in a way to engage in these other best practices. Hi, Clarissa, Jessica Polka from ASAP IO. I think the idea of coordinating multi-center studies is really exciting. I'm curious in this environment how this regulatory hurdles you're discussing, like is the funding agency helpful? Like how is this, is there a political will to overcome these issues and what is necessary to make that happen? Yeah, I think the key challenge there is that these are dealt with by different funding agencies that the ones that found the preclinical basic research is usually not well connected to the industry requirements and yeah, we're trying to also talk to them and how other initiatives, other funders in other countries have also tried to bridge this gap and provide more industry connections to the funded preclinical researchers, but yeah, this is definitely a challenge. There is a, in Germany at least, this incentive for connecting, having industry partners in their funding calls, like as part of the project, but I've also heard of some NIH initiatives that they provide as an addition, like Kinkite contributions that they make these meetings with industry partners for the funded project so that they can understand what kind of evidence they need to bring to industry to get something back.