How are GMO Regulations Impacting Clinical Development in Europe?

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Hello, and a warm welcome to the latest edition of Conversations in Drug Development, brought to you by the team at Boyds. This podcast is for our fellow community of scientists and clinicians working in the wonderful world of cell and gene therapy and drug development. Thank you for tuning in, and we hope you enjoy the conversation. Music.

Hello, and welcome to another installment of Conversations in Drug Development. My name's Harriet Edwards. I'm part of the Regulatory Affairs team here at Boyds and your podcast host for today's episode. I'm really, really happy to be able to introduce you to today's guest speaker, Dr. Sabine Ruler, and she's also part of our regulatory team here at Boyds.

Today's episode, as I'm sure you can guess from our introductions, is a regulatory-focused one, and we're going to be specifically talking about the topic of genetically modified organisms, mechanisms looking at clinical development in particular and also focusing on the territory of Europe because there are some very interesting and unique challenges with this particular territory. So Sabine, welcome to the podcast. Thank you very much for having me and I'm really excited to be here.

It's a topic I'm really passionate about actually so yeah quite glad to be in the discussion. And we're very lucky to have you because you are absolutely our resident expert within this topic so our listeners are in for a real treat today. Without further ado then Let's get into it and start at the beginning because this is even a tricky question to answer, I think. But how are GMOs defined with regards to clinical development and specifically with medicines in mind?

GMOs are defined in the legislation as an organism with the exception of human beings in which the genetic material has been altered in a way that does not occur naturally by mating and or natural recombination. And it's quite a general definition, which isn't specific to medicines, actually. And it was written with genetically modified crops in mind when the directive was put together. So, yeah, that's how difficult it is to apply to medicines in the first place.

And it is also quite vague. So it says in a way that does not occur naturally, which means that you need further definition, which is then provided in the annexes to the directives, which specifies which techniques can be used to actually make the GMO be a GMO under this definition. However, we also need to keep in mind that the definition was written in 2001. And since then, the technology obviously has moved quite a bit. Yeah, absolutely.

I mean, I can certainly think of many things that have changed. I think it's fair to say that we've undergone a paradigm shift, actually, in the way that we deliver medicines and healthcare since 2001. And when we think about advanced therapies as a whole, but then we talk about even newer and novel techniques such as genome editing, which I know we'll talk about later, that didn't even exist in 2001.

So we have a completely generic definition that's not actually defined with regards to medicines. And then it's completely out of date as well. So perhaps not the most applicable today as it was then, even if it was at all.

But sort of thinking about picking up on advanced therapies specifically, because I know there are lots of questions around GMOs and advanced therapies. Are all advanced therapies genetically modified and vice versa? Are all GMOs advanced therapies? Or is there some confusion around that? Because I know that's a question that crops up a lot. Yeah, there actually is lots of confusion.

So the short answer is that many advanced therapy medicinal products, especially gene therapies, do meet the definition of a genetically modified organism. And the first one to recognize here is that you actually need to have an organism involved, so like a virus or a bacterium. Otherwise, you wouldn't be able to meet the definition. And then the second part is the techniques through which the genetic modification can occur.

So we, for example, had a case where exactly the same drug product was made through different techniques. Originally, it was manufactured with a method that didn't fall under the genetic modification definition. And then they changed how it was manufactured with a newer method that actually met the definition. And although it was exactly the same product, it all of a sudden became a GMO. So that was quite interesting. Oh, gosh. Yeah.

So generally, a lot of the in vivo gene therapy products or most of them actually, such as adeno-associated viruses or other viruses or bacteria, whose genetic material is modified to, for example, deliver a missing or deficient gene to a patient. For example, Luxturna would fall under the definition.

Or also lots of cell-based gene therapies where patient or donor cells are genetically modified or reprogrammed by a viral vector, maybe a retro or lentivirus outside of the body and then re-infused. These would all meet the definitions of a GMO. And then also viral vector vaccines would also meet the definition of a GMO. But please note that these are not actually advanced therapy medicinal products by definition. So we already start at the beginning of this podcast with lots of nuances.

There's no hard and fast rule that people can apply with regards to making easy decisions on definitions.

So it's fair to say that the investigational products that do fall under the category of a GMO, they are a special regulatory case, right? Right. Yes, yeah, indeed. So clinical trials with genetically modified organism medicines are, of course, subject to the standard review. So you have a clinical trial review by the competent authority in the ethics committee. But in addition, you also have an assessment and approval process under the relevant GMO legislation.

Okay. And thinking about legislation, what do you mean exactly in terms of legislation? What exists for GMOs?

So yeah, it's brought on purpose because there are actually two different directives. The first one is the deliberate release directive from 2001-18. And then you also have the contained use directive from 2009-41 EC. So that's a little bit newer. But the main thing is these had different intentions when they were put into place. So the deliberate release kind of think about genetically modified crops out on a field, whereas contained use do things like genetically modified bacterium in a lab.

So these two are the ones which are applicable to GMO medicines. Okay, interesting. And then you mentioned that these are directives. And we know that EU directives are subject to somewhat interpretation at country level. So each member state can kind of take that directive and interpret it in their own way to some extent. Are there any differences or complexities that we know about due to that national interpretation? Because that's always a challenge in Europe, not just for GMOs,

I know. But are there any that you can note? Yeah, absolutely. So the application requirements and also administrative processes differ significantly between member states. And there are actually several layers of complexity. The first one being the classification. So we just mentioned the two directives.

Deliberate release and contained use and depending on the member state clinical studies may need to be conducted under contained use or they may fall under deliberate release or actually both of the framework in some countries.

So it's not as simple as simply going into one bucket or another there could be a whole mixture depending on the the countries that you select but as you said even both frameworks applying so what is that decision based on and as we said is it the same per product or per clinical trial or does it not matter it's irrelevant it's different per country.

Yeah, so it's quite tricky. So while the administration of a genetically modified organism medicine can be either or would possibly fit both frameworks, I think what we have to keep in mind that it was originally intended to treat a patient, not to be released or contained either way. So it's not always clear how well a GMO is actually contained in a patient because you give it to the patient to treat them. And then there might be something which we call shedding.

So after you administer, for example, a viral vector, it could be shed by the patient again. So think about an ocular gene therapy. It might come back out of the patient in tear fluid.

Fluid or if you if you think another route of administration like a systemic route of administration you could have shedding in other bodily fluids or excretions sorry it's a bit gross but yeah it's a good point to raise yeah what we need to think about and then the level and duration of that shedding do play a role for example if the shedding takes longer than a potential hospital stay for gene therapy for example then that would make it a deliberate release in

some countries other countries have a slightly different stance so you if you look at biological containment, which is used in some countries. You have, for example, if your virus is replication deficient and can't infect any other organisms or any animals spread to the environment, then that would actually not even fall under a deliberate release in some countries, despite the maybe shedding from the patient.

Okay. And in terms of whether genetically modified medicine fits into the framework of contained use or deliberate release or both both in some cases. Does that actually change how the clinical trial is conducted? Or is this sort of a paperwork exercise, a framework to fit in to get your application approved to then be able to initiate the clinical trial?

Or are there some distinct differences with, say, precautions that you have to take or handling measures depending on which framework the genetically modified medicine will fit in? No, not really. So from a product handling perspective, there are not actually big differences between contained use and deliberate release. So just because you have your trial approved under deliberate release doesn't mean you can pour any leftover vector down the drain once you're done.

So that's not what this means. Actually, it still is the case under both frameworks that waste disposal and precautionary measures like for the trial personnel or sometimes even patient close contacts, They depend on the actual risk that might be posed, which is what you assess under the framework, but they don't really differ between contained use or deliberate release. Okay, that makes sense. And I guess relatively pragmatic in a sea of difficult paperwork to navigate through.

So that's good to know that at the trial, it's pretty much the same across the board. So anyone that is thinking of doing multiple clinical trials across many different member states that maybe fall into different frameworks within this GMO legislation, actually the running of the clinical trial should largely be the same, which is good to know. So coming back to the complexities, you mentioned that there were several.

We've just talked about one, which was the GMO classification. What else exists in terms of complexities? Yeah, so the other ones are definitely application process and also review of the application.

So while the core of each GMO application is a risk assessment as per the applicable legislation there are differences in the responsible agency or agencies even it can be multiple for one submission in one country even the submission requirements they may differ and the review timelines as well and that not only depends on contained use or deliberate release but it goes so far that it may even depend on the activity class of a GMO.

Okay, so we've just talked about classification of GMO in terms of the framework that it fits under, so deliberate release or contained use.

But what do you mean activity classification? That's something else, isn't it? So what do you mean by that? So GMOs are also classified as part of their risk assessment in different risk groups, the so-called activity classes, which are then assigned a containment level. And that runs from no or negligible risk up to a very high risk, so from one to four.

Most GMOs fall under GMO medicines that is fall under no or low risk so risk group one one or two and then some countries have a risk group specific procedure or timelines for example in Italy they use a process based on the risk group.

Okay so what I'm hearing so far is that it's really important to know the process that applies to your country and to your product as well because it sounds as though it's quite difficult to navigate and having the heads up on exactly what applies to you with regards to your or genetically modified medicine for clinical development, it would be useful to know that process before you start. Yeah, definitely. So to navigate it halfway smoothly, it's very important to kind of know your way around.

What we tend to do if we work in countries that we don't know the process yet is do like a thorough GMO feasibility. Where we look at the countries and not just the countries actually, but even at site level, because it makes a massive difference if If you work with a site that has GMO experience versus with a site that doesn't, they don't have all the standard operating procedures in place. You need to train the staff. So, yeah, it just makes a big difference in terms of startup timelines.

And then the other thing, which is also really important, is to stay up to date because we see quite frequent changes of the local GMO processes. Okay. Yeah, definitely. And then just to throw a couple of others in the mix. So there are also potential publication obligations or public consultations.

Consultation so for example one country actually makes you publish your upcoming gmo deliberate release in a in a national newspaper yeah definitely and then there are also language requirements to think about so some countries actually want the whole dossier in local language which you then have additional timelines to account for gosh so i think there's a common theme that seems to be appearing here with gmos and i'm looking at you sabine and i know you're You're kind of smiling really

because complex is maybe a little bit too dilute of a word to talk about GMOs and navigating the clinical development phase. But it seems to be the most fitting that I can think of right now. It sounds quite complex, this process. Yeah, it can be. And also it does come with quite a high administrative burden, which then, as already mentioned, can make clinical startup timelines longer, which can be a problem.

And the products we are talking about are very often novel products, kind of out-of-the-boxy advanced therapies or viral vector-based vaccines. So we are in the rare disease space or working with IMPs that target an unmet medical need, where startup timelines are quite critical. And while thinking about this, it's not just Europe. Also outside of Europe, you have obviously obligations to make sure that everything is safe from an environmental perspective.

But yeah, I think sometimes it's a bit tricky working in Europe. And we're kind of looking at a couple of improvements hopefully coming up very soon or already being implemented. Yeah, and I guess the unique challenge with Europe that maybe other territories don't have is this lack of harmonisation aspect. So we saw this, it's not just GMOs that are subject to this.

I mean, clinical trials for all medicines were suffering the same issue of lack of harmonisation when there was a directive in place, which is now starting to get more streamlined and more harmonised under the clinical trial regulation. Regulation but how do GMO-IMPs, so investigational products, are going into clinical trials? How do they fit into the clinical trials regulation?

So the short answer is unfortunately they don't. So the environmental aspects of GMO-IMPs are currently outside of the scope of the CTR and you still have completely separate applications that are required. Okay and is that still Still true, even where there have been cases previously under the Clinical Trials Directive where there was actually a combined submission for your clinical trials application and your GMO submission as well.

Is that still the case under CTR? Yeah, so these countries actually had to revise their process as the portal for submissions under CGR. The CTIS portal can't be used for GMO submissions. So, for example, Germany had to tease their process back apart. And this has been flagged by many stakeholders. And hopefully there are future updates on the horizon to fix this. Okay, well, fingers crossed.

And I guess that's maybe a good point to raise the looming EU pharmaceutical legislation reform that's about to happen that is in process. Is there anything in there that hints towards making GMO applications a little bit more smoother or more streamlined, maybe? Yeah, definitely. So in the proposal that the EC has adopted, there are lots of aspects that help from a GMO perspective, while some of the other improvements are being a little bit more arguable.

Probably nothing we want to go into detail in now. Maybe a topic for another day. Yeah, definitely. So in terms of GMO medicines, there are some really good improvements on the horizon where the process could be modified to remove fragmented national requirements and also include the GMO risk assessment into the clinical trial application. So something to hopefully look forward to. And I know...

You've written a little bit about that. So if people want maybe more information, they can they can head over to our website and find some blogs and useful information as well. But obviously, the pharma legislation reform, that's not in the near future, that's going to be a long term project. Are there any other short term sort of novel developments, anything streamlining that we can look to plug the gap in the short term? Yeah, absolutely.

So there have been quite some improvements at both European and national level already.

So on the European level, the common application forms for common low-risk product types, for example, I don't know, associated viruses or genetically modified cells have been put into place. And the good thing about these is you can use the same form or an application under contained use and deliberate release. So you just have one set of documents and they only focus on the specific considerations for these product types.

Well, lots of aspects of a full risk assessment don't really apply to each of the products. And although the implementation was quite slow at the beginning, although countries had endorsed them, they still wanted their original dossier in addition. they now accept them pretty much to replace the original dossier. And there's like a move towards this, which is quite good. Yeah, definitely. And then on national level, we also see that countries are streamlining their processes and.

Some countries do, that is. One of my favorite examples are the Netherlands, who had one of the clunkiest processes at the beginning, and they have turned this around completely to the point that they even allow platform applications where you use the common application form and then the site can get a platform permit which covers multiple trials with the same product type if they get this approved. Oh, so that's a really positive, actually, really positive benefit and improvement.

On the topic of positive improvements and things like that, I'm just throwing a complete curveball in here and going back to what we talked about earlier of the genome editing technologies that are going to throw a spanner in the works. I think it's fair to say to all of these improvements, because they're difficult to classify anyway. We don't have a separate definition for genome edited technologies in Europe yet.

It falls under the definition of gene therapies, even though they're very different to that. Something that I will definitely come and talk about another day. It's an area that we're certainly looking into much more. But in the context of GMOs, Sabine, how on earth do these gene edited technologies such as CRISPR or other technologies that people may have heard of, they're brand new. So how do they fit in to GMO applications, legislations and clinical trials?

So that had quite a big question mark in the beginning. So according to the 2001 definition that we talked about earlier, they are not actually formally considered because they don't fit the traditional methods which are covered here.

So that was kind of difficult to start with. But then there was a European Court of Justice ruling in 2018, which said that gene editing techniques are covered by the GMO directive as they do alter the genetic material in an organism in a way that doesn't occur naturally. And that then has kind of been taken further in the Horizon Scanning Report on genome editing in 2020, which states that some genome editing products are subject to GMO regulations and requirements.

And that's actually also what we see in practice. is so if we if we talk with regulators about does that actually fall under the definition do you want to see an application then that's what we see in some countries yes indeed and as i said i think that definitely will end up being a topic for another day because genome edited technologies are a fascinating thing in themselves and the rate of development in terms of legislation and development of these products full

stop but the legislation is trying to catch up with that so So I'm sure the next time we speak about GMOs, there'll be even more developments about genome edited technologies and how they fit in as well. Sabine, we've covered absolutely loads already. And I'm just wondering whether there are any other sort of considerations with GMOs. We've focused specifically on clinical development and clinical development within the EU.

But do you have any other thoughts or comments around anything else GMO related? Yeah, so I mean, obviously, this doesn't stop in Europe. It's not a European specific thing, but there is a global landscape to consider. So other countries have similar applications procedures, but they do differ quite significant between regions. And also some countries have quite a different approach to things. So that's, I think, something to look into maybe another time.

And then in addition, it also doesn't stop at clinical trials, obviously, but you also need to consider what the requirements are at licensing stage. And there still is a risk assessment for GMO specific portion is needed at the licensing stage. Okay, that's really good to mention as well, because as you said, this often people think of applications as paperwork exercises and hurdles to get through in order to do the next task within your drug development.

But actually, we need to think about safety and efficacy of the product to patients. But when we think about GMOs as well, we also need to think about the potential risks to everybody else that the GMO may come into contact with. So really important to note that this doesn't actually just stop at clinical development. And I think within the time constraints that we have today, it's a shame we can't go into that a little bit further.

But certainly, we would love to welcome you back on another podcast another day to delve into some of maybe those developments beyond the clinic and into licensure and of course the global differences as well because as you said most people are looking at global development programs these days and GMOs are not just an EU specific thing so definitely watch this space for an episode coming up on GMOs later on but to summarize there's been an awful lot

of information that you've provided I'm sure everybody will agree it's been really fascinating and a very valuable reference point for anybody that's looking into developing GMO medicines in the future. Certainly listen to this podcast for a starting point. But Sabine, can you just summarise the key points that you wanted to get across today within this podcast? Because I know we've covered an awful lot.

Yeah, sure. So under the current framework, I think the most important bit is know how to navigate it, plan, be prepared, know your product, understand it well enough so you can actually navigate the systems well.

And then in the future, while it's important that novel and innovative products are safe from an environmental perspective, obviously, I'm quite looking forward to reducing some of the duplicative oversight, which seems to be on the horizon and moving towards a more risk proportionate approach, especially for low risk products for which a lot of experience exists by now.

And I mean, ultimately, hopefully, that will then support clinical trial startup timelines for GMO products to be more competitive in Europe again, which ultimately expedites patient access, which is the thing which matters most, really. Absolutely. And that's actually a really nice way to end the podcast today.

Everything that we do and all of the work that we put in to to go through drug development not just clinical but from the beginning that research all the way to the point of getting a medicine to market it's all to benefit patients that need it so a really nice way to end the podcast sabine it's been really fascinating having you on the podcast today really enjoyable and i'm sure everybody listening in will will agree um we'd really love to welcome

you back sometime soon so thank you for being on the podcast. Thank you so much for having me. Music. Thank you for listening to Conversations in Drug Development, the podcast series brought to you by the team at Boyds. Don't forget to follow us on the usual podcast platforms or visit our website to ensure you don't miss out on any. Music.