Clinical Data Transferability Strategies for Leveraging Evidence

Hello, and welcome, everybody. My name is Sean Smith from MedTech Leading Voice. Today, our webinar, Clinical Data Transferability, Strategies for Leveraging Cross-Regional Evidence. I'm going to turn it over to Alexia to take it from here. Thanks, everyone, for joining.

Thank you so much, Sean. Alexia Lynch here with the Acro team. I'm very happy to welcome you as well to our webinar today, hosted in conjunction with MedTech Leading Voice. and ACRA team. Indeed, we're going to be talking about clinical data transferability, which is obviously a critical challenge facing regulatory, clinical, and market access teams. Whether you're trying to justify US data for EUMDR or assess equivalence in Asian, Latin American, or Middle Eastern markets. Today's session offers tools and case studies to help you. We have 3 subject matter experts with us that I'm very happy to welcome to our session. We have Jessica Addison, Clinical Evaluation Manager with Serapedix.

Leslie Hammer-muller, one of my lovely colleagues who is Senior Consultant with the ACRA team, and Richard Halboro, Global Head, Clinical Compliance with BSI Group. Before we get started with the session itself, just a few housekeeping notes so everyone is situated with the Zoom platform for our webinar today. The session is being recorded, and you will receive an email within 24 hours with the replay and the available slides for today's session. If you would like a certificate of attendance, please put your full name and email address in the Zoom chat, not in the Q&A, in the Zoom chat, please.

You can also use the Zoom chat to interact with me or anyone else in the webinar. And please use the Q&A panel to submit your questions to the speakers. We will try to get to as many questions as we can at the end of the session, but do use the Q&A function of Zoom today to put your questions in. Right after a short presentation from Leslie, we'll have a three-question poll. That we hope that you will interact with, so that we get to know a little bit more about you and your needs with regards to this topic. I won't take more of your time, and I'll hand things over to Leslie for the beginning of our session. Thank you so much, everyone.

Thank you, Alexia, and thank you also, Sean, for organizing this webinar. Indeed, data transferability, this is the topic of today, a topic that I'm very passionate about, for those who know me. I'm very happy that we have ideal speakers, here on the call, with Jessica being from a manufacturer and Richard from a notified body, so we can be sure that we approach the topic from all angles, and let's make this a very helpful and interactive session. So, as Alexia mentioned. Please put all your questions into the Q&A panel. try to answer all of them. If that's not possible, because there are many, we will follow up with them later on.

So let's make sure that this is helpful for everyone, and let's start with a short overview and introduction before we then go into a great discussion, sharing experience from all sides of the speakers here. I'm going to share my screen now. And… I will also put in the presentation mode, and please. One of the speakers gave me a sign, if you can see it all right. Wonderful. So, you can… we've tested it, of course, but you can never rely on technique, so you always have to, yeah, make sure it works. So, we've all talked about the topic. Here is a short disclaimer. This is what I'm going to present now. It's only a brief overview, and of course, it's no legal guidance, but this is

the experience I made on this topic here, and I don't want to take a lot of time from the speakers, just going through a bit of an overview, and also maybe plant the seed for some questions in the end, things people, want to think about and want to ask everyone here on board. So what we are going to do is we will focus on clinical data that is collected outside the EU and should be used for a new submission. After all, we've got an EU notified body here, so… or a representant, of course, of this notified body. But I'm pretty sure that, if you ever have to defend data transferability from data collected elsewhere, or maybe in the EU for,

a submission in a different geographical area. On the aspects we are considering here might also be helpful for you. There are essentially two areas I want to focus on. that I think are important when you consider, data transferability. One is the regulatory, side, of the topic, looking more at, yeah, laws and guidances, and one is more patient-centered and, regarding patient factors and environmental factors directly connected with the patient. So let's not use any, more time. This, slide here… is, taken from ISO 14155, and you probably all know ISO 14…

14155, it's the ISO standard on Clinical Investigations. This… Should be representative for different kinds of clinical data. It should basically just mainly point out there are different kinds of clinical data. Already looking at clinical investigation data only shows us there are a broad range of different clinical investigation types, either pre-market and post-market, and even if you look at post-market only, different circumstances can Bring different requirements on, the clinical investigations. And then there is… are more types of clinical data. Real-world evidence comes more and more into focus nowadays. All types of those clinical data have their advantages, disadvantages, all of them, are

very important, and need to be assessed and can be considered in your clinical strategy. However. If you look at clinical investigations, this is maybe the one area that's Mostly regulated, so there are a lot of rules and guidelines, so it might make the regulatory assessment of this data type a bit easier. So, let's dive into the topic. As I said, Two areas here needs to be considered. We are starting with the regulatory data transferability. So… How would you approach this topic? How would you, Look at the data and be able to decide whether the dataset you are… you have been collecting somewhere around the world might be

also useful and can be used for your clinical evidence used for an EU submission. And there is already some, well, help and guidance directly in the EU MDR, which you can see here. It is Provision 64, and first part of Provision 64 directly speaks to clinical investigation and mentions The ISO standard I just mentioned, 4155, which is, in its 2011, version, also a harmonized standard. We've got a new one, that's a lot more advanced already, so… this is already a good step if you have clinical investigation data where you can find some guidance on the regulatory needs for a clinical investigation. If you don't have a clinical investigation, there is

also some, like, information that is helpful in this provision 64 of the UMDR in the second part, and you can see the bold part further below, which talks about the Declaration of Helsinki. So, ethical principles as such are also very well defined, and these are applicable for all kinds of clinical data, of course. Ethical conduct of Data collection is a very key concept, which is very important. There might be, of course, be further requirements, that might be helpful and, yeah, should be considered. For example, GDPR, all of this needs to be considered.

So, in looking at that in more detail, what are things you should discuss and consider when you put together your regulatory transferability rationale? There are, of course, all those pieces of information which are related to the device itself. The device itself, that sounds a bit funny at first, but, do think about different versions and variants of devices. There might be different variants or generations of a device on different markets. Was the data, I want to use, collected with the same variant, I will need for my submission later. What about the intended purpose? Is this the same, ideally, or at least

close enough. What about the indications? Let's look at the patient groups. Everything around that is very important, with, regards to the device. There are further things that should get into this discussion, which are the clinical methods and the standards that have been used for the data collection. I already mentioned ISO 14155 for the clinical investigations. Also, safety reporting is a key concept in collecting clinical data, especially in the clinical investigations. Reporting is very crucial. Look at the safety for the patients, that should be a cornerstone, and also all aspects regarding the quality of the data collected.

was, the data collected in compliance with the collection protocol? Were there deviations to the protocol? Things most people are familiar with, but, yeah, need to be considered there. Data reliability, I have already mentioned the ethics. And this will help you put together the regulatory strategy. But as I mentioned, this is only one aspect. The second aspect is then everything regarding the patient and the healthcare system. And, this is as important, as the first part, so both need to be really tied together. So where can we look for help when,

Evaluating whether the patient factors are transferable, the situation with the patient, around the patient, is comparable, so I can use the data. Now, there is ICHE5R1, This is an international guideline from the International Council for Harmonization of Clinical Da- Foreign Clinical Data, and it's actually for drug registration. Now, coming from… a bit from the pharmaceutical area myself, I have learned that while this is drugs, and drugs are different from medical devices, especially regarding conducting clinical investigations, collecting clinical data, the pharmaceutical world is

Or at least has been a bit ahead of the medical device world, maybe, already, and we can learn a lot, from the concepts that have already been billed. So, in this particular case, definitely, what's in this ICH guideline will be helpful when we look at the patient, factors. And this guideline divides the patient factors in intrinsic factors, which are more the genetics and the physiology, and extrinsic factors, which is everything coming from the environment, from culture, the healthcare system, and all that. So, these need to be considered when we, think about the data transferability, of one data set collected outside of the EU that we want to use,

for EU submissions, or manufacturers might want to use for EU submissions. So what is important in that case? There are a couple of items, which totally might make sense when you think about it. First of all, of course, there could be anatomical differences in different populations. Think of geographical areas where people are rather tall and big. In other areas, people might rather be smaller. Now, if your device is an weight-bearing implant, let's say. There might be a huge difference in biomechanical aspects, so, which might, make the transferability of data a bit harder, or even impossible, so this needs to be considered. This is not applicable for each and every device, but it needs to be discussed.

Also demographics can differ between different geographical regions, the age of date, of the patients, which may, might make, might influence everything. Also the work habits. In some areas, you have more, sedentary work, other areas, probably, people work more physically, so the, The forces on the devices might be different. Same with lifestyle habits, which is a bit similar. Then you also need to consider the spectrum of indications that you're looking at in In the different geographical areas, the standard of care, so look at the guidelines, it might or not… might not be the same. If you look at, like, first-line treatment, second-line treatment.

are patients probably treated already before and have a different state compared to another geographical region? So this can be mainly found in those guidelines. And then the healthcare systems as such can also be different. And as a last point, just to give you some food for the thought, this might even already be different in different EU member states, which makes everything just all the more complicated. So, I've already been talking way too much, and I could go on forever, I'm really sorry. Let's just… Before we open the floor for the discussion, put together a very brief checklist on what everything should think about when looking at the data transferability.

So what we mentioned are the regulatory aspects, especially, look at ISO 14155 as a guidance, look at the healthcare system and how this works, and discuss very intensely the patient factors Are they comparable, or are they not? So, this all shows us that, when someone comes to you and says, is my data transferable? The answer will always be, it depends. You will never be able to put together a template for your whole portfolio, because all the devices are different, and all the topics have to be reassessed for each device, unfortunately. At least that's not my take-home message. And…

I will close the presentation style here now, and get into the more active part. We'll start with a short poll. And I'll stop sharing. So please go ahead and… just very briefly answer these short questions, and while we are waiting on the results of the questions, which we do not necessarily discuss here, I'd like to get or dive directly into the discussion. So, let's start with one key onset from each of our lovely speakers here, to open the floor to the discussion, and maybe we'll start in the chronological order. So, Jessica, you are working at a manufacturer. You have to be active first. You have,

a data set in front of you that's not collected in the EU. What's your key message to help all the people out there in the same situation?

Yeah, so I think key kind of messaging would be, be proactive. So, if you've already got EU and non-data, or non-EU data already, you know, assess it to identify, are there any differences in outcomes in the actual data itself that could, you know, suggest that actually maybe it isn't transferable? Have you considered PMS data to identify any reactive indicators of differences, which could call into question the transferability? And overall, I'd say, if there are any differences, can they be addressed and address those as early as possible? Be sensible and pragmatic and present the data unambiguously. You know, don't try to hide it or hide away from it, kind of, you know, go for it and be proactive in addressing it.

Oh, Richard, I can see you smiling. I think that's what you definitely want to hear. Do you fully agree, or do you look at that from a an additional angle, maybe. Do you have another key highlight for you? to share.

I think what Jessica has said there is actually quite relevant, and I think what we look for as notified bodies is really for you to tell us the story, you know, the reasons why you've conducted that research outside of the EU, for example, and then why that data is still applicable to the EU population. You know, ultimately, as a job as a notified body is really to look at sufficiency of clinical data. When you think of sufficiency of clinical data, my mantra is always quality and quantity, and what really matters when we think about transferability of that data is really the quality of data that you're presenting.

And so there's things that, you know, need to be considered, and Leslie, you highlighted them really well in your presentation, you know, the intended purpose, which encompasses your indications for use. You know, we've had applications, for example, where the indications you're seeking in Europe are very different To the indications that the data was actually collected on, and that will raise lots of questions from a notified body. There's lots of concepts to think about. State of the art, Jessica mentioned there about, you know, the differences that might exist, and you had it in your presentation as well, Leslie, but the differences that exist in healthcare systems. And there's differences in state-of-the-art.

guidance or guidelines that exist for other parts of the world might not necessarily be applicable to the EU. So, really, fundamentally, what we are looking for is that quality of data, and for you to be able to tell the story to us to understand why that data is, in fact, transferable.

And I think this telling the story part is really… a fundamental principle throughout the whole clinical strategy, and maybe beyond that. So, this is always what's behind all this, isn't it? So, your clinical evaluation, as such, just needs to be M… Yep. everything needs to be tied together. It has to be… make sense. You can't, like, just put together some bits and pieces and present them, and no one will understand that. So, yeah, thank you so much. So, I think this is really essential, but let's… let's dive into that a bit deeper. Maybe to make this a bit more, tangible. Jessica, could you just share one example, one example you mentioned, where your organization collected clinical data in one geographical region, and then, you wanted to use that data, ideally for an EU submission? Is there

Something where you realized, okay, this was what made it work.

Yeah, so I think I'll kind of touch on past history when I was consulting for medical device manufacturers, so working at a consultancy that, you know, worked on projects for lots of different manufacturers, assisting with CERs, PMS, PMCF. Usually, this request would come to me, in my experience. in response to a notified body question, rather than it being a proactive, look, we're aware of this gap, can you help us address it? It was sort of, you know, we're being asked about it now, we have to address it, so can you help us? So an example where… where, you know, this was kind of successfully transferred, so we had EU and non-EU data.

It was summarized as part of the overall package. We considered potential anatomical differences, what would actually have been the worst case, which could actually, you know, cause a limitation in transferring that data. And we considered, do we actually see any differences in outcomes from non-EU populations to EU populations, based on that available, you know, clinical data package. And then also doing literature reviews. To actually identify, are there any differences, are there standard of care differences, and kind of putting the fundamental things in place. So that you can confidently say, are there differences? And then go more, you know, went more specific in analyzing the clinical data package, what was already there, to see, you know, are there any indicators that there are differences?

And… and that, in my experience, has worked. So… so yeah, I would say that would… that would be kind of a general, general example.

And I think what you've just mentioned is very important, also, according to my experience. You need to go back to literature, you need to show, that, What you're claiming, and we're back to claims which are, topic throughout all the clinical evaluation anyway, but you need to substantiate what you try, to tell. So, Go back to literature, ideally perform some systematic searches, and then you will see, whether there are differences or are not. Richard, is this also kind of.

of the funnel.

fundamentals applied, you would say, or is there anything that you would wish for in addition to that?

I think it's a good point to look at, and I think what will often happen is when you look at transferability of data, there's some fundamentals which are probably the same. So, if you look, for example, at pathophysiology of disease. pretty much across humans, it's always the same sort of pathophysiology, whether you're in Japan, Europe, or America. But what can be very influential in terms of the progress of that pathophysiology is, obviously, the age at which that disease state might take place, because of maybe there's poor living conditions, or there may not be access to healthcare for early diagnosis. So, you can get different stages. So, an example that we had quite recently, we submitted through the expert panels for a device, and

the expert panels, it was data that was coming from a Chinese population, and the expert panels, you know, had some concerns about that data that they wanted to make sure that we'd explored, and that was, well. In China, this disease state actually starts a lot earlier than it would in Europe, so suddenly we've got a differentiure of where, actually, we're going to be treating patients with this device in Europe who are a lot older than what the data actually represents. But I think what we have to try to get back to is there will always be differences in some of these extrinsic factors, for example, or intrinsic factors, as you mentioned, Leslie.

But I think what Jessica's rightly said is about looking at the scientific data that supports that. So what is not acceptable is, well, our clinician has said that this is acceptable in terms of transferable. What you need is those good scientific justifications to argue that and put that forward, and that's what we are looking for as a notified body. Of course, there will always be these aspects of, of, consideration. Where maybe you can't answer that question. But then you need to weigh up, okay, well, does this stop the conformity assessment from going ahead, or is this something that actually is more suitable to be plugged from post-market clinical follow-up, for example? Can we plug that data gap by ensuring? And that's in that example that I gave you that we've submitted to the expert panels, you know, the manufacturer had agreed to run a post-market clinical follow-up study.

in Europe to verify and confirm that, in fact, you know, even just because there is an age difference between the Chinese and the European population of where this disease state starts, then, you know, we can prove that the performance outcomes are the same. But, you know, there are obviously always things to think about, anatomical considerations, as you mentioned. those factors, you know, go without saying. We always have to think about, you know… I always quote the Netherlands. We're a Netherlands or Dutch-notified body. Apparently, they're the tallest population in the world. You know, so, you know, there are some aspects, and you mentioned this, Leslie, even between member states, you know, there will be differences in anatomical sizes, for example, that need to be considered, but everything should be done with pragmatism, of course, as well.

So… Now that you started the discussion yourself, how much do you go into detail when looking at differences, then, within European populations? So, let's say, the manufacturer has a lot of clinical data available, but they were all collected in just one single country. Would this usually be scrutinized, or in terms of pragmatism, does this go a bit far already?

Yeah, I think there's always factors we have to consider, and I think we always have to take a risk-proportionate approach to these things. So, if, for example, a manufacturer brings us a surgical instrument or a device that is perhaps, you know, 2A or 2B device, non-implantable. then there's probably a little bit more of a relaxed consideration there, in terms of something that is perhaps more patient-specific, which would be perhaps like a Class III orthopaedic implant. The scrutiny of consideration will obviously increase more with implantable devices, so we have to take that pragmatic approach.

One thing that you might be aware of is that under the new MDR, well, everyone says new, it's not really new. It's been around a while now, but under the MDR, notified bodies are required to employ clinical experts. And it's those clinical expert judgments during our assessments that they'll be thinking, okay. how… what's the considerations I need to think about? So the challenges that the manufacturer will often get are coming from a clinician's point of view, who is often a clinician working in Europe, to understand those principles. So, to answer your question precisely. It is proportionate. I think things like a diathermy unit, for example, or wound care dressing, might be actually acceptable, that we look at a certain level of comparison, maybe on the disease state, etc. But when you start to go into orthopedic implants or cardiac device implants, there could be lots more of considerations around anatomical sizes, et cetera, that will have an impact on the safety and performance of the device.

So we're back again at… it depends, it totally depends on the nature of the device, it totally depends on which Factors might… might become important for this specific device, right?

Absolutely.

let's… let's take a step back already when we, think about, what I've been showing at the beginning. We were, like, not only mentioning patient population, the comparability of patient factors, which are super important, of course, and really my… have a different weight depending on the device. What's more general is the regulatory framework and standards all around the data collection, data quality. You mentioned already, Richard, it's not only quantity, it's definitely also quantity. So, when the clinical data was collected outside of the EU, Richard, what are the first things you look at in terms for study counter, data quality, regulatory compliance? What…

And is… what happens if you… have a clinical investigation protocol in front of you that doesn't mention ISO 14155. Does this already flash a red light and makes you suspicious, or is it more a kind of, okay, maybe they just mentioned it, let's see if they followed the rules anyway?

Yeah, it's… you know, the purpose of ISO 14155 is to get that harmonization to drive the quality of data that is collected outside of the geographical region or internationally. So, when a dossier lands on the table, and it's got a clinical investigation that's been conducted outside of the EU, there's some fundamental principles that we are… we are looking at as a notified body, and you know, it's… obviously ethics consideration, right through to competent authority or government approval, again, where needed. Publication is also now mentioned in the new standard. As a new, it's 2020, it is being currently updated, but

from what we see in 2011, there's lots of things about the transparency of that data. It even talks about having an independent data safety committee, and also the level of documentation. And when you look at that, I think it's Appendix D or E that talks about that very, very long list of documentation that's required to support it. Those are fundamental in terms of being able to show that the quality of data that's been generated, and there's good quality reporting, that studies are being closed, things are being followed up, adverse events have been appropriately reported. Those are the, you know, key principles that we are focused on in terms of the quality of that data.

If we were to receive something that hadn't mentioned ISO14155, then we would, of course, look at the quality of the data that's being presented. we would probably be asking questions about, you know, how does this compare to the principles of ISO 14155? And there would be a lot more, sort of, rigorole, a lot more questions to a manufacturer if they're not citing that standard as a way of what they've complied to. So, that… that is a challenge, you know, if you're not following some good key… good clinical practice principles, which is what ISO 14155 is all about outside… when you're conducting clinical investigations outside of Europe, then be prepared, you're going to get some very difficult questions from the notified body.

we don't look at that entirety of documentation, you know, we've, you know, we look at what is key and what's important, but also, you know. what we need to answer is that sufficiency of evidence, and part of that I said earlier, is really making sure that that evidence is being collected free from bias, it's appropriately being collected in an ethical manner. And that the data has been independently verified as well. So, those are key factors that we look for. Once we can pass that stage, then we start to look at, okay, what is the meaningful nature of this data, and the transferability aspects as well.

This totally makes sense, and this kind of… addresses all the requirements, but this is also kind of the ideal work, and I'm pretty sure you don't always see everything you would like to see. So, in reality, Jessica, from your experience. How early in your clinical development planning, and let's talk about new devices now, because we all know for legacy devices, there is a lot of history, rules have been different previously, and very often you need to work backwards. officially or not, so you need to work with what you have. But for new devices, you can, like, start with all the knowledge you have.

How early in your planning do you… consider such issues like geographical data transferability, how do you… do I want to design my clinical investigation so that I probably can use it for multiple submissions in the same way? Would this then happen at the stage where you put together the clinical development plan?

It's… part of discussions, in my experience, part of the overall strategy from the very beginning, or it should be, you know, where do you want to sell the device? What do you want it to do? How do you generate the data to support that and support it adequately? Does that mean a European study? Could that mean a non-European study if the data is transferable? And I think, obviously, even for new devices, yes, certainly that, you know, that would be part of PMCF planning, you know, early on, early strategy planning, etc. But even for legacy devices. you know, for proactive PMCF for legacy devices.

you know, you're gonna do a study, is that then transferable and going to support that? Does that fulfill the needs of PMCF? How can that data be used? Etc? So, even for legacy devices as well. I would say it's also very, very relevant, and again, part of the overall strategy, you know, managing the life cycle of the device, how can we continue to support this? Is there a new issue that's come up? You know, we found a vigilance issue, some complaints coming up that are, you know, maybe signaling something there, showing you that there's possibly an issue. Could we address that with PMCF? And that would also be part of the consideration. Is it European, non-European?

This would, of course, mean that multiple departments would be involved, and you need to communicate very well, and have those structures available at your company. So, I think this is… Also, one of the key aspects that we needed to learn with the EU MDR, we're not working in our isolated silos anymore. We need our colleagues, and they need us, and we really have to talk to everyone to make the whole thing work, to be able to tell the story that Richard needs to hear. So… when… we are trying to consider this and put together everything and want to do it the right way. Richard. Could you give us some advice or insight whether there are regions or regulatory frameworks that are generally more kind of accepted or trusted?

So that we can use this data for multiple regions. And why are they… More accepted than others, maybe?

Yeah, it is a difficult question to answer, because, you know, I think… We know, in reality, that there are perhaps some concerns in certain geographies of the world about perhaps ethical considerations that might be part of data collection, and we have experience of that, where we've reviewed a clinical investigation protocol for a device where I won't go into details, but it seemed very unethical in terms of how they were trying to recruit patients into this. So again, you know, we had to stop that and say that that's not for, you know, this is not for us to be able to accept this, which puts us in a very difficult position as a notified body, because what we are looking for is, obviously, the level of evidence that is presented, and sometimes these questions go off into a tangent that

really starts to make us think about, you know, what is the role of the notified body, what is the role of the Compton Authority here in terms of these aspects? However. I think what we typically see is… is… at the moment, there seems to be an increase of studies being conducted in South America, particularly in the area of wound care. And again, that… what we see a lot of the time These regions, the reason why they're chosen is often because the speed or access to being able to get a clinical investigation initiated are actually one of the reasons why. So, for example, you know, we have a manufacturer who had a refusal. They seeked Article 6110, which is where clinical data is not required, and we had a discussion, so we probably do need clinical data.

And they said, well, we can do a… we can get a study launched within two to three weeks in South… a certain part of South America. Why? Because it means that we can speed up and get that data collection versus certain parts of the EU where the, you know, consent from certain member states, from where you're holding sites adds to delay. So, in terms of whether we have a a sort of preference of region. I think… I think to answer that probably is to say no, we don't have a preference of region, but what we will always be looking at is making sure those principles of quality of data, are, are appropriate. So, again, coming back to what I was saying earlier about, you know, compliance to standards, the consideration of independence of that data verification, but…

We will say that, you know, when you see clinical investigations conducted in parts of, say, let's say America, for example, where actually there might be a lot more transferability of that data into the, into Europe because of the factors that clinicaltrials.gov requires them to publish their clinical investigation protocols, so they're already starting to meet parts of that standard. They require FDA approval, they require, you know, ethics committee approval, etc. And all these factors, I think in that area, it seems that transferability of data, because the healthcare systems as well, are similar in the sense that

You know, we can go into the context of insurance, but the access to what is, you know, considered, what is state-of-the-art. often can be mirrored from these regions. So, if you look at what is state-of-the-art in perhaps an area with a low GDP, it will be very different to an area of where there is high GDP, in terms of what physicians are using, and that could be multiple factors as well. So, I think it would be unfair for me to say that we have a specific area that is More favored, but what we do see is that where it is easier transferability of data, it makes our job easier in order to assess that data, where there are less differences in the system, for example.

Yeah, this totally makes sense, and it seems like the assessment of the regulatory transferability might indeed be a little easier compared to all the things that go into the patient factors that we already talked about initially a bit. But you also mentioned healthcare system, which needs to be comparable, So, let's talk a bit about standard of care and the clinical practice and the influence of those systems on the data itself that… that we receive. So, How about the standard of care which might be different between different regions impact the transferability of data. Have you, Jessica, maybe

already experienced such differences that made it hard to transfer the patient data. Richard already mentioned there might be circumstances where diseases will appear in younger patients already, compared to other regions where they would Usually occur at a later age. So, in your career, have you ever… this issue?

So I don't think I have had direct experience of this, to be honest, but kind of theoretically thinking about it, obviously, again, it goes back to, you know, the fundamental foundation from the literature, can you demonstrate that there are differences in standard of care that would impact the, you know, the acceptability of transferring the data? I guess part of the consideration for differences in standard of care and, you know, procedural differences. For example, if one region clearly treats earlier than another, for example, then obviously you've got a question, is that data transferable? Could the data on patients that have more severe disease at presentation, just because treatment isn't as proactive.

could that data still be transferable? Because some patients in the EU might present with a more severe disease for another reason, you know? Just because there are differences doesn't mean it's not transferable. But I think something that comes to mind would be, again, with, you know, in terms of addressing this proactively and early, would be curious about this. If there's a question that you don't know the answer to. look, you know, look into it. If you're not sure what the answer is, or you're assuming that it will be fine, but you can't substantiate it with, you know, something to support it behind the scenes, then be curious about it and look into it, and you're gonna find the answer, kind of thing. So, and again, it always depends, right? But, yeah.

It totally always depends, and I think I'm hearing an echo now, do you…

Wow.

No, I think it's better. So maybe adding one more thing to that, which is totally in line with what you are saying, is, very often, guidelines are a helpful source to establish that. So if you compare the different guidelines from the different healthcare societies in the different regions of the world, there might be, examples where you can find that a device in one region of the world is used very often and is accepted very well, is probably used very early in treatment, whereas in another region of the world, it isn't as established yet, and is maybe not used as a first-line treatment, or maybe even more as a last resort. So, in terms of outcome comparison, of course, if you are treating

patients, like, early in the disease, your overall outcome might be a lot better than if you already have patients that are very advanced in the disease. And this is really something that, might be very, very important, in… assessing the data. What you do in a clinical evaluation is always compare yourself against the state of the art, but you need to make sure that you don't compare apples with oranges, right? So, yeah, we need to really, discuss the same issues.

On that point, Leslie, could I just… just add that I think that's really important, is to think about, you know, your user experience, because in different regions, you will have, perhaps, different experience, but also, you need to think about the clinical pathway of the patient, and Jessica said something that reminded me that it's so important to think about the actual clinical pathway, which is often reported in guidance in terms of even just, you know, if you're treating a condition, how is that diagnosed? Is those diagnosis methods still the same and appropriate to be applied? I think it's always helpful to give examples, and I always remember that we had a review here at BSI some time ago.

where a manufacturer had developed a coronary stent. And they decided to do a study in South America. And the coronary stent, for those that don't know, you have to go on to a medicinal regime, a dual antiplatelet therapy, for usually about 12 months after, and the reason for that is to make sure that you don't get clots forming on the stent, or stenosis of the stent in the first 12 months. And they did this study, and they came to us with the data, and the stent showed great signs of safety, you know, low safety, with great signs of performance. But unfortunately, what had happened was the dual antiplatelet therapy that patients were given in South America is not accessible to patients in Europe, so the data suddenly fell apart, because that stent's performance was based on the fact that patients needed, again, in guidance that came from the European Society of Cardiology, that patients need to be on dual antiplatelet therapy.

So, what we couldn't… couldn't be able to prove, or what the manufacturer couldn't prove, is that, in fact, that stent has patency at 12 months. with dual antiplatelet therapies that are available in Europe. So, when we think about these factors, they're so important to think about the care pathway, the journey, and other mitigating factors that might help to, or might be supporting the safety and performance of that device. Sorry to interject, but I thought it'd be quite important to say that point.

No, absolutely, Rich, because this underlines very well that all of the components we're talking about are so important. It's not just the regulatory aspects, it's not just the patient aspects, which might be the most evident, but the healthcare system is something that people might not be… think about, like. At first, but it can play such a crucial role, and interfere with all the outcomes so completely that it's… it might even be the most important part of the discussion in the end. So thank you very much for this example, and you're absolutely right examples are helping so much to understand the importance. Time is flying, and we could discuss another hour at least, I think, but we also want to get to a few questions from the audience. Before we do that, can I ask both of you, and I think

we'll swap the order now, because I don't want with Jessica, to have to be the first. Could you think for a second about M… common pitfalls, or the most crucial parts that you need to consider from your experience? What have you seen? Why did the transferability not work, even though it might… it could have worked? What did manufacturers overlook or forget to consider that could help everyone here in the audience to not redo the same mistake. Rich, please go ahead.

Yeah, I think the factors are that, again, it's important that you tell the story and you explore those differences. Jessica's, you know, comment of don't hide that information is really critical. Come and have a structured dialogue conversation with us, you know, if that's something that you are concerned about, have that conversation with your notified body, and say, look, we have this data, you know, we can explore our concerns with you, that's perfectly fine under structured dialogue. I think what I would also add here is that, you know, you're never going to get the perfect match, and you will get additional questions if you're using transferability of data from a notified body. That will be a fact.

But remember, you know, PMCF is really important, and I would say that, you know, if you are starting to see gaps in your data or concerns, think about what you can put into PMCF within Europe to prove and to verify that data as well. So, again, you know, sometimes gaps are too big, of course, you know, as I mentioned in some of those examples. But I think what I would say is that if the gaps are small, you know, really work with your notified body to look at how you can gather that data in the post-market phase in order to support your devices launch onto the EU market.

So I'm hearing two things here. First thing is communication is key. The notified body is not your counter, or maybe it's your counterpart, your sparring partner, maybe. You're not consulting anyone, but you're here for a discussion. And the second thing is that gaps can be bridged if they are not too big, as you say. So, if there are gaps, that doesn't necessarily mean it completely stops you from doing what you try to do. Jessica, Can you add something from a manufacturer's point of view, something that you really should consider, that your strategy doesn't fail?

In addition to that. Yeah, so I was gonna say, I like Rich, that you said, you know, come and talk to us, because I think that's something that isn't always a given kind of thing, you know, that sort of we're on two different sides of this, and you know, you don't want to show your cards or something, but I think, obviously, it's good that we're all trying to drive towards the same goal of making sure there's a lot of good devices available, they're safe, the performance, you know, as we believe they should. And that they're available for European patients, you know, from a kind of, you know, manufacturer professional perspective, and also a patient perspective. We want devices to be available, if anything, you know, if we need them. So, I think in terms of, again, would kind of just reiterate, you know, be open, tell the story unambiguously, be curious if there are gaps or questions you don't know the answer to, then look into it before you are asked the

question, and then all of a sudden there's all this pressure to address that question, potentially a time limit to address the question, you know, kind of try and address it early before you push to address it, and then there's other limitations on… on time, how you can bridge the gap. You know, be aware of the gaps and address them as soon as you possibly can.

And again, this is so important, because after all, the manufacturer, is the expert in his home. device. So, this is the group of people who know the device best, and who know the background, and who understand what is really important. Of course, there are sometimes questions that need to be asked, nobody's perfect, But yeah, I think, correct me if I'm wrong, Richard, but the notified body does respect the knowledge of the manufacturer, and this is why the manufacturer needs to tell the story well, So that it's really well understandable. Thank you so much. So, let's take a glance into the future, and I think we have

touched this topic already. For everyone who's on the audience now, here. If you start a new device now, you're putting together your clinical investigation program, you already said, Jessica, all the departments need to work together early on. PMCF is an important part that needs to be considered. Not everything can be addressed until submission, and not everything has to be addressed before submission, obviously. What else is there that you could give us a very, very quick feedback, to every manufacturer to think about?

Yeah, so I would say, again, consider as part of the overall strategy from the very beginning, look at the big picture, if it's on a legacy device, what do you already have available? Have you already addressed, you know, transferability of data from a population that you're looking at maybe doing a study in that area, and then, you know, that gap's already covered, or is it a new area you haven't done a study in before? Yeah, and just… like I say, proactive, early, tell the story really clearly, just lay it out, address the gaps when they come up.

Yeah, don't, don't hide from it. And I think it's even more important for the larger the company gets, because very often, then, the company will address multiple markets. So, of course, we've been talking a lot about transferring data collected elsewhere to, like, EU population, and think about an EU popula, EU submission, but actually. This also works the other way around, so there are other regions where manufacturers want to sell their devices, and there are other areas in this world that ask for clinical data the same way as the EU does. So, maybe you have collected your clinical data in the EU very well, and everything's set and fine here, but you also want to, for example, sell in the US, and don't invest

the whole… money again to do… and time, of course, to do the whole clinical investigation. I think it was also very helpful what you said, Richard. Think about The time it takes until studies start, so, there is just a difference in different regions in the world with the startup time, from putting together all the clinical investigation documentation until receiving ethics and authority approval, and time is money. That's just what it is. And, Yeah, we only have 5 minutes left, but I think we also want to look a bit at questions from the audience, and I'm pretty sure there are some.

Indeed, we do have some questions from the audience. A number of them actually were replied to along the conversation, so I won't get into those, but if our participants have more questions for us, we'll see what we can do post-session as well, as we won't have time to take them all, but we'll do our best to take at least a few. So, first, I wanted to ask a question from an anonymous attendee who, is simply saying, for data from global clinical studies, so EU plus non-EU, is there a minimum threshold required for percentage of EU-specific data collection?

No, the reality is there is no requirement in that, but again, you know, if you have a higher percentage of… if you're applying to the EU and you have a higher percentage of EU data, you're going to have probably less questions from a notified body on the transferability of that data. There are some standards that talk about numbers and quantities, but again, you know, it really does come back to the differences that might exist between those two those two data sets as well, or two regions, because again, if you're using, you know, small volumes from the EU, and you're looking to launch in the EU,

you've just got to prove that case and prove that argument that, in fact, that device does, you know, meet its intended purpose for EU patients.

Perfect, thank you. Can data be transferable from foreign health registries for real-world evidence to include an EUPMCF activity? This was somewhat touched upon, but can we explore that a bit further, perhaps?

Yeah, I think what I would say is that, you know, the whole point of PMCF is to prove that your device does, in fact, you know, support the EU population. you know, again, registries that sit outside of the EU should be forming part of your post-market surveillance activities anyway under Annex 3, so you should be looking at all your global data and considering risks, etc. What I would say is that for registries, certainly the European expert panels, when we submit an opinion, have said to us, you know, that we need to make sure that these devices are registered in European registries to reflect European practice or European patients, but it can be complementary data if you also have that supplementary data coming from other registries.

Perfect, thank you so much. One that I feel like I should address, even though it might be tricky, because we have no IVD-specific expert here in our session, but we do have an attendee who is asking if most of what we've said here in the webinar today can also be applicable to the IVD world.

I think, again, not an IVD expert, but the principles apply, you know? If you're using a device here in Europe as an IVD, you know, what disease… you know, the fact that the diseases that you might be detecting could be very different on prevalence, etc. So there might even be more of a need to be able to collect, you know, if you take Ebola, for example, not really a disease that we have concern here in Europe, but in Africa, it's a huge, huge problem. So again, you know, naturally, you might be led to actually get data for your device from those regions, and that might… but again, I think the same principles apply of consider the differences that are happening in the EU, but tell the story to your notified body as well as to why you've done that. I don't know if Jessica or Leslie, sorry, I'm taking the…

Take in a lot of these questions, but please interject.

Jessica, do you have anything to add to that? I'm… I don't know if you have experience.

You don't. You don't.

Okay.

But no, I think that all, that all tracks, and obviously, yeah…

The answer would be, in principle, yes.

I like it.

I think the reason why you can say definitely, most likely yes, is that most of our argumentation isn't even based on the EU MDR itself only. We're talking about general principles here, which would apply to IVDs and for medical devices. Agreed. So, yeah, absolutely.

In the one minute that we have left, I'm going to make you all ramble once more and repeat a bit of what has already been said, perhaps in a very condensed and concise way. We have a question looking at how is the heterogeneity within the European population, health systems, and standard of care assessed? there is diversity within Europe, not just outside of the EU, so how is that managed? So we did touch on that throughout the discussion a bit, but perhaps just two quick, more cents on the topic before we close.

Yeah, I was gonna, you know, when thinking about this before, I think it is an important point that, obviously, data from the EU isn't just going to include patients of EU origin, so in my opinion, in that aspect, it's gonna be more, you know, there's gonna be more of a focus on the healthcare system, how, you know, rather than… you're not always going to know what anatomical differences exist in that data set, potentially. So it's going to be more of a heavy focus on the, you know, the healthcare system, the standard of care, the patient pathway, etc, because that's what you have to go on. So that would be my kind of thoughts on that.

And for me, if you do a good, adequate, state-of-the-art assessment, then you'll get that data and that understanding of what is happening across Europe, if you do that well enough. And those principles then should still apply, and consideration be given, because what state of the art is, is, you know, what is current acceptable in terms of medicine and technology, and that is being reported. And again, as Leslie said, clinical guidance from parties, sorry, from medical societies is also very helpful, because European Society of Cardiology gives guidance for Europe, including the UK, it's not European Union as well.

And Leslie, anything to add?

No, I think everything was well said already. Just can, agree on that.

Perfect. Well, that concludes our session today, and thank you so much for all of the questions that we got from the participating audience. Thank you, as well, of course. to the three of you. Richard, I'll go with gentlemen first, as we did a lot of… ladies first, with Jessica answering a lot of the questions first right there. But thank you so much, Rich, for taking the time for this session with us today. Jessica as well, thank you. Leslie, of course, thank you for walking us through the details and the complexity of the topic with our speakers. And thank you so much, Sean. and the team at MLV for partnering with us to host this insightful session. We do hope that everyone took away some good content. We are getting thumbs up and applause. That is, of course, very appreciated. And we hope to see you soon in our further sessions.

Thank you all. Thank you for your time.

Thank you so much, goodbye, everybody.

Everyone. Thank you.