EU Orphan Devices Understanding the Regulatory Pathway and Clinical Evidence Requirements

Hello, everyone! I'm Sean Smith from Medtech, leading voice. And I'm excited about today's webinar eorphin devices, understanding the regulatory pathway and clinical evidence requirements. This event is brought to you by Accra team. Our speakers today are Matthias Fink, Senior clinical consultant at Acro team, Gavin Quigley, senior internal clinician in neurosurgery at BSI and Nebosha Nebo. Clinical Investigations assessor at Bas. This session will be recorded. A couple housekeeping announcements. The recording will be available to all attendees tomorrow. Please use the Q. And a function for submitting any questions that you may have. We'll try to get to them. During the discussion part of the call

attendance certificates will be available if you put your name as you would like it to appear on the certificate along with your email address in the chat, so use the chat for corresponding with me, and use the Q. And a. For corresponding with the speakers. The recording and slides will be available tomorrow there'd be a short poll about 10 or 15 min into the survey to get some information from you and yeah. And in case you didn't see the new publication Eumdr insider from Acro team during the waiting period. There's a message about it in the chat right now, along with a big announcement that we're gonna be launching the Mlv. 100 this week. 100

medtech professionals worth following on Linkedin this year. Which is exciting. So without further ado, I'm going to turn it over to Matthias to get us started.

Okay, thanks, John. And yeah. Good morning. Good afternoon. Evening. Depending where you're where you're joining us today. I hope everyone can see my screen. Maybe, John, give me a quick thumbs up if you can see my screen. Okay. how about now? Okay, great thanks. Yeah. I said, we have a very interesting topic for this 1 h. Webinar today is, Sean just announced for 2 very highly competent and interesting co-panelists. Later on, I'm going to start with a brief let's say, maybe, Max, 15 min quick introduction on today's subject, which are often medical devices, how they're going to be reviewed, regulatory and clinically in Europe, especially focusing on the

Latest Ncg. Document that was published last year, and afterwards we have a probably 35, 40 min time for a panel discussion. Taking questions from the audience. So, as you already mentioned as a Q&A you can put in any questions and we try to address as much questions as possible, and without further ado. gonna start right away. As I the usual disclaimer. So. But that's why we have a neighbor and Gavin here from the let's say, regulatory side, from the authority and from the from modified body. BSI, so they're probably able to address the questions more definite than than I do as a consultant. So why? Why we haven't having this? Why was saving this discussion about the Mdr. Is in place now for 4 years. So why, in 2024, they now decide. Okay, we need an Md document on that. And if you if you look at these, I mean

this is an ongoing discussion now, and it's really something that is apparently a problem that wasn't really there of the Mdd. I'm a physician by training. I cannot remember, during my 7 years of a clinical career, really discussing any shortage of devices and whatnot, but it looks like it's becoming a big big problem also in the media. And this comes from a a webinar of a core Md initiative from end of 23, and they said, and especially in pediatric cardiology. If you remember the previous slides, it was also coming from the European Cardiologic Society. Apparently there's a big issue right now with these type of catheters and and other devices specifically used in pediatric cardiology. And this is driving a lot of this discussion that at the end lead to this often device definition. So it looks like we have a shortage of devices. A lot of manufacturers have removed their devices with low sales numbers because they use for, let's say, niche indications for that reason. And there's currently clearly is a problem.

That certain patients with very rare indications, cannot be treated sufficiently in Europe. Hence we have this whole discussion. So, looking at other countries, as I said, under the Mdd. Or Amdd. It didn't look like it was a real problem in Europe. The Us. For example, the FDA has this humanitarian device extension program, which is similar than what we have now with this awesome program here in Europe. They have a similar definition. And this program runs since the beginning of the nineties. But if you look at this is data from 21, they only approved 78 devices in over 30 years on this program. So it's not really something that we're probably gonna see very often. As I said, it's a it's a rare disease. It's rare indications.

Australia, for example, allows the use of data? which is not approved for certain indications. So basically allow the off label use. Japan has a similar program than the Us with the FDA, but they only approved 22 devices in over 30 years. So they have less than one device per year in Japan that falls on this definition. And what does the European Union do as that? We got this Ndtg document published last year? In my opinion it's 1 of the best Mdgs we have seen so far. It's quite clear what it still leaves. Yeah, some a room for questions, interpretations. And we're trying to trying to dissect this a little bit. I'm not going to go into all the details is really like a high level introduction. But this, Mcg.

it's quite detailed. It has 3 parts. One talks about the clinical evaluation, because, as you can see, as you know, clinical data is always the relevant topic under the Mdr. It talks about procedural aspects. Now that probably more addresses notified bodies and even expert panels if they got involved, and it has really some pretty good appendices that provide some examples. Some templates that manufacturer can use if they are considering an often devices submission. So what defines an orphan device? There's a clear definition in this Ndcg document. And this is like it should be less than 12,000 individuals per year in the European Union that get affected by this disease. So it's not like, okay. The manufacturer says, we only plan to sell 11,500 devices per year. So we have an orphan status. It's how many patients

got diagnosed or treated with the specific rare condition per year in in the EU well, and this number is extrapolated from the Fda definition of of rare diseases. And then basically up calculated to the European number of population. And this is this is criteria number one that has always to be met, and there are 2 additional criterias. either one. There is right now insufficient available treatment options for these patients or the new, often device. And this is also, of course, targeting, let's say, innovative. Devices for the European market that the expected benefit for the new device. It's a higher, or it's better than the benefit of the currently available treatment option. So it's not just a number of devices that clearly have to show. Okay, there's a real benefit.

regarding the outcome of a treatment, either better performance or lower side effects. For the patients. So big question, how do I determine if I got 12,000 patients per year. So when I prepared for this webinar, I said, Okay, I do what everyone does these days. I looked at. I asked jet Gpt, talking about these pediatric interventional procedures and jet. Gpt said, Okay, it's between 10 to 15,000 catheter based interventions for pediatrics per year. Great 10,000 would be fine. 15,000 would be too high for the often device definition. So we have to look elsewhere, of course, and pretty sure Gavin will agree that an audit board is not only accepting jet Gpt as the substantiation, so we have to look a little bit more in detail. Yeah, look at registries.

the epidemiologic databases. There are a lot of publications that talk about incidents. Maybe in certain countries, in certain regions that can be extrapolated. I mean, you do not need to have a hard proof number of this 12,000. There are a couple of different data sources you can use to get this as long as you need to justify that. And it's a comprehensive justification while you come to this. And if it's 12,050. I'm pretty sure they're not going to deny this is this is not possible. There are no data bases in Europe that gives the exact number of cases per year per disease. So we always have to be a little bit flexible. But there are a lot of data. So then it takes a little bit of homework, of course, to come to this justification.

and then, of course, it's highly recommended. Also, in the guidance document. Get this clarification upfront. So not do not put everything together, and then submit to the notified body and say, I have an orphan device. Get that clarification. Either get in dialogue with your notified body. Then the G also clearly recommends, okay, talk to the expert panel the expert panel. The role of the expert panel could be that they could basically confirm your often device status upfront. Of course. what clinical data. And this is the big big question. I mean, this Mdcg document clearly allows for the clinical data of lower quality and quantity compared to the

this is what we would expect for a normal. Undr submission. But then the question is, what is lower quality and quantity? It's a little bit like this. When the Ndr was published and said, okay, you have to have sufficient kidding me data. No one really knew what is sufficient clinical data. It's always a little bit of a case by case decision, probably the same over here. So you have to look at the data. Is there other even non-clinical data you're able to use? And these are some examples that are coming from the Mdcg. I already said. It's quite a useful a guidance document. So certainly some laboratory and animal testing. I mean you can never replace clinical data fully with animal data, but you might have a higher weight compared to, let's say, non-offen devices similar to testing in silico. This is a field that's becoming more and more important. You can replace certain animal and even maybe a limited number of patient studies with these models.

Look at data from similar devices. So if they are similar devices and also similar devices could mean okay, maybe for similar conditions of use. But maybe if the device already approved for a non, often indication, you might use the data. Yeah. Ncg, explicitly allows use data from similar devices, even if they're not equivalent. Look at the state of the art, especially for the technology. As of that, like for the determination of the status. Look at the data that's out there. Look at any possible data sets. That you might be able to use. And also said, okay, any other relevant data, including humans which does not qualify as Mdr clinical data. So it is quite flexible. But of course, as I said, the previous slide, get in contact with your notified body quite early, and probably try to understand and get the

an output from them, what they would consider as qualified data that you're able to use, because that could be sometimes that not all notified bodies might have the same expectation on that. Of course, there's always limitations in clinical data, but you still need to ensure you have to follow ethical scientific standards. You cannot just say, oh, we found something here, and I don't know whatever a journal, and they didn't even say it's a study. They didn't say anything was followed like Gcp. Declaration housing key. Make sure it still has valid, ethical and the current scientific standards. Yeah, it depends, of course, the less you produce right now, and clinical data in the pre or for the submission. Yeah, you always need some. As you can see the last point, you need to always have a Pmcf. And the proper lower the quality and quantity of the data as you're able to submit in in initially, probably the more you need to put up in the Pmcf, yeah.

but I mean, it's still possible. A lot of these rare cases already. See this are treated in specific centers and not at various little hospitals. So it might be that if you go to a country like Germany or Austria or whatnot, that only a handful of specialized hospitals might treat this very rare indication. So you might be able to get some data out of there. Some of them even have like registries, because they monitor these patients because usually for certain, for a lot of reasons. There are not that many treatment options available. You might be to assimilate data you're having already. as I said it might be feasible to use data from from another like a common indication to transfer them to this pediatric indication, or it might also be possible to use as I just adult data and maybe extrapolate to pediatric data which normally is never feasible.

Also, that's the only time that the Mdr. Basically allows. If this Mdvg. The use of off-label data, as we all know but the Mdr. We're not allowed, but for legacy often devices meaning devices which already were Ce. Mark under the Mdd. Or Aimd. Now, probably, I got removed from the market, or will be removed from the market, and the manufacturer is aware. Okay? Well, in the past, our device, yes, even was approved for indication A and B. We know from publications case reports that it was used quite often for a rare indication which is not on label and the factual probably decided. Okay, the number of patients per year is too low. It doesn't make sense to get to the whole process of study.

This can be used, but it's very important to mention that this off label data can only be used for legacy device. If you have a new innovative, often device, you cannot use any kind of off-label data. and again, always the full Ndr. Requirements. You need a relation. You need the Pmcf. Strategy. You would always need some form of Pmcf. But as for the clinical data, probably the expectation on the modified body a little bit lower for this for the Pmcf. But in my opinion, would obviously some form of specific Pmcf. But again, it has to be adapted and reflected. The type of ray indications of this awesome device status so just to quickly summarize.

I think its energy is very important because allow allows the continuation of state of the art treatment for patients with the rare indications in Europe. The early exchange with a notified body. If you have your notified body, contact him very early, discuss with them, try to get their opinion, especially when it comes to the determination of this often device status. Get this upfront before you even start. Your whole process saves you. Time saves you money also. If you want to get a clarification of the expert panel. Get in contact with them early. You need a robot justification, I said. Look at out what databases, epidemiological studies, publications for a lot of indications. I did this for 3 or 4, just because I was interested for a lot of indications, it's possible to get this type of data from the Internet. And again, it doesn't have to be the exact number 10,855. But at least you can get an overview that you roughly, would be within this 12,000 patients per year.

again, there's a lot of, let's say flexibility when it comes to quality and quantity of the data, but you still have to make sure that you justify. Like with everything else, you submit to a notified body. If you come to the conclusion. This is depending on the often device. Status is sufficient data at this point to get the C mark. Make sure you justify this appropriately. and, as I said, you always need some specific Pmcf in most cases, because you usually have not sufficient clinical data. And of course, you need to collect more data in the post-market setting. And also we haven't talked about this. This was really more the Mdcg. But of course all the notified body treaties. If you look at the Mdcg. Was it? 20?

22 I think 14. They talk about structured dialogue. It also talked about that they might have. I didn't know if I was. Have to be a little bit could be a little bit more flexible. Yeah. it mentions certificates issued with a condition. So, for, for example, and I'm happy to hear Gavin statement on that later on, and and certificate with a condition saying, Okay, you need to include a certain number of patients in the Pmcf. Would also be a possibility for an unified body to issue certificate with a little bit of a limited data. Yeah, thanks. This was a really quick overview. And now we really jump into the panel discussion, which is the main focus here.

And I'm really happy to have 2 so excellent speakers. And yeah, 1st ask Gavin quickly. Before we jump into discussion. Maybe you and then Nebosha afterwards. Just maybe give a quick, let's say, summary of your thoughts. What do you think about this current? of the right status? And what do you think is really the added value here for manufacturers. Okay, Kevin. Maybe you want to go first.st

Thanks, Matthias. Thank you all for coming. So we don't expect to see huge numbers of these. I think that's probably fair, from what everybody's said, I think what we have got is a framework where we can work together with the Commission, with the expert panels, with manufacturers. To make sure these devices are available, because that's that's really what we want. And I think what we've got here is is a framework that will allow that. you know it. It's certainly something that we've been looking for. I think it gives us confidence where where we can be involved in discussions with the expert panel with manufacturers and agree a way forward. And I think that's what we're trying to do for these rare

you know, in orphan devices we understand there is a need, and we have no wish to slow them down. I'll hand over to Nebu.

Thank you very much. As a representative of a competent authority and one of 27. I can say that the reason for this guidance and this work came firstly, from the industry, and of course, healthcare professionals who saw the risks coming up in the future, and also with the Mdr. Leaving legacy devices that will be revoked from the market. Therefore the Mdcg. Recognized this issue in 2022 in its position paper. and we're we're very happy also in the Cie Task Force working group that this guidance has been published last June, and it's already ongoing. We have 4 applications selected for orphan device

advice. And this is ongoing. We, as Compton authorities, hope this guidance will lead to a fruitful and good solution, and we should keep in mind that this is an guidance that will also need to be developed in the next years. When we all gather more experience on that.

Okay, thank you. Nabel, and thank you, Gavin, for his initial thoughts. Yeah, I think, as I said, it's it's a very helpful guidance, because it at least provides some clarification. As Gavin said, I don't think we're gonna see a lot of these per year, because. looking at the experience that the Us. And Japan has a similar programs over 30 years. Now we're talking about maybe 2 or 3 devices per year. That really fall under that. It's not really happen manufacturers who probably just have limited data and probably sell to. Not that many patients per year. But looking at that the Mdg. Was published, I think, in June last year. Maybe Gavin did this. I already get some information already

had contacted. You got to request from clients if you already maybe went through a process. I'm not saying to certification, but maybe at least got some initial discussion, or maybe already have to have some insights. How this I is probably going to confirm that often device status at the end.

Yeah, thanks. I think we've not seen. I've been involved in one discussion with the manufacturer, but in the end I think we felt they didn't perhaps need to to use that. And and they, you know, obviously we can't advise them on their route to conformity. But we we felt they probably wouldn't qualify for this this particular designation. I'm aware of one other potential client who's who's discussing it with us. But we really haven't seen huge amounts, I think. There will inevitably be a number of devices that perhaps feed in early in the process. But, as you said, let's say per year. It's likely to be a relatively small number, but I think we hope there are maybe 5 or 10 devices out there

amongst all the notified bodies. Who will meet this designation, and we will be able to ensure that they're available. But I think the important thing is is the transparency of discussion. We're very much viewing it as as part of structured dialogue. We will discuss it. We will record it. We will make those discussions available to our competent authorities, you know, if they come and want to see it. we want to have that transparency and say, this is what we're discussing, and I think if manufacturers can lead in and lead in with the expert panel. Early, as you've said, approach us early. Approach the panel early, then we can. You know we can work out what the best way forward is, and make sure that they're not

well, ultimately, for the manufacturers wasting time and money to get somewhere where they don't need to be, or you know we can. We can listen to what advice been given the expert panel, and you know, and and come a way forward and a pathway for the manufacturers, if we're all agreed. So I think that's really what it's about. And I think for me, the guidance is about that. That need that was identified, but also the transparency of we're happy to discuss this with manufacturers. We're happy to discuss it with the expert panels. We want people to see how we make our decisions and our justifications.

Okay, thank you. They will. Any experience you as a representative from the common authority in Austria, have did you ever got? I don't know any, any feedback on that yet? Or is it still, as I said, probably too new. And since it's basically happening between the notified body and the manufacturer. Maybe the expert panel. Probably the authorities aren't really involved at this early stage.

Exactly so if we look at the numbers from 1990 to 2021, the FDA approved only 78 such orphan devices in this time period, and extrapolating from that. We also don't expect a big number on orphan device applications or requests in Europe. But the Mdcg. Did recognize the need for this issue, because it's a very important field. and the patients, if collected together, are quite high high number. If we look at all the patients in Europe. and therefore also asking a couple of my colleagues, we we did not have contact with orphan device applications, yet, whereas the expert panel has. So the after. In June the Guidance has been published. There was the project from July running until end of 2025,

but already already picked. 4 applications for orphan device advice. And I believe this work is ongoing. So we will see the outcome from from this 1st try of expert panel advice on orphan devices. When looking at the single Member State work with orphan devices, we see a lot of derogations where clinicians ask for derogations for devices that possibly have been on the market, have been legacy devices, and now are not on the Ce market anymore, and they often have orphan device status.

You know. Thanks. And I think this the last cover is really important, because, as I said, we've we've learned from this core and the webinar end of 2023 that a lot of especially pediatric cardiac device already were removed from the market, because the manufacturer say, the business revenue is not high enough, and all weights the costs, since, of course, this is very important. You still have to go through the whole conformity assessment procedure. There's not like abbreviated version. There's the Mvcg. Provides you. Some cut, so to say, how much data you need to provide, but it does not shorten the whole process. So talking about costs, and maybe there's a question for you, Gavin.

Since it's still the whole conformation procedure is required. But of course, manufacturers probably don't have. Let's say it's not a big field where I can sell a lot of these devices, because it's just such a rare number of patients that even if, even if there's, say, 77,000 patients per year, it doesn't necessarily that our 7,000 needs specific procedure of that device. So as a notified body is this, let's say. a limited number of devices that are going to get used for this indication. So somehow reflected in. Let's say all the costs for the notified review, because we all know especially. And we talked about a lot of these are class 3 devices, high risk patients? It could be quite expensive. The conference only doesn't review. Is there some?

I don't know. Did psi? Or do you discussing? I don't know if I bought this. Is there some leniency saying, Okay, we have a reduced T or whatnot to reflect this often device status.

We we don't at the moment because we have to be completely transparent and be fair to everyone. So we also have to play by the we publish our fees. BSI, I think. you know, do publish our fees. But there is work going on to look at what we can do, you know, for some of these either orphan type devices or supporting, you know, smaller innovative manufacturers. So we so that is a piece of work that's ongoing certainly within BSI, and I think within the notified body community in general. You know, I think we're seeing that. But at the minute. You know we have our set fees and our set rates. And you're right. You know these by and large are class 3 devices.

They're not on quality certificates. They require that extra period of consultation as well. So I think the other thing, I would say is, look to manufacturers. you know. Get in there. Now, let's get started. We can, you know, we can start the process we can in in, you know, engage with the expert panels. There's currently, I think, no fee from the expert panels. Nebu, is that right? I think they're not charging a fee at the moment. So you know, and that may change as things go on. So you know I would encourage people where they think there is a a need and a case to try and engage with your notified bodies.

you know, and and and see what what the most efficient way forward is for the device and what you likely. Obviously there are commercial decisions to be made, and we we can't get involved in that.

Okay, no, no, thanks for clarifying that. And I think probably it's really something that, of course, manufacturers are interested in saying, Okay, we still have to. Let's say they are. They are businesses. They are for profit organizations that we have to say, okay, we cannot pay more for a certification. The recertification every 5 years than there's revenue for this type of devices. And another interesting question when we just talk about this more logistics here, since we are all. I think we can all agree. We're not expecting to see that many devices looking at the other countries. And it's quite, let's say I'm not saying a dedicated process, but of course it probably requires a lot of a learning curve on the modified body with your side to understand. Okay, what limited limitations do are able to accept the clinical data. I mean

the Md. The Md. Provides some examples, but not in detail. Question to both of you maybe naval 1st from from the authority side, do you think it makes sense to say, Okay, we only dedicate a certain notified bodies in Europe to do this, let's say, give them a little more experience. Because if you only talk about 1015 devices per year with right now 15 notified bodies. then basically, every 4 years or so notified body would see one of these often device application. Do you think it makes sense to say, Okay, we decide on a handful. Let's say, 10 notified bodies. Who's gonna get this? Let's say designation, who often devices, or it's basically

nothing was discussed.

Not an idea that I heard of. We have to keep in mind that the guidance on orphan devices is not extending what is written in the Mdr. But just maybe trying to push some borders that we have here. We implemented a definition of orphan devices that has not been in the Mdr. But we are still in line with the Mdr. And have to fulfill all the provisions. Unfortunately, there is no easier pathway for c certification for orphan devices in the Mdr. That's the reason why the guidance has been written, but the guidance has only the possibility to clarify a lot of questions. A lot of issues for both manufacturer, and possibly also notified bodies to just give clarity and definitions here. So giving just a few notified bodies to designation.

not really something I could decide. But I think it's also not necessary, because for every orphan device it will be a case by case decision depending on the clinical data available. and the guide here gives the opportunity to rely on a lot of data that is not as strict for the conformity assessment as for not orphan devices, where we ask for really the highest quality of Rcts, of studies, of clinical investigations inside the European Union, but gives a lot of explanation and kind of ideas to gather data. That is, as you mentioned in your presentation, not non-clinical data data from outside the European Union extrapolated data, even off-label use.

Therefore, I believe, we have to grow with future requests from manufacturers and also from the expert panel advices.

Okay, thank you. And then I just saw that something in the chat that the often device expert panel pilot program is free and runs into the end of 2025. So anyone is interested. And you might have something. You can contact right now for free and get the advice or the the feedback from the expert panel. Yeah, Kevin, Kevin. Sorry. So apparently every notified body can do that. And as we all know there's always this criticism for manufacturers. Notified bodies are not that well aligned sometimes between the different notified bodies? When I was still working on a clinical reviewer for notified body. We initiated for the clinical evaluation, let's say A team and B level quarterly meetings to trying to get a better alignment. Are you aware? So currently, any discussion on team and B level trying to align a little bit better on these expectations to avoid that there are too many different interpretation, because it's probably something that everyone has to go through a certain learning curve right now.

Yeah, I think. You know rich Holber, who unfortunately couldn't be here today. I know many of you will have turned up to hear rich, and you're stuck with me. And despite my regional accent, it's not gonna help, is it? But.

We were. We were happy with you, Gavin.

I know, but the the audience, I suspect, want to hear that the lovely rich and I could never replace them, but he sends his apologies, but I know Rich and the rest of Team MB. Have been have been looking at this and trying to make sure we are consistent. I think that was right in the Commission are unlikely to restrict notified bodies. Who, you know, to specific things. There is a bit of restriction in scope. So it's not all notified bodies will have the full scope for maybe implantable cardiac devices that perhaps some of the notified bodies have so inevitably there will be some restriction. And we we've looked at it very much as

the clinical team are going to be the focus of our initial discussions. So we have a lot of experienced clinicians, certainly in our notified body 1314 now, and growing. who will be part of the central sort of discussions, and offer that degree of pragmatism. I hope to manufacturers to say, Look, this feels like. you know, a device that may meet the criteria, and I think what I would say as well is. Nebu has come to it as well. Nothing has really changed in terms of what the the guidance says for the requirements for Mdr. We still have to meet those requirements. The really crucial bit for us is that state of the art which we say to everybody, that state of the art search. Where does your device sit in this state of the art? Show us

where it sits, and why your device may be the best option or a particular option. And if there aren't comparable devices, what are the other treatments? You know? What are the other options? Because if there aren't good options, then that's a good justification for a device. you know. So we want to see that even if you say, Look, we don't have comparable devices. There aren't equivalent devices. That's okay. But make sure it's brought out in those discussions and really emphasize, you know where your device sits in this overall treatment pathway, you know, and perhaps why, there are limitations, you know. We know.

I mean Matthias was talking about the Septostomy balloons. They're used as an emergency. There is no long term follow up because the patients go on. And obviously another procedure by and large. But we know they're widely used. So registry data is, Matthias talks on it as well rest of the world data. Why is it applicable? Why can we look at it? Why do you think? And if you're going to start talking about things like adult data. Why can it be scaled down in the case of pediatrics? Why is it still, you know, appropriate? Have you got supporting evidence with in silico models. Can you show us these models that say, actually, if you change the stent size or the you know the weave, or whatever it is of your stent that it's still, and there are lots of really. There's lots of really good work going on in Europe in the Us.

The FDA have got us, you know, an in silicon modeling centers. you know. Let's let's look at that sort of thing, and we we want to. We want to reassure ourselves that there are models that support these devices, and that we can use that in a sensible way to support these devices going on the market.

Thank you. And I think this is a very, very important what you said at the beginning of of your comment here is, make sure. Look at the state of the art, and make sure. Look in where, in the whole realm of the state of the art for these indications? Your your device fits in, because quite often, manufacturers, they're fully aware. Okay, all devices use for these patients. But sometimes they are not having. Let's say, the full overview. Look in the state of the art, and they're quite often you can come up with the justification, probably. Why, you can use this lower quality of data. Looking at the poll you just had. I didn't want to ignore the poll results. So it looks like the majority is here because I want a little bit better. Understand? Okay, how is the determination? How do I determine if I have an awful device? And also it was the same question coming up in the in the Q&A here so I probably hand this over to you, Gavin. First, st because you're also a physician like myself.

How does psi! What? What is a psi's expectation? How should the manufacturer present the case? And what what is? Let's say I have one quick slide on that. What could be data sources? How to justify? Why, device would have Bd often status.

So, okay. So I think, again, start from your state of the art. Where does your device sit? Why does it only apply to this particular? Why is it likely to benefit this group? Specifically, you know. Go, go to the guidance document and bring your argument from there, and then construct it and say, Look, this is what we have. This is where our gaps are. If you can identify your gaps as well, it's much easier to have that transparent discussion and say, Well, look! That's an understandable gap. That's I understand why there's that gap, because there are problems with Follow up, or it's not entered in registries. Very well.

So look at, look at. You know where your device really sits in the treatment pathway for these patients, and which patients are going to benefit is, if you're you know, we're talking about a relatively small number here. And I think that's the the 1st thing is to really look at the definitions in the Mdcg guidance, and say, Where would our device fit? Because it may be a device that only applies to a very small number of patients, even though it's a device that can be used in perhaps other conditions. And it has a very specific indication where there are limitations. So you know there are ways of interpreting. I think we would try and approach it with our

pragmatic heads on, and say, Okay. there is some evidence we know. This has been widely used for years. We know what group of patients, what we need is a sensible, logical argument constructed around that basic tenant of of where it's used and why it's used. And and if if you can bring in that clinical, and and if you've been to the expert panel, and they have shared your view. and you've got, you know this is where our gaps are. We know what we're going to do. We know what our Pmcf. Is going to look like. It's much easier for us to say, Okay, that is a device we can hang our hats on. You know, this is about a bit of risk sharing as well. You know, we get reassurance from the expert panel, from manufacturers, that what they're doing is sensible and in the interest of patients. And that's really what we're, you know, from the notified body as well that we need to be convinced that we're we're doing the right thing

for for everyone, for the patients, for the risk. for the whole sort of ecosystem, and for the lifetime of your device.

But regarding that number of 12,000 patients, or are there any, let's say.

Okay.

Data sources that basically psi considers, let's say, as an example, registry. If there may be publications, there might be in some some countries even publicly available. Let's say epidemiologic databases and any any tips for the for the audience, for yeah, I think. Look at.

I think I think the whatever, whatever, wherever your device sits, whether it's pediatric cardiology or neurosurgery, or, you know, rare. you know, disease processes in the Gi system. Look at the professional societies that are involved in treating those patients. I think Matthias touched on it already. There tend to be very small groups of clinicians who treat these patients, you know, if you think about hyperplastic left heart. there's only 3 or 4 centers in the Uk for 60 odd 1 million people who actually perform that in children so that will inevitably apply across most of the European population where there's subspecialty find out from the you know the special interest groups from the patient, the patient groups as well. They have really good data by and large. So there are professional

patient groups who recognize these conditions, who will be able to tell you what sort of numbers you'll expect for your given population or your given genetic makeup, if that is relevant. And so those are the places I would always start the who is always a good bet as well. You know, FDA, data, Australian data. The Uk has a ton of Nhs data which hopefully will come available over the years. Almost you should be. You know, we're hoping that those sorts of things will be accessible.

Okay, thank good, interesting, interesting comment, saying, look at other countries, other regions of Europe. So for Nabo, is this something also that say, the authorities would agree on. If let's say, Okay, there's nothing, because we all know about the high data protection regulations in Europe. So it might be a little bit more challenging to get this data. And we know that other countries, Us. Australia, for example, might have a little bit more accessible data. So would this something that you would think as an authorities also be acceptable if the manufacturers actually couldn't find any real European database.

But we found, let's say, an epidemic database in Australia, and we extrapolated a certain incidence for certain indication to the European populations to something that could be considered as a relevant data source. Or this is something outside of Europe, is not acceptable.

Well, the guidance does outline the possibility of using data outside of Europe. This, of course, is focused on the clinical evidence that can be provided, based on possibly the use of devices that haven't been used in the European Union. On the other hand, we did extrapolate the number 12,000 incidents per year from the Us. Definition. therefore, I personally could believe that this is a possible source of showing how many incidents are to be expected also in the European Union, but that really depends on 2 entities, on the expert panels and on the notified body reviewing the application. So if we look at the definition. We have to also consider that there might be not only an orphan device, but also just an orphan indication, which is one of

a lot more than one indications for one device, and therefore this might be a solution, if not the literature. Research limited to Europe leads to to a result that is satisfying.

Okay, thank you. Yeah. And also one, I think interesting question we just got from from the audiences. Will the decisions on often devices be made publicly available, like a little bit similar, like what we see with the legalization, consultation? Opinions. Is there any plan to make us publicly available? Probably not because it is still follows the law. Formal. Mdr conformity assessment procedure. So I don't think there's gonna be something a plan. But maybe 2 of you could quickly address this question. Maybe, Gavin, you go first.st

I think as far as I understand it at the moment, it won't be publicly available. But, as I say, we we're very happy, you know, to share that with confident authorities I would. I would hope that the panels will produce some sort of summary document, but I think Neville may be able to to come to that a bit. More detail.

There were any thoughts on that. Yeah, from.

Maybe I start with referencing to very great website both of the European Commission and of the Ema for orphan devices that show the pathway of applying for a request for orphan device status, and also the process that is very helpful. Besides the guidance to reach this goal, as I understood it, but I'm not sure I thought it is intended to make something public. Possibly the opinion of the expert panels. as far as I have read it on the website. But just please refer to the website on this regard. That is very helpful and has very much information on this, and also one more aspect that I would like to mention here regarding the expert panels is that we differentiate between an early advice and then advice. If a clinical assessment is already advanced. So, as a manufacturer, you have the possibility for an early

request to the expert panels. As mentioned today, the project is ongoing until end of 2025. But I think the expert panels are picking limited numbers of requests and also have some criteria which requests they will pick. So we're looking forward to hopefully gather more information and also experience on that. And hopefully, we will get something published when the expert panel issues.

Yeah, just say that our conformity assessment bit remains between us and the manufacturer. But yes, I think there is hope that particularly where there is advice given. That that will be publicly available from the panels. and and again, hopefully, a kind of summary every year to give us a flavor of what's been happening, and because the notified bodies, as you said, there's what 40, 50 nearly. If if it's split between lots of them, we would like to be, you know. Get that consistency.

Yeah, because especially, I think, probably if it's say, 2 manufacturers, let's say, contact 2 different notified policies with a similar device for same indication and you do not want, because manufacturers met in Europe. There's other trade associations. They're talking to each other. And of course the worst case would that one manufacturer would get the often device designation and they could use. Let's a limited legal data might get the market advantage because they might access the market earlier than the other one who has to go through the full, let's say legal investigation. that's certainly I think some no one would like would like to see that. And is that this is ongoing discussion to be be more aligned?

Another question from the panel. Probably quite easy. I could answer it right away. But I would probably give this to Gavin, since my address and obviously notified body is the company certification. Iso, 13, 4, 8, 5 or 9,001 required for the off device pathway.

Well, I mean you. You must have a a quality management. So the Mdr. As you know, doesn't actually specify what it. So I think the wording is it a recognized quality? Management system? Is the is the phrase that it uses? But I think inevitably that means yes, you have to have one of those by default.

And yeah, I think never, never. You're just nodding. I think you can fully agree. And I mean looking at the Ndr. And just looking at my 10 years experience as a clinical reviewer. And now, as a consultant, I would say, everyone has an Iso 34 at 5. I think it is. If if you look at the the overlap between the iphone, 13 forward 5, and what's required for the Umdi Qms, I think it's pretty much. It's it's a it's a mandatory requirement there that you need to have. An Is013-48-1485. Another question from the audience, is about, okay, can you show an example? For in silico testing, regarding often devices?

I cannot. I mean in silico testing is something that's really picking up now, there's a lot of research in it, but it's still kind of new. I remember when I was at the notified body that was probably around 2021. We got some questions from manufacturers. Can we use that? And I know there was a lot of discussion within my notified body because this was really something new the Mdr. Doesn't mentioning in silico testing so Mabel again. Happy Weber would like to to to take his question. I think, maybe, how how is psi, if you get say something, including testing, how? How do you decide to use if this, if this is relevant testing that you that you can use, probably to leverage.

So we.

Certain part of our clinical data.

We see in silico at the moment in Europe as supportive data. We don't see it replacing human data, because when you look at clinical evidence definition in Mdr. It talks about human subjects. So that, aside, we do. I. You know we certainly think it has value. The FDA are a bit further ahead, and myself and one of your former colleagues, Rene, have been involved in discussions with the FDA. And Mdic. About in Silicon modeling, and what that will look like I can share an example. There's been a couple of good examples, one on fatigue fracture testing for pedicle screws in the orthopedic indication that the FDA and researchers have published in the last year.

and there was a recent webinar looking at stents and testing nitinol stent failure and predicting when it would occur, and they were able to show that the in silico model predicted the failure pretty pretty much spot on. So I do think there is benefit in in silico. But at the moment it can't replace human clinical data, it's probably the best way. But I do see value, particularly if you're thinking about maybe stents on what's going to be the worst cases. you know, we would perhaps start to expect manufacturers to produce this sort of in silicon modeling to say, Okay, we've looked at it. And even though we're getting very small, we still think it's within our.

you know, acceptable failure rates and our performance. And we can model a flow in the, you know. And and there were some very sophisticated modeling systems that we're going to see in the next few years. you know, even from digital twins, where you effectively can create a population and do a clinical trial on them virtually, and you may be able to enhance or pull out certain characteristics, so they may have a very small. you know, duct, or a very small aortic valve. Whatever it is you want to characteristic. You can then use that and model. and we know manufacturers are already doing this as part of their R. And D, because they won't waste time on designs that are never gonna work.

So it's already happening. What we have to find is a way of looking at it, validating the model and accepting it, as you know, supportive evidence.

Thank you. And neighbor, since in silico is quite new and really rapidly involving a little bit artificial intelligence, the Ndr. Doesn't talk about artificial intelligence. Now we have even the AI act. Do you think that maybe we're going to get maybe in the near future? Let's say 2 or 3 years. And then the Cg document that probably introduces, let's say, a little bit like you see, with this often device. that you see, probably the possibility that certain partially, or maybe some in silico data can be used to partially replace or additionally support clinical data. Any discussions on that? Do you aware of any.

Well, no discussions on that. In the Cie working group, in the Clinical Investigation Evaluation working group, we have the matter addressed, I believe, either in the already published Q&A. Or in the upcoming Q. And a. But this this is the level of of discussion. It's in the Q&A other than that we in our Member States to assess AI for the moment, as software as as it is. But yes, it's quite difficult, because it's not exactly the same in silico testing. Yes, of course, it's supporting, and it's also mentioned in the guidance for orphan devices to be very helpful. The examples I have are stress strain tests on tissues or even mechanic medical device parts that can be also done in silico, or another example would be a long term

resilience, long-term life of devices that cannot be tested for a lot of years. And therefore computer models can just extrapolate existing data into looking. What will happen in 30, 40 years other than that, I believe the orphan device. That is something that has been recognized from the Mdcg. And was born out of the need. Artificial intelligence is a more complicated topic. I would say.

No, no, certainly, and that's probably then part of another webinar. I think we have time for one last question from the audience. And I know we probably partially address this, but there's a specific question here. What would be the study? Population size for a clinical study? For device approval. So any any quick thoughts on that? I think there's no fixed number, because I think it's a very complex topic. But since since we agreed it could be a lower quantity. And of course, every if you do a pre-market investigation, the Ndr. Requires statistic analysis. So maybe any any hints how the statistic could be addressed in such a a study, for an often device.

If I may start what is also outlined in the guidance is to postpone gathering data in the post post market clinical follow up studies. So it's every device has to do its post-market clinical. Follow up. But you are encouraged to plan studies to show them in your clinical evaluation plan, for after ce marking and after putting your device on the market, and therefore I don't have an answer on a number for pre-market studies. But you can plan to gather information on specific areas that you are not able to show if your clinical evaluation pre-certification in your post-market plan, and therefore you can a little bit, using the guidance. Lower the numbers that are needed for your clinical evaluation, for your assessment with the notified body.

I would assume.

Yeah, I think I think what I would say as well is if Nibu said this already. If you're going before you're you've got a device in the market. Go to the panel. have that sort of discussion with them, you know, align the expectations, and and then at least a notified body can be aware of what's been discussed and what the you know the numbers are and what the feeling is. It depends. A lot of things depends on your effect. Size your population at risk, whatever it is you're trying to show. Some of it will not lend itself to randomized control trials because of the nature of these devices. So if it's post market

that was outlined, it really succinctly, you know. Think about what your gaps are. How can you close them. And again you can go to the panel and get that advice and say, what? What do we need to try and close off this device, you know. And what is the sensible scientific justification given the limitations of the population we're treating, it's not going to be perfect. And I think we all accept that. But what we have to be able to look back on is, say, if we look back at it from an auditing point of view, did we make a sensible decision? Is it in the best interest of the patient? And are we, you know, are we able to make those justifications? And and when you write your clinical evaluation reports?

That's the story that it should tell. Where do we start from? Why is this device important? What's the evidence we have? How are we going to cover the gaps? And what are we going to do in the post market phase? That should be a standalone story for your device that anybody with, you know, some scientific knowledge should be able to read and understand. That would be our usual advice.

Thank you. Thank you both. I think it's really sums it up very nicely. What you just said. Whatever you do, whatever you present to the notified body. Make sure it's it's sufficiently justified while you do that and notified ideally, can follow your thank you, everyone especially. Thank you. Nabo and Gavin for this very interesting discussion. I'm sorry we could not. We tried to address most most questions. We could not address all of these questions with the sake of time. But thank you, everyone. And the really important topic. And Sean back to you.

Thank you to the audience. Thank you to the speakers. I'm glad everybody was able to attend today. This is an important topic, and it's an evolving issue that we should keep an eye on. I would like to say that next month we're going to be doing a larger webinar on post-market surveillance. So look for announcements about that, and I hope everyone has a great day or evening. Thanks very much.

Thank you. Thank you.

Thanks everyone, bye.

Bye.