Clinical Data Requirements EU vs. US - Critical Differences and Strategies

Morning, everybody. Afternoon. I'm Shawn Smith. Welcome to Medtech. Leading voices. Presentation clinical data requirements EU versus us with Maria E. Donoa, Md. And Dr. Tom Melvin and David Fillmore a few housekeeping announcements. I'm gonna start a poll right now so that you all have something to do as you're logging in hopefully launch the poll. Are you? Seeing that great if you take a minute, it's just a 3 question poll. And we're just to give us an idea of who's in the audience today? There were approximately 940 registrants. And so we're very, very excited to have you all here. Welcome, welcome!

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so recording and slides will be sent to everybody in approximately 24 h. The email is generated automatically through Zoom and everyone who's registered should get linked to the recording. The password as well as links to the slides. When you download the slides you have to hover the mouse over the over the download button. I'll put that in the notes in the email as well. I am super excited to have Tom and Maria here. I've heard what they have to say on this subject, and it is fascinating. I'm going to turn it over to David to make his introductions.

Oh, and one last thing, if you're not subscribed to Medtech leading voice or Med tech strategist. Please do so. I'll put those links in the in the chat as well. I'm going to end the poll and share the results. So 49% are device manufacturers, 9%, 22% are consultants academic government regulatory. Other 21% are novice, 58% are intermediate. And then. are you currently planning to submit? FDA, Mdr, Ivdr, right? Okay, so that is the poll results.

I am done. You won't hear me again unless you do.

The notify. Thanks, Sean. The notified bodies, 0%. I know that they should know all this already. So that's fine. But no, thank you. Thank you for convening this Sean. I appreciate, appreciate, Medtech leading voice. and everything you guys do. I'm really happy to be here with Maria and Tom, who I'll introduce more in just a moment. My name is David Fillmore. I'm the editor of Market Pathways, which is a publication covering global regulatory as well as reimbursement. Other market access politics policy issues that impact the Med tech arena. So happy to be here discussing this topic just to give us a little bit of setup, and then we'll get to the real stuff from the experts, Tom and Maria. But you know, kind of if you know the Internet meme how it started versus how it's going. Hopefully, you'll come away with the answer to those questions with regard to EU and Us. Device clinical requirements today, and also the very important 3rd question, what to do about it? Sort of practical strategic considerations for companies to find their best way way through the challenges.

You know, I think when you think about clinical data requirements kind of key factors I think a company would want to have in hand is like them to be consistent and predictable ideally, and you'd equally like them to be proportional and reasonable for the device indications at hand. So I think there's, you know, distinctions between how companies are experiencing those factors in the EU versus Us. Which we will discuss today. And we'll also get a really interesting historical perspective of sort of how we got here, and what are some of the underlying basis for differences in the 2 systems and some of the challenges people face, and maybe how to how to get around those challenges or how to think about those challenges, at least particularly, you know, as the EU continues its complicated transition into the Mdr. Ivdr. Era.

So with that, I think you know. Let me introduce our 2 panelists here. Love that love that picture of Sean. 1st of all, we'll go in order of talking here. So just to introduce Tom first, st who who may need no introduction. Tom Melvin is the Associate Professor of Medical Device Regulatory Affairs at Trinity College, in Dublin. He previously was a senior medical officer, and devices at Ireland's Health Products regulatory authority. He has co-chaired clinical investigation and evaluation working group of the European Commission. Currently, he's actually a member of the expert panels convened by the European Medicines Agency, which obviously provides scientific advice kind of working at some scrutiny under the Mdr. He's a member of the International Rare Disease Research Consortium and National Research Ethics Committee for medical devices in Ireland, and he's previously worked as a medical

doctor. So great, great set of background there. I'm also going to right now. Just introduce Maria Dona, who really really brings great expertise as the president and founder of Dona Life Sciences in Rome, which is her medical device. Ibd. Cro. And Consultancy, which provide comprehensive EU and Us. Regulatory quality system and clinical services. Maria has 30 plus 35 years of regulatory experience. She used to work for the FDA at Cdrh. She's also, importantly for today's conversation. A member of the Iso. Tc. 194, working group 4, which is developed Is(014) 155-2020, and is for, of course, the international standard for clinical investigations for devices, and also is working on with Iso, the 18 9 6, 9 standard that's in development for

clinical evaluation. She both as well. She brings the Us. Degrees in pharmacy and medicine. So we're both bringing the medical part of medical devices today from both of our panelists. And she previously was a regulatory affairs columnist for European Medical device Technology magazine. So welcome, Maria. And with that, I think. Why don't we get started with our presentations? And I think we're going to start at the beginning, so to speak, with Tom, historically speaking. So, Tom, do you want to take the floor.

Thank you, David. I'm delighted to be with you all today. Hopefully, you can see the screen. Okay, okay, perfect. So what I'd like to do before we move to talking about some of the current day strategies and challenges that people face in generating evidence to meet us or EU regulatory requirements. I thought it might be helpful to give a brief historical perspective to explain. Where did these rules come from, and what were the driving motivations that underpinned the 2 frameworks that we have for medical devices in both the United States and the EU. So we'll talk about the origins of the rules, and how some of the challenges that regulators faced over the last century moved really from

quack devices to the advent of permanent, implantable devices that raised a whole new set of challenges. We'll briefly introduce the origins of the frameworks in Europe and the United States, and then we just have a couple of brief comments on what this historical perspective can tell us with relevance to today. So if we go right back, the very 1st rules that applied to medical devices were actually applied by the Postmaster General in the United States in the late 18 hundreds. If there was something in the post that was fraudulent, the Postmaster General could market fraudulent and return it to the sender. A very simple approach that tackled some quack products at the time.

The 1st legislation in the United States that led to the Us. FDA was enacted in 19 0 6, but there was no reference to medical devices, and at that time medical devices as we think of them today was often medical equipment, so simple things like stethoscopes or scalpels, and there wasn't really a need seen at the time to have a framework that applied to medical equipment or medical devices. As we moved from the early 19 hundreds to the 19 thirties, there was a lot of what you could think of as quack medicine, so essentially the promotion of unproven or fraudulent practices. And you can see one example of these in the image on the right. Here, essentially, there were a lot of products that made lots of claims that they could treat or diagnose a whole variety of maladies.

And when the Us. Congress moved to update their laws in 1938, they introduced the 1st minimal requirements for medical devices, so a product could be removed from the market, but only if it was either mislabeled or adulterated. As we move through the 20th century, the demands for regulation significantly changed. So, whilst in the late 18 hundreds we had the 1st attempts at things like hip replacement implants using ivory devices. You can see an example on the image here. It wasn't until the midpoint of the 20th century that we had the successful use of permanent implants with critical functions.

and this came, for example, with John Charnley when he did the 1st total hip replacement. but also in the late 19 fifties and early 19 sixties. In a very short period we had the 1st permanently implantable pacemakers and the 1st permanently implantable heart valves. And this completely changed the regulatory dynamic and challenged regulators. So what did they do? They didn't have defined medical device rules in any of these jurisdictions between Europe or the United States that dealt with these new challenges. So what they did is in places like France, Germany, Italy, and Spain. They started to treat some medical devices as medicines and put them through their medicine approval, framework, and this also happened in the United States, and you can see some examples there.

Things like injectable silicone or pregnancy tests the Us. FDA put them into their drug clearance platform to have some form of regulatory oversight. and this raised legal challenges because it wasn't very clear to the companies at the time what kind of approval was needed, and this rose to the level of the Us. Supreme Court, who noted that FDA had an ability to put other products into their drug approval. Pipeline, but it still left a quite chaotic, regulatory, dynamic. So from that grew the 1st detailed rules for medical devices in the United States. There had been initiatives going back to the early 19 sixties, and John F. Kennedy, for example, proposed a framework that would have been very much like the medicines framework for medical devices, but that was sidelined by the Thalidomide crisis, and Congress didn't tackle medical devices at that time.

but, following on from that Supreme Court decision, it was increasingly recognized that we needed a framework for medical devices. So Richard Nixon, in a Presidential address, noted that the Government needed some additional authority for pre-market clearance in certain cases. So it was recognized that for things like the high risk implants with critical function, they would need a pre-market oversight. But it wasn't quite clear what we would do for the lower risk products or medical equipment. So what they did in the United States at the time is they got a clinician and scientist called Theodore Cooper. At the time he was director of the National Heart and Lung Institute and the National Institute of Health, and they asked him to form a study group and to prepare a report, making recommendations to the government and policymakers as to what they needed to do.

and Theodore Cooper and a study group went out and looked at various challenges with safety associated with medical device products, and in a report to Congress in 1975 Theodore Cooper noted that the public is being exposed to an undesirable level of risk. so from that work with the Cooper report they made a scientific proposition that we needed threefold way of assessing all medical device technologies. And this, then, was worked into the 1976 amendments in the United States where we had essentially class 1, 2, and 3, where Class one had general controls meaning you didn't need a regulator to approve your product in advance

class 2 were envisaged to apply technical standards for their testing and for Class 3. They needed a form of pre-market approval, and this was then adopted in the 1976 amendments, and that was the 1st detailed framework that we had for medical devices. The European pathway took a quite different approach. So when we had the 1st implantable pacemakers from the late 19 fifties. They were in quite widespread clinical use by the 19 seventies, but there was a lot of challenges with things like pacemaker leads breaking, or batteries depleting, and a prominent cardiologist in the Us. At the time noted that manufacturers inherited both prosperity, but also an obligation to the patient.

and he noted that not everyone was living up to that standard by which he meant that people could introduce a pacemaker that may not meet the specifications of the highest performing one, and that could sometimes raise significant health challenges. Manufacturers came together and formed an association. In the late 19 seventies. It was called the International Association of Pacemaker Manufacturers, and that was then extended in 1986 to also include heart valves, and they were called the International Association of Prosthesis Manufacturers. They met and engaged with the European Commission, and at that time, in the mid 19 eighties, there was an enormous push under the Delor Presidency of the Commission to establish a single market for trade in Europe, because at that time, if you wanted to trade products from Germany to Belgium, you would have to meet the national standard in each country, but those standards could sometimes be different, or testing could be different.

and many Member States had some partial law that might apply to some medical devices, but no legislation in Europe covered all medical devices, and so it was quite driven by the trade associations, and by engaging with the Commission, and they built the confidence with the Commission to be able to propose the 1st legislative text. The other trade associations so ucomed and Cosir had also thought about proposals for legislation, and at one time the Commission was thinking of 3 different legislative approaches, one for active, implantable one for active devices or things like radiation devices, and one for general devices, each led by the trade associations in the event they reduced that down to 2. So we had the general medical device as well as the active, implantable device directives from the early 19 nineties.

But I guess the focus of the law was quite different, and so it was quite recognized at the time that the new approach or ce marking legislation that we adopted was set up in rather abstract terms, and it was predominantly intended to apply to industrial products. and these requirements were supposed to be given detail through the use of European standards at the time. So I guess we can see from this that there was a big trade imperative to try and focus the single market in Europe, and that was really the start of our laws in Europe, which is somewhat different to the Us. So what were the major differences that we can see from this in the United States, with the Cooper report there was a big, scientific and public health imperative that underpinned the risk classifications, and then the pathways that developed from that, whereas in Europe the single market was really the predominant driver, and we still see echoes today in terms of the way that we revise and implement our legislation.

and we often use policy evaluations or policy impact assessments where we try to understand how legislation would affect all the various actors in the system with notified bodies, authorities, and so forth. But that's quite different to the way that legislation started in the Us. across both of these frameworks. Resourcing has always been a challenge. So when you look to improve regulation in significant ways, implementing that in practice needs a huge amount of resources. And that's always a challenge. And we see echoes of that, especially in Europe today. Both frameworks are heavily dependent on standards. But one of the challenges that we've seen is that as the amount and variability of the technology continues to advance, and standards can sometimes struggle to keep up with all of these new technologies. So this is a struggle that we see across both regulatory frameworks and

in the United States they recognized that because there wasn't enough standards, they revised their Class 2 approach and their 510 k. In the late 19 eighties and in 1990 to accommodate that. So I hope that this brief historical perspective gives some context, and very looking forward to Maria's talk and the discussion that follows.

Thank you so much, Tom. That was great, and you know not not typical and usual to get that that historical background and sort of an explanation for it, you know, like almost philosophical understanding of kind of like where where some of the the baselines come from for what we're doing today. Which brings us to Maria Maria's presentation to get a little bit more present day context and some examples, etc, about dealing with modern day with the Us. And with EU clinical data requirements. So take it away.

Maria E. Donawa, MD: Thank you. Maria E. Donawa, MD: Okay, so I'm hoping you can see those slides. Maria E. Donawa, MD: Okay. So Maria E. Donawa, MD: I'm going to talk about clinical data requirements. I'm going to try to make certain points. And of course, you know, this is a huge subject. And so there's going to be. It's going to be quite interesting to try to Maria E. Donawa, MD: concentrate on some of the more important aspects. And what I'm so what I'm gonna do is try to Maria E. Donawa, MD: discuss Maria E. Donawa, MD: some of the more important differences between EU and us. And clearly this is going to be concise. But those differences where they're where they're going to affect the strategy, the regulatory strategy or clinical study or clinical data strategy.

Maria E. Donawa, MD: I do have a couple of actually have 3 examples from real life examples. And how strategy affected. What happened in those examples. And then I'm going to give you just a brief update on the standards. And this and David mentioned this before the 14, 1, 5 5, clinical Investigation Maria E. Donawa, MD: international Standard. Just in terms of the update of where it stands. It's being revised and also the standard for clinical evaluation. The working document which is in early days. Maria E. Donawa, MD: So 1st thing 1st point I want to make is this, and maybe we'll get questions that might

Maria E. Donawa, MD: cause me to go need to go into a little more detail. But Maria E. Donawa, MD: this 1st issue of EU versus us again, I'm talking about the differences. Maria E. Donawa, MD: and in the EU, as most of you know Maria E. Donawa, MD: the intended purpose. It's it's clearly a key requirement Maria E. Donawa, MD: or a key piece of information to define. The intended purpose is defined under the medical device regulation Maria E. Donawa, MD: indications are mentioned in the Mdr. But they are not defined. And so questions arose, what does that really mean? It's now understood. And also you can understand this from reading the Mdr. That indications in Europe

Maria E. Donawa, MD: are they, they. They apply to clinical or medical conditions. Maria E. Donawa, MD: And the key there is that they may or may not need to be backed up by clinical data, and to see and to look at the discussion of what indications are you need to go to the medical. The clinical evidence guidance document, Mdcg, 2020 to 6. It's actually defined there Maria E. Donawa, MD: now. In in contrast, in the Us. Has Maria E. Donawa, MD: indications for use. Now, if you look at in us guidance documents or even requirements, you will see Maria E. Donawa, MD: the intended use term used. But when you are filing an official statement about what the device is going to do. It is an indications for use statement. This is a pretty complex issue, because

Maria E. Donawa, MD: intended use in the States tends to be a general statement and indications. Maria E. Donawa, MD: and then indications are more specific. This is the point. The point is, I beg of you do not Maria E. Donawa, MD: automatically assume Maria E. Donawa, MD: that your indications for use in the Us. Are applicable in Europe. This has caused a lot of problems. Maria E. Donawa, MD: and an example is where in the Us. There's a discussion in the indications of what tissues are, for example, a cutting instrument, what tissues are applicable to that cutting instrument that's not applicable in the EU. So companies have actually used the Us indications for use in Europe and caused a lot of complications. And I can get into that. If we have questions.

Maria E. Donawa, MD: Clinical data, as you know, are required for all devices in some form or fashion in Europe, unless you can meet Article 61 10, which is the article that talks about. If clinical data are not appropriate. And of course there's a lot of discussion about what appropriate means Maria E. Donawa, MD: clinical data in the Us. May or may not be required. So you're, you know, from a strategy point of view, you need to find out Maria E. Donawa, MD: how the how the device is regulated in the Us. Versus Europe in terms of clinical data requirements. Maria E. Donawa, MD: There's another difference that's important for between us, EU and the us, and that is in the EU. And of course

Maria E. Donawa, MD: Tom talked about the history of medical devices when we were operating under the directives in the early days the expectation of of the quality of a study design. And I'm talking specifically about clinical studies Maria E. Donawa, MD: was not as high as it is now. Maria E. Donawa, MD: And so you had a certain level of expectation in Europe that's changing the expectation in Europe Maria E. Donawa, MD: for the quality of a study design is increasing. However, if you compare EU expectations with what's going on in in the Us. With FDA. Maria E. Donawa, MD: Then FDA almost always has a higher expectation in terms of study, design.

Maria E. Donawa, MD: and and follow up study design in terms of whether it's a randomized control study or patient numbers. And so there are a lot of important differences. And in general, the study that you're going to end up requiring under us requirements versus Europe is going to be more stringent. Maria E. Donawa, MD: This is key, of course. Maria E. Donawa, MD: clinical evaluation plans and clinical evaluation reports are required for all devices in Europe, including those where you are arguing that you don't need clinical data. You still need to have these 2 documents. Maria E. Donawa, MD: There is no requirement in the US. For a Cep or a Cer.

Maria E. Donawa, MD: I would urge you don't submit something that they don't require. They'll scrutinize it, and you'll just cause problems. Maria E. Donawa, MD: There is no requirement. But there is something FDA will sometimes use the term clinical evaluation. They're not talking about clinical evaluation. Maria E. Donawa, MD: The way we understand in Europe clinical evaluation, that term is sometimes used simply for clinical studies. Clinical data. It's not the process of clinical evaluation. Okay. Maria E. Donawa, MD: so Maria E. Donawa, MD: other differences. This is one of the most important, actually. So in in the

Maria E. Donawa, MD: in the EU as again, most of you know, if you have a device where you have a classification where a notified body is is involved. Maria E. Donawa, MD: there is only a limited process for getting advice or Maria E. Donawa, MD: getting any type of feedback from the notified body. Maria E. Donawa, MD: and the Mdr. Actually in the section in the annex that talks about requirements for notified bodies Maria E. Donawa, MD: has a very general statement about Maria E. Donawa, MD: what notified bodies can do. And this guidance document 2022, 14 Maria E. Donawa, MD: talks about structured dialogue.

Maria E. Donawa, MD: But it's very, very general. So what's happened is is that team MB, Maria E. Donawa, MD: which not all notified bodies belong to. By the way, I Maria E. Donawa, MD: didn't have a chance to check the numbers now. But Maria E. Donawa, MD: team MB. Has developed a code of a code of conduct. And in that code of conduct it's actually listed. What they believe notified bodies can and cannot do. Maria E. Donawa, MD: So. I'm just gonna give you for the. In the interest of time. I'll give you one example notified bodies can discuss project plans or submission requirements. They cannot

Maria E. Donawa, MD: review clinical development strategy. Maria E. Donawa, MD: They can't evaluate your clinical protocol. By the way, this is something that we would always advise companies to do years ago, under the directives. Maria E. Donawa, MD: when companies needed to conduct a very expensive clinical investigation, we would say, yes, we can, of course, give you our view. But what you should do is you should submit this, or at least discuss this with your notified body, so you can see that you're whether you're on the right track or not. Maria E. Donawa, MD: you can't do that. Maria E. Donawa, MD: Of course, the Us. Has a completely different approach under the pre-submission program, which, of course I could talk a lot about. It's a very, it has a. It's been going on for quite some time

Maria E. Donawa, MD: under that program. FDA will provide companies with very detailed information on various stages of of Maria E. Donawa, MD: development or at the clinical study design stage. It's not a consulting function, it's not. What do I do? You go to FDA under the presub program, and you explain what you want to do what your approach is. Maria E. Donawa, MD: and it's a good idea to ask 3 or 4 key questions about whether FDA agrees with your approach. Maria E. Donawa, MD: and in general, FDA will respond to those questions and actually provide additional information. There's no charge, at least at this point, for the under the pre-sub program.

Maria E. Donawa, MD: so Maria E. Donawa, MD: dramatic difference. Maria E. Donawa, MD: Another difference is notified. Bodies have in general a broad categories of expertise. You know, they have groups Maria E. Donawa, MD: that are expert with active devices. They have non active device expertise, and if they need specialized clinical expertise, they they will contract out. Maria E. Donawa, MD: FDA has an advantage on this process on this system, because the FDA offices are arranged according to device types. And so you have Maria E. Donawa, MD: FDA officials working in these offices and Maria E. Donawa, MD: and gaining a tremendous amount of expertise, depending upon the device that they're working on. And that means that when you are discussing clinical study

Maria E. Donawa, MD: needs or clinical data needs, then that expertise allows them to provide in general. Maria E. Donawa, MD: very sensible, sensible, very logical feedback. Maria E. Donawa, MD: I someone may correct me on this one I was trying to. I I was not aware of a device, specific guidance document in in Europe there could be one. So you know, if somebody is aware of one. Please let me know. Maria E. Donawa, MD: there are a number of device, specific guidance documents in in the Us. That FDA has developed Maria E. Donawa, MD: and Maria E. Donawa, MD: not not all devices, of course, because there are too many, but the ones where there could be a doubt about. Do I need clinical data or not? And those guidance documents will actually address that in general.

Maria E. Donawa, MD: Now the cost issue. Certainly I can't go into a lot of detail, but, as you know, if you're dealing with a notified body. You have initial costs, you have ongoing costs. You're now being charged. If the notified body is actually providing structured dialogue, there's a cost for that. Maria E. Donawa, MD: So it's a lot of repeated costs. Maria E. Donawa, MD: FDA has cost, submission costs and annual registration costs. Maria E. Donawa, MD: There's no cost for the presub, and there's no cost for quality management system, inspections or quality system regulation inspections. Maria E. Donawa, MD: There's even if it's if the inspections are done internationally. Now, of course, some of those costs can be important. So I just wanted to give you just a couple of examples. So if you're if you are submitting a 510 K. And most

Maria E. Donawa, MD: devices enter the Us. Through the 5 10 k. Substantial equivalence route. Maria E. Donawa, MD: Then the standard fee is $24,000, more or less. If you're a small business, it's 6,000. Now, if if you have a Maria E. Donawa, MD: if you have Maria E. Donawa, MD: something called a de novo, can't again go into a lot of detail. But de novo is where the device doesn't really fit cleanly into a class 2 or class 3. It's somewhere in between. That's that's that used to be no cost now it's a hundred 62,000 Maria E. Donawa, MD: dollars for a standard fee and 40,000 for a small business fee, and of course, the Pmas are very much more expensive. We're talking about 500,000 versus 100,000 for small business. So there is a cost. It's just not, they're not. There's not the ongoing cost.

Maria E. Donawa, MD: So I'm now just gonna briefly talk about some examples and hopefully convey the strategy issues here. Maria E. Donawa, MD: So in this 1st example. This is a this is a non-invasive. It's a monitoring device. It's it can be used in home or hospital. I can't go into a lot of more detail than that, because I cannot absolutely Maria E. Donawa, MD: it. Give you an idea of exactly who this is. Maria E. Donawa, MD: It was a class 2, a in Europe. Maria E. Donawa, MD: and in this particular case it was a 1st Ce. Mark. So the the company was going for the Ce. Mark the 1st time under the

Maria E. Donawa, MD: Under the Mdr. And in the Us. It also happened to be a class 2, which meant that it needed to be substantial equivalent to another device already on the market. Maria E. Donawa, MD: Now I'm going to go to the last column first, st because in what happened was this, company went to the Us. First.st We very often will advise companies to do that. But in this case they did. Maria E. Donawa, MD: And there was a randomized control study with a device versus a standard of care, and the device had 2 capabilities. So they kind of split the study up the second one. The second study had addressed the second capability. They took that data

Maria E. Donawa, MD: that they had gained from the Us. And because the patient population and the medical practice and the use of the device was the same in Europe, they were able Maria E. Donawa, MD: to actually use that data Maria E. Donawa, MD: in Europe for their Ce marking. Maria E. Donawa, MD: Okay. Maria E. Donawa, MD: now, this second example, this is where we're talking about a class 3 implantable device in Europe. It's a dental bone filler. Maria E. Donawa, MD: However, it's a legacy device it was. It was on the market under the Mdd. Maria E. Donawa, MD: And because of that there was no requirement for. And it's standard it's a well established technology.

Maria E. Donawa, MD: And so there's no need for a clinical evaluation consultation procedure which is the Maria E. Donawa, MD: the very detailed procedure where you need expert an expert panel to weigh in. Maria E. Donawa, MD: The interesting thing here is that in the US. It's a class 2. Maria E. Donawa, MD: And so you need to check. You need to not just assume, when you're working out your regulatory strategy, that automatically the classes are going to be the same they very often are. Maria E. Donawa, MD: They line up similarly, but they can differ. So you have to make sure you know what's going on

Maria E. Donawa, MD: in the EU. This is just an example of the clinical data that were used. So there was a feedback study. There was clinical experience, which is mostly complaints, and if there were any adverse events. There was an investigator initiated study that was done. The company did not sponsor the study randomized control study, however, and there was another observational study. So that's the data that were used Maria E. Donawa, MD: and generated for ce marking Maria E. Donawa, MD: US. Maria E. Donawa, MD: Animal study. Comparing the device with the predicate device. Maria E. Donawa, MD: there was, there was no clinical study required, no clinical data were required.

Maria E. Donawa, MD: and in this case what happened was there was a reclassification. The the device had been a class 3. Maria E. Donawa, MD: But in this case Maria E. Donawa, MD: dental bone fillers without drugs were reclassified, reclassified in the Us. From class 3 to class 2. So again, a reason to check Maria E. Donawa, MD: the last example is in this case. It was a very novel, cardiovascular implant device. Maria E. Donawa, MD: And the so it's a class 3 implantable. 1st Ce. Mark under the Mdr. And clearly this was going to be subject to the panel Maria E. Donawa, MD: because of its novelty.

Maria E. Donawa, MD: like a hundred percent chance, it was going to be evaluated. Maria E. Donawa, MD: And in the Us. It was also a Class 3 requiring a pre-market approval. Maria E. Donawa, MD: This is just a requirement. Maria E. Donawa, MD: So Maria E. Donawa, MD: in the EU, the company and this company came to us where everything was done and we we weren't able to advise them ahead of time. They had conducted a single arm study with 70 subjects, with one year follow up. Maria E. Donawa, MD: To make a long story short the application was rejected by the notified body. Now there was no process where the company was able to find out that this was going to happen other than

Maria E. Donawa, MD: having advice to to do more than a single arm study with 70 subjects. Maria E. Donawa, MD: So they found out, after making the application to the notified body, there was no Maria E. Donawa, MD: at least they were not able to understand that there was a way for them to discuss their approach, or what they had the data that they had before actually going to the notified body going through the application process. What happened in the Us. You see what happened here. Maria E. Donawa, MD: They had Maria E. Donawa, MD: several pre-markets Pre. Sub meetings with FDA. I was told that initially FDA wasn't very interested in their device and then became interested in their device.

Maria E. Donawa, MD: and FDA required the pivotal study to be a prospective, randomized, open-label, blinded endpoint evaluation Maria E. Donawa, MD: with 2,000 subjects. Maria E. Donawa, MD: 1,000 each arm four-year follow-up again. This is a very novel, very risky device. Maria E. Donawa, MD: and as I mentioned, several pre-subs were held Maria E. Donawa, MD: so Maria E. Donawa, MD: The point here is that it's obvious. Maria E. Donawa, MD: Which is that Maria E. Donawa, MD: in Europe it's very difficult for for companies to understand what is going to be required. Of course. Maria E. Donawa, MD: in this case

Maria E. Donawa, MD: it wouldn't have been. It shouldn't have been that difficult for a company with a very novel, risky device to know that. 7, that a single arm study with 70 patients with Maria E. Donawa, MD: no real statistical approach power. Maria E. Donawa, MD: convincing study design was was done. I mean, most companies or many companies would know ahead of time. This is not going to work. Maria E. Donawa, MD: It is happening where notified bodies that understand that studies have been already looked at by FDA or approved by another regulatory body. They're they're fine there they will. That weighs heavily

Maria E. Donawa, MD: with their judgment Maria E. Donawa, MD: on whether it's acceptable. Maria E. Donawa, MD: And then so Maria E. Donawa, MD: that's again. It was a, you know. Maria E. Donawa, MD: kind of a on roller skates in terms of what the differences are. So I'm looking forward to the questions. But I just want to finish up with Maria E. Donawa, MD: just a quick update on what's going on with these 3 guidance documents. I didn't mention the Med Dev, the Med Dev guidance document on clinical evaluation, which I'm sure everyone knows it's been around at least the Rev. 4 since 2016, and it was still being acknowledged as useful under the Mdr. That's being updated now.

Maria E. Donawa, MD: And so Maria E. Donawa, MD: and the and the comments from the stakeholders are due on the 7th of October. Maria E. Donawa, MD: It's not clear when the when it's going to be published. Maria E. Donawa, MD: Okay, so the Clinical Investigation Evaluation Working group. Maria E. Donawa, MD: which is where Tom used to be and used to chair. Maria E. Donawa, MD: And I've told him many times that we miss him. Maria E. Donawa, MD: Anyway. That's the group that's responsible for updating this this document Maria E. Donawa, MD: in terms of 14, 1, 5, 5, the 2020 standard. It's being revised

Maria E. Donawa, MD: the revision actually has finished. And a final an Fdis is is hopefully going to be available by the end of 2024. They'll be voting on that that final document, draft international standard. Maria E. Donawa, MD: And then the standard can be final. And also I didn't put it down here, but there's still an effort on harmonization of the standard. There's been a tremendous delay in harmonization. So we're hoping that even even though oh, the harmonization of the 2020 standard. I've actually mentioned that here and skipped over it. So Maria E. Donawa, MD: there'll be harmonization of that standard. There'll be a lag period, and then the 2024 version will be available at some point. The standard on clinical evaluation is still on. In early days there was a lot of work done on this, and then it was clear that it wasn't that the work wasn't getting very far.

Maria E. Donawa, MD: And so Maria E. Donawa, MD: we're starting now with another document. That's a little more mature. There's going to be a meeting in France. I'll be participating in this meeting. It's a face to face meeting. Maria E. Donawa, MD: and hopefully we'll we'll get somewhere and see how that progresses. Maria E. Donawa, MD: And I'm going to stop here. Maria E. Donawa, MD: Okay.

Yep. Sorry. I was like getting myself off mute. There, that was good.

Maria E. Donawa, MD: Now, should I stop sharing? Let me stop sharing.

No, it's it. That's fine. Yeah, we could. We could

Bring up your last slide. Yeah.

But it's.

Maria E. Donawa, MD: Thank you. That's a great place to leave it. Maria E. Donawa, MD: Oh, okay.

I appreciate both of those presentations, and that was a lot a lot of really details, but interesting points about the some of the differences between both kind of definitionally and practically, and with some of the examples. So I why don't we, you know, go into some sort of more, little more open discussion and questions, and I, you know, have been monitoring some of the the Q. And a. Put in by audience, and I think I can maybe use some as a starting point here, because I think there was. There was a number of ones that got prompted. I think, Berea, in your one of your early slides in terms of the intended purpose. Intended. Use indications for use, idea and sort of I know you you commented about.

you know. Maybe not. You can't use your Us. Indication for use for EU maybe a little more elaboration with examples on that sort of maybe different justifications and needs for those making that basic definition for what your your target is there in the EU and the Us. I know, Tom, you had gave a nice little to an original question on, on sort of helping with some of the definitions and written form there. But maybe we could use that as a starting point. Just because that's I think of, you know, fundamentally, what you're going to have to do is is based on on sort of that. These definitions of how you're defining the you know what what your device is doing and what context, it's doing it. So maybe I don't know, Marie, you want to start. And, Tom, you want to jump in and sort of just getting a little more onto that that point, and.

Maria E. Donawa, MD: Yeah, okay, let me just say this, that what happens under I'll start with I'll start with the EU. Maria E. Donawa, MD: Because what I see again is when I'm looking at documentation from a company that has Maria E. Donawa, MD: already gone to the Us. They market their product in the Us. Maria E. Donawa, MD: They have an indications for use statement that was fined for FDA. Maria E. Donawa, MD: And I'm not saying I don't want to give the impression that Maria E. Donawa, MD: a indication, an indication for use statement in FDA in the Us. Maria E. Donawa, MD: Will always be inappropriate for Europe. It's just that it very often is.

Maria E. Donawa, MD: The complexity of generating the indications for use in the Us. Maria E. Donawa, MD: Is high. Maria E. Donawa, MD: because Maria E. Donawa, MD: there are 2 concepts. One is the general, and the term intended uses is used in the Us. Not intended purpose so much, but intended use, intended use. It's the overall, you know. What does the device do? Maria E. Donawa, MD: And and then the indications for use tend to be more specific, and very often you will have a combination, so you will know what the general intended use of the product is, and I had an example. But I can't seem to find it.

Maria E. Donawa, MD: You will know what the intended use is. Maria E. Donawa, MD: And, in fact, by the way, FDA considers very important. If you're going to make any modification. They're looking at, both at general Maria E. Donawa, MD: intended use and all those, and also the specific indications for use. And somewhere in a guidance document. If you change your intended use, then you're going to have to have another submission, whereas you may be able to keep your same submission. If you simply change some Maria E. Donawa, MD: more detailed facet of an indication. Maria E. Donawa, MD: I think I gave an example of tissues, the type of in a cutting instrument, the type of tissues that can be cut with a particular device. If you try to use that approach in Europe. 1st of all, you're going to get questioned about, what are you talking about

Maria E. Donawa, MD: and and and I've seen more than once where a notified body will say, Well, you didn't give me your indications. Maria E. Donawa, MD: even if in Europe, even if in Europe. Maria E. Donawa, MD: defining or specifying indications is not applicable to the device, because in Europe you're talking about medical conditions. Maria E. Donawa, MD: and Maria E. Donawa, MD: you may not. Maria E. Donawa, MD: You may not Maria E. Donawa, MD: a need to specify Maria E. Donawa, MD: indications, because your device covers a whole range of medical indications. I think maybe I'll stop I'll stop here, and then I'll see if I can add something else because I could. You know I don't want to go. Go on too long.

Maybe just to complement what Maria was saying. I agree with how Maria described it, I guess when I try and describe it, when I'm teaching, etc. You know, I would say that the intended purpose is, what does the technology do? Whereas the indication tends to focus on? What does it do for the patient. and we have an example from the from the chat there, just from a thermography device. I guess in the European context there is a definition of intended purpose. But it's somewhat circular, you know. It's the purpose described by the manufacturer and their technical documentation. So that really doesn't help a developer to say, Well, how exactly should I frame this?

But it's very important in the EU regulatory context, because your intended purpose is really the capstone of all of the technical documents that you then build for your submissions. So your intended purpose will have to be reflected in your clinical evaluation and in your risk management, and in lots of the other aspects that you have to prepare. I guess maybe thinking about us versus EU. One of the challenges, maybe as to why it can sometimes be challenging to take your Us. Indication and apply it in your EU technical documentation is that the notified body will come back and will expect quite specific clinical data to support whatever indication you describe.

so that can sometimes raise strategic differences across the 2 systems. But I guess in general, it's important to just remember that the intended purpose is really important to think about at an early stage of development, because it helps to set your clinical development plan, as well as being something that you have to reflect across your technical documents.

Maria E. Donawa, MD: Excellent. I'm sorry, David. Let me just Maria E. Donawa, MD: Add to that I found Maria E. Donawa, MD: so again, if you are looking, if you're looking for further guidance on indications. Maria E. Donawa, MD: Then the Mdcg guidance document 2026. You really really need to look at that, because, again, that's the only place that you will find a detailed discussion of how you should interpret indications you can kind of assume. You can make assumptions reading the Mdr. But that guidance document will actually help you to understand that.

Great so I mean, I think another thing that I see that I will. Certainly I have question with, and I also see, you know, reflected in some of the chats. I mean the sense I get from the from overall. The presentations is, you know, the Us. Obviously clinical data requirements could be, you know, highly robust, etc. But there is more predictability and and and and transparency and understanding, while in the EU there may less so in that respect. So maybe we could. You know, 1st of all, you know, to what extent that that rings true. And but we're talking about. Maria talked a little bit about structured dialogue and to what extent? That's a that's a tool

in the EU for understanding some of these issues, and what your expectations will be versus the pre-submissions process I know notified bodies are clear, you know I was at the reps meeting this past weekend, and and certainly that there's some element of this structured dialogue offering. That is, that is, that is happening. But there's also probably more talk about what you can't talk about within the way you can. So maybe a little more clear clarity of how how do you think about getting this kind of information that you need about what your requirements will be in the 2 locations, and how you could sort of use that. Consider that from us as a device developer. Tom, do you wanna.

Yeah, I'm happy to start. So you know, I guess, thinking across the 2 systems with the Us. FDA, if you're a class 3, and you have pre-market approval. That's a high level of evidence. So that's quite a given, and you have to get your clinical trial design. It has to be robust. But you can engage with FDA for the class 2 or 510 K clearance pathway. General devices can often go through that without additional clinical data. So you say, I'm substantially equivalent to the predicate, and I get my market access. But what I think can happen with FDA is that sometimes, and especially for software. You might be going through the class 2 clearance pathway. But FDA may still want to see some additional clinical data, and in that case, what you can do is engage with FDA through things like the pre-sub process.

and they can be very particular. They can tell you. We want to study design with these kind of endpoints or this study duration, to satisfy us, to meet the requirements, to go through that pathway in Europe. It is a little bit more complicated because we use the more generalized concept of clinical evaluation. So that applies across all of the risk classes. But there's an expectation that you can be proportionate in terms of the data that you use, and things have also gotten a little bit more complicated in terms of your ability to claim equivalence. and I'd encourage people watching. They could look through the Mdcg guidance and web page, and you'll see there's about 10 guidance documents related to clinical, and there was one published last year about equivalence. So

you'd have to look at Article 61 of the Medical Device Regulation, and look at that guidance, and it will tell you things about what level of access you would need to claim equivalents as part of your approach. So when you figure out what's legally possible, and then you develop your strategy. One of the challenges in Europe is that it's difficult to bring that proposed strategy to get some greater surety. And so you might have seen from the notified bodies. They have a recently revised code of conduct, and you could get it through the team, MB. Webpage, but it now very clearly says that notified bodies as part of structured dialogue

can't help you with your clinical development strategy, because that would possibly cross over to line into consultancy. At the same time there is a push coming from regulators in the Medical device Coordination group to help developers through structured dialogue. And that 1st happened as a result of a guidance published in 2022, and that's called Mdcg. 2022 to 14, and structured dialogue is designed to help with the predictability and efficiency of the conformity assessment process. So it can do that. But it can't help you with your clinical development strategy. But if you have some refined questions about your clinical evaluation, you might be able to get some information from notified bodies. But it's not completely clear in practice, and there might be some variability around the system. So notified bodies can give some advice. But it's mostly about your conformity process and those kind of aspects. Other sources of advice are available, but they're somewhat patchy or in pilot stage. So

the Ema expert panels have pilots running. Now that would have given advice to about 15 medical device developers. And there is a revised pilot. And there's also an emphasis on orphan or pediatric devices. And so you can apply to that it's also free of charge, and there's something like a 90 day timeframe where the experts can give you some short feedback on your question that you propose. and if you're at the stage of a pre-market clinical study depending on the Member State, you're going to run it in. National competent authorities can sometimes give very good informal advice. So in Ireland, for example, we would have preliminary or pre-submission meetings, and when I was a regulator I used to really like that because, as an assessor, if you can put your hands on the implant.

you learn so much more than you do from getting the file in cold, having never seen it, and it essentially reduces the amount of formal questions that you raise during the assessment process. So if that's available in the Member State that you're targeting, and that's also something to encourage. But I guess our advice structures in general are at an earlier and less prescriptive stage compared to the Us.

Maria E. Donawa, MD: Fantastic, Tom, let me just add to you add to what you you've said, because you brought up some things that are extremely helpful. If you go to a competent authority, you and as you mentioned, certain competent authorities will provide this advice. Maria E. Donawa, MD: they will also tell you that they're not involved in the Ce marking process. Maria E. Donawa, MD: so they can certainly help with study design. So I guess the best advice in the absence of concrete advice from a notified body Maria E. Donawa, MD: is, if you are going to have to, or you think that you may need to

Maria E. Donawa, MD: conduct a clinical study which very often is the most expensive thing that a activity that a company does. Maria E. Donawa, MD: Then you really need to Maria E. Donawa, MD: have the have the expertise, either in-house or or outside of biostatistical expertise, so that you. You have an idea of how statistically valid your study is. There's a lot of emphasis now in Europe, and including the in the Med Dev guidance document on the statistical validity of clinical data of clinical studies. Maria E. Donawa, MD: So again, the very activity that causes companies to have investment in resources and and funds is the very activity that we don't have ideal methods in Europe to get feedback. That is why, when it's high stakes, we will tell a company if you are planning on going to the Us. If you happen to plan on doing that.

Maria E. Donawa, MD: then we would highly. We would suggest that you Maria E. Donawa, MD: engage with FDA, go through the presub program, get the advice that you that they will give you and use that, and then you can decide how you're going to use that in terms of your your studies, you know you may have a variation of that study suggestion that you would conduct in the Us. You've got to. I mean the EU. You have some options Maria E. Donawa, MD: that you would not otherwise have. So we're we're very, very often providing that advice. And I, by the way, it's very frustrating. Maria E. Donawa, MD: I mean, I

Maria E. Donawa, MD: well, I suppose I could be way more diplomatic. But I'm not gonna do that. Maria E. Donawa, MD: The point is this. Years ago, under the medical device directives. As I think I mentioned earlier, we would tell a company we would advise a company. Maria E. Donawa, MD: talk to your notified body about this Maria E. Donawa, MD: and and before you launch into some, you know, high high stakes, expensive Maria E. Donawa, MD: study. And it's way beyond the this, the time that we have and the structure that we have to talk about. Why. Maria E. Donawa, MD: this is no no longer possible under

Maria E. Donawa, MD: under the Mdr. Maria E. Donawa, MD: but yeah, it's it's very frustrating.

But so essentially, you're saying you might have a pre-submissions process. And essentially, it's the FDA pre-submissions process that you can use for your used to guide for for all, for your clinical considerations on both sides.

Maria E. Donawa, MD: Yeah, yeah, basically, basically, it's that. And of course, not. Every company is in a position to to go through the pre-sub, or maybe their their regulatory strategy doesn't call for them to consider the Us. As a market. So. But we've even. We've even suggested that companies, you know. Maybe in future. You're you're interested in doing that. So just get this feedback because it's it's valuable. Maria E. Donawa, MD: and you can use it in the Us. In in Europe. And of course, there the proviso is that the patient population Maria E. Donawa, MD: is applicable in in Europe. So if you are going to the Us. And you're talking about studies for us purposes. Clearly, the patient population and the medical practice needs to be applicable to the EU setting.

Maria E. Donawa, MD: And you need to definitely make sure that's the case, otherwise. Maria E. Donawa, MD: you know the advice is going to be faulty.

Right? Right? So I mean, and that was gonna get to sort of. And I noticed some questions in the chat on, you know, using right using data collected in the Us. For the using, I assume, vice versa. As well. You know that seems to be something that is both allowable. And perhaps the way to go in some cases with what we're talking about. any further thoughts on that or.

I would just like to interject before we run out of time, if everybody would please check the link to the survey in the chat and complete the survey. That would be very helpful to us in terms of framing things going forward. And that's all I'm gonna say. Thank you.

Absolutely well. considering we're we're getting close to time. Why, I don't know if we want to. Yeah, fold that into sort of, you know, kind of a a highest takeaway in terms of considerations for how to look at. You know, we're talking about it right now in terms of interacting with the 2 in a sense of thinking about. If you're going to go to the Us. Think about that to help you with your you as well. So, maybe, but overall sort of parting thoughts in that direction, or or with regards to you know what you'd want to leave the audience with, since we are running out of time. Tom, do you want to jump in with any.

Yeah, sure. And what I think. Maria's talk was really excellent, because it showed some applied strategies, and where there can be differences across the system. You know, we hear a lot of people talking about challenges with Mdr. And the introduction of technology. I think it's still very possible to introduce technologies in the European system. But it just means that there's a little bit more regulatory preparation and legwork needed. We have advice structures that are at a quite germinal stage, but will hopefully further develop over time. But it's still very possible to introduce new technologies in the EU. So please don't completely give up on EU as a 1st launch market strategy.

I guess, apart from that, you know, Maria mentioned some of the standards and guidelines in development, and hopefully they will be available in the forthcoming months. You know the new clinical evaluation, regulatory guidance as well as the 1st Iso standard on clinical evaluation. I think that would be really interesting if we can get those right, because, especially with the Iso, 1, 8, 9, 6, 9, as part of the Irish National Committee, we would have had some engagement, and I think one of the concepts underpinning that is, to bring clinical expertise to the earliest stages of design, validation.

Maria E. Donawa, MD: Very good. Point.

And and I think if we could figure out a better way to make that harmonized and internationalized, it might help us to move that bit closer to international harmonization. But I guess we'll have to watch and see how these things develop, and then how they get out and implemented. But there are some promising things on the horizon.

Maria E. Donawa, MD: I know we're running a bit over. So I'll just Tom. That's an excellent point. And the clinical evaluation standard effort, by the way. Maria E. Donawa, MD: is for the process. It is an attempt to describe the process of clinical evaluation and to try to stay away from the very detailed Mdr. Requirements, but yet still help the process. Maria E. Donawa, MD: So if we're successful there, then it could be very positive.

Great. Yeah, there's a lot here, obviously, and many questions in the chat which I think we're also we'll take a look at. I'll let Sean end us up. But I really appreciate the the kind of what we have been able to pack in Tom and Maria on this topic that everybody's kind of obviously dealing with and trying to address in their in their medical device development plans. So with that, I don't know if, Sean, do you want to? Kind of provide any closing instructions for us before we sign off.

Yes, the closing instructions are, the recording will be available. It will be sent to everybody that registered within 24 h, along with the links to the slides. we will review the questions, and where appropriate, we'll respond directly to the person asking the question. There will be a series of follow-ups. To this I would also like to get an idea of if anybody would be interested in a specific structured dialogue. Webinar, with notified bodies present as well as industry representatives. I think it would be very useful to put those 2 groups in the same room and let them try to raise the dialogue so to raise the discussion to a higher level. I think there's an opportunity here.

to facilitate the implementation of Mdr. And ivdr through structured dialogue. And we'd like to facilitate that if you're interested. please feel free to email me. thanks, great.

Thank you.