A Must-Watch DCN Dx Webcast from RAPS: Parallel Regulatory Planning for EU and US Market Entry

Dan Simpson: Hello, everybody. My name is Dan Simpson. I'm the Director of Regulatory Affairs at DCN Dx, and I'm very happy to be here today. My brief background is that I've been in In Vitro Diagnostics for over 30 years, both on the technical side and mainly in regulatory quality and clinical. I'm very happy to be here supporting RAPS. I'm a longtime RAPS member. I also have the RAC rep, I'm sorry, the RAC, so I'm very happy to be here. Sarah?

Sarah Barchard: Hi, everyone. It's lovely to be here. My name is Sarah Barchard. I am a Senior Clinical Trials Manager here at DCN Dx. I have been in the industry for just about 18 years. 15 of those years I've dedicated to working in the IVD space, primarily in clinical operations. I'm excited to be presenting alongside Dan today. This has been a tremendous learning experience for me, and I'm excited for what we have moving forward.

Sarah: So let's start with why we're here today. This session today, we'd like to focus on helping teams identify and avoid issues that tend to show up late, usually during design validation, when you're running parallel EU and US programs. There are more companies aiming to enter both markets simultaneously, and that introduces complexity. So we have three goals that we'd like to focus on today. First, we'll walk through the key differences between the IVDR and FDA framework that actually impact development, not just regulatory theory, but how these changes affect the design of your program. Second, we'll highlight common pitfalls, especially in analytical and clinical performance that teams don't always anticipate until it's too late. And third, we'd like to discuss specific examples so that you can apply these directly to your own programs. In the short hour we're going to have together today, here's what we're planning to cover. We'll start with a brief history of the IVDR, where things stand today, and what's changing, just to level set the regulatory context. Then we'll take a look at the EU and the US framework side by side, not just differences, but where they're going to overlap and where potential issues can arise. From there, we'll spend some time on parallel planning and where that actually breaks down. This is really the heart of our talk today. Then we'll go deeper into the performance evaluation, both from an analytical and clinical standpoint, because I think that's where the real work and the risks sit. We'll touch on post-market requirements, technical documentation, and then we'll close with a couple of key studies and key takeaways. We'll also try to save some time at the end for Q&A.

Sarah: Before we just get into the real meat of why we're here today, I just wanted to kind of set the stage. We think that it's important to understand where the IVDR is right now, and there's a lot of things that are happening. So in that way, it makes it a little bit difficult for manufacturers to make good decision planning.

Dan: Okay, yes, I was very excited to start talking about this. So yeah, so if you're here, you probably know this whole story because you have had a lot of angst around this. I mean, I know I certainly did when this first came out. And so when you talk about the journey from IVDD to IVDR, I really like to focus first of all on that. What does that journey from the D to the R really mean in the context of the EU and why was that so big in the first place. So the D being directive and the R being a regulation in the EU in their system of governance that really means a lot from a philosophical standpoint. So a directive is something the EC creates for laws like regulating In Vitro Diagnostics. And it gives those directives to the member states for them to consider putting into their law. And so most of the time, those member states just put the directive as is into the law. But sometimes in the case of this, there were countries like Italy and some other countries that added on additional things. So from a manufacturer standpoint, it was still harder to get into other countries and there was different considerations. So therefore, it wasn't very well standardized, even though it was a directive across the EU. And so that was one of the big things, right, initially. But then if you notice that first little gap, which is not obviously to scale. You had 98 to 2017 where you were under this directive, and then suddenly they published this IVDR. Well, why did that happen? I think a lot of people know that there was this breast implant scandal that happened in the early 2000s, and it really drove MDR and IVDR because it exposed some of the weaknesses in the system. Everybody knew you went to EU first back then because it was so much easier. In a matter of fact, there was 90% of IVD companies could self-declare under IVDD and now it's kind of reversed under IVDR. So now we're under this regulation that was published in 2017, as we're going to discuss. It is way more rigorous. That was just one example. The documentation, as you'll find out as we go through this, and I'm sure you've already found out, is way more comprehensive. And so because of this, there was a big burden on the system, especially notified bodies. At one point, there was only seven designated notified bodies. Now I think there's 19. But still, because there's so many transitional products compared to MDR, there's a backlog. So we get to 2022, which was the original date of application. People weren't ready. They kicked it out a little more to 2024. Still, people weren't ready. So now we have this amending regulation that they put into place for transitional products, and now the EC says this is the last time — we're serious this time. And so this is my class so you can just see here that starting with Class Ds in 2025, you had to have your application in place with a notified body. For more people probably on this call, Class Cs should have already, if you have a Class C, you should have already had that application in with the notified body. And then it's a two-year period for when you need to have your CE mark, sort of giving you two years. But as I said, they're saying this isn't moving anymore. So, yeah, so, you know, that's it, right? That's all we have to worry about.

Sarah: Well, now we have this new wrinkle, which hopefully will be a good thing. In December of this past year, because of still all of the burden, because we had the regulatory pendulum swing, right, and we went maybe a little too far. So now the EC is considering or has published proposals for simplifying both the MDR and IVDR. And so they've done this in a not so easy to read practice copy of the regulation. And so you can see the actual red lines. But one point to say here is this does not affect the transition that I just talked about. Transitional products, you should still be complying with those deadlines. But some of the main proposed changes is the certificate validity cycle, which is set at five years now. When that certificate expires, it's more paperwork on top of the paperwork you have to do already. And then they're considering doing a risk-based approach for these timelines. Obviously, lower risk products could be longer than that. Maybe even higher risk could be shorter than that. I don't know. The clinical evidence part is going to be the thing most people are concerned about or interested in. So we're going to talk a lot about the equivalence proofs that IVDR has, which are not really the same at all as substantial equivalence in the US. So they allow you to use an equivalent product to minimize your clinical evidence that right now is not standardized at all — it's all driven by the notified body and what they, that one in that particular viewer might want to see — so they're trying to standardize that and enhance that and then also use broader use of other sources of non-clinical data for your clinical evidence that kind of goes into well established technology. Obviously, well-established technology, there might be lesser requirements or possible exemptions. I wanted to add in the in-house IVDs because in the US here, we've been going crazy with the whole LDT issue, which is what in-house IVDs are. And so, obviously, the IVDR is much more stringent over there about it. And a matter of fact, they had in their original wording in the regulation that if there was a regular IVD on the market for something you were doing an in-house IVD for, you couldn't market it, but now they're taking that out and they're actually allowing transition in between institutions. It is important to note that regardless, it's still more difficult than in the US because you have to still put your in-house through the IVDR. Software driven more by the MDR, but when it comes to the software algorithms within IVDs, they're proposing moving the risk documentation level of these algorithms to a lower algorithm as opposed to something that would run a medical device. And then also, I think most people know there's an AI Act in the EU that goes along with regulation if you have AI in your algorithm. And it's being reduced in risk as well there on the use of AI in diagnostic products. And then with classification, some products may be reduced in risk classification. And then one of the big things is they're opening up more avenues for breakthrough devices and devices that meet unmet needs. Like the US, they have a similar breakthrough program use of orphan devices. And now my favorite, a regulatory sandbox. I mean, who doesn't want to play in a regulatory sandbox? So what this is, is that for certain devices, you would be able to try them out on market in a very controlled environment for certain situations. So that will be interesting to see how that plays out. And so what it means to you in the end, again, transitional products, same timelines. But then for everybody, really, you know, you should be planning. This isn't law yet. We don't know how it's going to change. It's going to probably be another year or so before this gets finalized. Worst case, probably. So you need to plan for the current law, but just keeping an eye on the things that might change. And hopefully they change for the better.

Sarah: Great. So speaking of planning, we're going to talk a little bit about parallel planning. We recognize that a lot of IVD developers are trying to commercialize a single product in both the EU and the US. And while that's efficient, it also has to be done correctly for all of the reasons that Dan was talking through. Parallel planning, it's crucial to a manufacturer's program when trying to satisfy multiple regulatory pathways at the same time. At a high level, the types of validation studies may look similar across the regions, but the expectations of the depth of evidence, the documentation, how things are reviewed, those can differ significantly. And the key point here is that parallel planning really starts in the design and development, and not later. If you're waiting until the assembly of your regulatory documents, you're really already kind of behind at that point. So we really encourage people to align early so that their evidence packages work for them in both regions without having to rework their programs later.

Sarah: Okay, so now that we've kind of set the IVDR context, we'd like to take a step back and look at the EU and US framework side by side. This section is geared towards understanding where those frameworks align and where they diverge in ways that affect development.

Dan: Okay, great. So where I always love to start is, of course, intended purpose versus intended use. And really, I'm going to start with that big point down there is that, you know, Sarah and I will see in different stages right — people come to us and they don't fully understand what their intended use is and how it's going to clinically be used in the field by physicians and how it can even be misused — and so that's something you need to have that information ahead of time so that's why this is so important because it's going to drive your whole development and your regulatory strategy. And so we can't stress enough to have this really well thought out. And so when you look at intended purpose versus intended use, there's really difference, but yet there is, and it's really kind of hard to quantify. The meaning and usually the wording are the same, but it's the weight behind it that can be different. And so if you look at the scope under IVDR, and you think back to why IVDR is in place again, it's because of the legal issues and there was all of these legal problems with these poor women that suffered from that breast implant defect. And so now the IVDR is all about legal responsibilities. So the intended purpose is a legally binding statement for that manufacturer. You are swearing that this is what this device does and will be safe and effective within this. And obviously the FDA, the implication is still there. It's just not as weighty as in the IVDR. And so then also in the US, you have intended use versus indications for use, and the IVDR intended purpose encompasses both. And really in the IVD space in the US, often the intended use will encompass both too, but intended purpose is really that whole picture. And so in the EU, the intended purpose completely drives the classification of the device. And we'll talk about the differences later in classification because it really makes a big difference. In the IVDR, you're classified directly by your intended purpose and your product, where in the US, it's more about fitting into classification regulations and product codes. And so the intended use informs that classification, but it doesn't directly drive it, and even the indications for use may have more of an effect on that. So I talked about the regulatory weight already. Along with driving the classification, it also drives all of your technical documentation in the IVDR, the intended purpose does. And so it's really mandatory in every section of your technical documentation. It's really the basis for all of your arguments of your clinical evidence, scientific validity, state-of-the-art performance evaluation. In the US, obviously, it will affect those things as well, but just not really on that high-scale level and not as early like as you're starting, and we'll talk about that as we get into the technical documentation.

Dan: So quickly side by side. So IVDs are IVDs really in both. There's really not much difference. The classification system we just touched on, but more directly here, there's Class A, B, C, D in the IVDR. And then in the US, you have one, two, and three, both risk-based. And then the way you get onto market is declaration of conformity through conformity assessment. Class A, you can self-declare, and then you have the other ones needing to go through a notified body with increasing level of documentation and rigor as you go for the US. You have Class 1, 2, 3 again. And so Class 1 are what we call general controls and then typically 510(k) or de novo if there's no predicate for Class 2. And then Class 3 requires the rigorous PMA. The output, obviously, CE marking on the IVDR side. And then you get your clearance or approval on the FDA side, labeling requirements, and then quality system requirements. And then for post-market, this is going to be a theme on the IVDR. It's called vigilance for a reason because it's more proactive. And then really with the FDA, though it's starting to be a little more proactive, it still will always generally be more reactive with everything kind of being driven by complaints. Okay, so quickly what they share — both risk-based classification systems. The evidence is usually proportional to the risk in both cases. Labeling in IFU generally will be the same. And then post-market obligations both require this subset here, which is the more reactive stuff of complaint handling, adverse event reporting, and recalls. And then quality system has become more aligned now, thanks to the QMSR that now references ISO 13485. Both, interestingly enough, don't necessarily require ISO 13485, but it's kind of the industry standard, and obviously other countries do require it, so it is usually what everybody uses, so that is very well harmonized now.

Dan: And then, so where they significantly differ, and this obviously is not all-encompassing. IVDR, the competent authorities, which are the FDA equivalents in the member states, source out the notified bodies to do the review. And then FDA will be reviewing the submissions themselves. Exemptions from that review, marketing review — it's very well-defined Class A's. You can self-declare unless you're a sterile medical device, which really isn't this talk. And then for FDA, it's really by the classification regulations and then the product code, because we did say Class 1 are generally exempt, but there are some cases where that can be a Class 1 510(k), and there are some cases where there can be a Class 2 exempt. So it's really driven by the specific product code. And then even additionally, if FDA decides a Class 1 has enough differences, they may require a 510(k). So it's definitely not as standardized and more open to FDA interpretation. Substantial equivalence, again, this is not defined like it is in the US, but they have this equivalency, which right now is kind of vague about how you can utilize other products to utilize maybe some of their clinical evidence and reduce your clinical evidence burden. Like I said, this new proposal may put some more guardrails around this process and may enhance it. So we'll see what happens there. Obviously in the US substantial equivalence is very well defined in that guidance document that they have. So it's a very much a different situation there. And then we already talked about that and we'll talk about it more about post-market and then early collaboration. So unfortunately, there's not the beautiful FDA pre-submission over in the IVDR. The MDR actually has a more established notified body early interaction process. IVDR does not. But what I am hearing from the field is that notified bodies are starting to require the application process earlier and then for transitional products, it's two years. So they're starting to have more communication, allowing more communication with the sponsors. So hopefully you can ask some of those questions you would in the pre-submission to your notified body earlier.

Sarah: So in this next section, we're going to take a look at areas where parallel programs encounter issues. We've grouped them together into four major pitfalls. Each one represents a place where kind of assumptions break down between the EU and the US, which is easy to do, I think, because of all of the things that Dan just highlighted. Importantly, these issues usually don't show up early. We wanted to point them out because they tend to surface later in the programs. And these changes are costing manufacturers time and money. So as we go through kind of the pitfalls, we encourage you to take a look at your current program and maybe try to see where you guys might be vulnerable. Before we actually get to the pitfalls, we'd like to take a quick poll today. We'd like to get a quick sense of where everybody is. So if you could kindly do that, we'd like to see which of these situations best describes your current IVDR position. Are you fully on track? Are you behind schedule? Are you still planning or are you not targeting the EU market at all? And we'll give everybody about a minute or so to do that before we move on.

Dan: I am very pleasantly surprised that we got that 50% of everybody is just rolling through this, no problems.

Sarah: I love it. So everybody can kind of take a look at what Dan was talking about — it looks like a lot of people have a strategy in place and they're kind of on track with their plan. So that's great. We're really excited for everyone. Okay, so as we go through the rest of the talk, I just encourage everyone again to try and map where we're discussing your current state, because the risks obviously look different depending on where you are in your timeline.

Dan: So for pitfall number one, this is the case where we kind of had alluded to this before because of the classification system differences — you can have the same product, same intended use, and they can end up in different classes and then require different amounts of validation. And so as mentioned before, the IVDR classification — you go through a rules-based classification system — and there's some examples here because really where the difference lies is on Class D and Class C, and you can see some of the examples there. They're not all inclusive again and then the fact too that a lot of self-testing, most self-testing are Class C, you go through these rules — you go, are you Class D, are you Class C, and are you Class A — and then if you're not any of those your Class B, which a lot of things will be lumped into, but so some of those tests that are noted as Class C may end up you know going into FDA since it's by-product code there might be predicate devices available or these easier pathways on the US side compared to what you're going to have to do for a Class C conformity assessment. So that's the consequence, is that what might be more moderate from a risk perspective due to a predicate device or something like that might have higher scrutiny over there in the EU. That could bring on heavier timelines, more documentation, more validation. And so really what the plan would be to overcome that would be to, you know, in a regulatory strategy, it says before design freeze here, but really in a regulatory strategy, if we're going for the US and the EU, you should be doing both of those strategies simultaneously. You should be noticing where the validation criteria could be a lot more on the IVDR side of what the differences might be. And so really that's the lesson of this pitfall.

Dan: So then for pitfall number two, it kind of ties in a little bit with that again, but going back to that, there is no 510(k) equivalent in the EU. So with that, again, so going back to the examples, there could be some of those product codes where it's a higher risk — let's say it's something for an infectious disease, right? That's not a highly propagating one, but is an infectious disease. It's an infectious disease status. That's Class C in the IVDR, but there probably could be a lot of predicate devices. So you might be doing a method comparison on the US side, but then need more clinical evidence on the IVDR side. And then you may also have to do some EU trials if the population is significantly different over there in the EU with that particular disease. So again, you really have to be developing a clinical and analytical plans of both markets in mind and seeing what the difference is. And this is where pre-submissions in the US are great. And then talking with your notified body.

Sarah: Okay, so similar to what Dan was talking about in the difference in classification, this is another very common and often underestimated challenge. With at-home and point-of-care products, at a high level, the issue starts with a mismatch kind of in regulatory frameworks, right? In the US, you have a CLIA waiver framework, which allows tests to be used outside of a CLIA certified laboratory if they meet a certain criteria. But under the IVDR, there's no direct equivalent to a CLIA waiver. Instead, most self-tests are classified as Class C, as Dan mentioned earlier, which is a significantly higher risk category than teams, I think, expect. And that classification then drives a much more rigorous conformity assessment under Annex IX with full notified body involvement. So it's important to highlight here that point-of-care or near-patient tests on top of that are then classified independently. So they're not thrown into a bucket just like the self-tests are. They're not treated the same way as they are here in the US as CLIA waived tests. Oftentimes, like Dan was talking about earlier, you know, your intended purpose is really going to drive your classification. And we see that specifically here with the near patient tests, that those are looked at not just as like we're throwing them into a Class C, but that they will be looked at and evaluated the same as like a professional test. So the consequence is that a product can be CLIA waived in the US but can require significantly more usability data, comprehension studies, flex testing in the EU. And if that work isn't planned early, it usually shows up later in having to add additional studies or delays in the timeline and increased costs. So the practical takeaway today that we'd like you guys to consider is leveraging CLIA waiver thinking to inform your IVDR strategy. But of course, it's better to start with a user risk assessment and develop a unified human factor strategy in your regulatory strategy that satisfies both of the regions from the beginning. This will ensure that your validation work actually addresses the needs of the user and the risks assessed. The last pitfall, I think that we've been kind of dancing around this a little bit, is relating to parallel planning and the notified bodies and their timing. This pitfall is more of a process, really, than anything else. In the US, the FDA reviews submissions directly, while in the EU, for most devices, review is done by a notified body, and there are a limited number of them. That capacity of notified bodies has to cover both new device submissions and all of the legacy products that are transitioning under IVDR. So it could mean that there is a significant wait time from application to certificate decisions. And if there are deficiencies, that can even extend your timeline further. The risk here that we see is basically waiting too long to engage with a notified body. It looks like we're moving towards a lot of the notified bodies being more engaged or pre-engaged with companies. So our recommendation is going to be to initiate contact early and to align with the notified body on the scope, classification, and expectations of your regulatory strategy because timing here is of the essence and it's really something that isn't easy to recover from later on. Okay, so we're moving into performance evaluation. This is really the core of our talk today and the IVDR compliance. I'm not trying to steal your thunder, Dan, because I know you're going to talk through the very structured IVDR approach to a performance evaluation plan. But I just wanted to point out that the difference here is not just the studies themselves, but the level of planning documentation and traceability required. I want everyone to focus as we go through this section to think less about individual studies and more about how everything fits together into a cohesive evidence story.

Dan: Yeah, no, thanks. So, yeah, you set it up perfectly there. So really, so we call these, you know, the three pillars and depending on if you're like in the middle of writing these or if you're just thinking about it, those three pillars can sometimes turn into the three-headed Cerberus of IVDR, which I sometimes get caught in, right? If you are late at night trying to make a performance evaluation report, it can seem a little more evil from that perspective. But so really what Sarah was talking about — this is really this first line here, a plan followed by a report. This is kind of what the IVDR is all about and really the difference with documentation between the IVDR and the FDA system. And so there's a plan and there's a report for everything at every level, I think is what most regulatory people know. And so you need a performance evaluation plan first, and then you execute on that. And then in the end, you have a performance evaluation report, both of which can be updated at any time for any reason. You should be updating your report once a year to ensure or at least saying that everything is the same. So that's really the difference is the constant maintenance, as we'll talk about later when we call technical documentation living documentation. So performance evaluation we throw around in the US a lot, you know, just to mean a clinical study or maybe your analytical studies. But really in the EU, it means so much more. It is this three headed Cerberus. And so you have scientific validity is the first thing you have to establish. And that is establishing that there is actual scientific evidence for even the idea of this assay even working right and so then you leverage the sources that are referenced there — literature, clinical guidelines, expert opinions, other things — and you really create that argument. That's where it all starts. If you can't get past that, you're not going to get to the study part. And then next comes the analytical performance as Sarah had mentioned previously. It's really very much the same at what you're doing because they're both standard driven. There can be differences on what standards you're using, but the standards are usually the same. But again, you have to have a plan, a high level plan, which we don't always do in the US. We just do our individual protocols and testing reports for each thing. You need to have that whole high-level plan. And then when it goes to clinical performance, again, maybe the same studies with maybe different populations. But again, it's more about having that plan ahead of time that goes with these other components. And then you have what's called post-market performance follow-up, which may be required, especially for C and D devices and maybe some Bs. And if you're not doing that plan — or sorry, you're not doing that PMPF — you're going to have to justify that in your clinical plan. And so we'll talk a little bit more about that in post-market too. So really the concept of state-of-the-art is what drives performance evaluation and the amount of evidence you need. And this is a big thing that they don't really think of in the same way in the FDA. State-of-the-art is really the generally accepted standard for what your technology is. And so if there's more out — so it's not good necessarily, or it could be good, but it's not good from a documentation standpoint to be state-of-the-art like you think on the patent side, right? If there's more state-of-the-art out there, it means there's less evidence you have to produce in your documentation. And so therefore novel products have to build state-of-the-art from the ground up, from everything you have, from scientific papers and things like that that you may have. And so there's much more burden there. And so, you know, FDA doesn't formally require a scientific validity report, but you may have sections in your submission that kind of build on that, but it's not as prescriptive as it is for IVDR. Okay, so analytical, real quick, like I said, is very much the same. What I caution people is that FDA is sometimes lagging in adopting standards where the IVDR may be much more quick to adopt a standard, and they have what are called harmonized standards that may differ from the FDA version. So that's one thing to be mindful of — again, you need to have that high-level plan with the IVDR. And then the documentation, really you have to be always analyzing when those standards update because then you have to go back and review your file, right? And we'll talk about that again later too, where the difference between being one and done with an FDA submission as opposed to never being done with IVDR.

Sarah: So this slide highlights how clinical evidence expectations scale across the different pathways. On the FDA side up here, you have a 510(k), which often relies on a predicate method comparison study. A de novo and a PMA require progressively more data due to the increased risk. On the IVDR side, expectations, again, increase significantly by class. For a Class A, literature might be sufficient, but by the time that you're in Class C and especially Class D, clinical performance studies are expected. And I think that's where we see the most misalignment. Teams often size their clinical programs based on what's needed for the FDA and assume that it'll translate over. But as you guys have heard us talk about at this point, under the IVDR, the expectations for — you know — the prospective data, the intended use populations and statistical rigor those are often higher than they are with the FDA. So the practical takeaway that we want you guys to hear us say today is basically design your clinical program to meet a more demanding requirement and I think Dan alluded to that previously — is that you want to be able to design your programs to a higher rigor so that then eventually you can leverage that for both of the submissions. So let's talk about what it looks like to actually run studies in both of the regions, the US and the EU. Even if you're aligning on study design, execution obviously will differ between the regions and documentation. In the US, many IVD studies are considered non-significant risk. They'll be run with IRB oversight and relatively streamlined requirements. In the EU, studies will fall under the IVDR clinical performance study regulations, and that includes, you know, competent authorities, ethics committees, and registration in EUDAMED. So if you're dealing with different approval pathways, timelines, and documentation requirements, the challenge can be coordinating all of that without fragmenting your study. The key here is really to plan early. The goal being that you have a study that accounts for both regulatory environments with built-in flexibility to meet regional requirements without duplicating efforts. So that's all going to be easy, right? It's not necessarily easy, but the good news is that it's achievable. With intentional planning, you can have one study that produces one data set with clearly pre-specified objectives, statistical analyses, prevalence assumptions that will meet both the FDA and IVDR requirements. In practice, that often really means that, again, we're designing to the IVDR requirements, so the more rigorous standards, potentially having to add sites in the region. If the intended use populations differ, so adding US sites if we're in the EU and vice versa. It'll look like confirming with the FDA that they'll accept data, often through the pre-submission, which Dan so lovely highlighted. And we just wanted to reiterate here that there's no pre-submission equivalent in the EU, but we're encouraging everybody to develop an early relationship with a notified body. And then it means documentation is consistent, you know, with notified body expectations. So basically, we want to design, again, once to the highest bar and then leverage that data for both of the regions. If this is done well, the approach we're hoping reduces duplication, it streamlines timelines and avoids late stage surprises.

Sarah: Okay, so we're going to move into post-market surveillance. This is another area where the EU and the US kind of take a fundamentally different approach. You'll see here in a second when Dan goes through it that the approach is something that you want to build into your program from the beginning.

Dan: Okay, yeah, I just noticed there was a good point in the chat. And I guess that's what I was trying to get at is that notified bodies are developing a more structured approach — is what one of our listeners has said. And that's what I've been hearing. It's been getting more structured, but it's still not up to that pre-submission level. So thank you for that comment. So then I'm going to try to move through this because we do want to have time for questions. So really quickly, we already mentioned that the difference is more proactive versus reactive. Really, the plan is why I wanted to talk about it now, because if you're in development, you should already be developing a plan for IVDR. The kind of things you have to put in that plan — you have to show that you're thinking about how you're going to monitor your product and its safety and effectiveness from the very beginning while you're developing it. So that includes literature. How you're going to get field input on more of a feedback level, what will trigger things on your complaint analytics. That post-market performance follow-up is really big, and whether you need it or not, and when will you do it prospectively or retrospectively — with going to need to be more prospective if you're not a state-of-the-art for something that is more state-of-the-art. And then the reports. There's the PSUR for C and D, which is more intense versus the post-market surveillance report, and you're going to have to define what are in those and then what's going to trigger a field safety corrective action. And so this is just kind of a summary of the reactive versus proactive and really the fact that everything is kind of driven by complaints in the US. One thing to note is that under QMSR now that the US now has those ISO provisions for feedback. So feedback might start to be more incorporated, but really FDA is more concerned on that reactive side and will probably always be more reactive.

Dan: And then quickly, so then the differences between submission and technical documentation. In the US, again, it's kind of — it's not really one and done, but it's more one and done right. You get your 510(k), you celebrate, you're happy. You put it, you know, in the proverbial shelf. And then when it's time to — when you want to make a change, you evaluate whether you need to do a new submission or you put it on file. With technical documentation, it is maintained for the life of the product, and you have to adjust for state-of-the-art changes, harmonized standards updates, PMS outputs, any type of thing that could change how your product profile looks — you have to update that technical documentation continually, and then it's reviewed at least once a year by your notified body during the audit. And of course, this requires a lot more staffing. And so that's always what it comes down to is you have to consider as an organization how you're going to staff this. So that really is the main point of this section.

Sarah: Dan, in the interest of time, do we want to — because the case studies are a more detailed version of kind of the pitfalls that we outlined earlier — do we want to move through these and then you can hammer the takeaways and then we'll do the Q&A? Does that make sense?

Dan: Yes, I think that's what we should do. Yes.

Sarah: Okay. So key takeaways, Dan, do you want to cover these?

Dan: Sure. So basically classify first. And again, regulatory strategy is the big thing, which, you know, I always press with my clients. So this should be part of your regulatory strategy, obviously on both the US and the EU side, but really getting that nailed down early because that's going to drive your requirements in your design and development process as well. And so really size to the stricter standard is everything that you do from a validation standpoint. Assume IVDR maybe more. And so really kind of look how that's going to affect the US part of it, too. Plan before executing, obviously. And that's, again, what I said all IVDR is about. Plan, report, plan, report. So always assume you need to plan before you do a report. Engaging authorities, notified body, and then the pre-submission, trying to align the two different studies, especially on the clinical side. And then building post-market early because that's what the IVDR requires. And really, you're just going to be a better product in the field if you do that anyway. And then really knowing that if you're going IVDR, it's going to probably be more of a burden on your organization.

Sarah: Awesome. Okay. So we made it to the Q&A section. DAN Barely.

Sarah: Yes, barely. And I've got a number of them here for you, Dan. So we have an attendee that's asking — they're in an early stage diagnostics company, still pre-revenue, and we know both the EU and the US are in our future, even if the US comes first. Every dollar is scrutinized right now. How early should we bring in regulatory help and what's a realistic budget for that first pathway and classification planning? They want to know the cost of doing it right versus the cost of delaying it, but the funding environment is challenging, which we both know.

Dan: Oh, yeah. Well, this is the common — all of my clients, that's exactly what I hear, obviously. So when to engage regulatory, it's like right now, as soon as possible. Really getting that regulatory strategy, and that's what I have to give in to my clients because a lot of clients feel like they have to wait to do that strategy. I think getting a deal down as soon as possible, even if it's just an idea or you have a pretty good idea, you have that valuable intended purpose and you assume that the technology is going to play itself out — as soon as possible to really identify those pathways. And then as far as budgets go, I mean, so I'm not sure exactly if you're seeing the total budget for the US versus the EU, which obviously the EU is going to be a lot more expensive, generally speaking. But, you know, just getting those early planning documents usually isn't a lot of money, and that will be hopefully saving you money down the road. So it's hard to answer that budget question, but hopefully that gives you an idea.

Sarah: Great. Someone is asking for tips for engagement and commitment with regulatory authorities, the FDA and EMA, to get positive outcomes for successful product registrations and launch on the market?

Dan: Yeah, so first of all, EMA is on the drug side, but not to be nitpicky there, but it's really with the notified bodies that you have to engage with because the competent authorities outsource those for the reviews. So the pre-submission process, you know, pretty straightforward guidance document again. Again, with the notified bodies, you have to have those interactions. So now it sounds like, you know, they're being — I haven't really engaged with a notified body in a while. So it sounds like from our population out there that maybe notified bodies are establishing more of these meetings that you're able to have. So hopefully that means you can have similar questions and packages you give to your notified body to get that engagement early — so you know it was — I think it's only a matter of time before we really get harmonization with that pre-submission process over in the EU and it sounds like notified bodies are moving to that because that's only going to make their life easier as well.

Sarah: We have someone who's asking about a Class C product that they have in development and have been holding off on filing to see what changes occur. They're asking about how do they plan a program right now without betting on revisions that may not happen. And if they design to the current IVDR and the rules loosen, they're asking if you think that they've overspent.

Dan: Yeah. So, you know, that's kind of what we've been saying through the whole presentation, but it's really a difficult situation, right, that companies are put in. And so that's why a lot of people are waiting. And what we didn't really mention at the beginning is the notified bodies went from saying, hey, we're way too busy. We're way too busy. And now with this revision, they're like, nobody's applying anymore and we could go out of business. And so it went from one panic to another panic with notified bodies. So, I mean, you're doing exactly what you need to do. And as far as going for the higher bar, you really don't have a choice at this moment. And I don't know if somehow you can plan a contingency that if it goes to a lower thing that you can shift and really not maybe take that hit that you're talking about. I really don't know how you mitigate that having a higher bar and then having it reduced to a lower bar and then — I mean more evidence is still good evidence — so it might, you know, streamline your pathway through the notified body anyway, but then you'll know in the future that you might not have to do as much.

Sarah: Okay, maybe the last question for today, and then I think the rest of these, Dan, we're going to answer them possibly in writing, and then they can get sent to an attendee that submitted them. But in your experience, does citing similar device performance comparisons help with IVDR clinical evidence? E.g. leveraging work from a 510(k) predicate substantial equivalence package. Example is a Class 2 in the US and a Class B IVD, and it's not a self-test.

Dan: Okay, can you repeat that one more time because you kind of read it a little fast and there was a lot in there.

Sarah: So, does citing — in your experience, does citing similar device performance comparisons help with the IVDR clinical evidence?

Dan: Yes, so I'll stop. Yeah, so I think I'm good now. So that is part of that equivalency proof mechanism, I believe, is that you can cite those similar products and be able to reduce your evidence appropriately. And that's hopefully what they're putting more emphasis on now. So I think that's what that particular person is getting at. So yes. They do have the ability to do that now, and hopefully that's only going to get better.

Sarah: So I think that's all the time that we have today. We're two minutes over here. But we're going to collate these remaining questions that we have coming in here and make sure that they either get answered, you know, in a written form and sent back to an attendee or if it's an anonymous one, the team up here will deal with those. We appreciate everyone taking the time.