The compliance dates for the European Medical Device Regulation (MDR) and In Vitro Diagnostics Regulation (IVDR) are quickly approaching. In response, Treximo is hosting a webinar series that will cover a wide variety of pertinent subjects applicable to the device / diagnostics industries as they relate to the change in the regulatory framework in Europe.
The first webinar in our series was held on October 7, 2020 and focused on “Avoiding Clinical Pitfalls on the Path to MDR Compliance.” Treximo’s Senior Vice President of Device and Diagnostics Ronald Freeze hosted the session.
A full transcript of the webinar is below along with a link to download the slides.
Topics covered included:
- Impact of Basic UDI-DI
- MDCG Guidance Documents
- Clinical-centric Data
Part two of the series, “Understanding the Concept of a CEP in the Context of MDR” is Tuesday, November 10th. Register here.
So I will go ahead and get us started. We do have a very full session today, and I do want to be mindful of the time of everyone. So welcome everyone, to the first part of a multi-session series that we’re starting here at Treximo on MDR and IVDR. Treximo is very actively involved with a number of companies that are working to navigate these changes and regulations. We’re excited today to kick off this new training series to further help companies with the transition. My name’s Ron Freeze, I’m the senior vice president of the Device and Diagnostics Group.
So regarding the structure, we are looking at having monthly sessions. The sessions will cover both MDR and IVDR, and it will at times cut across both MDR and IVDR and at times like today, it will be more focused on one or the other. We are going to go into depth in these training sessions and so depending on the topic, we might only focus on one or the other. In the end, and I’ll say that at the bottom point as well, the idea is that the topics are based on your most pressing concerns. We have a good idea of what those are from the work that we’re doing, but we know that those will continue to evolve as we move through the transition for both MDR and IVDR.
From a content aspect, again, these will be very technical in nature. We will have our experts sharing their knowledge from both their past experience and the current work that we’re doing with different manufacturers in the space, hopefully sharing some of the insights that we are gaining as we help different people navigate the changes. It will also be cross-functional as everybody knows, the MDR and IVDR is not limited to just one function, it cuts across everything. And so we plan to have a range of speakers. The first two are going to be more focused on MDR. There’s some very pressing things in that medical writing space of MDR that we think we’re especially timely to get out these first couple of months. But we expect to have from project management to quality systems, even maybe some of our clinical experts might be on the phone for future sessions, depending on some of the feedback that we get from you.
The whole idea is to keep this very interesting, but very applicable where we’re sharing real stories from our experiences. From a mechanic standpoint, unfortunately, we’re not going to have a Q and A. It’s always nice in some ways to have a Q and A at these sessions, but we do know that it’s also very hard to cover a set amount of material because Q and A while interesting can also take quite a bit of time. And it can also sometimes go into areas that aren’t as applicable or interesting to everyone on the phone. So what we will be doing in every session is providing an email where you can contact the presenter directly, and we will ensure that we are getting back to all of the questions that we receive. To help with that as well, we’re going to also make the slides and the recording of this presentation available after the training session, and that will hopefully as well, help you reconfirm things that you might’ve thought you heard in the training session.
And if you do confirm that and you have questions, we will help you target those questions back to us on what exactly you heard or you might see in the training material. And finally, to maximize the value for you, we are going to do a survey after this all to get some feedback on how this training went, what you thought about it, but most importantly, really is to align on and then prioritize future topics. Again, we have a couple lined up, we know some we need to cover from a MDR and IVDR aspect, but that survey will help us and ensure that we’re aligned with the biggest concerns of you, the people that we’re trying to benefit with this training series.
So let’s get started and jump right in with the agenda.
Both in writing and in reviewing many clinical related documents submitted for CE mark over the years, it’s clear that there are some real pain points out there. Now, understanding time constraints the goal here was to focus on a few that hopefully will have a bigger impact for you. The first and probably the biggest topic we’ll cover is equivalency, the second is specific to the MDR, and that is the new unique device identification system, specifically the impact of basic UDI-DI on clinical related documents. And then the third also specific to the MDR, involves the importance of taking into consideration the new MDCG guidance documents. And then lastly, we’d like to touch on a more visual concept when reviewing the importance and integration of your clinical data throughout not only your CER, but throughout your submission.
So in talking about equivalency and the common issues arising in using this strategy, let’s first take a look at why manufacturers have been caught off guard by this, by taking both a look back on the MDD and a look ahead with the MDR.
So MEDDEV 2.7/1 Rev 4 on clinical evaluation was published June 26, 2016, at which most time manufacturers didn’t know that there was a new revision in the works. As a result, manufacturers weren’t aware of the new revision for quite some time after its publication, with many not having awareness until early 2017. Now each notified body took their own transition approach with this, understanding that there are guidance documents itself didn’t leave any baked in time for a transition. This meant that manufacturers were technically supposed to be compliant immediately for most, if not all of the notified bodies eventually acknowledged to their clients that since the guidance document was just that, a guidance document, and not considered law, and that there were some pretty big gaps to fill like the requirement for a PMCF plan, that they would not require immediate compliance.
And for those of us actively writing CERs at that time, that meant having some pretty tough financial discussions with our leadership regarding how we would need to manage things differently, both in terms of the cost and now needing to have a PMCF plan, as well as the change in overall cadence of updates now required for the CERs, especially for class three devices. And specific to this topic, equivalency moved from a mere footnote in REV3 to an entire appendix in Rev four, and now described in detail the expectations. In the end though, most notified bodies understanding that CEOs are written on a schedule and having them all be compliant was going to take the manufacturer some time to get caught up, they chose to give manufacturers about a year to transition. Specifically, CEOs needed to be MEDDEV 2.7/1 Rev 4 compliant by the end of 2018.
So from a timing perspective, there were a few important factors that came into play. One, the timing of this meant that many of the CERs being sent in for early renewal in 2019 and 2020 in prep for the MDR, were actually the first time that the notified bodies had actually seen a Rev four compliant CER from some of their manufacturers. And so because of this, it was really actually the first time that manufacturers were then getting feedback on their approach when using equivalency. And then the second was the new stringency from the notified bodies to enforce the guidance document as it was written, which was feedback given to them from their respective competent authorities. The new stringency involved using only one equivalent device previously manufactured with claim equivalency based on three contexts, clinical, technical and biological using what we termed as the Frankenstein approach.
So for example, device number one was used to claim equivalency from a clinical perspective, and they would use another device to claim equivalency from a technical perspective and possibly a third device for biological, hence the term Frankenstein. So with Rev four now in place, this approach could no longer be used and the notified bodies we’re expecting to see the use of only one equivalent device. Yes, there are those of you that would kindly remind us though, that there is a caveat in Rev four that allows for more than one device to be used, but that also means that each equivalent device needs to meet the criteria for all three contexts. We’ve seen this approach successfully done only once. And it was actually the right approach to take because the clinical data on the subject device and the equivalent devices was so sparse that collectively between the three, there was enough, but if only one equivalent device had been used, it would have been insufficient.
But like we said, we’ve seen this done successfully only once. The biggest hurdles with equivalency strategy for sure are the assessment, the documentation and the comprehensive justification that’s needed. By adding a second device, you’re essentially just doubling your work. That said, many CERs were, and still are using two or more devices for equivalency, but without a comprehensive look in each of the three areas for each device, there will be more nonconformances given by the notified body and more rework for manufacturers. It’s also good to keep in mind that if you have a lower class device where equivalency is being claimed and the notified body hasn’t seen the CER for quite some time, because there haven’t been any changes and you haven’t need to send it in, you should be sure to go back and review to ensure that only one device is being used and that it’s been comprehensively assessed and justified. It’s better to be proactive in this area to avoid getting caught in an unannounced audit or in a tech file review. Now add to those two things changes from the MDR and the related guidance document, MDCG guidance document 2020-5, and there has and still will be more stringency and confusion when taking this approach.
So unlike the MDD, the MDR provides a definition for equivalency. In fact, they provide a definition for each of the core required context from a technical, clinical and a biological aspect. In the essence of time, and to keep the intended purpose of this discussion, we’re not going to read these to you, instead we’d like to highlight some of the pitfalls that some of the companies have fallen into when using the equivalent strategy and some of the anticipated pain points under the MDR.
So we wanted to first start with this slide since it’s really transferable to all three of the areas, which should be clear with some of our examples. So watch out number one is to use specific versus generic language. One example that was seen several times, relates to the use of a term hydrophilic coating also called PTFE.
One hydrophilic coating does not equal another hydrophilic coating. Both MEDDEV 2.7/1 Rev 4 and the MDR note the importance of viscosity and surface characteristics, that’s for sure. So take time to describe the differences in detail, especially for those that are tissue contacting. Another related example is stainless steel. There are many different types of stainless steel out there. So what’s the difference between your device and the equivalent? Folks first think that it’s important to talk about the strength because MEDDEV and the MDR, both reference tensile strength, and that’s true, but don’t leave the patient out of the picture here. If the stainless steel is tissue contacting, then the impact of a patient with a nickel allergy should definitely be considered as each type of stainless steel can have its own percentage of nickel content. And then watch out number two is to ensure you address all differences.
So think about where the device is being used, and if the differences will impact the performance of that device. So one good example relates to the verbiage on “Similar specifications” which is often overlooked or downplayed by the manufacturer. So say the subject device you’re writing about is a guide catheter, and it comes in larger sizes than the equivalent device. One would then expect to see a rationale and evidence why the larger is acceptable for this type of device. Why are the larger sizes of the guide catheter not deemed to cause trauma to the vessel it’s being used in? In these types of cases, it’s best to have someone both with a clinical background and a device engineering background, be involved to help you figure that out, which is actually best practice number one. This approach is quite okay, to have several people involved in these decisions, and it also aligns with MDCG guidance document 2020-6 on sufficient clinical data as that document points back to a MEDDEV Rev four section 6.4 on who should perform the clinical evaluation.
It’s the collective expertise and experience of the evaluators that adds credence to the evaluation. Best practice number two is to tell your story in a clear and consistent manner. Each CER should be telling a story regardless if it’s for initial CE mark, recertification or related to some type of change. Once you’ve presented all of the data, use summarizing and concluding statements. The reason we say that is keep in mind that the reviewers need to craft their own mini CER called the clinical evaluation assessment report for their documentation. You know your device best, show that in the CER. It’s likely that these summarizing or concluding statements will be used maybe in whole, or maybe in partial in the reviewer’s clinical evaluation assessment report.
So for example, let’s say that the CER is being updated to explain that a piece of the device is now being provided in the color yellow simply so that it’s more visible to the end user. Don’t let the reviewer wonder if you’re changing the color due to supplier issues, or maybe even due to complaints. And if it is due to a complaint, then say that too. The reviewers are smart folks, and they’ll be reading through your complaint data, so be honest. But in the end, be clear why you’re making that change. And what you want to avoid is presenting all of the information and then just hoping that the reviewer is reading through the lines and tries to figure out the reason for the change themselves. The CER is a story, stay consistent with the story and make it easy to follow. If the CER is easy to read and understand, it’s faster to evaluate, which means it’s cheaper for the manufacturer because they have to pay for that evaluation.
You get far less questions, and then it earns you more credibility from the reviewer standpoint. And then best practice number three is for you to do your side by side comparison via table format. So it’s easier to list out, highlight and address any of the differences between your subject device and the equivalent device. Remember when we said, it’s one of the biggest hurdles when using an equivalency strategy or the assessment documentation and comprehensive justification needed? Using a table will help you with that. It allows you to define and address each difference. Some though will be easier to do than others. And again, that goes back to involving the experts to help you with this. Let’s take the indication statement as an example for this though. If the equivalent device has a very broad indication and the subject device has a more narrow indication, it’s likely to easily see the differences in table format, and then address them as you see them.
Do this for each difference. Since the MDR now defines what is considered for each area, use that same verbiage to help you set up your table. You can’t go wrong with that. Okay. And then make sure that the difference noted are comprehensively discussed and justified. By justified, it isn’t just as easy as saying, “Well, we don’t think this will impact the clinical operation of the device,” and that the notified bodies should take your word for that. They’re held responsible for your assessment and their own assessment of the equivalency strategy. So provide how you came to your conclusions. Did you use some type of bench testing perhaps, or maybe in some cases, did you fall on applicable ISO standard? Reference those documents and provide them to the notified body if they haven’t already been submitted in the paperwork. And then best practice number four is really just to do a very thorough job in this area.
If you’ve missed an obvious difference, the reviewer is likely to take a lot more time there to see what else might’ve been missed. The majority of the time then in equivalency should be spent on addressing the differences and not the similarities. And that’s typically what manufacturers do is they focus on the similarities and not necessarily on the differences. So bring in the right folks to help you make air tight arguments and make this one area that the reviewer doesn’t have to worry about.
Okay. So now we’re moving into a few more specifics, and this is the technical area. Did anyone notice how the MEDDEV guidance lists out the three areas as clinical, technical and biological? Well, the MDR and the MDCG guidance documents list them as technical, biological, and clinical.
If we were gamblers, we would bet that is because they want manufacturers focused on technical, which historically has been where the most of the issues have actually been seen. So in regard to technical from an MDR perspective, there’s really two things that we’d like to highlight for now. One is the softening of the language needed for conditions of use. Under Rev four, the conditions of use were required to be the same while the MDR now states similar conditions of use. If anyone is confused as to exactly what conditions of use is referring to, because we’ve heard that question a lot. We would point you back to the 2018 IMDRF document on essential principles and safety and performance, which refers to conditions of use in terms of ergonomics, usability, interaction with other devices or diagnostics, user interface, that’s always a big one, and the environment where the device is being used.
So I’m going to use an example using that last one, which is environment. One example that comes to mind is the device is intended to be used in a hospital versus a device that’s being used in a clinic. Those to me would be very similar, so would now clearly fit the new definition that’s provided in the MDR. Related to user interface in the environment, this is just a side note. If you work for a large company, then you may have access to engineers focused on human factors. So what’s human factors? So if you’ve ever pulled a door handle and found out that you should have pushed it instead, that’s because human factors weren’t considered. They probably should’ve just put a sign on there that said push or maybe nothing at all. For medical devices though, human factor engineers can be very helpful. Maybe you weren’t sure if the subject device and the equivalent device that you’re looking at have similar enough user interface, which is where a lot of questions come from.
If you have access to a human factors department, they might be able to help you figure that all or find the documentation that you need. The other important change relates to the addition of software algorithms. So to clarify this, and we’re going to say this slowly because this isn’t an area of our expertise, for sure. But this does not mean that there needs to be similarity in the code itself. Instead, it’s referring back to the basic logic being used in the software. So in other words, what are the rules the software needs to follow in order for it to do its intended function? That’s really the question that you need to answer. And if you need help with that, you should raise your white flag and bring in a software engineer to help for sure.
Biological. So the next area that we’re going to hit here for equivalency is biological, which is where there may be a few new hurdles to overcome. We’d say that there’s some real changes here and ongoing discussions both even within the notified body and some confusion in this area. If you remember Rev four noted that the materials of the equivalent device that were either tissue contacting or body fluid contacting needed to have the same materials for the subject device as the equivalent device. This has not changed with the MDR, same equals same. However, Rev four had little leeway when the material in question was touching intact skin. In this circumstance, you might’ve been okay relying on just basic risk analysis to make your justification taking into the accounts of the role and the nature of the material involved.
It’s different now though, under the MDR. The previous exceptions have been removed, and this is causing some concern as small… Well, we guess it depends on how you define smaller previously minor changes such as a change to the material that only comes in contact with intact skin and is fully compliant with ISO 10995, may now undergo a lot more scrutiny. But according to MDCG guidance document 2020-5, the distinction between “same materials or substances and similar release characteristics of substances” is actually made to account for the fact that you might have some processing and design and use environment issues that all might contribute or introduce small changes, even when the same raw materials are used. So this would lead you to believe that the raw materials need to be the same as well as the final product due to the processing of those materials along the way that could involve material degradation or they might result in leechables.
The guidance document goes as far as saying that “The exceptions outlined in MEDDEV 2.7/1 Rev 4, do not use the same materials and are not acceptable under the MDR.” So understanding all of that said, the MDR and the guidance document, both state that the clinical, technical and biological criteria, “Shall be taken into consideration.” This then leave some wiggle room that some interpretation can be made based on the risk assessment of the change. We know this is heavy material here, but let us give you a quick example. So under the MDD, a manufacturer, due to unforeseen circumstances needed to move to a brand new material on their device that was tissue contacting. A solid rationale might be that we’ve assessed the material against the applicable ISO 10993 sections, we’ve also used the exact same material for another of our devices that’s been on the market for 10 plus years and have had no complaints and no issues at all.
Depending on the type of device that may have been good, but it’s less clear now with the MDR on how this will be managed, not only from notified body to notified body, but also from reviewer to reviewer. Things for the manufacturer to consider before taking this approach is the risk assessment that’s been done, the type of device that you’re talking about, the extent of time that it remains touching the patient, because that also increases the risk. Keep in mind too, that class three and implantable devices will undergo a separate assessment via that brand new CEAP process. And even if your reviewer and your notified body completely agrees with your assessment, it is possible that the expert reviewer from the commission may not agree.
So we are certain that we’ll hear more on this topic from both the notified bodies and or the working groups in the future. One more thing to note here too, is if your device has an ancillary medicinal substance, such as a drug alluding scent for example, the notified body is actually required to get an opinion from either the competent authority or the EMA, all of which should have been baked into your submission and approval timing. And we mention that only because there isn’t a clear cut timing on how much this can actually take. So just be aware of that and try to bake some into that submission timing.
So from a clinical perspective, MDD appendix A1 in Rev four is very straightforward. The same thing can be said about definitions provided in the MDR in annex 14 part A.
The key here is to be very patient centric in your thinking. If you can create the table that we previously mentioned, that helps detail line by line the requirements, the differences should then be obvious. And then the next step is to comprehensively address those differences. So companies tend to stumble when they don’t create a table and they just try to manually write out what they think that the notified body wants to hear, and if they don’t get input from experts across the company. So again, it goes back to make sure you’re using those experts and then use that table format. But what we would also like to add here is the importance of being very patient centric in this area. So for example, if device XYZ being used for the same medical condition, is it being used for the same period of time as well?
And when you hear medical condition, understand that this term encompasses both the severity and the stage of disease. So let’s stop here and give you just a quick example that might be helpful. So heart failure, that’s a pretty broad medical term that could be caused by lots of different reasons. So if patient A has just been diagnosed with heart failure due to coronary artery disease, then likely he or she would be given direction on probably diet, exercise and maybe put on medical therapy, like a statin or something. But if the heart failure has been caused by a long-term heart valve issue, then maybe a procedural intervention might be best. It’s the same medical condition yes, but the causes and the severity can be very different. Another common issue in clinical relates to the patient population.
If the reason you’re needing to use an equivalent device is because you have absolutely no clinical data on the subject device itself, which has been surprisingly common, then what clinical data is available on that equivalent device to support your target population? So here’s what we mean: if the equivalent device has only been studied in adults, then the subject device can also only be used in adults. This type of scenario seems to be hitting those devices that have been on the market for many years, but where the indication statement hasn’t been currently assessed against the existing clinical data. And then what that means is that there have been no changes to the IFU made over time. A note of caution here too, is that we’ve seen companies claim clinical equivalent to the equivalent devices indication statement only then to look at the clinical data supporting that equivalent device, and they don’t have enough data.
So if you need to take the equivalent route, put your reviewer’s hat on and do your own assessment of their clinical data. How does their clinical data lineup what you want to say about your device? And then other issues seen include devices used in other parts of the body from the subject device. So this would seem relatively straightforward from a clinical perspective, but if you’re focused only on the therapy itself, you might miss it. Another example would be good here. We’re going to use ablation. We’re not experts in this area, but we’re definitely aware that there’s a difference between surgical and interventional, between wet and dry, single, bipolar, and cryo. If your approach, if the way that you’re thinking about it is only from a therapy perspective, you might think that RF ablation in one part of the body equals RF ablation in another part. Not understanding that the different body parts might be thinner or thicker, they might require a different amount of energy and so on. So again, this goes back to create that table and bring in people to help fill in the gaps where you’re not an expert is really the key to success here.
Now from an MDR perspective, there is one new addition to the clinical context worth discussing, and that’s the addition of the new criterion requiring that the equivalent have the same kind of end user. Infusion pumps are a great example of why this addition is so important. Even for trained healthcare professionals, infusion pumps are notoriously complicated to work with, and they require a higher level of cognition and focus when you’re working with them. Now imagine that same device is being used by a lay person, such as the patient themselves. Add to the fact that a patient receiving an infusion tends to be sicker than a typical home health care resident, and the margin of error for the medication is very small, and this could be a real issue. So this addition, at least from a nursing perspective, makes a lot of sense.
And then just a few final thoughts on this, so since we just finished the last piece of the puzzle, which is clinical, I would be remiss in not reminding you of a few important changes related to the MDR. So if you previously under the MDD, used an equivalent device from another manufacturer, know that under the MDR, if the device is not a class three or implant, the manufacturer only needs to demonstrate sufficient clinical levels of access. And that’s per annex 14 section three. But things are different for class three and implantable devices. For these devices, there will be an expectation that a contract exists between you and the manufacturer of that equivalent device, and that the notified body will ask for that contract to ensure that it allows you as the manufacturer, “Full access to the technical documentation on an ongoing basis.” They want to make sure you’re getting that ongoing Christmas gift all year long.
And then additionally for class three and implantables, MDCG guidance document 2020-5 notes that it will not be possible to claim equivalence to a device certified with respect to the directives. This means that the equivalent device chosen will need to have CE mark under the MDR, not just the MDD. And again though, this is specific only to class three and implantable devices. Now the next one is if your device is a medicinal product that is intended to be used in the body and absorbed or locally dispersed in the body per annex 112.2, an extra step may need to be taken, which is that the notified body will need to obtain a scientific opinion from a competent authority. Yes, this even applies when you’re using an equivalency strategy, which is exactly why we’re giving you this gentle reminder here, because we think that’s been another thing that’s been missed up until now.
So please plan ahead for sufficient time to count for that extra step. And all that said, if equivalency is still your chosen approach, be sure you have an appropriate PMCF plan in order to confirm the device’s clinical safety and performance. You should expect to be asked for this from your notified body. They will want that commitment from you. And lastly, if there’s a device that you’re worried about not being able to comprehensively justify using the equivalency strategy for, then start having the conversation now with leadership and management on how this is going to be addressed. Is there another device that can be used as your equivalent device? Where else can we possibly find data? There’s a ton of registries out there that our hospitals are currently collecting. Is there something that you can do additional bench testing for? And then again, I know we just mentioned this, but what’s also the impact if it’s a class three and implantable devices is article 61.4 requires clinical investigations be performed.
In other words, what is your plan B? It’s best to have these discussions before submission versus delaying CE mark under the MDR, and then scurrying after the fact to go back and retrospectively, try to collect the data that you need here for this.
So our next topic is the impact from UDI. The regulations introduced an EU identification system based on a unique device identifier. Before submitting to the notified body, all the devices must be registered in the UDI database per articles 10 and 29. But it’s important to understand here that early on the potential impact that MDCG guidance document 2018-1 version three has on your documentation. This document makes clear that the only devices that can share the same basic UDI-DI, meaning they share the same intended purpose, the same risk classification, the same design and manufacturing characteristics, can continue to share some of the same documents.
So first, just to give you a little background, the concept of the UDI system was meant to allow for more traceability. It also applies to all medical devices with the exception of custom-made and investigational devices. In reference back to article 27 of the MDR UDI stands for Unique Device Identifier, and it contains two parts; the UDI-DI which refers to the device identifier and the UDI-PA which refers to the production identifier. But what we’d like to focus on today though, is basic UDI-DI. Basic UDI-DI identifies and connects devices with the same intended purpose, risk class and essential design and manufacturing characteristics.
Okay. So why do we have basic UDI-DI? It all goes back to our favorite topic, which is EUDAMED. As MDCG guidance document 2018-1 version three reports that basic UDI-DI is the “Main key” in the database to finding device-related information in EUDAMED. While the MDR notes that UDI-DI is the “Access key.”
So from an IT point of view, this may infer that the basic UDI-DI is how the information is being stored in the database. This theory would also align with the current understanding in that the UDI-DI is linked to only one basic UDI-DI. How this plays out though really kind of depends on the stakeholder. So if you’re the patient, you could use this information to learn more about the coronary stent that you just had implanted a couple of weeks ago, but for the manufacturer and the notified body, the impact of basic UDI-DI extends to the certificate, the declaration of conformity and the technical documentation.
To give you an idea of why this is so important, let’s run through a practical application. Here’s a quick example. So manufacturer XYZ sells four stents. Two stents are for neurovascular use, they share the same indication for carotid stenting.
One is a coronary stent, and the last is a peripheral stent. Under the MDD, they have all shared the same CER historically because of their clever branding name Super Sense. Yes, we made that up. But of these four devices, how many basic UDIs do you have? Well, you don’t have all the data here to decide, and we’re sorry you can’t see the visual of the four different steps up there. But you likely have three. One is inclusive of the two neuro stents, one for coronary and one for peripheral. Although they are all implantable and they share the same risk classification, which is three, there are differences in design and manufacturing characteristics, as well as differences in the indication statements. Now you could further complicate this example if one or more of these stents are drug alluding, as one would then argue that the addition of a drug coding is a change in the essential design and manufacturing. But just for simplicity stake, let’s just assume that all stents are bare metal and that we landed on a total of three basic UDI-DIs. Why is this so impactful?
So it’s impactful because if you’re the CER author, you may also be responsible for the other clinical related documents that you’ve now just tripled the work to be done. According to MDCG guidance document 2018-1 version three, the basic UDI-DI impacts the technical documentation, which is annex two of the MDR. So upon initial submission for CE mark under the MDR, this would now result in three clinical evaluation plans, three clinical evaluation reports, three post-market surveillance plans and three post-market clinical follow-up plans. And since these are all class three implantable devices, there are now three summary of safety and clinical performance reports as well. Along those lines, the risk management file is also in play.
So now the risk documentation that you initially submit and eventually that new PSUR, the Periodic Safety Update Report, will also be impacted. We wanted to stress this point as many manufacturers have historically constructed either family or therapy CERs, where types of devices have been combined in order to reduce the overall burden on the upkeep of the CERs. Personally, we don’t think that there’s been a big enough spotlight on this area. If you’ve also done in the past or currently working on a family or therapy CER, then it’s time to assess the potential impact that basic UDI-DI may have on your clinical documentation. And think about the submission timing too. They may be all on the same certificate, right? Likely they are, which means that they’re sharing the same expiration date. So if your devices need to be split out due to basic UDI-DI, it’s time to get monies and resources readied. We’ve seen this happen already and don’t want anyone else stuck in this kind of situation.
So the next thing we’d like for manufacturers to take a closer look at are the MDCG guidance documents, which we’ve been referring to up until this point throughout the call.
It’s clear that the manufacturers don’t completely understand their importance, or they’re just not aware of this goldmine of information they can provide you. From a clinical standpoint and similar to what happened with the medical device directives and their associated MEDDEV guidances, many of the clinical related MDR questions posed from the notified body to the manufacturers are addressing direct gaps identified in these MDCG guidance documents. The EU provides these documents to help stakeholders, manufacturers, notified bodies, importers, distributors, authorized reps, and so on, on their interpretation and implementation of the regulations. Albeit they are legally non-binding documents, they do represent the state of the art in many areas or so that will be argued from your notified body.
And their intent is to make sure that they help you ensure uniformity in the application of the regulations. So thus the guidance documents should be heated and will be expected to be heated from your notified body. And sorry we hadn’t mentioned this beforehand, but MDCGs actually stands for Medical Device Coordination Group. They’re the experts designated by the member states and each is chaired by the commission. These folks have been quite busy and there are new MDCG guidance documents that are being released every month. There were three that were released in July, a couple in August and actually zero in September. And we’ve been curious or joking to ourselves if that is because it now gives us a little bit more time to learn about the impact of Brexit on Northern Ireland that has all happened here in the month of September.
And no, we won’t be touching on that potato at all today. But back to the MDCG guidance documents, we think we would all agree that it would have been nice to have all of these published a year ago, but that’s really not what happened.
And unfortunately this has had a bit of a negative impact on the MDR early birds since some of the manufacturers took a proactive approach in trying to ready and submit all of their documentation only to discover that since they’ve submitted, several new MDCG guidance documents were published to now, which their submission isn’t fully compliant with. So although it might be great fun to debate over the fairness of it all, we’re sitting amongst clinical and regulatory folks, we know better, there’s no such thing as fair. You just have to be compliant to those MDCG guidance documents out there. Now since this discussion is clinical focus, we’d like to point out a few of the guidance documents that you should be aware of from a clinical perspective. If you don’t have this website booked yet, the link is at the bottom of the slide there.
Unlike ISO standards, the guidance documents are all free to download. And if you’re a Twitter fan, you can also get the latest updates by following EU Health on Twitter. We also don’t have time to step through each one thoroughly, but it would be good to highlight a few of the impacts to drive home the message that these are very important and the information needs to be integrated before you submit to the MDR. So we’ve talked briefly about MDCG guidance document 2020-5 on equivalency already. So let’s move on to 2020-6 on sufficient clinical evidence for legacy devices. There is just a few things we’d like to highlight, the first one is there’s a whole host of new terms defined in these guidance documents such as the ever confounding terms of, intended use versus indication, versus indication for use.
And then of course, the notorious state of the art, all of those are now defined. The guidance also lists appendices within Rev four that still apply. So for example, even though the MDR makes no mention of the need for curriculum vitaes and declaration of interest forms to be associated with the CER as they have been in the past, 2020-6 notes that appendix A10 from MEDDEV 271 Rev four still applies, which means you still do need to have updated CVs and DOIs associated under the MDR. MDCG guidance documents seven and eight provide templates for post-market clinical follow-up plans and evaluation reports. Why would you not take a look at them? Those are intended to help to walk through for both the manufacturer and notified bodies to provide clear expectations on what should be in those. MDCG guidance document 2020-13 is the clinical evaluation assessment report template. This one is keenly interesting for those who want a better understanding of what exactly is required from the notified body to report on when they assess your CER. So think about it. If you can tailor your CERs to ensure that you’re providing the notified body all of the information that they need to complete their assessment of your CER, you’ll be in much better shape. You’ll receive less follow-up questions, which means that the overall review process will be faster and less expensive and you’ll have a much happier reviewer. And that is a really good thing.
MDCG guidance document 2019-3, that is the CECP, the Clinical Evaluation Consultation Procedure. This one was used to bulk up article 54 of the MDR. And as a reminder, this extra step won’t be applicable to all devices, it only applies to classroom plannables and those that fall under that rule 12, which are class 2B active devices. If you have one of those types of devices, then you should understand that your notified body will be sending in their CEAR, the document that we just talked about, to an expert panel to see if they agree with the overall assessment. Now, it’s not clear if this process is fully baked on how it’s going to be worked or how long this extra step will take. So something else to think about your submission timing anyway. And another takeaway on this guidance document did answer the question if the CEA process is required, if the device is already on the market.
So in other words, is it… And the question was answered as yes. And then the next question was, well, when you say on the market, what did that refer to? And it also answered that, and it can be either the MDD or the MDR, which is good news. And then there’s MDCG guidance document 2019-9 on SSEP. So as previously mentioned, it should be limited to one basic UDI-DI. And then they use the words, we’re going to quote these, “when relevant.” And those are key words. The SSEP should have two separate parts, one for the HCP, the healthcare professional and then one for the patient. It even notes that these two sections should be separated by a page break, that’s kind of best practice and that’s to help with clarity on what information belongs to what intended reader, because the patient isn’t going to understand the same information as it’s conveyed to the physician.
This guidance document also makes clear that the document cannot be used or appear to be used as a marketing or promotional document. If though you need to use a pointer in the document that refers back to your website for some information, that avenue can actually only be used for specific types of information. Otherwise, the rest of the data should be contained in this one document. Think of it as another standalone document. And then lastly, although the SSEP initially only needs to be submitted to the notified body in English, it does need to be translated into other language of the member states where it’s intended to be sold. We don’t think that last note is of surprise to anyone, but it will involve some planning upfront. And then lastly, MDCG guidance document 2018-1 version three is the guidance on basic UDI-DI. And that’s what triggers a change in the UDI-DI number. Now, we spent some time talking about this one already, but if you’ve previously compiled CERs by therapy or family brand names, please take a look.
There are several more guidance documents that are being planned this year, just keep an eye on it. And then just one quick mention, although it isn’t a guidance document and it hasn’t been harmonized to the MDR, be cognizant of the fact that ISO 1455 on clinical trials was actually just released and updated here in late July.
So looking at the time and it looks like we have three minutes left which is probably not going to be sufficient to cover the entire next section on how to best use clinical data. We will use those three minutes wisely though, and we’ll keep moving forward to see what we can get to.
So the point here really is to make sure that your clinical data should be actually the main source of your indication statement. For example, if you have a large clinical trial maybe it’s an RCT, your inclusion criteria looked at the device in the peripheral vasculature, then just make sure your indication statement needs to specify peripheral vasculature instead of the broad term vasculature, which could cause confusion from the end user. This is needed for a couple of different reasons, the clinical data, no matter how old it is, and if it’s already been reviewed by your notified body, the data cannot simply be summarized in the CER, so you need to put the entire clinical investigation plan, the stats analysis plan, the final study report, all of that needs to be in your submission as if you’re evaluating the device for the first time.
Other big areas that will drive your clinical data, are target patient population. So take a really close look. Do you have clinical data to support the use of your device in pediatrics? If not, then that would be something that you should look at in your warnings or precautions statement of the IFU. And then what about clinical benefit? That’s remember one of those new terms that we’re using under the MDR and do you have it as measurable and defined? And then keep in mind going back to the SSEP you also have to provide the success rate of that measurable outcome as well.
And don’t forget about claims. So have you touched base with your friendly marketing department to see if their claims matrix is fully supported? Some of the manufacturers have separated claims that they deemed to be related to clinical safety and performance separate from their marketing terms. So make sure that you’re clear on that. Last is lifetime. Make sure that if the implantable device has a five-year expected lifetime, but you only have data out to two years, how are you going to address that? And then all of those pieces then should impact your PMCF plans. So if there are any gaps that you cannot address, that then should drive your PMCF plan. And then of course there’s risk management. So risk management kind of flows both ways where the PMCF can actually help drive the risk management, but then again, any clinical data should also be input into your risk management plan. Meaning that if there’s adverse events that happened in your clinical studies that those should be in your complaint database.
So it looks we are right at the top of the hour here, so thank you again for attending. We’re sorry we had to go quickly through that last slide, but the slides will be forthcoming. But if there are any questions on anything that we’ve addressed today, please feel free to reach out to us. There’ll also be a survey that Ron had mentioned at the beginning, asking how we did, how we can improve, what kinds of topics and questions that you might have that we can discuss in further trainings? And then speaking of further trainings, another reminder that our next discussion will be on Tuesday, November 10th, where we’ll be taking a look at the clinical evaluation plan. And we really do hope to see you there. Thank you everyone.