Understanding EU Medical Device Regulations: Key Insights for Developers and Innovators

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Hello and welcome back to Conversations in Drug Development. My name's Harriet Edwards, and I am your podcast host for today's episode. In today's episode, we're going to be focusing on medical devices in particular across the EU, although we will touch on some other territories as well. And for this topic, I am delighted to be able to introduce one of our international regulatory colleagues, Eamon McGowan.

Eamon, very welcome to the podcast today. We're really looking forward to speaking to you. Can you tell us a little bit about yourself before we dive into medical devices. Hi Harriet, how are you doing? Okay, so I'm an Associate Director of Regulatory Affairs in our Dublin office based in Ireland. I provide regulatory and quality management advice to our clients on the merge between medical devices and medicines.

Now in the last few years there's been an ever more rapidly changing landscape within the biomedical science field. So there's an evolving therapeutic landscape that is game-changing and mainly driven forward by the confluence of breakthroughs in the science itself, including such technology platforms as mRNA-based vaccines and gene editing tools of CRISPR.

Now, we're seeing a bioconvergence of these technologies whereby there's a merging of devices and medicines into an integral component, and it is this interface that I'm particularly interested in.

In addition, we've seen breakthroughs in the diagnosis of medical conditions with the introduction of next-generation sequencing, artificial intelligence the adoption of wearables mobile medical applications and digital health tools and recently we're seeing things like 3d printing manufacturing being introduced as well that's leading to the potential for personalized therapies very exciting and i think we do often overlook medical devices thinking they are just physical

items but actually as you said there is this real convergence now between what we traditionally see as medicines and and then these additional things that are helping medicines to only get better and more effective. So. We have said that there's a convergence. However, devices are distinct entities and they are, it's fair to say, I think, even totally different to traditional pharmaceuticals and medicines as we view them today.

So for maybe those people that aren't working in the medical device field, or maybe not medical devices in the EU, what are the key things that people should be aware of before we maybe talk in a little bit more detail about the regulations of devices? So if we talk about regulations, the regulatory framework of such products, it requires that innovators are expected to have an understanding of the full suite of regulations and guidance that covers these modalities.

So for devices, it's important to be aware of, obviously, the EU Medical Device Regulation, MDR, the EU IVDR, and also US FDA requirements. It's vital to be cognizant of the ISO standards. It's the International Standards Organization standards, such as ISO 13485 for quality and 14971 for risk management. And for the EU, you need to be mindful that there are numerous stakeholders

involved, depending on your classification. For example, notified bodies and then individual national competent authorities. Importantly, innovators are also now expected to consider the voice of the patient in their development plans too. and that's really important.

It's a very highly challenging process and the successful development and commercialisation of such modalities requires a real nuanced understanding of the scientific and regulatory challenges that are specific to the products and development.

Now whilst devices and medicinal products are regulated individually under their respective regulations, with the increasing bioconvergence and utilisation of combination products, we're seeing the regulation of these products becoming a lot more converged and it really is important innovators are aware of that convergence and I completely agree I think where we've historically seen people as experts in either devices or medicines actually those two fields now need to overlap and

your experts need to either have really good connections with experts in their respective fields or there needs to be an awareness of both so even though there are two separate sets of legislation for pharma and devices, which makes it even more complicated when you are thinking about combination products because you've got two sets of regulatory frameworks to work in. They are increasingly converging, as you said, and there is some overlap, which I know we'll discuss.

But let's just stick with devices for the time being. What is important to know with regards to the specific device regulations in Europe? Well, this is a huge topic, Harriet, and we could probably spend the whole day talking about this, but if I could really just focus in on a few interesting points.

So within Europe, as I've said, there are numerous stakeholders involved and every country has its own regulatory authority that's responsible for setting the rules, implementing regulations and issuing guidances. So in addition, there are guidances issued by the Medical Device Coordination Group, the MDCG, that deals with key issues from the medical devices sector, from notified body oversight or standardisation to market surveillance, new technologies and clinical investigations.

And then with the EU-MDR and the IVDR in place, developers are required to follow the details outlined within the regulation that covers not only placing devices on the market, but also the study of medical devices and ivds in clinical investigations throughout europe the legislation has been expanded as well to put patient safety to the forefront so post-market surveillance is of the utmost importance there's numerous things i could add to that yeah and i do actually want to pick up on

one point in particular because there is of course no product that goes onto the market without clinical investigation so although there needs to be an awareness of what's intended for marketing, authorisation and obviously beyond. There is obviously this huge clinical development piece before we get to that point.

So just to pick up on clinical investigations, what do you think, I mean, again, just to sort of pinpoint some key considerations, when we're thinking about combination products where the clinical trials regulation is as applicable as the medical device's regulation, what's the most important consideration for incorporating devices into those combination products in clinical trials. So one of the difficulties that many of our clients face is identifying the

relevant regulation that applies to their product. I can see why. Yes, so for example for those developing advanced therapeutic medicines or innovative medicines their marketing authorization application is likely overseen by the European Medicines Agency. However for the clinical trial aspect of these products. This is overseen by the respective competent authority where the trial is being run. Similarly, if there's a device component in that trial or an IVD.

This is also overseen by the competent authority within that jurisdiction. And each of the respective competent authorities can have a different approach as to how the device element is regulated and whether or not a separate device trial may be required. If a separate device trial is needed, this will be handled outside the CTR. So it's important that this is clarified as early as possible.

For US developers who come to Europe, they need to be aware that a device that has a clearance in the US will still require clearance for use in the EU. That also includes use in the trial. And when it comes to marketing the device, a notified body may need to be involved. Thus, it's really imperative to have early engagement with all the relevant stakeholders. It's these nuances and the different stakeholders where we see the difficulties arising.

I think it's easy to see why there's so many difficulties and complexities. It's not just two sets of regulation or frameworks, medical devices and medicines that need to be considered here. There's also the complexities of Europe as a whole. And when we think about Europe, we think one set of regulations and the EMA, but you're right. There's also national competent authorities, particularly for clinical trials.

And then, as you mentioned, notified bodies as well. So there is a real set of hurdles for device developers and combination product developers to navigate.

Have there been any learnings up to this point that we can maybe touch on? Because it feels like there's probably really been a lot. It's interesting you say that actually the Commission has issued a recent combined report where they identify some of the issues that have arisen. And as learnings are gained from the operation of the EU, MDR and IVDR, guidances, as I've said, are being constantly issued by the MDCG. So we can see quite recently we've had a number of guidances issued.

For example, there was a recent guide on medical device software with hardware combinations considered. And also a really, really interesting guide that has been issued recently is the investigator brochure content, which provides very detailed outline of what is expected to be provided in the investigator's brochure for a medical device clinical investigation.

Just to add to that, the EMA has issued guidelines on quality documentation for medicinal products when used with a medical device and a question and answers on implementation of the MDR and the IBDR. So there are learnings and the agencies are. Yeah, and that's really good to see. It's not just necessarily learnings that we've had collectively as an industry and they've not been taken into consideration.

There really clearly is some effort from the regulators to acknowledge these issues that have arisen and try and address them.

So just to pick up on the point you mentioned out of all of those guidances, the one I wanted to talk about was the investigators brochure, particularly when we think about clinical trials and preparing for that. In relation to that guidance, are there any sort of key highlights, key takeaways, or anything that people might need to be aware of? Obviously, it is a guidance, but as you said, it was very detailed and maybe quite useful for developers.

Well, first of all, I'd say don't be daunted by this guidance. Now, I've reviewed it a bit further and it's quite a very detailed guidance that gives you a roadmap for what is actually expected to be in place for a device. And it does help a sponsor develop their IB in accordance with both the EU MDR and the ISO 14155 standard for clinical investigations of a medical device. The guidance is really an attempt to reconcile what the standard recommends with regulatory requirements in the EU MDR.

After all, an IB ensures that investigators have access to comprehensive technical and clinical data about an investigational device before and during the study. And as such, it's going to include details such as the identification of a device, clinical performance, information about the labels and instructions for use, the pre-clinical and clinical evaluations, amongst other things and importantly risk management of the investigational device.

Just to be mindful as well, for devices that incorporate software, there is a need to address the software design and development process, and importantly, evidence of the validation of that software, and a focus on cybersecurity, which is becoming really important.

And I can understand why. And I think, as we said at the beginning of the podcast, we have traditionally maybe thought of devices as sort of physical delivery items for medicines, but actually that's not what devices are anymore and there is this increasing complexity when we think about including software and in particular when we think about that software maybe being built off AI.

I know this is a topic in itself and we have covered AI on the podcast before and we will continue to do so as it ever evolves but the interplay specifically between devices and AI is something we maybe haven't talked about and if you could briefly try and summarise that aim and what are the concerns there or or things for people to be aware of when there is a device that incorporates AI okay well key to be aware of is the use of AI in

the field of medical devices has increased rapidly and it's becoming an integral part of the development of devices and IVDs the power of AI is its ability to analyze large quantities of data and recognize patterns fortunately it also raises legal and ethical passions so the EU created the first government regulation of artificial intelligence it's the EU AI Act.

And there are implications for the medical device industry. Now the AI Act differentiates its scope of application on the basis of four risk group with medical devices falling in the third group for high risk. So developers will need to ensure compliance with strict standards in terms of risk management, data quality, transparency, human oversight, and robustness.

As well as the familiar obligations that device developers are really aware of, they also need to ensure their products are robust and protected against cyber attacks, as I alluded to earlier, from outside the area of the AI-based system. High-risk AI systems must undergo a conformity assessment procedure, and there's a need to ensure that you contact a notified body with sufficient accreditation when authorizing a product that's equipped with AI.

Now, the regulators have been busy trying to catch up with guidances on how to apply the use of AI in medical devices, but also in medicinal development. In fact, the UK have been very strong leaders in pushing guidance in relation to this. For example, their recently announced AI sandbox. Yeah, which is really interesting, actually. And obviously, the UK is outside of the EU now. I know we often forget it and we consider the EU as including the UK, but sadly not to be anymore.

It's really nice to see that the UK are still pushing the fore and being innovative when we think about these types of new technologies so really great but speaking of the UK and as we mentioned obviously a separate entity now with regards to legislation what are the UK doing in terms of device regulations because it is separate to what the EU are doing isn't it?

Yes it is but look look they're they're pushing forward so in early January the MHRA issued its new roadmap for new regulations to set out a route to deliver enabling regulation via a series of new statutory instruments, SIS, and I've left the regulatory speaker behind now a little bit. So there's priority measures to protect patient safety to be put in place this year, where core elements of the new framework intended to be in place by 2025.

And I think this is something we can revisit as well in later podcasts. So just near the end of May, the MHRA also announced the proposed framework for international recognition of medical devices. So here, the UK will recognise regulatory approvals from Australia, Canada, the EU and the US, depending on the type of device, its class and its prior approval. And as I've mentioned, the MHRA launched their AI Airlock. This is its new regulatory sandbox with AI as a medical device,

AI AMD. And this identifies and addresses the challenges for regulating stand-alone AI medical devices. First aim is to support four to six virtual or real-world projects through simulation. And there'll be learnings from that which we can bring forward to other products as well.

And then, just to highlight to people as well, that the MHRA also launched a four-week consultation which will support improved safety for certain high-risk and vitro diagnostic devices by introducing a common specification for high-risk devices. So as you can see, the MHRA are doing quite a lot of work in this area.

Certainly. It sounds very encouraging, actually. I really like the sound of the initiatives and the opportunity for people to engage and particularly the interactions and collaborations with other regulatory agencies around the world, which I think is so important, particularly now that we're outside of the EU, but, you know, collaboration is important across the globe anyway.

But just to pick up on the bits that you mentioned there about in vitro diagnostics, because we briefly touched on them at the beginning of the podcast and then we've kind of left them to their own device as it was throughout the episode. But what is the interplay between the clinical trials regulation moving back to EU and the IVDR? Because this is a separate set of regulations to the medical device regulation. It's its own entity.

So what's the interplay there? Well, there's quite an interesting overlap and there's difficulties coming to the fore here. But the EMA has issued a question and answers on the implementation of the MDR and IVDR, which provides a degree of clarity in relation to combination products but also companion diagnostics and other in vitro diagnostics as well.

Similarly the commission has issued guidance MDCG 2022-10 on the interplay between the IVDR and the CTR to enable developers understand the interaction between the two regulations when it comes to running clinical trials that involve the use of an IVD. Remember, assays used in clinical trials may range from CE-marked IVDs to trial or medicinal product-specific assays.

That are not always meant to be developed as IVDs. This is really a complex area, Harriet, and it needs to be assessed on a case-by-case basis. I'd strongly recommend that that question and answers document is consulted if you're running a trial with an IVD involved. Really good advice, and definitely one will add to the show note captions for people to find easily. I think wherever there is guidance, it's great to use at least as an example.

But as you said, often these types of products, particularly when we're thinking about the more innovative therapies and personalised medicines that incorporate such diagnostics, then case by case is always the way that we have to move forward. There are lots of developments though, so it sounds very positive, it sounds as though the regulators are responding to the need for increased guidance and legislation around devices, diagnostics and everything else in between.

Is there anything that we need to be aware of for future developments particularly when we think back to this idea of combination device trials which are becoming more and more popular aren't they yeah well for europe the important aspect is to be mindful of the ongoing guides that have been issued by the commission and the mdcg for uk obviously monitor the rollout of the mhra roadmap it's imperative that developers continually

conduct what i would say horizon scanning to keep an eye on regulatory intelligence to ensure that they are aware of upcoming actions by the regulatory agencies and also updates to standards. Remember, devices, developers, you need to apply state of the art. So you have to keep on top of your standards. I think in the area of artificial intelligence, we'll see a lot more efforts being made by regulators to further strengthen the regulatory regime.

And hopefully there will be attempts at a harmonisation of combined review of medicinal and device clinical trial applications. And I think the combined report that was recently issued shows some of those moves. Yeah, completely agree. Really positive. And there's still huge strides to be made. But I think there is now this awareness, particularly that we're incorporating combination devices throughout clinical trials and beyond as a matter of course, actually.

So when we go back to thinking about clinical development, particularly for a combination product that we've talked about a lot or maybe a product that has an in vitro diagnostic or maybe even a combination product that has an in vitro diagnostic just to make things more tricky. What should developers be thinking about when planning that clinical development program?

How long is a piece of string? If you can quantify. Well it's important to clarify if your planned study includes a novel device or IVD that may require to be CT-marked. It's very important that you reach out to the local innovation offices or the appropriate clinical trial unit of a competent authority in the jurisdiction where you plan to conduct a study to clarify what exactly is needed.

Be very mindful again of the applicable ISO standards that apply to the development of your device and ensure that your product is meeting these standards. Also, you need to become familiar with risk management techniques for medical devices and IVDs. The application of risk management and design and development for devices is a key foundation stone.

And if you follow these, you show that you are developing and releasing to the market a safe and effective device that always puts the patient first. And that's the key takeaway really, isn't it? With whatever we're developing as people involved in medicines or devices, whatever we're developing, it is ultimately to ensure patient safety at the end of it and that we produce a product that is effective as well as it is safe.

So really good point to end on there. I know we've touched on lots of topics. Unfortunately, not in too much detail, but hopefully in sufficient detail to be able to give people ideas and signposts of where to go next. But there is such a broad field here with medical devices that it's impossible, as you said, to cover in one small podcast. But is there anything else that you'd quite like to highlight today, Eamon, that we maybe haven't covered, but you would at least like to signpost people to?

Well, we mainly focused on EU considerations, but we didn't touch on US requirements or the global perspective. We haven't discussed in detail about conducting trials at a global level, transferring a program from, say, for example, the US into the EU. Many US developers often overlook the requirement for CE marketing, and that's a really important message to impart.

Yeah, and I think that definitely is one particular topic that we should cover on another podcast on another day, because we really should give it the airtime that it deserves. is a really important consideration, as you said. But to summarise today's podcast, we are unfortunately heading towards the end of today's episode. And I'm sure everyone will agree it's been incredibly insightful and valuable with lots of practical advice and key takeaways.

But can you summarise maybe the main messages that you want to get across with device development, particularly when we're thinking about combination devices as well, Eamon? Well, based on my experience to date, I'd recommend the following key pillars. I'd say speak to the regulators early in your program, include horizon scanning in these programs, focus on what you intend to launch to market just as much as what you're developing today.

Think about what you will be placing on the market in the future. Identify the applicable standards that apply to your device and incorporate risk management into development as soon as possible. For example, ISO 14971 for devices and ICHQ9 for medicines. And really importantly, make sure you understand all the acronyms. It sounds so simple, but yeah, this is one of the things that actually trips people up a lot.

And we talk in a different language half of the time in regulatory affairs, but I think this is even more apparent in medical devices as well. So a really good practical piece of advice to end on.

Eamon it's been wonderful having you on the podcast today we really appreciate your insights and we'd very much like to welcome you back to talk all things medical devices another day but for now thank you very much for your time and your insights we've really enjoyed speaking to you thanks Harish. Music. Thank you for listening to conversations in drug development the podcast series brought to you by the team of boys.

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