Hi everyone, I think we can get started. So today's session is on Global Regulatory Perspectives on Pediatric Electrophysiology Device Development, which is a lot of words. We hope to have an engaging and engaged session. This little barcode we are going to try to keep up as long as possible because I know I miss it in every single session. So we do hope you have questions. You can of course get up to ask questions, but you can send us questions through this portal. Please download it, scan it, whatever it's called. And so again, we're going to have a relatively informal session. We're just going to ask the panelists a few questions, but we're going to start with slightly longer than usual introductions. My name is Yaniv Barko, and I'll say a little bit more about my involvement in this space after the other intros, but we're going to start with Jen Silva. Thank you all for deciding to put this session on your calendar here at HRS. It's lovely to see so many familiar faces. My name is Jennifer Silva. I was just telling Yaniv I'm going to special request to chair all sessions with him because he is so organized at dealing with this that it makes my job very easy. My relationship to this topic is sort of multifold, but really probably stems directly from my work in innovation and my two startups where I've interacted with the FDA numerous times through their various processes and have achieved now two FDA clearances for products. I'm also involved with MDIC, which is the Medical Device Innovation Consortium, and have been working with MDIC for longer than I would really care to admit. So I come at it from the perspective, certainly not of the regulator, but if you sort of saw it as a table where regulators like George are sitting on one side and industry like me is sitting on the other side, that's my hat in this. Ann? I'm Ann Dubin. I'm at Stanford, and I'm taking a completely different look at this. Instead of being a regulator or industry, I'm the clinician who is really interested in having more availability of products that we need to take care of our children. And how I got involved in this space is about six years ago now, after some conversations with George, decided that we were going to start a group through PACES initially that has now become the pediatric arm of the EP Collaboratory, specifically trying to bring together industry, regulators, patients, and clinicians to try and ease the burden for industry and to explain to clinicians and academics why it's important to have pediatric labeling. And we'll talk a little bit more about that later. So I'll stop there. Hi, this is Mohsen. I'm from Pakistan. My interaction with the regulatory authority of Pakistan is because there was no pediatric EP before, and as there was no devices available or hardware available for pediatrics. So I have to reach out to them many times to get it approved. So I have a little bit of exposure to them. I'm here more of a learning, how does it work, rather than telling you new things. So I am looking forward to it. Thank you. I'm Andreas. I'm originally from Germany, as you can hear, so I have some exposure with the EU system as a clinician mostly. Since I moved to Australia, I also have seen the other side, being part of a startup or at least an advisor for a startup. Interestingly, because Australia is so small, what you end up is either applying in the European Union or in the US, and then go back to Australia and present what you got from the FDA. Because in the end, Australia was a very small market of 25 million. Although we have a regulation area, they don't actually accept new things, they basically just accept things from other countries. I'm Gabrielle Hessling. I'm from Munich, Germany. I'm a pediatric EP person, but I'm working in a department that is interdisciplinary. So we are one department with the adults, which gives me, from my perspective, a lot of chances. I'm at the verge of the technique. So we get the newest systems, the newest catheters from the adult world. So I was never involved directly with my regulatory body, but indirectly we're doing studies for the industry. And this is mainly painful for our study nurses in our department who do the arrhythmia studies, because it's a lot of bureaucracy. We're the ones that do the studies, but they do the work. So this is my indirect relation to those bodies, and I'd be interested to hear from the others how important it is to work together with these bodies. Because I think, from a pediatric standpoint, there is much, we say, air that is open. We as pediatricians are always the junior partners, and how can we get off this role and get more into an active role? Thank you. I'm Jan Janosik, coming from Prague, Czech Republic, from a tertiary university hospital from pediatric cardiology environment, with close connection to adult congenital heart disease service. And I think I come across these issues in three levels. For the local level, it's ensuring availability of non-registered antiarrhythmic drugs for our patients, which is a big hassle, and that includes flaconide, and includes maxilletine and nadolol. So that's an administrative hassle. The second level is cooperating with some startup companies for diagnostic devices, mainly usable for the pediatric population, which are based in the Czech Republic, which is an easy thing. It's much easier than influencing worldwide companies. And the third level is I am the incoming president of the Association for European Pediatric and Congenital Cardiology. On that level, we have to cooperate with the European Society of Cardiology to influence and change the currently very unsatisfactory medical device regulation process in Europe. That's a high political level, and we as societies have a relatively low power in that, unfortunately. Okay, great. And while Jen puts up disclosure slides, I'm just going to say a couple things about my own background. So there's a program called the Pediatric Device Consortiums. It's a program funded by the FDA to try to help people develop devices in kids. I am a co-director of a program called the Consortium for Technology and Innovation in Pediatrics, which is centered both at Lurie Children's and at Children's Hospital Los Angeles, where I'm from. And we are basically funded by the FDA to help develop devices for kids, because it is hard to develop devices for kids, and we're going to be talking about some of that very shortly. Harrison, could you put up the disclosure slides for me? And my own personal involvement with devices is I've been trying to work on developing new pacemakers, including a fetal pacemaker, most recently a leadless pericardial pacemaker. I don't have any formal disclosures, unlike Jen. Wow, that's impressive. But I do have patents related to the technology I've been working on. Did they all come up, all the disclosures? Yes. Great. So we're breaking this talk or session up into three parts. The first is sort of a background, like why are we even talking about all this. The second is sort of what are efforts being done in the U.S. and across the world around this. And the third is sort of what should we all be doing in terms of HRS and PACES and individuals who could potentially help with this. And even though we have a panel of experts here, there are also experts in the audience. So feel free to help with any of the stuff that we're talking about. And to just start off the background, I want to just go around and ask the panelists, why is it hard to develop in kids? Why is it different? Why is it hard? Why are we even talking about this? So Anne, can you start us off with that? Sure. I think we should move around. Can we get that first slide? Oh, yeah. Yes. I can do it. Can you do that? I think it is quite interesting. I spent a little bit of time thinking about this. I would bet just about everybody in this audience can talk about the issues that they've faced when confronted with a child who needs some kind of device or some kind of therapy, and we don't necessarily have what we need. To start with, and this was kind of a sobering list. It's a little old now. It's about six, seven years old. These were all the cardiovascular devices that were approved for children. If you think, not EP devices, all devices that had been approved for children by FDA. It's kind of sobering to think that this was all we had out there. It's grown a little, and I need to update it, but it's not like we have pages and pages of devices available to us. And there are lots of reasons for that. There are issues in our population is smaller, both literally as far as how big our kids are as well as how many there are who need these devices. There are very different conditions that devices have to face for children than they do for adults. The financial incentives are not there for companies, quite bluntly. If you think of how many people there are in the world with AFib versus how many children there are with Heart Block, it's quite sobering when you look at that difference. While companies would like to help us, often it's financially not feasible for them to help us, and so they can't put their resources into those kind of things. There's a lot of reason, and there's always been the thought that it's harder to do studies in children, their vulnerable population. This is one of the myths that's always been there. We can't do, IRBs won't approve studies in kids. There are lots of different strategies for dealing with this now that we've started looking into, but those have all been things that have gotten in the way of saying, well, everything should be made for children and approved in children. Am I missing anything? Anybody else think for why? I think the main issue in preparation of this, I talked to the companies, to the main companies we're working with, and I've tried to find people that are interested in pediatrics. It's always the same. They tell me, there is no market. We go where the market is. You have to give us ideas. You have to give us other factors why we should be interested in doing this, and so I think the one thing is the reimbursement thing. We have to talk about, can we kind of go to political people to, I don't know how you say it in the US, but to people who decide about this, to go over the reimbursement. I'm quite pessimistic. Do we find other factors, like soft factors? Is it interesting for a company to have babies on their advertisement or whatever? Can we define soft factors that make industry help us? Because without industry, I think we're lost. We cannot do it. I don't know. But yeah, let's think about this. So I think it's mainly the volume that dictates the less interest in the industry, unless we attract the industry with something, it will not going to change. The unfortunate thing is this medical industry is going completely on the business model. From the HRS forum or other forums, we have to agree or make them realize that some part of their business has to be dedicated for kids, probably either, even if it goes into the loss, financially loss, it's a big deal for them, but I think that's the way to go. I might add that probably small companies are the companies more interested because they want to start a small business. They like to start small. Nobody wants to offer something which is for a fifth because you have a huge market and you have so many people you work against. So you can have small companies supporting you. The problem though is that those small companies then have those high hurdles of getting things through the FDA or whoever it is. So that is a big thing, which varies from electronic, it's not a problem. The other problem is that then products get, in case they are innovative and even interesting for adults, like for example cryo-ablation, get bought up by a company like Medtronic, which then has no more interest in the pediatric population. So there is often a, you know, we as pediatricians or pediatric EP people, we have the chance to be innovative because we are the people who think around corners and give those ideas, but they disappear pretty fast. I mean, if you look at 3D systems who pushed them through to use them for simple AVNRT or AVRT and developed all those things, fluoresce working, that's coming all from pediatrics. Other people are watching us and saying, oh, you do that without fluoro, how do you do that? So it is not true that we are not innovative or not helpful, but I think we have to sell us better to them. I'd like to add what Gabi has mentioned about the European situation. So on the one side, we have this non-financially rewarding market for the companies, and on the other side, unfortunately, in Europe, the medical device regulation process has become much more complex nowadays and unforeseeable for the companies. So what happens is that the small companies are withdrawing their products from the market because they have re-accredited their products, which is so expensive that it doesn't pay off anymore. In terms of numbers, I would just look at this as about 17% of diagnostic devices and about 20% of medical devices will be discontinued in cardiovascular segment in Europe because of the cost of transitioning to the new regulations that outweigh the revenue expectations. So that's a tremendous risk for rare disease, orphan disease patients we face nowadays. And so far, the law has not changed that could make it smoother. To also go back to what Gabi was talking about where companies don't really have incentives, we have in some ways figured this out in the U.S. for drugs. The Congress has made it a law that if companies want an extension of their patents on their drugs, they need to do pediatric studies. So there is a carrot for this. It's not just a carrot and a stick model. We don't have any of that in the device arena. And I think people say, well, why doesn't FDA just make them do this in this country? I often get asked that. Why is FDA just allowing this to happen? It's not FDA. Poor FDA has to just follow the laws. It's Congress. And so I think one of the things that we do need to think about as we're getting more serious about this is we need to be lobbying. And we do need to lobby our, and I think this is probably true across all countries. We do need to start lobbying our Congress people to be thinking about children and to be coming up with a mirror law for pediatric devices. Just on the political level, it's interesting you have touched the political level. Oh, here we go. I'm with you. We have discussed it within the Association for European Pediatric Cardiology. It's interesting. You cannot change a law in Europe with the same parliament that has imposed the law. So you have to wait. That will never go to re-change its own law. So you have to wait for the new election and for the new people to change it. Now we have it. So now we have some change to change the medical device regulation law on the European. How often are the elections? Each four years. Oh, okay. I think some... Oh. Some of this conversation is reminiscent to what Dr. Califf was talking about in his opening plenary. If you had a chance to hear him, he said very clearly that these soft things, like what you touched on, Anne, can be very potent. And I wouldn't call it necessarily lobbying. I would call it advocating, right, for our patients and for what they need can be done through these soft metrics. Certainly in the US with our Congress people, it sounds like there is a whole nother barrier that our European colleagues have to face. I mean, talk about basic European civics. I had no idea that was a thing. No idea. But it does impose a certain set of restrictions that you have to sort of solve for. Anybody? Dr. Van Hare, would you like to take the microphone? I just wanted to comment that there are actually some incentives with respect to devices that are not at the same level as drugs. So if you have a PMA, those reviews are all funded with user fees, and it costs nearly a million dollars to actually get a PMA. That's for free if your device is specific for children, okay? So that's one thing. HTE pathway is a sort of a lower level of effectiveness evidence that you need to sort of meet if you get on the HTE pathway as opposed to the PMA pathway. But the HTE pathway, it's a little bit more regulatory burden, and if you make it for adults, you're not allowed to make a profit on the device. But if you make it for children through the HTE pathway, you are allowed to make a profit. So there are some incentives. They're just not at the level of drugs, so anyway. Any other comments from people that we know have been working on device development in pediatrics with either on their own or with other companies? I'm looking this way, to that side of the room. Do you want me to walk a mic over to you guys? She's talking to you, come on, John. Come on. And Dr. Karpowich back there in the front as well. Oh, yeah. Nothing like peer pressure. Yeah, it's potent. I think the biggest incentive or way to convince, there's two ways. One is if you use, one of the things I've used is one of the company's annual reports one year had an infant on the cover of their annual report to shareholders. And I've used that against them to make them feel guilty. If they're putting this patient on the cover of their annual report, maybe they should be providing devices suitable for those patients. That was 20 years ago, so sorry to the people from that company that are in the room, and they have been. And the other is to look for larger applications. So even though we're trying to develop devices for infants and children, they may have advantages for older children and adults, who may benefit from those same devices. And so you have to think creatively what the bigger market could be, even if it's not our market of interest. I think it's sort of a challenging thing to reconcile with some of the things that Dr. Van Hare brought up, which are very specific incentives to exclusive labeling in a pediatric market, which from a business standpoint can be a little tricky. Thank you, Dr. Karpowich. You're all correct. And I guess the issue is not so much are they making a device for children, but is it applicable to a child, and therefore evolves into an adult device. So I think some in this room remember the Microneed pacemakers, Microminix, a little bit bigger than a quarter. The market was great, but then the adults stopped putting it in, and then it went out. The 3830 lead was designed for children, but they marketed it as a small device, and then as soon as conduction system pacing started, it took off, because basically they were going to stop making it, because the adults weren't using it because they didn't want to have a catheter-delivered lead. They wanted to play with stylettes. So I think when we're talking about something specifically for children, it's not so much is it going to be for the small people, is it going to be applicable to everybody coming down the pike in the future. So we might be saying, you know, don't market it for kids. Market it applicable to kids, but industry is going to say, can we put this into the big market? And if they can, then a particular device might take off. I think that's a great point and leads to my next question. I'm curious as to pediatric indications. How do you find that devices with pediatric indications are prioritized either by your institution, from what you know from your regulatory body, locally, supply chain, et cetera, instead of starting with Anne? You're starting with me again? Okay, Dr. Janicek. Okay, Anne, thank you. You want to go, Jan? I'm quite pessimistic about it. We don't really get any support, I think, in that indications. And just a comment to what has been discussed before. I think my argument to other companies is, yes, we have a pediatric patient. It's a small market, but you can multiply this patient by a factor of seven or eight regarding devices because they will get it many more times than an adult recipient of a pacemaker whose average age is 75 or whatever. But in terms of support, I don't think we get really support from somewhere. We have to fight for our patients. I'll say, and I'm happy to talk. I'm sorry, I was just teasing you. I do not think that if we queried the audience, anybody would know what was approved in children. Here we go. Okay, thank you. I think I talk loud enough. What was approved in children and what isn't approved in children. I don't think people tend to. We did a very informal survey several years, actually about now, back in 2018, about what people's understanding was about the process for FDA approval in children and why that might be important. Quite honestly, I think the biggest thing that we recognized through all of that, as well as through beyond just the fact that there were so few devices available in children, was the fact that our members really did not understand the process, didn't understand the advantages of FDA approval for any of these, and I think you can translate that to any regulatory body, didn't understand that in the least. And on top of that, their hospitals and their medical centers really weren't paying any attention to that either, and many of them are now, especially in this day and age where there is such concern about reimbursements, are looking more for what kind of good deals they can get on devices rather than are they specifically aimed at children or are these companies interested in children. And at least in Europe, as I understand it, this CE mark, which is kind of corresponding to the FDA approval, if companies get this CE mark, it's not depending on age. So it's up to us then. You can use it in every age group, so we don't have this thing. It's only for children, only for adults. It's this one CE mark, and this is age-independent. So they give it back to us. Do we want to use it? Okay. But it's not apt for children. You can use it. So they're not interested to kind of putting a 4F ablation catheter on because nobody will use it even if they get the CE mark, which is expensive. So this is the process. It's very tough to go to the pediatric side because it's all one. It's not divided. That's just for clarification around how Europe handles this. So just to sort of clarify the big picture here, if there's a device available, we tend to put it in kids in the United States, if we think it's appropriate, under practice of medicine. So the device is there. Even if it wasn't labeled for what we're going to use it for, we have a fair amount of discretion. And I do think we need to talk a little bit more, if that's the case, then really why does it even matter to have a pediatric indication? But anyway, under practice of medicine, I think we're all used to not caring if it's approved for kids because we can use it. My understanding is that's not exactly quite right in Europe, partly because the EU, which is what looks over devices, doesn't have really supervision over practice of medicine because that's an individual country thing. And so that they treat those things as different. Can you clarify that? Right. Do you want to answer that? I mean, the current medical regulation process is proceeded by so-called notified Buddhists, which are commercial organizations which have got from the European Commission the status in individual countries to be in charge of the medical device regulation. And they decide whether the particular device is acceptable. And the problem is that if you want to ease the process for specific, like, orphan devices because the data cannot be as large as for big, large populations, these notified Buddhists are not really interested in simplifying the process because they earn money by complexity. So if it's more complex, they earn more money. So from a commercial aspect, they are not really motivated to make it smoother. That's one of the obstacles. So now the biggest aim of the European Society of Cardiology is now to try to change the law in the way that there is one body for all the Europe, as we have it for drugs, but we don't have this for medical devices. So this is the difference to US. You have one FDA for both. But in my understanding, once you get the CE mark, no matter in which country, this is apt over all Europe. So this is how it works, no? Yeah, this is how it works. Once you have it, it's OK. Once you have it, you have it. So anyone can use the device for anything? Anyone can use it in Europe. In the countries that are affiliated with those notified bodies, is my understanding, and it should be already... In all countries of the European Union. Except, well, yeah. Not outside the European Union. Correct. They have their own country regulatory processes. And then, again, in Australia, it's, again, different because we have so little actually approved devices. We have what we call an SAS. So you can apply as a doctor for an exemption to use a product which is not approved in Australia. And that's what we do actually for every balloon septostomy. I'll just tell you that. Oh, my God. For example, they're not approved in Australia, the balloons for a septostomy. We do that for every nadolol prescription I do as an exemption form. I mean, it's kind of smoothed out. In the end, it's not so hard to do that exemption form. But basically, every parent has to sign that they use a drug which is not allowed in Australia. And, of course, that means also they have to pay for it. In terms of nadolol, it's not so horrible. For other drugs, it can be quite expensive. So it's different. You can access everything if the company is happy to deliver it to you. So we also had, for example, access to the new Charlie Berul slash Medtronic device. But I have to fill a form, and it has to come from overseas, and it's a bit of a process. I was talking with a colleague from South Korea at APHRS when, thankfully, you were so kind to host it in Australia and Sydney this year. And what he told me in South Korea, the processes, is that the physician has to create the documents to submit to the regulatory body to initiate review. And I asked him how anything ever got approved in South Korea. I can't even imagine taking that on. But it just goes to show how the wide variation in practice is. Sorry, you were going to ask a question, I think. No, I think I was going to say that, thank God I work in the U.S. based on what you just said. I thought we had it bad. Wow. Okay. Do you want to talk about why it's important? Yeah. Yes. So, Anne, do you have any thoughts on why a pediatric label is important, even though we theoretically can use the product anyway? Well, I can start, and George, you can fill in if I miss anything. So pediatric labeling is important for multiple reasons. Number one, it allows your companies to talk to you about a product in the U.S. If a product is not labeled for pediatrics, they are not allowed, your reps really are not allowed to kind of help you and fill you in on it as far as telling you about that product. Number two, you need to sometimes have pediatric labeling on a product so that you can use extensions of that product or get extensions of that product looked at. If you do not have, say, an ICD that is pediatric approved, you can't necessarily expect the device company to start thinking about making shorter leads or making leads with coil spacing that's different because they have nothing to attach it to, technically. It also allows for there to be much more robust monitoring of devices after market approval. It allows FDA and the companies to do some work looking at complications, etc., after a device is released that we have absolutely no access to ahead of time. What else am I missing? Actually, before you say anything, someone just asked a question which you're answering and George is about to continue answering. Can you highlight some of the downsides of continuing to use devices with off-label status in the pediatric world if it gets the job done? In other words, how is it beneficial to have an FDA-approved indication? What else did I forget? I agree with everything you said, just a few more things. Yeah, I can't remember. We do what we do, and generally we think that what we do is safe and effective based on our personal experience. Sometimes we're right and sometimes we're wrong. When you go for pediatric labeling, then there's a process of FDA actually evaluating what evidence is available, and a lot of that evidence is preclinical, and then real-world evidence and everything. If at the end of that whole process of sort of critical review by essentially an outside body from the pediatric community comes to the conclusion that actually the device is safe and effective, that has some value because it basically tells you that what you thought was true, actually somebody agrees with you about that. So that's worth something as far as I'm concerned. I think you hinted at this a little bit, but when a device gets approved, then for the most part these days, FDA will sort of mandate a post-approval study, which is basically funded by industry, and so that's an opportunity to gather data prospectively, which has a lot of advantages over retrospective data. And just to put in a little parenthetical thing, Medtronic's Omnia Secure defibrillator lead, which is a four-fringe defibrillator lead built on the backbone of the 3830, was actually approved on Monday with a pediatric indication down to 30 kilos and 12 years of age. And what that means is that the post-approval study is going to include children, and so we'll get some prospective data. So that's actually worth a huge amount. And then the third thing, and then I'll shut up, is that we get to write the instructions for use. So if you think about the fact that most medical devices are going to be used in high volume, incredibly competent centers, that's true, but then they'll also get used in very, very low volume centers where you may find yourself with maybe an adult-like physiologist who's faced with a 12-year-old who needs a defibrillator. Perhaps they would like some guidance about how to go about doing that. So it's sort of good for children to actually have instructions for use that actually help everybody that actually might use this device, not only CHOP and Boston Children's Hospital and stuff like that. I'm going to play devil's advocate for one second. Please, come. You're right, there is value in it. So here's the devil's advocate part. My investors don't care unless it's economic value. And this is that tension that I think we're trying to negotiate. One of the issues that were raised in the past with industry is liability over time. And this is an important fact. Yes, the device can be put into a 2-year-old. And if the device lasts for 30 years, is there going to be a problem with that device? You don't worry putting in a device in an 80-year-old. But if you put in a child, one of the issues we ran into, it took seven years working with the FDA to convince them that the one milligram of dexamethasone at the tip of a steroid lead was not going to cause them to be Arnold Schwarzeneggers. They were adamant. You're giving drugs to babies. It was a no-brainer to industry, but the FDA didn't want that, so they had to keep showing it. But one of the issues was growth. Ann talked about the length of a lead. Yes, the lead can be whatever you want it to be. Remember, at one time there was a yo-yo. Some of you may remember the device. The lead was supposed to wrap around the device itself, and then it was supposed to rotate, and parsonite had the pouch. The lead would unfurl? Yes, that was the theory. There was another one where you put the lead inside of a pouch, and you coiled it, and it would uncoil as the kid grew. None of this ever worked out. But they were trying to compensate for growth, and that's one of the industry's main issues. It's not so much you can put it in a child. It's small enough it works, but what's going to happen 20 years, 30 years, 40 years if something happens? The AcuFlex lead, most of us could remember that, where all of a sudden it started tearing. So that was a main issue with industry, is there potential liability down the line, not so much the immediate implant type of problem. All right. I think we can actually move on to Part 2. We just finished Part 1, which was background. Part 2 is what's being done, how sort of our various regulatory bodies, including just folks like us, are trying to make things better. Ann, do you want to do the opening? Do you want to just advance the slides? I'm happy to do that for you. So I will thank an unnamed person for helping me with these slides. So why, and, again, I'm being very jingoistic and looking at the U.S. here. Why is FDA interested in real-world data, which is really kind of the bulk of what I think we need to be thinking about when we're looking for pediatric approval in these groups? Because, as I think everyone here has said, we do tend to use these devices in children. We have a lot of experience doing it off-label. How can we use that experience to help industry and to help FDA evaluate these devices for children and therefore then make sure that they're safe enough for us to be using? And there are several things. One area is computational modeling. It's something that's being used more and more frequently to help, and I know that that was actually used with the new ICD lead that was just approved in order to show that it would actually last with a minimum amount of breakage. Another is real-world data. We have a ton of real-world data. We tend to publish a lot. There is a lot of databases available to us on real-world data of using these devices in children. And why do we want that? Well, first of all, randomized clinical trials are expensive. They're also incredibly difficult to do in children. We do not have the power for them, even if we've got worldwide involvement in them. Open-label prospective trial with performance goals are also difficult for us to be doing. FDA often is going to need post-approval studies, which usually includes real-world data anyhow. And as I just mentioned before, there are lots of different sources for this real-world data. We have a lot of publications. we have registries, we have medical claims data, which is difficult for us to get to in pediatrics, but I think it's something, it's probably the next frontier for us. And we have the electronic medical record, which I don't think we have harnessed the power of that yet, which I think is going to be important. Oh, there you go. And so I think one area that has, that we've been involved in and that we've been looking at, and which I kind of alluded to, is the pediatric arm of the EP Collaboratory. This was formerly the PACE's FDA Industry Committee, and we have now moved this committee to be a part of the general EP Collaboratory, we're one of the arms of this. This committee was initially formed back in 2015, with the main aim is to improve device availability in children. What we do is we consult with industry regarding pediatric needs, we educate our members as well as industry and FDA regarding the requirements for pediatric labeling, and as well as why we should be labeling. The EP Collaboratory was just formed within this last year to address medical device challenges, and we are in the midst of joining the Collaboratory right now to aid in this. And what have we achieved? We have kind of started off slow, and we're gaining momentum as we go. And probably the one that we have completed so far, there are several others we can't talk about at the moment because they're in the midst of working with FDA, but one that is completely done is the cryo-cath system. In the U.S., we had mapping capabilities in the 4-millimeter-tip cryo-cath, but while 6-millimeter-tip cryo-cath could map in Europe, we were unable to do that in the United States. We did not have FDA approval for that. We felt that this was an important safety for children if we could achieve that, specifically since a good number of our members tended to use cryo for AV nodal reentry tachycardia. And so we took a real-world evidence approach. We worked with Medtronic as well as FDA and said, this would be important to us. This is an important thing to do, and hey, we have a lot of data that might help you in getting there. We did a literature review and found 16 papers with over 1,000 pediatric subjects. And I think this is where the power is, is that we've actually done a lot already. We just have to harness what we've done. We extrapolated adult data to pediatric population using an FDA guidance document, and we were able to show that over two years of age that this was a safe and efficacious equipment. And so it has now ultimately been approved by FDA with a 6-millimeter-tip with cryo-mapping capability. Interestingly, what a lot of PACES members were concerned about was the fact that, well, if we say two years, then anybody under two, we can't use the device. That's not true. It basically, they were silent on this, and basically the FDA was silent on this. And so the indications for use doesn't even address this. If you, as a physician, feel it is in the best interest of your patient to use this in under two, you're still able to do it. You're just using it off-label, which we do anyhow. So I think that's an important misconception that a lot of us in the room have, and the worry is that if we do get FDA approval, we can't use the devices in other patients. That's not true. So I'm going to keep going fast because I know we're getting late. So lack of pediatric labeling doesn't impede our ability to use these devices, as I just said. There are advantages, as we've been talking about. I won't go through these again for actual pediatric labeling. And the FDA has been incredibly helpful to us in helping us, as well as educating industry on how to try and make these pediatric indications happen using real-world evidence, using extrapolation, using computer modeling. We are really happy to work with PACE's members, as well as industry, to continue to advocate for devices and to work basically as a conduit in some ways. Is there any more? I don't think I have anything. No. Now we have, Dr. Jahn. Okay. Actually, just before Jan's slide, a few questions came in, and I'm going to just ask two of them really fast. One is, is there a pathway to seek FDA approval based on long-term safety established by off-label use in pediatric population? I think that's everything Ann just talked about. The other, just to briefly get to, do you think that pediatric labeling can be used to decrease the amount of insurance denials that we are currently seeing, and therefore translate that to an improved economic advantage for that device? And my own answer with that would be that theoretically, yes, in the future, I can definitely see it. I have not personally seen examples of that where something wasn't approved just because it was not indicated for pediatrics, but does anyone have any different experience in that? I haven't seen that, but what I have seen is the ease with which supply chain will bring that into the hospital. So instead of, I think somebody alluded to this earlier, that hospitals are always looking for the best rate with their devices, which is absolutely true. We certainly experience that, but the minute something comes in with a pediatric indication, I just hand it over and I say, that will now be available to me, and they always make that available to me. Okay, great. Jahn, do you want to address that? I think we have touched the topics of those slides. So I would stress something else regarding what you reported about the FDA processes and about the trial data and so on. I think there is a strong support by the European Society of Cardiology to harmonize the clinical trial protocols resulting in data that is accepted by major medical device regulation bodies throughout the world. So at least between Europe and the United States, it would be a great thing to have such a unified trial design and also a register design, both public and company-based. I think that would help a lot, and this is something PACEs could be really active in. And again, in Europe, once we have this unified accreditation body for medical devices, we will hopefully be able to go forward to have some negotiations between FDA and that one. I guess on that topic, harmonization, which is exactly what's next. I'm going to talk very briefly about harmonization, and then I'm going to ask Dr. Van Haer to get up there and talk a little bit more about harmonization. This is what it was like at work, too. So International Medical Device Regulators Forum, the IMDRF. This was established in 2011 from medical device regulatory authorities actually from all over the world, Australia, Brazil, China, EU, Japan, and the U.S., as well as the World Health Organization. And what they were fundamentally trying to address was, was there a way to align the regulatory bodies, align technical requirements so that we can have some uniformity across the participating authorities, which would in turn be useful to industry and then hopefully be able to rapidly deploy devices that had met these standards. In September of 2023, CDRH issued a draft international harmonization strategic plan. Dr. Van Haer, I'd love to hear where it stands practically. Well, most of this stuff is stuff I don't know that much about. My experience is that we actually do have something called HBD, which is harmonization by doing, and it's primarily related to harmonizing with Japan. And it's a thing, and there's also sort of a sub-segment, which is harmonization by doing for children. And a number of devices have actually gone through that process, specifically the Medtronic Harmony Valve, and then Ronada's new infant expandable stent. Both of those things have been approved. And I guess the idea is why this might be good for device development is if you can basically get, if you can double your market for the same investment in clinical trials, then your return on investment is better, basically, is the bottom line. And so I'm sort of a member of that, or sort of joined that group just before January 20th. So we'll see where that goes. What's interesting is that the drug side has had harmonization for quite a while, and they've leveraged it to great effect. So this is one of those areas where we can learn from what another group is doing and apply it in our own sector, and harmonization is one of those, certainly one of those categories. So the last section is what should we all be doing? And before we kind of open that up to the panelists, I just want to ask a question that came up on this topic here. How do we improve resources for faculty to learn the important early stages, design history, et cetera, of device design, of device development for the FDA? So I think the question is, it doesn't sound like a lot of people know how any of this works, and how do we broaden the education around it? And just, I will say, I was surprised that my own institution, Children's Hospital Los Angeles, actually asked me to give a Grand Rounds on this and go through aspects of device development. I was surprised that people showed up. I think the same people show up every week, fortunately, so there was an audience. But there is some interest in this, and there's certainly very much a lack of education about this, but I do wonder if people have any words of wisdom of how to make sure more people understand this stuff. I think one of the things we talked about in the EP, I keep doing that, I'm sorry, thank you, thank you, in the EP Collaboratory meeting this morning was specifically educating our members about this. And I think what would be a really interesting thing is to actually have a webinar that people can join to kind of go through each step-by-step of what we're doing, and so stay tuned. I think we can do that. I think it would also be, I'm not sure if it would be too big to try and include the rest of the world, but I would think it would be very helpful if we could. Maybe we do a separate one with that as well. I guess I'll ask a follow-on question. For those of you who've been working with industry partners, what have you learned in working with them? I feel like that's educated you on this aspect. I think there's a natural resistance or feeling unwell with any contact with administration and doctors for a good reason. So you try to minimize the contact, I would say, and for that probably makes us feeling uninterested in those processes, and of course, in the end, we get played by those processes. I mean, it's the same for, you know, if you're not interested in your financials, you also get played by the bank, you know, it's the same problem, and doctors are very typical uninterested in both of those things. So I think that's probably generational or, you know, what we get in medical school because we are thinking we are, you know, doing the good and, you know, we don't have to deal with those administrative things. And I have to say, I'm not different. So when I was pushed into doing that, I was feeling uncomfortable. I can just say, just don't feel uncomfortable, just otherwise you get played. I think one thing, talking to industry, I think they want something from us, and I think they want us to define the need, and this goes back to this one question. I mean, if I have a 14-year-old and can use the same 3D patches than the adults use, so there's no use saying, okay, I need a pediatric approval for that. So I think we have to define the need, where is really a field where we want pediatrics to go forward, which is special and specialized for pediatrics, and then we have to give them data. I think this is the next step. Once we define this need, we have to work together, and this would be really a global working together and giving them enough data to say, hey, that makes sense. And I think this is the way to go, because they will not come and say, oh, we are so interested in you, we want to develop something for you. I think we have to go, and we shouldn't underestimate what we were talking about, the soft factors. This is something we can maybe work with also, because they are interested in pediatrics. This is my feeling when I talk to industry. But they want something from us. Another question that came in, it was very well stated. What can a lowly, regular pediatric electrophysiologist who isn't on any of these fancy committees do to help advance pediatric labeling? Join the committee. Join the committee to find the need, yes, to find the need. And I think the role is important to get the real-world data. They have very soft indications at times. Like for me, at times there are no hardware to get the epicardial ICD placed, or the surgeon has no experience, so you have to push yourself to do it in a smaller or younger patient. So you may have reasons to do it, which the countries like US or Europe does not have, so they push themselves for the epicardials and those things. But for those smaller countries, the real-world data is important from them. So use the devices and collect the data. I have one more thing. I would challenge everybody to go to the expo floor. It's big and it's intimidating and it's loud and it's very shiny. And talk to one company. Just one. Introduce yourself. I am certain that some idealistic young engineer who wants to save the world, particularly the kids, is going to have a million questions for you if you do that. Just one. I think it's okay. Andreas' point is well-taken. We've maybe been taught that that's not a great idea. So just one. So does anyone in the audience or any of the panelists have words of wisdom on how to get us all more involved? I'm actually kind of impressed at how many people showed up today. Just because I don't know how interesting this stuff is to people. One can get bogged down. No, I just mean in terms of the regulations. To Andreas' point, some of this does not feel like how you want to use your time when you think about regulatory processes, et cetera, even though it's ultimately very important for the practice and what's best for our patients. So how do we get more of us involved with this stuff? Any sage words on that? Yes, please. Microphone's here. Sorry. Had to do a little walking. It would be interesting if industry is in there. Is there anybody from the industry? So I am an engineer from industry. And I've loved taking part in this session and listening to the thoughts. One thing that we have as a problem from industry, and you mentioned that a little bit with your sales reps, is that we're hamstringed from reaching out and communicating with the clinical world because things aren't on label. And so please do come approach us. I work for Medtronic, and I know we have an internal pediatric working group. We have people who are desperate to try and get our therapies into the pediatric space because either they care or they have family that have pediatric issues, or they just see it as part of our mission. A big thing that would help is also data availability. So a lot of data, I work specifically in computational modeling. Some of the work you referred to we can use for regulatory evidence, but getting the data is so hard or impossible, or it's behind academic firewalls where you have to be a researcher to access it. And so being able to have more openly accessible data and lines of communication could greatly accelerate our ability to generate the evidence we need to bring it to regulatory pathways. And that's exactly how the Pediatric EP Collaboratory can help you. We can be the conduit of getting this data to you. We can help as far as talking to you about the needs of our constituents. I think that this is a really ripe time for us to be working with people like you, who really, I don't mean to make industry sound like the villains here. You guys aren't. There are a lot of people who are really invested in taking care of our patients, but there are a lot of firewalls that are up that we need to be trying to break down somehow. Thank you. Don't everybody approach him on the expo floor. I'll say something too, so you don't have to just have him. So I'm also from industry. I am actually regulatory, so exactly what you guys all just went through. But a lot of what we end up needing to get to the pediatric population is that you are using the product and that you go, you collect your data, you publish on it. And while doing that, you're like very specific about, hey, I used this product in these patients, and it could be using everyone's product, but we can't mine that data and look to see that the desire is there without someone doing the work and putting it together. And same deal. We can't come and approach you because it's off-label. But yeah, go to the exhibit floor, because I know every company down there has a, hey, new stuff coming, go look at it. I think you probably have to send an NDA for every company, but you can go see what's coming, what's under development, talk to the engineers in there, and you can probably get some feedback to them of, hey, this is what I would like to see you guys do. This tool seems like it might fit into the pediatric space. How can we make that work? That kind of thing. I just have one thing to add in terms of why it's important to have pediatric indications that wasn't brought up. I'm actually very impressed that we didn't go down this path, but I'll be brave enough to do it. So we're living in a time, at least in the U.S., where these regulatory bodies are actually under threat, and we should be voting with our feet to show the value that they add by partnering with the FDA and not circumventing or trying to obviate it. Good point. Very good point. Okay. So, I personally have taken a lot away from this session. Everything from truly basic understanding of the variations country by country to more complex levels of thinking about regulatory science, particularly around the real world evidence, and what are actionable items that we, everybody in this room, we, the Collaboratory, and we as PACES could all do together for the benefit of our patients. Thank you so much for being with us today. Have a wonderful rest of your meeting, and I'm sure people will be around if there are questions to follow. Can I make one final plug? So for any quote-unquote lowly pediatric electrophysiologist, which I think we all are, who is interested in joining the Pediatric Collaboratory, please just reach out to me, amdubin at Stanford. We are actually looking to change the makeup of the committee, expand, et cetera, and rethinking a lot of what we're doing, so just reach out. We would love to have you involved. Excellent. Thank you.

pediatric electrophysiology

device development

regulatory perspectives

medical devices

pediatric labeling

real-world data

market access

collaboration

regulatory challenges

innovation opportunities