So, our last presentation is the FDA's Perspective to the Future of His Bundle Pacing. Unfortunately, Dr. Kimberly Seltzman has overlapping presentations, but fortunately, we have Dr. Roz Kazmersky, who is here to give her presentation. Thank you. So, all right, hello, everyone. I'm Roz Kazmersky. I'm a biomedical reviewer, a biomedical engineer and reviewer at FDA. I review devices that would be used for His Bundle Pacing. I am not Kimberly Seltzman, and please note the difference in degrees. I am not an M.D., so please be nice. So I wanted to take a very brief look at the timeline and the gust where we are today. So as was mentioned by my other presenters, His Bundle Pacing was originally presented or proposed over 50 years ago, where the authors suggested that in contrast to direct stimulation of the ventricles, His Bundle Pacing produced no change in ECG from normal sinus rhythm or pacing from the right atrium. This was an acute procedure and was suggested as a more exact means for studying electrophysiology and hemodynamics as the normal pattern of ventricular activation is maintained. So this was proposed as a research method only. And it wasn't until 30 years later that Dr. Deshmukh used existing medical devices to provide permanent His Bundle Pacing in patients. So that was almost 20 years ago. And since then, the idea has generated a significant amount of interest. A lesser known event may be the first device approval with indications for pacing of the His Bundle. This large, almost 20-year gap between the first permanent implant and the first device approval helps illustrate where FDA fits into the scene. The use of existing pacing systems before 2018 would be considered practice in medicine or off-label use, where the implanter used his or her best medical judgment to determine it was appropriate for use in their patient. FDA comes into the picture when a device manufacturer wants to include claims or specific indications for His Bundle Pacing and needs to demonstrate a reasonable assurance of safety and effectiveness for the intended use. The first approval has the following indications, with the standard language for the pacingly grayed out and the His-specific indication at the end, stating is it intended for pacing and sensing at the bundle of His as an alternate to right ventricular pacing in a single or dual chamber pacing system. If you look at the grayed out text, pacing and sensing in the atrium or right ventricle, you may ask why this doesn't cover the His, and that's a good question. Simply put, we believe that pacing the His is different from pacing the apex, and it raises new questions about safety and effectiveness of the device specific to the new intended pacing site, including increased dislodgements, more difficult implant technique, different sensing capabilities, and usually higher pacing capture thresholds. In order to demonstrate safety and effectiveness and receive an indication for His Bundle Pacing, we have asked that sponsors either collect robust, real-world evidence or conduct a small, well-controlled confirmatory study that can adequately demonstrate performance of the device in these areas. So I think this gets us to where we are today, but for the future of His Bundle Pacing, I did a quick search on clinicaltrials.com and came up with 19 trials, so I will compare with the other presenter that had 42, but I did eliminate some that were either no longer active or were not using permanent implant systems. So 12 of these, more than half, are focused on the ability of the His Bundle Pacing to resynchronize the ventricles. Even this morning at late breaking, Dr. Dung presented the results from a pilot trial called His Sync, further supporting the role of His Bundle Pacing resynchronizing the ventricles. And on top of that, there are at least half a dozen other talks at this year's conference discussing this topic. So the FDA perspective is that the future of His Bundle Pacing is to demonstrate its ability to resynchronize the ventricles safely and effectively. Given the signals that this is where His Bundle Pacing is going, what is FDA's perspective on this? Well, we think this is exciting, as this may be beneficial to patients, but I would like to emphasize the importance for clinical equipoise for this and any new therapy. As there are many questions yet to be answered for using His Bundle Pacing to resynchronize the heart, we believe that prospectively replacing biventricular pacing with His Bundle Pacing can pose a significant risk to the patient. And here I'm using significant risk as defined in our regulations that would require an FDA investigational device exemption application rather than just IRB oversight of the trial. We have been contacted by IRBs in specific cases, and we acknowledge that different trial designs represent different levels of risk to the patient. I want to clarify that the statement on the slide is very generalized perspective for a very complex area. And let me say that one more different way just to help drive home the point. This is a very gray area, and whether or not you need FDA approval to begin your trial depends on the specific aspects of your trial. So we would encourage anyone with questions to reach out to us. So why do we believe this represents a significant risk to the patients? The primary reason is because traditional CRT has known benefits, and by foregoing that therapy you could be placing the patient at risk with a new and relatively unproven therapy. Also we have concerns with other unanswered questions like the potential for disease progression affecting his conduction or the limitations with currently available devices as we've seen many unique his pacing strategies. And the concerns noted earlier such as higher dislodgements, pacing capture thresholds, and even bigger questions like what arrangement of pacing configurations may be the most beneficial. And here I'm calling out the results of a recent study by Dr. Vijayaraman and others that suggest his bundle pacing combined with LV pacing may be more beneficial than his bundle pacing alone. Now to share our perspective in an idealized scenario, we would love to see an adequately powered randomized control trial to answer the question of whether his bundle pacing can resynchronize the ventricles. This trial could answer the questions noted above, potentially including real world long term follow up to help alleviate some of the burden of running such a trial. So we agree, this is exciting, but we need a large clinical effort to answer these questions. So here we're back to my original timeline and I've added an additional yet to be determined time point, the first approval for his bundle resynchronization. We'd love for these questions about this application of his bundle pacing to be answered sooner rather than later as we think it is in the best interest of patients. To do this though, we really need this effort to be led by the academic and industry leaders so that the timeline doesn't continue to stretch out for many more years or decades. So this is my last slide and I just want to put it out there that we want to help in any way that we can. If you have a trial that needs FDA approval, the submission fee is $0. If you're not ready to submit your trial or you have large questions such as trial design, you can submit a cover letter, an agenda, and any information you'd like us to review and we'll have the right people ready to give you feedback and listen to you. The total cost for a pre-submission is $0. If you just want to know what to include in an IDE submission or want to have an informal discussion about your work, we can do that too. Just email or call and if I can't answer your questions myself, we can usually get the right people talking to you relatively quickly. We charge $0 for this. If you remember the credit card commercials from about 10 years ago, you know where I'm going. Of course, it all comes back to the patients. I think we owe it to the patients to collect this data to ensure the most effective and safe therapy is being provided. And I'll end on a note from our website down here at the bottom. I know that some people may think FDA is just getting in the way and this can happen entirely without us. I would only respond that we want to help where we can, whether that is protecting patient safety or providing an unconflicted review of the collected data. Our mission is to protect public health, but we also are charged with helping to speed innovation to make medical products more effective, safer, and affordable, and by helping public get accurate science-based information, they need to use medical products. So I would leave it on just that, how can we help? And here is my contact information, but you can find us on the FDA website through various links. So that's it. So, miraculously, we actually have four minutes for questions. If anybody has one, fire away. Did Dr. Meyerberg stick around? Is he still in the audience? No takers. I guess everybody's up. Maybe I have one question to Dr. Ellen Bogen. Martin Stockburger from Berlin, Germany. I really noted that you talked about pacing the conduction system and not just the hiss. And this reminded me that there may be some similarity between the approach to screw in deeply to the left bundle and was Fritz Prinzen is no longer here now. But you know that he has an approach to screw through the septum to the left ventricular endocardium. And I was wondering if this isn't a very similar method or if this isn't lastly the same. The question is a great one. And that is this technique in the Netherlands with I guess it's Kevin Renoy. Kevin Renoy is doing with Fritz Prinzen where they're pacing the inter they're going through the interventricular septum to pace the LV endocardium. So we talked a little bit about that earlier. It's funny you mentioned that. I asked I don't know that they're actually pacing the conduction system. So I tried to show you you know I tried to show you that in some of these patients in our hands we record very sharp potentials 20 to 30 milliseconds for the cures. Now that's our experience. Other people I think Dr. Wong and other people record those left bundle potentials far more commonly. But I think what's critical in this whole field is that when you're implanting these leads you have a 12 lead EKG on the patient. And if there is an isoelectric period between the stimulus and the QRS 20, 30, 40 milliseconds then something's happening and you're getting into the conduction system you're just not seeing it reflected because you're not activating the ventricular myocardium. There's a lot of these other ways of pacing. When you're pacing you're pacing RV septal myocardium. And when you pace the RV septum endocardially or the LV septum endocardially as I think Dr. Princeton and Dr. Bernoy do you get a pretty narrow QRS. You get a pretty narrow QRS but you don't get that isoelectric interval so you're not pacing the conduction system. Now I don't know what the results are when you pace septal myocardium and you get a narrow QRS but you know I think we just don't know. I think the results with conduction system pacing are quite good. I think we thought in the beginning when we were pacing the his bundle selectively, non-selectively we're above the tricuspid valve all the time. But we're clearly not and I think we tend to be migrating a little bit lower and more inferior. I have a view on that as well. When I look at Dr. Princeton's work my assumption is that if you're not touching the fascicular tissue you're getting into it much more quickly. It makes me think of the most sub-study analysis that correlates the width of QRS with the probability of poor outcomes. The point being that even in the RV the variation in QRS duration is an important factor in determining congestive heart failure incidents in AFib and that width almost certainly has to do with how quickly the wave front wants to get probably into the right bundle system which is also highly variable and complex though more discrete than the left fascicular system. Any other questions? Going once. Going twice. No? Guys are hanging out. Thank you very much. Thank you very much. Thank you.

FDA

his bundle pacing

safety

resynchronize

clinical efforts