RQM+’s Post

Transcript

Number state ladies and gentlemen, I'm sure you've all heard about the FDA's recent approval of Edwards Life Sciences Transcatheter tricuspid valve replacement device. It is an absolutely huge moment for a structural heart technologies as well As for patients experiencing severe or higher grades of tricuspid regurgitation now. In fact, even for those patients who have no other options available when you talk about tricuspid interventions and now I'm going to refer to tricuspid regurgitation STR in the future course of this conversation. Now following this huge development, I'd like to share some insights on what may be certain underappreciated regulatory aspects that may help other manufacturers dabbling in the same area. I'll have a short introduction section covering the. Basics of the approval, right. I'll talk about some items to bear in mind in terms of regulatory uncertainty for manufacturers in connection with future submissions. And I'm also going to talk about what regulators could be, should be, perhaps should be looking for in the future. All right. So let's get into the first section, which is the introduction and the basis of approval to put things into context for the uninitiated TR is caused by. Cardiomyopathies left ventricular valve disease, congenital or otherwise acquired pulmonary disease. Patients typically present what's called degenerative, also known as primary TR. That's one type of ideology and the other ideology is functional or secondary CPR, and both these ideologies result in shortness of breath, swelling due to fluid retention and fatigue now. For the uninitiated once again. Degenerative TR is regurgitation caused by a faulty valve apparatus. Functional TR is caused by enlargement of the ventricle, and a mixed ideology is basically a combination of both degenerative and functional causes. The top residual risks associated with this device type in this broad patient population, or the risk of heart block or conduction system issues as I'll refer to it, and the consequent need for pacemaker implantation. To go with thrombosis, bleeding risk due to the medications that they're on and long term value durability. Let's talk about the clinical data as far as this particular approval, submission and approval are concerned. There was a randomized clinical trial which compared the results of 96 patients treated with the evoke valve and medications to 54 patients treated with medications only. Now this patient number varies depending on what report you look at. But if you look at the actual Edwards Life Sciences IFU, which talks about the data that was used for approval, these are the numbers that are stated in there. It's probably another registry and there are somewhere, but these are the basic numbers. Remember, the standard of care treatment for this population is beta blockers, antiarrhythmics. Diuretics and oral coagulation, so it's optimal medical therapy. The approved indications for use statement clearly reflects the data from the RCT such that it states the EVOKE device is indicated for improvement in health status of patients with severe symptomatic TR despite treatment with optimal medical therapy in whom a tricuspid valve replacement is deemed appropriate by the heart team. So it's clearly going after functional status improvements. Right. With patients with severe or more TR as approved by the heart team, that's that's what it's going for. And from what I understand of what has been published, 80% of the patients in the device arm had functional TR, OK, as it is a significant and overwhelmingly significant majority of TR patients present with functional disease and that's accurately reflected in the patient population that was studied. So to summarize the outcomes, the device significantly improved. PR grade and led to meaningful improvements in functional status and symptoms. That's what has been published out there. And the discussion around the outcomes was primarily focused on significant improvements in patients symptoms that are symptom relief and quality of life, including not feeling short of breath and being able to care for themselves, which actually ranked very high or if I may say ranked highest on the patient preference survey. Conducted at baseline with the pivotal trial patients. So these were the outcomes that were ranked as the highest from a patient preference survey. This is the first time something like this has been tried out in the structural heart space. I think it flies because it's on the right side of the heart. That's something to bear in mind and one thing that isn't clear. Is that what great improvement is considered or was considered significant in this data set? Or for that matter, what grade improvement in TR tracks with improvement in patient functional status across the gamut of PR all the way from mild to moderate, severe, massive or torrential. Specifically in the case of this data set, severe, massive and torrential, that part isn't known and this data set isn't entirely out there. They're going to present one year data at TCU. Before, so something to bear in mind in terms of. Grades of TR and what was considered clinically significant and how the improvement in patient functional status tracks with TR at baseline and improvements thereafter. Moving on, what are some of the uncertainties from a regulatory perspective that device manufacturers dabbling in the space should bear in mind when it comes to the future? Now it was rather surprising that the approval was granted by the FDA with no FDA advisory panel. Was this because there was nothing of note when it came to hard clinical endpoints and the FDA perhaps did not want a repeat of the renal innovation situation where the FDA advisory panel said one thing, the FDA went another in terms of its approval. For example, a 3% mortality rate is much higher than transcatheter edge to edge repair data at the same time point. I believe it's closer to 5 to 6% for A. Transcatheter edge to edge repair, but then again mortality benefit is not something that a right sided technology is setting out to achieve at the onset. It remains to be seen if the 3% mortality rate becomes higher in a real world setting where patient selection, physician training and proctoring may not be as tightly controlled. Something to bear in mind. Also, it's not clear what proportion of the population had concomitant left sided. Disease or had congenital disease in the pulmonary circulation. Certainly none of this is reflected in the Indications for use statement or even elsewhere in the IFU, moreover. What grade reduction in TR is considered clinically, clinically significant? We know what it is on the left side of the heart, but what is it on the right side of the heart? I realize this is a valve replacement technology and they're going for complete elimination of TR, but it begs a basic question in terms of what grade reduction we should be targeting on the right side in general. Now like I said, this is an open question on the right side of the heart. Is it the same across the gamut? Of all TR grades now this being a valve replacement. I realized complete elimination of TR is expected and not surprising but on the right side of the heart given that a third of the healthy patient population, or rather 1/3 of the entire population you and me included. Present mild TR. How does elimination of TR impact right matriculate or remodeling in the short term? The perspective certainly seems to be such that if TR symptoms are alleviated, then one can wean patients off of diuretics, which improves their quality of life. Because they're not running to the bathroom all the time, they're not afraid to leave their house. I get it. I'm also surprised. That evoke with a pacemaker rate of around 13 to 15% and a significant bleeding rate of greater than 20% perhaps due to the need for anticoagulation. I understand despite these high numbers got approval in the US before the trip clip for which both these rates. I think are in the single digits. So why is this the case? And it's perhaps to do with the patient population. The target patient population for this device and this technology platform is likely those who are not eligible for open surgery or for that matter, those who are not eligible for transcatheter edge to edge repair. Tri clip bearing in mind, right, also patients with very large coaptation gaps, highly dilated tricuspid annulus or those with pacing leads that are leaving the valve open. Basically, this device is aimed at patients who have no open surgical or minimally invasive options and whose only option is medical therapy, including the use of diuretics. The point that I'm trying to make here is that it's not always the quantity of. Data or specifically hard endpoints. It's really about the benefit risk story within the target patient population, which likely explains the FDA's approval without even a physician advisory panel. That's not all, there's more to the story. Let me move on to the third section of what I'm trying to communicate. What are some of the postmarket areas that regulators could be focusing on for this device and that based on my experience they almost certainly will be focusing on for other devices to follow in the perhaps the pre market phase for those devices. There are four specific items that I want to bring to your attention and the first one, call it an area of weakness or an area of potential future regulatory scrutiny or an area of design expertise improvement, call it what you will and that is the unpredictable nature of the onset of heart block. For example with Tavi. Right. The counterpart on the aortic position, there are very clear predictors about who's going to get heart block and we have strategies to mitigate it. But in this case, if it doesn't happen when the patient is in the hospital, but it happens when they go home, they develop syncope and heart block and you've got to get them back into the hospital setting for a subsequent pacemaker implantation. That's additional burden not only on the patient but also on the entire system. Obviously you can send the patient home with Holter monitors. Get that, But all those ads to the residual risk that the patient is exposed to and also a potential for reintervention. Now another challenge maybe the potential to jail existing pacemaker leads. Props to leadless pacemakers. I guess yet another very interesting and unanswered point is around repair versus replacement. In fact, this debate will rage on and on for time to come, but frankly. Very frankly, our patient reported outcomes adequate to secure regulatory approval. And more importantly, reimbursement and time to follow. Yes, quality of life is an important outcome from a patient benefit perspective, I get it. But there are severe limitations to patient reported outcomes, quality of life outcomes, especially in unblinded studies. But on the flip side, very few devices show a mortality benefit per se, especially on the right side. They're probably not even needed. What about sham controlled studies? What about the placebo effect? A sham controlled study, in my opinion, won't quite be feasible in such a device trial given the lengthy duration of the follow up and issues around the need for oral coagulation in the placebo or control group. And in terms of device lifetime and associated? Hard endpoints, right, clinicians always like to see hard endpoint based clinical outcomes. So in association in connection with device lifetime and these hard endpoint based clinical outcomes are regulators considering that as follow-up continues, we will see improvements in quality of life scores corresponding to the improvements in TR directly correlate with reduced risk of mortality and perhaps even heart failure hospitalization as well. Is right ventricular remodeling and right ventricular size? Will we see better outcomes in even sicker patients or will we see mortality benefit and perhaps younger patients? Or will hard endpoints improve simply as a factor of time as we have longer follow up? These are some of the questions that manufacturers who may be fast followers really need to bear in mind in terms of their regulatory submission and the subsequent benefit risk story that they hope to present. Thank you very much everybody.