Thank you so much, Dr. Chan. It was a fantastic talk and also just fun to hear experiences from someone who's done such a great job with this. I actually have a question for both of you about something you both mentioned, which is you just touched on the concept of industry support. You know, Dr. Burns, you touched on a little bit about the firewalls that can be in place to protect the research, the integrity of the research, any level of biases. Dr. Chan, what is the best way you approached industry with these? Or have you been the one that's been approached? Have you used any sort of techniques to protect yourself and the integrity of that research as you're approaching them for that industry support? And how have those conversations gone? Who are the sort of the point people in the positions within those companies that you've approached with? And Dr. Burns, I'll let you go first. So, you know, I think that that some of the things that are important when thinking about working with industry are the data and who owns the data. And and this is true of any study, but I think it's particularly important with industry. You know, we have different models of how we have worked with industry at NHLBI through the Pediatric Heart Network. The kind of traditional model was very hands off. Industry would hand us the drug and walk away. And that was it. More recently, with in some incentives that have been passed by the FDA to encourage more pediatric research, industry gets patent extensions on their adult devices and drugs if they do a pediatric study. And they are now required to do pediatric studies as part of their submission packages. So we've had a lot more industry partners approaching us saying we need we have a study we need to do. You have patients and the expertise to find those patients help us do our study. And the conversations that we've had in that newer model have been a lot around data sharing of what happens to the data when the primary results are done and submitted. We as academics have a million more questions that we want to ask. And, you know, tons of different ways we can slice and dice the data. And we have to get the companies to agree to give us that data set afterwards. And so that makes the contracting process a lot more complicated. But it's really important because I think we all know that you invest so much time and energy in these studies. The patients invest by giving you the data and sharing their experiences. And we feel like as academics that we owe it to the community to get as much out of that experience as we possibly can. But industry is not really interested in funding 12 secondary papers after their main results are done. So those are the kind of conversations you have to have of who owns the data. How do we work with each other so that we can have the data afterwards? And then publications is another issue where main results, you know, what is the company's role in the publication process? And are they authors on the manuscripts or not? And some companies say, we don't want to be authors because we don't want the research to be perceived as biased. Whereas the others say, well, we ran the study with you. We should have authorship. So again, those are things that you need to sort out at the beginning. As Dr. Shanaha said, it's really important to have those conversations at the very beginning up front. The one other piece related to data that we have insisted in the Pediatric Heart Network is that we use our data and safety monitoring board. A lot of industry partners have their own, they call them data monitoring committees. It's the same concept, but we have felt like it's really important. We sort of trust in our processes and that's a really clean, easy firewall to put into place. So that's been one of the things that's been really important for us, that the monitoring of the study does not involve the industry partner. Yeah, I didn't know about that patent extension sort of loophole. That's really interesting. Thank you for that. So Aarash, in my experience with working with industry partners, it was a direct approach from me to industry itself. And one of the things for us to remember is all of these companies have ERPs that you can put in. I mean, it's for funding of projects like this and small amounts to large amounts have gotten both from companies. You submit it, but the things you talk about, for me, I'm asking for funding for this particular part of the project. And it is usually my, the way I've approached it is you will not have the data. That is when you have the data, it's going to be aggregate data, definitely not all the data so that it doesn't get twisted or published in a way that's not suitable to me. The other way I've approached it is manuscript privilege is purely author-based and not company-based at all. They cannot, they're not allowed to publish part of my study on their website. That is the other thing you have to be careful about in terms of what the publishing rights are going to be. And finally, approval for devices and everything. We, when we wrote about stuff, we wrote about off-label use of certain devices and one particular study I'm doing, they might use it for FDA approval, but then my whole data monitoring is very different. We make sure the charts are analyzed, angiograms are evaluated and all of that to make sure it's not only retrospective data that's been third party collected. It is actually, I mean, 10% of the charts at each site will be evaluated then more if the sites contributed more. So that's something you have to be honest about. So that when you're publishing the data, you know it's not been influenced by industry at all. So, and they have been willing partners to all of that in terms of saying that, look, applications are going to come out also. And that's something they have to be aware of. Have you ever been at any point told or coerced by industry to not publish third party research that wasn't in their favor? Luckily, I've had great mentors in terms of industry funding. So who were very, very of what industry funding bought. And my legal team was on top of, you know, every language they needed to be. I, you know, it was a phone call with my legal team to say, hey, what do you want them to be involved in? What do you not? And I said it in simple English, they translated it to way more complicated language that I would never be able to break apart or understand. And they said, look, this translates to what you said. And there was no question about then, you know, getting influenced by industry after that. And finally disclosures, right? Disclosures are a big, have to be a big part of all of that in terms of not only your publications, but disclosures to IRB, disclosures to other sites and to make sure that everything's on the up and up. Great talks for both Dr. Burns and Dr. Shahnawaz. If I may ask one question for Dr. Burns, but Dr. Shahnawaz can jump in as well. You have tremendous success with the PHN network doing prospective clinical trials and whatnot. I mean, this is a forum that's through SCI and SCI represents a lot of interventional cardiologists. And this is a research forum of the congenital heart disease council. Now, if let's say SCI wants to do some kind of a collaborative effort, just like the PHN is like, what does it take for SCI to make that first step into more serious research? I mean, will it be like funding into the research forum and congenital heart disease council is that the way to go or partnership with NIH? So if you can talk more about that, please. Yeah, I'm really glad you brought that up. Actually, I was thinking about that earlier today, you know, and the types of research that often come to me when people are thinking of doing their studies. I think, you know, one of the things so the PHN is a network. It's been around 20 years. And the reason it's been around so long is because 20 years ago, nobody was doing multi-center research, right? And so the Institute has invested in that infrastructure and recognizes sort of the importance of that for our small field. The problem is we can't fund 45 networks because we wouldn't fund any science. And so what has happened over time is we used to fund registries. We used to fund more sort of network infrastructure and the infrastructure costs kind of chipped away at the yield of the science that we were doing. So they've moved away from funding the infrastructure. So you can't propose another network to NIH. It's not going to get funded. So when you come in with your research project, the research and the science has to be front and center in the application. That has to be the big thing that you're selling. It is fine to have infrastructure, but you need to kind of bury that in the background. The ideal model that NIH and NHLBI would love to fund is to have an existing infrastructure. If Sky had a multi-center collaborative that they would fund PI time and coordinator time at each center and stat support if necessary. And then you apply to NIH for your particular study that's going to leverage that infrastructure. That's the ideal model that NIH would love. But I think many fields don't have that existing registry or network or infrastructure to build from. So if that is something that and we've tried to encourage honestly some of the foundations and advocacy organizations, disease specific entities to get in that space, to use the dollars that they have to fund a registry or an infrastructure that then you guys could take that infrastructure and the data that comes from those groups and then fund a trial from that. So that's much more appealing to the institute these days. Dr. Perez, is this pediatric device consortium that you mentioned within the FDA, what role is that going to play? What resources do those provide? That's the name itself rings bells because it's something that we wish we could have. And it sounds like there is something now in the works that allows us to get on that level. So can you explain more about that? So I have to admit, I went on maternity leave earlier this year when that was created and have been sort of pretty arm's length, haven't been involved, but there is a lot of momentum. And I think that some of the partners at FDA approached us and said, we want to create a PHN for pediatric devices that's run out of the FDA. And so there's actually multiple institutes involved, NICHD, the Child Health and Human Development Institute is also involved. And so there's a lot of stakeholders that are trying to come together. And as you can imagine, government, there's a lot of bureaucracy. So they're sorting out a lot of processes now. But the hope is to be able to create some sort of infrastructure that's going to enable more organized research in the pediatric device space. So I don't know a whole lot more than that, but I imagine that once the infrastructure is organized, there will be funding announcements to follow after that. But I don't know what those will look like. I imagine they'd probably be looking at at least another year before that's kind of at a stage where you could access it. I want to jump in and ask a question of Shabana about, you know, when you're organizing a multi-center trial, this is true, I think as much for retrospective as prospective, but the challenge I've seen has been less the support from industry, but oftentimes the coordinating with multiple centers that all have their own IRBs that have their own rules and regulations. What's, I guess, what strategies have you found useful? Not so much, because actually when you're an institution, you kind of know the ins and outs of your own institution, but what have you found has been useful to help the other institutions that you're trying to bring on board to overcome some of those types of hurdles? The major thing that you have to be very, very clear about is that your protocol has to be very clean and consistent throughout everywhere it's written, right? The number one question that tries to get you into trouble is what happens to the data once the research is done? And that's where most people get hung up on. They're, okay, if you collect PHI, you have verbiage that, you know, where you're storing the data, that only two people in the world and one of them's dead can access the data and stuff like that. But every IRB gets concerned when you say, I am going to save this data for future research. And then, so you have to be very careful and think about, am I truly going to use this data in the future? Or am I going to let the science handle it? And so in one of the studies that I'm doing, we made it registry-based. So instead of making it a retrospective trial, that saved some of the language of, you know, saving data for future trials, because it was a registry. The other one, it was, you know, small patient sizes at each group. So we decided we won't save any of the data at the PI level or the center that I was at, that in five years, I'm going to go back to those sites and say, hey, remember those patients you collected data on for that bioprosthetic bowel fracture? Can you go back, put a new IRB in and now collect follow-up data? That was way easier for me than saving the data. So you have to be very strategic on how you, kind of as a game of, you know, verbiage of, and how you want to do this. The other thing, the challenge you have to remember is if you're involving European sites or international sites. A lot of my trials have international sites and they have very different rules, especially the current European rules are very, very interesting, so to speak. So you have to make, honestly, what I did, I cheated and asked them to send me one of their approved IRBs for a retrospective trial and work through verbiage in my protocol of, you know, what they would approve in terms of getting that. Sometimes it's like data birds are not allowed, but, you know, aided intervention is, aided surgery. So making sure your data collection fields kind of is nuanced enough to not anger the IRB gods is very helpful. What has everyone's experience has been with the concept of umbrella IRBs, umbrella DUAs, things that sort of allow for extended research beyond, you know, a single study, but more a series of studies. Is that, I know Shobhana sort of bridges onto what you just mentioned, but is there, has there been more of that concept of, you know, something that encompasses several studies, but over a single topic like, you know, PDA stents and whatever else there may be out there? So single IRBs are great, usually for protocols that can change along the course of what you're doing. It saves time and effort of individual IRBs, but for smaller retrospective trials with fixed protocols, it ends up creating more work per site and at the site that's serving as a single IRB and is not worth the financial dollars that it takes out of you, which is, has been my experience. So a lot of my retrospective trials have not used single IRB, but some registry-based ones have, you know, been more related to look into single IRBs. Can I ask a question to Dr. Burns again? The PHN has, again, has been super successful as it's going for 20 years, got the infrastructure and the people necessary to run trials, but let's say someone is not part of the PHN, but they do have a good idea, they don't have the infrastructure. How do they approach PHN with an idea and will PHN be open to collaboration? Great question and something we need to advertise better. So the SVR trial was proposed from a site that was not in the PHN, and that's kind of our landmark trial, the one that we talk about all the time. So any investigator with an idea is welcome to approach the PHN. We call it the policy manual or the manual of operations is on our website, pediatricheartnetwork.org, and there's an entire chapter because we had to create a 12-chapter manual to deal with all the process. There's an entire chapter on publications as well because it's crucially important to set those things out at the beginning. But there's an entire chapter on how to propose a study. So the point here, the take-home message is anyone can propose a study to the PHN. There's a process, we like people to have kind of shopped around their idea to some of the PHN centers, and we like you to pair up with someone who is at a PHN center, mostly because of all the process. It's good to have kind of a chaperone who can help kind of guide you through some of those steps and a partner in the study who's worked within the network before. But absolutely anyone can apply. We encourage it. We need great ideas from everybody. And I will say that the PHN, there are 10 centers that are funded with a grant, an infrastructure grant from NHLBI. But the COMPASS trial, which Dr. Pettit is involved with as the study chair, there's 23 sites in that trial. The music study, there's 38 sites in that study. So we're way beyond the 10 sort of infrastructure funded sites for most of the research that we're doing these days. And so we worked with sort of the vast majority of the congenital centers in the country. And so, just wanna sort of echo that it's open, the brain trust is big and we need ideas from anyone who will bring them. So I would encourage you to look at the manual of operations on our website. I'm happy to talk you through the steps in a much more streamlined fashion, if that would be helpful. But it involves submitting a study proposal that's like a two pager, that gets sort of triaged by leadership. And then you do a presentation to the executive committee with your idea. And then if it gets past that step, then you do a presentation to the PHN universe, we call it, which is about 650 people at all the sites. And then there's kind of a voting process after that. So that's the quick and sweet, but ideas welcome. Can you give a sense of the timeline for that? Because I mean, I've been through that process. And as far as from the initiation of a study suggestion with the two page report to where, assuming, cause I've seen the voting, I've been a part of it. You're successful at each of those stages from kind of like birth to actual enrollment. What type of timeline should people be realistically looking at? I mean, I would say it's, we'd like to think we're efficient, we're not. But I would say it's probably equivalent to peer review. I mean, from the time you submit an NIH grant to the time you start is like nine plus months. And I would say it's comparable, if not even a little bit longer within the PHN. It sort of depends on how early we are in our funding cycle, right? So the later you get in the funding cycle, the less money there is to go around. And so we're really being picky about the studies that we're starting at that point. Whereas at the beginning of a funding cycle, there's gonna be much more enthusiasm to start a bunch of projects. And so some of it has to do with timing, but I would say nine months is realistic. Optimistic. And maybe something you could talk about, cause I think this is important, because many people are familiar with several of the big studies that have come through the PHN. As far as the ability to suggest a study that's based upon existing data that was generated by the PHN. Cause certainly there's been a lot of that, but I think many people may think that the only people that can do those are the people that are already a part of it. But that might be something you could talk about. Yeah, I would love to dispel that myth. It makes sense though, that the assumption would be that the people who were sort of within those studies from the beginning would have the best working knowledge of the data. But I would say that there is a requirement from NIH now that we make public use datasets from all of our studies. And we have, I think seven of them now from PHN studies that are publicly, they're de-identified datasets that are on the Pediatric Heart Network website. It's actually fabulous for fellows and junior faculty to develop projects from, but it's also a great place to kind of mine the data and see what's available when you're developing your next research study. So I think that we could do a great job of leveraging the huge amount of data that we have to develop new studies. We did a little bit of that with the fuel study, which was eugenophil PDE5 inhibitors in the adolescent Fontan population. We used exercise data from the Fontan cross-sectional study to help us understand event rates, because that's what's lacking in our studies is we don't know the expected event rates for a lot of the things that we're trying to learn about. And so it's hard to power our studies when we don't know how often they're gonna meet the primary outcome. So we did use some Fontan data to power the fuel study and get our sample size calculations, but I think we could do a lot more of that. That's really interesting. So what are the regulatory processes that go into using data from those public datasets? Is there any additional things like IRBs and data use agreements, anything that extra that goes into that extra application periods, things like that to get access and analyze that data? So my understanding is that you go to the website and you put in like your email address and then there's like probably something you need to sign, but then they just send you the de-identified or they give you access to the de-identified dataset. We've tried to make it as easy as possible. I don't know on your institution side what would be required because it is de-identified data. So it could probably be IRB exempt or at least expedited at a minimum. So I don't know that that's gonna be a big hurdle, but it is intended to be as widely available as possible for the community. Here's a question about contracting because I mean, at least within the NIH, sorry, the PHN, it's again a well-oiled network, but Shabana, when you do your multicenter studies, especially if it's funded through industry, how does the contracting work? Does the industry does most of the contracting or do you do the contracting? And what kind of like barriers, because it's totally a legal team, right? So as a PI, your hands are tied sometimes like what each individual institute may ask for. So how do you negotiate through all that? Yes, excellent, excellent question. And that's where making sure you collaborate with people who care about what you do is important. I've had sites that come back and say, no, instead of what you're willing to pay us, we want you to pay us five times more than the other sites or we won't participate. So you call the PI and say, hey, your people, your legal people are saying this, you should talk to them and that's what happens. But that's the challenge of multicenter research when you're not familiar with the individuals that you're working with, right? The industry will not want to run the contracts because any contracts that are coming through industry, the IRB fees at most places are five times more than a center started research. So you have to be very careful about what the fees look like. The way fees get added on for industry funded research. So the way we have run industry funded research is we have taken the funding and kept the industry out of it and run it as a center funded research where our funds came from industry. And that's brought down costs significantly at every level. Otherwise actually every, I mean, just to give you an example, a storage binder to keep all your patient data is $50 if it comes out of a center-based research. It's actually $250 if it is industry funded. So that's how silly it gets. And to keep costs down, you have to be careful about how you channel your funds. But on the flip side of that, so one of the studies that we've done through the PHN, we're working with Bristol Myers Squibb and this is a much more integrated model than our traditional models of donate the drug and walk away. They did all the contracting. We're using their data management system. They're much more hands-on because it's part of their regulatory requirement for the European Medicines Association, not the FDA, but regardless. And they pay the PIs a whole lot more than we do at NIH. So that has been one of the upsides of this is that the sites feel better supported. And because we recognize we don't have the money to pay you, we know you're doing work essentially for volunteer when you get an NIH funded study. So there are some upsides to doing the contracting through industry. Yeah, absolutely. If industry is willing to put in all the money, I think some of the challenges with what we try to do is a smaller number of patients. So, and the benefits are not directly relate to industry in terms of device approval or drug approval, which in that case, these ERPs go only to a certain distance with the funding. Question from Carissa Baker-Smith, can the THN data be combined with other data resources? Dr. Burns. Absolutely. Yes. I mean, if it makes scientific sense, we would love people to leverage and combine wherever you can, especially in our field where the numbers tend to be small, there's power in numbers. So absolutely can be combined. There is, I will say, there is a funding opportunity announcement. It's pretty competitive, but it's worth mentioning. There's an R21 mechanism, which is unusual for NHLBI to participate in the R21. It's a smaller grant, but secondary analysis of datasets is one of the R21s that NHLBI does participate in. And THN public use datasets combining with other datasets and doing secondary analyses, merging the datasets is absolutely appropriate and perfect for that funding opportunity. So something to consider. While you're waiting, I have a question. Did COVID impact research a bit? Because many centers lost their like data coordinators and those who collect data. And then especially Shibana, like when you do multi-center study, which are not funded, centers are going to give priority to the funded studies than the ones that are not having the funds for a study. So has that been a challenge during COVID or is that getting better? Yes, it has been a huge challenge. The timelines have shifted by a year because of, you know, not only data coordinators, but even contracting people being at a stretch. A lot of those jobs were lost and have not been refilled. And when refilled, have not been refilled with someone who has got experience with that. So contract things are much slower than they used to be pre-COVID. For sure, data collection has slowed down and, you know, timelines have shifted and these are all challenging. Even for funded studies, I think timelines have shifted. The bigger challenges, if you've taken funding, you have the way funding works with a lot of industry funding. You have either timeline-based funding, which means they'll give you X amount at the startup of a protocol, 50% at collection of, you know, 50% of data and, you know, 20% at all data collection and 20% at manuscript phase, right? So when you do that, but your timelines get shifted, then unless industry is okay with, you know, the shifting timelines, your funding might dry up. So that's another thing to consider with getting outside funding. I think in terms of NIH funding related to COVID, you know, not necessarily COVID-funded research, but I think NIH is trying to be as flexible as possible with what we know are gonna be delayed studies. Everything got delayed. Institutions shut down, labs shut down. I mean, you all know this. And so people are ending up with large, unobligated balances on their grants that they're having to carry over into subsequent years of funding. And so we're trying to be as flexible as possible to accommodate that. The budget office is getting a little cranky about it, but it is something that people just recognize as a reality. And we're trying to, you know, let people keep doing what they can in a really difficult time. So that's been a little bit helpful. I really appreciate the time that everyone on the line has spent on this session, and then particular Dr. Hrishabhanavaz and Burns for their talks and their expertise that they shared with everyone, as well as Dr. Brian Holton, Dr. Sathanandam for co-moderating. This is the first in a series from the research work group of the CHD Council of SCCHI regarding the CHD Forum. And the next one will hopefully be in a few months. We'll get some great speakers again, and hopefully have some more interactive discussion that will be valuable to advancing research in our field of congenital cardiac cath. So thank you so much, everyone. And I hope everyone has a great night.

industry support

data ownership

data sharing

funding

multi-center studies

Pediatric Heart Network

COVID-19 challenges