All right, welcome everyone. My name is Arash Salabitabar, Pediatric Interventional Cardiologist at Nationwide Children's Hospital. Thank you so much for joining us in this session. This is going to be the first in a series that's newly dubbed the CHD Research Forum for Sky. This one's going to be on the topic of multi-center research. We have a great panel of speakers, and really the key for this and the goal for this session is for this to be interactive. What we're going to do is we're going to have our speakers talk a lot about their experiences with their different roles and the different research they've performed, but then try to make an interactive discussion later. You can feel free to put things into the chat box, I'll try to moderate that, and we'll maybe ask for some volunteers to ask their questions to prompt some good discussion amongst the group, which should be the most valuable part of this whole process. Welcome everyone. Just a couple of things, housekeeping, this will be our agenda, which you'll hear more about on the intricacies of multi-center research, retrospective and prospective multi-center research experiences. My co-moderators are John Breitholt and Shyam Sathanandam, who will be speaking a little bit later as well. I'd like to introduce our first speaker, Dr. Kristen Burns, who is the Branch Chief of Heart Development and Structural Diseases within the Division of Cardiovascular Sciences at NHLBI and NIH. We're really excited that she was fortunate or generous enough to donate her time to this session, and I welcome her to give her talk. Thanks everybody. Thanks for the organizers for inviting me to this forum, and thanks to my fellow speakers for sharing their experiences on the various types of multi-center research that they've had with all of us. As you mentioned, I'm Kristen Burns, I'm a pediatric cardiologist at the National Heart, Lung, and Blood Institute at NIH. I've spent the last decade or so at NIH managing a portfolio of research grants and contracts on congenital heart disease and other pediatric cardiovascular conditions. And then I also helped to run some of NHLBI's larger programs on multi-center pediatric cardiology research, which include the Pediatric Heart Network, the Bench-to-Bassinet Program, and at the NIH CDC Sudden Death in the Young Case Registry. So during our time today, I hope to share some thoughts with you on the nuts and bolts of multi-center research, some of the necessary components, and then talk a little bit about some of the funding options for multi-center research studies. Again, this is meant to be interactive, so please feel free to ask questions and interrupt. I'm happy to take questions at any time. I know that we'll do some at the end as well. So I'll begin with a typical federal employee disclosure. The ideas that I share today, whether they are brilliant or ridiculous, they're mine. So they don't represent official government positions. But I do hope to be able to share some wisdom that I've gleaned over the past decade or so from a pretty unique perspective at NIH. You know, it's a venue where we interact with many of the stakeholders in the multi-center clinical research arena. And one of my favorite parts of the job is to be able to sort of connect people who are doing similar or related research to one another. So it's a pretty unique perspective. So I think it's important to define what we mean by multi-center clinical research. I like to think of it like an orchestra. I think the hallmark of multi-center clinical research is that there's a standardized protocol that's going to be executed at the same way in multiple locations. The protocol is the music in the orchestra. Each participating center brings its own instruments to the orchestra. That is, you know, their unique expertise, their unique patient populations and the typical flavors of that center. The data coordinating center is the conductor of the orchestra. They help to ensure that all the instruments are working together, that they're working in harmony to create beautiful music. And the goal is really to enrich the experience of the listeners who are the scientific and the patient community. So that's kind of how I think of multi-center research. And when it goes well, it's really beautiful music. But there's a lot of pieces to that puzzle. So when you set out to design your study, I think it's the tendency is to sort of jump immediately into the weeds and think about how you're going to operationalize it. But I really encourage you to take a huge step backwards and ask what it seems like a really simple and silly question of, does my research require a multi-center approach? Because multi-center just increases complexity. And so you may not need that many centers to answer your question. So to answer your question, you know, it's usually based on two things. The first is, you know, in a small field like ours, the resources and the expertise are often spread over multiple centers. So the beauty of multi-center research, it has the power to bring together expertise and resources together to be able to do something novel or interesting. More often than not though, the decision of whether you need a multi-center approach in our field is determined by sample size. Congenital heart disease and the various conditions or the various subtypes of congenital heart disease are rare enough that it's often really challenging to be able to make any meaningful conclusions based on data from a single center. There simply aren't enough patients to go around to answer some of the important questions. So in that case, you may have to use a multi-center approach. I frequently get inquiries from investigators who are interested in executing their study through the Pediatric Heart Network, and they want to know how to begin. And I can tell you that the first question that we ask when we're triaging studies and evaluating them for the Pediatric Heart Network is whether they need the PHN infrastructure, you know, and all the process that comes with it. And Chris probably will talk about that, or Dr. Pettit will probably talk about that in his presentation. We worked together on the COMPASS study. If your center only requires two or three, if your study only requires two or three centers to be able to answer the question, then you don't need PHN with its 10 plus centers and lots of process to get your study done. So you have to sort of think about the scope of what you're trying to accomplish when you're trying to figure out if a multi-center approach is necessary and if there are any existing networks or infrastructure that you can leverage to do your study. So related to that increased complexity, there are a few necessary components that you really need to think about when you're planning your study. This is the dry stuff, but it is very important when you're designing your study. They're certainly less exciting than the research, but they're really essential pieces and they can impose significant delays in your study if you don't plan well for them. And I will say that even if you do plan well for them, they can still cause delays. So it's just part and parcel of doing the research. So I'll start with contracts. So you're going to need contracts between whoever holds the funds, whether that's a clinical coordinating center or a data coordinating center or your university institution. You're going to need contracts between your institution where the money is and the people who are doing the work. So every center is going to require a contract. If you are using core labs to analyze data in a central way, each of those core labs will require contracts. So contracts can take months, six plus months to execute. And I can tell you that the lawyers who are executing the contract aren't particularly interested in your enthusiasm for moving things forward. But I would say as the PI, you play a critical role in keeping the ball moving. So make friends with your contracts people and nudge them early and often. In this case, the squeaky wheel often does get the grease in the contracts office. And so be the squeaky wheel because this is something that can delay your awards or your research study by quite a bit. Related to that, DUAs and MTAs, so data use agreements and materials transfers agreements. So these are really essential for data sharing and biospecimen sharing or transfer between institutions. They're necessary for core labs and for biorepository functions. And they're a type of contract. So they take a while. So start early. The FDA, so for device trials, you'll need an IDE or an investigational device exemption or an IND for a drug study, investigational new drug. The FDA has its own calendar. And often every interaction comes with a 30 day response time, meaning they'll get back to you in 30 days, or they won't. And if you hear nothing, then you have the green light to proceed. This is true for some of the interact, many of the interactions that you will go through. But every interaction, you know, add 30 days to your calendar in planning for their responses. It doesn't always take them that long, but it often does. The it's really important, the FDA can be super helpful if you involve them early in the design of your study. They have an agenda. They have things that they are interested in researching more, getting more data on so that they understand the safety of devices. You know, coronary stents is one good example of that drug eluding stents. They want to know more about what people are doing off label with these devices. And they want that data gathered in a systematic way. So they have an agenda and they can be really helpful in you designing your study to be able to meet their needs as well. And that certainly helps with your regulatory approvals. I will say that it is now a requirement of NHLBI funded studies that you have your IND or your IDE before we issue the grant award at the beginning. And the reason for that is that we were burned by trials that were taking two plus years to get through the regulatory process at FDA or eventually never got FDA approval. And then we funded this whole trial that can't proceed because it didn't have regulatory approval. So super important to involve the FDA early. And then finally, the SIRB, so single IRBs. This is a brilliant idea that's still suffering in the execution phase, but it's going to get there. I promise. I'm optimistic. Having one IRB for the whole study that everybody relies on and trusts is a great idea in theory. In practice, a lot of sites have not come around to the idea of fully seeding reliance on the other IRB. They often will insist on inserting local language and there are local contexts that absolutely need to be considered at every site and are important, but they're not always important for every study. So this is an area that is getting better. But I would say if you're going to do a multicenter study, pick a central IRB that has experience, that has dedicated staff and has done this before, that knows how to do the reliance agreements and understands kind of the back and forth of negotiating with each site with language and it will make things a lot more efficient as it goes along. So I'm optimistic it's going to get better because I think it's the right idea, but I think we're not quite there yet. So these are things you have to consider. In terms of funding options, there's a couple different options to consider when you're funding multicenter clinical research. Multicenter studies are expensive. They're very expensive. They're getting more expensive because we keep adding a lot of ornaments to the tree and wanting to study other things. So you're talking big ticket dollars here. So you have to think about different ways to get that done. Your institution grants, even many of the foundation and AHA grants are not big enough to do a multicenter clinical trial. I would think about industry, especially if you're interested in device trials. They have really deep pockets. They have much deeper pockets than the government, to be honest. And they have a vested interest in making their devices more available and well known at all of your centers. They want you to know their products and use their products. And so they can be really helpful as partners in funding the research. Some people are a little nervous about involving industry in your studies, but I can assure you that they are just as worried about conflict of interest as you are. And there are plenty of firewalls that you can put into place to make everybody feel comfortable that there's no bias in the research that you're trying to do. So I would encourage you to reach out to industry. There are relationships that sometimes you can develop where you'll have a third party agreement. So you get a grant from NHLBI and that grant is supplemented by funds from the device company or the drug company. So that's one approach we've used. So it can, you know, increase the possibilities for your trial. So don't count them out. FDA, a lot of people don't think about the FDA as a funding source. We certainly think about it in the regulatory domain, but they have funding opportunity announcements, particularly in device related areas. They have an orphan drug product funding announcement or an orphan product, I should say, it's not just drugs, it's drugs and devices. And then they're actually developing a pediatric device consortium because they're particularly interested in that area. So if that's relevant to what you're doing, it's definitely a possibility for funding. NIH is sort of the typical place that many people look for funding and that's certainly my bread and butter. We have in the past several years at NHLBI and at NIH entirely have sort of created separate funding opportunity announcements for clinical trials because there are a lot of requirements for a clinical trial, again, complexity that we have been able to build into those funding announcements. So I've included the numbers, the PAR numbers, the program announcement numbers here for the Data Coordinating Center and the Clinical Coordinating Center at NHLBI for multi-site clinical trials. If you're interested in doing an observational study that is not a clinical trial, there's no intervention involved, you can apply through the typical parent R01 mechanism and it'll say on it clinical trial not allowed. And so they really want all clinical trials to go through this specific funding announcement. Just for context, between 2016 and 2020, NIH and NHLBI in particular funded nine clinical trials related to congenital heart disease. This is investigator-initiated clinical trials. This is not through our networks like the Pediatric Heart Network, so to the tune of about $16 million. And then within the networks, there were 22 awards made to 22 different centers to do studies to the tune of $33 million. So there is money going to congenital heart disease research. We desperately need more clinical trials, as you all know, to increase the evidence base of the work we're trying to do. So I would be happy to talk to anyone with ideas. If you're trying to figure out what mechanisms are appropriate for the work that you're trying to do, this is the fun part of my job. I get to hear about great science. So please don't hesitate to reach out to me and I can put you in touch with other people in our group, or I'm happy to talk to you myself about the options that you have available. But we are here to help, and I'd be happy to answer questions when appropriate. So thanks.

multi-center clinical research

expertise and resources

sample size

FDA regulations

funding options