#338: Site Selection for Clinical Trials

Samantha Pickett: For a study startup. You really, Isabella was saying before, as much stuff in front as possible, so try to do it right so you don't have to do it again.

Etienne Nichols: Welcome to the Global Medical Device Podcast, where today's brightest minds in the medical device industry go to get their most useful and actionable. Insider knowledge direct from some of the world's leading medical device experts and companies across the globe, visionaries and innovators are building the future of medical devices. Devices that redefine boundaries, extend possibilities, and improve the quality of life for millions of people. But every innovation encounters obstacles. Regulatory complexities, data management hurdles, evolving quality standards, transitioning from prototype to the patient is filled with challenges. There are a multitude of regulations and requirements that can get in the way. Many teams have inherited or relied on legacy tools, outdated systems, and manual processes that can move the product cycle backward rather than forward, turning potential medical breakthroughs into nothing more than long held ideals that just couldn't quite make it. Time is of the essence, and with every delay in getting to market, the potential to change real lives for the better gets diminished. And this is where Greenlight Guru can help. Our suite of purpose built solutions helps companies modernize quality management, streamline design and development, improve clinical trial operations, and keep up with industry trends and changing regulations, ultimately getting high quality medical devices to market faster and keeping them there. We help companies pivot from pitfalls to progress, moving devices forward, not backward. Over a thousand medtech. Innovators trust Greenlight Guru to help them move faster, get more efficient, reduce risk, and ensure quality, so that in every innovation, every device reaches its full potential, improving lives around the world and setting new standards in healthcare. Greenlight Guru moving medtech forward. Welcome back to the Global Medical Device podcast. My name is Etchen Nichols. I am the host of today's podcast, and I hope I got my name right, because this is not Take One. That's okay. Hit me up sometime. If you ever want to talk about, take one. Today. With me is Samantha Pickett, who is the associate director at Proxima Clinical Research. As well. To help support the conversation is Isabella Schmidt, who is the vice president of Life Science Solutions at Proxima Clinical Research. Today we're going to be talking a little bit about site selection and diversity planning for your clinical investigations. But maybe before we get into the conversation, we can give a little bit of background on where you're coming, maybe an origin story. Samantha, would you want to kick us off?

Isabella Schmidt: Sure.

Samantha Pickett: I started in Clinical Research about seven years ago. I started entry level as a CTA, and I was a CTA for a few years. I was promoted to in house CRA at that same institution, and we went under an acquisition. So I changed institutions at that point to a site startup specialist, and then I moved into a management position of the CTA team. And after that? That's when I moved to Proxima as manager of Study Startup. And just recently, I was promoted to Associate Director of Study Startup.

Etienne Nichols: All right.

Samantha Pickett: Held a few different positions.

Etienne Nichols: Well, congratulations. I'm sure that sounds like you have a great experience all the way through from the beginning to managing. So that sounds really good. Maybe we can get into some of that. But pass the mic to Isabella if you want to talk a little bit about where you are and maybe where you're going.

Isabella Schmidt: Yeah. So I will try to make this brief. I think a lot of people know me from the regulatory affairs side. So was Director of Regulatory Affairs at Proxima, as you may have heard. Etienne said a different title. So what a lot of people don't know is that I actually started off in clinical. So when I started in industry, I was also a CTA, and then I was CRA, and then I did regulatory clinical, and then I worked on a bunch of biotech NDA stuff. And then I moved into regulatory quality and clinical strategy for Med Devices. And then I landed at Proxima, where I was actually in clinical first, and then I built up the regulatory department at Proxima, and so now I've an expanded scope to include all of Proxima services.

Etienne Nichols: Fantastic. And we were kind of joking about this before we started recording, but just how you have to step jump in your career to really have expand what you're doing. I'm always impressed when people are able to do that. It's like unlocking parts of your brain. So maybe after you're in the role for a few months, just be intentional and thoughtful as you go through this, and you can give me a little bit of advice on how you're going through that. Because it's always interesting to see how people grow.

Isabella Schmidt: The biggest thing for me is to build the people underneath you. So underneath being a relative term, I don't like the hierarchy talk, but you build up the team, and then they take on responsibilities and you empower them, and then they grow, and then you're able to level up too. So it's a bunch of different leveling up that happens.

Etienne Nichols: Okay. No, that's a really good answer. And unprompted too, so that's very cool. I love that you've already been thinking about this. Okay, so let's talk a little bit about site selection, and maybe a good place to start would be the protocol. Or is that a good place to start? Maybe I'll just ask that question. If I'm a medical device company who's thinking about selecting a site, what is the right place to start?

Samantha Pickett: No, that's the perfect place to start is the protocol, because that's the foundation. That's the source of information for the sites and the rulebook for how the clinical trial is run. Right. So you want to make sure that you have a well written and complete protocol. When you start out, that's the first impression that you're giving to the clinical investigators when they look at your trial, when they decide, do I want to participate in this or do I not want to participate in this? If your protocol isn't done, they're probably not going to be interested. We send out feasibility surveys all the time to sites, and we send a little blurb about what the protocol is about. And it can take a really long time for them to complete a feasibility questionnaire because they don't want to do that until they've seen a full protocol. Or they can just immediately say they're not interested because they don't know immediately what they're getting into, and it's not the first thing on their mind. So that is a great place to start.

Etienne Nichols: Okay. And we'll talk a little bit about what it means to have a well written protocol. But I'm curious. I want to ask one layer deeper what you just said, did you call it a feasibility it sounded almost like an executive summary that you would send out. Can you go a little more detail?

Samantha Pickett: Yeah. So a feasibility questionnaire, once we start working with a sponsor, that's part of our process of how we select the sites is we kind of send a questionnaire to see if they're generally suited for the study before they have a qualification visit, just to gauge their interest. Are they remotely interested? Are they seeing the patient population? Do they have the general equipment? It takes kinds of things like that to see if like I said, in general, if they would be a good candidate to run the trial at their institution.

Etienne Nichols: Okay, so this questionnaire that we're talking about, it's kind of a two way questionnaire. It sounds like you're evaluating them based on the answers, but they're also evaluating you. Is that safe?

Samantha Pickett: Absolutely. Yeah, absolutely. We want to make sure we're working with someone that has experience in the trial, but we also want to make sure that our trials are a good fit for their institution. If we've got a device trial that's a diagnostic for this one thing, we don't want to be at another institution that's running a device trial for the same thing because it's competing, and we'd be competing for patients and things like that. So it's got to be a good fit both ways. Like every relationship, like the relationship with the sponsor and the CRO and the relationship with the site and vice versa.

Etienne Nichols: That makes sense. Well, I tend to latch on to something that I think, hey, that's a great idea, and I love this thought, but maybe we're getting a little ahead of ourselves because and of course, correct me if I'm wrong, is this an output of the actual protocol? Does it make sense to I mean, I'm just going to go through this and you tell me where I'm right or wrong. It seems like it would make sense to write the protocol, and this questionnaire would come later based on the content of the protocol. Is that accurate?

Samantha Pickett: Yes, absolutely. So we develop that questionnaire essentially from the pieces of the protocol that we need, the patient population, are they able to run this trial at their institution? And we can't ask them those questions if the protocol is not complete and we know what we need to run the trial. So having that complete protocol is the very first step in site selection. So we have the rules of the game, basically.

Isabella Schmidt: Well, and if we don't have a protocol, we kind of don't even know what sites to reach out. We would need to know, hey, this is what the indication is. This is kind of what we're doing. So we would need a protocol. And I guess, like you're saying, Sam, if we don't have a protocol, it's also hard for us to know when to begin to reach out to the sites, because we don't want to reach out to them a year before the study is actually going to happen, because then it's just a waste of our time. A waste of the site's time. So having that protocol at least is the first step to being serious about the trial, right? Not just saying, oh, I'm going to do this trial at some point in some indication, yeah, exactly.

Etienne Nichols: Okay. So I'm sure some listeners are saying, okay, Etienne, just get to the actual question of what we need to know. So the actual protocol, you've probably seen a lot of these different protocols. When you say a well written complete protocol, what's the difference in that? And what you might say is that one's not well written. What are the differences or common pitfalls you see people getting into with this.

Samantha Pickett: Regulatory would you like to take that question?

Isabella Schmidt: That's a really big question at the end, so let's talk about it. One is you really want to design your protocol to address the patient population and the intended use that you're trying to get a labeling claim for, right? So you need to be intentional about who is going to be using the device, how it's going to be used in that patient population, what your study objectives are, what your endpoints are going to be. And then you also want to make sure that you have comprehensive schedule of assessments. So even at the very early stages, sometimes we'll do what's called a protocol synopsis, where you're basically outlining the high level things, how many patients there are, what are your objectives, how many sites you think you're going to need. Sometimes maybe you have ideas of some sites, obviously the title of the protocol and some of the analysis that's going to be planned. Another good thing is to do the schedule of events or the schedule of assessments, which is basically all of the activities that are going to happen during that clinical trial. And that's really important for Sam to know kind of what facilities does the site need, but also for budgeting at the clinical trial. Because depending on how many assessments there are, that could tend itself to more what we call case report forms, which is probably the data management discussion that we talked about earlier, which would also be indicative of how much monitoring, which is another discussion in and of itself, is necessary. So it also has a lot to do with the budget and then also the site. So how much time does the site need to allocate to this study, which also has to do with site selection. So I'll pass it back to you, Sam.

Samantha Pickett: Yeah. The budgeting piece for the sites is really important. That negotiation can take a long time. There can be a lot of back and forth if things aren't clear, what standard of care, what is required for the protocol, what kind of information are we just going to obtain if you happen to have it as an institution, but we're not going to make you run this test as part of the protocol. So having that well written protocol, again, having that schedule of assessments of all those activities is a really important piece of how quickly things can move with a site when you're getting them started because of those different types of discussions.

Isabella Schmidt: I think one thing that she said right there was like, what we're going to make you do versus what you're just going to maybe do anyway, and can we collect that or can we not? We're not going to make you do it. I think understanding the level of importance of those things is important because you need to understand the analysis and what data elements are important for you because you do want to enforce those things are collected. Right. So even if it's not part of what they would routinely do, if it's really important to get to your endpoint and your study objectives, you really want to be able to collect that data. And so when we talk about selecting sites, we want to make sure that we're selecting sites who are willing to do that or capable of doing that.

Etienne Nichols: Yeah, okay, that makes sense. And I appreciate you all letting me kind of anchor to the protocol when I know if we zoom out, the broader discussion about selecting a site is maybe a little bit different, but it starts somewhere, so I like to start maybe where a company would start. Okay, so now that let's say we've got our well written protocol, what's the next step in selecting a site? Is it the questionnaire? Is it evaluating sites? What's next?

Samantha Pickett: Yeah, so we always want to come together with a sponsor if they already have relationships with sites that they've had in mind. Or we, as a CRO, kind of evaluate our bank of sites that we've worked with to see if any of those would be a good fit and recommend them. But either way, whether we have to find new sites or use an existing relationship, we send out feasibility questionnaires to see who's able and who is a good fit for the site. First, let me back up. We negotiate nondisclosure agreements. That is clinical trials 101. Negotiate that and then we can do the feasibility questionnaire, send them the final protocol. And the final protocol allows them to give us the most accurate information because they have those details of what needs to go on in the trial so they can reply to the feasibility questionnaire more accurately. And then if it seems like it'll be a good fit, then they'll move on to a site qualification visit, which is kind of what we're doing here. It's just like a monitoring visit to see if to be more detailed about the things to talk with the principal investigator and see do they have enough staff to run the trial, which is extremely important. If they don't have a study coordinator at the time. That trial is not going to move very fast because a Pi can't do everything on their own. They need a study coordinator helping them screen for patients and things like this and also see if that site is going to provide enough patient diversity, which I think Isabella wants to talk a little bit more about that because it's becoming more and more important in clinical.

Isabella Schmidt: Um, so I can add about the diversity. But also just a note. NDAs are important in clinical trials, but they're important in everything. Don't talk to anybody without having an NDA. Don't share any information. Okay? So diversity in clinical trials is important, and this is tying into the site selection conversation too, and the protocol conversation, because you need to understand what the diversity is expected for your product and for your patient population, right? So you can kind of do that in different ways. The best way to go about it is if you can get epidemiologic information about the disease state and the different minority groups, whether it's race, sex, gender, socioeconomic status, all of that, about that particular indication, particular space. That's the best case scenario. Now, a lot of the times, that information is not available. And so then what you typically default to is what's the representation of the general population of the United States, if you're in the United States, or wherever it is that you may be, and kind of making sure that you're able to have representative numbers of the patient population, whether that's the disease state or the United States within your study. Obviously, this is because historically a lot of clinical trials were not tested in a representative patient population. Mostly white men were in clinical trials, and so the tests were not necessarily applicable to women, to African Americans, Hispanics, et cetera. And so now we want to make sure that any devices and drugs are truly able to be efficacious and safe in the full patient population. And so when we think about site selection for that, we want to make sure that we're going to sites that either have a good socioeconomic racial ethnic distribution so they may be know, cultural hotspots like Houston or Chicago. Place los Angeles, big cities like that. Or you're going to locations where you have large numbers of certain minority groups to kind of balance it out within the entire study. And there are lots of different besides site selection, there's things that you can do during the management of a clinical trial to kind of maintain that you're actually getting that good distribution within the patient population. That's very deep and detailed and we probably don't want to go into the nitty gritty of that, but it's stratification and paying attention to the enrollment and all of that within the sites and just keeping a close eye on that. And so what you'll want to do is kind of plan what your diversity needs to look like at the front end of the clinical trial and how you're going to ensure that the diversity what's the word I'm looking for? Requirement is met. And then how you're going to monitor that throughout the trial and any sort of risk mitigations that you're going to be putting in place to ensure that you're able to get that truly representative patient.

l populations. I think it was: 2020

Isabella Schmidt: Am I mistaken, draft guidance that came out recently? It's very short, honestly. And it's just kind of basically further talking about how to enhance diversification and that they're putting more of an effort to this. And so they're really looking more into the diversity planning to kind of address what the historic challenges were with seeing equal representation.

Etienne Nichols: Okay, I know there's a lot of different aspects. I do want to ask one more question around the diversity and choosing your site. So you mentioned Houston, a few other geographical diverse places within the United States. What are your thoughts about maybe I'm a US company, but I want to go maybe for economical reasons, maybe I'll go somewhere else. I know historically people might have tried to release or do first in human overseas in Europe. A lot of companies now are talking about maybe Latin America. What are the pros and cons of some of the site selection on a more global looking at it globally, what are your thoughts?

Samantha Pickett: Things can definitely get a little more hairy know, Europe has different regulations to follow. So if you're kind of running dual in the US and Europe, it can get a little more difficult because the European sites are held to different standards than the American sites are. So we try our best to get the diversity within America. That is part of the very beginning of study startup that's one of the things we look at is we are trying, like Isabella said, to address the diversity up front. So we've got the epidemiology know the United States for the disease and then we also have kind of where the minority groups are know, concentrated and mapped out. So we definitely try to know Florida and Texas for Hispanic population, southern California, you know, the Pacific Northwest, New York, and then just different hotspots around the country that have those pockets of more diverse populations.

Etienne Nichols: Okay, that makes sense. So if we go back to the conversation about we're interviewing the sites and we're talking to them about different things. One of the things you mentioned was that clinical manager. So I'm curious a little bit about what this actually happens on a tactical level. You said you go to the site, have that interview with these different people. How do you ascertain whether or not they have the bandwidth, the correct equipment, so forth, competing studies even I know you mentioned. How do you go through and ensure that all of that is going to work out?

Samantha Pickett: That's all part of that site qualification visit process. We're talking to the Pi, the person that's going to be responsible for all the things on the trial, who's signing their name, saying these things are accurate. So we talk to them like, does this institution have other competing trials? Do they have a coordinator? Do they have a backup coordinator in case that person gets sick or are they having a lot of staff turnover? Do they specifically have X, Y and Z from the protocol? We have a study we're running right now. They specifically needed a negative 80 deg freezer. So when we're talking to the site, do you have one? If you don't have one, are you open to one being rented for you? Do you have space to put it all of these things? You try to take as much into account up front as possible. Once you get past that feasibility, like.

Isabella Schmidt: Oh, are you interested?

Samantha Pickett: Could this potentially be a good fit? That site qualification visit is really getting down to the nitty gritty of are we serious about this? Are we going to move forward? Do you have all the things that you need to run this trial successfully? If you don't have them, how can we get them to you? Or do you not have enough of the things that we should just stop here and move on to another site?

Isabella Schmidt: I want to add something. Site selection is a critically important part of the clinical trial and I think that it may not be emphasized enough. A lot of times what we'll see with startups is that they will have sites that they have preexisting relationships with and want to use those sites in their clinical trials. And sometimes that works and sometimes it doesn't. It's really good for these sites to have these relationships with these docs or these KOLs, but that relationship doesn't necessarily mean that they're a good fit for the particular clinical trial. So what happens is because they have these relationships, they want to lean on the relationship a whole lot to get the trial to run smoothly. But there are a number of different factors that go into site selection for a clinical trial that Sam has been mentioning. And sometimes the sites don't have the support that they need. So maybe they don't have the research staff that's trained in that area, or maybe they don't have research staff at all, or maybe they don't have the patient population, right? So they may have some patients, but they may not have enough to really hit the enrollment criteria for the trial. And so it's really great to have those relationships, but I wouldn't default, say, just because you have the relationship, that necessarily means that that physician is a good fit for a Pi for a clinical trial or that site is a good fit for the clinical trial. And so just be I think going through the site selection process and not just defaulting to having sites that you already know be a part of your study is important. And in addition on that, I think folks need to remember that when you select sites, the sites are working for you, you're paying the sites to do the study, right? So that means the sites are going to need to be managed, right? Just like you would with any employee, any team you want to manage, make sure that they're doing things correctly, that you're interviewing them. That's what the site qualification visit and the feasibility questionnaire and everything is you can think of it like an application process, right? Like, do they like going through your application process? Do you like what their application says? Are you going to take them on an interview? Right? And so that's what the site qualification visit is. You want to make sure that it's a good fit and that they are a good fit for the study and that they continue to be a good fit throughout the trial. So it's not we selected them and then we're done monitoring them. That's all the clinical monitoring stuff that's keeping track of how everything's going, really reassessing the site as the study progresses and making changes or addressing things as it goes along. But the first step is really making sure that you got that good fit in the door the same way you would with any hiring process, right? Because if you got a good fit in the door, then hopefully you don't have a whole bunch of issues later down the line that you need to address.

Etienne Nichols: And what does that look like, the reassessment? Do you actually have an employee go out and look at that? Or do you recommend during the study?

Isabella Schmidt: You want to talk about that soon? Samantha?

Samantha Pickett: Yeah, we do. Injure a monitoring visit. So going on site, they can make sure that they're keeping their equipment up to date and making sure that's what an IMB is, is for the CRAs to double check things and make sure that the site is running things per protocol, the way it's supposed to be run. And if they're not, then if an offense is serious enough, then they can be closed down. And like Isabella said, finding sites that are working properly that are enrolling patients, that's a huge deal. I've seen so many sites just closed because they're not enrolling the patients that they said they would or they thought they would, because the sponsor, they're still paying them money to search for these patients. But if they're not producing patients, then the sponsor is essentially just wasting money. So they'll close down a site for low enrollment as well. And to piggyback on what Isabella was saying, know, sponsors assuming or defaulting to using those relationships they already have. I mean, I'm sure we've both seen it go south. When you choose a site, you're going on a journey with this site. And if they're being difficult in the beginning, if they're not giving you things on time like they said they would, do you want to deal with that for the entire rest of your study? Because the protocol is the site's first impression of the sponsor, but then the sponsor and the CRO also take their first impressions to account as well. If a site's difficult up front, you can just assume they're going to be difficult the entire time. And do you want to take that?

Etienne Nichols: Yeah, yeah.

Isabella Schmidt: And I would add to that Samantha mentioned the competition earlier, too, as a big factor when you're selecting sites because, well, first of all, you want to know, not only do they have competitive studies, but how many studies are they assigned, like, is the coordinator assigned or how many studies does the site have?

Samantha Pickett: Do they have time to run your study?

Isabella Schmidt: Yeah, because the resourcing is a strain for sites as it is for everything now. Right. So we've seen strains in resourcing across industry, across FDA, across sites, across everything. Right. So the great resignation happened. Now we're having a lot of people getting laid off all over the place. So there's just resourcing issues across the board, I think, and that also impacts sites. And so you want to make sure that they don't have too many studies for the staff to support them, that they do have the time, like Samantha said, because a lot of know not only for your study, but for the staff as well. Right. Because they'll get overwhelmed with having too much to do. And so you'll see that they have so many studies that they're overwhelmed. And if they're overwhelmed, that's not a good situation for anybody, even if they're trying to give you the time. Right. Even if they're going for. Giving you the time. That's a recipe for mistakes to be made, for oversight. So you really want to take a look at how many sites, how many studies does the site have? Are they competitive? Because that's also a place where you'd have enrollment potential issues. If they're competing for one, that's multiple studies that they're trying to target the same indication, but also a place where they could, if they're overwhelmed, be making mistakes, confusing things between the similar studies. So you just want to be mindful of all of those things when you're selecting a site. And that, again, goes to the fact that you might have this kol, but he may have competing studies. So you don't necessarily always just go to the sites that you know.

gs that people are facing for: 2023

Samantha Pickett: Timelines the ever changing, right? There's so many moving pieces in a trial, and timelines are targets, right? Nothing is written in stone. Anything can happen. Sometimes anything that can go wrong does go wrong. Like you said, we're all human beings, right? So there's room for error, and we're kind of at the mercy of process and guidelines and things like that. I think it's really important for sponsors to go into it with realistic expectations of timelines. Sometimes we get sponsors and they're like, we want first patient in by March, and it's January, and we're just like, where'd you come up with that? We just want first patient by March. Well, there's processes we have to follow. The sites have their processes that they have to follow. It's always nice, and you get the clout for having this large big name institution participating in your study, but with that large, big name institution. They're a large big name institution because they're a well oiled machine. They have their processes that they go by. They probably have a local IRB that they use, and they probably have separate budget and contract committees. And things just take more time. It could be a linear process instead of a parallel process, and it can just take longer and longer to get things started at that institution.

Etienne Nichols: And there have been a few acronyms, I apologize for not getting this clarified earlier, but so IRB internal review board. I know there was another one, IMB or IMA. I may be misremembering that. It doesn't matter, we'll look at it later. But anyway, I'll try to catch the acronym. So the local IRB that you mentioned, so what are some different options when it comes to selecting a site and utilizing an IRB? Kind of enlighten me there, if you could.

Samantha Pickett: Yeah, so there's local IRBs and central IRBs. Central IRB is typically faster. A local IRB can know this one institution has their own IRB or this group of institutions have their own review board that they go through, which would.

Etienne Nichols: Be essential for that group. Is that right or no, sort of.

Samantha Pickett: Which can get a little confusing. A central IRB would be for like a multicenter study and then each site can some groups or sites have agreements with the central IRB? Yes, we'll use, you know, if somebody the trial wants to use you, we'll use you. Or yes, we'll use a central IRB if X, Y, and Z criteria are met, or no, we just use our own local IRB. So we make sure that everything is going the way we want it to. And the purpose of the IRB is protecting patients to make sure that everything is patients are aware of what's going on in the trial, what risks and benefits, and just to protect their privacy. And everything about the IRB is patient focused. So the like, they kind of all have the same standards. Local IRBs can have a little more stricter standards, they can have specific language that they want used that's presented to patients, and all those things can kind of take a little more time. The central IRB, if a site uses them, when just say you have six sites on a trial that are using the central IRB and there's a protocol amendment, you submit that protocol amendment with any other additional updates to the central IRB. And when it's approved, it just gets approved automatically for those six sites. So it's much faster than those six sites having to submit to their own local IRBs. And then we have to wait for six different time points to get approval for the central IRB. It's kind of all approved in one go and then we can just move forward a lot faster.

Etienne Nichols: Okay, that makes. Well, what kind of recommendations do you have for a medical device company who's trying to select their site and they're weighing the options between these different things. And maybe the specific pain that I'm thinking about is I created a protocol. I'm going to send it to this. Maybe it's a local IRB and a central because they're outside the scope. And so I'm doing multiple. I'm assuming that's maybe a situation that you run into. What if I have a situation where I need to change the protocol halfway through the study? How do those changes get disseminated across multiple sites? And I don't know. If you could just kind of elaborate on how to overcome certain specific challenges with a multi site study. Yeah, long question.

Samantha Pickett: That happens all the time. I prefer to utilize central IRB whenever possible. That's going to be the sites that are going to get up and running, usually faster. We kind of use a two tier approach. Like, these are the sites that are going to get up and running fast, but then we also want these academic sites that have this really big patient population and they're going to boost enrollment and things, but might take a little longer. So we get the ones up running faster that might be a little slower to recruit. And in the meantime, we're getting the ones that take longer started up, and then you'll get a bolus of enrollment later. So we kind of take that two pronged approach. And then when it comes to protocol amendments and things like that changing in the middle of the study, like I said, you just submit to the central IRB and those sites get it done. And then we have site startup specialists and our CRAs. Also, if the site's already active, just going through and helping the sites with the local IRBs, making sure that they submit and get the new information approved and up to date.

Etienne Nichols: Okay. Anything else about timelines and things like that that you would maybe recommend or not? It looked like you were going to say something.

Isabella Schmidt: Isabella so one thing about the academic sites and KOLs too, is sometimes you have the situation where they have this large patient population. You also sometimes have a situation where they're slow enrollers, right? So you may spend a year trying to get this site up and running and then a year getting two patients in. And all the other sites are like, oh, I've got so many patients, and they're kind of like hitting enrollment, and then they may only have a handful of patients, but you still want that site because you have a Kol at that site. Kol still wants it because he runs a publication, and so there's this sort of symbiotic relationship there. So it still benefits you to have it because you want that kol and he wants the publication. And so just be mindful that the site may be a slow enroller. That just because it's a kol doesn't mean that the site's going to enroll a whole bunch of patients. Sometimes they do, sometimes they don't. And so you really want like Sam was saying and kind of you were hinting at that you really want a balance of, okay, I have these KOLs whose sites may take a really long time to get up and running because I got local IRB and there's all this bureaucracy getting contracting and all of this stuff in place. And maybe they're a slow enroller or maybe they have a really great large patient population. But I also have these other sites that are not necessarily the KOLs, not necessarily the academic institutions. They can go run through the central IRB, and I can get them going really fast. And if you really want to have patients that come from the sites that have these KOLs just being mindful of not exploding the patient population in one site, and that's part of that sort of diversity planning too, right? You don't want to have one site that is so good at enrolling that they enroll the entire study. And you don't have diversification throughout the United States and the sites and everything because you don't want it to. If it's a multi center study, you don't want it just at that one site, and FDA is not going to want to see that if they agree to a multicenter, make sure that you're balancing it.

Etienne Nichols: Okay, sorry to interrupt. You bring up a really good point, and that is kind of like diversifying your portfolio of trials or investigations because ordinarily I might think, just as maybe I'm a project manager or something, I might think, well, we just have to get through this investigation so we can get to the next one, so that we can get to market. When in reality it sounds like there's a little bit more of a bureaucracy political side from the business side, the business standpoint. We've been utilizing these key opinion leaders, we've been utilizing these specific sites for other relationships. And so you want to maintain that and maybe that's going to help you even post market when you're actually trying to get into the hospital and so forth, things like that. Is that accurate?

Isabella Schmidt: That's accurate, yeah. Having kol advocates is always beneficial. I mean, you want to have those physician advocates out there for you at the sites and just like in the industry in general. So you want to balance that out. Some of it is like I was saying earlier, even if you're not going to use them in your study, you still want to maintain that relationship. Maybe you use them in some other type of study. Maybe you use them in a post market study where it's a better fit. You really want to make sure that you have the good fit for the study. And sometimes you go into that knowing, okay, this site is going to be a slow enroller. That's okay. I know that. But you really want to still make sure that they have all the other things that they need to be able to conduct a study. Right. They have adequate research staff. They have the facilities that they need. It's not going to be this major headache bringing them into the study. And then you had asked about timeline, and I don't know if you just hinted on it now or thought you were going to to Sam's point, there's all these moving parts into getting the study started up. I think there are so many different factors that go into the timelines that the companies are thinking about there's on their end funding, right? So they're like, I've got this protocol, but they don't have the funds to kick off the study. So that's one thing. So the timeline of funding and that's really hard for them to predict. Right. They may think that they're about to get the investor to sign. Maybe they signed an Loi, but then, nope, the investor pulls out. You just don't know. Right. So funding is a hard thing to anticipate. Usually what they'll do is think about the timelines outside of that. So you need to get all of your doctors in a row up to the point for the clinical trial. If you have to file an IDE with the FDA, you need to make sure that you're getting rolling on that, that you got everything that you need, that you file that IDE with the FDA. Most cases, you probably want to anticipate a little bit longer than that 30 day timeline. However, we've had it approved within 30 days. So that's one part. But then all of the things that Sam was talking about, it depends on how many sites that you have that you need to start up to get the study really rolling right. The types of sites that you're getting started up, how quickly they're able to enroll, how eager the sites are to be on the study, and then the enrollment process throughout the trial too. So there's that startup chunk that we've been talking about that takes, I don't know, Sam, like three to six months on average, probably, right?

Samantha Pickett: Yeah. For central IRB sites, 812 weeks, three to six months. But for larger institutions, especially academic ones, it could take six, eight months, sometimes even a year to get started, just to get through all the processes.

Isabella Schmidt: And what we're hinting at, too, is that's largely a part of picking the sites as well. Right. You need to understand those timelines because that's not something that we can necessarily control it's within the site too. So it's a balance of us engaging with the site. So if we were just, like, chilling and not doing anything, of course it's going to take longer. But it's also some things that are just outside of the sponsor's control, outside of the CRO's control. It's the site. So that's one thing. But then as you move through the study, like we were talking about, you got to pay attention to enrollment. You got to pay attention to what the sites are doing because if you're not hitting your enrollment numbers, then your study is going to be dragged on for longer. So what Samantha was talking about before was if you close down a site because they're not enrolling and so you're paying them to keep the site open, but they're not enrolling, so you're just paying them to keep doing it, but you're not hitting any of those milestones that you need to hit. So then you might need to spin off another site, right? So then you have to go through the site selection if you haven't already selected those sites. And the study startup not study startup, site startup process again. So you just are kind of viewing these things throughout the entire clinical trial. So that can also impact the timeline. If you have slow enrolling sites, if all of your sites are slow enrolling, or if you were banking on this one site is going to be my top enroller and they're just not hitting it, that can slow down your trial overall. Contrarily, if you have awesome sites that are all enrolling like crazy, your trial may finish earlier than you originally anticipated. So it's a lot of the CRO working with the sites to manage how quickly they're enrolling and to manage all the sites collectively for the study's enrollment overall. So managing like we're saying, if the site is a slow enroller, do we close this site? Do we need to add a new site? Do we need to help them with enrollment? Right? Do we need to get marketing out there? Do we need to reinvigorate their interest in this trial? Because sometimes what you'll see is a site's doing really great and they're enrolling enrolling, and then all of a sudden they kind of like dip, right? Or they start to dip and maybe they're distracted with a competitive trial or something, or something bright and shiny is distracting them. Now particularly you see that with trials that have really long periods of time that they're ongoing. So stuff like that, you're always managing. I mean, that kind of goes in more to the entire clinical trial management, but it unpacks when you're starting up and maybe spinning off new sites or closing them down. Okay, all of ours.

Etienne Nichols: So we kind of talked a little bit strategy. I want to get one last tactical question in because I like focusing on the things that I can control. And a lot of times I look at this, we've done protocols on paper before, and I know there's other options. Now. What is the most technological way to do this, to have the most efficient process? Are there any tools you recommend or things that you use to handle this, especially multi sites?

Samantha Pickett: My favorite tool is having a 21 CFR compliant Esignature system. And you would not believe how many people I just have. I get the blank stare like, what's that? So that's one red flag that we're going to have a little bit of trouble with the site. But after the Pandemic, we were forced to do so many things remotely and it's just so much faster to be able to get a Pi signature, you just send it through your system, it's signed, and then you email it right back to the CRO instead of having to physically take it to the Pi's desk. And then we have to wait for them to rifle through all the papers and sign that one and then give it back to us. And then we have to fax it or scan it in and email it. It's just so much faster. The Esignature keeps things moving so fast that it's been amazing how much faster that is. And some sites, that's a question we ask in feasibility. Do they have these systems in place or do they still use paper forms or paper medical records? Being able to do remote site visits, having an electronic medical record. Those kind of things are revolutionizing the clinical trial world because it can be not hands off in the sense that just letting things go, but it's saving. The sponsor money for the CRA not have to travel to a site. And they can get a lot more done online for eight straight hours sitting at their desk. If we can do a remote site visit every now and then instead of having take a whole day to travel to and from a site. So electronic systems are fabulous.

Etienne Nichols: So basically what you're saying, if I could sum up, is in your site selection, part of the criteria is a post pandemic 21st century software that you're using, something like that?

Samantha Pickett: Yes.

Isabella Schmidt: Tech savvy is the question.

Samantha Pickett: Yes, it accelerates the timelines is what I'm saying.

Isabella Schmidt: What an esignature is.

Etienne Nichols: Excellent questions for that question that we're talking at the very beginning. Okay. Anything we missed, I know we need to wrap up, but I really appreciate you joining the conversation or carrying this conversation, presenting it for us. Anything we missed or you want to last little words you want to throw.

Isabella Schmidt: Out there, I do have one. Back to your question about the Ous trials. So usually what we'll see is sponsors do that as a first in human study, it's less expensive, et cetera. First in human. Sometimes that's okay because it's not your pivotal trial. And your criteria for selection may be somewhat different. You're probably doing that more for investors than for regulatory. Sometimes you might be able to use it for regulatory. I would say never plan on doing that for your pivotal trial. Only Ous. At least if you want to do a global trial, that's okay, but only Ous. What typically happens is FDA wants to see US. Population, and particularly if you're going to a location that is not diverse ethnically. So if you're going to somewhere where regardless of whether it's all Caucasians or it's all Asian or whatever it might be, they won't typically accept that data. And it's really just a challenge to get them to agree that the racial differences and the ethnic differences not really gender, but those differences when you're moving ous don't impact the use of the device. It's a lot easier to say no than it is to say yes. So I would just make it as easy or as hard for them to say no as possible and as easy for them to say yes as possible. So just plan once you're getting into pivotal territory and maybe even pilot that, you're at least having some and a good number of US sites. If US is your real first target.

Etienne Nichols: I think that's good advice. Samantha, any last piece of advice?

Samantha Pickett: Yes, I read this somewhere, I don't remember where, but it's profound. In its know for a study startup, isabella was saying before as much stuff in front as possible, so try to do it right so you don't have to do it again. It's kind of the takeaway. We really strive to get all our ducks in a row and select the best sites for all of the different reasons, so we're not closing and reopening, wasting time, wasting money, wasting effort, so we really try to do it right, so we don't have to do it again.

Etienne Nichols: Fantastic. Well, thank you both. We'll put links to their LinkedIn as well as other ways to get a hold of them, however they would like that in the show notes, so definitely check out the show notes after. Samantha, Isabella, thank you so much for being on the show. We'll let you get back to the rest of your day. Thank you so much. Take care. Thank you so much for listening. If you enjoyed this episode, reach out and let us know either on LinkedIn or I'd personally love to hear from you via email. Check us out if you're interested in learning about our software built for Medtech, whether it's our document management system, our Kappa management system, the design controls risk management system, or our electronic data capture for clinical investigations, this is software built by Medtech professionals for Medtech professionals. You can check it out at WW greenlight guru or check the show notes for a link. Thanks so much for stopping in. Lastly, please consider leaving us a review on itunes. It helps others find us. It lets us know how we're doing. We appreciate any comments that you may have. Thank you so much. Take care.