In this episode of Inside Look, experts Dr. Andrew Pucker and Yesha Raval discuss a paper recently published by Lexitas entitled “Running the Enrollment Numbers on Ophthalmic Clinical Trials in the United States.” Throughout the episode, Andrew and Yesha discuss the methodology for this paper, how valuable site relationships are to the success of a trial, and how to maximize your partnerships with your CRO.

The following is a transcript of the above video.

Dr. Andrew Pucker: Hello, everyone, and welcome back to this episode of Inside Look, which is a podcast from Lexitas where we take a look at common things we do on a daily basis at the company. My name is Andrew Pucker. I’m the Executive Director of Clinical and Medical Sciences at Lexitas. My background is in optometry, so I’m an optometrist by training. I have a master’s degree in tear-film chemistry, a PhD in myopia development, and I’ve dedicated my career to better understanding dry eye, myopia, and contact lenses. I’ve now been at Lexitas for about three years. I serve as a medical monitor, research coach, and really I help with whatever comes up. I’m joined today by Yesha Raval. Yesha could you please give a little background on yourself?

Yesha Raval: Sure. Thank you so much, Andrew. My name is Yesha Raval, and I am the Operational Strategy Director here at Lexitas. I am very new here, but I’m not new to the world of CROs and ophthalmology. I spent about sixteen years before [joining Lexitas] at an ophthalmology-focused CRO. So, very excited to talk about enrollment rates, which I believe is the topic today. Back to you, Andrew.

Exactly. So today we’re talking about a paper that we published at Lexitas, which is called “Running the Enrollment Numbers on Ophthalmic Clinical Trials in the United States.” This is something that we do on a daily basis. We have new projects come in, we bid on them, and we have to estimate about how many sites and how long it will take to get the subjects needed to successfully enroll a study. So, we look at this a few different ways at Lexitas. When I came into the picture, I wanted to make it a little more scientific.

So what we did is we got access to a program called Global Data. It’s actually a registry database. It’s a subscription, so you can get a subscription if you want. What they do is they take data from common registries such as clinicaltrials.gov, they upload it, and they then also try to find everything they can about that study. They might go to PubMed to read the paper, pull all the little tidbits out. Then they put it in a database that is easily accessible, and you can analyze things in different ways.

What I did, along with our team, was I went to Global Data, I refined a search method, and what I did is I pulled all the data on the ophthalmic clinical trials that have been done ever in the United States, at least ones that have been registered. So, we have data going back to 1982. We have organized it based upon all the common indications within ophthalmology. What we do with Global Data is we ultimately look at the number of subjects we can get per site per month, and with that, it helps us project out how long each study will take. And a cool thing was that when we have a lot of data for specific indications, we could even look at it by the study phase. So, stage I, II, III, or IV, and from there, we could even further refine our rate. So that’s the data side of things, and then we also look at it from the site side, which I think Yesha wants to talk about next.

Yeah, thank you so much, Andrew, to chime in for that. So for your larger studies, as you mentioned, we absolutely need to take a look at what the industry average is, right? The larger studies, the law of averages applies. The smaller studies, though, you want to talk to your sites directly. And it’s not only the smaller studies. You talk to your sites and you do feasibility for all studies, but I think it’s a higher weight to take just the opinion and the experience of your sites because it’s a smaller sample size. You really are relying on those investigators.

For a smaller study, I think you tend to go to sites that you feel can deliver, and they feel more committed. I think it is a slightly different strategy, but even if you’re going for a larger study, you want to understand what the industry enrollment rate is and take a look at what the historical rate within the organization is. If we’re taking a look at a presbyopia study, we want to see what we’ve done in the past, compare that with the industry, and compare that to what the investigator says. However, I think in the smaller studies we tend to rely a little bit heavier on the investigators because they’re really our thought partners. So they understand, they’re more committed. We tend to go to the sites that we know can commit to that, and so that data tends to be a little bit tighter.

Yeah, so at Lexitas, we have a database of over a thousand sites, and we know who knows what. And we can potentially, I would think, go to the best site in the world for dry eye or— name your condition. So that enrollment rate there will probably be way higher than your average site. I think we need to take that into consideration, but at the same time, Yesha, what do you think about just asking sites? How accurate are they going to be on their numbers? If they say they’re going to get 30, do you think they’re going to always get 30 or how would that play in?

You want to assume and you want to hope for the best, but I think we all know that life sort of gets in the way, right? We have our specialized sites, as you mentioned, and we have a large number of them in different indications. And I do believe that they could deliver on those numbers had they been doing it in a bit of a vacuum, but there are competing studies, there’s vacations, there’s holidays, all types of things happen. I think oftentimes, it is a slight overestimation. So just something to keep in the back of your mind. But again, if it’s a smaller study, it’s a dialogue, you know. The investigator knows that you’re sort of relying on them, and you’re partnering up with them. So I think that partnership and having industry connections, working with a specialized CRO, really makes a difference for your study.

Just as an aside, if sites are watching this, we really take you at your word, and we think that you can do it most of the time. And with that, just be honest. If you don’t think you can get the subjects just say so, and we’ll come back to you next time.

Yeah, I agree. You know, we want [the site’s] success. You are such a big part of our success and our sponsors’ success. But it is a true partnership, and even if you overestimate sort of in the beginning, and things change, we want to sort of be there with you so that we can identify that quicker and just put together, you know, any sort of mitigation strategies to get us back on track for enrollment.

So now I’m thinking about some things that were maybe surprising to me in the analysis I did. So, I want to think about dry eye and myopia. Dry eye is a really common condition, and we found that it enrolls a median rate of around three subjects per site per month. At Lexitas, we often do much higher than that, maybe eight or ten. That didn’t necessarily make sense to me. I wanted to kind of think about that and maybe we just have the greatest sites in the world for that so like maybe you kind of have to think about your data and then put it all together like Yesha said with the sites.

The flip of that, a thing that I found surprising with myopia, which is the most common eye condition in the world, there’s going to be five billion people with myopia by the year 2050. And those studies enroll at a rate less than one subject per site per month. And thinking about that, there’s a lot of treatments in the market right now. And not all of them are on-label. Actually, most of them are off-label. But you have contact lenses, you have atropine. There are spectacles in some countries that are shown to slow myopic progression. If I’m a parent and I have a child who I want to potentially get treated I may be more likely to pick the contact lens that everyone’s already using with a known safety profile than a new drug that could be amazing, but we don’t know anything about it yet. So I think that you’ve got to take this all in as a whole, right? So it’s not necessarily based upon the prevalence of a condition in your area of the world. Yesha, what do you kind of think about that with respect to some studies that we’ve done at Lexitas?

Yeah, I know that when I came in, I realized that there was an ongoing study that I was quite shocked at because it was a Phase IV study. It’s a safety study, I believe, for dry eye. And if I’m not mistaken, enrollment was completed in two instead of six months. And as you mentioned, one would say it’s not a surprise because dry eye is fairly prevalent, and so you expect that to be quick. I think in this case, it was a unique scenario because it was a safety study. So it’s a very relaxed inclusion-exclusion criteria. The focus was safety, not really efficacy.

I think that the team probably thought that we would need a little bit more time to find these patients because they were looking for treatment-naive patients, and you would assume that that’s hard, especially in a place like the United States, where there are many, many treatment options available. I think that’s why we assumed that it would take longer than it did. In reality, I think, as you mentioned, having that strong network of sites available for a specialized CRO like Lexitas comes in so handy because yes, it was an added inclusion-exclusion where you had to find the treatment-naive patients, but it wasn’t as hard as we had anticipated. Luckily, Lexitas was able to deliver sooner than expected for the client for this case.

I was even surprised. That one just like blew way past our expectations. We do a lot of dry eye Lexitas, you know, it just was way outside of the norm. And again, that’s because there was very few requirements for their dry eye in their study. And kind of going with that, I don’t necessarily think it’s bad for a study to end quickly. The thing that I worry about most at Lexitas is a study that runs long, and we really try to avoid that. Specifically because we’re planning a study, we have a sponsor who goes and raises some money for this study. And if you don’t get done on time, you might run out of money and then you have to close the study, which is actually the number one reason why clinical trials fail in the world is because they just don’t project the enrollment rate correctly and it takes too long to find the subjects.

We thankfully don’t have that much of an issue with that at Lexitas, but it’s something that we think consciously about on every bid, and we want to make sure it’s right, again, just to make sure everyone’s successful. And if we get done quick, well, everyone can have a little party, and we can celebrate that, and you can have a little press release, right? So any other tips related to that, Yesha, you want to give?

Yeah, I would say that’s such a good point, Andrew, because we want to try to get it as right as we can or as close to that for our clients. We don’t want to overestimate and then hit you up with change orders later because we understand that’s obviously a different challenge. We want to be as close to it as we can. It is sometimes mistakenly thought, though, that if you have a high enrollment rate, that means that you’re going to complete your study on time and that it’s going to be a successful study.

In reality, I think there’s so many other KPIs that will outline whether the study is successful or not. A high enrollment rate may not always mean that the retention rate is high, and every study is so different. Every indication is unique, and there are other challenges you have to balance that with. Of course, it’s great to complete a study as quickly as you can, but you want to make sure that you have qualities at the front of everything and not only speed. It’s a little bit of a balancing game for everything.

And then I also think all of this puts site selection really sort of at the top of the pyramid here. It’s so important because, especially for the smaller studies where each site has such a larger contribution, we want to make sure that you’re selecting sites that can understand your study, for the client, at least they can understand the timelines. They can understand the challenges and can work within the ecosystem that is built between the CRO and the client. Again this is where if you are a client and you’re seeking a CRO partner you should make sure that you’re finding the right partner for you. It is very important and can really add to the success of your trial.

At Lexitas, we think of site selection as a partnership with a sponsor, right? We have some sites that we could propose. You might have some that you want to propose, and we can kind of go from there and pick the right sites to make sure you have a good mix. And typically, that is really experienced sites, but we also like to work on some newer sites, right? You know, we can’t live forever, so some sites retire, and we need to bring new people in too. We work together to come to the right mix of people like that. Any closing thoughts?

My closing thought is, yeah, you said something very important and I just wanted to also mention, it’s not only that you want to bring in the new sites for all the right reasons you mentioned, Andrew, but I think more and more for certain indications. We’re looking for that treatment naive population, right? And I think that’s really the area where new sites can really help. There’s less competing trials. There’s just a different study that sort of works with that. So it is important to have those in the mix as well as our experienced and top-delivering sites.

Some other closing thoughts are if you’re a client, you have a candidate and you’re looking for a CRO partner, be a partner to your CRO as well. And by that, I mean, you know, sit through those assumptions, understand the timelines and costs and challenges CRO. We certainly appreciate when our clients challenge us because we want to make sure that we’re getting it as close to where we think we will get to. So, you know, challenge them, understand what their experience is, how many patients do they feel they can get out of their sites? Who are their sites? And then marry that with information that is available to you, as well as the information that your CRO already has from their past experience. So, yeah, I just wanted to tie that in with site selection, which will be part of that package.

I think that’s a great point, Yesha. With a sponsor, they’ve been developing their drug probably for years, and they would know it the best, right? So we can give suggestions, but they know it the best, so they need to help us come to the right conclusions on how to move forward.  Lexitas is an ophthalmology-focused CRO, so we know ophthalmology really well, but we don’t necessarily know all the ins and outs of the sponsor’s drug. So with that, we need to work together to try to make sure that we’re all on the same page and then we can make our studies successful. What do you think, Yesha?

Yeah, I one hundred percent agree, Andrew. This is where, if you are a client, my advice to you would be to find a CRO that knows your indication best. They should have experience, ideally in the phases that you’re looking for. We know all the phases are going to have their own unique challenges, so you want to pick a CRO that understands what the landscape is, and who the investigators are that will give you that successful study. And then work with your CRO to really understand everything that they put into your proposal and your budget and your strategy, right? So challenge them. I mean, I certainly love when my clients come and they ask us, you know, why do you think it’s going to be these many patients a month? Or why do you think we need X, Y, Z sites? So understand that and don’t be shy about that. You can sit through, you can ask for a meeting to go through the budget, the assumptions, the timelines, the investigators, all of that, because it really is a partnership. And as you said, Andrew, while we know ophthalmology very well and we have that experience as an ophthalmology-focused CRO, we don’t know that drug particularly well. The client might have done different phases of it before and can bring in that experience to help us better design the strategy for their next trial. My advice is ultimately make sure that you know, you as the client, that the CRO you’re working for is your partner, but they’re relying on you as well as you relying on them. And a lot of this also comes into the fact that obviously the right selection of the CRO will give you access to those investigator sites. which as we mentioned, especially for the smaller studies, they’re really sort of going to make or break your study. So connect to a CRO ultimately that has the experience that you need for your indication.

Perfect. I love the idea of scientific discussion. That’s like the favorite part of my job, helping with protocols, working through those sort of things. So I think that’s perfect. So with that, I’d like to thank you, Yesha, for being on the podcast today. I’d like to thank you all for tuning into this episode of Inside Look, which is Lexitas’ podcast talking about the nuts and bolts of clinical research. So with that, I’d like to have you hopefully tell friends about this and like and subscribe, and hopefully I’ll see you again in another episode soon.

Visit the Optometry and Vision Science website to view the full article, or request a meeting with the team to discuss your upcoming trial.

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