First in Human: The Panel Series on “Navigating the Ophthalmology Clinical Operations Landscape: Insights for Advancement”

Bruno Gagnon: Welcome to the panel series called First In Human,

presented by Vial. My name is Bruno Gagnon I’m going to start, presenting

webinar when we have this nice, panel discussion with

experts in the field of ophthalmology and in clinical trials. It’s called Navigating the Ophthalmology 

Clinical Operations Landscape: Insights for Advancement.

So let’s go with a round of introductions. Thank you to Vial for organizing this. As I said, it’s called 1st in Human, but we’re not going to talk only about the early stage clinical trials. We’re going to talk about various clinical trials. I’ll start with introducing myself. And then, we’ll go in the order of the slide here. My name is Bruno Daniel. I’m the SVP of Global Clinical Operations at Opthea a small biotech company based in Melbourne, Australia, although we’re global. I’m personally based in the San Francisco Bay Area. The indication I’m working on is wet AMD. We are developing a drug called uh, Sozinibercept, and it’s an  NT VEGF-C  and D, so a new class of drugs, and we’re developing Sozinibercept in combination with standard of care with the ultimate goal of improving visual outcome.

So, Raj, if you wanna go ahead and introduce yourself, please.

Rajat Agrawal: Thanks, Bruno, and thanks, Vial for having me here in this webinar. My name is Raj Agrawal, or the full name is Rajat Agrawal, but it’s sometimes difficult for people to pronounce, so people call me Raj. I’m a retina specialist by training and experience, having worked in the field for over 20 years now. Having worked in clinical medicine, academics, teaching, and also research. On the other side, but now working with industry since the last couple of years.

My current role is I’m the VP and the ophthalmology lead, at the company Rezolute, which is again a small company based out of Bay Area. We are focused on a drug which is RZ-402, focused on the indication for diabetic macular edema. Interestingly, this is an oral medication to be given to patients once a day.

Currently, in a clinical phase two study, which is currently ongoing across the US and hoping that this shows some kind of benefit in terms of outcomes, which will hopefully take us to the next stage of the clinical development.

 I’m also the founder and CEO of a nonprofit called Retina Global, which works both within the US and around the world, providing care to underserved patients. Thanks, Bruno. And I guess it’s Jen now.

Jen Watts: Thank you, Raj. Thank you, Bruno. Hello, everyone. My name is Jen Watts. I’m the vice president of Clinical Operations for Early Development at Oculis. My entire career has been centered around clinical operations leading global clinical trials with the biggest emphasis in ophthalmology. I’ve worked in retina, uveitis, glaucoma, dry eye disease as some of the indications over the last two decades. I’m really excited to be a part of this panel today and hopefully get an opportunity to share some of the insights and reflections that I’ve seen over the last two decades. Thank you.

Amy Del Medico: Thanks, everyone. Thanks, Jen. So hi, everybody. I’m Amy Del Medico, and I’m VP of Ophthalmology here at Vial. I’ve been in the industry for about 20 years now, just over 20 years. I started my career working at Quest Diagnostics, the Central Lab and then, moved into a role with IQVIA, where it was Quintiles at the time. So my experience spans, uh, feasibility and operations.

I actually set up IQVIA’s Ophthalmology Center of Excellence back in 2017. So, I’ve worked in a variety of different therapeutic areas, but pretty much solely ophthalmology since then. And, across all different therapeutic areas or diseases within ophthalmology, so anterior segment and retina and currently working on a couple of trials through Vial. One is an AMD study, gene therapy. And the other is a device study in retinopathy. So really looking forward to our discussions today.

Bruno Gagnon: Excellent. Well, thank you all. I think we’re going to have a great conversation. So let’s start with the 1st question. And perfect. I’m going to read some of the high level here. So we know ophthalmology is a rapidly evolving field, and there’s many new drugs, new therapies in multiple indications. So my 1st question, and I think we’re going to start with Jen on this is that how do we ensure effective collaboration between clinical development and clinical operations to speed up the access to these new drugs? And how do we, how do we go from the no, kind of the vision, which is more like the theory into the practice. 

Jen Watts: Absolutely. You know, one of the things I think that is truly essential for operational success and acceleration is consulting early with your clinical operations colleagues. During development, especially in early development, there are so many questions. And teams are working so hard to truly break the therapeutic knowledge that you can get from our First in Human, early phase two trials.

But if you bring up clinical operations into the [00:05:00] discussion early, what we can do is give you some insights in operational feasibility. You have a beautiful patient population that you have with inclusion-exclusion criteria. Do they even exist in the current landscape? Is it even feasible to do the recruitment? You build these beautiful integrated development plans, but are your timelines realistic truly to the clinical trial study that you’re trying to develop and operationalize?

My thought here is bring us in early so that we can be part of that early development team, um, in order to help accelerate, down the line this study.

Bruno Gagnon: Very nice. Raj, what is the perspective of clinical development on that?

Rajat Agrawal: [ laughs] And I was, I was going to add to what Jen mentioned, which is I totally support what she said in regards to the fact that clinical development should work early on with ClinOps 

in terms of trying to set the stage, so to speak, in terms of how we go ahead developing a program.

It’s funny, in a way, sometimes, clinical development, personnel work in isolation thinking that developing a protocol, developing a clinical design is something that they are supposed to be experts in, which they may be to a certain extent.

But the point as Jen mentioned, it is important for real-life evidence, so to speak, to come into play in designing a study. That’s where ClinOps actually plays a significant role. And all of you guys, most of you are, fairly experienced people in the ClinOps, side of things. And you have experience conducting studies as well.

So you do know the real, world out there which helps potentially provides a feedback to a clinical design. And so, focusing on inclusion-exclusion criteria, not being overtly academic in a way, if I may use that word, in terms of trying to look at every little aspect of things that you want to put into place in a design, can complicate a study.

So it is important for conversations to happen between the two. And also, I would add to this is adaptability. So, based on the feedback we receive from the field, it is important for us to maybe make some changes in the protocol in the clinical trial design. So getting that feedback from the ClinOps, people who work in the ClinOps team, is useful in terms of maybe, for example, making an amendment to the protocol.

So all those factors come into play. So I totally agree with Jen in regards to the fact that there has to be an open line of communication going on from early on when we start designing a study.

Bruno Gagnon: So you’re discussing important aspects of like flexibility and adaptability. Like when you get feedback from people from ClinOps or other areas, or from other areas, like sometimes people say, “Oh, this protocol is set in stone. We can’t change it anymore.”

But before the study starts, sometimes, though you need to make changes. Amy, any particular perspective from the CRO here, like this collaboration and maybe I call it cross functional collaboration and also maybe listening to the client? What’s your view on that?

Amy Del Medico: Yeah. I think we’ve all been at the receiving end of having to operationalize a protocol that perhaps had maybe too many questions or wasn’t asking the right type of questions. I think it’s easy to get over excited by trying to answer a lot of questions in a protocol. And you need to be as streamlined as possible, not overcomplicate that protocol.

As Jen mentioned, make sure that your eligibility criteria actually make sense in the real world, but also make sure that your schedule of assessments is as close to the standard of care that you might see at sites as possible. Obviously, there might be strategic reasons why it may have to differ slightly, but I think especially in areas where the landscape is really competitive, sites and investigators often have the opportunity to turn down a study if it’s particularly complex, and therefore not worth their while in doing.

Bruno Gagnon: Okay, thank you. Let’s go to the next one. You’ll see a lot of these questions. They follow logical kind of smooth path. So we’ll come back to some of the same things. So the next theme is about maybe obstacles. So the question reads like this: What are some common pitfalls and bottlenecks that can come up when there’s a disconnect between the departments, between cleanups and how can we prevent these from happening? So maybe I start with Raj on this 1.

Rajat Agrawal: This is again an important question because it again goes back to the previous question, which is, there has to be a collaborative spirit going on between ClinOps and ClinDev in terms of developing a study design and a protocol.

I usually call this the two sides of a coin, so to speak. The two tend to face away from each other, but they are stuck together. So, you have to work together and make sense of what is going on. It’s been occasions where, my colleagues in ClinDev have come up with a study design that potentially they feel that’s probably the best there is out there.

But it may not be practical in a sense to put together and get it going. So it’s important for us, again, going back to the earlier point, which is that we have to make sure that whatever we do in terms of designing a study, inclusion, exclusion criteria and whatnot have to be practical.

Again, we should not be expansive, and especially in early stage of clinical trials like phase one and phase twos. We don’t want to be too expansive about what we want to achieve in terms of getting a signal, trying to get safety aspects to be taken care of. So all those things matter in a way for us to make sure that there are no issues going on between ClinDev and ClinOps. 

I mean, again, going [00:10:00] back to this point about the fact that clinical trial design is not to be done in isolation. It is an important perspective that we need to keep in mind that without clinical operations pitching in with their perspectives and real-life scenarios. If we do that, we’ll probably be fraught with issues as we go along into the study. But on the other side, the ClinOps team also should be aware that ClinDev may have some role to play as well in how the clinical trial is put together i- in terms of, planning and execution. So some of the clinical development folks may have ideas about site selection. They may have ideas about which PS to include in the study and because of existing relationships and whatnot.

So it is important for both sides to work together in that respect and then create a situation where study, execution, planning, and, ultimately, outcome works out best for everybody.

Bruno Gagnon: Very good. And then, I think Jen, you have some best practice about protocol development. You want to share a little bit about this?

Jen Watts: Absolutely. My passion is early development research. And I know being in early development, primarily for at least the last 10 years, there really is this true desire to learn as much as you can in phase two, right?

 I’ve seen protocols with up to 20 exploratory endpoints. And, one of the things I’d like to mention that I think has worked very well on some of my close collaborative development operational teams is performing some type of futility review or a protocol leaning round table exercise where both sides of the team get to sit around.

We go through to see what is the scientific importance of the exploratory measures or maybe it’s even secondary measures that we’d like to learn more about and, really understanding is it true scientific exploration, or is this measure going to be something that is either interesting to the streets or maybe that will help with future decision making on, moving into phase three trials.

Something else that I think is really important during this protocol-leaning exercise is really see what is that site and patient burden? Like Amy had alluded to just a minute ago, if there are too many assessments, we’ve got to think, is it even feasible for this patient population to take a whole eight-hour day out of their lives so that we at this sponsor, in collaboration with our sites, are able to obtain all of these exploratory assessments?

 And what are we doing with that data? Is it something that we are just curious about, or is it something that’s really going to be impactful to the patients and, also, to our company as well?

And I think that comes with a very interesting point of cost. So, are we able to take what, perhaps development or ClinOps and development have created in this early protocol study design? And if we lean it, how can we efficiently use the cost savings over time?

I’ve been on protocols where by taking out enough exploratory measures, you could literally fund another project. So, [laughs] you know, that’s something I think that is a great mitigation technique during this early process that will help definitely, you know, cure some of these pitfalls and bottlenecks that we see in development. 

Bruno Gagnon: We’re going to go to question 3. I’m going to start with Amy this time to get the perspective of the service provider. Amy, could you share some insights into the challenges and specifically unique challenges and opportunities that happen in clinical trials and ophthalmology?

Amy Del Medico: I think we all know that it’s more efficient and cost-effective, if possible, if you can recruit within the timeframe that you need to conduct your trial in a single country. And, obviously, you need to have enough sites to be able to do that. But, sometimes strategically, that isn’t possible.

So you need to look to go outside, perhaps, of the United States and look at other countries or regions. When doing that, there’s a number of different considerations that you need to think about. Those tend to sort of span across therapeutic areas, right?

So you, you want to make sure that the country you’re going into has got enough potential sites to make it worth your while going there in the first place. Thinking about the standard of care in those countries is important, the competitive landscape, and also the startup timeline. So, those tend to be the four sort of key things that you might want to think about that could apply in any therapeutic area.

There are some ophthalmology-specific considerations, as well. For example, with the ETDRS chart, on the assumption that that’s being used, which is in the majority of trials, you need to think about the patient population that you are going to be including in your trials.

So, the standard chart that you would see with our standard alphabet is only for those patients that can read the Cyrillic alphabet. So, you need to think about the other optotypes that you might need to include.

 For example, if you’re including Japan or countries that don’t read that alphabet, you might want to use other types of charts. So there’s the Landolt C or the Tumbling E. And those are also considered to be ETDRS charts. So it’s perfectly feasible to use them, but it’s important. And I think we’ve got a question coming up about, diversity and inclusion.

And I think it’s really important because using charts like that can help to make sure that we’ve got a diverse patient population and perhaps [00:15:00] patients that are illiterate can be included if you use those charts. So, that’s one of the challenges.

In terms of opportunities, I’m gonna go back to my point about start-up timelines. And I know a lot of sponsor companies are, perhaps, a bit unsure about using South American countries because they do have longer start-up timelines than, say, the United States or Western Europe.

But what I’ve found is that those countries actually have excellent professional sites, and they do tend to recruit very quickly. So I think an opportunity is to include those countries more in clinical trials because while they might have a shorter window of recruitment because of their longer start-up timelines, they do tend to catch up and recruit very well.

Bruno Gagnon: Very good point about starting a new study or a new program. Anything else in terms of unique aspects, Raj or Jen, open question here about like I would say, specifically to ophthalmology, things that you don’t see in other therapeutic areas?

Rajat Agrawal: If I can add to this, in my opinion, there are positives and negatives. And Amy did, fairly describe it really well. One important thing we need to keep in mind, and there are sites out there, outside the US, outside Europe and routine sites that we usually go to where pIs are hungry for studies. I mean, they’ve not been exposed to clinical trials. They’ve not been exposed to any of the things that we routinely do.

And so reaching out to those sites, who are fairly underrepresented, in terms of clinical trials potentially may give you more patients, you know? And so, that’s something that we have to keep in mind. And Amy’s point about South America and some other countries is definitely, something that we have to keep in mind as we go around planning a study.

We also, because we can reach out to other sites that have not been part of clinical trials before, we potentially may be able to get access to more patients, primarily because of especially in a case where a study is looking for treatment-naive patients that are extremely difficult to find in the [laughs] United States at this time.

But on the negative side of things, there are, as Amy mentioned, a couple of things that you have to keep in mind, is lack of experience at the new sites, right? I mean, the PI may not have experience at all in conducting studies, so that can play a role in how the study is conducted.

Also importantly, sometimes, there is lack of seriousness about documentation. Some of these, sites in some other countries, people don’t really give, much importance to keeping [laughs] all kinds of documentation fairly as, part of the study. So that can be another issue that can come up.

And also,some of these sites can potentially need more hand holding in a way to get up and running. So all those factors do play a role in decision making regarding that site to be pulled up into a study and on.

Bruno Gagnon: So training becomes important if they have access to the right patient population, maybe as a pharma, as a sponsor, as a CRO. It’s important for us to invest time. in training these sites to make them like the sites of the future. Very good point.

Okay. Let’s move on. And, I think Jen And, I think Jen is going to start on this one. So when you are, and I know you have a passion for early development, Jen, so when you were looking at early development, what are some strategies to kind of navigate the complexities of these clinical trials in ophthalmology? 

Jen Watts: Thanks, Bruno. Um, one of the things I love to say to my teams, especially when I mentor future operational experts is the mantra, slow down to speed up. So in early development, we are racing usually to first patient, first visit and trying, because time is of the essence for the development, of our programs.

And so when I say slow down to speed up, I found it so valuable to say, “Okay. Time out. Let’s take a few meetings, maybe a couple of weeks, do a deep dive and really thoughtfully discuss the strategies, the potential risks, and what we can do to mitigate that early on prior to getting into clinic.” What I’ve seen is, it results in better protocols, so less protocol amendments overall, for the duration of the program, and actually higher quality data and results.

So, that would be probably the first thing I would say is a great strategy is take the time up front, invest those couple of weeks or few meetings, versus being reactive, later on when, you know, things come up that have not been thought through.

The second point that I would say in early development is, you know, we don’t know everything yet. You know, we’re not.. we’re still in this beautiful exploration period. and I think it’s so important, once you’re in the clinic, listen to your team, listen to your study coordinators, listen to your CRA and monitors. They have the best feedback.

I have seen projects where we’ve called the sites, the CRAs and had group meetings to really get their feedback. And guess what? They’re happy to tell you the good and the bad, which is, in my opinion, great. I want to hear both sides so that I can implement what do they need? What is missing? What quality can I help to improve? And what can we do to optimize the site, the CRA, the study team, working with the CRO, everyone’s experience on the trial? So, I would say those would probably be my, top two strategies in really trying to efficiently navigate early development [00:20:00] complexities.

Bruno Gagnon: So the slow down to speed up and then, maybe the next point is like the value of planning, spending time planning and plan early, right? I like that a lot. Anybody else on the topic of of, early early development?

Amy Del Medico: No, [inaudible No, I just want to say I love that, Jen. And I wish we saw more of that. I think sometimes things snowball. And, obviously, companies have got deadlines that they have to meet. But I think your methodology is a fantastic way of doing it. So, yeah, let’s see more of that.

Bruno Gagnon: And rise briefly, your point? 

Rajat Agrawal: My point was that, you know, just to add to what Jen and Amy have mentioned, just keep it simple. You know, early stage development, we are looking for safety, obviously, but also looking for a signal so that we can help continue the process of clinical development. So don’t complicate matters, and just keep it simple. 

Bruno Gagnon: All Hey, let’s go to the next 1 so what are some innovative approaches or technologies that have advanced clinical development in ophthalmology? And how are these new techniques impacted your respective role? So we start with it right here. 

Rajat Agrawal: as in any other field, you know, innovation is a constant, so to speak, in clinical trials as well. innovative approaches start with the clinical study design and planning itself. has been fairly, go to, so to speak, in terms of, getting a registration FDA. But with newer indications coming into play, like geographic atrophy or, or any of the rare indications like Leber congenital amaurosis, there has been a push for endpoints that are different compared to BCVA and that have been approved for using racial studies. So I think there has been some. in terms of moving away from, being focused on BCBA. 

In regards to other innovations and probably more focused on technological innovations, the idea is to reduce, rather improve patient experience. You know, patients, generally, when they come into a clinic to be part of a clinical study, as we discussed earlier, they have to spend a lot of time sometimes in the clinic for various reasons.

And so trying to see whether we can reduce those aspects, and also easing the burden of the sidestep. So all those added advantages to technological innovations do play a role in trying to reduce the issues that we have been facing in clinical trials for a long time.

You know, Some of the buzzwords that we keep hearing about in clinical studies is artificial intelligence and also digital health. And AI has been supposed to help with a lot of factors in clinical studies, you know, primarily focused on patient recruitment, also in patient monitoring. that it might help also patient retention. in my experience so far, I mean, I have played around, so to speak, with AI in the space of our, clinical studies. But it does not really played a significant role in, in ophthalmology clinical trials so far. But I’m, sure there will be something coming up in the future.

In terms of, let’s say, having patients being monitored, with the data coming in from a clinical study, there might be a potential for that data analysis to be done by an AI software where adverse events potentiality can be assessed early on. And, hopefully, we can reduce the ease and all that stuff in a study.

Also wearable devices. People have, in other indications and other specialties, people have used various aspects of technology like sensors and devices that can collect real time data.

Unfortunately, we’ve not had that kind of, aspect play a significant role so far in ophthalmology. Maybe, in glaucoma, for example, iOP measurement in real time would be something that we can look at. There is obviously multiple developments going on in that space.

to digital health solutions, talked about home OCD machines, which are, currently in development. Hopefully, we’ll get approval soon enough where AI and machines can come together and help reduce the patient burden for coming into the clinics all the time to get an OCT done in the clinic.

Hopefully, that will, again reduce the patient burden. also been attempts, in, regards to patient vision being checked, at home rather than coming into the clinic. And that also may play a role.

Again, this is not something that has been used so far, in my opinion, or in my understanding, in a clinical study so far. In the same aspect, virtual reality, visual field testing glaucoma has been approved for patient management. Again, that may potentially play a role in glaucoma studies.

In addition, there can be telehealth and tele-ophthalmology systems that have played a role in patient management. Again, something that we have to see in times 

to come.

But in general, there are a significant number of attempts currently going on both in artificial intelligence and digital health that I’m sure will play a significant role as we go along, into the near future.

Bruno Gagnon: Very There’s a lot of stuff in there, And as you say, like maybe a lot of potential for improvement and developing even more, because we know about these technologies may be being used in other areas and maybe not so much yet in ophthalmology, but it’s coming, right? Anybody else with comments on that? 

Amy Del Medico: Just to mention, Raj, that was, that really [laughs] comprehensive. And I think you covered most of it. Just also to mention perhaps some novel endpoints, which I know you mentioned at the [00:25:00] beginning, Raj, but also novel biomarkers as well.

I know there’s a number of companies that are developing novel biomarkers, which are now, we’re seeing a bit more use of those within clinical trials. I think there’s some sort of caution, because, obviously, if they haven’t been tested before, companies are not sure that they want to do it. But I think some of these companies are seeing a success. So that’s quite exciting, I think. And sorry, Jen, I spoke over you again. [laughs]

Jen Watts: Oh, no, you’re fine. No. I was just going to mention just to throw in operational aspects here with some innovative approaches is, considering, is a decentralized clinical trial something that, could potentially be utilized in your program? And when I say DCTs, I’m really saying, “Go beyond what we’ve used in the past, not just mobile nursing, not just direct deliveries of IMP to patients homes, but really truly bringing the experience of the trial to the patients.”

In ophthalmology, we definitely have to overcome the imaging. And there’s some other big factors that come into play, but I think it’s something that, in the ophthalmology field, especially in clinical operations, if it’s a potential to be an opportunity for an innovative approach such as this, operations should be bringing that to the table to development and giving it as a suggestion and a future opportunity or an innovative opportunity to our teams and to our patients as well.

Rajat Agrawal: Bruno, if I may add a point here and just to pitch in Vial, Vial is obviously a technology focused CRO. So, you know, we expect a lot more technological solutions to clinical studies and clinical management, hopefully from coming from Vial. 

Bruno Gagnon: Yeah. Well, it’s a typical, CRO selection criteria, right? Why do sponsors outsource? It’s either because you have a gap in resources or knowledge. But sometimes, you need to complement with the technology. So the small sponsors. And a lot of us come from smaller companies. We don’t have this technology. We cannot necessarily buy or adopt the technology. So we use a CRO who has done it multiple times. So very good for us to partner with service providers.

Let’s go to question number 6. six. It’s 6 of 7, by the way. So if people are participating, wondering where we are, we are nearing the end. We still have plenty of time, and we’ll have time for a Q and a also at the end. 

So, let’s talk about diversity and inclusion in kind of clinical trials and patient centricity in general. So, what practices have you found to be most successful in running clinical trials and ophthalmology and how have they improved the patient experience and outcomes of clinical trials? I think I start with Raj on this one., 

Rajat Agrawal: As we know, people from racial or ethnic, minorities and other diverse groups do not usually partake in clinical trials. And that has been a reality for many years now. And we also understand that FDA has a guidance out there that is encouraging, clinical studies to broaden the scope of patient recruitment with diversity playing a role because end of the day what we develop as a drug or a device, potentially will be used by patients from different backgrounds. So we need to know what the real world is out there versus only focused on certain subset of populations. 

So that is an important aspect. The main issue, I think, why there is issues with not having much of diversity in clinical studies so far has been, you know, most of these patients are located in areas where sites… you know, clinical trials or, clinical sites may not be; they may not have access to clinical trial sites, primarily because of location.

Generally, in that space, we know that underrepresented, communities do have difficulty accessing health care, And that’s one reason why we need to make some changes there. Hopefully, focusing on sites that potentially are close to those, communities and things like that.

I think the second aspect is mistrust. We have a history behind us, which has showcased the fact that underrepresented or, some of the communities have not had good experience with the clinical studies. And I’m referring to the 1940s and 1950s, very early stage in clinical trials where people were literally forced to go through a clinical trial without their knowledge, which, obviously, is not something that we do now.

 The third thing is compliance, aspect from a site, CRO, and a sponsor perspective. We believe sometimes that people from underrepresented communities, will not be compliant enough for various reasons. And one of the things, in my experience, has been the fact that transport for these people has been, an issue. People to come from wherever they live to a clinical trial site on a regular basis multiple times over a clinical trial, is something they have challenged with.

So, obviously, we have options for transport and things like that, that can be part of the clinical trial. So, the whole issue comes down to, finding these patients, trying to explain to them in very clear terms what the whole issue is all about, terms of a clinical study, and then trying to make sure that they participate in the clinical trials as they move on. And that’s, where, it’s important for us to, expand the reach to more patients.

Just to mention as an add on. I do run a clinic here in Orange County, California where I live. And it is actually meant for underrepresented patients. And what the experience from there has been that there are patients who are interested in being part of a clinical study. They have never heard of what a clinical trial is what they have to do and all that [00:30:00] stuff.

So what we do in the clinic is we actually identify patients who could potentially be part of a clinical study. We have a staff talk to them in detail about the study and then refer them to local sites where the patients can go and be part of the study.

And one of the big things also from a site perspective, also, if you have to look at that angle, is that a PI or a study staff will wonder what will happen to this patient who potentially may not be able to, you know, have no insurance and not be able to, pay for their own self in terms of treatment. What happens to the patient after the study is complete? 

And that’s where also a big issue comes in, why sites may not be, inclined towards including patients, of, that nature. So all of those factors have limited access, for these underrepresented communities and clinical studies, but I, think we are getting there and trying to involve more of these patients as we go along.

Bruno Gagnon: Very good. Jen, what’s your perspective, maybe your experience with it’s patient or creating awareness? What are some thoughts there?, 

Jen Watts: I’d like to go beyond a little bit about just patient education and outreach and speak a little bit more to also maybe if you’re able to if time permitting, is to form patient panels. Especially in early development, before we even get into protocol writing, what’s important to the patient?

Now, what I love about patient panels you can do them virtually, in-person now, is that you can bring patients from all across different areas. For example, in the United States, um, I performed one, uh, during COVID. It was virtual, but we had very different perspectives, but very insightful perspectives from patients, you know.

Someone on the East Coast may have different concerns or educational level on what a clinical trial is, concerns about their disease progression than someone maybe in the rural area of Texas, um, for an example.

So I think, you know, I’ve learned so much from patients in patient panels, even to the point that on one patient panel, we actually pivoted a little bit on our primary endpoint because it was interesting how the patients were more concerned about something that we didn’t think about than what we thought was the most important thing to learn from the trial.

So, I think that that’s something that definitely to help foster this diversity and inclusion that we try to do is go beyond just the typical community engagement and really speak one-on-one with patients. You know, tell them your purpose, and find out what’s the most important for them for the treatment of their disease.

Bruno Gagnon: Yeah. So that’s an important aspect of including the voice of the patient, right, in the way you’re designing, and you’re planning your clinical trials. Like, excellent. I’ve done a lot of that when I worked in rare disease. So now I’m not the logic and can apply it as well. So very good.

Okay. Well, maybe I start with, Amy on the next slide, to be fair. So let’s go to the last question. And then, we opened Q. A. But What are the key considerations and challenges and protocol design and how do they impact the success of a clinical trial? 

Amy Del Medico: Yeah. So I think we’ve covered quite a lot of this in the previous questions, but there’s one point that we haven’t brought up, which tends to be fairly specific to ophthalmology, in terms of the design of the protocol, and that is that often protocols require both a masked and an unmasked investigator, right?

That can be quite limiting in terms of site availability, because as we know, sites are extremely busy. They’ve got their own clinics to run. And I think what I’ve found sometimes is that that’s not necessarily been clear up front to investigators when they’re asked if they are interested in participating in a trial. We know that they sort of often would maybe skim a protocol and perhaps not realize that. So I think it’s really important that that’s very clear up front that both types of investigator are required for the trial. uh, And it can have a huge impact if they’re not available. I’ve found that it’s had a huge impact on re- on recruitment ’cause they just don’t have the staff available.

Bruno Gagnon: Very good. Raj, any ideas there? , 

Rajat Agrawal: I generally describe a protocol as a cookbook for conducting the study. and hence everything that needs to be, And all part of the clinical study has to be, defined very clearly in that document, which is obviously the basis for, defining clinical investigation, but also importantly for ensuring that patients are safe and also data integrity is kept intact. So, that’s an important document.

What I usually say is that we have to be very, very clear from the very beginning about why we are doing what we are doing, the objective of the study, right? So we have to be exceedingly clear about that because clarity will allow us to define a study and then put into execution what we need to do.

Again, going back to the earlier point, we have to be rational. We have to be mindful about the fact that we cannot achieve everything that we want to be achieved in a study. As Jen mentioned earlier about 20 exploratory endpoints, obviously, that complicates the study a little too much. Sites and patients will not be happy being part of a study of that nature. And so, it just doesn’t make sense for us to define anything and everything that we need to do.

Also, we need to be very specific, again, going back to the point about what is the objective of the study. So we have to be specific and stay within the premises of what we’re doing [00:35:00] in terms of the study. But also be creative. Think of trying to find a different pathway of solving an issue or focusing on an inclusion exclusion criteria there.

For example, going from a phase 2 study to a phase 3 study obviously time is of value, in a clinical trial design. Adaptive design that we can sometimes come into play in protocol design, which can potentially take a phase 2 study into a phase 3 study. That’s a topic by itself for a conversation, but I’m just mentioning as an expansive view, adaptive design can play a role as an example.

Also, don’t complicate the process. Again in conversations and points that were raised earlier, we have to be very, very clear about what we want to achieve in the study. And also, patient recruitment and retention. So patients aspects have to be kept in mind all the time because they are the primary factors, as that play an important role in a study.

So if we don’t think from a patient perspective and also equally from a site perspective, uh, we may end up with a very complicated, very difficult, very expensive, and a study that potentially may not come out with good results at the end of it all. 

Bruno Gagnon: Very good. Jen, any thoughts? 

Jen Watts: Just to make a slight comment regarding adaptive designs, I love them, actually. And I think that, you know, sometimes, it’s quite brilliant to have a seamless phase two, three, or phase one, two with a SAD/MAD POC, design. A basket umbrella platform trial designs are so interesting to me.

But I’m going to put a pitch in here for clinical operations again, and why we need to come in early, um, because, if your teams are looking at potentially using an adaptive design, you really need to understand these large, operationally more complex designs, what do you need? You’re gonna need strong study teams. You’re gonna need a CRO partner that understands and has experience, and that can operationalize your protocol based on this design.

And, what I’ve noticed over the years working with teams that have used adaptive designs is that you gain with all of the, um, amounts of operational complexity that comes with this. But you do gain protocol flexibility, patient enrichment, early decision making.

So, I think that efficiency and cost savings over time over the long haul is something to consider, uh, during your protocol design, um, and protocol development early on.

Bruno Gagnon: Very good.

Jen Watts: Yeah. 

Bruno Gagnon: Okay. So, now I would say to anybody on the… who’s a participant, you can type your question. I don’t know if people can unmute themselves, but we will start with the 1st question was actually regarding question number 5. What we were talking about. I think number 5 was about the technology. The person says “Considering material that we have for participant, such as informed consent, sometimes, informed consent can be 25, 30 pages long, we should start considering AI to get involved and help participate specifically in ophthalmology trial. Imagine if they can’t even read too well.” So I don’t know if anybody has thoughts on that, but anybody would use or if you are aware of technology to help with informed consent. 

Jen Watts: I’ve actually participated in a clinical trial myself, and consented completely virtually. In this particular project, it was presented to me as videos. And so, there was a series of videos where I did acknowledge at the end of the video through a DocuSign type of platform my consent and participation. So, As a patient being in a clinical trial, I’ve seen that. It worked very efficiently for the type of study that I was participating in, and was quite a unique experience.

Bruno Gagnon: Yeah. So like, he can say, I mean, there’s no providers of consent. Something, I can actually share something we’ve done recently is basically, very low, I would say low technology, but put the informed consent in the form of little panels almost like little flip charts.

 And when you explain, you still need your informed consent document but you can show to the patient little flip charts like one panel at a time and say, “Okay. Like, what are… what is this study? Why am I asked to participate in the study? What are the risks?” Like almost like 1 page per topic, and you can show this to them as you would be presenting like, almost like a PowerPoint presentation, but you can do it on, on like panels. And then, the sponsors can help develop this for the, for the site obviously. And these need to be approved by the IRB since they will be patient facing, but very good point.

Jen Watts: Can I-

Bruno Gagnon: Yeah.

Jen Watts: I’ve seen participation guides such as that-

Bruno Gagnon: Mm-hmm.

Jen Watts: before implemented on clinical trials. And, there is something that’s truly captivating that you can really; if you have a 10, 15, [laughs] 20 page, 12 font, [laughs], informed consent form, that can be daunting, not just for the site staff, but really for the patient to truly understand and absorb that, but with participant guides such as you described, I think that it helps bring that communication and bring that at the question and answer as the patient sees this visually, not just on a black and white sheet of paper. So I think that’s an excellent idea, Bruno.

Bruno Gagnon: Any other ideas, techniques? 

Rajat Agrawal: Yeah, Bruno, I wanted to make a point in regards to AI coming and playing a role in, informed consent. One of the issues we face is informed consent is 20, 25, 30 [00:40:00] pages, not because we choose to, but because of the regulations. Because we want to make sure that we cover all the aspects of the patient can understand what he or she is getting into in terms of a clinical study.

So, in my opinion, again, AI may have a role to play in terms of trying to reduce, and ease up the process of informed consent. But because regulations require us to provide each and everything, information to the patient, Yeah, potentially may not play a significant role in, reducing it. I don’t know. I mean, I’m just thinking a lot of this time. Maybe, it might, but, it’s, difficult to comprehend whether it’ll be able to reduce the number of pages that we have at this time. 

Bruno Gagnon: The next question, I have a question from the audience. And, I’ll ask Amy to help me a little bit here. But there was one question targeted to me specifically about our trial and I’ll make it more general, is in general, why do clinical trials take so long to enroll?

So let’s say I’ll give the example of our trial, no, it’s a very large trial, and it’s for Web MD and it’s a study for treatment naive patients, but also it’s a superiority design. So, we have very strict inclusion exclusion criteria ’cause we need to show is that our drug on top of of care is better than standard of care alone.

Like for a bioequivalence study in ophthalmology, you only need to show non-inferiority. non-inferiority. So you’re as good as the other drug. But when you need to demonstrate superiority, your trial design will be by definition, like it’s a feature of the trial to have a high screen failure rate because many patients will maybe approach to be part of the study, but may not be eligible. Otherwise, you wouldn’t be able to show improvement.

So Amy, other reasons why clinical trials, and I’m not talking about planning, but let’s say the study is enrolling, is up, no, it’s live. Why does it take so long to enroll these clinical trials, especially the large large ones?

ones? 

Amy Del Medico: Well, I would say some of them aren’t so bad, and some of them do go quickly. But a lot of them do end up going at a slower rate than was anticipated. There are so many factors to think about. First of all, just going back to what we discussed at the start, right, about the planning. Every company wants their study to be done as quickly as possible. They wanna push through. They want aspirational timelines.

And, of course, that’s important. But I think they have to be careful to make sure that those timelines are also reasonable as well. That doesn’t answer the question as to why some trials recruit more slowly. I think, in terms of some of the aspects, competitive landscape is a huge factor.

I know that there are sites that will take on multiple studies, but they may find that some of those studies are easier to… not necessarily easier to actually recruit patients, but they’re easier to conduct. And so, therefore their focus will be on recruiting into those studies that they find easier to do.

So, again, we go back to what we discussed at the start, which is protocol design. Also, I think something that we haven’t discussed is differentiation. So I think it’s also really important that sponsor companies are able to explain how their drug differentiates in the first place and why they think it might be worthwhile to study. Because that then will pique the interest of investigators.

There’s other things that can be done. Making sure that grants are the right level. And things that we discuss like listening to your team, if there are aspects of, for example, the eligibility criteria that could just be tweaked slightly, you know, maybe vision is slightly the range is too big. Maybe, if you tweak that, you might get more patience in e- looking at things like that. I think having that flexibility can really help.

Bruno Gagnon: Yeah. Yeah. Very good. Other about enrollment or about-

Jen Watts: I was just gonna make a quick mention, just talking about the competitive landscape.

Bruno Gagnon: Yeah.

Jen Watts: Sometimes, I’ve, noticed that the right trial, right time is something that, sometimes, especially early in feasibility, take a look, when you’re reviewing your sites or potential sites that you would like to consider, and ask them pointed and detailed questions on what studies are coming up, what studies will directly compete for the patients, or, so you can understand at the site level what are you going to be competing on a study coordinator resources, not just patients at the site.

And I found that if you can focus some of these sites that may have during your recruitment duration, two or three new trials pop up. If you can focus that and make them some of the top focused sites for study activation, get your patients before they open up other studies at the site. So, there’s a nice balance there of understanding the competitive landscape, but also how can you use that to your advantage? 

Bruno Gagnon: Okay. I have the next one which is maybe more a comment, but it’s about, early patient engagement, and a little bit of patient perspective. So maybe again, Amy, you can comment on that. So not Amy, but me, both of of you. So, early patient engagement to understand what would motivate them to participate is key to developing education and communication materials. so think about it. you know, if you know what their motivations are.

So, the more questions we ask of the patients, the more we learn from them, so we can customize our communication materials for them. Here’s also why diversity comes into place. I think this was a [00:45:00] little bit a comment to what you were saying, Jen, and the uh. Follow up comment. [laughs]

Jen Watts: You know, just something that popped into my mind just now regarding that is one of the things that I thought, over time that I’d like to implement into my trials, if at all possible are, we do site newsletters.

Bruno Gagnon: Mm-hmm.

Jen Watts: What about patient newsletters? Let them know-

Bruno Gagnon: Yeah. Yeah.

Jen Watts: … how the study is going on, spotlight their potential things that they can do to help relieve some of their disease issues that they have. You know, have a-

Bruno Gagnon: Yeah.

Jen Watts: -crossword puzzle on the back or something like that. So that’s… I, I’ve done that before, and that’s been receptive, very well by patients. And then, another thing that, for patient engagement materials are thank-you cards. You know, a patient goes through a screening and think of all of the hours. They’ve overcome the fear of being a participant in a clinical trial. They sat through the hour discussion on informed consent. And now, they’re pumped up. They’re ready to participate and be part, um, of the clinical trial experience. But then, they’re a screen failure.

And that truly, you know, just, just think about that and think of like, you know, all of that awesome anticipation that is just taken back because they’re not the right fit for the study. Something that I’ve seen that’s worked great is having the sponsor CRO work together to create a thank-you card for screen failures, something very simple that the study coordinators and the PI can sign, but something that they can either meld to them to let them after letting them know that they are a screen failure, but something just to say thank you.

Bruno Gagnon: Yeah.

Jen Watts: And it’s amazing how much little things, gratitude like that, and keeping patients informed during their participation in the-

Bruno Gagnon: Yeah.

Jen Watts: -trial can go quite a long way.

Bruno Gagnon: The ongoing engagement with the patients, anything you can do to give them news about how the study is going, even how the drug development is going, because they want to know, especially patients who are participating because, no, they want advanced science, but the thank you card or like an anniversary when it’s a long study, they get to their 1 year anniversary, sometimes, little things can be done. And even little gifts can be given to patients if it’s approved by the ethics committee and the IRB. So it’s possible, I forgot a question there.

 Oh yeah, go ahead Raj. And then, uh, Yeah. Go ahead 

Rajat Agrawal: Sorry. Can I just make two points? If you don’t mind? In regards to patient engagement, I think one of the things, especially in rare disease spectrum, it is important for us to also work with advocacy groups who usually have access to patients, because patients are looking, as you referred to, for information. So reaching out to advocacy groups and working with them and trying to identify patients would also play a significant role.

In addition, I think, to Jen’s point about patients having problems and issues with being screen fail, one way to tackle that would be pre screening patients. So, if you design a study with pre screening as part of the study, it potentially can help reduce the stress of screen failure of a patient going through all the informed consent and the whole process.

So sometimes, that can also play a role. And in that context, I wanted to provide an example here. I’m on an advisory board of a company out of Boston called, 20/20 Onsite. And they have this van, fully equipped van, that goes around, especially in rare disease spectrum. They actually go close to a patient’s house, and pre-screen those patients. 

And so that patients don’t have to come to a clinic and go through the whole process and then end up being screened for later. So I think those kind of things, small little things here… Again, they’re not small, but, things that can potentially play a role in patient engagement and solutions to their issues can play a role in their staying in the study.

Bruno Gagnon: Yeah. So the idea of a mobile clinic to go close to the patients, and it’s also you can penetrate some of the communities where normally people would not go to the hospital. Okay. We’re climbing close to the end. I have one question that popped in a different area. And I’m gonna ask Raj, but I’m even gonna start with giving my opinion. It’s a question about what are the key components that you are considering, when evaluating partners or vendors, you will be utilizing for your clinical studies. So I’ll start with my, my… and then, maybe Raj, briefly.

For me, when I choose a CRO, therapeutic area or specific indication. I want to make sure this CRO has more experience than us. The second one is geographic reach because like you do clinical trials and to reach patients, you need to go all over the world, so they need to have the reach. And then, 3rd, 1, maybe the most important is the team that they will put in front of me. you. Raj, what are your criteria to select CROs?. 

Rajat Agrawal: I think I’ll second whatever points you raised here.

 I don’t think there’s anything else to add to that. We just have to make sure that the CRO and the partner, end of the day, the sponsor and the CRO are going to be partners in the success of the study. So you want to make sure that the value proposition the CRO brings to the table is expansive enough and compliments you. So the point you raised earlier is that they have to have experienced more than you have. They have to have a global footprint potentially for a phase three study, where we’re looking for patients all over the world. And, they also have access to sites where those sites may not be part of. It’s a fight for patients, right? Each site has multiple studies going on, and we want to make sure that our study stands up in front of a PI. 

So it is important for us to have CROs who can actually play a role in, helping us out, with a clinical study.

Bruno Gagnon: Very good. We’re coming to the end. Maybe, there’s one that is maybe a comment, and then, maybe people… Maybe Amy, if you want to add another [00:50:00] perspective to that is awareness of studies is also key to recruitment success. Many people, patients, caregivers, and doctors are just not aware of studies available to them so early. So early broadcasting is key.

So again, Amy, even about like creating awareness about clinical trials, not just with patients, but maybe with doctors who are not typically investigators, so referral networks, what do you think about that?

Amy Del Medico: Yeah. And it kind of takes me back to our discussion about diversity and inclusion, actually. And maybe, I will be a little bit too blunt here. But I actually think a lot of the time, [laughs] companies don’t do enough when they could do more to get patients in, right?

And I don’t think that’s necessarily their fault. I think part of the problem is that the FDA guidance is quite fluffy. It’s not… It’s guidance, you know. They’re not telling companies what to do. And so, companies, they wanna recruit their study, right? They don’t wanna spend huge amounts of money advertising. But I do think a more diverse patient population could be recruited with the right sort of targeted advertising. Um, and it would be nice to see more of that being done proactively by companies.

Bruno Gagnon: This was a lot of fun. And then, you can tell that these are experts in ophthalmology and running clinical trials and designing clinical trials. So, huge thank you for, organizing this, Vial. And then, so Amy represented Vial, thank you, Amy. Thank you, Jen, and thank you, Raj, for your perspective. And, I wish you a very good day. 

Jen Watts: Thank you too.

Rajat Agrawal: Thank you.

Amy Del Medico: Thanks, everyone. Bye.

Rajat Agrawal: Thank you.