Welcome to Farmer Talk Radio. This podcast is focused on enverching clinical trials with patient reported outcomes, discussing best practices, potential pitfalls, and new approaches from the twenty twenty five Chief Medical Officer summ at three sixty. For more information, I'm on the CMO Summit. Editorials, podcasts or webcasts, please visit CMO three sixty dot org. Thank you enjoy the podcast.
So we'll start with some introductions and then get into the heart of the discussion. I'm Barry Tico, I'm chief Medical officer at Stoke Therapeutics, and we'll just go down the line here. Everybody introduce themselves in their affiliations.
Hello everyone, My name is well Sam samble CeON, founder of delve Health. We focus on patient engagement pros wearables will probably have one of the more prominent set of wearables for collecting patient outcomes.
Hi.
I'm Dave Vessels. I'm the chief medical officer of Signant Health. We are a clinical endpoints company, so we focus on patient reported outcomes. Clinical reported outcomes. We have about two thousand employees, fifty of them are scientists and physicians, and we will we help our clients to select the right patient reported outcomes to implement them and then also to make sure during the trial that the quality of the data that you collect is of the highest standard that.
It can be.
Hi, good morning. My name is Natalie Agafonov. I'm chief medical officer of company and Drivon. We are clinical stage company phase two move into phase three dvincient therapy using bond marrow derived missing humans themselves. Our focus is a rare pediatric indications such as hyperplastic left heart syndrome and
also we're working with Alzheimer disease. Over twenty years in clinical research, I develop really deep passion for the patient reported outcome, for the patient voice to shape up clinical outcome assessment. Very excited to have this conversation.
Thanks.
Hi. I'm Jason Sager.
I am the chief medical officer of Accent Therapeutics. We're a small molecule clinical stage oncology company running two phase one for a modifying protein enzymes inhibition and really looking forward to deciding how to incorporate this in oncology because it's always been a challenge to look at pros and something that I think is getting more and more important as we move forward.
Thank you everyone, So as Jason mentioned, PRO is becoming more and more commonplace. And let me just get a hands here of how many people have used the clinical trial PRO in one of the article trials that they've designed. Yeah, pretty much almost everyone.
I expected.
Now the question how many of used the PRO as a primary endpoint.
In one of your trials?
Okay, so it's already pretty good that they're that many, because, as we'll talk about, there are quite a few challenges in you using pros in general, but as primary endpoints they are especially challenging. But they're going to become more and more needed, both from the regulatory perspective, where right now probably about half of all trials have some PRO and in Europe about half of all labels include some
PRO information. FDA is a little bit more reticent, so recently only about twenty percent of labels actually are including PRO information, but that's likely to change. We heard from ken Getz this morning about how trials are becoming complicated and their.
More and more endpoints.
Well, one of the main contributors to the additional endpoints is likely many of you know, are the pros that are being collected, but they're not even being collected for regulatory purposes. They're they're becoming, I think, even more required for payers, and that's part of why. So I'll tell you we have a Phase three program for genetic form of epilepsy called drave syndrome, and we have made our trial quite complicated because we're including additional endpoints just for
the payers. One of them is a collection of the impact of the disease on the family and the parents work time, employment time. So I can tell you that there is no regulatory agency that cares about that, but the payers want to know how much time can this person be full time employed and pay premiums? And we've had to incorporate video is, we've had to incorporate EEGs, there are quite a few other patient reported outcomes that
we've had to incorporate, especially for payers. So what I like to do is have the panel members talk briefly about one or two p r ohs that they've they've focused on. And I know we're going to hear about wearables, We're gonna hear about others that can give some advice to this audience as to how best to incorporate p rros into your clinical protocols.
Yes, I mean so pros and co as our core capability for what we do. So we do we work across multiple disease dates. On cology Alzheimer probably two of the most sophisticated ones that we see. Compliance by far is probably one of the biggest issues that everybody deals with, especially if you're you know, well, really depends on how often you want to collect that that diaries and the p r os.
And one of the most.
Complex aspects that we see often is how many diaries are you actually trying to collect on a daily basis or on a weekly basis, you know, take bristle mile stool for example, right, you're trying to get compliance how many times the patient goes to the bathroom, especially in an oncology trial. So some of those aspects are complex, and one of the ways that we look at it is more of every patient is different, right, every environment
and disease state is different. And even are you really trying to push out three pros a day for oncology patients? Cancer patients that go in for a treatment and go home and they're really sick, and yet we're complaining that compliance is really bad. So I think what we've seen is what models can we incorporate to help ease the patient burden, but also ease the site burden as well.
And that can be from whether it's from a protocol design, whether it's from you know, patient engagement rules, et cetera.
So from our side, it really depends on the therapeutic area. So if you look at at oncology for example, so we see that, I'm gonna let me just step that back. So one of the principles that I brought in earlier in my career that I still believe is that you need to make sure that you know what you're going to measure and why you're measuring it. We spoke a lot about the the earlier today about the complexity of
clinical trials. Your phase three trial is not the time to test e pro You have to do it much earlier because you don't want to learn anything new in your phase three trials for that. For the rest of it's it depends so much about the patient situation, It depends about the environment that the patient is in, and then also it depends on the disease area for that. So it's it's something that we're going to have to
bring out more and more in the future. But let's make sure that you just understand why you're doing it.
I actually have the same idea to initiate thinking about the PRO as soon as possible and don't use phase three as a validation study for the PURO. I think we always have to be mindful that perro a very
important tool to understand patient voice, to understand fit for purpose. Also, I think the biggest challenge is sometimes when you in phase two to understand this disease area, and even with the available tools, you can actually develop your PRO and validate during the phase two and incorporate and phase three, or in my experience, sometimes when you get to phase three and you have this aha moment, it's a little bit too late, and then you have to overcome this
regulatory hurtle and be creative how to overcome that.
Yeah, I mean in oncology, and I'm glad it's come up already from my perspective.
You know, really things.
Are we're moving away as we develop these molecular targeted precision medicines, especially the oral ones that are going to be used on a day by day basis for months at a time. You really need to move away from the model of the traditional dose limiting toxicity where you see in a cute dose it's reported to the doctor. You get into like sort of how do those patients feel on a chronic basis thing, and then there are
those and you already mentioned diarrhea. There's only a handful of things, but fatigue, nausea, these things are not reported well and they're not reported well in the paper versions of the pros because of just you know, a lack of timing and you know, if you only get to see the patients once every three weeks, you're not going
to find those things out. And so getting a tool into the patient's hands that you could be handheld on a handheld device and making it so that they benefit from using it with a report that comes to them that they can then bring to the doctor to actually ease the burden of that communication is something that we're looking into and working with a company called represent with a puro in there and to see if we can
actually optimize that patient reporting from the get go. Just so you know, in oncology we now have to deal with project optimists and it's a huge question of how are you going to choose that second dose? And I won't get into that but I would love to see pros start to enable some of that decision process in a smart way.
Yeah, it's interesting. We actually just published a paper on that exact idea. So and what we did is we postialized and this was together with industry we published it, and we postialize that that you actually miss a lot of the adverss event if you don't do it as part of a ePRO, and your dough selection becomes a
problem later on. And if you look at the phase three trials, the majority if your phase three trials, you start it off and then you have to reduce the dose afterwards, and that's a huge cost burden to the trial that you have to put through, administrative burden for protocol amendments and safety reports, all these kind of things. So yeah, it's definitely there, and we bring your own devices the way that you can design e pros. It makes it really very easy for the patient to collect that data.
So this is an important discussion the difference between paper and the e pros. And I'll tell you running an epilepsy trial, we collect daily seizure record from the families and this is a method that's been used now for decades we're still using paper. I just got a copy of the binder that the families are going to take paper home with and record every day, and it really
disappoints me that that's actually the way we're going. But I tell you that we spent months and months trying to figure out how do we use an electronic diary. Do we give the family a device, do we make the family use their own device, what's the cost, the time for startup, and then all the regulatory requirements because that's an issue around the differences between what the FDA wants,
EMA wants in terms of collected collection device. And then on top of it, one of the regulatory agencies wanted a paper copy to verify what we're collecting on the phones from the family. So after all that, we ended up with paper. But I'd like to hear a little bit from the panel on thoughts about trying to move us more into the electronic age as we go forward with our trials.
Yeah, I've seen I think the first time that I saw a paper diary was back in twenty ten and it was an Alzheimer's study and it was interesting because I was managing a study for a larger company and as you talked to the investigator, they're talking about you know, they were actually explaining the situation.
They're like, hey, I'm sitting here with this patient.
And it was a patient and their caregiver and asked me like, hey, how was your pain like two days ago or something like that, and he's like it was a seven and then the caregivers like, are you sure it sounded more like a nine? Right, So it was like it was one of those initially interaction and then twenty sixteen, actually I started del because my mom had cancer and she was part of a study.
And you know, like we go to Mayo Clinic.
And they're like, oh my god, I didn't fill out all these pros. Right, So you said there in the parking lot filling out all the pros. But now, like we pass forward to kind of where we are today, we want more of that real time aspect what really happened to you. And that's the reason why a lot of prs are like a diary needs to be responded to within twenty four hours, maybe forty eight hours of max.
Right of course, depending on the diary.
And I think we're really seeing that, we're seeing the change, we're seeing the results, and what we're seeing from our perspective is how do we design the pros and make sure that if we're doing pr if we're doing BYOD, for example, we need to make sure that every single device that a patient's gonna pull up is going to look exactly the same in every single device. And that's you know, that's one of the you know, probably the
biggest things that we've seen from regulatory agencies. So how do we make sure that we identify the pros design and make sure that they look exactly the same. But patient engagement also like a huge component as part of this.
If we're really worried about compliance, we got to think that it's not just like a website that you're going to give to somebody, right, how are you going to nudge their make sure that they're aware, hey, you've got a pr O that's ready for you, or how do you nudge maybe like a caregiver and maybe that network of people around them. So technology is here, I think it's how can we really utilize it better in today's agent world?
Ye, So we've been working with the Epilepsy Consortium on exactly developing that epilepsy diary. So we understand the challenges of it, but I mean there's and it sounds obvious coming from a ePRO, so it's a vendor. But there's already there's a lot of studies out there. There's a study that's quite old, I think it's more than fifteen years old, where it was quite eloquently designed. It was a paper diary. It was giving two hundred patients and they were told to complete it. But that wasn't the
real study. The real study was there was a chip at each page and you can actually see when they open it and complete it. And something like eight percent of the patients finished the diary before the month, so they were just proactively writing out what they're going to do. The majority of the patients actually did it in the parking lot while they were waiting to come back, so
you could see it all those dates times. So the challenge with paper, unfortunately is that we see that people don't I mean, people have busy lives, they forget to do this, and so that's one part of it. The other thing that we also see is that if you use electronic diaries, for example, you can identify abnormal patterns
on when the data gets completed. And you can identify some sites that completes the data at very different times than the rest of their sites as well, and it's something that we don't talk a lot about, but it is out there. Clinical trials is expensive, there's a lot of money in there, and there is still fraud that's
happening there. But basically coming back to the epilepsy part, so our approach is to work worth a consult with the epilepsy consort, Tium or the epilepsy group and just work through all these processes with regards to timelines, setups and so on. AI has really made a difference in that and where we see the biggest the biggest difference is actually in the user testing because you can now do in a few minutes, you can do ten thousand tests and then you can identify exactly where the problems
are and fix it very accurately. So it improves your quality and you don't have to get any programming down to one day or something like that. You just need to get it off your critical path and that's already been done. So there's a huge movement with that in the last year and you'll see more and more of that.
Yeah, it's very challenging and and as you, I would just want to emphasize the al Zeimer disease especially. It's very surprising to me that not only patients but also caregivers have difficulties to work with electronic data. But I know we have issues and problems. I want to bring fresh idea. If it's if I made that we have
AI people in a room. A couple of days ago, I just visited MIT Museum and there is an amazing tool predict whether or not you have opportunity to have Parkinson disease based on how you type, how many letters you miss. I think in the future, it just brought just idea came to my mind. We can actually use difficulties for patient to complete data electronically and predict their severity based on how patient type. So it's just an idea, let's do it.
So the way I've been trying to get at this is when we had discussions because obviously your safety in phase one for oncology is the primary goal, and yet it's very tightly regulated, and so that's where you know there's a lot of questions, Well, what if the pro database doesn't match your hospital database, what's the after you're going to say to us, and all these sorts of things. At the end of the day, what it came down for us is to basically slip it into an exploratory
endpoint in phase one. I think in sort of in honor of don't wait until phase three, let's learn about what the signal is, but let's do it in a way that's more flexible, where we have the opportunity to do an pro such that once it's validated and you start to get that data, you can then escalate it as you go through so that by the time you're in phase three, you can make it a primary endpoint or something that is akin to something that's going to get into your label.
One of ken.
Gets his favorites the exploratory endpoints, right. It's complexifying exactly, and well, I'd like to turn a little bit two wearables now and just where you as panel members see from those of you who've had experience with wearables, how are we going to be able to incorporate those? Are those going to be used more and more or are they too complex for us to utilize at this point, especially when you consider the number of data points that
was talked about before. One wearable one heart monitor can generate five million data points in a day. So when you're thinking about data complexity and the data we need to collect, how are we going to start using wearables efficiently in our studies?
So we live and breede wearables almost every single day, you know, we've got we have had studies that do as much as five wearables on the same patient, and we've had as little as one. I think the time is coming for wearables. We're definitely seeing that wearable data can enhance pr O data. Right, it's all part of patient outcomes. Right, you've got the pr O data here's how I feel. Then you've got the wearable data that
tells us here's what really happened at home. There's been a couple of studies, probably a few studies that have used wearables as a primary endpoint. I don't think it's not I don't think it is for every study, at
least not yet, but they're here. If you're considering it, I'll probably go back to the same mentality as use it on a phase one or a phase two, so that way you understand how wearables work in your clinical trial and think at the end of mind, Right, what exactly are you trying to understand is it their movement, is it their sleep patterns or you know, And you have to think about it as patterns over time rather than just one data point for a day.
Right.
So it's a different mentality, different mind shift from the PR data. I think it's but I think it's coming. We're seeing definitely a lot more interests in almost every single disease state.
Yeah, I think that's very very valid. We're learning a lot st all about wearables. Were currently just starting a study with Lead University where we are looking at wearables e pros and then also some of the hard biomarkers genetic testing, et cetera in elderly patients with cordiovascular disease and diabetes. And there's some glucose monitors, etc. And then heart monitors. It's a lot of data and again you
need to understand why are you doing that? And then secondly you just have to think about the practical part of it is how are these patients going to remember to charge the device, how are they going to wear the device every day? How are they going to forget about the device? And all those questions. You have to sit down and really think about it before you come up with yeah, I'm going to implement this on my
study or not. It's otherwise it just becomes another shiny tool and then we end up with massive amount of data that we don't know what to do with.
So I see this as a future, and especially working with pediatric rare diseases. One all of our pros basically come from parents the infants.
We inject.
Cells during the second stage sogery when the infants are four month old, and using right vigicle ejection fraction as a primary endpoint. But there are biases and evaluation based on evaluator assessment, etc. So and the way parents describe milestones.
Et cetera.
This is all we have right now. So I'm actually right now designing new clinical trial thinking about how we can use wearables in this tiny patient population, how they move, how they breathe, what they do. But again, I think more work needs to be done because I'm always nervous when I get a lot of data. It's not just getting data, it's exactly what question you ask, what data do you want to receive, and how you're going to
analyze it and why you're using this. But I see this as a big future, especially for rare disease indications patient cannot express themselves.
I'm interested in actually surveying the audience on this because how you know that like almost everyone raise their hand when you ask about the pros, But how about for wearables? Anyone integrate that into your protocols? Okay, and then keep your hands up if it was in an oncology protocol. Yeah, that's what I kind of thought. So no respondents, just a bed a couple, Yeah, maybe one in the back.
I'll talk to you later.
But you know, I think that it's been a challenge, and especially for the elderly population, all the technical aspects that you mentioned, and I just haven't seen it get there yet. I'm hoping that kind of maybe the phone itself becomes the wearable, that that's the thing that's most attached to them, that they're keeping charge for whatever reason, and therefore we can get more information out of it.
Yeah, And actually that's one of the points that we're going to measure in the study with leads, is whether you have a smartphone or not, whether that has an outcome on your and positive or negative outcome on your life. As an endpoint around that, so yeah, great.
Thanks.
Well, we have some time for some questions from the audience, so if you want to step up to the mic any of you see someone walking up here, we'll take your question first.
People are CMO I want to treat so thank you, Thank you very much for these I would say, very inspiring panel discussion. I was convinced before the penal discussion of the importance of PIERO, but even more convinced. And I do agree that understanding patient perspective is challenging, and I do agree that Piers can really help. Now my question is, oh, my next challenge is a following, how can we do even better than understanding but considering the
patient perspective into the clinical trial design? And I would say, not on the secondarian points, but really in the heart of the design of the new studies. I think this is probably the next challenge. I'd like to get your opinion on this one.
You want to do Yeah, yeah, I can. I can try that one. I think it's so important, especially on rare diseases. Actually to really make your selection of what clendros or E pros or pros you're going to choose, spend a lot of time on focusing on that because these patients have such tough diseases and such tough lives and there the care takers are exhausted all these kind of things, you have to be very practical in doing so. Again, it sounds repetitive and boring, but it's it really depends
on your disease. It really depends on the situation and what do you want to get from it. So that's why I would say spend as much time thinking about it and finding out why you want a certain pro as implementing it.
Sor And when I think we've done in the past, we've done you know, smaller like patient surveys and we're actually we contractor with a third party say like hey, can you interview maybe like five or ten patient population from within the specific disease and kind of walk them through what we're going to do and give us that feedback. And that's been like amazingly helpful. So if this is something that really kind of top of mind, something i'd recommend.
Yeah, I recommend it too as well, you know the question of back here.
Yeah, thank you guys so much for the information.
I appreciate it.
And your collective experience is where have you seen the best practices of real world evidence being leveraged to show investors the value of the data that you're getting as it's happening before it goes to market. You know, one of the things that is key now with capital strap markets is figuring out how you can say their phase one top line is going to show value for the
future when it could get to a registrational pathway. Are there ways that you all have seen railword evidence being brought into that into maybe combination studies or different programs where you've had access to the information to help assist with your protocols.
Maybe I can't, so I'll answer very quickly and then share. You know, recently Astrozenica presented their part one selective inhibitor. Now, obviously they had the wherewithal to be able to do three doses and so, but you know, they had some really nice data where they showed that the efficacy of the top two doses were the same, but you had a lot less nausea with the second lower dose. Unfortunately, for biotech where we are limited to two doses, I
think it's still going to remain a challenge. But that's where I've seen this data lay out in a way that I think would be very powerful.
Thanks for the question. I think actually real world davidence is becoming a part of our lives right now. You can use syneatic arms using real patient data on publicly available domain. For example, there is a single Vincicola trial with twenty years worth of data an Alzheimer's disease near abnormalities. You can use this data as a synthetic arm to kind of compliment your clinical trials. So you can do open label trial and complimenting this with the synthetic arm
and present to the a FD. And they're really really accepting this idea right now. It's it's really hot right now.
Time for one more question here, sorry, thank you very much.
So Anil Dargent, Dunny Edward Genomics and we're running an LS study with a weariable remote monitoring as well as pros in there. Just a question for the audience what kind of correlations have you seen between pros, whether it's ePRO or paper versus what has been collected by remote monitoring or wearables? Is it one to one when they say the patients say I walked two times a day, did the wearable also show that same data? Or is it not correlated.
I don't know that there's ever really a true one to one, to be honest with you, because when we look at this Steffa, so correlation between pros and wearables is definitely core part of this, right, But as you look at the wearable data, we need to look at trends where it happened, right. So for example, if you've got the pro that asked, you know, how many miles did you walk yesterday?
And they said one? Did you really? You know? So that's kind of what the wearable would really show.
Yeah, I think it's it's important to understand what the patient's going to gain from that answering that question. So one of the things that we focus on a lot is training and PA see mitigation training as well, and this falls into that part. If the patient's going to gain something by lying, then they'll lie thinking that is it?
So thank you very good.
Well we're all set here, so i'd like to think again the panel and thank you all for your attention. Thank you, thank it.
We hope you enjoyed the podcast. For more information about the CMOS Summit three sixty, editorials, podcasts, or webcasts, please visit CMO three sixty dot org. Thanks for listening.