Cortex Conversations: Insights in Neuroscience | Ep. 6 | Bridging the gap in rare neurological diseases–aligning regulatory expectations with real-world needs

Rare neurological diseases present unique challenges for clinical development, where progress is often limited not only by scientific complexity, but by gaps in meaningful, high-quality data. In this episode of Cortex Conversations, experts explore how aligning regulatory expectations with real-world patient and caregiver needs can help overcome these barriers.

The discussion examines the critical role of natural history data in supporting external control arms and alternative trial designs, while also addressing the burden traditional site-based trials can place on patients—particularly in pediatric and neurodegenerative conditions. Participants share perspectives on emerging hybrid and decentralized approaches, the growing value of patient-driven data, and the collaborative efforts required to build natural history datasets that are both scientifically robust and practical for rare disease communities.

Together, the conversation highlights a path forward for advancing research in rare neurological diseases through innovation, partnership, and patient-centered trial design.

Host: 
Amber Burg, Therapeutic Delivery Head of Neuroscience and Ophthalmology at Fortrea 

Participants 
Louise Kearney, Executive Director of Cell and Gene Therapy at Fortrea

Hannah Simonds, Director of Patient Recruitment and Engagement at Fortrea

Karmen Trzupek, Senior Director of Scientific Programs, Global Genes

Transcript

SPEAKER_01 0:09

Welcome back to Cortex Conversations, our for Tria Neuroscience Podcast. Today's episode dives into rare neurological diseases where one of the biggest barriers to progress isn't always the science, it's data. Many communities still lack the high-quality natural history data needed to support external control arms or alternative trial designs. At the same time, traditional site-based approaches place a significant burden on patients and caregivers, particularly in pediatric and neurodegenerative conditions. I'm Amber Berg, therapeutic area delivery head at Fordria. In this episode, I'm joined by my colleagues from Fordria, Louise Kearney, Executive Director of Sullen Gene Therapy, and Hannah Simmons, Director of Patient Recruitment and Engagement. And we are also lucky to have Carmen Trupec, Senior Director of Scientific Programs from Global Genes, to explore how we can bridge this gap in rare neurological diseases, aligning regulatory expectations with the real world needs of patients, families, and rare disease communities. Together, we'll discuss emerging hybrid and decentralized approaches, the role of patient-driven data, and what it will take to build natural history data sets that are both scientifically robust and truly feasible. Let's get started. So, my first question is to you, Carmen. Many communities have investigator-led single-site natural history efforts. What are the inherent limitations of these, especially for external control use?

SPEAKER_00 1:43

It's a great question. And I think that there are inherent limitations to these kind of natural history studies that are done at a single academic site that kind of come to mind first. Um, those being that, you know, it's very difficult for many of these families to travel, especially if you have a child with a neurodevelopmental disorder or a child with a complex neurologic disorder where they have multiple disabilities, and travel is just inherently difficult for those families. So it places a real burden on them. Um, you end up with many inequities. You end up with geographic inequity, you end up with inequity related to who can really take time that much time off work for travel. Um, and then I think because of the the first point that I made, you also end up with inequity in your study population, right? Because like if your child is sort of sick enough or severe enough to warrant you putting in that much effort, but not quite sick enough or severe enough to prevent you from travel, you fall into that sort of perfect sweet spot where you might you might actually choose to participate. And so I think when you ask the question about and how does this pertain to control arm data, right? Some of that is particularly important. This idea that we're really only capturing the experience of the Goldilocks middle band, that's problematic. Um, in rare disease populations, especially, like we have to think about does the data that we have collected leading into these trials really reflect the entire population? Because you have to make these trials available to the whole population. This is not diabetes. You can't define like a narrow band of here's who's gonna qualify for our study, right? So that in some ways is is like to me the most problematic piece. Um, I'll also just mention before I stop, and because there's gonna be bound to be lots of other thoughts on this topic, that there is this issue that happens with these studies that they often last like five, six hours in clinic. For many of these assessments, if a child is cognitively able to recognize that, oh, I'm performing, right? So there's lots of there's lots of data in neuromuscular communities that show this. Like kids get there and they they're like, oh, I'm gonna do my best, right? This is like this is like excelling in PE class. I'm gonna do my best. But that has an impact, which is that kids who had who experience fatigue, kids with hypotonia, kids with neuromuscular or neurodevelopmental conditions, like putting that much effort in leads to pretty severe fatigue. And that fatigue is gonna last them the rest of the day and it's gonna impact other assessments, right? So these stacked natural history studies where you you ask someone to do so much in one day has inherent impacts to anything that gets put late in the day.

SPEAKER_03 4:56

If you're doing your interventional trial, maybe you've thought about that as well. Maybe you've gone to your investigator and you said, do this test first and this test first, because this one's our primary endpoint and this one is not so important. And it's that level of robustness that you see on interventional trials that maybe you wouldn't see in a single-site um um natural history study, in the fact that you may not be standardizing in the same way. And you also, yeah, you won't be thinking about that. You're doing it in the order that that makes most sense for that day as well. So I think there's some of that extra level of robustness that we put on interventional trials that you might not capture in that kind of trial as well.

SPEAKER_00 5:34

Right, right. But you have to think about it early enough for this for the design of the natural history study if it's going to be used as control arm data because it needs to be collected in the same order and in the same way. And and it's different for different communities. So I think it's really critical to understand the patient experience and the family's experience, because you know, there are some neurodevelopmental conditions where children are extremely hyperactive. And if I were designing a study in in a couple of those, I think I would put something really physically active first because you're gonna settle that kid.

SPEAKER_01 6:12

So these are really good points. And given, you know, some of the things that you guys have already talked about, Hannah, I'm gonna kind of push this over to you. This next question is what what principles actually should guide these so participation isn't asking too much of the families or these kids or um, you know, sites even.

SPEAKER_02 6:35

Yeah. I think it's important to remember within this that when you're looking at these rare kind of neurological conditions, these patients and these families often really want to help and they want to be a part of these trials. It's just making sure that they actually are feasible and we're recognizing those very kind of unique or individual challenges that they face kind of day-to-day. The solution to this, as always, is I would recommend, is to work directly with the patients that you need in your trial to kind of co-develop the trial with them and do that early engagement work, get them involved in those discussions as soon as you can, because no one knows more about what is going to be best for those patients and what is fair to expect from them than themselves things. So we know that this kind of this can change depending on the particular type of patient, as Carmen was saying, you know, they're they're not all going to be the same in terms of what works for them or what doesn't, or what's easier or not, um, depending on the severity of their condition, the type of the patient. We can't assume that what worked for one study is going to necessarily work on the next one. Um, if we kind of take some of those examples that Carmen just highlighted, you know, wearables are great when you're looking at things like real-world gait and mobility in adults who are more consistent with that. But it can be really, really challenging in kids who might run around or forget things or kind of knock devices. Um, equally, when we're looking at a lot of these neurodevelopmental fatigue is a massive factor in them. So we have to be careful with how we're designing the trial and what we're putting into the trial to manage that within those clinic visits and make sure that we're getting that critical kind of data first. So working with the patients will help us to understand, you know, what is the best way of designing it around them. And then we recognize that we, as always, need to then balance that with the requirements of the trial and what we need to collect from a data perspective to get the best solution. And there are lots of different ways that we can do this. Um, it might be early engagement with patient groups, working with patient experts who know these conditions really well, often for the pediatric conditions, that's parents and family members, or running kind of early focus groups and developmental sessions talking about different ways to approach the protocol and bringing together the patients with your investigators and often with some of your kind of research nurses and teams to look at the how we can come up with practical solutions in that.

SPEAKER_01 9:33

So, Louise, I have a question for you. Um, you know, as we're talking about a rare population, right? So logistically, sometimes that can be challenging for these patients and families. So for patients and families who can't travel for whatever reason, um, what end-to-end logistics need to be in place? So I think there's a couple of things.

SPEAKER_03 9:59

I think you have to look at what can't travel means for a stop. So like it is difficult to travel for some of these families, but um, we need to make sure that we're putting provisions in place to enable it whenever we can. So that's not just providing cash. That means um making sure that the the form of travel is going to work for that particular patient and their family, um, that we're making it as easy as possible from beginning to end. So maybe putting concierge services and that I think that is all really important to enable people to go on site if that's what they want to do. I think it's really important to know that um people don't always want things happening in their house. Sometimes they want their healthcare sort of separated out from um their home, which can be their safe space as well. But then if we're gonna measure things from within the home, I think we have to go back and you have to talk about the things that Hannah's just been talking about, about working with patient communities and seeing how well that's gonna work within how they within their lifestyle and within what they're able to do. Um if you need if it needs particular things, then they need to we need to provision. So if there's a wearable, we need to make sure that that wearable is provisioned and that also that the family understands how to use that um provision as well. Um so we have to make sure that um instructions are really clear and also that patients are and their families are aware of what they're consenting to and what data is going to be collected. I think um we're all used to having our phones on our wrists, but do we really know what's being said about our location to other people? Um and I think that's all right if we've made a decision to have that wearable, but if we're looking at a trial participation, we need to make sure that we are making uh that kind of information available and they understand exactly what they're doing. We have some, you have to think about where your families are gonna be living as well. So, do they have regular access to the internet? Some rural communities might find that more difficult. Um, so making sure that there are facilities in place. Um, is the RDRs is going to be uploading all the time or is that gonna happen at one particular point in time?

SPEAKER_01 12:05

It's a really good point. And, you know, all three of you at some point have talked about wearables. Um, and you know, I I know that that's one of the tools that is often put into place um to help these manleys, you know, be able to manage and us be able to collect this remote data. So this question is to you, Carmen. What is the current situation on wearables or any remote data endpoints in clinical studies? And where do you think we want to see this in the future?

SPEAKER_00 12:35

I think we wish we were a little farther along than we are. Uh, I wish I could list for you like the 10 studies that are most exciting that are currently ongoing that are using wearable technologies as a primary or secondary endpoint. I think the reality is what we're seeing is um lots and lots of interest from both um biopharma companies and patient communities to use wearable data. We are seeing clear willingness from the FDA on evaluating that data, but they are asking for side-by-side data for evaluation. So I think that's the that's the real step that we're in, honestly, is um we we need this data side by side with kind of traditionally accepted clinically uh collected data and patient-reported outcomes and experience data. Um you know, I think the neuromuscular disease communities um have been really leading the way, I would say, in um video analyses, especially and video assessments, which are sometimes paired with with a digital, a digital wearable, um, and sometimes not, sometimes it's just a video assessment. And so I think they're probably the farthest along. So when you look at like DMD, uh deshen muscular dystrophy or SMA, they've made some like real strides in this. I think when you look at communities um, you know, like neurodevelopmental disease communities where seizure activity is a significant unmet need in the population. And this is very common. There are many neurodevelopmental disorders where seizures are are relatively uncontrolled and there's a significant need. And measuring that in one-time bursts or even overnight studies in a hospital setting are just capturing a fraction of what actually happens, right? So there's a big push in those communities to start to collect that data side by side with other types of data collection, but doing like, you know, at-home monitoring using uh headbands that that have actually been shown to produce clinical grade EEG data.

SPEAKER_03 15:02

So come and I've got a question, sorry. It's just like what you've seen successes and and and tools that are really going to work. Who is it that's doing the work towards developing them? Because I know there's a huge, there's a there's a burden to making sure they're validated enough in order for regulators to be able to protect them. Like where is that, where is that role falling to? Is it it because it feels to me like it doesn't quite fit with the patient communities, but it also doesn't quite fit with the with the drug developers that are developing drugs for the indications either?

SPEAKER_00 15:35

Yeah, it's a fair question. Um, I mean, a lot of patient communities really want it, but wanting it and getting it done and getting it paid for are different things. And so patient communities are often very willing to lead the charge, but they don't have the resourcing to make it happen. So it is like this this three-part, it's always this three-part collaboration, I think, between the patient communities, the academic medical center that is running, um, leading these studies, and and ideally, hopefully, a biopharma company or more than one biopharma company in a in a you know kind of pre-competitive, very collaborative space working together. I I think where patient communities really struggle is when they're trying to really push progress in this area and they don't yet have a biopharma company that isn't vested enough to help support it.

SPEAKER_03 16:29

Yeah, you have to have that collaboration and you have to leave behind maybe some of the traditional concerns people have about sharing data and that kind of thing in order to push it off.

SPEAKER_00 16:38

I mean, the reality is that if they work together with each other and with the patient community, it's going to be a cheaper study. They're all going to get access to data that can be used and reused in clinical trials in ways that they'll understand the outcomes of that data that they otherwise wouldn't, right? Because if a competing company leads a trial and they're using like a semi-proprietary endpoint and the clinical trial fails, like that data is usually just gone, right? And nobody's learning from it. So it just makes sense.

SPEAKER_01 17:14

So, Louise, this next question is directed at you, but everybody, you know, feel free, feel free to jump in. Is why does the FDA really require patient-level data for external control arms? And what does acceptable quality look like in practice?

SPEAKER_03 17:33

I mean, so the gold standard that you've got is that you use a placebo and that you have a placebo controlled study or a best standard of care controlled study. And that's the gold standard that we see in clinical trials generally. Um, but that's not always possible, especially in um some of the trials that we run, mainly if they're gene therapies, or if you're looking at a um at uh something that's hard to blind, or you're looking at a degenerative disease where it's not ethical to run sort of placebo studies on these patients as well. Um and I think there is a uh there's an acceptance that that's the case, that people sometimes can use placebo and they can't, sometimes they can't. But what we see in some of these diseases is that the pathway for a patient is not a straight line. It's not we start at this point and we go uh straight down and then it girls and we get worse and we get worse. What we see is that patients, um, they are pediatric patients that are developing, so they will be getting better at some things as they develop and get stronger, but then their disease state might mean that that's getting worse. And so that makes kind of like a wobbly line of what your disease is like. Um and and sometimes it's not status. Sometimes we don't know the reasons why some patients do well and other patients don't do well. Um, and so that's the reason why you really have to have that control in order to look at um for this patient population at this time um what is the overall sort of progression that you would expect. And I've seen sometimes you see patient matching where you use patients that you use the same patient and you just use the same data, you have a natural history study, and then you go, and that allows you closer patient matching as well. Um, so that's where they really ask for it, and sometimes it can be difficult to achieve what is wanted. I think the data standards that we an acceptable quality, when we run a natural history study that's going to be used as an external control arm for an interventional study, we're using the same level of robustness as we would do for that interventional study. So if something needs standardization then and adjudication, then it needs to happen in the control arm of the study as well as that that's being treated. So what it often looks like is maybe two parallel studies running at the same time, or one after the other, uh, but patients being asked to come in and do those six-hour days, even if they're not having treatment, and go through all the rigmarole and the data is just clean, just as it would be for an interventional study. So I think sometimes sponsors can think that the natural history study would be an easier study to run. But actually, if it's gonna be data that the FDA is gonna accept, it's gonna be pretty on a par to the to what you're doing with the interventional study.

SPEAKER_02 20:21

I think one of the challenges with that in a natural history study is that often when we're looking at these studies and these designs, we're assuming a lot of it is standard of care and it's gonna happen anyway. So we don't automatically think about how we as the study need to be supporting the patient or those families because they're coming to sight anyway, or well, I have to have that blood test, or they have to do this assessment, and we'll just collect the data. But the more that we're trying to regulate that to get a consistent control arm, or even just because we are also requiring that as part of our study data, we should be recognizing that that's no longer just their standard of care. And that is a commitment that they're giving to the study and making sure, as you said, we then put the travel support in, we're offering that reimbursement, we're helping them with the home health or provisioned devices because it's something that we need as part of the study, not just their standard of care, which will enable them to, you know, not only participate for that one visit where they're there and they're engaged and everything's great and happy to provide the data, but do that consistently for us to actually get that control data for the trial as well. Um, so I think there's a slight mind shift sometimes when we're doing that early planning on the studies of really looking at, you know, it's not just standard of care anymore, even though, yes, it probably would be happening anyway.

SPEAKER_01 21:59

And I'm gonna go. To the final question, and I'm gonna throw this out to all of you is where does a CRO like Fortria add the most value? Is it regulatory navigation, data quality governance, logistics? Where can Fortria or a CRO like us really add that value?

SPEAKER_03 22:21

I mean, I think that we we see a lot of these trials. I think that's one of the things, and they may not be exactly the same um indication, but they we can see the patterns to it. So I think a CRO um can be really helpful in the fact that we've seen what has worked before and what hasn't worked before and where burden can is gonna be pushing over the edge. So I think when it comes, I think one of the things that CRA can really offer is sort of um in your protocol design stage, like thinking about what to look at and how you might want to change your design ahead of when you're approaching sort of patient groups, so that you're not coming out with something that's completely off the wall. I think because we see so many of these studies that that we can really help set the baseline right in the first place.

SPEAKER_00 23:10

I think that's right. You know, we were just talking earlier about how so much data, especially that comes from clinical trials that um aren't, you know, kind of quote unquote successful and move forward, that data just gets lost. But that doesn't mean that the experience is lost, right? So we need organizations that have the experience of seeing um big and small uh successes and failures to be able to share. You know what, we've seen this before, it didn't work. Let's explore, let me explain why and let's explore how we could do it differently.

SPEAKER_02 23:48

And I think when we see those the natural history almost be treated as the run-in, it's those remote and those kind of wearable digital, kind of alternative, let's say, solutions that are put in as the exploratories, that are put in as the, well, we'll add them, we'll try them, we'll see if we get the kind of quality of data that we need so that we could pull them into the interventionals. So they're not so much being used as ways to reduce the burden at that stage, because they're added on top of everything else anyway. So I think as the confidence and the experience in that grows, we will start to see that more being used as a replacement rather than kind of extras. But it's again, it's these things that it's important to recognize. And I think, Carmen, to your point, like if those are they're too intensive that they drop off after one or two visits, but you also have these families where the unmet need is so high and the desire is so strong to get to those treatments and to be part of something that they will kind of go through it and they will commit a lot with the potential to get into those investigational trials and things at the end of it. And they will do that essentially at their cost at that stage if that additional work and travel and commitment is not being recognized purely out of the need within these patient groups. So I think the more that we can do to support them through that, again, yes, they might be willing to, but is that really fair to be asking as well?

SPEAKER_01 25:21

Thank you everybody for your time today and sharing your perspectives on what is a complicated and nuanced area. What's clear from this conversation is that improving natural history data in rare neurological diseases isn't just a technical challenge, it's a human one. By designing studies that respect patient and caregiver realities, embracing validated remote and hybrid approaches, and engaging regulators early, we have an opportunity to generate better data and ultimately better outcomes. At Fortria, we believe progress happens when science, operations, and patient experience are designed together. Thank you for joining us, and we look forward to continuing the conversation.