Designing Better Clinical Trials for Brain Injury Patients | Patient Advocacy Part 2

There is still no standard treatment developed specifically for concussion.

In this episode of Rupture: The World of Best Guessistan, Wendy Lurrie continues her conversation with clinical trial experts Kelly McKee and Mindy Cameron to explore why that is, and how clinical research could better serve people living with traumatic brain injuries.

From decentralized clinical trials and home visits to caregiver support, accessible informed consent, wearable technology, and patient-centered study design, this discussion examines how reducing patient burden could improve both participation and scientific discovery.

If we want better treatments for brain injury, we need to stop asking patients to adapt to research and start adapting research to patients.

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Transcript

SPEAKER_01 0:00

Welcome back to Rupture, the world of Esgastistan. I'm Wendy Lurie. Participating in a clinical trial is demanding, and that's true for just about every study. So demanding that the industry has developed language to describe it. The language is a patient burden. And that should say a lot. But what happens when you're dealing with a population that's already facing so many challenges? Sensory, cognitive, speech and language, memory, physical, emotional, all of these challenges, which by the way, is a good description of people with TBIs. So what today's conversation is, is actually a thought experiment. With two experts in clinical trials, we're going to imagine a hypothetical trial for people with brain injuries to develop therapeutics for brain injuries and ask the question: what would we change? What could we change? What should we change? Here's that conversation. So in this part of the conversation, this is a hypothetical trial. This trial does not exist. But researchers are looking, let's say, for a new therapeutic to help people with traumatic brain injuries. And let's keep that at, I hate this term for so many reasons, mild TBIs, which are concussions, right? And we've had a lot, I've had a lot of discussions with a lot of people lately about the whole the language problem of mild and all that. But let's this is not for people with severe TBIs, okay? But there's a huge population of people with concussions. And let's assume that there's some pharma company that's working on something that could help, and they need to recruit patients who have brain injuries into these studies. And they don't want to just recruit them, they need to retain them with the hope that maybe on the other end of it, something will come out that will actually stand as a standard of care. Because there really isn't a standard of care in concussion. There just isn't. By the way, all the drugs that are used in concussion are repurposed migraine meds. There are no therapeutics specifically for concussion. So when you think about, let's just think about it. I mean, Mindy, you were talking about the travel and the burden, right? And there's there's a lot of that that's baked into a trial. And now you have a population that has an incredible diversity of symptoms, right? No two people with TBIs have the same symptoms, which is a problem by itself. But some of the common ones are, you know, there are executive function issues, there's cognitive overload, there's fatigue, there's the phrase I hate brain fog, there are memory issues, there are sensory issues, right? I mean, the long list of things that make it very, very challenging for someone with a brain injury to even consider. So, I mean, the idea of being in a clinic setting with the harsh lights and all the noises to someone with a concussion is like it's it's really, really jarring. And people with concussions, brain injuries in general, can't predict how they're gonna feel the next day, right? So it's like you can make plans, but you don't know if you're gonna be able to keep the plans, and there are all of these things going on. So, oh, and and I'll get and the back to the sensory thing. If you have a lot of visual issues, reading is really hard. Like I hear you talk about informed consent and four and uh you know, 40 pages. And I know as someone with a concussion, I can barely read a page of text. It's really, really, really challenging. What can we do to adapt as any aspect that's possible of the trial to make it easier for people with these brain injuries to join and to stay?

SPEAKER_02 3:43

So I work a lot with kids and kids, and I also work a lot with people who have physical disabilities and some cognitive disabilities too. So those are all things to consider, along with things you might have that are unique to brain injuries. Be prepared for all these patients to have a caregiver care that bringing that person into a trial with them, somebody they trust, somebody that they know, somebody that knows their partner's limitations, whether it's your kid, your spouse, your you know, your parent. Um, I think in a lot of neurocognitive stuff, you've got parents, I mean kids bringing their elderly parents in. So always be prepared for that caregiver from at a trial site. Make sure they're comfortable too, because a lot of times people even need two caregivers if you've got a like a physical mobility issue. So caregiving is one, making it easier on the patients, sharing data with sharing anything that you can with their regular health care team, and then actually really thinking about how we can bring these trials closer to the patient. You can either you can think about local labs so they don't have to be coming, they don't have to be traveling to a site which may be hundreds of miles away. They could get some of their stuff done at a local lab, or even better, if if some of their visits or all of their visits are happening in their home.

SPEAKER_01 5:04

This is the decentralized clinical trial proposition, right? I mean, what can be done without making people go to a site that can be what, two hours away, require a plane ride?

SPEAKER_00 5:16

Two hours, plane rides. Yeah, absolutely.

SPEAKER_01 5:19

So and what is a decentralized clinical trial?

SPEAKER_00 5:22

Yeah, so in a direct-to-patient model, the clinical trial comes to the patient's home. The physician is uh providing virtual care uh via a computer just like we're talking on today. And then the eyes and ears of the physician are actually the research nurse who travels to the patient's home. So these are not home health nurses, these are research nurses who have been trained, passed tests, and are fully qualified to provide patient care at the home. So the the nurse comes to the home, all of the drug and shipments, any supplies are sent directly to the patient's home. And then the doctor is providing medical oversight virtually. We've seen that this model opens up the entire country so more people can participate rather than people who live in close proximity to a major, you know, metropolitan area or where the investigator study sites happen to be. So that's one way that we can make clinical trials easier. We can also make clinical trials easier by limiting the number of visits, limiting the number of procedures to those that are only necessary to show that the treatment is safe and effective. Sometimes, oftentimes, we get these brilliant doctors who are actually designing the protocols who say, Well, I want to look at this and I want to look at this and I want to look at this. And suddenly your five-visit study of 30-minute visits becomes 15 visits of three-hour long with additional procedures because the science is so amazing, but it comes at a price, right? It comes at a price of burden. And we see that that's really hard on patients and that patients may be more likely to drop out. I think another way that we can make trials better is by paying participants for their time.

SPEAKER_01 7:15

And so explain that because I don't know if people are familiar that there's any kind of compensation account at all.

SPEAKER_00 7:23

Traditionally, clinical trials were done out of the goodness of patients' hearts. So they had to travel to the sites, they had to take their time off of work or school or caregiving responsibilities because they were receiving the clinical trial procedures and treatments free of charge. But it's really hard to take off a lot of time off of work. It's really hard to get child care. Gas is super expensive and seems to be climbing every single day now. So we're seeing more and more sponsors, rightfully so, giving patients what we call patient visit stipends. So an amount of money that will cover that time and cost of travel. When you're going to the informed consent, you know, Mindy said sometimes a caregiver is needed, sometimes a translator is needed. Sometimes the informed consent needs to already be translated into the language. Not everyone in America speaks English. We are a melting pot. And also some people are auditory learners, right? So if you have a traumatic brain injury, maybe it's easier to actually listen to the informed consent rather than read it.

SPEAKER_01 8:30

I was actually going to ask you that because I know for me and for a lot of people in my position, I mean, I listen to the articles I want to read more than I read them. I mean, I will opt for audio in every case where audio is available. So that was actually one of my questions is could a lot of this informed consent be handled through audio?

SPEAKER_02 8:47

Yeah. I think it's also really important to think about electronic consent, letting a patient, especially with like a traumatic brain injury or somebody new to research, let them take that home and really study it, take their time looking at it. Another thing that has occurred to me over many years of participation is the there's something called PROs, patient reported outcomes. These are usually questionnaires. Some of them are quite lengthy. I hate doing them in clinic. I hate doing them at a visit because you've got all this overstimulation happening, you're a little bit nervous, you might be upset a little bit. There's nothing like seeing disease progression, like going to your trial visit. You know, they're measuring how you're doing compared to last time you were there. And in a neuromuscular disease, my son has Duchenne muscular dystrophy, which is how I got involved in all this. You're actually kind of measuring decline sometimes. So the last thing I want to do is sit down and answer questions about changes since last the last visit. I would rather do those at home in my own time, maybe in my own private space where my child's not there watching my answers, because sometimes these kids are asked to take the same questionnaire and they kind of want, how did you answer that, mom? Well, it doesn't matter how I answered it. They they really want to hear from the kid. So having the ability to do those things in the comfort of your own home is really important, in my opinion.

SPEAKER_01 10:07

That makes a ton of sense. So, Kelly, when you were talking about, you know, the nurses coming to the home and you're basically bringing the trial to the patient. What percentage of trials are running that way now? Like is that is this a new thing? Is this happening? Is it a wave that's happening to all trials? Like, where are we in that curve?

SPEAKER_00 10:24

Not enough. So this is, it's, you know, we've been doing this for a number of years, but we're seeing an uptick now, as we should, right? So I'm hopeful that in five, 10 years, we're seeing that the majority of trials are offering some flexibility. The company that I work for, Science 37, works, you know, in all 50 states. We have physicians who are licensed in all 50 states and research nurses within about an hour and a half drive of, I'm gonna say 90% of the you know, nationwide population. If we want to bring drugs to market faster, we have to make it easier to participate. And that's this is one of the ways that we can do that.

SPEAKER_02 11:08

And the hear so much about, you know, nobody's enrolling in the trial. Well, that's usually because it's hard. So if you make it easier, you can get I think what Kelly said about diversity of the of the study population is very important as well. Think about if you had a if you had somebody coming to your home to do your study visit, you could probably still work half a day. You could still go to school half a day. You wouldn't need to trial, you're not gonna miss out on your entire workday, your entire school day, your entire school week sometimes. If you're traveling by plane and you've got to be fresh as a daisy the next morning, you're you know, you're thinking about one travel day, one trial day, one travel home day. Who can do that? Who can take three days off of anything in in modern life? So it's unsustainable. And patients may think it's oh, uh, this will be no problem to participate. They get they get six months in and like, I can't take any more time off work. I'm gonna have to, oh my God, drop out of the trial, which is terrible. That's terrible for them. It's terrible for the sponsor, it's terrible for the field, it's terrible, it's terrible for scientific discovery. Drop out, dropping out of a trial is, in my opinion, one of the worst outcomes that a that a sponsor or you know, any kind of disease indication could have because you've got somebody that's committed to it, and then they get in there and they're like, this is too hard. I I have to stop. And then they have to find somebody else to take that spot and start from square one. And that's why trials take so long as well.

SPEAKER_01 12:37

How how much churn is there? I mean, I I'm sure it varies by by disease and by a lot of other things, but how high can these churn rates be?

SPEAKER_00 12:46

They can be very high. If a study is not properly designed and very hard on patients, then you know you could see the majority of patients wanting to drop out or dropping out. Patients have the right to drop out as they should. And so it's really important that we design trials that meet the needs of the science, but also meet the needs of the patients. So some many trials over-enroll because they anticipate that a certain number of patients will drop out, but sometimes those estimates don't match up to what is actually really happening. So if we design trials from the beginning that are more patient-friendly and easier to conduct and either, you know, done in the home or close to the home, then you're gonna, you know, most likely see more patients uh complete the trial.

SPEAKER_01 13:34

Right. I had just for my notes, put the question this way instead of asking how do we make patients fit the protocol, what if what if we ask the question, how do we design protocols around real patients?

SPEAKER_02 13:45

Exactly.

SPEAKER_01 13:45

Perfect.

SPEAKER_02 13:46

Yeah, that's the idea.

SPEAKER_01 13:48

That that is the idea. So, okay, so sensors can help, right? Because that that will reduce the number of visits to the site.

SPEAKER_02 13:56

Sensors are are very helpful. They also produce a lot of data. And sometimes the data I I personally believe that we need electronic diaries connected to these sensors so patients can actually maybe record something that's happened. Because I think there's a lot of data that comes off sensors, certainly with like blood pressure, heart rate, those kinds of things are probably consistent. But we do a lot of activity monitors in the diseases I work in, and there's a any host of things that could could be a factor in why a patient may be moving differently on a on any given day. So I think we need to use sensors, but we also need to tie them to to what's happening in the patient's life. You know, are they sick? Did they fall? Did they have an injury? What why were they not moving around so much on a given day? Maybe they were working and sitting at their desk. So I just feel like sensors are great, but there is scope for missingness in data from them. And we need to be better at correlating what's happening in the patient's life to what these monitors may be recording. I've I've worn heart monitors before. You know, if you feel something, press a button. You know, so there's we have to we have to tie those sensors. But yeah, sensors are an amazing advancement. Can you explain maybe the electronic diaries? Yeah, so you have an app, or you know, you in uh instead of writing it down in a book, some some companies are still using paper diaries. Say that you had an adverse event or something that you think may be related to the drug, you jot it down. But from an activity monitor, I would love to see if you're wearing, we wear a lot of I shouldn't call them ankle bracelets. They're they're you know, actographs that you wear on the bottom of your leg because they're trying to measure how you're how you're walking, how far you're walking, are you getting tired while you're walking? Is your gait changing? And gait changes are hard to pick up, but as a patient with a neuromuscular disease progresses, their gait changes. So, and that's that's one of the reasons why somebody coming into the home and observing that patient walking, they're gonna see things that might not necessarily be picked up on the activity monitor. This patient is still walking the same amount of distance, but they're walking differently. They're they're leaning back, they're swinging their leg out, and that's that's progression, that's disease progression. And that's why to Kelly's point about these are research nurses, these aren't nurses that are coming into the home that don't know the disease. These are trained in the indication, they are trained in the functional outcome assessment, and they are they are standardized, they're they're reporting these in a standardized way. So you're gonna get the same information across all your patients. It's um when you get into movement disorders, there's a lot of complexity around everything's tied together. How patients moving is could be related to disease progression. And these are again, this is the difference between a research nurse and a home health care person coming in. Yeah, it's both important but different.

SPEAKER_00 16:55

A diary is really a questionnaire. It's not like dear diary, today I fell, right? Today I fell.

SPEAKER_01 17:02

Are you there, God? It's me, Margaret. Yeah.

SPEAKER_00 17:05

They're questionnaires because physicians and regulators like the FDA want to know how patients not only are doing by the data that's collected through sensors or through measurements, but how they're feeling. So are you feeling happy? Are you feeling sad? Do you hurt more? You know, do you think that your gait was the same as yesterday's, et cetera? Because the per our perception doesn't always align with what the data shows. So for example, if you wear an aura ring or an Apple Watch and it gives you a sleep score, you could wake up and say, Hey, I had a great night of sleep. But then if your sleep score says actually you got a three out of 10 or a 30 out of 100, there's a mismatch there, right? I would argue. Let's go with how you're feeling because that's how you're feeling. But the data shows, you know, different things are different. So it's really important that we are able to combine that quantitative, the data that's being collected, with the qualitative, how you're feeling. And one of the ways we do that is through these diaries.

SPEAKER_01 18:09

Okay, that makes that makes a lot of sense.

SPEAKER_02 18:11

Sometimes there's an outcome that that maybe wasn't in the protocol, that then that's where this patient experience data comes in that you hear a lot about now. And that and for good reason. And it's a wonderful advancement that we are looking more about, okay, maybe you didn't walk better, but you know, I I I I used my upper body. My upper body seems better. That's important. That might not be in the protocol. This is, you know, when you're when you're developing these advanced drugs and these rare therapies, we don't there's sometimes there's unknowns about how a drug is going to affect any given individual. And that all needs to be captured.

SPEAKER_00 18:45

Well, Mindy. Oh, sorry, just wanted to mention adverse events. So Mindy mentioned adverse events. Adverse events are anything that happens that's different than what you normally go through. They can be either adverse events or serious adverse events, and that's just how how serious they are. Whenever you experience that, you need to talk to your study doctor because then your study doctor is going to either, you know, make sure first of all that you're okay and you're receiving the care that you need, but then also report that in. So some adverse events actually aren't bad. They're good, right? So sometimes we're testing a drug for something like hypertension. And then it turns out that one of the adverse events is actually that it helps men in the bedroom. And so many of those drugs that lots of people take now were because of these events, adverse events that were reported during the hypertension trials. So it's really important that you maintain that communication with the study doctor and the site of, hey, this is what's happening to me, so that we know how the treatment is affecting.

SPEAKER_02 19:50

It's too bad we call them adverse events. Exactly. It's a little bit of a misnomer that you're calling that an Yeah, I hadn't really thought about it that way, Kelly. That's a good point. And and sometimes this goes into how regulators look at benefit risk. Yeah, you know, I bruised a little bit easier, but boy, I I I was less tired. I was moving better, I felt better. So that are there's a you know, a little tiny thing that maybe could or could not be. Sometimes these things are not related to the drug. I think that's an important distinction. Sometimes these are just things that have happened, and you'll hear in when a study reads out, you'll say the investigators felt this was not related to the study drug. So there's always it's always important to pay attention to that. But sometimes there is uh, I see this all the time, there's something that is different in in a slightly negative way, but the outcome far outweighs that. So that's what we talk about when we talk about benefit risk.

SPEAKER_00 20:47

When you watch a commercial for the drugs which are on all the time, you know all of those symptoms that they list at the end, like oh my god, yes, everybody knows.

SPEAKER_01 20:57

Yes.

SPEAKER_00 20:57

That comes from clinical trials. So everything that anyone reported at any time is listed, and so that's why it seems so crazy.

SPEAKER_01 21:07

Yeah, the list is endless, yeah.

SPEAKER_02 21:09

Yeah, yeah, that's a good point. I have two not related at all to the drug.

SPEAKER_01 21:13

It's that's also true. Two follow-up questions on what you guys were just saying. One is we talked about like maybe putting some of the informed consent consent information on audio and things like that, but in addition to that, can it also be turned into plain language? Because it is very intimidating.

SPEAKER_00 21:27

Yes. It should be at like a fifth grade reading level or below. Most of the times it's not, and it's something that we need to work on.

SPEAKER_01 21:35

Yeah. And the other question is all of these things that we're talking about, whether it's the nurse, the electronic diaries, the sensors, all of these things that reduce the per the patient burden, who makes those decisions when they're designing a trial? Who of all of the players that we talked about is actually inputting with this population, these are the things we need to think about. Just as I said that my concussion pain kicked in. Wow, that was universal. But who's who's making those decisions? Decision, those recommendations and those decisions?

SPEAKER_00 22:02

Ideally, it should be all of those three groups. So it should be the sponsor who's designing the study. It should, they should get input from the sites who are taking care of the patients in the study. And patients should also be involved in the design of studies. We're seeing this happen more and more, but it's not happening all the time. And then I would also say that it's important to note that there are things called IRBs or institutional review committees or ethics committees who are responsible for reviewing a protocol and everything that's patient-facing to ensure that it meets the rules and regulations and is appropriate for patients as well. So there are lots of safeguards and they review the protocol. But an ideal protocol really involves all the players. So patients, sites, and then of course the physicians and scientists at the sponsor site, at the sponsor company.

SPEAKER_02 23:02

And I always think it's important to bring in, you know, that patient voice early because sometimes you're, you know, that's really going to help you determine endpoints that matter to patients. I you see it all the time, endpoints that really aren't making a significant difference in a patient's life. So it's very important that you understand your population. Patient advocacy groups can be a really rich source to go to. They they can connect you. I think it's important to talk beyond those patient advocacy groups, though you need to talk to real patients who are do, you know, living life with these conditions. You need to be able to reach patients that aren't connected to a lot of knowledge. We talked a lot about how decentralized trials can bring trials into rural settings and places that typically people aren't participating in clinical trials because there are that's hard to get into a site. And so you need to be talking to those patients too about their challenges and participation. So you can get you can get it right and you can get a wide range of patients participating because that can be important when your drug goes up for review, and it can be important when your drug goes up for reimbursement.

SPEAKER_01 24:05

Yeah.

SPEAKER_02 24:05

Who's paying for it?

SPEAKER_01 24:06

That's what tends to matter most of all.

SPEAKER_02 24:08

Yeah. Well, there's nothing more frustrating than there being a therapy available and you not being able to get it because your insurance won't pay for it. Or your Medicaid or Medicare or whatever. Whatever the payer is, yeah. Or your or your national health authority. We're seeing this a lot in rare. We we thought getting these drugs across the finish line and getting industry interested in developing them was going to be the hurdle. Now we have a whole new world of hurdles with access and reimbursement. So these this can be an important part when you're thinking about how your trial was designed. And if you if you're going into the home and patients feel more comfortable and you're getting better outcomes because patients are more at ease and they're they're not dropping out, this could be it's all it all piles on top of each other, all these different things.

SPEAKER_01 24:53

Okay, final question. Given the long list of TBI symptoms I rattled off before, which isn't even doesn't even include all of them, and one I forgot to mention was speech and language, which is a huge one. Are there any other parts of the trial that you think could be adapted to make participation easier for people in the with with this basket of symptoms, this panoply?

SPEAKER_02 25:15

Well, getting them into sites is I think is the number one thing. And because you say there's so much variability, and I'm sure there's there's um probably there's probably movement you know issues related to that too. Caregiver support is big. Being able to do things at home, uh especially the PROs. You get a you get a person with a with a brain injury or a neurocognitive problem, and you take them out of their home environment and you're asking them a bunch of questions about how they're feeling, you're gonna get a whole different set of answers, potentially.

SPEAKER_01 25:44

That is absolutely true. Absolutely true.

SPEAKER_00 25:46

So more things about longer visit windows so that if a patient's not feeling great, she can reschedule and still be in compliance with the program.

SPEAKER_01 25:55

That's a great one, too. That's a good one. Yeah, yeah, yeah. Thank you. I can't thank the two of you enough for joining me today and sharing all this expertise. And I think this is gonna be really useful and interesting to our listeners. And I just wanted to thank you. Thank you.

unknown 26:10

Thank you.

SPEAKER_01 26:11

Thank you. And if there's a trial for brain injuries, we're gonna all jump on another call.

SPEAKER_02 26:16

Sounds good. Yeah, I can imagine that's it's challenging. I'm gonna be thinking about that.

SPEAKER_01 26:20

It is it's very challenging. And as I've mentioned, and Kelly and I have talked about this before, every time I look at a farm at the pharma pipelines, I'm like, why is there still nothing? You know, you know, where is the work? So we need a lot of work.

SPEAKER_02 26:31

But this is we used to feel that way in in Duchenne muscular dystrophy. And now that now that we got once it seems like once you prove, we have I'm working in a lot of areas where we're getting our first approval and an indication, and you'll find that once there's a drug approved in your indication, a lot of times it's like a landslide after that. You have to kind of prove that this indication is worth pursuing, that there is a market for it, that there is it's a viable commercial product. And I think once you prove that, and we've done that in Duchenne, we have dozens and dozens and dozens of companies working in the space now. But it took, it took a couple of approvals to get to kind of whet everybody's appetite. Uh yeah, this is this is something worth pursuing. So something like that. Not I guess I shouldn't have said worth pursuing, but something that is it's possible. I mean, there's a I'm sure there's a huge variance, and this is I'm sure it's one of the challenges in working in this indication.

SPEAKER_01 27:24

Absolutely. Absolutely. It's a very, very challenging condition for a lot of reasons. Thanks for joining us for this week's edition of Rupture, the world of best guestan. Today's episode took us inside a clinical trial and featured Kelly McKee and Mindy Cameron. To hear more stories and to support our work, the best way is to subscribe to our YouTube channel. Until next time.