Dr. Emily Largent: Making Clinical Trials Better for Participants

With research for the recently FDA-approved Leqembi still in clinical trials and other Alzheimer’s research ongoing, many are considering whether to be a part of the research. While some participants, like Live Talks guest Gordon Van Slyke, have positive experiences with clinical trials, some participants don’t feel fully supported or heard by centers running trials. 

With many trials ending early, some researchers are investigating how trials can treat participants better and support them through the process. Dr. Emily Largent is the Emanuel and Robert Hart Assistant Professor of Medical Ethics and Health Policy at Perelman School of Medicine at the University of Pennsylvania. In her recent study, she examined some of the critical reasons Alzheimer’s clinical trials can end early and some fundamental approaches to improving the trial experience for participants. 

Her work focuses on neurodegenerative diseases like Alzheimer’s, and she focuses on the social, legal, and ethical aspects scientists should consider when research findings are applied to care. She joined Being Patient Live Talks to discuss this research and how more trials could put participants with Alzheimer’s first.

Watch the full conversation, or read a transcript from the conversation below.

Being Patient: Someone once told me that, in the Alzheimer’s world, almost 85% of trials are not filled to capacity. Is that accurate?

Emily Largent: It’s a huge barrier to completing studies. It’s very difficult to identify people to recruit into studies, and retaining people in studies can also be a challenge. I would say that it’s really a huge problem.  It slows things down a lot, and it can lead to trials that aren’t as good at answering the scientific questions we’re posing. It can take a lot of resources that we all know are essential to continue moving research forward. When we have studies like this, I worry, too, that we are exposing participants in those studies to risks where we don’t have the benefit of everything we could learn. So, it is a real problem.

Being Patient: What was the motivation to take on such a study? In addition, what problems did you think this information could possibly solve?

Largent: At Penn, I’m part of the Alzheimer’s Disease Research Center that we have. I have the opportunity to see what’s happening with a lot of the clinical trials that are being conducted there. We were seeing in the 2018-2019, sort of time period that there were a lot of trials that were ending early in the Alzheimer’s space. I’m sure that folks who are joining us are familiar with some of these big trials that ended. They were ending for a variety of reasons, right? Sometimes for futility. So for analyses, people felt like they couldn’t answer the relevant scientific questions, even if they kept going with the trial. Sometimes, unfortunately, for harm. So, there were safety reasons that said, “we need to pump the brakes on this study and end it.” 

Like others, I was very disappointed to see these trials ending. What really stuck out to me and what motivated the research is that we had a chance to talk to participants who are coming in after these studies ended. They were telling us how difficult it had been for them when their studies ended. You know, they had invested a lot of time and a lot of hope in participating in research. Unfortunately, some of them were finding out that the study they were in had ended, not from the research site, but really just through scrolling on their smartphone through the news, or even sometimes a call from an adult child who’s like, “Hey, I saw the news this morning.” That’s how they learned the study ended. We felt like that was really not the kind of respect that we want to treat participants with. So, we tried to figure out how to do a better job.

Being Patient: It’s funny because I always make a joke with my team that I feel like we’re filling in all the gaps for people. You know, because once they’ve finished a study, and they don’t know what’s going on, we’re kind of providing them with that information. We’ve actually gotten questions from our audience about the consent forms in particular because they can be really complex. So, did you find that at all? We’ve had multiple comments from people saying that they thought they were going to learn more about their status in the disease, but they didn’t hear anything.

Largent: So, I think you’re touching on sort of two hot-button issues. One of them is really about the consent form. What do people understand when they’re participating in research? There have been years of research on trying to make consent forms better and easier to understand, right? I have a law degree and sometimes don’t feel like I understand what’s happening in the consent forms. I think a lot of science can be in there, and they’re not always written as eloquently as we might like. That is one piece of it. We have to do a better job of communicating key information to people.

The other part you’re touching on really is about the return of results. This has been a fascinating moment where I think there’s been increasing pressure from participants in research. You say, “this is valuable information to me, and to recognize my contributions to research, it’s important that you share information about me and my brain with me.” At Penn, we’ve really been at the forefront of this, thinking about how we give back information that matters to people. 

Being Patient: Are there compliance issues that prevent the sharing of information? Is that why it doesn’t always happen?

Largent: So, sometimes there really are barriers in terms of how the testing was conducted. It can come up with certain lab results that need to be through what’s called a CLIA-certified lab. This is a certification the lab has that has not just a research quality result, but it’s thought to be something that’s clinically validated, and you can get that information back. So, sometimes you’ll see results withheld just because the level of confidence in the result is not the same as a CLIA-certified result. So, people don’t want to share those. There are also some fears on the part of investigators around returning some of these results. Amyloid is an example of this.

“We have to do a better job at
communicating key information to people.”

There are a lot of people who may be participating in research, who undergo an amyloid PET scan, and they’d like to know what their result is. For a long time in the field, there were real debates and controversies amongst researchers about the appropriateness of returning that. The reason for that is that they were worried people wouldn’t understand the results if it was given back to them. Because it’s probabilistic, right? We know a lot about amyloid, and yet don’t always know what it means for the individual if they have amyloid or not.

So, there was sort of an understanding concern, there was a safety concern, there were a lot of people who were worried we would tell people, and that they might become depressed or anxious or other sorts of things. So they didn’t and weren’t interested in doing it in that respect. Then, sort of the third big concern is that we aren’t giving this information to people sometimes because what are they supposed to do about it? Right? We don’t have the kinds of treatments we might want for people to really make a difference in their brain health. So, if it’s not medically actionable, as the term that’s often used, then there’s no reason to give it back. But I would say there’s been pushback on all three of those arguments.

Being Patient: What did your research find in terms of what the biggest barriers were and what some of the solutions are that could be employed today?

Largent: In terms of our research, we really tried to break out the clinical trial process into three phases. We talked about it in terms of a pre-trial phase, right, where somebody’s trying to make a decision about whether or not participation is right for them. Then there’s the mid-trial phase. Are we treating people with respect throughout the process, where they’re coming in for their visits, and then when the trial ends? I think that you know, the commitment of researchers to participants shouldn’t end there. We still have this post-trial period where we need to ensure we’re treating people well. So, we want to think about all three of these, and our hope in our study was really to try to figure out what advice we can give to researchers that they can implement and make sure they’re paying attention to all of these parts of the study. So, we have recommendations around communication, participant support, and more communication. I think a lot of what it comes down to is: we need to just have much more open lines of communication.

Being Patient: So, face-to-face is always the best way, right?

Largent: We’ve talked to participants, trials, and study partners as well, and it was really important for us as we were doing this to collaborate with these individuals. We interviewed some folks to find out about their experiences and research, and all of them think that it’s really valuable to have a face-to-face conversation, or at least a telephone conversation where you’re really talking with somebody and getting feedback. 

It’s ideally a person that you trust and know from your research participation. They recognize, too, that sometimes there are limitations. Sometimes speed is important. So, you can have email or text messaging or other methods people are okay with, but as long as there’s a promise that you’ll follow up at some point with that face-to-face component.

Being Patient: I guess what surprises me is there aren’t better standards in place. I don’t want to criticize the field altogether, because you see wonderful examples out there of trial centers that almost become like family to patient-participants. So, there are people who are doing it right out there. But how do we standardize this? How can we move the needle to provide a better experience for the patient?

Largent: Trial sites, as you know, are just wildly different from each other. Sometimes people are participating in an academic medical center with all of the affiliated and associated resources and people who can be brought in. I think we’re really proud at Penn of all we do. We have a communications team, we have a social work team, and we have all these resources we connect people with. 

Sometimes people are actually just participating in more of a clinical trial center where all they do is research, and they don’t have the same resources that we’re able to have. They offer a different experience to people, and it’s still a great chance to participate in research. So the question is, how do we standardize? How do we think about things across these sites? 

I think so much of it will come down to the study funder or the sponsor, right, the pharmaceutical company that’s wanting to run the clinical trial, really setting standards and expectations. Building that into just the DNA of the trial itself that these are expectations is part of our contract with us that if you’re going to participate as a site, you’re going to do these things to help participants out.

Being Patient: There’s a great question that’s come in asking if there are any lists of clinical trial participant rights. Do you know if that exists and where people could find information like this?

Largent: I would say that there isn’t one that’s been formally endorsed by like NIA or other places, but the group Agreed Dementia, and there has been an effort amongst various members there to put together a participant Bill of Rights. It calls for things like better communication and better return of results. So, if you’re interested in these participant rights, I’d suggest looking at that organization to see at least some of what people are starting to argue for as being important to important things to offer to participants.

Being Patient: Someone in our audience actually just commented that a participant bill of rights was published in The Journal of Alzheimer’s recently. We also have another question. What are funders doing to fund clinical trials of participants and patients, or key stakeholders being part of designing the people part of the trial? Are there efforts by pharma and people running these studies to really improve the people part of it?

Largent: There’s a lot of necessary attention right now in the field of Alzheimer’s research that we need to have more participants and really more representative participants. This is because there’s been a lot of attention to the fact that we are not getting the full spectrum of people who are affected by the disease, and need to think about how we can bring more people in. So, there have been a lot of people talking about the science of recruitment, the science of retention. How do we do this? There is a big focus within those groups on the people piece of things. But I think it’s still in development. How do we really think about the soft skills piece, right? It’s not just about starting registries, which is a big focus and an important one, but it’s also really about how we treat people so that when they come in, they feel good about their participation, and they go out, and they tell other people that they should participate because of the great experience that they had.

Being Patient: So, what you’re referring to is the need for more diverse populations to participate in research, right? Has Penn undertaken any initiatives that we could all learn from to encourage more diverse participation in these studies?

Largent: We have, right now, a great community outreach coordinator who has been going out into our local communities and really trying to talk about research with people in our community. You know, like reaching out to West Philadelphia, which is a predominantly Black neighborhood. So, it’s a great way to reach out and try to do that. 

We’ve also just done some research, so not as much in our community, but trying to better understand what are the barriers to participation amongst diverse communities. Some things we’ve seen are just that there are issues around financial barriers to clinical trials. Most of the time, you do not need to pay to be in research, and yet, we can all recognize that you have to have the luxury of time. If you have to travel to the site, there are money and expenses associated with that. Potentially, if you need to stay at a hotel overnight or take time off of work, these all create financial barriers for folks. So, it’s been a big push of mine. I want to see that we have more reimbursement of reasonable expenses that compensate people, including study partners, for their time. Because a huge piece of what we talk about in the space of why we need to find better treatments for dementia is the caregiver piece. Yet, in research, sometimes we aren’t acknowledging the things we’re asking of caregivers. So, we should be compensating them as well. 

“Not all potential research participants have a spouse, or
somebody who can take hours off of work on a
Wednesday to come in for visits.”

I think another interesting aspect here that we focus on is the idea of the study partner itself, right? So, in a lot of these clinical trials, it’s not just the person who has Alzheimer’s disease, but they need to have somebody, a friend, or a family member who comes in with them for some of their visits. That person is really essential scientifically, I think oftentimes because they provide information about cognition and function that the researchers use to understand how things are working. I would also say they’re just very important, providing emotional support for participants, and they provide logistic support driving in. Some people will tell us they hate driving into Philadelphia to come to visit. So, I totally get that. So, the study partners are critical. 

It turns out that most of the time when you ask people, “who is your study partner,” they point to a spouse or they point to somebody who’s retired because they have time. The reality is that not all potential research participants have a spouse or somebody who can take hours off of work on a Wednesday to come in for visits. So, we’ve really been pushing to have more flexible approaches to the study partner. Can we have visits on nights or weekends? Can we go to virtual visits if we’ve learned anything from COVID? I think telemedicine can be really effective. I would say that I think study partners really do affect the representativeness of research because of the requirement to have somebody come in with you. That’s part of why we see populations that are, you know, wealthier, whiter, more educated.

Being Patient: If we can’t rely on every single center to do best practices when it comes to this, is there a checklist for patients to ensure they get the best treatment possible?

Largent: One of the important things in the group that I was part of was that we really did want to talk about self-advocacy. How can we empower participants to really speak up for what they need and ask for things? I want to say that we don’t want to put the burden on participants. You guys are already committing a lot in terms of time and resources. So, this should be something that the research community is working on also. But, you know, insofar as you’re thinking about participating, it’s really important to understand things around the consent process, right? What are the requirements for the frequency of visits? What kind of intervention am I getting? Will I be randomized? Will it be a placebo or a drug? Or is something else happening? 

We see that there are a lot of times there are misunderstandings around whether or not people are always getting the drug. So, that’s an important thing to think about, are you or aren’t you getting it? Additionally, right, asking specifically, what results will I get back? That’s a huge piece of things. And, you know, and that includes all kinds of results, right? Is that genetic testing results? Is that biomarker results? Is that cognitive testing results? And at what frequency? Will I get them back? And then, if a trial ends, one of the things we’ve called for is a closeout. Meeting, we think that’s a really important idea. And then it’s important to ask questions like, when will I be unblinded and find out? Was I on the treatment? Or was I on the control? You know, are there more results coming back to me? And is there anything else that I need to do or know about participating in future research studies?

“One of the important things in the group that I was part of was that we really did want to talk about self-advocacy.”

Being Patient: What would the ultimate gold standard treatment be post-trial? What should it look like, and how long should it take to be followed up with?

Largent: One of our big recommendations was really to say that we need to see that there’s more funding. Sometimes, as soon as the trial ends, funding runs out. So, what we wanted to see is that funders would offer more money in their budgets for an orderly trial closeout so that you really have a dedicated person who can continue to support participants in the post-trial period. 

One of the things we call for is a face-to-face, whether in person or on Zoom, right, but this idea that you have a dialog that is the closeout where you give people the top-line results for the study if they’re available. You tell people about their own, you know what you were assigned, and you tell them what their results were. Then, that should also include a chance to say goodbyes to the study team because of the relationships that have been built over time. 

People told us that was really important. They wanted a chance to give feedback on how things went and also to say goodbye to people who have become really important in their lives over the months or years of research participation.

This interview was edited for length and clarity.

Katy Koop is a writer and theater artist based in Raleigh, North Carolina.