AGS Alzheimer’s Disease: New Diagnostic Technologies and Treatments Podcast

Advising Patients Who Are Underrepresented in Clinical Trials: Applying Care Equitably When the Evidence Is Not Inclusive

• American Geriatrics Society • Season 1 • Episode 7

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Join Dr. Michael Harper, Professor of Medicine at the University of California, San Francisco; Dr. Sharon Brangman, Professor of Geriatric Medicine, Chief of the Department of Geriatrics, Director of the Center of Excellence for Alzheimer's Disease (CEAD), Director of University Geriatricians, and Chair of the Department of Geriatrics at SUNY Upstate University Hospital; and Dr. Alejandra Sanchez Lopez, Assistant Clinical Professor of Neurology and Geriatric Medicine at UCLA, as they discuss Advising Patients Who Are Underrepresented in Clinical Trials: Applying Care Equitably When the Evidence is Not Inclusive.

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Michael Harper:

Hello and welcome. My name is Michael Harper. I'm a geriatrician and uh faculty at the University of California, San Francisco, where I'm a professor of medicine. And I'm really pleased to be moderating our podcast today, which is part of a new series from the American Geriatric Society's based on a new educational curriculum titled Alzheimer's Disease: New Diagnostic Technologies and Treatments. And we designed this curriculum for both experienced clinicians and geriatrics fellows as they navigate this changing landscape around both the new diagnostic tools for Alzheimer's disease and also some of the emerging treatments. We really feel it's important that we prepare our members and our trainees for this new world. I'm really excited to be speaking today with Drs. Sharon Brangman and Alejandra Sanchez Lopez. They are the authors of the module titled Advising Patients Who Are Underrepresented in Clinical Trials, Applying Care Equitably When Evidence is Not Inclusive. Let me introduce both of our speakers. Dr. Brangman, I know many of you know, is a geriatrician and the distinguished service professor of geriatric medicine at SUNY Upstate Medical University. She's also chair of the Department of Geriatrics and Director of the Center of Excellence for Alzheimer's Disease, where she conducts research and provides care to people living with dementia. She's also a nationally recognized expert in Alzheimer's disease and a leader in making access to clinical trial participation more equitable. And I'm also really pleased to introduce Dr. Sánchez López. She's a geriatrician and an assistant professor at UCLA and the David Geffen School of Medicine, where she holds dual appointments in neurology and geriatric medicine. After completing a geriatric medicine fellowship at UCSF, where I had the pleasure of working with her, she went on to complete a behavioral neurology clinical fellowship at the UCSF Memory and Aging Center. At UCLA, she provides care to patients with cognitive and behavioral changes in the UCLA Mary S. Easton Center for Alzheimer's Disease Research and Care. She also is a consultant at Olive View Medical Center, where she also cares for patients with memory disorders. And she also evaluates patients who are potential candidates for anti-amyloid therapy. And finally, she also conducts and participates in observational research there. So welcome to you both.

Sharon Brangman:

Thank you for inviting us. Thank you very much. Mike, happy to be here.

Michael Harper:

So I want to start out by acknowledging that part of the reason we're having this discussion is really around some of these clinical trials of anti-amyloid therapy. So when the trials for Lecanemab and Donanemab were first published, a lot was made of the fact that there was relatively little diversity among the subjects who were studied. But before we talk specifically about these trials, it'd be useful to know some details about the population of people living with dementia in the U.S. So what's the prevalence among different racial and ethnic groups?

Alejandra Sánchez López:

Yeah, so there's uh there's a big disparity in terms of like dementia prevalence in the US. So in general, we think about like somebody who's uh older than 65, in like the white population is about 10%. But in it's different in uh in other groups, being like in the black adults being about uh 19%, and Latino groups about 14%. So yeah, there's uh much more uh prevalence in these groups.

Sharon Brangman:

So uh the part that's interesting is that Alzheimer's disease is twice as prevalent in African Americans and one and a half times as prevalent in Latinos. However, they were not represented in the clinical trials. So it's kind of ironic that the groups that could potentially benefit the most were not included in those studies.

Michael Harper:

When we think about this, it's sort of interesting to recognize that the while the prevalence is greater in those two populations compared to a white population, what are the disparities that exist when it comes to both identifying and diagnosing cognitive impairment and dementia and also the treatment?

Alejandra Sánchez López:

In addition to just being you know more prevalent, that there's these groups, uh, you know, Latino and black adults, they actually are diagnosed much later in the disease course. So even like much later, like months later, up to a year later. And then when they present, they're more advanced, right, in this disease. So that it has implications in terms of like their eligibility for this type of treatment, because we do want to see them when they're early in the disease, when it's uh most helpful.

Michael Harper:

We're aware of these disparities, but why do they exist?

Sharon Brangman:

Well, it's very complicated because we have so many disparities in our society and how people can access care, who we value when we see them and what we ask them, what kind of questions, people's trust in the system that they're gonna go there and get the care they need. And then we look at our evaluation tools. Our evaluation tools were not set up to equitably diagnose some of these diseases. So some of the most common screening tools that are used in our workup for patients with Alzheimer's disease have inherent biases in them so that you may not even be getting accurate scores that help you make a good diagnosis. So, you know, we always say in geriatrics it's never one thing, it's always lots of little things. And I think this is another example when there's complexity that are really on both sides from the patient's perspective and also from the clinicians and the health systems perspective that gets in the way of people accessing care and getting the right diagnosis and treatment.

Alejandra Sánchez López:

And I would add also like yeah, the um the groups, the same group that were underrepresented in these uh clinical trials, yeah, like like Sharon mentioned, is complicated, right? What we think is like they've been exposed throughout their lifetime to different environmental reasons, right? And then there's socioeconomic factors, right, including the increasing prevalence. Some of them also have increased risk of vascular risk factors that increases your risk of cognitive impairment as well. But then also access to care that is as well so important.

Sharon Brangman:

So, yeah, we know, for example, that hypertension and diabetes is overrepresented in these groups, and that's a risk factor. We also know that stress is a risk factor, and the stress of discrimination or racism can play a role. We have new information about environmental risk factors, and these groups of people often live in areas where pollution is a big issue. So it really does become a complex problem to kind of sort out.

Michael Harper:

So, Sharon, you mentioned the some of the limits of some of the cognitive screening tools that we currently have access to. When we actually have, let's say, a patient from one of these typically underrepresented groups in these clinical trials, and they're coming to us either because they recognized a concern or a family or a loved one has recognized a concern, you know, maybe it's a patient who's for whom English isn't their first language. What are some things we should think about and be aware of as we're trying to make this evaluation that may be different from the population for which these studies are more applicable to?

Sharon Brangman:

So I think it's really a clinical diagnosis in many ways. And I don't think I would put as much weight on a score as the clinical history and the functional status. Especially, you know, Alejandra can speak to this, but if you don't have someone whose primary language is in English, most of these tests can't be simply translated and still evaluate the same cognitive function. And we may not have staff who are fluent in other languages. It's also known that if you have a higher level of educational attainment, you tend to do better on these tests. And um many people have not reached that level of attainment, or even if they have, it's not equivalent depending on where they got their education. If they got their education in a different school district where we know the educational um content is very different. There are socioeconomic factors, there's many different factors, and many of these screening tests were again tested in highly educated, primarily white populations. So even the screening tests were not broadly evaluated in different groups of people. And the other thing I just wanted to add was the other piece, as geriatricians, we see patients who are in their 80s and 90s, right? And these clinical trials mostly studied people in their lower 70s. So in terms of the typical geriatric patient, as geriatricians, we're really at a loss to know what to do with patients who are older in their 80s or maybe even nineties. So the trials are done often in people who have the least amount of complexity so that the results can maybe not be impacted by so many variables.

Michael Harper:

So, Alejandra, when you're seeing folks that we've just described, again, that don't aren't typically represented in these diagnostic trials, for example, or when we're sort of getting the norms for cognitive testing, I imagine that you see a diverse population of folks where you are in LA, some of whom perhaps English is not their first language. What is your approach to thinking about this in terms of making this evaluation?

Alejandra Sánchez López:

Right. So, you know, I think that it's important to you know remind ourselves of like, yeah, those limitations of the cognitive screeners. And you know, we all use probably the most common ones, and I'm sure it's like hooky to mention it, but we all use like MOCA, right? That's a very common type of um cognitive screener that we use. And you know, I speak Spanish, so even if I administer the test in Spanish, I know that there's some limitations with how many points can the patient get, especially if they have a low educational attainment. And there's plenty of studies that show that Latino population in the US, right, and also black adults as well in the US, they score lower, even if they speak the language too. Just keep that in mind. And then, like Sharon mentioned, it's also like understanding, you know, that it's not just the score, right? But we do pay attention to it because like the guidelines, you know, they give you a score, right, of what's appropriate in terms of the stage of or the severity of the cognitive impairment. You know, I think that uh we have to bear that in mind when determining eligibility in this patient population. They may score lower and then may not be as impaired as we think.

Michael Harper:

That's all helpful context, especially when we may be trying to use some of this information to advise our patients about whether or not they are potential candidates for anti-amyloid therapy. So as I mentioned at the top of the podcast, those trials, the anti-amyloid monoclonal antibody clinical trials, came under, I think, well-deserved scrutiny for their lack of diversity and representation of racial and ethnic minorities. Why do you think this happened and what are the implications for applying the results to such patients?

Sharon Brangman:

Why do we think the trials weren't inclusive?

Michael Harper:

Yeah.

Sharon Brangman:

Well, I think um they're used to doing things the way they've always done them. They have a clear pathway and plan to carry out clinical trials in the ways they are most used to. Many of them occur in academic centers that may not have good connections or good um relationships with communities of diverse participants. And it takes work and time to develop those relationships. And when you're doing a study, you want to enroll quickly and keep it moving. And if you don't have those relationships, you don't have time to build them. So you have to have a long view to develop trust. You have to take good care of people when you don't even want them in the study so that they will trust you when you suggest a study. I also found in some of my work that people aren't even asked. So sometimes we as clinicians may have in our mind who would participate in a study we may not even ask. So there's a whole variety of reasons why we seem to repeat the same formula across all specialties and drug classes, that when we do trials, we go after the people that we traditionally go after.

Michael Harper:

So, Alejandra, are these studies, do they have any value when we're trying to make recommendations to patients who may have not been well represented and we don't have enough data to say what the outcomes might be in a particular group of people?

Alejandra Sánchez López:

Right. I mean, we always want to consider, right, like the medication that you're giving has been tried in like the patient that you're seeing, right? So um, you know, I mean, there is definitely value, right? Like there's some information there, but we have to be honest with our patients, right? In telling them, like in general, you know, they were not really included in this trial, so we don't have a lot of information in patients just like them. But we assume just that they would have benefited, the same possible side effects, right? But we don't know. So I think that's what we just have to say to our patients. And that's what I normally say.

Sharon Brangman:

The other thing I would add is there's not necessarily a biological difference between races. You know, there's only a few little genes that get changed that change the shape of your eye or your skin color. So it's not necessarily a biological difference that we're looking for, but the social determinants of health can have a big role in how someone does on a particular therapy. And so that's why it's important to make sure that you have a diverse group of people.

Michael Harper:

Yeah, Sharon, I think that point is really important to make, right? We're not talking about whether or not they're gonna respond differently because of the color of their skin or the language they speak. It's because of these other things that we know are associated with the reasons why we don't make the diagnosis as early, right? So how are they gonna respond? Maybe less about the biological effect, but all those other factors. But it leaves us still without the information we'd like to have.

Alejandra Sánchez López:

Sharon was mentioning that in general, you know, these patients in uh or participants in clinical trials, they're you know generally healthy, right? Uh and then injury at least, we see a patient with uh so many comorbidities. And that comes up because sometimes patients, you know, they have a certain level of current kidney disease. These patients were really excluded if they had significant kidney disease, but then we have to try to figure out um in terms of like the medication, you know, is it excreted or metabolized by the kidney? And we found that no. So then we have to like just kind of figure out after the clinical trials in these particular questions.

Sharon Brangman:

Another thing to add is that there's some question about the impact of ApoE in different groups of people. And you know, with um these anti-amyloid therapies, people who have ApoE are considered at risk for some of the side effects and maybe should not even participate in these therapies. But we have a little bit of research that suggests that in people of African descent and some Latino populations, ApoE may not provide that same risk as it would in white patients. But again, we don't have enough information to know for sure. So we err on the side of caution, and anyone with ApoE would probably be excluded if they came to our center for um anti-amyloid therapy.

Alejandra Sánchez López:

Yeah, and to add to that, I think, yeah, you're mentioning like Apo E4, yeah, that would increase the risk of Alzheimer's disease, right? Uh, and then we don't know about the risk of ARIA, like the side effect with anti-amyloid.

Sharon Brangman:

Right.

Alejandra Sánchez López:

But again, we just assume, right, that it'd be the same.

Sharon Brangman:

So we have to err on the side of caution because there isn't even enough information on the different ways A4 might impact different groups of people.

Michael Harper:

Yeah. And I think you know, part of the challenge we have now is we're still learning about the long-term effects of these drugs. And obviously, there's lots of questions raised about the true efficacy in terms of improvement. So, caution probably is a relatively reasonable approach, probably with most of our patients. I think you guys drive home the point, however, which is we are left to have to make assumptions. And that's a hard place to be when we should be able to, putting the right efforts in place, have the data that we would all like to have to be able to make well-informed decisions and recommendations to our patients.

Sharon Brangman:

So, yeah, we were never trained to guess when we are providing care to our patients. We were trained to have some level of knowledge and assurance about what we were doing. And in this case, we don't. And we have to be honest with our patients about that. Yeah, it's an uncomfortable place to be.

Michael Harper:

Yeah. So I think if tell me if I if you think I have this right, which is given this lack of information, the thing that keeps coming up is being honest about that, saying that we have limited information. But based on the information that we have, we can make some recommendations, understanding that it's based on some assumptions, but that this should not exclude people who are potential candidates if the shared decision making falls down pursuing it. So we want to be sure that even though we're not sure about these drugs, we also don't want to exclude groups who could potentially benefit just because we don't have the information.

Sharon Brangman:

So that's true. We're not talking about excluding people just because they weren't in the trial. And we would also encourage participation in some of the data banks so that we can collect information as they proceed with therapy, and this may help inform us about some of the gaps that might have been left in the clinical trial. So, yeah, we're not trying to discourage people. We just want to be honest about what we know and what we don't know.

Michael Harper:

So we covered a lot of ground. I want to be sure that there's anything important that we didn't miss. Are there any other concluding comments that either of you would like to make?

Alejandra Sánchez López:

Yeah, I think that it'd be an opportunity now that you know there's so much interest in early diagnosis and potential treatment with these medications at the amyloid therapy for you know geriatricians and you know, primary care, right? To make these diagnoses. And when we're trying to evaluate these patients, I think also giving them the opportunity to do as best as they can on their testing, right? And just doing the typical things that we would do, you know, making sure that they have, you know, they can hear us well, they can uh we have a quiet area. If they need uh an interpreter for you know the testing, that we do that, right? Like even if they speak a second language but they don't speak it as well. And yeah, just keeping in mind that this patient population might do a little bit lowering scores in testing, but just trying to figure out with their function if they're on an early stage. That's the thing.

Sharon Brangman:

And then the other thing we talk about are what is actually involved in taking these therapies. You have to have access to an academic center, you have to be able to handle the out-of-pocket expenses with all the testing and the MRIs, etc., that may not all be covered by insurance, or certainly you have to pay co-pays. So there are other economic factors that also come into play that we have to make sure our patients understand. They have to have time to have these infusions, you know. With Lacanomab, it's every other week, and the infusion can take at least an hour. So they have to have the time, and they may need someone to help them get there. And so it is involved, and we want to just make sure that people are making a good decision, and uh we don't influence them one way or another. We give them the information and we help them make that decision.

Michael Harper:

Yeah, and I think Sharon, I think as we hope more effective treatments do emerge, we also want to make sure that we don't increase the disparities because of those challenges that you just described. Thank you both very much for being with me and for sharing your expertise in this subject. I think this topic is really important for our listeners, getting your perspective on this, which is, I think, to say we have to be cautious, but we also want to make sure that we are equitable in the way we talk about these emerging treatments and making sure that all of our patients get as much information as they possibly can so that we can all make informed decisions about their care.