Lia Barros, DNP and Tijana Milinic, MD - phaware® interview 529

Dr. Tijana Milinic and Lia Barros, DNP, from the University of Washington take a deep dive into the world of pulmonary arterial hypertension (PAH) clinical trials and discuss why diversity and inclusion matter. They explore the hidden biases in medical research and the real-world consequences of exclusion.


Lia Barros, DNP:
My name is Lia Barros and I'm a pulmonary vascular disease nurse practitioner specialist. I work at the University of Washington, where I've been practicing as a pulmonary vascular disease specialist for about the last four years. I was born and raised in this area. I'm really passionate about diversity and equity inclusion in clinical trials as I'm the daughter of an immigrant. This is something that I believe has affected me personally. It’s something that I see a lot professionally, that's sort of led me into this intersection of trying to understand equitable inclusion in the space of pulmonary arterial hypertension.

Tijana Milinic, MD:
Hi, my name is Tijana Milinic. I am a pulmonary and critical care physician here at the University of Washington in Seattle. Much of my work is as a pulmonary specialist. I also am a physician scientist. I specifically study equity and inclusion in clinical trials in pulmonary disease. I came into this work because I'm very passionate about having equal access to care for all groups of people. I, myself, am a refugee from Eastern Europe. Similarly, my background really is the reason why I have such a passion for people having access to medical therapies, and specifically new and potentially life-saving medical therapies in clinical trials.

The work that Lia and I did together was the paper focusing on equity and inclusion in PAH, pulmonary arterial hypertension studies. The crux of the paper highlights that certain groups, specifically those who are ethnically and racially minoritized in the United States are not represented fairly in clinical trials.

First, what do we mean by ethnically and racially minoritized people? Specifically, we're talking about individuals who have racial, ethnic, or cultural identities that have historically or presently experienced discrimination, marginalization, or unequal treatment in society. When we talk about clinical trials, we're specifically thinking about those studies that look at medications or new drugs, and evaluate whether they work or cause unintended side effects, whether they're safe and effective. Overall, what we found and what we know based on a lot of the research we've done is that clinical trials don't represent the overall population of people that will eventually end up taking a medication or therapies. In the United States, and this is generally among all disease conditions, we know for example, that over 20,000 studies done in the US, out of those only 43% included or reported race or ethnicity.

Today, we'll be talking a little bit more specifically about PAH and we'll discuss a little bit about the inclusion in PAH trials, but we'll give kind of a broad view of who's included in the registry and also who's included in clinical studies.

In order to understand who is included into clinical studies, we really have to have a good understanding of who has the disease overall. Specifically, for pulmonary arterial hypertension, we do that in something called disease registries. What we do know is that black African-American, Hispanic, Latinx, and indigenous communities, but more specifically for black and Hispanic communities, in pulmonary disease in general, we know that those populations experience worse health outcomes and potentially have limited access or more limited access to medical care in general. In PAH, there's some signal with small studies, for example, objective measures like how people are feeling or things like six-minute walk tests or functional status, may be worse in specifically groups that are historically ethnically or racially minoritized. When there is limited access to things like clinical studies that further worsens those already comparatively worse health outcomes.

Lia Barros, DNP:
If we take a step back and we think about pulmonary arterial hypertension, this is a rare and severe clinical condition that is characterized by progressive remodeling of the pulmonary vasculature. So when you are operating with a rare disease state, sometimes it becomes challenging to understand the data and demographics being an example of that across the population. Over the last several decades, there's really been a proliferation of therapies that have been approved for patients with PAH that have made really meaningful improvements in outcomes. However, little is known about the inequity in the care of patients with PAH. Even less is known about racial and equitable inclusion in participants with PAH in clinical trials. When we were preparing for this paper, what we really discovered is that we don't know. Is this something that we need to continue to explore or study? As Tijana mentioned, the way we try to understand do these clinical trials offer an equitable representation of patients living with pulmonary arterial hypertension?

We went to look at these voluntary registries. We found that many of these registries did not report race or ethnicity. Several of the registries did not have patients selecting or informing how they identify with their race or ethnicity. So, there are many different challenges when trying to understand the population at large. If you go all the way back to when the first registry was published in the 1980s, this showed that patients living with PAH were predominantly young white women. This racial and ethnic impression was further reflected with subsequent registries that included the Reveal Registry, as well as the PFAR and SPHERE Registry.

In general, they reported somewhere between 70% and 80% of participants reported their racial or ethnic background as white. About 10% to 15% would report identifying with black, and 9% would be Hispanic. Is this consistent with the broader range of racial and ethnic demographics within our country at large? What we found when we looked at that is that patients who were historically ethnically marginalized, were under-reported in these patient registries. What we wonder and what we reflect on is the barriers for patients to participate in voluntary registries… maybe those same barriers impact people and patient's abilities to participate in clinical trials. What happens is we get this false belief that because this representation is seen in the registries, that therefore our clinical trials do have equity in their representation. When in reality just both struggle from the same systemic barriers.

Tijana Milinic, MD:
When we think about the mechanisms that produce a lot of these systemic inequities, I think it's really helpful to approach it across multiple levels. What I mean by that is going from the level of the individual or person and the barriers they may experience, all the way to large systemic policy barriers, in the United States for example. All of these could equally apply to participating in a clinical trial or a drug trial and to participating in something like a registry.

The first level is kind of the individual level or the level of the person, whether a person can take time off work, the cost of transportation to getting to study centers, the burden of potentially participating in a study for example. Clinical trials involve things like lab draws or more invasive procedures. Depending on what kind of study it is, could involve more barriers and more burden to participating. That also lends itself to thinking about the risks of participating. So, on an individual level, for a person living with PAH, the risks of trying a new drug could potentially outweigh the benefits of symptom relief or feeling better for example.

The next level we looked at in our study was the interpersonal levels, things like how a person when they go to a study center with the study staff. When we think about participating in a trial or even in a registry, there may be a certain level of bias. Even though the person is there and has access to go to their appointments, there may be bias in whether staff thinks that they are a candidate for the study or would be willing to participate or would consistently be available to participate. That bias can be conscious or unconscious. But we know based on studies that we've done outside of PAH that that's a known barrier to people having access to studies.

Along the same lines, the diversity of a study team really impacts someone's care in general, but also whether they can participate in studies. If people don't see other individuals that potentially identify with their culture or race, they're less likely to participate. Also, we actually know based on studies that when there's cultural congruency, that someone's race or ethnicity aligns with their providers, that they actually receive better medical care. That, we think, also is related to some of the biases that exist.

Another similar barrier is translation services. In something like clinical drug trials, consenting is a really important part of the process. So talking about the risks of participating or the benefits and talking about really explicitly about what the drug involves or the trial involves is a really complex and difficult conversation to have. So, not having adequate translation services is yet another known barrier. One specific thing to point out is when that translation service happens. So how early on in a study also influences whether people have access to the study. Specifically, who I mean, is those who do not speak English as a primary language.

Organizational and more center and study level barriers are the next level. When we think about organizational barriers, we think about things like the inclusion criteria of a study. So, whether somebody is eligible to participate depends on whether they fit the inclusion or exclusion criteria. In PAH, that's often things like six-minute walk tests or other objective clinical measures, BMP, people's functional status. When we design studies, if those criteria are too limited, then that restricts how many people can participate potentially, and could potentially restrict in a biased way who can participate. Along those same lines, the level of bias within those objective measures is also really important to think about.

In pulmonary disease, in general, we think about things like the lung function. Some of the equations we use actually are biased toward the estimating lung function incorrectly among black or African-Americans. I use that as an example not specifically related to PAH, but just to think about that some of our objective measures can also be biased and influence whether somebody participates.

When we design our studies, we have to think about the level of time commitment involved, whether that excludes certain groups of people because for example, they have multiple jobs or they are responsible for child care. Then, the geography of a study could potentially be restrictive. If an academic center or a PAH center is in a large city for example, that could increase the distance to travel or the commitment for people who live in more rural areas. That could potentially limit the population of people, especially if they are in a specific minoritized racial and ethnic group.

On a community level, we often discuss the idea of mistrust in communities. For clinical trials specifically, there is a history of exploitation of black African-Americans and Hispanic and Latinx people in the United States. Oftentimes, people cite studies like the Tuskegee trial, but there are multiple studies where the process of consent was taken away or undue harm was caused on a population of people. That legacy has left mistrust in the medical community, but we also highlight that it's made medical research less trustworthy. That affects whether people feel comfortable to participate in medical research and even in registries where part of the risk in participating in a registry could potentially be loss of privacy of information and so on.

On a broad scale, we also have to think about how national policies in the United States that don't necessarily even affect medical research, how those can disproportionately disadvantage groups of people, and therefore indirectly affect whether people can participate or are asked. It's a really complex system that operates on multiple levels, and that's what makes it really hard to study and to think about, because there's so many different levels that can affect whether somebody is asked to participate in a registry or even a trial and whether they can. That also makes the solutions difficult to address as well, because of that level of complexity.

Lia Barros, DNP:
Taken all together, when looking at the population of patients living with PAH, what we believe to understand is that about 20% to 30% of those patients identify as a minority, while about 70% to 80% identify as white. There could be a very cautious support that this is a good representation of the actual population living with PAH. If we look at the US census, that suggests about 71% of people in 2020 identified as white and about 65% or so percent identified as white only. So, while understanding the demographics of the PAH population at large is likely imperfect, the breakdown of what we understand could be a reasonable benchmark when we look at the clinical trials within therapies for patients with PAH, to say, are they representing the population that they're trying to serve? So, looking at PAH clinical trials, we found that the landmark study looking at epoprostenol actually did not include race or ethnicity at all within their trial. But, following the next decade or so, there were a proliferation of studies that did include this information.

Time and again, what we found is that white participants seem to be overrepresented ranging anywhere from about 80% to 86% of the participants in the studies. Even looking at more contemporary trials, in the last few years, this representation continues to persist. Most specifically, I think it's important for us that we highlight that black participants are consistently underrepresented. When we talk about barriers to participation, understanding the history in America becomes important when we think about why this may be true. When we look at different clinical trials, consistently, participants who identified as black only made up anywhere from about 2% to 4% of participants in those clinical trials, which is far less than we would expect based on the US census and based on what we understand about PAH demographics at large.

Tijana Milinic, MD:
When we're thinking about study design, it's also important that patients are involved through the whole process. First, we actually start by evaluating what the community's needs are, whether the study that we're doing even addresses a community's needs. Specifically, this is important for minoritized communities, because historically these communities and their voices have been marginalized. Their voices, their needs, have not historically been addressed. So, community engaged research is actually a really important and powerful tool to bring patients to the table and include patients throughout the whole process.

First, we start by understanding the needs of the community. Then, we incorporate and include the community into the research design process. Then, we actually bring our results back to the community and give them an idea of what we're finding and how we're doing the research so far. This allows our research to center the voices of marginalized people and people who've historically been excluded from studies, and also to ensure that our trial conduct is safe for those communities, and is welcoming.

Lia Barros, DNP:
I think just sort of in summary, that these inequities in PAH clinical trials are important. They're important for us to name, and they're important for us to understand. Clinical trial recruitment that doesn't represent a PAH population more broadly may impair our understanding in drug effects, may impair our understanding and understanding outcomes of treatment. I think overall, is a disservice to those we serve as clinicians. I think that from this paper, one of the things that's really hit home for both of us is that more effort needs to go into understanding who is living with PAH, and are we including those patients when studying therapies targeted for their disease.

Thank you for listening. My name is Lia Barros…

Tijana Milinic, MD:
And I'm Tijana Milinic, and we're aware that our patients are rare.

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