Drugmakers are taking steps to make sure clinical trials include participants from a variety of backgrounds—and they are steadily making progress, as evidenced by new studies of multiple sclerosis and sickle cell disease. Milliman health researchers Ellyn Russo and Chris Page unpack a history of distrust in medical research, the implications of failing to attract diverse study participants, and how simple strategies like rideshare vouchers, childcare, and check-in apps can help expand a study’s reach, so more patients have access to the latest treatments and medical research moves forward.

Transcript

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Jeremy Engdahl-Johnson: Hello and welcome to Critical Point, brought to you by Milliman. I'm Jeremy Engdahl-Johnson and I’m going to be your host today. In this episode of Critical Point, we're going to talk about diversity in clinical trials. We'll look at why tests for new drugs have often failed to reach a diverse group of participants, and what that means for those patients and the healthcare system overall. We'll also look at some bright spots in this area, including the U.S. Food and Drug Administration’s (FDA's) recent approval of new treatments for sickle cell disease.

I'm excited to have two Milliman experts here with me to discuss this topic. Ellyn Russo is a healthcare consultant out of our Hartford office who writes frequently about health equity. Her current work includes research to better understand and inform actions regarding disparities in the U.S. healthcare system. And Chris Page is a senior healthcare consultant based out of Indianapolis who does a lot of work in the oncology space. This includes work related to healthcare inequities, including access to clinical trials and novel therapies. Welcome to both of you.

Chris Page: Thanks for having us.

Ellyn Russo: Hey, Jeremy, thanks for having us.

What is a clinical trial and how does a clinical trial work?

Jeremy Engdahl-Johnson: All right, well, let's just jump right in. This is a deep topic. We've got a lot of different ways we're going to shine light on this, and I'm going to start out just, I'll address this to you, Chris. Let's start with some basics—and it's going to get more complicated in a hurry, so if people in our audience kind of know this already, bear with us—but what is a clinical trial and how do these trials work?

Chris Page: I'll gloss over this, not to get too in the weeds, but clinical trials are voluntary research studies conducted in human volunteers with the goal of making sure that the drugs are safe and effective. So patients can opt into these trials in coordination with their healthcare providers. And throughout the process, there's different phases of clinical trials but, most of the time, it will include three phases, with the first phase looking to make sure the drug is safe, and then, from there, trying to better understand how the drug works and ideally how it works compared to currently available drugs. But again, these are voluntary. It's up to a patient to participate, and usually that's done in conjunction with the patient and their healthcare provider.

Why have clinical trials failed to attract diverse participants in the past?

Jeremy Engdahl-Johnson: So historically, there hasn't been much diversity among participants in clinical trials in terms of race, age, and geography. Ellyn, can you talk about why that is?

Ellyn Russo: Sure. So this is a big topic. I'm going to break it down a little bit. But, in general, there's trust issues, right? So distrust here with clinical trials, human experimentation. Historically, over the past couple of centuries, this experimentation has often been associated with themes of dehumanization, eugenics, genocide. It's been affecting historically marginalized populations in horrific ways. So that's where there's been a lack of diversity because of this distrust. There's a lot of examples, and I'll just touch on one that I've studied a lot, and that's the Tuskegee syphilis trials that we've heard about in the United States. It's the most prominent one for Black individuals. Of course, there have been numerous other ones for Black Americans, but this one in particular, this study started in the 1930s. It continued throughout World War II. It took until the ’90s for, I believe it was President Clinton, that finally apologized for what happened in Tuskegee.

So we've had years, decades, generations of mistrust in the human subjects research proliferation of how it works and sort of what's gone on. Fortunately, that's being changed. It's taken powerful leaders in these communities to reset that trust, let alone the researchers themselves to sort of correct the wrong that they've done and make sure they're following all of these principles that were set out. But that's really what it's been about. It's been about fixing the wrongs, making it known to these marginalized communities that we treat everyone the same in clinical trials and that we're not about these dehumanizing effects anymore.

“Do I just get a sugar pill?” and other misperceptions and barriers to clinical trial participation

Chris Page: Yeah. And as Ellyn said, I think there's absolutely a need to address the historical mistrust, and understandably so, for populations who have been part of those trials. In addition to that, I think there's some other considerations that we've been thinking through with our clients too. And one is just perceptions of clinical trials and not from a trust issue, but just concerns that, if you enroll, you're just going to get a sugar pill or a placebo and it's not going to benefit you or has no chance of benefiting you. And that's something we'll come back to a little bit later on because I think there's education that can be done there, especially in the oncology space.

And then another big thing is access, and that's both geographical access—so are you 10, 15, 20 minutes away from a trial site?—and then also logistically, can you make it work? If you have to be there multiple days a week, do you have a job where you can take time off work to be there? If you have kids, is daycare available to help with that? And making sure that just the patients can access, not just from a geographic perspective, but also a lifestyle, because these can be time-intensive trials, require a lot of follow-ups, a lot of monitoring. So we need to make sure we're meeting patients where they’re at and accounting for things such as children, grandparents, work, and transportation. That’s something we’re thinking through with a lot of our clients.

And then, finally, the FDA has published some guidance around this too. So in late 2020, November 2020, they included four sets of recommendations around increasing diversity in clinical trials. And that includes broadening eligibility criteria to avoid unnecessary exclusions. The second is designing trials in ways that achieve participant diversity. Next is improving practices for recruiting participants to clinical trials. And then, finally, applying the recommendations for broad eligibility criteria to clinical trials for drugs intended to treat rare diseases or conditions. So making sure, for things that we're getting into like sickle cell, if it's a small population, making sure that we're making patients aware of these and outreaching them to have broad diversity as we review these drugs for safety and efficacy.

What’s the impact when a clinical trial fails to reach diverse participants?

Jeremy Engdahl-Johnson: What are the implications? You know, it's an understandable, long kind of historical march up to this point. What are the implications of not reaching and engaging a diverse group of participants?

Chris Page: I think there's a lot to unpack there and I think we'll tackle it from a few different angles. But I'm a pharmacist by background, so putting my clinician hat on, we know that there's a lot of differences in people. We have difference by sex, by age, by race, by comorbidities. And we need to understand how these drugs work or don't work in different patient populations. Are there certain drugs that may be better options for certain people? And to achieve this, we need broad diversity in clinical trials. You can't give it to a group of 40-year-old white men and extrapolate those results and assume it works for everybody else. So I think it's really important to have that diversity so that we understand, one, if drugs work; two, how they work; and then three, how do they work in different populations, as we think about getting the best medication to the right patient at the right time.

Ellyn Russo: And unlike Chris, I'm not a pharmacist, but I do look at data. So something I did in prep for today's discussion, I looked at the reports from the FDA, the Food and Drug Administration, who oversees all of the clinical trials and approval of new drugs and new treatments and therapies. And they have been providing a breakdown of clinical trial participation since at least 2015. There were 39 trials in 2022. The pool demographics for them showed 80% of participants were white, 5% Black, and 10% Asian. The U.S. general population in 2022 was 75% white, about 13% to 14% Black, and 6% Asian. The 5% in the trials versus the 14% Black, that's a little bit of a discord, right? Five percent is a little bit less than half of that 14%.

But also when you have 5% of a population in a clinical trial, you can run into some issues with statistical significance. And what that means is your conclusions around efficacy could be at stake, meaning you cannot maybe derive how well it works because you have so few participants. So your conclusions may not be as strong.

Recent progress: Clinical trials for sickle cell and MS

Ellyn Russo: What I will say, though, is the reports were through 2022. The 2023 report should be coming out soon. And I will say, promisingly enough, 2023 was a record-breaking year, in my opinion, for clinical trials. So, not only do we have the first-ever clinical trial to be conducted exclusively in Black and Hispanic and Latinx people living with multiple sclerosis. So it’s literally a trial just including people in historically marginalized communities. And, you know, we know about MS—so multiple sclerosis, the acronym is MS—we know people living with that. We’ve studied it very well in people of the white race and sort of understanding different interventions there, but we are exclusively seeing this trial in folks that are not white, so that's huge. So we can understand how different drugs and particularly this one drug is going to work in those populations.

But the other part of 2023 was that we saw not just one but two clinical trials complete for gene therapies that will treat sickle cell disease. And I know we mentioned this earlier in this episode here, but we want to really focus on this for a second here. This is monumental for two reasons. One is that sickle cell disease rarely affects people of the Caucasian race. So it's very unlikely that it will be in anyone who is not of African or Hispanic ethnicity. That's not to say it can't be, but it just, it's very rare.

And so how'd they do? Let's rate the clinical trials for the two drugs. One was 86.5% Black or African-American. The other one was 97% Black. So that was very promising that they enrolled patients that were actually having the disease, matching the disease description.

And the second point about this one is that the treatments that have been developed were actually designed and developed to treat the disease, not just the symptoms. So the pathophysiology of sickle cell disease is that it creates these very, very excruciating pain episodes in individuals. They're very debilitating. They change the trajectory of individuals' life expectancy, their mental health, everything. And so there are existing treatments for those who suffer from it, but these treatments in particular, because of their design, the gene therapy, it's actually going to combat the shape and type of the hemoglobin that is in their body. And so it will actually have life-altering effects. Now, they're not calling them curative therapies because we have not studied them long enough, but these are truly remarkable therapies for a disease state that is rare and that has not had anything like it in the past.

Why clinical trial participants should reflect that disease state

Chris Page: Those are excellent points, Ellyn, and a lot of progress being made, which is really promising. Just to add on to that, a few of the things we're thinking about through our work with our clients is providing guideline-concordant care and addressing healthcare disparities and inequities. And a lot of times that starts as we think about clinical trial design and diversity in patient participation.

There was a recent study published late 2022 that kind of dug into this. In this trial, investigators randomly provided patients with hypertension results from one of two trials for a hypothetical drug. Both trials showed that the drug was equally effective at lowering blood pressure. But in one trial, 15% of patients were Black, and then in the other trial, less than 1% of patients were Black. And when those results were given to patients, there was a 20-percentage-point increase in the likelihood that Black patients believed the drug would work for them if it was from the trial with higher Black participation. So, like Ellyn said, it doesn't always need to be 75%, 85%, but, if it's more representative of the patient population, it's easier for patients to trust and believe that, and for physicians to have those conversations with their patients, which is great news for everybody.

Another more specific example of work we've been doing recently is in multiple myeloma. So with multiple myeloma, Black patients are disproportionately affected. They make up 20% of people living with multiple myeloma. And depending on certain factors and age and geography, they're anywhere from two to four times more likely than white males to be diagnosed with precursors to multiple myeloma, and then ultimately die from multiple myeloma, which is really concerning and something we need to address. But with that being said, a recent pooled analysis found that, across 19 trials, only 4% of patients were African-American in those trials. So we really need to be thinking about how we're attracting patients who reflect the disease state and doing this from the ground up so that we have the data points once we have the drugs available. We're seeing very similar trends in prostate cancer. And then Ellyn, I know you also have some insights on lung cancer and how we think about that going forward.

Making sure providers inform patients about available clinical trials

Ellyn Russo: Right, and I think it corresponds both to what you're saying here and also sort of how I think you set it up in the beginning, Chris, of this conversation. In particular, for this question, is access to life-changing or any kind of treatment. Often at the end of the line, especially in cancer, your only option might be in a clinical trial, right? A new drug that's coming out or a new treatment. And so if you're a patient for whom you have no other options and you don't know what else you can do, that may be the only place to go.

The lung cancer, what I did was I dove a little bit into the active guidelines on the American Society for Clinical Oncology's website. They all mention getting enrolled in a clinical trial as an option for treatment, right? So statements like “patients and providers should consider enrollment in a clinical trial when available.” “Enrollment in a clinical trial is encouraged.” “Patients should be offered the option of enrolling.” Right? So these need to be at the forefront of a provider's mind. They need to be aware of them. Patients should be as well. I mean, that's a lot harder for patients because usually the providers are the ones aware of them, but the more that we are thinking about this and offering it to everyone who walks in, especially the ones that are at highest risk, like the Black patients who are at much higher risk for, as you were saying, the multiple myelomas and death from them. Anywhere there's disparities, we want to make sure that we're increasing awareness that these do exist and are available to those patients.

Rideshare vouchers, diverse trial managers, and other ways to foster participation

Jeremy Engdahl-Johnson: So we've seen some progress recently and 2023 was a notable year. What's next? How can we continue to improve this? How do we work towards seeing fewer disparities in clinical trials?

Chris Page: I think a lot of it just comes with building on the momentum we already have. And we're thinking about this through the work that we do with both pharmaceutical manufacturers and advocacy groups. But a big thing we're thinking through is racial concordance with the clinical trial team. So how do we make sure that the clinical trial team looks like the patients they're trying to attract? And if there's a certain vernacular that that patient population speaks, how do we develop the resources and materials and account for that as part of the trial development process? Like Ellyn touched on, there's a lot of historical mistrust and distrust because of past clinical trials. But I think it's become a little more clear that these communities are willing to engage in clinical trials once trust is established.

But we also need to make sure we're addressing any barriers that come with that. So we talked about geographical barriers, logistical barriers. It may be as simple as providing a Lyft or an Uber credit. And we've seen some clients in clinical trials do that so patients can get to and from trials. And I think it's also, we need to think about long-term investments here. So we need to think about how can we lay the groundwork now so three years from now, five years from now, when we need a clinical trial in a certain area, we already have some trust in that space and that geography, and we can build on that. One thing we've heard from a lot of groups we work with is you cannot helicopter in and say, “Oh, we have this drug. We need this patient population. So let us fly in, set up shop, and then disappear in 18 months.” We need to be thinking about that 18 months ahead of time and building out trials with that in mind, thinking of locations with that in mind, and thinking of this as a long-term process.

Spreading awareness, and the impact of the COVID-19 vaccine trials

Ellyn Russo: Definitely that awareness and education piece is crucial. I think knowing what's available, making sure that networks of clinical trials are not just available in the academic medical centers. You know, I think that kind of gets back to the geographical point you're making too, Chris, is that most times a lot of the recruitment is happening in those academic medical centers, but partnering with these other institutions or other communities. A lot of these health systems have gotten bigger, so a lot of the footprints of the academic medical centers are reaching out. So I think that's definitely going to be helping. And I think also just the public awareness, too, so back to empowering more patients.

And I think a lot of this did happen with COVID. I've heard several stories about how the clinical trials for the COVID vaccine kind of really started in grassroots efforts, right? There's been a lot happening in local leaders trying to sort of reset that mistrust and sort of explain the benefit of it, right? You've got church leaders or you've got the hairdressers in the Black communities, right? I know there was a group down in Baltimore that did a really excellent job at sort of restructuring that and re-fostering that empowerment amongst their communities in order to drum up that participation and engagement in clinical trials.

Education, too, just that what clinical studies are, they're those—as you said in the beginning, Chris, they're voluntary research studies conducted with people. We need healthy volunteers to answer these questions. Safety is a priority. We take your safety first and foremost in here. We have to study it. And that's kind of like a first step. And if we pass that, then we move on, right? And then we can sort of test out the dosage. And then there's always an informed consent process where you agree to it before you start. There's no lying in it, right? It tells you everything that's going to happen, and you can withdraw at any time, and there's sort of that free will that's in there. Those are those ethical principles that have been rooted in law ever since really World War II. So making sure that that's clear to everyone involved and just not ignoring people because there's been mistrust, but taking the time to reeducate and make sure that, now that the trust has kind of flipped the tides a little bit, that there is awareness of what is possible. And that if you're suffering from something, trials are out there and it is an option.

Harnessing geographic data to reach more trial participants

Jeremy Engdahl-Johnson: So taking this conversation about some of the solutions a little further, have you done any work with clients on this and what does that work look like?

Chris Page: I can take that first. We have done a lot of work on this. And I think it comes back to the fact that we have really, really robust data sources along with the expertise that comes with those data sources. So really thinking about like Medicare and Medicaid. And I think we have a really unique library where we can understand where patients with certain conditions live, what comorbidities they're experiencing, what diseases they're experiencing. And so we've done some work where we'll take our claims analysis and identify geographic areas where patients of most particular interest might be living. So thinking about patients with multiple myeloma, are there certain pockets of the country where there's a large Black representation and many patients with multiple myeloma compared to other areas? And so we've done some mapping exercises where we'll identify where those patients reside and then where current clinical trial locations are. And unfortunately right now we'll see a big delta. We'll see some pockets in the South and other areas of the country where there's heavy African-American and Black populations, but they may not be close to clinical trial sites as they exist right now. So as we try to close that gap, where should we be looking for clinical trial sites in the future? And how can we think about building out those networks and having a presence there so that we can better capture that diverse set of patients?

I think another important thing is education, which we touch on a lot throughout this, but developing resources for our clients that can be used with patients. And going back to the placebo concerns, in oncology—and we try to educate on this quite a bit—in oncology, you're very unlikely to get the sugar pill or a placebo. There's some cases where that might be the case because there's no other treatments available. But more often than not, at a minimum, you're getting the current standard of care in that disease state. And I think it's really important for patients to understand that. You're going to get more frequent monitoring. You're going to have access to really, really talented physicians who know this area really well. And so making sure that we're educating patients and stakeholders on these considerations. Ellyn teed it up on lung cancer, too. Sometimes a clinical trial is your best treatment option, but a lot of times that may not be communicated, may not be made aware to patients. So we're thinking through resource development, both educating healthcare providers, as well as patients and advocacy groups.

Ellyn Russo: I would just add that looking at what difference this makes in your overall healthcare experience is something that we're actively working on as well. So think about usually someone who's enrolled in a clinical trial, you're usually pretty health conscious, or at least aware of the healthcare system, probably because you're interacting with it or you've been going to an academic medical center for a while or whatever it is, you're more likely to sign up because you know you can get there or you can get there easily, you can take the time off of work and sort of participate. And so trying to see what that trajectory means for your healthcare experience over time is something of great interest to a lot of stakeholders in the healthcare system. And so if that can change, you know, future use of healthcare, that could again make the proposition, the value proposition for enrolling in a clinical trial different. So that's something we're actively looking at. What does this mean over time for somebody who's involved in a clinical trial? There are some drug trials that are very different, right? They're not always oncology, end-of-life care. So there's different reasons to study kind of what that long-term care looks like or that longer trajectory.

How technology can help expand access to clinical trials

Chris Page: Yeah, that's great. Another thing we're looking at is just how can we address those logistical concerns to trials that we teed up? So one example of that is working with clients on patient-reported outcomes, but not even patient-reported outcomes, but ePROs, or electronically reported patient outcomes. And can we develop an app? So then instead of a patient having to go to a clinical trial site three days a week to say how they're feeling, can they just do this on their smartphone via an app, and thinking through technology to help ease some of the barriers that we're seeing. I think there's a lot of potential there, both as we think about technology and artificial intelligence (AI) and how we can enhance access to and awareness of clinical trials. So I think there's a lot that could be done there and we're really excited to work with our clients on these initiatives.

Jeremy Engdahl-Johnson: Well, Chris, you kind of took the conversation in the direction that I was going to go for our final question, and that's what you see in the future and what maybe you're hoping to see in the near future. I mean, there's probably no single tipping point. There's a number of really important points along the way. What are things that you're looking for in the, you know, let's say a few years out, that would really indicate that we're continuing to make a lot of progress towards a more equitable approach to clinical trials?

Chris Page: For me, it's kind of how can we tap into technology to close these gaps that we're talking about? So we know that patients are spread throughout the country. Some of them may be two or three or four hours from an academic medical center, but they could benefit from these treatments. We need to capture them in trials. We need to understand their experiences. So how can we use technology to tap into that? And a few examples we've heard are having phonebooths at libraries or having retail pharmacies that have phone booths and can help be a segue between the trial and the patient and the healthcare provider. So I think, from my perspective, really just tapping into technology and seeing what we can do to decentralize clinical trials as much as possible so that, whether you're four hours or four minutes from an academic medical center, you have the opportunity to participate.

Ellyn Russo: The decentralization is something that I very much look forward to as well. I've heard several times from a variety of individuals who work with electronic health record data, and sort of at that level of data instead of just claims data, right, where you've got access to clinical information at the same time you're seeing their interactions with healthcare. What they sort of say is, every interaction with healthcare is kind of like a clinical research trial in and of itself, right? Like every individual is having their own little clinical research trial, and that's absurd to think about because there's so many of us and there's so many trials that could be going on. But the more we can sort of harness data from these interactions, the more we can look for using data real-time that are coming in. Most data now is collected electronically that 10, 20 years ago, right, it wasn't. Clinical trials were really truly unique because they collected so much data objectively from people, and so we could actually say, drug X compared to drug Y performed better. Now that's not as hard when we look at, you know, all the amount of people having data entered on them.

Easing recordkeeping to extend follow-up on clinical trial participants

Ellyn Russo: Now, do I think in a few years this could happen? No. But I think that decentralization over time is really what's going to progress these sorts of learnings to happen faster. I think it has to be done rigorously, so I wouldn't say we rush and try and do a clinical trial using observational data, but are there ways we can start to blend the two a little bit more? And to your point, Chris, can we start to utilize resources that already exist? Clinics or urgent care clinics or the pharmacy clinics, can we start to have better access to points of measuring clinical status that we need from patients participating in clinical trials instead of having to rely on all these transportation issues? Which is exactly what you're saying, right? Loss to follow-up is like the biggest issue with clinical trials and it's so important.

A lot of times clinical trials also say, back to my example about sickle cell, you know, we can't call it curative yet because we haven't studied individuals for long enough. Well, let's get longer follow-up on individuals and really see the long-term effects of different therapies, of different types of exposures to different radiations or these chemotherapies in cancer treatment, right? Like what happens 10, 15, 20 years down the road? We don't know. A lot of trials weren't done for that long, but now they can be because we're seeing this data be entered for longer terms on patients. And you can change what types of data you're entering a lot faster and easier. So again, I think this isn't to say that I want it to mix up observational research with clinical trials. They're done very differently. They're done, you know, a clinical trial is very robustly done for a reason. It's randomized, it's got very specific data that are quantified at intervals so that we can really assess that effectiveness. But if there's ways to start to blend them and increase that access so that fundamentally we can see more representation of individuals that we haven't seen before, I think we'll start to be able to get drugs to people who've never had them before, who've never had as great access as before.

So really that's the end goal, Jeremy, is if we see that access to drugs ultimately is equal sort of across all races, across all ages, across all geographies, right, then we know the clinical trials have had their impact because that awareness has increased and we've tested it. And if ultimately every patient is getting access to the drugs they need, then we know that the clinical trials have really been successful at being as representative as possible.

Jeremy Engdahl-Johnson: Great. Well, thank you both for your insight. To learn more about Milliman's health equity research, visit milliman.com.