Diversity in Clinical Trials Leads to Richer Data

Dr. Daniel Kraft: Welcome to Healthy Conversations, an original podcast from CVS Health. I'm your host, Dr. Daniel Kraft:. And today we're continuing the conversation about broadening participation in clinical trials. If you miss part one, it's available on cvshealth.com, or wherever you get your podcasts. First up, I got to speak with Josh Rose, Vice President and Head of Clinical Trial Delivery, Site Solutions and Strategy for Clinical Trial Services at CVS Health. Glad to have you, Josh. Josh Rose: Hey, thanks for having me, really excited to be here. It's an important topic, and I'd love to talk about it. Dr. Daniel Kraft: So the traditional model of conducting clinical trials in large academic medical centers or dedicated research clinics can often create challenges for recruitment. How's the approach of CVS Health's new Clinical Trial Services Unit different? Josh Rose: It's a terrific question. There's actually challenges across the board, both in getting patients into studies, and also getting them to stay in studies, what's known as retention. One is access to patients understanding where they are. The second thing is overcoming barriers patients may have in terms of trusts in whoever is conducting the clinical trial and trust in the healthcare system, sometimes in general. And the third thing is burden. As you mentioned, sites are not necessarily in the area where patients are, really leads to low patient participation. We have great information about patients, over 100 million identified patient lives through either Aetna or our retail pharmacy. Patients really trust CVS, it's a highly regarded brand. 85% of the US population are 10 miles away from a CVS location, and that's where we conduct clinical trials. So if you take the three of those, we really provide a superior model. Dr. Daniel Kraft: Can you talk about the importance of diversity in clinical trials? How can expanding the patient mix provide value? And what about the clinicians who participate in clinical trials? How do we expand diversity there as well? Josh Rose: When a drug is bring brought to market, it's typically been intended to use by a broad patient population, not necessarily one ethnic patient population or one economic demographic. The challenge that historically we've seen in clinical trials is patients tended to be, you know, more localized and ethnic groups, African Americans, Hispanics, and others, were excluded from clinical trials. And as a consequence of that, the drug that was being brought to market didn't necessarily appropriately represent the more broad use of drugs that is intended, kind of ties back to the comment that I made earlier about the fact that clinical trials historically have been in academic medical centers, places that are far away from where certain ethnic populations are, inner cities, because of the fact that our clinical trials are located in those areas, and studies that we run, we typically see 35 to 40% of diversity patients being included in our studies. On the other side, there's also an issue with lack of diversity in investigators and in other care providers. And that's something that the clinical trial services at CVS puts a lot of emphasis on. We have a goal to have at least 10 to 20% over time of diversity PI's within our network, primary investigators, otherwise known as PI's, oversee our studies. Dr. Daniel Kraft: One of the goals you've outlined is creating a community centric models for clinical trials. What do you think that will look like? And how are you planning location placement to maximize access for clinical trials? Josh Rose: CVS has around 9000 pharmacies across the US and within those, we have around 1200 MinuteClinics, we've converted around 100 of those to be fully blown clinical trial locations. So, uh, clinical trial grade equipment, clinical trial grade technology, staff that's trained in clinical trial conduct. Now, we specifically picked out those locations along the lines of the type of patient population that we were hoping to enroll. Urban areas, areas with high patient density, areas with high diversity, going back to the question that we talked about earlier, to ensure that we are getting much more representation of the broader population. Dr. Daniel Kraft: What are the keys to this, and I think many other health care efforts is data. Can you talk a bit about how having a rich data set will help this effort? And what specific insights can your data provide? How do you share information, if at all with the pharmaceutical companies or clinical investigators? And what about patient confidentiality? Josh Rose: Data is really the most important thing and that data becomes part of your statistical set that ultimately is submitted to regulatory bodies in order to gain approval for the drug, regardless of whether it's done in one of our locations, at a patient's home, using our home research services, or conducted remotely, every piece of data is collected electronically. And it's only collected once. That's what's known as source data. So we don't collect data on pieces of paper, we don't write it down on a notepad and then transcribe it, because it's only entered once, you don't have transcription errors. So, A, it's easy and efficient to collect, and B, it's of high quality and integrity. Dr. Daniel Kraft: And what about patient confidentiality? How do you share information, if at all with the pharmaceutical companies or clinical investigators? Josh Rose: Patient confidentiality is, is not only important for the clinical trials group, you know, it's an important tenant for CVS period. And in that DNA is really the ethos of how we treat patient data and patient confidentiality. Within the clinical trial business, there is a lot of attention to make sure that patient name, patient identity, patient information is being safeguarded, you know, abiding by HIPAA regulations and other patient privacy requirements. Even though CVS has relationships with large pharma, you know, there's really strong firewalls in place, so that patient data that we collect is intended strictly for clinical research. Dr. Daniel Kraft: What is the breadth of your effort? How many trial sponsors are you working with? And are you focusing on a specific set of therapies? Josh Rose: So we've been fortunate to see substantial growth in the clinical trial services business, there really is a need in the industry for different models, in this case, retail clinical trial model, in order to drive higher enrollment, higher retention, higher diversity participation. That's what we provide. And CVS is somewhat unique in the way that we do that. We are seeing a lot of interest and a lot of excitement from large, medium and small pharma, we work often directly with pharma themselves. We also work with what's known as contract research organizations or CROs that have relationships with pharma, and we'll see that they pull us in in order to support studies. With sponsors, we're fortunate enough to be working with many other very large ones, household names like Moderna and Pfizer, we also work with medium and small. We're building a very strong relationship with a small biotech called ProKidney that is really aiming through their drugs to prevent kidney transplants for those with, with chronic kidney care. Dr. Daniel Kraft: Is this effort scalable? Josh Rose: When CVS first got into the clinical trial space, our emphasis was on vaccines and infectious diseases. COVID was where we kind of got our start, and that was really the kernel. But we really expanded our therapeutic capability well beyond that. So today, other areas that we focus in our chronic diseases, whether it's metabolic, cardiovascular, respiratory, CNS, whether it's neurology or pain, and dermatology as well. Dr. Daniel Kraft: Can you talk a bit about your achievements to date, and any data to share? Josh Rose: We've enrolled upwards of 30,000 patients into our studies, that's over the last year and a half to two years that we've been running clinical trials, we are running, or have run more than 40 clinical trials across a wide range of therapeutic areas. And it's interesting, when we ask patients, what are the drivers for their participating in clinical trials? The first thing they say is, what does my physician think about it? Less than 5% of physicians refer patients into clinical trials and much of it is just because of the burden that they don't want to add on to their sick patients. The second question that comes right after that is how far is the location from my home? Average time by the way that a patient drives to a clinical trial location in the US is two hours. In our case, you know CVS is located 10, 15 minutes away. It's a much more familiar setting. Dr. Daniel Kraft: I also had the opportunity to talk to Dr. Joseph Stavas, Senior Vice President of Global Clinical Development at ProKidney. ProKidney is a really exciting company and one of my favorite spaces, regenerative medicine. Dr. Joseph Stavas: Yeah, ProKidney is a biotech company that deals with cell based therapies to slow down and prevent kidney failure in order to avoid the need for dialysis or a kidney transplant. We've been doing this for many years, almost 20 years in preclinical and now in clinical phase trials. Dr. Daniel Kraft: Scope out how big a problem CKD, chronic kidney disease is in United States and some of the underlying factors that exacerbate it and obviously it leads to renal failure, dialysis, needs for transplant. Dr. Joseph Stavas: We hear a lot about chronic disease, whether they're in the heart, uh, the lungs, the liver, the brain in the sense of dementia. Chronic kidney disease, though, is really one of the largest in the world, it's predicted that this is going to be one of the largest global problems in the next 20 to 30 years. Currently, there's no greater than 10% of the global population, with this in the United States, it's about one in seven. And globally, there could potentially be over 800 million based on studies that we have. Now, the thing that's, I think, most important about this, Daniel, is that people that do have it have a lot of other comorbidities. So there's a lot of disease acuity with just this one organ, the kidney, because it does so much in the body besides just be the filter and the plumbing system. And you know that gets a lot of people in trouble when their kidneys begin to fail. Dr. Daniel Kraft: Right. And CKD is often the result of uncontrolled hypertension, or type I or type II diabetes. And so both of those are on the rise. With, uh, ProKidney, you guys are taking again, an autologous cell therapy approach, can you tell us a little bit more? Dr. Joseph Stavas: There are hundreds of thousands of kidneys biopsies done throughout the world, and it's an autologous cell therapy. So it's your own cells. And it's a homologous because the people that provide the biopsy tissue do receive their own cells back. So the biopsy is done as an outpatient procedure where needles and numbing medicine and imaging guidance is used in order to obtain the tissues from a very specific area of the kidney now, then those biopsies cells are then sent to a manufacturing plant, which is very specific, the bio processing aspect of this technology and manufacturing then brings out a specific cell types that we're looking for. And then this is formulated, and in the case of our phase three, it's frozen, frozen and sent back to the site where an interventional radiologist uses CTE guides to precisely placed these cells back into very specific area of the kidney from where they came. And then that is where the cells then begin to take effect with their bio activity. And our goal is to show through our phase three trials, that this does have a potential for improving kidney function, and then allowing the kidney to either stop the progression of the kidney disease, slow it down, or in fact, potentially improve it. Dr. Daniel Kraft: That's fantastic. So you mentioned you're now in advanced phase three trials, and you guys are working with the Clinical Trial Services Unit of CVS Health, give us a taste of how that trial works, and, uh, why you chose CVS Health as a partner. Dr. Joseph Stavas: First of all, the phase three, it's a big leap, it's one of the few FDA approved phase threes cell trials for chronic kidney disease, will be in over 2- 25, potentially 30 countries, it's a large trial of over 1200 participants that we will be enrolling over the next few years. And kidney disease is not equal in certain population groups. It's higher in some and it's lower in others. And as you mentioned, this population does have hypertension, they have elevated lipids, many of them heart problems, strokes. It's a defined level of kidney failure that we're looking for. But also this has to combine with hospital settings or outpatient settings where the interventions can be performed. Now, being a large global trial and a trial that requires much diversity because it's a very heterogeneous, very diverse group racially as far as their location, urban, suburban, and rural areas, and in multiple areas of the world. And we felt that CVS was the best partner out there with their background in data and data management and in accumulation of trial sites. Dr. Daniel Kraft: I imagine this is not a simple trial. It's not like here, take this pill, and let's check back in a month. What are some of the lessons learned whether it's working with CVS or in a complex trial like this, that might be illustrative? Dr. Joseph Stavas: We've done a phase 1, we've got a number of phase 2's, and now we're doing the phase 3, the learnings have been immense at just understanding the team dynamics of the challenges of diversity recruitment, because of the locations of the trials, whether it be transportation, weather. We've also learned a lot about the treatment of kidney problems. Now, we're a cell based therapy, but much of the treatment for kidney disease are pills for a variety of reasons. Because of the kidney's, uh, inherent diversity itself of what it does as far as managing blood pressure, it has management over our bones and metabolism, fluid balances. There's issues that these people have with anemia is because of the poor function of the kidney and the inability to make erythropoietin. So we do run into a lot of other trials that are also looking for similar populations. But again, as trials go, you need these fine points for the randomization, for the control of the trial in order to make sure that the comparator that you're trying your therapy against is also very equal in the match in the groups themselves. So those are some of the errors that we find working with CVS, we've got another wealth of knowledge in their store banks of how they're working with their home healthcare processes to make it a more, uh, robust trial. Dr. Daniel Kraft: Since there are different underlying causes for CKD, whether it's diabetes, or, uh, sometimes congenital issues, can you d- explain some of the applications across the CKD spectrum, and which one are you going after first? Dr. Joseph Stavas: The two most common causes are hypertension, and type II diabetes in the adults, the metabolic syndrome, uh, due to lifestyle, due to a lot of underlying comorbidities. So that's the largest population that there is, and that's the treatment group that we are now targeting with our therapy. Dr. Daniel Kraft: And many of those patients get picked up a bit late, we had an earlier episode of Healthy Conversations, Yonatan Adiri, the CEO and founder of Healthy.io, which can now use a smartphone to screen your urine, maybe get you into a pathway for a clinical trial. I recently spoke with Dr. Owen Garrick from CVS Health about the ability to, you know, recruit that more diverse set of patients as one of the reasons CVS Health decided to launch the Clinical Trials Services Unit. From your perspective, what value does diversifying the patient mix provide in a phase three trial? Dr. Joseph Stavas: The diversification is key, because it does give you the perspective of multiple walks of life, so to speak of the disease and who it affects w- why it affects that population, and just makes your trial more rich in the data that it can provide. So that that diversity can be come part of the trial, and that we will be able to reach many populations. Dr. Daniel Kraft: You've done phase one and phase two, what's your medical endpoint? Are you looking at creatinine? Are you looking at progression to transplant or dialysis? What's your sort of measure of success here? Dr. Joseph Stavas: For the phase three trial, we did pick e- endpoints that needed to be approved by the regulatory agencies, we have been approved for our trial by the FDA in the United States, by the EMA, European Medicines Associations and by the regulatory agency, uh, in the United Kingdom. Dr. Daniel Kraft: And what barriers have you faced so far in recruiting trial participants? And how do you think your collaboration with CVS Health helps overcome those barriers? Dr. Joseph Stavas: Because the awareness, Daniel, of kidney problems and diabetes, uh, for example, there is a lot of competition for patients in this particular space, uh, because there's so much innovation, this does give us this bit of a barrier with all the multiple products that are currently in the pipeline for many companies. The other thing is, you know, we've had campaigns for strokes, we've had campaigns for heart attacks, but for kidney disease, it's still a little silent. And we need to get that word out, because there's so much crosstalk between all the other comorbidities that the diabetics have with their heart disease, their strokes. So bringing those all together and then saying, Okay, here's the potential impact on the kidney, you know, has been a bit of a challenge getting individuals interested in a kidney only trial that is actually more of an improvement in not only, you know, function, but also the structural aspects of a regenerative therapy has been bared. And that's where our collaboration with CVS and their knowledge of trial sites, of data collection, of patient behaviors, has come in handy, and giving us insight into where we can work with that. Dr. Daniel Kraft: So maybe a public service announcement for all the clinicians out there is get your, uh, high risk patients screened for proteinuria to see if they have early CKD. (laughs). Hopefully, they need to progress. But it seems like as you said, it's a bit of a silent disease until, uh, your creatinine gets up there and you end up in fluid balance issues. I always used to be of great awe of the nephrologist I work with. That's one of the toughest fields. I imagine even the role of pharmacists could be enhanced here to identify folks for trials help recruit them, is that something you've been seeing? Dr. Joseph Stavas: Yes, and I believe that that's possible because the role of pharmacists has taken on a new dimension, just the last two years. And again, pharmacists are now being educated and trained for a broad distribution of diseases and the knowledge that they have and the populations that come to see them, could be transferred to that pharmacy role in the way that it makes sense for the trial and is within their scope of, of work. Dr. Daniel Kraft: So now that you've been working with CVS Health, can you tell me what's different from working with other partners, let's say in the trail space? Dr. Joseph Stavas: Data. CVS has a lot of valuable data that can be evaluated in a multitude of ways. There are hotspots of CKD of renal failure in various parts of the world. For example, in the United States, we do know where there are more prescriptions for dialysis related medications, then that would be a natural for an easier recruitment, potentially, where that population is there to then potentially screen them for trial participation. And I think that's what we feel is going to be a big asset for our trial. The surrogate markers are out there for this population with their high, uh, incidence of strokes of needs for lipids, of gout medicines, of anemia medicine. So we find that to be in a very exciting time at ProKidney. Dr. Daniel Kraft: And how do you end up sort of collecting the data and, and sharing it? Do you end up sharing it back to the patients themselves? Dr. Joseph Stavas: Currently, in what we're setting up now is that the data is collected by the sites, transferred to the CRO, and then we will work in methods of de-identifying that because these trials are blinded, and you have to protect that blind in order to incorporate that into our learnings during the trial. Dr. Daniel Kraft: You mentioned this trial has a sham arm, I'm curious, how do you pull that off? Are you actually biopsying the cells, expanding them and in some of you put them back in and some you have just a empty needle? Dr. Joseph Stavas: No, we will be making Shakespearean actors out of many of the trial involved people, for example, the study team. No, the sham is a procedure that is totally fake, we have to fake a biopsy, fake the two injections, nothing goes inside the body or deep, because of the risk of this population, this is what was recommended to us by the regulatory agencies to simulate in a psychosocial way that there would be any biased. Dr. Daniel Kraft: Got it. Fascinating, because you would think that this wouldn't really have much o- of a placebo effect. But someone might take better care of their kidney health when they think they've had the procedure versus not. Cell therapy is, you know, still an emerging area, by transplant or by clinical training. And that's obviously a cell therapy here. But here you're taking autologous cells out, expanding them, manipulating them, and delivering them back. Any sort of pearls of wisdom that you picked up that might be useful? Dr. Joseph Stavas: You see one cell therapy, you've seen one cell therapy, I've recommended people go to the FDA website on approved cell therapies, and you will see the paucity of cell therapies. If you look at the medications, the drugs, there's 1000s, not 10s of 1000s. And if you look at the devices and the radiologic health side, there's 1000s there. But if you look at the, uh, FDA of what's approved in the United States, EMA and Japan, it's all about the same number, there's less than 30. And most of them are cancer related. So it's a very new group of therapies that are in the pipeline, though, Daniel, I'm must stress that we find out with markers and other methods of bringing that cell line out through the, uh, ex vivo processing. One of the things that I didn't want to mention is that there's cell licensing that's required by many countries, because we do take live tissue out with the biopsy tissue, it's not placed in a formula and/or something that's processed by a pathologist. But we do put it in a transport medium that has nutrition, and nutrients in order to keep it alive. So there's a lot of then moving parts j- just transporting the cells away from a site and then back to that, uh, particular site. Dr. Daniel Kraft: Yeah, if you want to challenge, cell therapy is it, so hats off to what you and ProKidney are doing especially with such a challenging, and large and important unmet need to solve. Any things I haven't asked you about are things about or things you'd wanna make sure you covered today? Dr. Joseph Stavas: One thing I think we have to remember is that there is a lot of kidney disease out there and it starts potentially at a younger age, and then it proceeds to the adulthood. So I believe that there is a point of education even early on in a family. It's like anything else, it's kitchen talk. And it could be something that's brought up at the, at the table just as simple as that and not just at the adult because sometimes, like we've seen, it's too late. And then how does that then get back to learnings for other family members that might be having the same genetic problems or the same lifestyle? Dr. Daniel Kraft: Well, thank you so much, Dr. Joseph Stavas, Senior Vice President for Global Clinical Development at ProKidney. Godspeed on your clinical trials and your work with CVS Health, we'll be looking for this trial results.