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RealTalk MS
Special Episode: Dr. Aaron Boster Explains MS Clinical Trials
00:33:37
You're living with MS, and maybe you're thinking about participating in an MS clinical trial. But how do they work? Are they safe? What's the difference between Phase 1, 2, and 3 trials? What are the real patient risks and benefits of participating in...
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Transcript34 lines
- [00:01]
A
I'm john strum and this is realtalk, mississippi.
- [00:18]
Welcome to the first in a RealTalk Ms. Special series on Ms. Clinical trials. This special series is made possible through a generous grant from Sanofi. In today's episode, Dr. Aaron Boster gives us an overview of the clinical trial process, including a detailed discussion about patient risks and benefits. Dr. Boster is the founder of the Boster center for Multiple Sclerosis in Columbus, Ohio, where He brings over 20 years of experience as an Ms. Clinician. And Dr. Boster has participated in more than 65 clinical trials. In a moment, we'll hear my conversation all about clinical trials with Dr. Aaron Boster.
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Doctor Aaron Boster brings over 20 years of experience as an Ms. Clinician and he's participated in more than 65 clinical trials. It's always great to welcome you back to the podcast, Dr. Boster.
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B
It's great to be here. Thanks for having me back.
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A
Today we're talking about clinical trials and you're a principal investigator in a clinical trial for an investigational disease modifying therapy called Fraxalumab. While many of our listeners might hear the term principal investigator or PI, they may not fully understand what it entails. Could you explain your role as a PI in a clinical trial like the one for Fraxalumab?
- [01:47]
B
With pleasure. When drugs are developed, typically a manufacturer, in this case a company, Sanofi, develops a molecule or a drug or a potential drug that they think is going to be fantastic. And they think that because they've tested it in a bench science environment, maybe even with mice or something like this, and then they get ready to move into testing in humans. But the manufacturer is a drug manufacturer. They don't have like a group of people that they could test with. And so what they do is they partner with clinical guys like myself. And we are doctors who run clinical trials and in partnership we will conduct their experiment at our center. So I'm considered a principal investigator, meaning I'm the guy that's running the trial at my center. Now There will be 100 plus principal investigators throughout the world that are all enrolling patients with Ms. Into the trial at their individual center and then all that data is pulled together to be able to conduct the proper science.
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A
So what are your primary responsibilities in this role? Both toward the study participants and toward the scientific integrity of the study itself.
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B
So it's actually a very large task. And I am responsible for identifying appropriate patients who meet the criteria for the clinical trial. I'm responsible for liaising with those patients, talking about the trial, seeing if they're interested and if they express interest, educating them about what they're being asked to get into, I am responsible for going through a rather in depth consent process where they're made fully aware of the risks, the benefits, and so on and so forth. Then I enroll them into the trial, and then I am legally and medically responsible for all things that happen in the trial at my site. So the administration of the study drug, which we keep in special locked refrigerators, the monitoring of the patients, drawing their laboratories, all of the clinical investigations they go through, all of the MRIs they receive, are done under my supervision. Now, I obviously don't do the trial in a vacuum by myself. That would be impossible. In fact, I have a very large clinical research team and I am responsible for all of their actions. So I'm sort of like the shepherd to make sure that the trial is executed properly, with integrity, and that the patient's well being is always first and foremost in all decisions.
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A
I want to backtrack a little bit and ask what first sparked your interest in wanting to be involved in the research side of multiple sclerosis?
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B
I wanted John to go into Ms. When I was a kid because my uncle had Ms. And I wanted to learn to do it better. But I didn't know what that meant. And I went to med school with the goal of being an Ms. Doctor, although I didn't really know what that meant either. Then I went to neurology residency, and while I was in neurology residency, I applied to go on to become a fellow in Ms. So back up a step. I'm applying to medical schools and I'm an undergraduate, and one of the medical schools I interviewed at, a neurologist was interviewing me and he said, what do you want to do when you grow up? And I said, I want to do Ms. And he said, well, are you going to do that in private practice or in academics? And I honestly said, I don't know the difference. And he smiled. He says, let me explain the difference to you. He said, if you go into private practice, all you can do is pedal what's currently available, which in your field is terrible. At the time that was true. He said, if you go into research, then you can help develop new therapies to help more people. And at that moment I decided that I was going to go into academics and do research. Now, fast forward a bunch of years and I'm actually in private practice running my own research clinic. But that's beside the point. I learned very early on that if I wanted to move the field forward and I wanted to help fight back and find new ways of trying to beat this disease. That it was important that I participate in that research process. And so then the, you know, the rest is history.
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A
What do you find most challenging about being a PI for an Ms. Trial? And I'll ask you the flip side of that same coin. What do you find most rewarding?
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B
I'll answer it in reverse order. What I find most rewarding is the opportunity to bring an option to a family in my hometown where I practice Ms. Neurology that they otherwise wouldn't have access to see. Most people, John, they're more than happy to have their disease treated right, which is wonderful for some people. And I would say they're the minority. That's not enough. They want to stick it to the disease. And there's arguably no better way to stick it to the disease than to volunteer your body to help find a new therapy which you might not even benefit from. But someone who will develop Ms. In the future, someone who's maybe not even born yet, will benefit from that endeavor. And so to be able to offer that opportunity to someone I think is really special. It's a really awesome thing to get to participate in.
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What's the toughest thing? Honestly, the trials are very, very tedious. So the day to day operations of a trial is extremely tedious and requires a tremendous amount of very close attention to detail. Just to give you an example, when someone comes in for a clinical trials visit, they may need to have several MRIs, they may need to have 20 laboratories done, they may need to have a series of papers that they fill out, questionnaires, and they may need several specialized exams. All of those things are timed perfectly. They have to happen on certain days, sometimes at certain hours. Nothing is allowed to be missed. And so the attention to detail is something which bluntly is a little bit less fun. But it's very, very important.
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A
Clinical trials happen in phases. We hear about phase one clinical trials, phase two, phase three clinical trials. Could you briefly explain what researchers aim to learn at each phase, perhaps using the fraxalumab trial as an example of where it fits?
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B
Absolutely. So as I was mentioning earlier, a drug manufacturer will develop a potential drug, a molecule, let's say, that they think is going to be fantastic, and they'll test it in animal models of Ms. So one of the most common animal models, models of Ms. Is called the EAE model. It's a mouse model. But I don't treat, I'm a doctor. I don't treat mice, I treat humans. And so at some point you have to transition from experimenting in mice to actually testing the drug in human beings. And that happens in stages. So the first phase, which we call appropriately phase one, is, I joke, when you give the drug to poor college kids and see if they blow up. I'm saying that tongue in cheek. What you're doing in phase one is you're testing the safety in dose finding, typically in healthy controls. And that'll oftentimes be done in a very formalized, safe setting, like in a hospital sometimes. And you're not trying to prove the drug works, you're trying to prove that it's safe. You're trying to understand exactly how the drug works in the human body because humans are not mice. And you're trying to figure out which doses you're going to be testing. So that's a phase one experiment. And any drug is going to start off with a phase one in humans. Once you establish, okay, this is a drug which is safe to give humans, we understand how it works in the human being, like how long it takes to get out of their system, et cetera, et cetera, and we start to get a sense of dose finding, then we move into phase two. Now, phase two is where for me, it starts to get exciting because in phase two is where we now test the drug in the patient population of interest. So friclizumab is a medicine, it's a potential medicine, it's investigational product which had a very successful phase two trial. And in the phase two trial, you're testing it in people impacted by ms, but you're not testing it to prove that it works clinically to the satisfaction of say the FDA or the ema. You're doing what's called a proof of concept, where you're showing that the medicine is safe and effective in people with ms, in that it cleans up a surrogate or a biomarker, almost always the MRI. So in the fraxillumab trial, we enrolled patients with MS, relapsing MS, and it was a 12 week, three month period of time where they were getting a placebo or the real drug. It was a placebo controlled, double blind study. So for three months they got an infusion in the vein which was either, and I oftentimes call the drug Frexa, which is either Frexa or it was placebo, dummy drug. And after three months, everyone left the double blinded phase and they went into a long term extension where everyone was on Frexa and they Knew it. Okay. And what they Learned during those 12 weeks was the people that were getting the real drug, their MRIs look much, much, much better than the people that were getting placebo. Now, they also tested a lot of other things. They actually showed that it decreased relapses and so on and so forth. But again, the goal of the Phase two is a proof of concept, and you're testing it for the first time in people in the population of interest. When a phase two is successful, then you move on to the phase three trial, which is what we're doing right now. So I'm in a primary investigator for the phase three trials. Phase three trials are used again tested in people with ms, but this time it's to prove that the drug works clinically to the satisfaction of a regulatory body so that it can become FDA and EMA approved. And so we have a very successful phase two trial which has been presented, and it's actually very robust and exciting. And now we're conducting the phase 3 trial to prove unequivocally that it works for people impacted by Ms. How important.
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A
Is diversity in terms of race, ethnicity, age, Ms. Type and disability level among participants in Ms. Clinical trials? And what efforts are made to ensure that clinical trials are truly representative of the Ms. Patient population?
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B
Simply put, John, it's super, super, super important that the people that we enroll into a clinical trial represent the people that have the condition. And to speak about history for a second, very humbly, until recently, we Ms. Neurologists did a bad job of that. And I'm very ashamed that there were trials conducted in the 90s that didn't enroll anyone that wasn't white. It barely enrolled people over the age of 50, and it really enrolled groups of patients that were not representative of the population at large. And the reason that's a travesty? Well, actually, there's several reasons. One of the biggest reasons that's a travesty is we then have to take the data from a clinical trial and apply it to people with Ms. Well, if you never tested, let's say, an African American with Ms. With a given drug, you don't know if it works in an African American with Ms. And that is something I'm very proud that we have worked very diligently in the last, I would say, 10, maybe 15 years to correct. And so there is a giant push amongst Ms. Neurologists like myself and amongst academic institutions and amongst pharma, the manufacturers of these medicines, to insist upon as much diversity to include ethnicity, to obviously to include gender. And to include age. Why? So that we have a representative population. When we look at a human being in my clinic, someone with ms, and I say, okay, I need to put you on a therapy. I'm going to make sure that human being kind of looks like the trial population so that we can apply that drug to them. And so that's why inclusion is really, really important. If I can say another two words about that.
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Historically, something horrible happened in the 1960s. This was maybe one of the darkest times in modern medicine ever. And it happened here in the United States and in the south, where there were some very, very unethical clinical trials conducted amongst African American laborers who had syphilis. And this is called the Tuskegee Trials. And some people listening may have heard of them, where scientists, doctors, would identify gentlemen, African American gentlemen that had syphilis, and not tell them they had it and not treat them. And they watched what happened over time. And even saying it out loud makes me emotional, because that is absolutely abominable. Now, two things came out of that. Number one, we have created something called institutional review boards, or IRBs. Institutional review boards are governing bodies that every clinical trial is required to go through. So I can't do a trial at the Boster center for Ms. Unless it's run through an irb. And that IRB is created to ensure that the patient safety is always maintained at all cost. Right. And so that's something that's very, very important that came of it. A second thing is that there's been a cultural fear, largely with African Americans in the United States, to participate in clinical trials for a really good reason. And some of the recent research done looking into this, which identified that, for example, African Americans aren't invited into trials as frequent, was largely because doctors didn't have the guts to ask. Right. And so I think being aware of our history, even as dark as it is, understanding what we're trying to do and what we're trying to overcome is really important if we're going to be successful as a community of Ms. Treaters.
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A
Well, while we're talking about who participates in clinical trials, I'm hoping you'll talk a little bit about how eligibility for a trial is determined, maybe share some common reasons why someone with Ms. Might or might not qualify for a specific study.
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B
Absolutely. In clinic, if you have multiple sclerosis, you and I are going to find a treatment for you. And there is a label which is made by the fda, which is like a guideline for me, but I'm not required by law. To abide exactly by it. And we can find a drug that fits for you, even if, like, maybe you have some other medical issues or you're not exactly the perfect example of who is tested. But when you do a clinical trial, it's actually a bit different, because what you're doing with a clinical trial is you're trying to ask a very, very specific question. So with fraxillumab, the question, is this infusion better than a standard of care drug, in this case aubagio? So it's a very specific question. In order to answer that question, we have to try to control for all the other variables.
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So in order to do that, the inclusion and exclusion criteria for a given patient is actually pretty, pretty significant. For example, we would not want to enroll someone that had liver disease into a trial because the drugs are processed by the liver. And you can imagine that might muck up the results. It also might hurt the person. For example, we wouldn't want to enroll someone in the trial that had active cancer because the cancer might interfere with the way the drugs work. When we do a clinical trial, we try to control for as many variables as possible. That translates into rather strict inclusion exclusion criteria. The one that probably emotionally bothers me the most and the one that statistically makes sense is the degree of disability and the age of the patient. So let me talk about both those, please. When we enroll, for example, the relapsing frex trial, we allow people with masks to enter as long as they have a disability up to the level of a cane. But they don't allow people to enroll that are, for example, in a wheelchair. Why? Well, it's not because the people that made the trial are like, mean or evil. It has to do with math. When you reach a disability of a walker or a wheelchair, statistically, those people don't have much fast progression. They plateau there for years. When you're doing a clinical trial, you only have a couple years to find a difference. We enroll patients earlier in their disease process so that there's a higher likelihood of catching change. And mathematically, it actually makes a tremendous amount of sense. But emotionally, it's painful because I don't want to tell someone they're not allowed. Similarly, when we do a clinical trial, there's an age cutoff, and oftentimes for relapsing trials, that age cutoff is about 55. And with secondary progressive trials, now we're extending into 60, which is really kind of emotionally rough because people don't stop having Ms. At 55. They don't stop having Ms. At 60. But again, there's a statistical reason, statistically speaking, you're more likely to have new disease activity in the form of an attack or a new MRI lesion the earlier you are chronologically in age. So if we enrolled, for example, a bunch of bunch, a bunch of people, let's say in their 70s, they could go through three years and not have any change because statistically they weren't going to. And then you can't learn anything. So the inclusion exclusion criteria from a mathematical standpoint, from a statistical standpoint, actually makes a tremendous amount of sense. But again, I'm someone trying to help a family live their best life. And when someone says, I want to participate in a trial, golly gee, I'm excited about that. And so it's very painful when I say, ah, you're not allowed because X and Y.
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A
Earlier you talked about the lengthy consent process that's required for a clinical trial. What are the potential benefits for an individual participating in a trial, and what are the potential risks or downside that they should be aware of?
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B
Absolutely. This, John, is very, very important. Really, really important. So we spent a lot of time talking about this in clinic. And when someone goes through the consent process, which can take a couple hours.
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By the letter of the law, the benefit to the patient, they're not supposed to do it because they're going to get a benefit. Now, that sounds weird. You say what you know, but the goal of entering into a trial is not. So you get something. There may be a benefit if the patient's on a drug they respond to, but that's not why we sign them up. The goal of the intended goal of the trial is to answer a critical question that only they can answer now. But let's be honest, right? There are oftentimes benefits to participating in a trial, whether they're supposed to or not. Number one, it's heroic to participate in a trial. You're helping a population of people, many not even born yet, in a way that only you can help. Nobody else can help. I, Aaron, can do the very best job trying to take care of Ms. I want. I can't develop a drug unless someone with Ms. Volunteers their body. So that to me is actually really, really awesome. Sometimes patients struggle in the United States because of difficulty with access to care, right? Like, so their insurance products or lack of insurance makes it so they don't have easy access to care. In the clinical trial, we don't use insurance. Everything's paid for by the sponsor. And any lawyer listening to this Conversation will quickly say, but that's not a reason to enter a trial. Okay, But I live in the real world where things have to get paid for. And so entering into a trial, it is lovely that it doesn't cost the patient or the family anything. And the MRIs and the treatments and the doctor's visits in the labs are all covered. So that's a nice thing. In recent trials, we now have better appreciation for the fact that the human being participating is being massively inconvenienced. They have to leave work, they have to take time off work, sometimes they have to travel. And so we now compensate them for their time. They get a small stipend. They're not going to get rich, but they get a small stipend to cover their travel and sometimes their lodgings if they have to travel, you know, and for their participation. And I think that's appropriate. I think that's a very, very appropriate thing to do. And when the trial is concluded, the, let's say, the phase three trial, like the FREX trials that we're talking about, after three years of being on either drug A or drug B, everybody gets a chance to go on the study drug, open label. So it's no longer an experiment. And I view that as exciting because if that drug is successful, you know that you're on it, right? It's no longer an experiment, and you get to have it and it's being provided for you. So although we're not supposed to enter a trial because you gain something, I think in the real world, those are things that we consider, and I think those are fair. What's the risk of being in a trial, John? There's a lot of risks being in a trial. We're testing a therapy, so we don't know if it works. We may put you on a therapy that doesn't work. So you could participate in a trial for several years and then not have it, be helpful to your disease. Whereas we could have just put you on a drug through your insurance that we know has been proven to work. So that's a real risk. You might be excited about the study drug and you might be randomly assigned to the standard of care, which might not work out as well. And that's another risk that you don't get to know about when you do a clinical trial. By almost by definition, we don't know all the things that could happen with the therapy. And so you may uncover side effects from the therapy, the investigational drug, which could be scary. And I'll give you an Example I'm currently involved in, we're doing several clinical trials at my center, and I'm commenting on a trial, a different trial than the one that we're talking about here. And a patient on study drug suffered a brain bleed. They bled in their brain. Now, they didn't have symptoms. They're fine. They're doing great. But that was unexpected, and that was on a study drug. And we have to assume that it's related. Right. Another quick example, and I'm using a different study, is someone on a study drug, their liver enzymes shot through the roof, like, scary, and they had to be taken off drug. So I never want to minimize the risk of a drug. And when we go through the consent form, we're literally sharing with the human and with their family every single thing that we know about the therapy with an understanding that there could be surprises. Another risk of a trial is that during the trial, they're blind to what they're on. And I, as the primary investigator, I'm blind to what they're on. And we're not allowed to look at the MRIs together during the course of the trial. The MRIs are reviewed by very, very exquisite neuroradiologists, but they don't inform us of the results. And so that's another thing that we have to grapple with during participation.
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A
One more thing that I know gets in the way. It encourages people, yet gets in the way of their participation. As you pointed out, in the real world, some people choose to participate in a clinical trial hoping they're going to receive a medicine that's going to be more effective at managing their Ms. Some clinical trials don't even use standard of care. They may use a placebo, and that is a concern for potential participants. Can you explain why placebos are sometimes used in Ms. Trials and the ethical considerations around them?
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B
Absolutely. So let's talk about two different kinds of Ms. Which are currently being tested with Frexa. Okay. So right now we're doing two trials at the Boster Center. One is in patients that have relapsing Ms. These are people that are at risk of having relapses. There's another trial in non relapsing secondary progressive Ms. These are people with a relapsing form of Ms. They used to have attacks, but they haven't in quite some time, and they're getting worse in the absence of attacks. So two different populations, if you will. The first population for relapsing MS, we have, I count, 28 drugs currently FDA approved to treat that like 28 different drugs that I could prescribe you to start.
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As a result, when we do a clinical trial. So the Frex trial for relapsing Ms. Is done not against placebo, but, but against a known drug, in this case a Baggio. And the reason is it's ethically, completely not okay to put someone into a three year clinical trial on a placebo drug because we know that there are drugs that work. However, in the non relapsing secondary progressive trial, there is no proven drug that is FDA approved for that type of ms, so we can't compare it to something that doesn't exist. So in order to figure that out, we still ethically must use a placebo. So the patients with non relapsing secondary progressive Ms. That enroll into that trial for Frexa are receiving either real drug or placebo during the course of that trial. And if the drug is found to be effective, it will become hopefully FDA approved and then we will have something to offer those people, meaning in future trials we'll compare it to that drug. This is quite a discussion and I, as a primary investigator for clinical trials, I have to make some ethical decisions when I choose to take on a trial. So I'll give you an example real quick, John. I was offered a phase three trial for relapsing Ms. It was a trial done by a manufacturer in Europe and they were doing a placebo controlled trial. And I said pound salt. I refused to enroll my patients into a phase three trial where they were getting a placebo. And I think a lot of American investigators probably would do the same thing because we have all these drugs available. I do agree with doing a placebo controlled trial for an area where we don't have a known therapy. And so that's what we're seeing right now as we start to study non relapsing secondary progressive Ms. Well, now I.
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A
Have a question for you that may not be specifically clinical trial related, but I can't resist asking, as you look at the landscape of Ms. Research today, what excites you.
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A lot?
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B
I'll separate my thoughts in two. One area that's very, very exciting is an increased ability to monitor and understand the disease. So within the last few years there's been the development in the validation of a blood test which gives us information about Ms. Disease activity. Now, it's not prime time in that it's not covered by insurance yet it's not used ubiquitously, but gosh darn it, that's a really, really big deal to be Able to draw a blood test and then to be able to learn about someone's level of disease activity. So developing biomarkers like that are really exciting because it enhances our ability to monitor the disease and then to make real game time decisions about how we change what we do. So I'm very excited about that. In the world of therapeutics, there's a bunch of things that excite me. There is ongoing efforts at remyelinating therapies, trying to put the plastic coating back on the wire. There are ongoing efforts at neuroprotective agents to help preserve the neurologic reserve. There are ongoing investigations. We're getting better and better at studying stem cell transplantation, for example, which is when I first started to study Ms. Stem cell transplantation could kill you. That doesn't do that anymore because we've gotten so much better at how to do it. And here in the United States, it's not prime time yet, but it's really close. There's even some provocative things that are coming down the pike. For example, I'll share. There's a type of therapy called CAR T cell therapy, which is super amazing precision medicine where you design a special antibody specifically for the individual to target their kind of Ms. And you inject it back in their body and it kind of goes around and finds the naughty autoreactive cells and knocks them out without the risk of massive immunosuppression. So the future is very, very bright. It's very exciting time to be involved in Ms. Research because of all the things that are coming to fruition and for people that are listening, if you're impacted by Ms. Or a loved one is impacted by ms, keep in mind that if nobody volunteered to be in a trial, we'd have no therapy. Zero. And that it's only by virtue of people who are brave and willing to do something heroic to test the therapy out for us to figure it out. Also, if you're impacted by this disease and you don't qualify for a trial, that doesn't mean all is lost. It means that we need to keep you healthy through the currently available therapies so that when those exciting breakthroughs occur, you can benefit from what we come up with.
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A
Well, Dr. Aaron Boster, I want to thank you once again for all you do to improve the lives of people living with Ms. And to improve everyone's understanding of Ms. It's always great to talk to you.
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B
Thank you so much for having me. And until next time, take care.
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A
This RealTalk Ms. Special series on clinical trials has been made possible through a generous grant from Sanofi. Sanofi has two ongoing phase 3 clinical trials in Ms. Studying Frexalumab, an investigational study drug that's a second generation anti CD40 ligand monoclonal antibody. If you're interested in learning more about these clinical trials, I'll invite you to check out Sanofi studies dot com. You'll find that link in today's show notes and be sure to speak to your neurologist about clinical trial participation. I'm John Strum. Thanks for listening. Stay safe and make healthy choices.
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Sam.