What medical trials accomplish, and how to volunteer for one

Host Amber Smith: Upstate Medical University in Syracuse New York invites you to be "The Informed Patient" with the podcast that features experts from Central New York's only academic medical center. I'm your host, Amber Smith. Many advances in medicine are made only after people have volunteered to be human subjects, testing a new drug or procedure, in what are known as clinical trials. Each of these controlled scientific experiments is overseen by a principal investigator, and today I'm speaking with someone who has vast experience with a variety of clinical trials, including some that are ongoing. Dr. Stephen Thomas is a professor of microbiology and immunology, and infectious disease, and he also leads Upstate's Institute for Global Health and Translational Science. Welcome back to "The Informed Patient", Dr. Thomas.

Stephen Thomas, MD: Thank you, Amber. It's good to be back.

Host Amber Smith: I know that clinical trials are very regulated. Can you walk us through, in general, how and why they're done?

Stephen Thomas, MD: You're right, they are very regulated, and there's a number of different steps that a trial has to go through before it can actually be implemented, and you can start advertising and recruiting and engaging potential volunteers. So, the first thing that has to happen is that the plan has to be assessed for its scientific rigor.

And so there's usually a scientific review committee that looks and makes sure that the questions you're asking make sense and can actually be answered with the trial that you're proposing. And then, once scientific review is acquired and you pass that, then you typically go to an IRB review, so an institutional review board. Sometimes they're called ERC's, ethical review committees. These are groups ofobjective, disinterested parties, so they're not involved with the conduct of the science, and they look at your plan primarily for safety. And they want to make sure that, in addition to adhering to sound ethical principles of doing human research -- which, there's lots and lots of literature, and there's federal guidelines and state guidelines and institutional guidelines -- they want to make sure that there's a plan in place to ensure the safety of the volunteers. So that's kind of locally.

And if you're doing something with an investigational drug or medical device or vaccine, then the FDA (Food and Drug Administration) often gets involved, and they have to also have a review of what your plan is and what the product is that you're testing, and they have to sign off, again, primarily on safety. So, there's lots of checks and balances before a study can even begin.

Host Amber Smith: So people can't participate in something until it has cleared that first hurdle about being found to be safe.

Stephen Thomas, MD: These early-phase trials, so these phase 1 trials, those are typically done in small numbers of people, and their primary focus is on safety.

So, there's always going to be a first, and they're called "first in man" studies or "first in human" studies. but to even get to that kind of first in human study, you have to go through all the reviews that I just mentioned. And usually, the way it occurs is there's what they call a preclinical development program, which involves doing things in the laboratory, doing things sometimes in animal models, ensuring that the manufacturing process, if it's a vaccine or drug or device, make sure that that process has been audited and is high quality. And again, the FDA looks at all of that prior to allowing anyone to participate even in those phase 1 safety trials.

Host Amber Smith: How many more phases are there after phase 1?

Stephen Thomas, MD: Well, it used to be there was phase 1, 2, 3 and 4. So phase 1 is, again, a small number of people. It could be anywhere from 10 up to a hundred people, although that would be a a bigger phase 1, and the primary focus is safety.

And then phase 2 trials, those are bigger studies, and those can be hundreds of people. And the focus is still safety, but this is also where you're looking to get some early indication that the vaccine or the drug, for example, is doing what it's supposed to be doing.

So, let's say for a vaccine, they would start measuring immune responses, or they would do large-scale measurements of immune responses in these phase-two trials. And then phase-three trials are typically what we call clinical endpoint studies or efficacy studies. And this is where, even though safety is still a priority, you do trials on thousands and thousands of people.

So just for context, the Pfizer, BioNTech and Moderna COVID vaccine trials, those phase 3 trials were 45,000 people each, and this is where you see if the vaccine or the drug is doing what it's supposed to do, and in most cases, it's having some kind of positive clinical benefit for the person who receives it.

There are some variations on those themes. So there's, phase 1-B trials and phase 1-2 trials and phase 2-B trials. But the 1, 2 and 3 are the primary phases.

And then, phase 4 trials: Those are the types of trials that a manufacturer might do after they actually get a license and they get a marketing authorization to sell their vaccine or their drug or their device, in a widespread way.

And those are trials that are done to answer some additional questions. Or they might be trials that are done to satisfy a post-licensure or post-marketing requirement from the FDA. So the FDA could say, "You've shown us that the product is safe. You've shown us that the product does what it's supposed to do, but we have these additional questions, and it is a requirement for you to maintain this license that you do studies that will answer these additional questions." And those are typically phase-four studies.

Host Amber Smith: I understand some trials focus on prevention, others on screening, others on treatment. What types of trials does the Institute for Global Health conduct?

Stephen Thomas, MD: We do all of those types of trials, so we have worked with companies that are trying to make different diagnostic tests. And so those trials might involve a volunteer coming in and giving a small blood sample, for example. We do treatment trials, so we test different drugs to help control HIV infection. We did a number of treatment trials around COVID, so testing antibodies and testing immune system modulators, things like that.

And then we do trials known as experimental human infection trials or challenge trials. This is where you take healthy people and you expose them to weakened viruses or bacteria, when you have a disease that's very hard to study, where maybe the disease occurs primarily in vulnerable populations and you want to do some explorations prior to going into those vulnerable populations. You can do these experimental infection trials.

And then we do lots of vaccine trials. That's probably the thing we do most frequently.

Host Amber Smith: This is Upstate's "The Informed Patient" podcast with your host, Amber Smith. I'm talking with Dr. Stephen Thomas, the director of Upstate's Institute for Global Health and Translational Science.

Before we resume our conversation, I want to let listeners know the website upstateglobalhealth.org contains a list of clinical trials written in plain English. So if you're interested in learning more about any of the trials we discuss, upstateglobalhealth.org is a good place to start. Also, the phone number to call if you're interested in volunteering is 315-464-9869, or you can send an email to [email protected].

I'll be speaking with one of your colleagues about clinical trials involving children later on in the program, but I'd like to ask you about adults who volunteer for clinical trials.

Where and how do you find people to volunteer?

Stephen Thomas, MD: It's changed over. my career, I've been doing this about 20 years or so, and it's changed probably in a way that you can imagine. Advertising and recruitment through social media has become a lot more popular.

We still do radio and TV once in a while, and we will have billboards. You might see billboards up around the city. We, send emails. We send flyers, our recruitment team will go to social events, you know, a baseball game or a football game, or they'll go to some other kind of social outing where folks might want to hear about what we're doing.

And then we're on Facebook and Instagram and LinkedIn and these other places. Sometimes we're recruiting or advertising a specific study. And sometimes it's a little bit more generic, but social media is the primary way to get in front of a lot of people with relatively, I won't say little effort, because it's a lot of work for the recruitment team, but it's a different kind of effort than pounding the pavement, which is what has had to be done in the past.

Host Amber Smith: Do scientists ever volunteer for their own research, or can their colleagues or students volunteer?

Stephen Thomas, MD: We have pretty strict rules about that. Again, mostly from an ethical standpoint. You hear all these stories from the past of scientists inoculating themselves with things or trying treatments, on family members and. that's really kind of frowned upon. Now, you really want to make sure that, in addition to being extremely safe, you want to make sure that the data you collect is high quality, and you don't want family members or people who are actually part of the research team to be part of the studies. And there's also concern about the potential for coercion, right? You don't want bosses asking their other people who they work with or who work for them to participate, because they may feel like they really don't have a chance.

All that being said, I will tell you, I did volunteer when I was in training at Walter Reed (military hospital). I participated in a malaria vaccine trial. Actually, that was well outside my area. I didn't do any work in malaria, really, so it was an interesting experience, one I thought that if I was going to do this for a living, I should see what it's all about first.

Host Amber Smith: Well, what's in it for the people who volunteer, beyond altruism?

Stephen Thomas, MD: Well, we really hope that that's the primary reason that people explore and then ultimately volunteer. You know, in a lot of these studies, there really is no direct benefit to the person, and it is the advancement of science. It is the answering of questions. It is the potential indirect benefit that, they, but more than likely, the greater society will. get from their participation.

One example, I mean, recent example, of course, would be the COVID vaccine trial. We had thousands of people wanting to participate. In the end, we had, about 470 people or so who participated. And, you know, this was a placebo controlled trial. So it's possible that, you know, some people got placebo, some people got vaccine, no one knew who got what, and so you were not guaranteed to be first in line to get vaccinated.

It's possible you might have gotten placebo. So, altruism in the advancement of science is really what we want the driving force to be behind our volunteers.

Host Amber Smith: I'd like to hear about some of the trials you have underway. I've seen billboards recruiting people for a trial about a vaccine for dengue fever.

What can you tell us about that and how the trial works?

Stephen Thomas, MD: Dengue, it's a disease where people, get fever, they get eye pain and headache, and, they can get bone pain and muscle pain. They can have, fatigue. it's a disease that is, caused by four different viruses.

And those viruses are transmitted by mosquitoes, and it's primarily spread in tropical and subtropical parts of the world. There's about, they estimate, around 400 million people a year who get infected globally. So it's a big problem, and anywhere from 10- to 20,000 people die every year because of it. And unfortunately, primarily children.

But we have had dengue outbreaks in the United States. We have it in the Texas-Mexico border. We've had it in Miami and parts of Florida. Hawaii has had outbreaks. Key West had a big outbreak, and we have lots of travelers who come back from Southeast Asia or the Caribbean and territories like Puerto Rico.

And our military is at great risk of dengue when they deploy servicemen and -women to these different areas. So, that's dengue, and that's why we work on it. And we do lots of different work. We work on vaccines. We work on drugs that we hope will prevent dengue. We work on drugs that are intended to treat people who develop severe disease. And then we do these experimental infections with weakened dengue viruses to improve the information that we get out of these trials.

We're doing a trial right now. We're in the middle of a trial that is looking at an experimental drug that would prevent and / or treat dengue. And you know, unfortunately this problem has been around for a very, very long time, and we've been working for a long time on vaccines and drugs, but we just really don't. Have that many tools. And so these trials are really, they're extremely important, especially as the mosquito finds a permanent home in places like the United States or even in parts of Europe, and its habitat is expanding as the climate manipulates and changes over time.

Host Amber Smith: How do you convince people to willingly be injected with the dengue virus? Some people will be injected with the virus, is that right?

Stephen Thomas, MD: It's the same process that we go through for any of these studies, and it's called the informed consent process. It's probably the most important element of human clinical trials that we do. And so this is the process where people, first of all, we will provide them information in writing, that they can read and look through. And it has information about the problem we're working on and what we think our potential solution is, and how we want to study that solution, and what their role would be, and what the risks are, and what the potential benefits are, and very specific details about how many visits are you going to have? What's going to happen at those visits to the clinic? Are we going to text you? Are we going to give you phone calls? Are we going to, everything from the science, to the logistics to financial reimbursement for expenses that they incur. It's all part of the informed consent process, and it's a process, so it doesn't happen once and then stop. It's a continual process that goes on throughout the entire, the entirety of the study. Sometimes we will, to ensure that people understand the risks and the benefits and the purpose of the studies, we sometimes will have tests that people have to take, and they have to score a certain grade to be able to be in the study. And sometimes people will clearly kind of not understand what we're doing, or their schedule versus our schedule really won't work out. So we recruit lots and lots of people, and we screen lots of people for these studies, in hopes to get what is usually small numbers.

Host Amber Smith: What happens if someone in the dengue trial develops a bad case of dengue? Do the researchers take care of that research subject as a patient then?

Stephen Thomas, MD: Even when you're not doing these experimental infection studies, there is always the potential that somebody -- one in a million people have allergic reactions to vaccines, right? -- or somebody might a sore arm, or they might get a rash. Whatever the issue is, these trials are designed to identify the issue, to provide them a direct link to a healthcare team, which, our investigators are doctors and nurse practitioners and physician assistants. And we have a large nursing staff that are part of the study. And we have research pharmacists. So when a problem, or a potential problem is identified, we are on top of it, quickly. And you know, this is one of the good things about being an academic medical university. We have the medical infrastructure to take care of people if they need it.

In the dengue studies, the earlier dengue infection studies we did, there are some studies where we automatically will put people into the hospital, not necessarily for safety, but to do some of the research that we need to do. So, for example, if we have to take vital signs multiple times in a day, a 24-hour period, or we have to get multiple blood draws, or if someone has a persistent fever or something like that, then we will proactively admit them to the hospital for, usually, it turns out to be about a day or two, maybe three. So, yep. Safety, again, is the No. 1 priority. That's what we're committed to. And so we have all the infrastructure in place to ensure volunteer safety.

Host Amber Smith: That's good to know. Well, what other trials do you have the most pressing need for volunteers at this point?

Stephen Thomas, MD: We're finishing up our COVID vaccine trials now. So that's two-plus years that we've been involved, so those are closing down.

We're involved in influenza vaccine trials, made with messenger RNA technology, similar to Covid (vaccines.)

We have a big registry that we're doing with the National Institutes of Health and the University of Maryland. So this does not involve any products. Per se. This is people registering and us following them over, we see them a couple times a year, and we draw blood and we track influenza or other influenza-like illnesses, and we track their vaccines, because we're looking at, we're trying to figure out what types of immune responses are maximally protective against flu. So that's a big, huge multi-university project that we're involved in.

We're doing a yellow fever vaccine study. That's another virus transmitted by mosquito. But we're not enrolling right now. We've completed our enrollment.

I would say that the most pressing trial we have right now is the one we've been talking about, which is the dengue drug trial. That's one that we're right in the middle of, and we're really hoping, we need about nine more people to finish the study. So we're advertising a lot, and we're looking for people who are interested to hear more.

Host Amber Smith: So tell me those people, what age range, and is there anything that would disqualify someone if they're interested in participating? What type of person are you looking for?

Stephen Thomas, MD: We're looking for young, healthy people, so they have to be adults, so they have to be over 18. And they have to be healthy, so meaning no acute medical problems. If they do have medical problems, they're mild in nature, and they're adequately managed. One of the benefits that people do receive when they screen for our trials is, they basically get a full medical history. They get a full physical exam. In many cases we do blood work looking at kind of routine sorts of things like how their bone marrow's working, their kidneys, their liver. In some instances, we will do EKGs, so we'll look at their heart rhythms and the electrical activity of their heart. In some cases, we even do ultrasounds of the heart.

So generally, basically young, healthy folks. But sometimes we have trials that are specific for older folks. Again, you remember the Pfizer BioNTech vaccine trial. We enrolled people up to 85 years of age. So it all depends on the trial, but for dengue, it's young, healthy folks.

Host Amber Smith: So up to age 65 for dengue?

I think that one's up to 50.

Host Amber Smith: Up to 50. Let me ask you, do volunteers ever get paid?

They do. We typically, for most trials, we reimburse people for expenses that they may incur for participation. So, we understand that people, they have to have transportation. They might have to pay for parking, if we're not paying for it directly. They may miss work, and in some cases people might miss some wages, right? If they have to come to the clinic as part of their research activities. Sometimes we have to have people stay in a hotel, and so obviously we will pay that bill. And, in some of the studies, if people have to come to lots of visits, and they're getting lots of blood collections or they're doing other activities, the pay can be significant. But, I will just say that I highly recommend that people not focus on that. If they're considering volunteering, they really should focus on whether or not this is something that they want to do for altruistic reasons or to advance science. Because we make sure that the reimbursement is, it's reasonable and it is not going to coerce or convince somebody to do something and participate in a trial that they otherwise would not want to. Do the people who participate have to have their own health insurance, or does that matter at all?

Stephen Thomas, MD: In many cases, especially for, like, the dengue trials, we do look at people's medical records just, again, as part of that health screening to make sure. We will learn from them whether they have a primary care physician or not and where they get their care and those sorts of things. We do not get into people's socioeconomic status, if you will, right? We're interested in whether people are healthy or not, and whether or not they can meet the requirements of the study. And so we want to make sure that they can participate safely, and that they are able to complete the study, that we can remain in contact with them, that we can make sure they'll make it to the appointments.

Those are the types of things that we're interested in. And there's very clear language in these consent forms about how illnesses or injuries, if there are any, will be will be managed. And it's our responsibility too, to make sure that anything that happens as a result of participation, that we make sure that people are properly taken care of. So, again, I've been doing this for a long time, and the pretrial processes and checks and balances and reviews are robust and rigorous enough that we really don't go to these human trials without a great sense of confidence that we're embarking on a safe activity.

Host Amber Smith: So at the end of the trial, do the researchers let the research subjects know the outcome and what happens? Or do you send them copies of the paper you write? Do they find out what a difference they made?

Stephen Thomas, MD: It depends on the trial, and it depends upon what we're actually testing. So for the Covid vaccine, you remember this trial was ongoing when the FDA issued its first emergency use authorization. And there was discussion amongst the FDA and the advisory boards to the FDA about, well, what do we do with these 44,000, well, and if you count Moderna, the 90,000 people who volunteered for trials? Half of them got placebo; half of them did not. And now every adult in the US is eligible to get the vaccine. We can't put these people at the back of the line, right, because they decided to serve their community and volunteered. So, we had to go through an unblinding process and offer the opportunity to people "hey, if you want to know what you received, and then if you received placebo, if you want to receive vaccine, then we will make that happen for you."

So in that case, yes, but most of the time, there are sort of very intensive and very kind of technical tests that are being run on these blood samples. That's not information that volunteers want. You know, for the most part, they don't want that information. And oftentimes, obviously, it's information that needs to be, checks and balances on that information before companies can make it public, right? So usually the volunteers are not asking for that very detailed information. They just say they hope they made a difference, and they were glad to participate, and then they wish us luck.

Host Amber Smith: I wonder -- because it seems like human volunteers are essential to these trials -- I wonder how development of the COVID vaccine would have been affected if you didn't have people who were willing to volunteer.

Stephen Thomas, MD: Well, if you remember, people initially were very curious and in some cases dubious, about this messenger mRNA technology, right? And, they were surprised to hear that this is something that had been worked on for 30 years. That technology was first explored a long, long time ago, and that technology had been used to make candidate vaccines against a number of diseases : influenza and Zika and HIV are a few of the examples. And, those trials, and they did trials, they did early phase 1 and phase 2 trials, and so, thousands of people had received a messenger mRNA-based vaccine candidate, but there was never there just the situation was just not there to motivate the advancement of those vaccines into much larger studies. And so unfortunately, COVID presented that opportunity and that, "OK, well, we have a pandemic. We have thousands, millions of infections, and we have people getting sick and..." All that being said, if people did not volunteer to be part of the trials, and to either receive placebo or receive an experimental vaccine and then to allow us to watch them over time in their environment, the vaccine would've never, certainly not within a year, but potentially never would've demonstrated that it was safe and that it was effective. There are very few ways, other than doing human trials to get something approved, right? And, it's more than just getting an approval, right? It's developing a fund of knowledge and experience, and past performance of something so that everyone can feel comfortable about rolling their sleeve up and getting vaccinated.

Host Amber Smith: Well, Dr. Thomas, I thank you for making time to talk about clinical trials.

Stephen Thomas, MD: Well, thanks very much for having me.

Host Amber Smith: My guest has been Dr. Stephen Thomas. He's the professor of microbiology and immunology and infectious disease at Upstate, and he's also the director of the Institute for Global Health and Translational Science, which has the website, UpstateGlobalHealth.org. The phone number is (315) 464-9869, and the email is trials -- t r i a l s -- @Upstate.edu. "The Informed Patient" is a podcast covering health, science and medicine, brought to you by Upstate Medical University in Syracuse, New York, and produced by Jim Howe. Find our archive of previous episodes at Upstate.edu/ Informed. This is your host, Amber Smith, thanking you for listening.