How clinical trials work; preventing the common infection RSV; ADHD in adults: Upstate Medical University's HealthLink on Air for Sunday, Nov. 6, 2022

Host Amber Smith: Coming up next on Upstate's "HealthLink on Air," a physician scientist discusses clinical research into dengue fever, and he explains how, and why, you can volunteer.

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. ...

Host Amber Smith: And a pediatric infectious disease doctor tells about wrapping up several years of work on a preventive for respiratory syncytial virus.

Joe Domachowske, MD: ... This is the most common reason why infants are hospitalized in the U.S., and really everywhere else in the world. So to see an 80% reduction from this phase 2 clinical trial was so impressive. ...

Host Amber Smith: All that, followed by a visit from The Healing Muse, right after the news.

This is Upstate Medical University's "HealthLink on Air," your chance to explore health, science and medicine with the experts from Central New York's only academic medical center. I'm your host, Amber Smith. On this week's show, we'll hear about research into preventing a common and sometimes deadly childhood virus called RSV. But first, physician scientists in Syracuse are studying dengue fever, and they're recruiting for volunteers. We'll talk about what to consider before signing up.

From Upstate Medical University in Syracuse, New York, I'm Amber Smith. This is "HealthLink on Air."

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 "HealthLink on Air," 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: 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: 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: 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: This is Upstate's "HealthLink on Air," 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'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 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's 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 ... I mean, 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 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 health care 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: So tell me, 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, 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: 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, they did trials, they did early phase 1 and phase 2 trials, and so, thousands of people had received a messenger-RNA-based vaccine candidate, but there was never, 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 a 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 [email protected]. Coming up next: Are we close to having a new preventive for respiratory syncytial virus?

From Upstate Medical University in Syracuse, New York, I'm Amber Smith. This is "HealthLink on Air." Pediatricians around the world would like to be able to prevent respiratory syncytial virus, or RSV, which causes mild cold-like symptoms for most children, but it can be deadly. And, it's the chief cause of hospitalization for children 5 and under. Dr. Joe Domachowske is a pediatric infectious disease doctor and professor of microbiology and immunology at Upstate, and much of his research in recent years has been on RSV prevention. He's here today to tell us about the RSV prevention clinical trials that have taken place here at Upstate. Welcome back to "HealthLink on Air," Dr. Domachowske.

Joe Domachowske, MD: Thanks very much. It's exciting to be here and to talk about this topic in particular.

Host Amber Smith: I understand you're close to wrapping up the last phase of your trials, and you're now seeking FDA approval for the study medication. That must mean that your study showed that this medication works, is that right?

Joe Domachowske, MD: Everything indicates that it works extremely well. And it's very safe. It's a very exciting time because if this meets its promise, we can change the landscape of RSV infection.

Host Amber Smith: Well, can you give us a summary of what phase 1, or the first part of this trial involved?

Joe Domachowske, MD: Yeah, back in 2015, we did the very first phase 1 trial, and there were about 90 babies enrolled in this trial. Phase 1 is very low enrollment, and it really was a dose selection study to make sure that we were giving the right dose and to do some safety information as well. We were the only site in the Northern Hemisphere to enroll any babies. We got three babies before it closed, to enrollment at the beginning of RSV season. Most of the rest of them were enrolled in the Southern Hemisphere.

Host Amber Smith: So this is an international trial?

Joe Domachowske, MD: Absolutely. All of the studies, phase 1, 2 and 3 are international studies.

Host Amber Smith: So what did phase 2 focus on?

Joe Domachowske, MD: Phase 2, we looked at the preemies who were born 29 to 34 weeks. A term pregnancy goes out to 40 weeks. So these are later preemies. And they're not eligible for the currently available prevention medication that we have. So enrollment for this particular group was a little bit easier because many of these folks wanted access to this type of medication for their infants, but they didn't have it, according to the standard of care. So we began that study in November of 2016, and it continued for one calendar year. It was almost 1,500 babies. And we found an 80% reduction in RSV medically attended lower respiratory tract infection. And that means going to their own private doctor, going to the ER (hospital emergency department) or being hospitalized.

Host Amber Smith: Eighty percent is huge, right?

Joe Domachowske, MD: It is. This is the most common reason why infants are hospitalized in the US, and really everywhere else in the world. So to see an 80% reduction from this phase 2 clinical trial was so impressive.

Host Amber Smith: And then phase 3, what has that been about?

Joe Domachowske, MD: There are three phase 3 studies. One is finished, and two of them are going to be done in the next month or so. The first one, and I think the most important one, was the one we did in the preemies, the same group as the phase 2, but more efficacy information. We always collect safety information. That particular phase 3 study also included a subgroup of high risk infants because they were defined as high risk based on having congenital heart disease or chronic lung disease from their prematurity. So the effectiveness of the particular medication in that group and that phase 3 was almost identical to what we saw in the phase 2 study.

Host Amber Smith: Can you explain, it's called nirsevimab, is that how you say it, the study medication?

Joe Domachowske, MD: That's its name, yes. Nirsevimab. Yep.

Host Amber Smith: So can you explain how that compares with a medication that's already available for RSV prevention?

Joe Domachowske, MD: The current standard of care for the highest risk newborns for RSV prevention is an antibody medication called palivizumab. That medication has to be given every month during RSV season, or during the period of time when a baby's potentially exposed to RSV, in order to maintain that protective effect. Because of cost issues and other related logistical problems, we really have only focused on the highest risk infants for receiving that particular medication. In 1998 when it was first available, we gave it to all of our preemies, even preemies that were born at 34 1/2 weeks, close to term. But gradually over time there's been increased restrictions to its use, largely because of the cost.

Host Amber Smith: So, nirsevimab, when was it discovered or created?

Joe Domachowske, MD: Nirsevimab was a product of two discoveries that were made in back in 2014. The first discovery, which made my jaw hit the floor, I was sitting at the RSV International Conference in Argentina -- which was beautiful -- and I was listening to a protein chemist describe one of the proteins that sits on the outside of the RSV virus. And I thought, "I'm a clinical pediatrician. I do clinical research. I'm not sure a protein chemist, I'm going to even understand what's going on here." But everyone in the room listened to this guy's story and what he discovered, and everyone was just sitting there with their mouths open saying, "Wow."

So what he discovered was that we'd been working on the wrong protein up until 2014. What happens is, if you envision the RSV particles themselves, they have these things sticking out the surface of the virus. And if you think of them as sort of daggers with a handle. As soon as those daggers touch a cell to try to infect a cell, the handle of the dagger flips, and the whole confirmation, the whole structural component of the protein changes. We need to have antibodies to protect us based on the pre-fusion, before this dagger touches the cell, not afterward. And we'd been working on the confirmation of the wrong protein for decades. So that was the first thing that happened.

The second thing that was discovered right around the same time was that if we take any antibody, these monoclonal antibodies in particular, and we change the part of the antibody that attaches to the cell. Not the part that attaches to the virus, but the part that attaches to the cell. If we change it by just three amino acids, very small changes, it can enhance the half-life of these molecules from 19 days out to more than 120 days. So now we have the potential of making a very high neutralizing antibody against really whatever we want, that will last a fairly long time, out to five months, maybe longer. So nirsevimab is the first product that's taken advantage of both of these technologies and these discoveries. The company also refined the virus binding part of this antibody so that it's about a hundred times more neutralizing than palivizumab, the product that we're using right now.

Host Amber Smith: Wow, that's interesting. So does it prevent RSV infection entirely then, or does it just prevent the babies from becoming severely ill?

Joe Domachowske, MD: It clearly prevents hospitalization or lower respiratory infection caused by RSV. And there's some indications -- we don't have the final phase three information yet because two of the three studies are not closed up yet. We haven't finished them yet. And so the data are top secret until those last few pieces of information are collected. So at the very least, it prevents lower respiratory tract infection, reducing hospitalizations by 80 to 85% compared to a placebo. And we know that it's very, very safe because when we use the placebo to compare, the side effects from the placebo are identical to the side effects of this medication. So that's how well tolerated it is. Babies are used to having antibodies around because they make their own. And this is a completely human antibody. It's just made in a test tube instead of in the person. So we make it and refine it, and we give it to the babies. And because it has such a long half life, the expectation is we can give one dose, and it will protect these babies for five to six months. That's an RSV season for all of them.

Host Amber Smith: So it's meant to be a preventive. Could it be used to treat a baby that's already sick with RSV?

Joe Domachowske, MD: I suspect not. And the reason I say that is related antibodies have been developed over time -- including palivizumab -- have been tried as adjunctive therapy to treat RSV, and there isn't a single study from any of those other types of antibodies that indicate that that's the right path to take. Will those studies be done with nirsevimab? Probably. But they will be small studies, and I don't think there's going to be very high expectations for it to offer anything, once the babies are infected or once an older child, for example, would be infected. We still don't have any effective treatment for RSV, unfortunately.

Host Amber Smith: I know your trials have obviously focused on children, babies, but RSV can be a deadly infection in the senior population as well. Do you know, or do you think that nirsevimab would work in seniors the same way it does in babies?

Joe Domachowske, MD: I think that the logistics of doing that would be very difficult, bordering impossible, because the amount of the antibody that would have to be given is essentially based on weight. And so, our studies, for one of them, we gave the kids the nirsevimab two seasons in a row, and some of them got up to about 10, 11 kilograms, which is, you know, 22 pounds or so. And that still was a large enough volume that we had to divide it into several different shots. We couldn't give it all in one injection. So if we take that one year old, that 10 kilogram 1-year-old, and we magnify them into an adult and say, "What is this dose that's going to be needed?" It's almost prohibitive to be able to deliver that type of dose.

But there are some strategies. Certainly we learned a lot about monoclonal antibodies with Covid and how they can be both preventative and, in some cases, effective at treatment. So there are some strategies that are being developed using a similar antibody structure and antibody system that may offer that type of treatment or prevention in elderly adults as well.

Host Amber Smith: Upstate's "HealthLink on AIr" has to take a short break, but please stay tuned for more information about respiratory syncytial virus.

Welcome back to Upstate's "HealthLink on Air." This is your host, Amber Smith, and I'm talking with Dr. Joe Domachowske. He's a professor of pediatrics and microbiology and immunology at Upstate, and he's the principal investigator for a series of clinical trials of a new monoclonal antibody designed to prevent respiratory syncytial virus, or RSV.

Now, counting all the phases together of the studies that you've done on this from all countries, how many different babies participated in these trials?

Joe Domachowske, MD: Internationally, I think altogether, more than 150 different clinical trial sites, in over 80 different countries. There were around 4,600 babies studied, for all of the phase 3 trials, the single phase 2 and the single phase 1 trial. So we have the safety information and efficacy information on nearly 5,000 newborns and young infants.

Host Amber Smith: Now, you enrolled the first two infants in the world to receive this investigational medication, more than seven years ago. What can you tell us about these babies?

Joe Domachowske, MD: These are amazing kids. They're twin girls. They're now 7 years old, and they just finished up the Covid 19 vaccine trial that I was doing for pediatrics because they, their family is all very much engaged and interested in clinical vaccine research.

But when they were born, they were born middle of December of 2014, and my site wasn't quite up and running yet, but I was talking to the parents because I figured, if we could get up and running and have all of our regulatory requirements fulfilled, this is a perfect family and a perfect circumstance where we could enroll both of these newborn girls. They were born a little bit premature. They were born at 33 weeks gestation. Twins are often born a little bit early. And it was the first or second week of January 2015. I brought them to my office because I didn't want them in the clinic, being exposed to other kids who are coming in sick. In my office, tiny little girls, put them on a makeshift bed on my desk, did their physical exams, drew their blood and gave them these doses, their first dose, the first two ever, first two babies ever to get this particular antibody product happened right by me, right in my office, oh, seven years ago. It was very exciting.

Host Amber Smith: Was it difficult to persuade their parents to participate?

Joe Domachowske, MD: I don't see my job as a clinical trial investigator as persuading. I like to give information, talk about potential of new products that are available and the potential that we gain information even if this stuff doesn't work. And, I knew this family very well, because they were both teachers in the area, and my kids both had one of them as their teacher years ago. The dad actually went on to become a respiratory therapist and was well aware of the potential consequences of RSV, especially in premature infants. So, they basically came to me and said, "When are you going to have an RSV prevention trial?" So it was not difficult at all to recruit them for this.

The third baby, which, we enrolled three altogether before RSV season started that year. And once RSV season started, the sponsor for the study asked us not to pursue additional enrollment because they wanted all of the kids to be RSV naive (not previously exposed to RSV), and there would be potential for them to have been infected already. So, the third one, the dad is a physician, and he heard about it because he heard me talking about it, and he had a premature baby girl, who he came up to me and said, "What do you think? Do we fit the inclusion? And can we come and talk with you maybe about participating?" So that's how it happened.

Host Amber Smith: Earlier in this program, I spoke with a colleague of yours about clinical trials involving adults through the Institute for Global Health and Translational Science at Upstate. And obviously you being a pediatrician conduct studies that involve children. Can you explain the main differences between clinical trials for adults and clinical trials for children?

Joe Domachowske, MD: Well, I guess I do it naturally. But explaining it and talking about it is very important because children by definition, are a vulnerable population when we're talking about clinical research, just like pregnant women would be considered in that category. When we have a vulnerable population, we need to add additional layers of ensuring protection for their safety and their well-being. And the Institutional Review Board, the IRB, is responsible for making sure I, as a clinical trial investigator, take care of those issues with my clinical trial participants and keep their information private and keep them safe. Above everything else, it's patient privacy, patient safety. So anytime there's a volunteer, we need to take that into consideration and for vulnerable volunteers, there's additional regulatory requirements that need to be fulfilled. For example, if the intervention is more than minimal risk and doesn't really offer the possibility of a true benefit, it's more for the advancement of science, for example -- that's not a clinical trial that likely would be approved by the IRB unless there were other contexts that said it's important to do so. So, there are some nuances and some fine print about doing clinical trial work in vulnerable populations. We've been doing this now for nearly 30 years. It's changed. The regulatory requirements certainly have changed, I think all for the better. But we have to be well trained. I have to make sure my team is well educated and know the protocol, back and forth and upside down, so that we are doing exactly what we're expected to do and we're keeping our babies safe.

Host Amber Smith: Do I understand correctly that decades ago children were excluded from clinical trials because researchers had the feeling that they're a vulnerable population, that it would protect them by not enrolling them in any trials. And, what happened to change that?

Joe Domachowske, MD: Well, gradually and really very slowly it became clear that there are certain medications, certain interventions, and certain opportunities that would be uniquely important for children. That wouldn't really be relevant to study in a phase 1, phase 2 and phase 3 kind of way in adults. But at the time, we needed to have phase 3 studies in adults. You know, we're talking about decades ago, in the U.S., at least. And we needed to have something that was FDA approved before we could suggest doing a trial in young children with that same product. It had to be proven safe and effective In the adult age group. That's no longer the case, although depending on what the product is, what it's meant to prevent or what it's meant to treat, there may be instances where the FDA still requires at least a phase 2 trial that's completed in adults before they will allow a phase 1 trial to be started in children.

This one's an exception. The FDA identified nirsevimab before it was even named that, back in 2015, as a breakthrough medication. As we progressed, this changed into a fast-track designation because the FDA recognizes that this has the potential to meet an unmet public health need for the pediatric population.

Host Amber Smith: So nirsevimab is not technically a vaccine. It's monoclonal antibodies. If it is approved by the FDA, would the American Academy of Pediatrics still list it on its vaccination recommendations for children?

Joe Domachowske, MD: I suspect they will. The one big difference between how nirsevimab is expected to be handled compared to how palivizumab was handled when it was FDA approved back in 1998 is that rather than having guidance come only from the American Academy of Pediatrics Committee on Infectious Diseases, nirsevimab will be reviewed, and guidelines will be developed for how we should be using it by the Advisory Committee on Immunization Practices, the ACIP, so that federal agency that reviews and offers advice to the Centers for Disease Control, where the CDC director then signs off, or disagrees and comes up with a different plan.

We didn't have those ACIP type of a review for palivizumab, and I think it did result in some underuse because of concerns about cost, not safety, but cost. Every context that it was studied and showed that it worked. It just requires monthly dosing. The ACIP involvement in the review of this, I think folks are generally familiar with ACIP (Advisory Committee on Immunization Practices) now because we hear it so much when one of the COVID vaccines finally got FDA authorization for use. Then, of course, the separate review happens by the ACIP, and they would make the recommendations to the CDC director, and the CDC director would finally say, "Yep, push the button," and then vaccine was shipped, right?

So, that, I think, is a much better process because we have the federal agency review and the guidelines that we have for how to implement it will be crystal clear. It also has the potential for being included in the entitlement program, which is called the Vaccine for Children program, which says at the federal level -- this is entitlement, so it can never go away -- that these particular vaccines, if approved, would be available at no cost to those who are underinsured or not insured at all for everyone who lives in the U.S. under age 19. So that would include all of these babies, if the VFC referendum is passed when the A C I P makes their recommendation.

Host Amber Smith: I know that pediatricians have been seeking a reliable preventive, basically since respiratory syncytial virus was discovered. And your trials have shown that this monoclonal antibody works. So at what point do you and the rest of the research team celebrate?

Joe Domachowske, MD: We've started to celebrate, because of the potential, but really, we've got a lot of work to do because if we're not careful, this monoclonal antibody will not reach its potential and its promise. So we've been very clear with the manufacturer that they have to price this like a vaccine, not a biologic, not like palivizumab. This has to be affordable, and it has to be available to the world because RSV, yeah, it causes severe morbidity. In the U.S. We're talking about almost 2% of our birth cohort hospitalized every year for RSV infection. At our children's hospital, it counts for 10% of all of our hospitalizations, and it's only happening in the wintertime, but 10% of all hospitalizations are for RSV. It's huge. And to have something with that promise to have an 80% reduction, with that impact, and not be able to use it would be criminal. And we really need to be careful that this is vetted the right way. That's why I'm so glad the ACIP will be helping us develop the guidelines. I'm hoping for a VFC vote, because that will make sure that there's no disparity as far as who is going to get it, and it's going to be available to all babies, not the haves or the have nots. That's just not fair.

Host Amber Smith: Well, Dr. Domachowske, I really appreciate you making time to tell us all about RSV and this new preventive medicine you've been studying.

Joe Domachowske, MD: It's my favorite thing to talk about.

Host Amber Smith: My guest has been Dr. Joseph Domachowske. He's a professor of pediatrics and microbiology and immunology at Upstate specializing in pediatric infectious disease. I'm Amber Smith for Upstate's "HealthLink on Air."

Here's some advice from professor Stephen Faraone from Upstate Medical University. What's important to know about attention-deficit/hyperactivity disorder in adults?

Stephen Faraone, PhD: The first thing that's important to know is that just because you were not diagnosed with ADHD in childhood doesn't mean you don't have ADHD. Many adults with ADHD never had a diagnosis. They may have had problems in childhood that were caused by ADHD that were just never recognized. That's the most important thing.

The second most important thing would be that there are very good treatments for ADHD in adulthood, treatments that have been tested now for decades, that we know work very well and have very few adverse effects, if any.

And when they do have adverse effects, they're usually well managed, so you shouldn't be afraid of the treatments for the disorder, either.

There are also adults with ADHD who have had a long life of difficulties because their ADHD has not been managed. And then maybe in their 20s or 30s, they realized, "Oh, these problems seem to be ADHD." They get diagnosed. It also is important to remember that pills don't replace skills, that although the medicines for ADHD will definitely help you in your current life, they won't replace any life skills that you may not have learned because of your ADHD in the past. And for that, sometimes it's useful for adults to enroll in a cognitive behavior therapy program that is especially geared for adults with ADHD.

Host Amber Smith: You've been listening to Stephen Faraone, a professor of psychiatry and behavioral science and neuroscience and physiology at Upstate and president of the World Federation of ADHD.

And now, Deirdre Neilen, editor of Upstate Medical University's literary and visual arts journal, The Healing Muse, with this week's selection.

Deirdre Neilen, PhD: Poets often break down actions or emotions into smaller components, so the listener or reader can really see or feel. I have two poets here to demonstrate how artful their ability is. First is Jerome Gagnon from Northern California, whose first prize-winning full collection of poetry, "Rumors of Wisdom," appeared last year.

Here is "Invisible Ocean":

It's sometime around 5 am

when I wake him for medicine and water.

Each sip has become a struggle

confounded by almost constant thirst.

Small sips, I say, to minimize choking.

How could I have forgotten how essential it is to swallow?

How we take the world in daily, an act as vital as breathing?

How the world will swallow us whole and expel us

into measurelessness?

How water receives water, a process so pervasive

it becomes almost invisible?

Jasper Kennedy is a trans organizer and avid crocheter whose poem "Starling's Law of the Heart" reveals the miracle that is our heart muscle's function.

The heart is a machine

in a circuit of vessels.

Pump more out, more will return,

get back what you put in,

reap what you sow,

as if anything works that way.

It's a nice idea.

I close my eyes

and my fist is a ventricle

that I tense and relax,

systole and diastole

in the palm of my hand.

I pop up my thumb

and audibly suck in air,

extend my fingers like

I'm holding a water balloon

filling with blood.

Behind my eyelids

I see sparks as I clutch,

current arcing at my wrist

and feel what it's like

to hold the magnitude

of what I've been served

in the flat of my hand

and dish it back out

with a squeeze.

Host Amber Smith: This has been Upstate's "HealthLink on Air," brought to you each week by Upstate Medical University in Syracuse, New York. Next week on "HealthLink on Air," a pathologist explains how prostate cancer is graded and staged. If you missed any of today's show, or for more information on a variety of health, science and medical topics, visit our website at healthlinkonair.org. Upstate's "HealthLink on Air" is produced by Jim Howe, with sound engineering by Bill Broeckel. This is your host, Amber Smith, thanking you for listening.