A new birth control pill; a new virus preventive for kids: Upstate Medical University's HealthLink on Air for Sunday, July 30, 2023

Host Amber Smith: Coming up next on Upstate's "HealthLink on Air," a gynecologist discusses the birth control pill that for the first time will be available without a prescription.

Maureen Burke, MD: ... This is a very big deal. Hormonal birth control is much more reliable for pregnancy prevention than barrier methods that have historically been available without a prescription. ...

Host Amber Smith: And a pediatrician explains how a new medication protects babies from respiratory syncytial virus.

Joe Domachowske, MD: ... 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. ...

Host Amber Smith: All that, and a visit from The Healing Muse, coming up 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 learn about the new medication that protects babies from respiratory syncytial virus -- and the research done here in Syracuse.

But first, what's important to know about the new over-the-counter birth control medication called the Opill?

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

The first over-the-counter birth control pill (the Opill) received FDA (Food and Drug Administration) approval, and its maker expects it to be on store shelves in early 2024. What's important to know about this pill compared to other birth control methods?

For answers, I'm turning to Dr. Maureen Burke. She's the chief of general obstetrics and gynecology at Upstate.

Welcome to "HealthLink on Air," Dr. Burke.

Maureen Burke, MD: Thank you for having me, Amber.

Host Amber Smith: Over-the-counter means women won't need a prescription from a medical provider in order to get this birth control pill. How significant is this?

Maureen Burke, MD: This is a very big deal. Hormonal birth control is much more reliable for pregnancy prevention than barrier methods that have historically been available without a prescription. Things like condoms or spermicides and needing a doctor's appointment to get a prescription can actually be a big barrier to getting hormonal contraception.

So, being able to get it without a prescription is going to be a game changer for some women.

Host Amber Smith: Do you have any medical concerns about this being available without a doctor's visit?

Maureen Burke, MD: Absolutely no. This is a progesterone-only pill. And this is a medication that is incredibly safe for almost everybody.

Host Amber Smith: What does it mean -- "progestin only"? (Progestin is a synthetic form of progesterone.)

Maureen Burke, MD: There are two types of hormonal birth control, some that have just a single hormone, progesterone, and some that have a combination of two hormones, progesterone and estrogen. Progesterone is really the one that has the biggest impact on preventing ovulation, which is the way birth control pills protect against pregnancy.

Estrogen can be used in combination to help sort of regulate hormones in the body, but it's not necessary for pregnancy prevention.

Host Amber Smith: So, what type of woman would benefit from the combination with the progestin and estrogen versus progestin only?

Maureen Burke, MD: One of the most important things to know about a progestin-only pill, like the Opill, is that it needs to be taken at very close to the same time every single day and is less effective if a dose is missed. Adding estrogen into a contraceptive pill increases its efficacy, which means that it's not quite such a big deal if a woman forgets one day of her pill, or if she takes a pill in the morning one day, and then the next day realizes at 3 p.m. that she hasn't taken it yet and takes it at that time.

So, it provides a little bit more reliability, but other than that, there's not a big difference in terms of progestin-only versus the combined pill.

Host Amber Smith: But nevertheless, the birth control pills are not effective if you don't take them every day, roughly regularly. Are there concerns about these over-the-counter pills being misused?

Like, I'm wondering if someone takes more than one of them, or takes the whole pack at once, what could happen?

Maureen Burke, MD: Really very little in terms of risks to the patient. Progesterone can have some GI (gastrointestinal, or digestive) side effects when taken in large quantities, so someone who takes more than one pill a day or multiple doses in a day might feel nauseous or vomit or have diarrhea, but there's not any significant risks to the body from taking too much progesterone at once.

Host Amber Smith: What if someone who is pregnant takes birth control pills?

Maureen Burke, MD: It does not impact the pregnancy, actually. So progesterone levels increase in the body at the beginning of pregnancy, and having a little bit of extra progesterone on board from a progesterone-only pill does not make a difference or put the pregnancy at risk.

Host Amber Smith: What happens if a man takes these pills?

Maureen Burke, MD: Nothing. It's not going to reduce their sperm count or prevent pregnancy from their side, but it's also not going to have any long-term impacts on their health.

Host Amber Smith: Does having had one or more births versus not having had children make a difference in whether a woman can take Opill?

Maureen Burke, MD: No it doesn't matter whether a person has been pregnant before or not in terms of how the Opill works. And one thing that's really important for people to know is that using the Opill or any type of hormonal contraception is not going to impact a patient's ability to get pregnant in the future.

Host Amber Smith: How long after a birth can a woman start taking the Opill?

Maureen Burke, MD: Any progesterone-only contraception can be started almost immediately after delivery, so it's very common for us to discharge a patient from the hospital with a prescription for a progesterone-only contraceptive. And if somebody doesn't get discharged with a prescription, it's certainly something they could pick up and start taking at any time.

Host Amber Smith: So, are there any side effects for a woman to look out for if she starts taking the progestin-only Opill?

Maureen Burke, MD: Not really. This is a very low dose of progesterone, so the women are not going to feel many side effects. Sometimes people will feel nauseous or have a little bit of GI discomfort when they first start taking a pill, but that's generally a side effect that goes away once they've kind of adjusted to the dose.

Host Amber Smith: How soon after you start taking the birth control pills are they effective?

Maureen Burke, MD: That's a really good question and something that it's important for people to realize -- that the progesterone-only pills are not effective right away. It takes seven days of continuous use before we can reliably use it as a contraceptive.

Host Amber Smith: That seems important, because I'm imagining that drugstores will put these on the shelves near the condoms. And the labeling must be pretty clear that you've got to take it for at least seven days for it to be effective, right?

Maureen Burke, MD: Yeah, I think that this is going to take some information and advocacy on the part of reproductive health providers to make sure that people who are picking up these pills off the shelf know that they need to take it for seven days. And I imagine that that will be pretty obvious on the packaging as well.

Host Amber Smith: Are there any women who should not take this medication?

Maureen Burke, MD: Really there are very few contraindications to using a progesterone medication.

People who have active breast cancer or a personal history of breast cancer, it may not be safe to use progesterone. People who have significant liver disease, the pills are going to be less effective. And then there some people who are taking seizure medications where the seizure medication may interact with the progesterone and make the progesterone less effective.

But that's a very small group of people.

Host Amber Smith: So, if these are being picked up in pharmacies, in drugstores, can the people who are buying them get questions answered by the pharmacist there?

Maureen Burke, MD: Yes, anytime somebody is picking up an over-the-counter medication, they can go ask a pharmacist a question about how to use it.

Host Amber Smith: Is the effectiveness expected to be the same for women using this product of any age, whether it's young teens or closer to menopause, is it going to have the same effectiveness?

Maureen Burke, MD: Yes, the effectiveness of progesterone-only contraception doesn't change based on age.

It is important to realize that the pill is only effective as the reliability of its use. So, a person who is missing doses isn't going to have the same effectiveness as a person who's remembering to take the pill every day. But that's really the only thing that changes how effective it is.

Host Amber Smith: This is Upstate's "HealthLink on Air," with your host, Amber Smith.

I'm talking to Dr. Maureen Burke. She's the chief of general obstetrics and gynecology at Upstate. And we're talking about contraceptives and the new over-the-counter birth control pill for women that was recently approved.

The first birth control pills were approved 60 years ago. Can you tell us in general how things have changed over the years with contraception?

Maureen Burke, MD: Yes, it was really revolutionary when the first birth control pill was put on the market.

It was the time women really had autonomy over their bodies, in terms of deciding whether sexual intercourse could potentially result in pregnancy or not. The two components of the birth control pill -- estrogen, progesterone -- are still the same, but the dosing and the exact way that those hormones are made in the pills has changed over time.

One of the things that's changed is that we've come to understand that the effective dose is a lot lower than what was in the original formulation of the pill. So, some people may have parents or grandparents who remember significant side effects from a birth control pill. Some people may really have in mind that it's risky for people who have high blood pressure.

That's really the estrogen component of contraception that has some of those risks, and the risk is much less today than it was 60 years ago because the doses are lower. But also, those aren't concerns for people who are taking progesterone-only pills, which weren't an option in the past.

That's a more recent development, the progesterone-only pills.

Host Amber Smith: Well, let's talk about how the pill compares to other forms of birth control. It's considered the most effective method. Is that right?

Maureen Burke, MD: Well, when we talk about forms of birth control, we kind of divide it into two categories, hormonal and non-hormonal.

And generally, when we think about non-hormonal, we're talking about things like condoms, spermicides, tracking one's menstrual periods and trying to avoid sex during the fertile window of the month. And those types of decisions to prevent pregnancy are significantly less effective than hormonal birth control.

But hormonal birth control actually comes in many, many different forms. There are pills, there are patches, there are flexible rings that a person can put inside their vagina. And then there are forms of hormonal birth control that can last longer in the body. So, there's an injection that lasts three months, there are implants that can go in the arm and last four to five years, there are devices that can be placed in the uterus called IUDs, which can last anywhere from five up to 12 years, depending on the device. And the longer-acting forms of hormonal birth control are actually more effective than things like pills.

So, a pill, if used correctly, is probably about 90% effective. But the longer-acting hormonal contraceptives, the implant and the IUD, are really closer to 99-plus% effective. And we actually consider those longer-acting forms to be as effective as permanent sterilization or tying the tubes.

So the pill is definitely more reliable than condoms or spermicides, but there are still other forms of birth control that are even more reliable than a pill.

Host Amber Smith: It sounds like there are a lot of options these days, and maybe that helps you get things more specific to each individual for what their needs and desires are.

Maureen Burke, MD: Yeah, that's exactly right, Amber. Having so many options available really allows each individual to make the choice that feels right to them.

Some people really appreciate the convenience of a pill. They appreciate that if they know that they're not going to be having sex for a prolonged period of time, they can stop taking the pill if they want to, whereas some people feel like the convenience of something that's longer acting and sort of lives in their body for a few years is a lot more convenient because they don't have to think about whether they're on the contraceptive or not when they're thinking about whether they're ready to have sex, so it really just depends on what's most convenient for the person as an individual.

Host Amber Smith: Which is the most popular method with young women?

Maureen Burke, MD: A lot of young women are still opting for short-acting options, like the pill.

And I think that this will be a very popular option for teens and young adults who may be in a phase of life where they're just starting to make decisions about sexual activity and may appreciate the convenience of being able to pick something up at the pharmacy without having to make an appointment.

However, long-acting forms of contraception are becoming more popular with younger people who realize that it can be a lot more convenient to have something on board all the time for pregnancy prevention.

Host Amber Smith: Which works best for women who've already had children?

Maureen Burke, MD: It really doesn't matter. It's still whatever works best is the one that an individual finds most convenient for their body and their lifestyle.

Host Amber Smith: Do any protect against sexually transmitted diseases?

Maureen Burke, MD: Hormonal birth control does not protect against sexually transmitted infections, so anybody who is at risk of a sexually transmitted infection, because they have multiple partners, or maybe they're having sex with somebody who they know has other partners, or they're just not sure whether their partner has other partners, should still be using condoms to prevent STIs.

Host Amber Smith: So, when someone comes to you and is considering a birth control method, what sorts of things do you tell them to think about and consider?

Maureen Burke, MD: Well, I kind of give them all the options just like I laid out with you, Amber, and see what their initial thoughts are about what they think would be most convenient to their lifestyle.

And then we have kind of a conversation from there. I answer questions about what their concerns might be about potential side effects or drawbacks to having something in their body for a longer period of time. And we just have a conversation to work out together what's best for them as an individual.

Host Amber Smith: If you recommend a progestin-only birth control method, and the patient wants that, is there a benefit to getting a prescription from you versus going to the pharmacy and getting the new Opill?

Maureen Burke, MD: We're talking about a progesterone-only pill. There's probably not a difference in terms of what can be obtained over the counter versus with a prescription.

Host Amber Smith: Dr. Burke, thank you so much for making time for this interview.

Maureen Burke, MD: Thank you for having me, Amber. I'm really excited about the Opill.

Host Amber Smith: My guest has been Dr. Maureen Burke. She's chief of general obstetrics and gynecology at Upstate.

I'm Amber Smith for Upstate's "HealthLink on Air."

It was an international study that began in Syracuse and culminated with FDA approval -- next, on Upstate's "HealthLink on Air."

From Upstate Medical University in Syracuse, New York, I'm Amber Smith. This is "HealthLink on Air." The Food and Drug Administration recently approved a new medication for the prevention of respiratory syncytial virus, which can cause serious disease in babies and toddlers. This drug was first tested on babies in Syracuse, in a trial overseen by Dr. Joe Domachowske. He's a pediatric infectious disease specialist and professor of microbiology and immunology at Upstate. "HealthLink on Air" spoke with Dr. Domachowske last fall about RSV and his study of this medication as it was working toward FDA approval.

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 room) 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 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: 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 it's 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 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 3 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: Is there any benefit to a baby getting RSV? Assuming it's a mild case, that is, would RSV strengthen their immune system for life, or offer any sort of lasting protections?

Joe Domachowske, MD: RSV is an interesting virus as far as the immune system goes, because the first infection does tend to be the most severe. But we get reinfected throughout our whole lifetime. And older children, young adults, they tend to get maybe a little bit of a cold, not typically severe unless it triggers their underlying asthma, and then of course, they can get into some trouble. But it's not until the other extreme of age, the elderly folks, where RSV causes severe problems again, where the rates of hospitalization in people over 65 years of age from RSV are second only to those for influenza as far as respiratory infections go.

So does getting RSV really do much as far as additive protection year after year after year? I think it probably does, but it's not one of these infections where you get it once, and you never have to deal with it again. Like chickenpox, you get it once and most people are considered to have lifetime immunity. Measles, you get measles or measles vaccine, you're considered to have lifelong immunity. But RSV is more like strep throat. You get it once, and it doesn't do you much good, as far as being susceptible to getting strep throat again. You can get infected over and over again, and your immune system just doesn't kind of do what it needs to do to completely prevent you from being infected again.

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 1-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 about the new RSV medication with Upstate's Dr. Joe Domachowske.

Welcome back to Upstate's "HealthLink on Air." I'm 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 about 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: And in general, what was involved? Was it blood draws or vital statistics? I mean, what did you do with the babies?

Joe Domachowske, MD: They would come in. We'd make sure that they fit the definition for the particular phase of the protocol. Phase 1, there's always more blood being drawn, unfortunately, because we really have to get a good sense for the stability of the product, of the medication in the blood. And we were also looking to see if the babies would generate antibodies against, the antibody. Because then if the antibody's being neutralized by something that the baby's developing, it will stop working. So that was also a concern.

So for the Phase 1, they did get six blood draws over the course of the six months that they were on the active phase and being followed. Anytime they got a sniffle, a sickness, any kind of respiratory anything, we asked the parents to notify us, and we'd bring them in, and we'd swab their nose and their throat to see if they had RSV as the cause. So it's asking families to do a lot.

The Phase 2 and Phase 3 are a little bit less burdensome, as far as the number of blood draws go. Those kids, every time they had a respiratory illness, we'd have to ask them to come in so that we could collect the swab and test them, because that was the clinical outcome we were most interested in: Did this antibody protect them from RSV? And was this cold or other respiratory infection that they had, was it being caused by RSV, or was it being caused by something else?

Host Amber Smith: Were there any adverse events during the trials that concerned you?

Joe Domachowske, MD: Well, the trials were all placebo controlled, so the side effects or the reactions that the babies had, I didn't know if they had gotten a placebo saline injection, or if they got the monoclonal antibody injection. And the types of injection, local injection site complaints, that we see with other immunizations weren't as frequent from nirsevimab. There was a little bit of maybe swelling or injection site tenderness for a day or so. But when we did unblind everything, and we compared the placebo to the medication itself, the side-effect profile was identical. So it's basically as safe as giving a saline injection.

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, we 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 (never having had 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: 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 maybe that'll change the timeline. I was going to ask you to kind of walk us through what you expect the timeline to be with the FDA in terms of approving nirsevimab as an RSV preventive.

Joe Domachowske, MD: Yes. We expect what's called the biologic license application to go in within the next several weeks. So we're talking about sometime in October of this year (2022). And typically, once that BLA (biologic license application) is submitted to the Food and Drug Administration, they have nine months to review it and get back to the sponsor or the manufacturer with comments, critique, "Oh, we need to do this," "We need to tweak this," "We don't have enough data about this," "Can you redefine this?" I mean, these applications are enormous and provide granular information down to the last detail. And the FDA reviews it, granular, down to the last detail. So nine months is a long time for the review. And once the response goes back to the person or the agency that has submitted the application, they have six to nine months to develop a response, unless the FDA is asking them to do another clinical trial, another Phase 3, for example, and then they'll give them longer.

So you can imagine that whole process can take years and years and years. Typically for a product that enters Phase 1, that does make it through all the way through a Phase 3 and is shown to work, and be submitted to the FDA, typically, once it's submitted, it will take about a year, to a year and a half, for final approval -- if the FDA decides to approve it.

The agreement with the FDA -- because this is a breakthrough designation and fast-track designation -- is that everything should be wrapped up within nine months. So it compresses the timeline, but does not change the vetting procedures. All the same review still happens. It just happens in a compressed way. And we've learned exactly how much these things can be compressed if the FDA drops absolutely everything and only focuses on one issue with the COVID, because our vaccines became available within a calendar year for adults, at least, from the time those first phase trials were started. We're not talking about that type of fast track for RSV. But the review will happen much quicker than it would have otherwise because it has these special designations.

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 (VFC) 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 ACIP 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 (illness). 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."

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: Aging can assume many guises. Poet Lisa Wiley teaches English at Erie Community College in Buffalo, New York. Her poem "Sundowning" describes a common occurrence in elder care, the eternal hope that this time the parent might remain calm and be able to sleep.

"Sundowning"

I used to race the feathered sunset

on summer nights when I embarked too late,

realized I had too many miles to make it home

before stars pierced an indigo sky.

I'd sport a white t-shirt so traffic might see me

a scout leader neighbor would pull over

to my side of the road, instructing me

to wear a headlight or start earlier.

I'd just pump my arms harder.

Now we race to my father-in-law's side

on late winter afternoons

when a cotton candy sun drops too soon

on his sharp, mathematical mind.

Gentle, humble, Teddy bear, his students said.

If we arrive in time, we guide him through

simple tasks like shaving, as he offers

lucid moments of secret childhood handshakes

before bedtime combat settles in.

Joanne Clarkson has published five poetry collections. Her poem "The Last Piece" describes a part of her job that was probably never in the job description, but which defines caring for the vulnerable.

"The Last Piece"

When, as a nurse, I visited homes

of the dying, jigsaw puzzles

were often spread across tables: kitchen,

coffee, card, bedside.

A thousand pieces a common theme.

I watched a wolf come together

in the woodlands. An orca leap

from the Salish Sea.

"It passes the time," Karl, always cheerful,

explained as his ragged heart stuttered

then thrummed. "It all makes sense this way,"

John's wife Nancy told me

since John could no longer speak.

It gave visitors something to explore

besides grief. They felt useful

finding a splinter of the weathered barn.

I drove boxes of fragments from house to house,

trading, and never lost a piece

as I listened to the whining breath

and measured pain on an impossible scale.

Karl gave away every puzzle except

the wolf. His daughter glued it

to a board, framed it after, tribute

to small connections

when the greatest was taken away.

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," the benefits of Reiki in the hospital.

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.