Betsey Zbyszynski: This is Betsey Zbyszynski. I am Head of Clinical Operations at Vial Health Technology. And today we’re here talking to Dr. Elaine Siegfried about pediatric dermatology trials.
Can I give you a few minutes to introduce yourself?
Dr. Elaine Siegfried: Sure. I am a pediatric dermatologist at St. Louis University in St. Louis, Missouri. I’ve been practicing for 35 years and doing clinical trials for just as long. I started doing that when I was a resident in training at the University of Iowa. And, I really appreciate the chance to air some important issues I think about trying to do trials in children.
Betsey Zbyszynski: Oh yeah. It’s a big area and even more and more with a lot of these dermatology indications that go down to young babies. It’s been a very popular area lately.
So let me get into some of the questions we have. First, what are some common pitfalls in dermatology pediatric protocol designs?
Dr. Elaine Siegfried: Before I mention the pitfalls, I do wanna follow up with what Betsy said about becoming a hot area. I never in my career really dreamed that we would have so many new opportunities to have actual great, level one data to treat our patients. So we’re really grateful about that. But it’s true that there are a lot of pitfalls [laughing].
And one of the biggest ones is just that pediatric clinical trials are different than adult clinical trials in many ways. And one of the most important is probably that it’s a very small number of subjects. So all in all, maybe a tenth of the subjects numbers required in pediatric clinical trials compared to adults. So they may have a thousand patients, we’ll have 100 patients.
And because the standard model of doing clinical trials reimburses you based on number of patients, we’re in catch 22 because, the trials just are not set up to have the potential to generate revenue that’s comparable to adult trials.
And then in the end of the- of the studies, we as pediatric dermatologists are also somewhat disappointed that we have such small numbers. Because small numbers are less informative compared to adult trials. And as we pediatric subspecialists and pediatric generalists know, children are not just small adults. They have many unique features about them. So it would be nice to have more robust numbers in clinical trials.
But at this point we, we just will take what we can get. We’re glad that we have [laughing] clinical trials at all.
Betsey Zbyszynski: Yeah. And it’s hard. With a smaller sample size it’s hard to show efficacy or superiority over placebo with a smaller sample size.
Dr. Elaine Siegfried: It can be. And it- but in that regard we’ve had some incredible blockbuster medications. One trial that we did for oral propranolol, in fact, the primary end point was a visual analog scale for how much better kids did at the end of a trial and it was a single radar for that. So it was a pretty powerfully assessed trial. And the P value was like 10 to the minus 12th. [laughs] So-
Betsey Zbyszynski: Wow.
Dr. Elaine Siegfried: … and the trials were very small. That particular trial, I believe, was done under the auspices of an orphan designation. So there weren’t a lot of kids that were required to be in that trial.
Betsey Zbyszynski: What are the biggest blockers in the progress of pediatric dermatology treatments?
Dr. Elaine Siegfried: One of the things that’s been a big problem from the get go, and as I mentioned, I’ve been doing clinical trials for 35 years, but for the great majority of the time and where I was really- learned my training and participated in the most in clinical trials, was doing adult trials. And that’s because there was this misconception that people didn’t want their children to be guinea pigs. And that nobody would enroll children in clinical trials. And even the agency had a sense of protecting children from potential drug-related adverse effects.
And where this sort of became a little bit more well recognized was in about 2008. So concomitant with the explosion of new biologic medications that were being studied in adults, there were some companies that decided to go into the pediatric space. So psoriasis, for example is a disease primarily of adults. It does start in, in childhood and can even start in infancy. But the majority of patients with psoriasis are in the adult age. And a majority of people are in the adult age.
But when Amgen developed the first pediatric indication for psoriasis with their drug etanercept and they went for FDA approval they weren’t giving it for their pediatric trials. And I think, even though that same drug had pediatric approval for juvenile idiopathic arthritis, but because psoriasis wasn’t considered a life threatening problem they decided to not give FDA approval.
And that was a big blow and it had a giant unintended consequence on the pipeline. So while as a pediatric dermatology trialist, we had the beginnings of contracts in place and explorations in place to do additional trials for biologics for children in psoriasis, they dried up. They just [00:05:00] stopped. It had a very negative impact on development of the pipeline.
Betsey Zbyszynski: Interesting.
Dr. Elaine Siegfried: So there were no- at that point in time. And it’s interesting. I know that this was something that, that was experience but I could not find the publication data to support that, which is interesting. What I recall is that there was a moratorium put on pediatric psoriasis clinical trials for seven years after any drug was on the market. And that was something that the agency had decided. But I cannot find evidence to really back that up. Only that etanercept wasn’t given approval because, it wasn’t a life threatening condition.
But fortunately, the pipeline has really expanded because, the success of treatment for a non-life threatening but, severely life altering disease like psoriasis inspired, new investigations into atopic dermatitis. Which is the other very common inflammatory skin disorder. But unlike psoriasis, atopic dermatitis is a disease that starts in childhood. And it affects a bigger percentage of children than it does in adults.
Now as I said, the minority of people in this country are children. So even if you have a bigger percentage of children affected, the absolute numbers of adults who are affected is gonna be bigger. But just because it’s a disease of childhood it really I think inspired the agency to reexamine, what their approach had been to doing pediatric clinical trials.
There was an agency meeting that we considered the wisdom of excluding children from clinical trials. And in fact, one of the quotes that was presented at that meeting which I’ve taken to heart was that, that the former approach was to protect children from clinical trials. Meaning nobody wanted their their child to be a guinea pig. But then they recognized that if you don’t include children in clinical trials, then all children are like guinea pigs. And they decided that what was most important was actually protecting children through clinical trials.
So that was a big leap and something that I think was really important for the health and welfare of children with skin disease.
Betsey Zbyszynski: Yeah. I agree with that. And even of late people are much more educated now about clinical trials, what they are, their purpose of them. And even parents willing to enroll their child in a clinical trial, they’re much more open to that now.
Dr. Elaine Siegfried: I do think in general that’s true. But we have some issues with recruiting, for pediatric clinical trials. I think one of the biggest ones is that when trials like what happened with the psoriasis pipeline are not available to children until well after the drugs are available on the market, that can leave those kind of open label, outside of clinical trials therapeutic options for kids with severe skin disease. But the people who aren’t the most eligible for getting that kind of treatment are people who have higher health literacy and more resources.
50% of children in this country are Medicaid insured. And so lack of resources often goes with lack of health literacy. And those are those- that patient population is very challenging.
From my perspective, and I work at a tertiary care children’s hospital where we have a greater than 50% Medicaid population, more like 60% because we take care of children who basically have nowhere else to go because their disease is so severe or because their insurance acceptance is very limited. But we offered the opportunity to participate in trials to those children as well, even though, the low health literacy makes consenting more difficult. There’s a lot of mistrust. And so you have to really overcome those things to offer children opportunities for great treatment that they wouldn’t otherwise have.
Betsey Zbyszynski: Yeah. And even just regular care by a physician when you’re in a clinical trial, that’s a benefit also.
Dr. Elaine Siegfried: Yeah. And that is a- actually a benefit to having a pediatric clinical trial center at a tertiary care center. Because, having drawing and recruiting your patient population for clinical trials from your clinical patient population where you have an established relationship with patients, especially patients who have chronic, severe disease, I think that’s really important and it’s a good way to conduct clinical trials. And then when the clinical trial is over, these patients aren’t abandoned. Their- their care has been done, for example, by a private office, a private trials office that’s not prepared or equipped to take care of them long term once the trial is over. So having that continuity, I think, is really important, especially for children who have moderate to severe disease.
Betsey Zbyszynski: Yeah. And the parents. That doctor/patient or caregiver relationship is huge.
Dr. Elaine Siegfried: It is. It- you know, that’s part of, the trust that is built to help people understand the value of participating in a clinical trial, as well as the long term care that you’re gonna be providing, before the trial and after the trial is over.
Betsey Zbyszynski: Good. Which indications in pediatric dermatology do you think get the most attention? And which get the least attention?
Dr. Elaine Siegfried: I understand, the principles of a capitalist society. It costs about a, last figure I heard, it was about a billion and a half dollars to bring a drug [00:10:00] to market. With that kind of investment, you have to, know, you have to get a return on your investment. And because children make up only about 20% of the population, you have to do clinical trials in children that are gonna give you enough numbers really.
There are some incentive programs from the agency that really help support orphan indications. And I think that there have been some really exciting advances that have happened. But, the most attention originally was for psoriasis. Certainly acne, had big attention. But even for acne, which is a disease of adolescents also, clinical trials didn’t really go down. 12 was about the youngest. And we know that children are getting acne earlier and earlier. So even at- for acne studies that is moving into the pediatric population. And that was followed by psoriasis, just because it followed the adult trials. And then that, of course, has been followed by atopic dermatitis.
But along the way, we’ve had some really exciting drugs, as I mentioned. You know, propanolol, which is an old drug that was approved as an orphan indication but a hugely needed medication for a disease that had nothing that really worked well. And particularly that worked well and that was safe. So it’s made a huge difference.
But there are some other exciting medications that have been approved recently. There was just a new topical sirolimus for facial angio fibromas that followed many years of using a compounded drug at really 10 times higher concentration. So when you have a, an investigational drug where you can optimize the formulation and do drug delivery and you really know about percutaneous absorption and potential for adverse effects and toxicity, it’s just a game changer for us.
Multiple biologic for psoriasis now have pediatric indication. The breakthrough of dupilumab as a targeted biologic treatment for atopic dermatitis has I would say, revolutionized our treatments.
And then there are a couple of pipeline drugs right now emerging for the treatment of molluscum contagiosum which, again, is not life threatening. But it’s an infection that really has a big economic and psycho social impact on the population. So we’re really excited about all of those.
Betsey Zbyszynski: Yeah. There’s a lot going on. Just curious do parents prefer a topical or they don’t mind the biologics for their children? What do you see?
Dr. Elaine Siegfried: Oh that’s, atopic dermatitis isn’t a single disease, it’s a phenotype. And then while it’s true that the majority of children who have atopic dermatitis have mild or mild to moderate disease that can absolutely be managed with topical medication, there’s still a very large population of children who have moderate to severe disease or severe disease that cannot be managed by topical medication. So there’s a lot of criteria that really add to why somebody is what I call beyond topical therapy. Topical therapy’s difficult to do. Frankly, there’s even difficulties in accessing some of the best corticosteroid topical medications. And then for children who have more pan atopy, because atopic dermatitis is just one of the features of atopic disease in general. Allergic rhinitis, food allergy, asthma. Having the systemic treatment to treat this constellation of systemic disease is I really think the way of the future in dealing with this spectrum of diseases.
Betsey Zbyszynski: Good point. Thank you. What is the most exciting development in pediatric dermatology that you did not expect?
Dr. Elaine Siegfried: We have so many of them. But, in addition to biologics for atopy with the pipeline being so robust, it’s very exciting. Actually taking trials down to six months of age. So Dupilumab was just FDA approved down to six months of age. Truthfully, I never thought I would see that in my career but I think it’s so beneficial because those of us that treat this disease really feel like early intervention with targeting biologic therapy may be something that actually changes the natural history and the prognosis of the disease. We don’t know that yet but, having the drug available at such a young age is really important.
There have been some other things that, as I mentioned, propanolol, another sort of game changer for treating hemangioma of infancy as well as other hemangioma-like vascular tumors. And then, another really exciting thing has been the availability of affordable genetic mutation panels.
It used to be so difficult to make precise diagnosis for a- a variety of uncommon and rare disorders from the spectrum of congenital ichthyosis to epidermolysis bullosa to a whole host of other what we call geno-dermatoses. And now, it used to cost thousands and thousands of dollars to get genetic testing. And now you can do it for, a couple hundred out of pocket where you can do a spectrum, a panel spectrum.
So having that kind of testing available not only helps us to redefine, what genetic mutations mean but also to build a patient database so that if they are treatments that are available in the future that can target some of these genetic disease mutations, then that’s [00:15:00] really exciting.
And one of the most exciting things has been something that has been in the works for several years. But I serve on the Scientific Advisory Board for the National Foundation for Ectodermal Dysplasias. And the most common of those is called hypohidrotic ectodermal dysplasia. And the X linked variant we know that is caused by a mutation in a protein called Ectodysplasin. This protein is only important in embryo genesis. It’s not important- that protein’s not important post embryo genesis. So people have a variety of abnormalities with hypohidrotic ectodermal dysplasia. They have sparse hair. They have unusual teeth and often need a mouthful of implants. And they can’t sweat. And so infants often will present with just recurring fevers of unknown origin. And other of their glandular function doesn’t work well. Adult women can have problems breastfeeding, for example. So there are a variety of things that go with hypohidrotic ectodermal dysplasia.
But there hasn’t been a treatment for it. And people don’t have progressive disease because it’s only important in the formation, of these organs as opposed to, ongoing developmental, progress like your immune system or your brain. It doesn’t have impact on those.
But now we have a protein analog to ectodysplasian and that is being used in clinical trials right now passed the mouse model and the dog model. It’s being used in humans right now to treat anti-natally in utero, to correct the defect before children are born. So if you wanna know about something that’s brave new world and a trial that was incredibly difficult to design but is happening, overcoming all those challenges, talk about exciting. That’s pretty exciting.
Betsey Zbyszynski: That’s really exciting. And even that FDA recognized it and approved it- the go ahead too. That’s really exciting.
Dr. Elaine Siegfried: Yeah. It’s amazing, really. [laughs]
Betsey Zbyszynski: I’m seeing more and more d- protocol designs for rare disease, more and more rare and orphan disease. So it’s good people are recognizing that. And I think even the access of home healthcare and a lot those those companies that offer travel for rare disease patients is more and more popular.
Dr. Elaine Siegfried: Yeah. And I think truthfully, gotta give credit where credit is due. The opportunity to have, some economic support and advantage actually for developing a drug for for an orphaned designation, that the agency provides is really important and has helped a lot. Yeah.
Because before that, in, in the years, probably like in the 90s, when all- most of the new drug development was, geared towards me too drugs. Anti-hypertensive that you only had to take once a day. Or, another lipid lowering agent that maybe is a little bit more well tolerated. But, now we’re really getting to new drug development for unmet needs and unmet needs in children so that’s wonderful.
Betsey Zbyszynski: When was the last time you changed your practice in favor of a new approach to treating skin disease in children?
Dr. Elaine Siegfried: That is a great question. And I just have to say that, I continually change my approach [laughs]. As I teach my residents I learn new things every single day. But adopting a new medication that you haven’t used before and you’re not familiar with, I think there’s a spectrum of fear that happens among all the clinicians. And what it does, I think, is it narrows everybody’s focus a little bit. So we are all becoming super subspecialists.
I particularly am most experienced and have really the most interest in more moderate to severe inflammatory skin diseases in children. So I know the most about that. And I know that the pipeline is expanding for new drugs, for example, with difficult overgrowth syndromes, and vascular anomalies. And I don’t know as much about that. And I’m a little bit more hesitant to change my practice to the newer and possibly, more risky drugs that have potential for more adverse effects.
So everybody has to feel comfortable, in their own skin. And it funnels many of us, I think, into being subspecialists. But in my own subspecialty world I am continuously evolving and adapting new treatments where I’m convinced that the data supports safety and efficacy. Or [laughs] where the risk of the disease is well beyond the risk of a potential medication adverse effect. Those are the kind of the balances that we use.
Betsey Zbyszynski: Understood. So five years from now, what do you think everyone will be talking about in pediatric dermatology?
Dr. Elaine Siegfried: Oh, there are just so many things. And, one of the things that I mentioned was these new medications for overgrowth syndrome. These are a terrible group of disorders that can be so life altering and even life threatening. So that’s one thing I think that’s really gonna have a lot of new development.
What are some of the other things? I can’t, go without mentioning JAK inhibitors. I don’t like to use the word target for JAK inhibitors because JAK inhibitors are broad spectrum immunosuppressants. But I think that there’s a role for this group of medications. And I think as the the focus gets finer and finer with selective, more selective JAK inhibitors, I think they’ll be more useful. But right now I think, using these [00:20:00] medications in children for inflammatory diseases does carry these unanticipated risks that we don’t really understand. While I think we need, a little it more time to feel comfortable with using these medications in children.
Betsey Zbyszynski: What about the combination? The JAK TYK combination?
Dr. Elaine Siegfried: I think, again, that focusing on the JAK pathway and inhibiting, those cellular responses, it just comes with a lot of downstream effects that I don’t think people understand very well. I know that there’s a lot of research that’s going on and this is an area that I’m certainly trying my best to keep up with and understand. [laughing] But in terms of actually using them in children now, I’m waiting until we have a little bit more safety data to help me feel, more comfortable about it.
But I’m certainly open to seeing that data and helping to participate in creating that data. Because I think that we still have a lot of unmet needs in pediatric dermatology inflammatory diseases, morphea, scleroderma, discord lupus. There’s many inflammatory disorders that we have nothing for that we’re looking forward to having options to treat.
Betsey Zbyszynski: Yeah. And what about the microbiome movement now?
Dr. Elaine Siegfried: Oh yeah, no. That is another… I’ve been very closely following and interested in that. Really since since people started just- since the word was coined. [laughs] and I think it’s incredibly exciting and I think incredibly important, particularly the impact on immune maturation, which can direct a huge variety of conditions. The problem is our current model of doing clinical trials is, based on a single active ingredient. And that’s what Western medicine is all about.
I have a disclaimer. My oldest son is a- practices traditional Chinese medicine. And the approach to traditional Chinese medicine is really diametrically opposed to that of Western medicine because they are very used to combination things and doing a little bit more homeopathic approach. Whereas in the United States, we have an enemy and you can kill that enemy. And without recognizing, that there’s not just straightforward good guys and bad guys. There’s a big combination. And, there’s fall out if you try to, kill the bad guy, you’re gonna have fall out by killing the good guys sometimes too.
The model of studying multiple ingredient products like like probiotics is just fraught with so many issues. And not to mention that for many of these products, you can formulate them and make them available, without a prescription. So there’s some oversight on that. But, not enough to incentivize trials that will actually give us some level one data. [laughs]
But, it’s not that I think it’s that they’re worthless or bad. I think they’re very valuable. We have to have a new model to study them.
Betsey Zbyszynski: Yeah. And I think people are at least the population is more open to that, whether, the physicians or scientists, it’s still a little unknown. But I think people are willing to try different things now as well.
Dr. Elaine Siegfried: Yeah. That gets me down to the difference between, a prescription, FDA approved, studied product, and one that is available without as much data. I really think that the biggest risk of some of those products that are available over the counter is, it’s a pocketbook risk. It’s how much money is somebody gonna spend on something that may be, not effective for what they have? And, people are free to spend their money on whatever they want.
But, in my mind, and we see this a lot with skin care products and cosmeceuticals. Look at the millions of products that are available… Well, Not millions. But many for, treating wrinkles. That there’s really no data for making wrinkles disappear. But people are very susceptible to that. It’s a giant market. It’s not one that I’m intimately familiar with [laughing]. But it’s something that also needs to be grappled with. And I do spend quite a lot of my time trying to educate families and parents about how to read labels and know what’s in the products that they’re purchasing.
Betsey Zbyszynski: That’s great, Dr. Siegfried. It’s been wonderful speaking with you today. And-
Dr. Elaine Siegfried: I gotta put in one more plug about decentralized, decentralized clinical trials.
Betsey Zbyszynski: Oh yes!
Dr. Elaine Siegfried: The Vial is going down that pathway but, telemedicine has made a huge difference, I think, in healthcare in this country. I’ve been fighting for it for 10 years. And it wasn’t until, this silver lining of COVID, if you can say that there is one, that it incentivized the system to make the administrative support, available for doing telemedicine. But I think, moving into that realm with clinical trials would really help subjects and make things a little bit easier in terms of recruiting and retaining clinical trial subjects.
So is Vial moving into that at all?
Betsey Zbyszynski: Oh yes. It was a blessing in disguise with COVID because it accelerated decentralized clinical trials. Whereas, clinical research is conservative by nature. And things take a long time to implement a new process. So I think we were very fortunate in that way to have home healthcare, videos. A lot can [00:25:00] be done through electronic capture. Yes. Definitely our clinical trials that we run are typically 50% remote.
Dr. Elaine Siegfried: Oh that’s just wonderful. And I think that will be a big help to pediatric clinical trials as well.
Betsey Zbyszynski: Yeah. Especially with kids. That- and daycare and parents having to, if they have other siblings, what do they do with their other siblings when they’re bringing the one child in. So it helps everybody.
Dr. Elaine Siegfried: Yes. So a good note to, to end on.
Betsey Zbyszynski: Exactly. Thank you so much, Dr. Siegfried. It’s been really a pleasure speaking with you.
Dr. Elaine Siegfried: Nice to talk to you again. And thank you even just for giving me a chance to vent about this.
Betsey Zbyszynski: Oh, no. It’s great. Enjoy the rest of your day.
Dr. Elaine Siegfried: You too.
