Hi, I'm Dr. Amy Paller. I'm professor and chair of the Department of Dermatology and also a professor of pediatrics at Northwestern University's Feinberg School of Medicine in Chicago. I also direct the Pediatric Dermatology Clinical Trials Unit at Northwestern and the Ann and Robert H. Lurie Children's Hospital of Chicago. We'll be talking today about pediatric clinical trials. So the first question is, why do studies specifically in children? Now a few decades ago, that didn't exist. Testing was only in adults and we just got lower doses for systemic medications. We got the same medications, including topicals, using the lowest possible strength and concentration to treat and maintain. So why is there such a paucity of pediatric studies now? And the answer is they are more challenging. There's lower market appeal for any, for many medications and, and industries that produce them. There are ethical implications. There's a smaller patient pool for many of the subgroups who might undergo testing. And there's that need to tailor formulations for giving it to children. Also, there tends to be lots more cost for industry for doing the pediatric studies because of these special needs. We need to remember that children are not just small adults. Children have unique diseases and unique physiology, psychological features, and metabolic features, and they're all age dependent. We define neonates as being in the first month of life, infants up to two years of age, children under 12. And then we can divide that into preschoolers and school-aged children who are in that preadolescent age group. And then adolescents being 12 to 17 years of age. And you'll see this study after study. For treating children, we need more accurate dosing because we need it to be age-based or frequently weight-based. We also have to consider that efficacy may differ in a child versus in adults. It has to be easy to administer. And then of course, very importantly, there are long-term concerns about safety in children that may be less problematic, especially giving it in adults and older adults. Fortunately, there has been key legislation requiring testing in children. The first was BPCA, the Best Pharmaceutical for Children Act, which was first enacted into law in 2002. This incentivized pediatric studies, including off-patent drugs that needed further study, especially for diseases with therapeutic need. It allowed for an extended market exclusivity of the drug by six months. PREA, the Pediatric Research Equity Act, came next, and it authorized the FDA to require pediatric studies of drugs or biologics if anticipating use in children for a specific indication. Now, with this act, one could defer studies in children and use extrapolation from adult studies as long as there was also PK testing that looked at the specific metabolism in children so that the dosing could be correct. There were separate rules for orphan drug designation for treating rare disease. And then in 2023, there were some new FDA guidance documents, but they were still based on the BPCA and PREA. What are the economic burdens of doing these studies in children? Well, first of all, it's a smaller patient population. There are more studies needed, and there's a great amount of site inhomogeneity within these studies. Also, the infrastructure is not always there for pediatric trials. That can involve the expertise of investigators, but it also can involve the expertise at the site. Is a child equipped to be able to do blood draws, to have distractions, to have specialized equipment that accommodates for smaller individuals? There's extra costs for making pediatric formulations, including the fact that with younger children, it needs to be a liquid, and then you have to be particularly worried about the taste. You sometimes have to use a smaller dose or a different topical concentration in a child, and there may be differences in volume required. There are also the higher safety risks, and with that comes that longer risk of liability. And of course, there are a lot more regulatory issues, and this all takes longer for approvals by regulatory agencies and by IRBs. Let's talk about the drug formulation challenges first. This requires extra toxicity testing, for example, in young animals to simulate children. The excipients may be acceptable in adults, but they may not be considered acceptable in children. I mentioned before about it having to be weight or age-based, and that means that there have to be strata, perhaps different doses available, and then ideally something that's longer-acting that allows for giving the medication less frequently, particularly if it's challenging, for example, an injection. Trial design and conduct needs to be innovative, and for that reason, we as dermatologists often need to be involved in helping industry to design trials that really make sense for the population of children and families. We overall like to reduce the number of children required. We like to maximize children who get the active agent, and often you'll see either an open-label study, particularly in the very younger children, or a two-to-one randomization to allow more to get the active drug. It's much easier to recruit if there are open-label trial long-term extensions, so you may have an early part that is a double-blind randomized, but then if everybody can get the drug later on, it's very helpful. This is not always the case. For example, a pharmaceutical company that has a relatively small amount of drug and needs to be gearing up to get enough for long-term extensions within trials or needs to have the safety data back before being able to let someone continue on the drug. We need to consider discomfort in younger children. For example, children who are on a placebo arm, who have severe atopic dermatitis, who may be in a systemic drug trial, just can't be on monotherapy, and that's why you'll see monotherapy studies with adults and adolescents, but then as we get younger, for example, the use of topical corticosteroid to be able to mitigate some of the discomfort. And then we, of course, need to limit the acquisition of blood, for example, or biopsies by limiting invasive procedures and interventions. So one of the things that we do is we limit the blood volume to three percent of the total blood volume every four weeks. And another is instead of biopsies to consider doing tape strips. And I'm showing you here on the left what a tape strip actually looks like on the arm of a young child. And then, of course, showing when you hold it up to the light, you can see that skin is accrued. And this is outer epidermis. We'll do tape stripping in the same place multiple times and get down to, let's say, the middle of the stratum corneum or a little deeper. Nothing that causes pain or causes a problem with healing, but certainly enough that we can look at disorders that have epidermal changes and get information about what's happening at baseline versus what's happening on an active drug without causing any issues for the children. I've had babies sleep right through this. We need to limit durations of visits, and that means if we're doing surveys, we need to keep them short and keep the numbers down. And we need to consolidate visits so we minimize the number of visits as well. We need to use age-specific validated tools to measure our endpoints and to measure the adverse events. And if possible, we need to consider telemedicine visits, which allow us to just touch base with families, perhaps not do the most comprehensive examination of the skin, but we can couple those with good photographs and still do evaluations. And certainly we can walk through surveys. We also want to use more remote tracking devices. I'm showing you here in the upper right, a device that's worn on the hand that is able to detect sleep and scratching. And this is a device that we've used in trials that actually distinguishes between movement and real scratching, as opposed to, for example, rubbing or some other kind of a movement, so that we can actually know how much a child, including a young child, scratches during the night. And we have found that these are very helpful in knowing even what the family and the child doesn't know, because when you're sleeping, you don't even know how much you're scratching. Let's move to ethical issues. Children should not be the subjects of trial if research can be performed in less vulnerable populations. So that's why we do studies first in adults or first in the combination of adults and adolescents. Remember that children cannot provide informed consents for themselves. We need parents signing for anybody who's under 18 years of age, although it's really important to engage the child in the informed consent process and obtain an assent. The age of that differs from institution to institutions. In some places, it's as young as seven years of age, and in others, it's 12 years of age. We need to have data protection for minors, especially after the trial terminates. For example, if we have biological samples, they can't just be used for anything. We have to up front think about what we might want to use it for and get that consent, or we need to go back to the family and get them to consent for the utilization of biological samples. And just to be able to retain them, we need that permission. There's higher discomfort and distress in children and their parents, so providing analgesia that helps the child is very important. And of course, it's more complicated ethically to assess safety, especially when you're considering the fact that we do studies in younger children who cannot themselves understand or communicate directly. And of course, there's long-term liability for insurance coverage that is needed when we're considering studies in children. Let's talk about the consenting process. Of course, we need to fully disclose the risks and the benefits. And when we talk about assent, that is in those children seven to 12 years of age, we often will present the trial in an even simpler form, sometimes showing age-appropriate clear language, but often with pictures or videos to assure that the children are understanding the risks and the benefits. We also want the parents to be able to talk with each other and think about being in a study carefully. We don't want someone to go into a study and then drop out early on. That's not going to help anyone. The decisions can be affected by family dynamics, so we need to think carefully about moving forward with enrolling someone without getting both parents to agree. For example, if there's a divorce going on, or if the adolescent or parent disagree, and the parent's trying to force the adolescent to be in the study, that's probably not a situation we want. And certainly we can't be forcing an adolescent to assent to a study. There are situations where both parents may need to sign the consent. For example, we've had that when we have biopsied infants. We can't just talk to the parent who's with the child. We actually have to get the other parent to sign that consent before we can do it. And then of course, we need to keep in mind that the trial can be stopped at any time. This is a decision that is possibly by the doctor, but certainly can be made by the parent, and if you have an older child, as a decision by that older child. Well, enrollment and retention is actually critical. We looked in clinicaltrials.gov and found that 19% of these clinical trials were terminated early because of difficulty in patient accrual. And this is true of many pediatric trials as well, particularly if we're talking about a fairly rare disease. Small patient populations, and with these rare diseases in particular, are big problems that may require us to need multicenter studies and even international trials. And then if we think about that, that brings in geographic differences, the requirement for translation, numerous amendments, probably a longer duration because it takes longer to get this accrual, and then this all multiplies the cost and the complexity to conduct such a trial. We need to realize that inherently patients and families distrust the concept of trials. You're doing an experiment on my child, and we really need to be honest and we really need to be available and to discuss how there is potential value. There is a lower threshold in children for a high rate of withdrawal. And in general, just to get enrollment and retention, sometimes we have to make concessions. And these may limit our data and sample accrual and introduce the possibility of more confounders which can interfere in trying to interpret results. So are you thinking about doing a trial in children? Well, I would say you can do it. You need to think carefully about the feasibility and choose the trials that you want to do carefully. If it's clearly going to be impossible or not something that you think you can enroll for, don't sign up for it. But is there an unmet need that actually it would be helpful for your patients? Those are the very best ones. You need to think about whether the organizers have designed the trial around children and their special needs. You need to think about whether there will be ethical issues that come up that will make you and families uncomfortable. Will you feel good about presenting the trial to parents? If blood sampling is required, is that going to be feasible at your institution or with the patient population? And is this trial a good fit for your patients? And will the family that you're considering comply with the requirements and the visits? So consider the investigator-initiated study as an alternative if you don't like how things are going with studies that you're being presented with because then you can design your own trials to meet the needs of the family and to accomplish your goals. Now here are a few tricks and tips for studies in children. First of all, with respect to enrollment and retention, it's not a bad idea to pull for interest within your patient population and talk to your colleagues. Will they be feeling good about referring to such a study before you sign up to do it? You're most likely to recruit from your own patient pool. Advertisements can be done, but in my experience they rarely help and sometimes we just end up screening a whole lot of patients who are inappropriate for the trial and that takes a lot of bandwidth on the part of your investigative team. I like to keep registries of our pediatric patients based on what skin disease they have so that they're lined up in advance and we can hit the ground running when a trial finally opens up. Personally, we like to reach out to our patients because that trust and relationship with the physician is a huge decision maker for families who are considering enrollment. And then if families are waiting, and that sometimes happens while we're waiting for the process of consent and IRB approval, it's good to send out periodic notes so the families are feeling engaged and still want to be part of it when it may start rather than having to reach out to you saying what's happening or consider a different route. And then again be ready to hit the ground running with potential patients and everybody well trained and ready to roll when it starts. Well one thing in children that's a problem is missing school and of course it's a double whammy because the parents have to miss work. So be well organized. Make sure that the visits go smoothly and that the time is minimized, working as best you can around minimizing missing of school. The team needs to have that inclusion exclusion plan down. We often carry pocket-sized notes about each study to our clinics so that if somebody comes in who might be appropriate, we can pull it out and remind ourselves of the inclusion and exclusion criteria as well as how many visits, whether there are blood draws and when, just all the questions that the family may want to ask. It's always good to do an initial run-through before any patient starts with research personnel to make sure it goes smoothly and put in the first person and then wait a little bit and see if you can fix any issues that arise before you enroll the next. We keep the visits as short as possible and we consider what can be done remotely. Sometimes we can just get on the phone or Zoom meeting with patients and go through the surveys remotely and make sure that they have time to do it, especially since they can take a lot of time during the visit. If we can do odd hours for visits, that's great and very importantly, respond quickly to family questions and concerns when they come up to really encourage them about the trial to enroll and then to stay in it. I like to say make it fun and cut the pain. So if you have volunteers in your clinics available to play with the children so the parents can concentrate, that really helps. If you have games available or a TV or using the video on the phone of a parent or even virtual reality devices so that kids can have fun while they're there and if it's something like an injection, you can really reduce the pain. Have snacks for hungry kids and families. It really becomes a problem when these visits go on and on and there's nothing there to feed. You should best examine a child on a parent's lap if a young child because that reduces anxiety. Don't get the child up on an examination table. That's the first step in causing anxiety and don't even think about telling them to lie down. The minute you have a younger child lying down on a doctor's bench, they're going to start screaming, crying, getting very anxious. So keep that in mind. Now for drawing blood, try to use pediatric venipuncture experts. They have small needles and they have tricks that help to reduce the pain. I always like the parental bear hug with the child on the lap, especially for these younger children and we use anything from cryospray, which is my favorite, to tactile stimulation near the area of the blood draw and a variety of other distraction techniques. So can you run a clinical trial on children? I would say that if you have the motivation and having heard this video, the answer is yes. And with that, I'd like to thank you for your attention. I'm available at any time if you decide you want to do a clinical trial in children and need a little assistance.

pediatric clinical trials

children's unique traits

ethical considerations

BPCA and PREA

drug formulation

innovative strategies