Why Pediatric Clinical Trials Need to Grow Up - Cindy Jackson

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HANNAH LIPPITT: Hello

and welcome to the Totally Clinical podcast, brought to you by Teckro. Totally Clinical is a deep dive into the freshest trends, big-time challenges, and most excellent triumphs of clinical trials. I'm Hannah, your host. Join me as I chat with industry experts, trailblazers, thought leaders, and most importantly, the people benefiting from clinical research. So, tune in, settle back, and don't touch that dial. It's time to get Totally Clinical.

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HANNAH LIPPITT:

This week, Cindy Jackson, Chief Operating Officer at the Institute for Advanced Clinical Trials in Children, joins the podcast to discuss developing medicines for children. During our discussion, we talk about why there's such a huge lag between children and adult trials and how children wait for new cancer drugs for a median of six and a half years longer than if they were an adult, as well as the shocking revelation that more than 90% of the drugs used in new-borns are prescribed without adequate data to verify their efficacy and safety.

Welcome to the podcast, Cindy. Could you start by explaining more about your background in the field of pediatric medicine and drug development for children?

CINDY JACKSON: I trained in pediatrics oh, several years ago, and then I went on to do a fellowship in pediatric infectious diseases. During that fellowship, I had an opportunity to participate in clinical trials as part of a team at the University I was working at, and we were really focused at that time on HIV transmission, perinatal transmission from mothers to infants. And I had tremendous mentors at the institution I trained at, which was Duke University in the United States, and I really got the clinical trial bug from them.

Subsequent to that, I went to a pharmaceutical company called Burroughs Wellcome, which then became Glaxo Wellcome, which is now GlaxoSmithKline. But while I was there, I worked in one of the laboratories that actually was the discoverer of zidovudine, or AZT, which is the first treatment which was approved for use in patients with HIV infection. And this further got me interested in doing clinical research and especially drug development.

I then went on to work as a pediatric ID consulting physician, as well as being a physician investigator in pediatric clinical trials. And then I transitioned into the industry as a medical advisor in the contract clinical research organization Quintiles, where I was there for 16 years and had a variety of jobs. The last jobs were running the pediatric and rare diseases centers of excellence.

I then moved to another large CRO, Covance, and did a very similar job before I moved to being the Chief Operating Officer at I-ACT about one year ago.

HANNAH LIPPITT:

It's rather understating it to say you've got a lot of experience in your field! So, in terms of clinical trials, the process is easily misunderstood, and I think this is doubly true when it comes to developing medicines for children. Could you explain more about the process for our listeners?

CINDY JACKSON: So I think most people are completely unaware of the drug development process, probably in general, a little less so now that COVID has taken over the airwaves and people are talking about clinical trials. But I think this is doubly true for development of drugs for use in children. And I think most people don't realize it's a little different from drug development from a regulatory standpoint, but it's also a little different from drug development, from an incentive standpoint. And let me talk about that a little bit more.

The majority of therapeutics are drugs developed for the adult market, and there's very real and common reasons for that. Pediatrics only makes up about 25% of the population of the world. So the market isn't that big. Children don't tend to have a lot of chronic conditions. They tend to have more acute illnesses. And so those drugs, which are developed for chronic conditions, would be targeted towards an adult market. So when an IED is filed here in the United States, the process moves forward with adults, and very few drugs are targeted for children at the outset.

I'll give you a couple of examples of drugs that would be targeted for children: one would be surfactants for use in pediatric neonatal intensive care units for premature babies that have underdeveloped lungs that obviously would be developed for pediatrics first; and also for infant vaccines, those vaccines that we all mostly received as infants and small children. And there is really no incentive for pharmaceutical companies to actually do trials in children without regulatory requirements, encouraging that these trials be done for those reasons that I've already explained. So not to get too much into the regulatory weeds, but I think the listeners should be aware of what the regulatory process for children is, and I think it will inform much of the discussion as we go forward.

So in the United States, there are two laws that are applied to drug development for children; PREA or the Pediatric Research Equity Act and BPCA, the Best Pharmaceuticals for Children Act.

PREA is also often called the ‘stick law’, which means it requires studies to be completed in children in the indication for which a new drug application was approved in adults, if it would be appropriate. And I'll use an example, if a drug is approved for adult community acquired pneumonia, it must be tested in children for that same indication, so community acquired pneumonia in children. That's the PREA law.

The BPCA law is voluntary, and that is that a company can submit something called a PPSR – a proposed pediatric study request – to the FDA to study a drug for a certain indication, not generally the indication that the NDA was approved for. Or the FDA can request a study in another indication that they feel might be more appropriate for children. And again, this is voluntary. A company can choose to or not to participate under BPCA for that particular therapeutic. And the European Medicines Agency has similar rules regarding doing pediatric clinical trials.

So in one case, the study must be done and in other cases, it's voluntary, and there are incentives for companies to do those voluntary studies. And those incentives include being able to market the product under patent protection in the United States for six months for any indication. So that gives a company some monetary advantage to doing these extra pediatric trials.

HANNAH LIPPITT: So once

they're designed, how do clinical trials work in terms of adults versus children?

CINDY JACKSON: Well, once the trials are designed and started, the process forward is very similar to that in adults, so Phase I through Phase IV clinical trials, usually after Phase III, an application to market is put into the regulatory agencies. The only difference is that in pediatrics, normal healthy children cannot be included in Phase I clinical trials. In pediatric clinical research, Phase I trials are done in children, with the indication to be studied. So they may only get a dose or a couple doses, but they have to have at least the condition for which the drug is going to be approved. And I think that's confusing for some companies, and it's also confusing for the listeners who may be on this podcast.

And I also think most people don't realize that many therapeutic agents are used off label in children, which means that they're used before a certain indication is approved. And I have to say that off-label prescribing is often the rule and not the exception in pediatrics, because we, as pediatricians must do this to appropriately care for our patients before these studies are oftentimes done.

So let me give you some statistics. 40% of clinical trials that start in children fail, 60% stall and 30% never enroll a single patient due to avoidable delays. So in the absence of any approved new therapies, more than 50% of the drugs used in children and more than 90% of those used in new-borns are prescribed without adequate data to verify their efficacy and safety. These numbers should not be acceptable to anyone.

HANNAH

LIPPITT: Could you explain a bit more about why this is the case?

CINDY JACKSON: Yeah, I'd love to. So why is there such a long lag time between adult and pediatric approval? And there are many reasons for the lag time, but I'll give you the two biggest ones that I commonly see.

First, there may not be an appropriate formulation or dose which is manufactured that would be appropriate for children. So if you think about this, it makes sense. Small infants in neonatal intensive care units often aren't feeding. So they'll need IV formulations of drugs. Smaller children can't swallow pills, so they'll need solutions, suspensions, or powders. And if you think about adult medicines, most of those are in pill form. So we have to then do the studies to do the manufacturing of those different formulations to be able to even start the pediatric clinical trials in some cases. But the biggest reason is not including pediatric age patients during the course of the adult development.

So that means (a) not allowing adolescents to be enrolled in adult clinical trials or (b) not even starting clinical trials in children until the adult clinical trials are completed. And this makes sense from a business standpoint because companies are worried that simultaneous trials would put the adult licensing at risk. And there have been many studies that have looked at this issue, and they've found no new contraindications, warnings, or adverse events identified during pediatric trials that would negatively impact adult licensure. And a study done by the FDA supported the simultaneous development of adult and pediatric medicines, and allowed concurrent approval in both age categories when those concurrent approvals were asked.

So, the bottom line is, if you start pediatric clinical development early – so during the course of adult clinical development – it certainly will reduce that lag time. We know this is the case and we have a really good example in the COVID vaccines. Pfizer elected to enroll adolescents down to 16 years of age in their adult clinical trials, so therefore they kickstarted their pediatric clinical development program and quickly went into children. And therefore we had an approval within a year of an adult approval for the Pfizer COVID vaccine, Moderna shortly thereafter. So we know it can be done – it just isn't commonly done.

HANNAH LIPPITT: And

how long do these lag times tend to be?

CINDY JACKSON: This long lag time between adult approval and pediatric approval in the same indication can be upwards of a decade or even longer, and I find this statistic really sad. It's estimated that children wait for a new cancer drug a median of six and a half years longer than if they were an adult patient with the same cancer. So that was a median of six and a half years. The range in one study was up to almost twenty-eight years. This lag time has unintended consequences for those patients who are forced to use these drugs for chronic lifelong conditions like Crohn's disease, ulcerative colitis, some cancers, and the fact is that insurance companies won't approve payment for this off-label use because it's off-label.

So the other problem is that there's no way for data to be captured on this off-label use to look at what the long-term consequences of using some of these medicines in children are, because there's no systematic way to track that over time with off-label use. So it's a double prime. This lag time issue should not be acceptable to anyone, and we need to get the word out and make patients, parents, caregiver physician advocates all really pulling on the same side of the law to get this lag time decreased. It's really not acceptable for clinical care for children.

HANNAH LIPPITT: If we

go back to the clinical trial process itself, could it be that the problem is that it's harder to conduct pediatric clinical trials in comparison to adult trials?

CINDY JACKSON: First, I always tell people that doing pediatric clinical research is not harder or more difficult. It's just different, and we have to take a different tactic. We have to redefine our expectations and we have to think about things differently. And I think there are both macro and micro things that we have to do to be successful working in pediatric clinical development, and on clinical trials at the site level.

The macro part is making clinical trials and clinical research part of good patient care, making clinical research as common and expected as having your vitals taken when you go to the doctor's office, I really think should be our goal. Make it be an expectation of your patients and families to be offered to participate in a clinical trial. There have been clinical trial sites that have been very successful at doing this, and multiple studies have shown that clinics and institutions that provide clinical research options for their patients have higher patient satisfaction and most importantly, have better outcomes. So I think this should be the goal for anyone who cares for patients. I'd like to make it part of everyday care, not as a sideline and not as a bolt on to your clinical visit. I think you should be offered a clinical trial every time you walk through the door, if there is one acceptable for your particular case or condition.

HANNAH LIPPITT:

So that's something at Teckro we’ve talked about a lot as well. The fact that access to best possible care through trials there needs to be an automatic referral process.

CINDY JACKSON: Absolutely: make it easy for the clinician to find a clinical trial for a patient to be participating in. In two separate surveys done by colleagues and I over the last several years, the surveys were done to parents of school age and adolescent age patients, and the questions were around “Why do you or do you not participate, or would you consider participating in a clinical trial?” And the most common reason the parents gave for not having their children participate in a clinical trial is that they were never asked, and I think we need to change this paradigm.

HANNAH LIPPITT: Yeah, it's absolutely incredible that it's still not part of the process and people aren't aware, not just with adults, with children as well, of course. So you talked about some companies understanding the process and getting on board with running these trials simultaneously. Could you explain more about the role of sites as well when it comes to pediatric clinical trials and elaborate on best practices?

CINDY JACKSON: I talked to just a few minutes ago about the difference in doing pediatric clinical trials and adult clinical trials, one being that there was a macro thing that everyone should be expected to participate or offered to participate in a clinical trial.

But on the micro-level at the site level, enrolling pediatric patients takes effort and commitment from everyone at the site, from parking to ease of getting to the clinic, to the receptionist at the clinic, to the study staff and to the investigator. And most people may not realize – but if you're a parent, you realize – that most families have more than one child, so more than one child shows up at a clinic visit. So the patient and then their siblings because the caregiver has nowhere to take the siblings. So you have to have a clinic or a study site who has a safe place and activities for those siblings to wait.

A successful site always has involved investigators, enthusiastic study coordinators. I recently heard from one investigator – and this was just literally in the last couple of weeks – that masking due to COVID made it harder to consent his patients because they couldn't see him smile. And I just want to say I'm a huge proponent of masking, as is he, but it really illustrated the need for investigators to be heavily involved in the process, and some research colleagues and I have done over the years indicate that the most common reason parents consent to having their children participate is because their physician, who is a trusted member of their health care team, recommended participation to them. And that can't be overstated.

HANNAH LIPPITT: It's interesting that you highlight these quite straightforward things when it comes to best practice at sites, these things that we take for granted in other places.

CINDY JACKSON: I talked about ease of accessing the site, so parking instructions on how to get to the clinic, where to wait, where the receptionist is, etc. Again, the ability of the site to engage the siblings while the patient is being seen. I think one that we kind of forget about is extended hours, such as before and after school and on weekends. It's not convenient for some institutions to be able to do that, but those institutions that can do that generally have a much easier time enrolling their clinical trials. A phlebotomist who is skilled at working with pediatric age patients is able to draw that blood, able to use distraction techniques to make sure it's not a very traumatic procedure for them and activities for patients to participate in during long visits. And I'll give you an example.

Several years ago, I was participating as a medical advisor in a Phase II clinical trial for an asthma drug, and the study required an eight hour visit for the children. And they were younger children. They were probably six to eight years old, and the visit was eight hours, one time a week for several weeks in a row. When I first looked at that protocol and I thought: “Oh my, this is never going to enroll, it's going to be just an albatross around our necks. It's going to be very difficult.” And I was absolutely floored when that trial enrolled early. The satisfaction of the participants in the trial was very high. And here's the reason why; the asthma sites that we used were very good at doing trials in which the patients needed to be there for multiple pulmonary function testing visits or multiple pulmonary testings during the course of the day. They had activities for the kids. They brought in food for them during the day. It almost became like a camp experience. The kids got to mingle with each other during the day. The parents literally had a day off of taking care of their children. And it really was due to the fact that the sites were so well prepared. And also these sites had a very engaged patient population. They were used to being asked to be participants in clinical trials. In many cases, these children who participated in this trial were siblings of older children in the family who had also participated in clinical trials, which again goes to that... the thing I was talking about... the culture of clinical trials being embedded into the clinical care of a patient.

HANNAH LIPPITT: This

idea of making sites more convenient, if you like, has also been mentioned by other guests we've had on the podcast in relation to the idea of diversity when it comes to underrepresented communities. It's such an important topic right now in the industry. It would be great to hear your thoughts on this.

CINDY JACKSON: So I think we as an industry are not doing a great job at diversity. At the Institute for Advanced Clinical Trials for Children – where I am now – we actually have assembled a diversity panel that is available to sites. It's available to biopharma clients. It's available to literally anybody who wants to reach into this group and talk about how to increase the diversity of clinical trials – in our case for children – but I think across the board for adults as well. So I think it's a very important issue. I think that we need to talk about it more. We need to involve people that really, really understand these issues, which is why we put together this diversity panel.

HANNAH LIPPITT: And

before we finish our discussion, do you have any final thoughts you'd like to share with our listeners?

CINDY JACKSON: There is a huge need here. I think that there's just a general lack of knowledge about the issues faced in pediatric clinical development. I think when I tell people about what I do for a living and I tell them why I do it, I see nothing but shock on their faces. When I say things like, “Did you know that this medicine you're using in your child now has really never had clinical trials?” and it's literal shock. And I say, “Look, you know, we understand what's happening. We understand your doctor is not doing anything wrong. Your doctor is doing what your doctor needs to do to take care of your child because we don't have any other choice.” But I think that's wrong. I think we do have another choice, and the other choice is to become informed and to really allow people to understand that there is a significant need and problem here and it needs to be solved.

But it's going to take more than regulations. It's going to take more than a few individuals who are going out. It really takes knowledge of everyone to know that this is a problem and it needs to be solved. And I think if we can get more people on board, we can solve the problems. And that's really what we're trying to do at I-ACT for Children.

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HANNAH LIPPITT:

And that's your dose of Totally Clinical. For all the listeners out there, you can follow Teckro on Twitter – the handle is @TeckroOfficial – LinkedIn, and Facebook, and subscribe to our YouTube channel. And of course, download the Totally Clinical podcast on Apple, Spotify and Google. See you on your next visit and remember to bring your friends. Thanks for listening. Goodbye!

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