Barry Mangum talks the importance of pediatric research, its evolution over the years, and the obstacles and opportunities that the industry faces as it moves forward.
How long have you been in pediatric clinical research, and how did you enter the field?
I’ve been in the pediatric arena since 1976, and in those days, I was going to develop my career in pediatric oncology, specifically acute lymphocytic leukemia (ALL). At the institution where I was being trained, we had a large group of people doing that work, and I was going to be part of that group. But unfortunately, back in the late 70s, most children diagnosed with ALL didn’t survive past age 3. That changed my whole perspective while working in the field.
I then pivoted to neonatology in 1978, where I thought I could make a real difference. In 1981, I got my doctorate degree in Clinical Pharmacology, but more importantly, my research was heavily involved in neonatal medicine, developing drugs there. So I’ve been working in that space about 43 years.
What would you say have been the most significant changes to pediatric drug development and clinical research in that time?
In 1994, the FDA came out with what they called the Pediatric Rule. Between 1981 and 1994, there was basically nothing for children. No guidance, no new guidelines from the FDA or EMA, none of that sort of thing. So in 1994, the Pediatric Rule came out, and it basically gave the pharmaceutical industry a heads up that legislation was coming that was going to mandate pediatric drug development. In 1996 the actual process started, and in 1997, Bill Clinton signed into law the Best Pharmaceuticals for Children’s Act (BPCA). The piece of legislation’s purpose was basically to look at drugs that we had used over the years in children, and then go back and study those drugs that were approved in adults, and study them for children. And then along that trajectory, in 2007, the European Medicines Agency and the European Commission crafted their legislation and passed it, and now they have a pediatric mandate to do clinical research.
In 2012, Barack Obama signed the FDA Safety and Innovation Act (FDASIA) into law, making the Pediatric Research Equity Act (PREA) and the BPCA permanent and thus mandating clinical research in children going forward. And that was the impetus behind a lot of people in Europe and the United States trying to reach equipoise on both sides of the Pond for a legislative initiative to address the unmet medical need in children. We then began to think about how we could all work collaboratively together, the FDA and the EMA.
I think what’s changed is that we’ve gone from no pediatric drug development to every drug being developed for children that can be developed in that space. I’ll give you an example. I was lecturing in London some years ago, and I made the statement that there are drugs that will probably not be developed for children, and one of those would be Viagra. There were six Pfizer people in the audience. They immediately stood up and said, “No, we’re doing six clinical trials in pediatrics now, specifically in the infant population, for something called pulmonary hypertension in these kids.” So many drugs that we see in today’s world that have an approval for a specific indication have all these off-targets that potentially could benefit children.
What is one significant reason that you believe pediatric clinical research is important?
One of the things about pediatrics that most people don’t realize is that 51 percent of the population on the planet are children. And before we had legislation in place, the medical needs of those children had remained largely unmet. We used drugs we developed in adults off-label in children. That became an issue because we created all sorts of toxicity. We created damage to children.
I’ll give you another example. When I first started in this space in 1998 as the Senior Director of Pediatrics for Quintiles, we were developing Prozac. And Prozac actually, in the female population, stunts growth by as much as two inches. Until we studied the drug in children, we didn’t know. You think about how many children were exposed to Prozac before this was known – who knows how many kids were affected? But now it’s a warning in their package insert. There are a number of those examples, where things have really gone off the rails.
What obstacles confront the industry as it pertains to the pediatric space?
Well, the first obstacle was that the pharmaceutical industry does not want to develop drugs for children. Why? Because it’s not profitable. Also, it’s a risk to their adult portfolio. If you develop a drug for a child and uncover an untoward effect to that child, then you’re going to get a black box warning.
Now, I’ll give you an example of that. When I was in clinical practice, one of the drugs I really liked was the first-generation fluoroquinolones ciprofloxacin. Cipro had a black box warning simply because of animal toxicity data that was done in six beagle pups, that resulted in cartilaginous damage to the supporting joints. After we started studying that drug in 1999 and 2000, I got to explore if this toxicity was real in children. Well, I already knew it wasn’t because it had been used off-label for years in kids. Now, we’ve studied it in 35 countries around the world. We overenrolled the study twice, we got a line-item extension for their drug, and the sponsor also got $500 million in exclusivity to ciprofloxacin. It was a big win.
Another challenge for the industry is reformulating drugs for pediatrics. There’s a whole mandate for that now, which wasn’t around until 2006 or 2007. Now we have to manufacture these drugs in a liquid formulation, a suspension formulation, injection, whatever we can get into a child. You can’t just use the adult form and give it to a kid. A child who’s six years old trying to take a large tablet, like a prenatal vitamin, is never going to swallow that drug.
My premise is this: If you can’t get the drug in the baby or in the child, you’re not going to get the drug to the site of activity, and it won’t work. Many drugs you can’t solubilize. Many drugs you can’t put in apple juice or orange juice because of the acidic nature and degradation of the compound. You have to study these drugs over time in different media, whether liquids or solid foods.
Are there any particularly common misconceptions about pediatric clinical research within the industry now that it has become so prevalent?
I think one of the misconceptions is that pediatrics is an easy place to do clinical research. And in fact, it’s not. Everybody has these unmet expectations, and they want it done yesterday – it’s probably not so different from the adult world. But the number of qualified investigators is limited in pediatrics simply because we haven’t been doing research in pediatrics as long as we have in adults. The pediatricians who are out there are not trained in medical school to become investigators. They learn this on the fly once they get into practice for a number of years.
Those who are coming from academia, however, learn how to become researchers pretty quickly because the transition in the academic world began a long time ago, to get almost every patient that you have into a clinical trial. I know that was the impetus at Duke University when I was there for 13 years. And it’s also the impetus at most of the major medical academic tertiary care teaching facilities in this country, of which there are 125. I think that’s really helped a lot, and I think the legislation has helped a lot.
But at the same time, the misconceptions are that we can do this for a limited amount of money. Everybody wants to cut the dollar on pediatric studies, and certainly CFOs and CEOs are hesitant in the pharma industry to allocate those dollars for pediatrics.
However, now it’s a mandate – you can’t get around it. In Europe, the EMA has the right to hold up your market authorization for your adult indication if you don’t get an approved Pediatric Investigational Plan before you launch your drug. In the United States, we’re not quite that punitive. However, some of our legislation is catching up.
In the Pediatric Study Plan, you have a defined timeline and a defined plan, a clinical development plan that has to be approved by the FDA. If you miss that, what we’re starting to see is the FDA becoming more punitive, and the punitive component is no longer just shame and blame. They’re going to give you a Failure to File Letter, which means that the FDA is going to request you take it off the market. So that’s really where the rubber meets the road. I can’t sell my adult drug if I don’t do the pediatric work. And I think it just needs to get tighter and better. And it will. But it’s going to take time.
What do you believe will be the future of pediatric research?
Honestly, I think what we’re going to start to see (and we’re seeing this in our business) is that a lot of work is directed, not to the adult population, but to the pediatric patient population, without going to the adult space. That has to do a lot with the work in gene therapy and rare disease and the ultra-rare space because there are 7,000 rare diseases that have been identified. About 3,500 of those, or half of them, are in pediatrics. What we’re starting to see is that the pediatric rare disease legislation and thus the Priority Review Voucher, which is worth somewhere between $100 and $125 million, are incentivizing the biotech world to explore pediatric drug development in some of these rare diseases. I know that we have about six of those at any given time going on in our organization. And these are not easy studies to do or subjects to find.
So there’s going to be an evolution of drugs developed for children, specifically as we begin to march into this gene therapy space. I believe that gene therapy and cell therapy is going to be where the action is going forward, not only for children, but for adults as well. I know some people would argue with that, and that’s fine. But I believe that there’s enough gene therapy development now in the US and around the world that we will soon see drugs developed specifically to cure diseases.
So I think that the future is really bright for children, and I think we’re in the right time and the right place to do it. I would like to see it speed up, but as we know, the FDA and the EMA and other regulators around the world want to be cautious when we study these children. And what you’re seeing is that over time we’ve evolved a fairly, I would say, efficient knowledge of what we need to do. Have we acted on every touch point? No. But I believe that the future of pediatrics is going to be in gene therapy, cell therapy. There will be a continued emphasis on small molecules and large molecules, but those will not be as impactful, I don’t believe, as gene therapy will be going forward.
With a strong commitment to improving the lives of children and their families through pediatric research, the Camargo/Paidion team has deep experience in pediatric clinical studies and a thorough understanding of the evolving landscape. Contact us to find out how we partner with you to plan and execute your pediatric clinical program today.