Barry Mangum, Senior Vice President, Pediatrics at Premier Research, talks about the importance of pediatric research, its evolution over the years, and the obstacles and opportunities the industry faces.

Q: How long have you been in pediatric clinical research, and how did you enter the field?

A: 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. At the institution where I was being trained, we had a large group of people doing that work. But unfortunately, back in the late ‘70s, most children diagnosed with that condition didn’t survive past age 3. That changed my whole perspective while working in the field.

I pivoted to neonatology in 1978, where I thought I could make a real difference. In 1981 I got my doctorate in clinical pharmacology, and my research was heavily involved in neonatal medicine, developing drugs there.

Q: What is one significant reason you believe pediatric clinical research is important?

A: One of the things about pediatrics that most people don’t realize is that 51 percent of the people on the planet are children. And before we had legislation in place, the medical needs of those children 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 was Senior Director of Pediatrics for Quintiles, we were developing Prozac. In the female population, Prozac stunts growth by as much as two inches. Until we studied the drug in children, we didn’t know that. 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.

Q: What obstacles confront the industry in the pediatric space?

A: The first obstacle was that the pharmaceutical industry does not want to develop drugs for children, 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 on that child, you’re going to get a black-box warning.

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 of fluoroquinolones ciprofloxacin. Cipro had a black-box warning simply because of animal toxicity data from six beagle pups. It resulted in cartilaginous damage to the supporting joints. After we started studying that drug in 1999 and 2000, I got to explore whether 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 the 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 6 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.

Q: Are there any particularly common misconceptions about pediatric clinical research within the industry now that it has become so prevalent?

A: I think one of the misconceptions is that pediatrics is an easy place to do clinical research. 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 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 in the pharma industry are hesitant 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.

Q: What do you believe will be the future of pediatric research?

A: We’re going to see a lot of work directed not to the adult population, but to the pediatric patient population, without going to the adult space. That has a lot to do 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 million and $125 million — are incentivizing the biotech world to explore pediatric drug development in some of these rare diseases. 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 are 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 U.S. and around the world that we will soon see drugs developed specifically to cure diseases.

So I think 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 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 and 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.

With a strong commitment to improving the lives of children and their families through pediatric research, Premier Consulting 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.