Paediatric Trials and Tribulations

18 November 2010 (Last Updated November 18th, 2010 18:30)

In the lead up to the Arena Paediatric Drug Development and Clinical Trials conference many issues are set for debate. Chris Lo spoke to Karl-Heinz Huemer of the European Medicines Agency's Paediatric Committee about the unique challenges of developing drugs and medical devices for children.

Paediatric Trials and Tribulations

The Paediatric Drug Development and Clinical Trials event, taking place in Brussels on November 22-23, will bring together some of the world's foremost experts on paediatric medicine to discuss the most pressing issues facing this vital field.

Faced with a relatively young and complex regulatory structure, pharmaceutical companies are still finding their feet when it comes to paediatric drug development and the tricky issues surrounding the conduct of clinical trials involving children.

Here we talk exclusively to Karl-Heinz Huemer, a member of the European Medicines Agency's Paediatric Committee, which has been made responsible for assessing pharmaceutical companies' initial clinical trial proposals (called paediatric investigation plans, or PIPs) and collecting data on the safety and efficacy of new paediatric drugs.

Huemer sheds some light on how to prepare an efficient PIP, the challenges ahead for the industry and some of the toughest aspects of developing drugs for infants and growing children.

"The main problem is children need drugs, but they are not tested in them. That means every paediatrician has to give a drug to a child without having proper data on that use."

Chris Lo: What are the major differences between paediatric trials and trials within an adult population?

Karl-Heinz Huemer: Well, it's a bit difficult to generalise, but one thing that is very often referred to is the difficulty of recruitment. You have to involve parents, and parents are much more reluctant to say yes if their children are involved in the trial.

The second, rather more difficult issue, is that the number of patients is lower in general, and the patient population is more heterogeneous. You can't just involve children; you always have to consider which age groups are represented in your trials.

So you very often need stratification, or even trials that are not applicable to the whole range. You have to look for a different end-point in smaller children; you have to look specifically for different dosing.

Dosing is the next problem. Very often, you need a different administration form for a paediatric trial.

So it's a lot of things that together make it much more complicated. That's the reason that for such a long time, it hasn't been done.

CL: How do you think drug developers can persuade parents to allow their children to become involved in trials?

KH: Actually, I think that's the easiest point! Because, quite simply, the main problem is children need drugs, but they are not tested in them. That means every paediatrician has to give a drug to a child without having proper data on that use.

So if you can communicate that, actually, it's the same thing that is done, a drug is given to a child, but it is much better monitored, then I don't see it as so much of a problem but compared to the current situation it's an improvement because children are better monitored and it is standardised within clinical trial regulations. There's no more risk than treating a child outside of a trial.

CL: What about medical devices for paediatric drug delivery; are there different considerations from the adult market?

KH: A device, as such, is not part of the portfolio of the European Medicines Agency. If a drug product has within its approval a device, for example an inhalator, then of course that's part of the application, and very often these inappropriate devices are a problem – that some drugs cannot be delivered appropriately to children. So we see this rather regularly, for different kinds of devices, when they are part of the drug product.

For example, different types of inhalators, or sometimes having a single-dose in a syringe, where this device can't deliver the smaller doses that are needed in children. So if the syringe has a 6:1 dosage volume that's too large for children, then we would require a smaller dosage for paediatric use.

CL: To what extent is the pharma and drug development industry involved with the PDCO's work?

KH: A PIP is an extensive exchange between a company and the PDCO anyway. So there are many other issues that the PDCO has on its portfolio. We involve scientific committees with regards to establishing guidelines and things like that.

"Inappropriate devices are a problem – some drugs cannot be delivered appropriately to children."

I think, directly and indirectly, we welcome input from industry because in the end we have to find solutions together with the industry. I'm not quite sure whether the industry sees it that way, but that's really the approach of each individual company.

You can see in an application when a company wants to make constructive proposals, or rather be restrictive, where they would rather send lawyers than scientists. I think, in general, we are open to input from industry, not only on the PIP, but also on a general level where applicable.

So for example, a little while ago, we had a rather long discussion with a European allergy group, with industry represented as well, to discuss end-point applicability and so on. So I think we really try to get input from all sides.

CL: How would you describe current regulations for paediatric drugs in Europe, and could they be improved?

KH: Well, you can always improve! It's still rather new; I know that industry has problems with some of the requirements, because it's also new to them – they have to implement new strategies. As far as we can see, another problem for industry is the difference between the US and Europe.

I think, mainly, industry would have to take a more harmonised approach to this problem in the US and Europe. Europe requires a rather early approach from the company to the agency with a proposal [paediatric investigation plan - PIP], whereas in the US it's later. It would make sense if the US and the EU could find a more accorded approach, so that companies don't have to go through approvals twice.

CL: Is it more likely that the US will adopt the European system or vice versa?

KH: That's a political question! I would say that I cannot imagine the US will accept the European approach, but I also don't see why we should go the US way. I think, in the end, it might make sense to meet somewhere in the middle with regards to what companies actually have to do and when they should declare what they are doing. That's something that companies often misunderstand.

When they have to come early with a proposal in Europe, that doesn't mean they have to start development early. They should make up their mind early. And I think that's something the US could, in principle, agree on. How many details we need at that time is the contentious part.

"If you need a PIP, you should have a plan for your whole development, based on scientific, not regulatory aspects."

CL: What advice would you give to pharmaceutical companies for putting together an effective paediatric investigation plan (PIP)?

KH: What the PDCO is mainly doing is considering scientific aspects. That means many generics or biosimilars don't need a PIP. And if you need a PIP, you should have a plan for your whole development; you should have arguments about why you want to do something and when you want to do it, based on scientific, not regulatory aspects.

For example, very often we will hear something like: "We will start the clinical trial in paediatrics after the adult marketing approval." That doesn't make sense from a scientific point of view.

Practically, it might end with that, but normally you have the data available when you apply for the marketing authorisation, so that means at that time you could start with paediatrics before you have the approval, which is very often more or less a year later.

If companies are aware that mainly scientific reasoning on a development plan – when can this step be planned based on the data that are available, and what is not an applicable drug for children based on epidemiology, so if there is no need or if there is some problem that makes it impossible to develop – this is the line of argument that companies should focus on, I think.

The Paediatric Drug Development and Clinical Trials conference will take place in Brussels on November 22-23 2010.