The need to do more in paediatric drug development

The pharmaceutical industry is capable of producing sophisticated medicines that can deliver their therapeutic payload with exquisite accuracy to target tissues, but there is still one patient group that has yet to benefit from these technological advances.

Children around the world are still routinely being treated with medicines that have not been designed or developed with their own specific physiologies and needs in mind, putting them at risk of inaccurate and suboptimal dosing and side effects from potentially toxic ingredients.

In fact, parents and healthcare professionals are often still forced to break up and divide adult dosages and mix them with food or a drink to try to deliver an appropriate dose for a child, generally calculating the dose proportionally according to body weight. That is a tough challenge, considering that by definition a child's body weight can range from a premature infant right through to a near-full-grown adolescent.

In some cases so-called 'extemporaneous' formulations will be made by a pharmacist on request from a doctor, which provides a little more reproducibility but is still a long way from having fully tested formulations ready for use.

For instance, a team at Glenfield Hospital in Leicester, UK, has been looking at 20 unlicensed liquid captopril formulations sold on the UK market by special manufacturers to treat children with heart failure. They found that paediatric cardiac centres and referring hospitals use these formulations interchangeably, even though there are inconsistencies in bioequivalence that raise issues about optimal dosing and potential toxicity.

All change in 2007
In some respects, the formulation science is racing to catch up with the legislative environment in Europe, following the passage of legislation in 2007 which required developers of innovative drugs to conduct a Paediatric Investigation Plan (PIP) as part of their marketing application dossier, unless they could argue for a waiver.

The regulation effectively forced companies to develop paediatric formulations for all medicines coming on to the market that could potentially be used in children.

Before this, industry was reluctant to carry out this sort of research because of the complexities involved in developing formulations for children and ethical, logistical and economical concerns about paediatric drug testing, according to Dr Catherine Tuleu, reader in pharmaceuticals at the UCL School of Pharmacy in the UK.

“Since 2007 this mentality is gradually turning around with an understanding that it is unethical not to carry out clinical trials in children if they could benefit from a properly researched and developed age-appropriate dosage form,” she said.

Tuleu has been involved in paediatric formulations for almost a decade, through her work within the formulation work stream of the National Institute for Health Research Medicines for Children Research Network, set up in the UK in 2005, and the five-year-old European Paediatric Formulation Initiative (EuPFI).

She believes that the pharmaceutical industry was taken somewhat off-guard after the 2007 legislation came in as it was not fully aware of how rigorously the European Medicines Agency (EMA) would oversee the formulation of medicines for children within the context of the new regulation.

There was (and still is) a lack of clear European guidelines on paediatric formulation, although these are in the process of being drawn up. In the absence of these, the EuPFI was set up to operate as a forum between industry, academia and regulators, linking academic, clinical and drug development expertise to facilitate the preparation of better and safer formulations for children.

EuPFI has five workstreams, on extemporaneous preparations, taste-masking and testing, administration devices, age-appropriate formulations and on excipients with a major database project, known as STEP (Safety and Toxicity of Excipients for Paediatrics), designed to provide information for the risk assessment of use of excipients in children.

“One of the main issues at present is that while the EMA is pushing for innovative medicines for children, there is a big gap in terms of reimbursement policy,” Tuleu continued.

In Germany, for example, reimbursement of medicines is in some cases partly determined by the dose of active drug delivered in a product, which clearly could have dramatic consequences for a medicine specifically designed for use in children, particularly if it required a costly delivery system.

“Companies are reticent to invest much in this area, not least because the paediatric market is smaller,” she added. “We are trying to find ways to allow manufacturers to bring forward innovative new products that are commercially viable.”

One clear example of the difficulties facing companies is the Gruenenthal 'straw', a novel delivery system that reached the market in 2005 in a generic antibiotic product called Clarosip. The drinking straw housed dry medication in the form of coated, taste-masked granules and delivered a controlled dose as the child enjoyed his or her preferred drink.

Patient surveys indicated this was immensely popular with both children and their parents, but people were unprepared to pay the relatively modest premium for the product, choosing instead the traditional liquid suspension, and it was withdrawn as a commercial failure.

At the time of writing there were rumours that the technology may make a comeback using a branded product that could allow viable pricing, but these had yet to be confirmed.

A similar delivery idea is being developed by Danish company Egalet. In this case, a dispensing spoon has been produced, which contains the medicine in the firm's 'Parvulet' composition under a film that is peeled off before use. Water is added to the spoon and it swells to form a flavoured 'pudding' that is ready for use.

Egalet has already started testing the Parvulet technology for the delivery of medicines for children in collaboration with Novartis' generics subsidiary, Sandoz.

Curiously, the over-the-counter (OTC) medicines sector has plenty of examples of innovative delivery and packaging systems that are well-received by the public, but there is resistance when this approach is applied to prescription medicines.

“In OTC you see innovative stuff for children on the shelf, and people will clearly pay for it, but as soon as it is on prescription, for some reason they won't,” explained Tuleu. “We are still stuck with more traditional technologies when it comes to prescription medicines.”

Outside Europe there are other factors to consider, which have implications for pharmaceutical manufacturers. Medicines destined for the developing world also need to be easily stored and transported and while child-friendly formulations have traditionally been syrups, these are bulky and can require refrigeration.

For this reason, the World Health Organization suggested in 2008 that drugs for distribution in the developing world should be flexible, solid oral dosage forms, although there are clear benefits for a similar approach in more developed markets as well.

One focus at the moment is on tablets that can be divided up into more manageable sizes, or minitablets that are easier for children to take. Novartis has adopted this idea in the development of a new antimalarial product that delivers minitablets in a stickpack, which can be emptied into the mouth and swallowed with water, for example.

Meanwhile, other projects are looking at orodispersible tablets that dissolve in the mouth, multi-particulate systems within capsules, which allow doses to be divided more easily, and even fast-dissolving films that could have active ingredients printed on them, using technology similar to inkjet.

Cost issues
“There is work going on in these areas, but this is somewhat limited by the fact that many of these technologies are patented, raising the cost issue once again, while the doses that can be delivered in this way are relatively low,” noted Tuleu.

Of course this route of administration also brings taste considerations to the fore, which has been a key hurdle even for conventional liquid formulations used in children. This is an enormously challenging area at the moment, according to Tuleu, but there have been interesting advances in the area of taste assessment, such as the use of 'electronic tongues', that could facilitate formulation development in the future.

For example, the ultimate outcome would be for electronic tongues to be used early on in the drug development process to allow taste to be a factor in the selection of drug candidates alongside safety and activity considerations.

These in vitro systems are still in the early stages, mainly because of problems associated with validating the technologies, but there is a lot of effort going into this area from both industry and academic groups.

“In the coming years we can expect to see innovative formulations for children reaching the market, but at the moment we're still at the R&D stage,” concluded Tuleu.

 

The Author
Phil Taylor is a freelance journalist specialising in the pharmaceutical industry