EU guideline aims to deliver child-friendly formulations
A new European guideline, which came into effect in February 2014, aims to encourage the pharmaceutical industry to develop drug formulations that are more appropriate for children, according to Diana van Riet-Nales of the Medicines Evaluation Board in The Netherlands. She was speaking at the 9th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology held in Lisbon, Portugal, this week (2 April 2014).
“Children require special attention because they are not small adults,” said Dr van Riet-Nales, who trained as a pharmacist and was closely involved in developing the European Medicines Agency’s “Guideline on pharmaceutical development of medicines for paediatric use”.
The guideline aims to address several problems. All too often, Dr van Riet-Nales explained, adult medicines are used off-label for children, despite a lack of clinical evidence that these formulations are suitable. “There is a general lack of age-appropriate formulation,” she said, adding that “crushing or mixing tablets with food is no alternative”.
And until recently, there has been relatively little research on which formulations are most likely to be accepted by children of different ages – ranging from syrups or oral drops to tablets and capsules. Finding the right formulation for children should now become an integral part of drug development, said Dr van Riet-Nales. Children involved in early clinical trials should be asked whether a medicine tasted horrible, for example, or whether they could swallow it easily. “They don’t need to like it – but they should be able to take their medicine without problems,” said Dr van Riet-Nales.
The guideline also focuses attention on excipients, such as ethanol or propylene glycol, which should not be taken by children. Products containing these compounds may have been given to children off-label for decades, with little more than a vague feeling that the benefits of the medication outweigh the risks of the excipient. “Now it’s the responsibility of the company to convince the regulator that their product is suitable for children,” said Dr van Riet-Nales.
The guideline will principally apply to new drug applications, but the EMA also expects the pharmaceutical industry to ensure that older medicines comply. If companies refuse to follow the guideline, the EMA has the option not to license their new drug. “They can’t ignore it,” Dr van Riet-Nales told PJ Online.
“This new guideline will change a lot of things in the pharmaceutical industry,” said Professor Jörg Breitkreutz, of the University of Düsseldorf, Germany, and a member of the European Paediatric Formulation Initiative (EuPFI), a consortium of industry, clinical and academic partners that formed in 2007 to help develop better paediatric medicines.
One of the most contentious debates surrounding the guideline has been about whether young children can be expected to take tablets. Dr van Riet-Nales said that there was a large variation in attitudes across different European countries, yet relatively little research on the subject.
She highlighted three studies, however, that could surprise many parents who have wrestled with infants needing medication. One found that almost half of two-year-olds could readily swallow a three-millimetre-wide tablet, a proportion that rose to 85 per cent in five-year olds. A second, in December 2013, showed that infants and pre-schoolers took two-millimetre-wide tablets better than a syrup formulation. And Dr van Riet-Nales herself found that one- to four-year-old children preferred to take four-millimetre-wide tablets rather than powders, liquid suspension or syrup formulations. “There is no longer any reason to debate the acceptability of tablets in children,” said Dr van Riet-Nales.
But she emphasised that the guideline does not favour – or ban – particular formulations for children. Instead, it requires pharmaceutical companies to justify their choice of formulation, and back that up with evidence. This flexibility means that meeting the requirements “should be doable for industry”, Dr van Riet-Nales told PJ Online.
New guideline builds on EU Paediatric Regulation
The new guideline builds on the EU Paediatric Regulation that came into force in January 2007, and which obliges pharmaceutical companies to consider running child-specific clinical trials. In a quid pro quo, industry can win extended patent protection for drugs developed under these paediatric investigation plans (PIPs). The EMA can also waive this requirement in order to avoid unnecessary clinical trials on children, for example, or to ensure that the process does not delay approval of drugs aimed at adults.
But PIPs have been controversial. In February, the UK’s Institute for Cancer Research argued that the rules were causing children to be denied potentially life-saving drugs and haemophilia researchers have also echoed this complaint.
The EMA says it will closely monitor the impact of the new formulation guideline.
Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2014.11136957