Children (particularly those 0-28 days old i.e. neonates) respond to drugs in a very different way to adults. Typically, doses in children are calculated by weight and occasionally by body surface area but the dose should never exceed the maximum adult dose. This, however, is only a guide as for some drugs children require a higher dose per kilogram than adults because of their higher metabolic rates. In addition, working out dosage by weight should not be applied to an overweight child as it could result in a much higher dose being administered than is actually necessary, safe or desirable. In this instance, the dose has to be calculated using the ideal weight and not actual weight. To say that a child is half the size of an adult and therefore should receive half the adult dose is too simplistic and could well be dangerous.
The British National Formulary (BNF) for Children provides healthcare professionals with up-to-date information on the use of medicines for treating children both within the realms of the medicine's licence (Marketing Authorisation) and for "off-label" use i.e. the use of licensed medicines (in adults) for unlicensed uses. This resource is invaluable for the effective and safe treatment of children.
The use of unlicensed and "off-label" medicines in children has caused concern, however, throughout the EU for a number of years now as at least 50% of medicines used to treat children have never been tested in children, only adults. This lack of supporting data for the treatment of children was felt to have contributed to an unacceptable number of adverse events. As a result of this, and the overall need to improve on the information available, the European Paediatric Initiative came into being with a new EU Paediatric Regulation1 entered into force on 26 January 2007.
This new regulation has several implications with the overall purpose being to provide "better medicines for children"2 and these are as follows:
New product marketing authorisations
From July 2008 any new products which were not authorised within the EU before 26 January 2007 have to include results of studies carried out in children. These studies must comply with an agreed Paediatric Investigation Plan (PIP) unless, of course, a deferral or waiver has been agreed with the EMEA. A waiver may be granted, for example, when a new medicine is intended to treat a condition which only occurs in adults (for example Parkinson's disease). As an incentive for pharmaceutical companies, once authorisation has been granted for a paediatric indication the new medicine is then eligible for a 6 month extension of its patent protection. This patent protection is further extended for Orphan-designated medicines by another 18 months giving a total of 12 years of exclusivity (as opposed to 10 years).
Existing product marketing authorisations
From 26 January 2009, the requirements above will also apply to marketing authorisation variations.
Paediatric-use Marketing Authorisation (PUMA)
This is a new marketing authorisation which applies to off-patent medicines which have been developed specifically for paediatric use. Again, product development must comply with the agreed PIP and provided there is compliance, a pharmaceutical company will benefit from 10 years of data protection.
Paediatric Investigation Plans (PIPs)
Otherwise known as a "drug development plan" this is a development plan which ensures the collection of relevant data from studies in children (when it is safe to do so). It must include details of these studies and the ways in which the medicine has been adapted to make it suitable for children. For example, children will more readily swallow a syrup than a tablet. In some instances studies in children will be deferred until the studies in adults have been completed. This ensures that studies in children are carried out only when it is safe, and ethical, to do so. Of course, there are some illnesses which do not affect children which means a PIP will not be required and hence 'waived'.
For many companies the Paediatric Regulation is a completely new challenge and, up until recently, they will not have incorporated it into their business strategy. With ever decreasing headcount, it is becoming more and more difficult to keep up-to-speed with all the latest legislation and the implications of enforcement. Regulatory Consultancies such as GRS can help companies by offering the services of senior regulatory professionals who already have working knowledge and experience of the Paediatric Regulation. With the pharmaceutical industry, the Health Authorities and regulatory professionals working together we can have a positive effect on the development, availability and safety of medicines for the treatment of children and improve the availability of information on the use of these medicines. This new legislation may be challenging and time consuming however it will provide a safer future for our children.
1 Regulation (EC) No 1901/2006 of the European Parliament and of the Council on medicinal products for paediatric use, amended by Regulation (EC) No 1902/2006.
2 Source: EMEA
by Greer Deal