5. Special cases in marketing authorisations: Paediatric medicines
1. Paediatric medicines
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There is broad consensus that children deserve access to medicines that have been specifically developed and researched for their use in young patients. However, for considerable time the development and testing of paediatric medicines has historically been unsatisfactory.
Reasons for the absence of suitable medicines for the paediatric population included:
- inadequate dosage information (many medicines used in children were prescribed and administered based on physicians’ own experience rather than on the results of clinical research*)
- absence of suitable formulations and routes of administration (paediatricians had to adapt the dosage and form of medicines authorised for adults, for example, by using only a portion of a tablet for adults after dissolving*)
- ethical concerns about clinical research in children
- economic considerations hindering proactive investment in this sector (for example, the needs and biological and physiological characteristics of neonates are very different compared to teenagers, therefore additional age-appropriate research is required, increasing the complexity, time and cost of developing paediatric medicines).
- non-availability of therapeutic advances for the paediatric population,
- high variability or missing normative physiological data for different paediatric subgroups up to young adults on which to base the development of medicines
* These can be considered off-label use of adult medicines in children. This carries the risk of either lack of effectiveness or poses safety problems in children, the latter perhaps of lesser concern in adults but possibly important and serious in children. A 2017 study on off-label use of medicines in the EU suggested that in children 0-18 years of age the prevalence of off-label use was still widespread.
FOR THE INTERESTED: in hospital settings with a mean of 33,8 ± 15,5 SD and outpatient setting with a mean of 40,8 ± 28,1 SD. The introduction of the Paediatric Regulation (1901/2006/EC) was introduced to lower off-label use in paediatrics. According to the publication, this has not yet led to a lower prevalence of off-label use primarily due to indications where satisfactory treatment exists for adults (32 studies on off-label use (including data from 16 EU Member States) in various paediatric populations in the hospital setting showed a range of 13-69% of the investigated prescriptions being off-label. In 40 studies (including data from 12 Member States) in the outpatient setting, a wider range of 2-100% was found).
In general, off-label use of drugs is common and occurs in every specialty of medicine. It may be more common in areas of medicine in which the patient population is less likely to be included in clinical trials (eg, pediatric, pregnant, or psychiatric patients) (Wittich et al 2012 Ten Common Questions (and Their Answers) About Off-label Drug Use).
A study from 2006 reported, in a group of commonly used medications, 21% of prescriptions were for an off-label use (Radley et al 2006 Off-label prescribing among office-based physicians). In an intensive care unit setting 36.2% of the medication orders were for off-label use (Lat et al 2011 Off-label medication use in adult critical care patients, in a headache specialty practice the amount of off-label prescriptions was 47% (Londer and Biondi 2004 Off-label prescribing of drugs in specialty headache practice). In oncology, according to one study from 2017 up to 71% of patients received at least one off-label chemotherapy (Saiyed et al 2017; Off-label drug use in oncology: a systematic review of literature).
Regulation (EC) No 1901/2006/EC, the Paediatric Regulation, came into force in the European Union (EU) on 26 January 2007. It was seen as a response to the absence of sufficient numbers of suitable, authorised medicines for children. The regulation was adopted to “ensure that medicines are regularly researched, developed and authorised to meet the therapeutic needs of children”. Its objectives were to:
- facilitate the development and availability of medicines for children aged 0 to17 years of age;
- ensure that medicines for the treatment of children are subject to ethical research of high quality and are appropriately authorised for use in the paediatric population;
- improve the available information on the use of medicines in various paediatric populations.
- achieve this without unnecessary trials in children or delaying the authorisation of medicines for adults
It applies to both, “nationally” (MRP, DCP, national) as well as to centrally authorised medicines.