Paediatric Drug Development and Formulation Design-a European Perspective.
The availability of licensed paediatric drugs is lagging behind those for adults, and there is a lack of safe formulations in suitable doses that children are able and willing to take. As a consequence, children are commonly treated with off-label or unlicensed drugs. As off-label and unlicensed drug use are associated with a greater risk for harm than on-label drug use, a range of global initiatives have been developed to realize "better" medicines for children. This review describes the challenges and achievements of the European Union to realize this goal, with a focus on paediatric drug development and formulation design. In 2007, a European Paediatric Regulation was installed enforcing companies to consider children in the early development of drugs with a new drug substance, for a new indication or with a new route of administration. The Regulation, e.g. requires companies to develop a paediatric investigation plan discussing the proposed clinical trials in children of different ages and the formulations for future marketing. Since 2013, the pharmaceutical design of any newly marketed paediatric drug should comply with the "Guideline on the Pharmaceutical Development of Medicines for Paediatric Use." Companies should, e.g. justify the route of administration, dosage form, formulation characteristics, safety of excipients, dosing frequency, container closure system, administration device, patient acceptability and user information. In this review, the guideline's key aspects are discussed with a focus on novel formulations such as mini-tablets and orodispersible films, excipients with a potential risk for harm such as azo dyes and adequate user instructions.
Medicines Evaluation Board in the Netherlands, Quality department, Team I (chemical pharmaceutical assessments), P.O. Box 8275, 3503 RG, Utrecht, The Netherlands. da.v.riet@cbg-meb.nl.|Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands. da.v.riet@cbg-meb.nl.
Diana A
DA
Van Riet-Nales
European Medicines Agency, Evaluation Procedures B Service in Procedure Management Department, London, UK.
Piotr
P
Kozarewicz
Health Products Regulatory Authority, Dublin, Ireland.
Brian
B
Aylward
Medicines Evaluation Board in the Netherlands, Quality department, Team I (chemical pharmaceutical assessments), P.O. Box 8275, 3503 RG, Utrecht, The Netherlands.
Rutger
R
de Vries
Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.|Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht, The Netherlands.
Toine C G
TC
Egberts
Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht, The Netherlands.
Carin M A
CM
Rademaker
Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.|Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht, The Netherlands.
Alfred F A M
AF
Schobben
D002626:Chemistry, Pharmaceutical / Q000379:methods*; D055808:Drug Discovery / Q000379:methods*; D005060:Europe; D005079:Excipients / Q000737:chemistry; D006801:Humans; D056687:Off-Label Use; D010372:Pediatrics; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D013607:Tablets / Q000737:chemistry
D005079:Excipients; D004364:Pharmaceutical Preparations; D013607:Tablets
EMA; child; formulation; guideline; pharmaceutical; technology