BPharm(Hons) MRPharmS MCPP
Lecturer in Paediatric Clinical Pharmacy
Academic Division of Child Health University of Nottingham
Paediatric Clinical Pharmacist
Derbyshire Children’s Hospital
The lack of drugs licensed for children creates problems on an everyday basis for paediatric healthcare professionals, parents and children alike. The licensing process was originally introduced following several drug-related tragedies. These included the birth of babies with phocomelia (a shortening or complete absence of the limbs) and other defects, following maternal ingestion of thalidomide. “Grey baby” syndrome resulted from the use of chloramphenicol in neonates, leading to cyanosis, cardio-
respiratory collapse and death. The lack of knowledge of the differences of drug handling by the fetus and the neonate resulted in these consequences. The licensing process aims to ensure that drugs are safe, effective and of a high quality; however, it is currently failing the patients it was introduced to protect.
Unlicensed and off-label drug use
Most drugs used in adults have undergone the regulatory processes needed to gain marketing authorisation. Substantial information is provided by the pharmaceutical manufacturer demonstrating safety, efficacy and quality. However, children every day are required to take medicines that are either unlicensed – because they have not been subjected to the licensing process – or are used in an off-label manner – because they are being used outside the terms of the licence. The safety, efficacy and quality of these prescriptions cannot be guaranteed. Table 1 provides a reflection of the size and nature of this issue. Other studies have demonstrated that paediatric patients treated in all hospital clinical areas and in the community are affected, with many of the drugs involved being commonly used.(8–18)
Unlicensed medicines must be used when no appropriate formulation of a drug is commercially available. This may involve extemporaneous dispensing with little information on bioavailability and stability; purchasing from a manufacturer on a “named-patient” basis or as a “special” product; importing drugs licensed in other countries; or using chemicals when there is no pharmaceutical-grade material available.
Off-label drug use refers to use outside the conditions of the marketing authorisation. This may involve the use of different doses, routes of administration, age groups, indications or contraindications compared with the licence.
Provision is made in law to allow the prescribing, dispensing and administration of unlicensed and off-label medicines. Statements from UK and US paediatric professional bodies highlight that unlicensed and off-label drug use is a vital part of children’s drug therapy.(19–22) It is in fact considered that prescribers could be neglecting their duty of care to patients by not prescribing the best treatment just because it is unlicensed or off-label.(19,21,23,24)
Problems created for healthcare professionals, parents and children include the lack of appropriate formulations needed to ensure accurate measurement and administration of paediatric doses. Lack of licensed paediatric dose advice may result in suboptimal therapy or adverse drug reactions, a risk increased by pharmacokinetic and pharmacodynamic differences between neonatal and paediatric populations and adults. Patient information leaflets (PILs) reflect the licensed information. If the drug is unlicensed there will be no official PIL; if it is being used in an off-label manner then the PIL may contain information to concern a parent.
Problems of consent, ethical issues and practical difficulties have all been suggested as obstacles to testing drugs in children. However, these can be overcome by performing trials in centres involving experienced paediatric clinical investigators. Realistically, the paediatric drug market is small and considered unworthy of investment by many pharmaceutical companies.
“Better Medicines for Children”
This document from the European Commission was long awaited and very welcome. It outlines suggested means of addressing the lack of licensed products for children. In the US, where similar initiatives have been introduced in recent years, much has been done to generate clinical studies and useful paediatric prescribing information.
The objectives of the European proposals include:
- Increasing the availability of authorised medicines adapted to the needs of children in different age groups.
- Adapting pharmacovigilance mechanisms to aid detection of long-term effects.
- Avoiding unnecessary studies.
- Establishing priorities for research.
- Developing European excellence in paediatric clinical trials.
- Ensuring that the highest ethical criteria are met.
Possible means of achieving these objectives may include:
- Introducing incentives to industry for completing trials of drugs in children (eg, extending drug patent protection) or for off-patent drugs, introducing a new type of paediatric authorisation with patent protection.
- Creating a fund to support paediatric research.
- Introducing regulatory powers requiring manufacturers to perform studies in children as part of marketing authorisation applications.
- Creating a central database of existing experience of medicines in children, including unlicensed and off-label use.
- Creating an EU expert group as part of the European Medicines Evaluation Agency with specific responsibility for paediatric medicines.
- Creating a pan-European network for performance of paediatric studies.
The proposals are well written and welcome. Following the closing date for comments of 30 April 2002, formal regulatory laws are to be developed. European pharmacists should begin to see improvements in availability of medicines for children, with appropriate prescribing information and formulations facilitating safe, accurate administration of medicines acceptable to children. Day-to-day problems and dilemmas encountered by paediatric healthcare professionals should reduce. More importantly, the rights of children to expect treatment with safe, effective, high-quality medicines will begin to be satisfied. The document is a very positive first step towards achieving these rights for children.
- European Commission. Better medicines for children. European Commission; 2002. Available from URL: http://pharmacos.eudra.org/F2
- Turner S, et al. Lancet 1996;347:549-50.
- Conroy S, et al. Arch Dis Child Fetal Neonatal 1999;80:F142-5.
- Conroy S, et al. BMJ 2000;320:79-82.
- McIntyre J, et al. Arch Dis Child 2000;83:498-501.
- ‘t Jong GW, et al. N Engl J Med 2000;343:1125.
- Chalumeau M, et al. Arch Dis Child 2000;83:502-5.
- Thompson DF, Heflin NR. Am J Hosp Pharm 1987;44:792-4.
- McKinzie JP, et al. Am J Emerg Med 1997;15:118-21.
- Turner S, et al. BMJ 1998;316:343-5.
- Turner S. Aust J Hosp Pharm 1999;29:265-8.
- Turner S, et al. Acta Paediatr 1999;88:965-8.
- Avenel S, et al. Arch Pediatr 2000;7:143-7.
- Gavrilov V, et al. IMAJ 2000;2:595-7.
- Wilton LV, et al. Pharmacoepidemiol Drug Safety 1999;8:S37–S45.
- Martin RM, et al. BMJ 1998;317:204.
- Conroy S, Peden V. Paediatr Anaesth 2001;11:431-6.
- Lifshitz M, et al. Eur J Clin Pharmacol 2001;56:839-41.
- Committee on Drugs. Pediatrics 1996;98:143-5.
- Bendall C. Paediatr Perinat Drug Ther 1999;3:49-54.
- RCPCH and NPPG. Medicines for children. London: RCPCH Publications Limited; 1999.
- Joint RCPCH/NPPG Standing Committee on Medicines. The use of unlicensed medicines or licensed medicines for unlicensed applications in paediatric practice. Policy statement. London: RCPCH; Feb 2000.
- Cote CJ. Acta Paediatr 1999;88:925-7.
- Cote CJ, et al. Pediatrics 1996;98:118-23.
Neonatal and Paediatric Pharmacists Group
European Society for Developmental Perinatal and Paediatric Pharmacology