A literature review on off-label drug use in children

Abstract

The aim was to compare results of studies performed in different settings worldwide and identify common therapeutic areas to allow for focused interventions, because off-label drug use can be a measure of the lack of knowledge concerning paediatric treatments. A secondary objective was to provide a brief review of efforts to date. A literature review of articles on off-label and unlicensed drug use in children involving general prescription samples was performed using Medline and Embase. In all, 30 studies from 1985–2004 were included. Eleven involved paediatric hospital wards, seven neonatal hospital wards, and 12 the community setting. The off-label and unlicensed classification methods varied, making results difficult to compare. In general, off-label/unlicensed prescription rates ranged from 11%–80%, and higher rates were found in younger versus older patients and in the hospital versus community settings. On the paediatric hospital wards, off-label/unlicensed prescriptions ranged from 16%–62% and most often concerned acetaminophen, cisapride, chloral hydrate, and salbutamol. In the neonatal wards, rates ranged from 55%–80% and often involved caffeine. In the community setting, rates ranged from 11%–37% and the most commonly implicated drugs were salbutamol and amoxicillin. Conclusion:A lack of harmonisation between the evidence, the information available to doctors, and its use in clinical practice exists and this is part of the reason off-label therapies are so common. Attempts have been made to improve knowledge concerning paediatric treatments, but more focused interventions are needed, also taking into consideration this lack of harmonisation.

Appendix

Legislation concerning off-label drug use in children

In the United States, a series of regulatory measures have been introduced to increase knowledge of drugs in children and to change the labelling to provide better prescribing information on appropriate dose, use and safety of drugs [1]. The first FDA regulations on drug use in children involved the introduction of a paediatric section in the package insert in 1979 [41]. In 1994, the FDA’s “Pediatric Rule” [24] allowed adult efficacy data to be used, in some cases, to demonstrate drug safety and effectiveness in children. The results were not sufficient, however, and other measures followed. In 1997, the FDA created the Pediatric Exclusivity provision in the 1997 Modernization Act [82], in 1998 the “Pediatric Final Rule” [57] was created, and in 2002, the Best Pharmaceuticals for Children Act [5] was established. Paediatric research grew as a result of the effective incentives for the pharmaceutical industry. From 1998 to December 2004, 87 products underwent paediatric information labelling changes (http://www.fda.gov/cder/Pediatric/labelchange.htm). Although the results were positive, the Rule was challenged on the grounds that the FDA did not have the authority to impose paediatric research requirements on drug companies. This led to a legal battle and to the “Pediatric Research Equity Act of 2003” in December 2003 [56] which gave the FDA the power to require drug makers to conduct paediatric tests.

In Europe, the European Medicines Agency’s (EMEA) Committee for Proprietary Medicinal Products created the “Note for guidance on clinical investigation of medicinal products in the paediatric population” in 1997 [18] describing when and how drugs should be tested in children. However, no significant difference in the resulting situation was found [13, 38, 69,83].

In 2001, the International Conference on Harmonisation’s (ICH) Guidance for Industry: Clinical Investigation of Medicinal Products in the Pediatric Population [39] went into effect in the United States, Europe, and Japan. In 2002, the European Commission published a consultation document “Better Medicines for Children” [28] highlighting the need for suitable paediatric medicines. Recently, the European Commission adopted a proposal entitled Regulation of the European Parliament and Council on medicinal products for paediatric use [29] which would require paediatric studies for drugs of possible use to children.