Risk Factors for Unlicensed and Off-Label Drug Use in Children Outside the Hospital
* Groningen University Institute for Drug Exploration (GUIDE), University of Groningen, Department of Social Pharmacy, Pharmacotherapy and Pharmacoepidemiology, Groningen, the Netherlands
InterAction Working Group, Northern Netherlands, the Netherlands
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Objective. To establish risk factors of unlicensed and off-label drug use by children outside the hospital.
Methods. A cross-sectional study based on 66 222 pharmacy dispensing records for the year 2000 was performed in the northern part of the Netherlands. All prescriptions were divided into the following categories: unlicensed (no product license), off-label (licensed drugs used outside the terms of the product license), and on-label (licensed drugs used according to the product license). For identifying possible problem areas, the proportions of unlicensed and off-label drug use were determined per age group (0–1, 2–5, 6–11, or 12–16 years) and per drug group. For all systemic drugs, a logistic regression was done that models the odds of receiving an unlicensed or off-label prescription as a function of several possible risk factors.
Results. Unlicensed drug use in Dutch children is the highest among 0 to 1-year-olds, and off-label drug use is the highest among 12- to 16-year-olds. Drug groups with highest percentages of unlicensed and off-label drug use were ophthalmologicals/otologicals (80.7% of all prescriptions in this group), blood and blood-forming organs (mainly vitamin K for breastfed newborns; 75.7%), cardiovascular drugs (74.7%), and dermatologicals (73.3%). Prescriptions by specialists (outpatient), prescriptions for new drugs, prescriptions for drugs with a low use in the pediatric population, and prescriptions for infants were risk factors for using a systemic drug unlicensed or off-label.
Conclusion. Efforts to improve pediatric labeling are important and need full support. The present results can be used to focus these efforts.
Key Words: children • pediatrics • drug utilization • unlicensed • off-label • pharmacy dispensing data
Abbreviations: GP, general practitioner • ATC, Anatomic Therapeutic Chemical • FDA, US Food and Drug Administration
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INTRODUCTION |
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Before a drug is allowed on the market, a favorable balance between beneficial and harmful effects has to be demonstrated. Often this has been established in adults only; as a result, there is not sufficient information about safety and efficacy for use in children. In addition, specific pediatric formulations will often not be available because children are not included in the research.
Approximately 75% of the drugs licensed since the early 1970s have been approved without pediatric drug labeling.1,2 Although not all of these drugs are of use in children, studies in various pediatric wards showed a considerable proportion of drugs used either outside the product license (off-label) or without any license at all (unlicensed), ranging from 25% to 66% of all prescriptions.3–8 More recently, it has been demonstrated that this is a problem outside the hospital as well. A study among 95 French office-based pediatricians showed approximately 33% of the prescriptions to be unlicensed or off-label.9 A study in one English general practice found a figure of 11%.10 Recently, a larger study of all prescriptions for 19 283 Dutch children showed 16.6% of all prescriptions to be unlicensed and 22.7% to be off-label.11
Although the studies performed so far clearly identify a problem, more insight in the determinants of unlicensed and off-label drug use is needed to establish a solid basis for a solution. In this study, we examined a large number of drugs used by children in the community, based on all pharmacy dispensing records of both general practitioner (GP) and outpatient prescriptions. The specific aims were to identify problems in therapeutic areas and in age groups and to identify factors associated with unlicensed and off-label drug use.
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METHODS |
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Population
In the Netherlands, people commonly register with a single community pharmacy and obtain all of their medication from that pharmacy so that a complete medication history is available in the pharmacy dispensing records. Outpatient medication is also supplied by the community pharmacy and thus included in the dispensing data. Drugs used during hospital stay (inpatients) and over-the-counter medication are not included. Previous studies have demonstrated that dispensing data from Dutch pharmacies offer an accurate survey of the use of prescription drugs.12,13 This study was performed with pharmacy dispensing data from the InterAction database, which is part of the collaboration between community pharmacists in the northern part of the Netherlands and the University of Groningen.14 Registration is irrespective of health insurance (including people who are not insured) and thus is representative of the general population.
Analysis
After exclusion of health products (bandages, functional foods, herbs, vitamin A–E, etc) and homeopathic products, all prescriptions for children aged 0 to 16 years in year 2000 were selected from the database. All drugs were classified according to the Anatomic Therapeutic Chemical (ATC) classification system of the World Health Organization and were divided into the following exclusive categories: unlicensed, off-label, and on-label.15 We defined unlicensed drugs as all drugs without a product license. For drugs dispensed by Dutch community pharmacies, this applies only to extemporaneous preparations: Dutch pharmacies are allowed to prepare their own formulations and to modify commercial preparations. Other types of unlicensed drugs, such as trial medication, are not supplied by Dutch community pharmacies. For each prescription of the remaining (licensed) drugs, the official license information was examined (Summary of Product Characteristics, available in PDF format from the web site of the Dutch Medicines Evaluation Board www.cbg-meb.nl/or from the Web site of the European Agency for the Evaluation of Medicinal Products for products with a European registration www.emea.eu.int/). The Summary of Product Characteristics is comparable with the US Food and Drug Administration (FDA)-approved labeling in the Physician’s Desk Reference. Details about the examination of the prescriptions can be found elsewhere.11 In short, per prescription, it was determined whether the Summary of Product Characteristics mentioned use in children and, if yes, the minimum age for use. A drug with a product license was considered to be used according to the label (on-label) in case it could be used in children according to the Summary of Product Characteristics and the child was at least the minimum age for use; otherwise, a drug was considered to be used off-label. Because indications are not available in pharmacy data, it was not possible to distinguish between different indications in the license information.
For identifying possible problem areas, the proportions of unlicensed and off-label drug use were determined per age group (0–1, 2–5, 6–11, or 12–16 years) and per ATC subgroup (third level). For additional analysis, we divided the drugs into 2 categories: nonsystemic drugs were defined as dermatological, ophthalmological, otological, nasal, throat, and vaginal preparations; all other drugs were defined as systemic. For all systemic drugs, a logistic regression was done that models the odds of receiving an unlicensed or off-label prescription as a function of several possible risk factors. Risk factors under investigation were age, gender, estimated market share of the drug group in the pediatric population, type of prescriber (GP or specialist), and year of introduction of the drug to the market (not applicable to unlicensed drugs). Estimated market share was calculated as the number of prescriptions for children in the drug group (ATC subgroup third level) divided by the total number of prescriptions of systemic drugs for children. For preventing distortion by oral contraceptives (all off-label, used only by girls aged 12–16 years and almost exclusively prescribed by GP) these were excluded from all analyses and mentioned separately. All analyses were performed using the statistical package SPSS (version 10; SPSS Inc, Chicago, IL).
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RESULTS |
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In total, 66 222 prescriptions for 18 943 different children aged 0 to 16 years were analyzed. GPs were responsible for 55 258 (83.4%) of the prescriptions; the remaining 10 964 (16.6%) prescriptions came from specialists (outpatient prescriptions). In total, 20.6% (13 659/66 222) of the prescriptions were used off-label and 16.6% (11 288/66 222) of the prescriptions were unlicensed.
As can be seen in Table 1, the unlicensed and off-label drug use was highest among the youngest children and adolescents: 53.6% (34.7 + 18.9) and 35.8% (8.4 + 27.4), respectively. Focusing on the unlicensed drug use, it can be seen that the percentage of these pharmacy-based preparations rapidly decreases with increasing age. The percentage of off-label drug use differs less between different age groups but is somewhat elevated among adolescents (27.4%). Table 2 shows unlicensed and off-label drug use per drug group. Drug groups with the highest percentages of unlicensed and off-label drug use were ophthalmologics/otologicals (6.2% + 4.5%), blood and blood-forming organs (mainly vitamin K for breastfed newborns; 58.9% + 16.8%), cardiovascular drugs (51.5% + 23.6%), and dermatologicals (39.% + 33.8%). Of these groups, dermatologicals are most frequently used by children (12 114 prescriptions). Despite the relatively low percentage of unlicensed and off-label drugs in the group of respiratory drugs, the high number of prescriptions in this group results in many unlicensed and off-label prescriptions. The group of drugs for the nervous system seemed to be a diverse group; for antiepileptics and psychostimulants (mainly methylphenidate), unlicensed and off-label use was low, but for other drug groups, such as antimigraine preparations, antipsychotics, antidepressants, and hypnotics/sedatives, unlicensed and off-label drug use was high. Overall, 33.0% of all unlicensed and 33.3% of all off-label drugs involved systemic drugs, indicating that systemic drugs are less likely to be prescribed unlicensed or off-label than nonsystemic drugs (data not shown).
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Table 3 shows the adjusted odds ratios of possible risk factors for off-label drug use of systemic drugs, and unlicensed or off-label drug use of systemic drugs. It can be seen that an increase of 1% of the estimated market share in the pediatric population for the particular drug group (ATC third level) decreases the odds of an unlicensed or off-label prescription by approximately 18%. Children in the age groups of 6 to 11 and 12 to 16 years had the highest odds of using a drug off-label (1.19 and 1.53, respectively). However, including unlicensed drugs as well in the analysis shows that the youngest age group has by far the highest chance of receiving a unlicensed or off-label drug. The odds for unlicensed or off-label drug use increased 78% when the prescriber was a specialist instead of a GP. Finally, newer drugs were more likely to be used off-label than older drugs (applicable to drugs with a product license only): the odds of drugs introduced between 1980 and 1990 were >2 times higher and for drugs introduced after 1990 were 4 times higher than drugs introduced before 1980.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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This study shows that unlicensed drug use in Dutch children is the highest among 0- to 1-year-olds, and off-label drug use is the highest among 12- to 16-year-olds. Systemic drugs were less likely to be used unlicensed or off-label than nonsystemic drugs. Nevertheless, 33.0% of all unlicensed and 33.3% of all off-label drugs were for systemic use, and logistic regression analysis showed that prescriptions by specialists (outpatient), prescriptions for new drugs, prescriptions for drugs with a low use in the pediatric population, and prescriptions for infants were risk factors for using a systemic drug without a license or outside the terms of the license.
Compared with other countries, Dutch pharmacies prepare many preparations themselves; overall, these amount to approximately 5% of the total prescriptions.16 That this is 16.6% in children (all unlicensed prescriptions) suggests that commercial preparations are often not tailored for children (eg, dose, formulation, route of administration). For systemic drugs, young age was one of the major risk factors for receiving unlicensed drugs. In many cases, the pharmacy-based preparation seemed to be a reformulating of a solid dosage form to a liquid dosage form. In older children, pharmacy-based preparations for systemic drugs often concerned the processing of tablets to capsules with an appropriate dose. Although it is reassuring that Dutch pharmacies are able to adjust commercial preparations to the proper dosage forms and proper strength, that this needs to be done for 10.7% of the prescriptions for systemic drugs indicates that this is a problem area in pediatric pharmacotherapy outside the hospital. Moreover, it raises the question of how this problem is solved in countries where pharmacy-based preparations are less common.
Nonsystemic drugs are more likely to be prescribed unlicensed or off-label than systemic drugs. In the product license of nonsystemic drugs, such as dermatologicals or ophthalmological preparations, use in children is often not mentioned at all. This is peculiar, as children have a higher body surface relative to body mass, and for some drugs the skin of children is more permeable than that of adults.17
The results of our analyses (Table 3) clearly show risk factors for unlicensed and off-label drug use of systemic drugs. Young children and, to a lesser extent, adolescents have a higher risk to use a systemic drug without a license or outside the terms of the license. For young children, the lack of proper dosage forms (unlicensed) and the use of minimum age bands in product licenses (off-label) may serve as an explanation. The elevated risk for adolescents of using a drug off-label might be a matter of language: manufacturers, prescribers, and researchers all may have different views of the meaning of the word "child." In this study, we interpreted "should not be used in children" as "should not be used under 18 years of age," but others may have different views. These findings show that the efforts of regulatory bodies, such as the European Medicines Evaluation Agency, to come to standardized age bands are very much needed.18 Another explanation might be that some doctors treat adolescents as adults, which is, looking at for example the maturing hormonal system, in many aspects, not fully justified.19
Various initiatives have been taken in the past decade to improve labeling for children. In 1994, the FDA introduced new regulations (Pediatric Rule) allowing adult efficacy data to be extrapolated to pediatric patients in certain cases. Because of a lack of effect, an incentive approach was chosen in 1997 with the Modernization Act, which offered a 6-month extension of patent protection for certain drugs that were considered essential (Written Request list). The final Pediatric Rule introduced in 1998 required the manufacturers of new drugs to provide pediatrics studies.20 The results of these regulations are encouraging: according to an FDA report of January 2001, there had been >332 new pediatric studies initiated, with 58 completed; in 2002, these regulations were for the greater part continued as the "Best Pharmaceuticals for Children Act."21 In contrast to the United States, the developments in Europe have been limited so far. In 1997, a European guidance on clinical investigation of medicines in children was released but lacked specific measures, such as financial incentives for the pharmaceutical industry. However, the measures currently proposed by the European Agency for the Evaluation of Medicinal Products in the consultation document "Better Medicines for Children" are similar to those already taken in the United States and are the first positive steps toward addressing this issue in Europe.22 Perhaps future measures can also take action against the situation of different availability of products licensed for children in different countries, even within Europe.
Finally, it should be noted that unlicensed and off-label drug use does not necessarily mean that safety and efficacy have not been investigated at all: missing safety and efficacy evidence at registration is sometimes supplemented by the medical literature. In the United States, for example, this gap between label and literature is filled by pediatric information in the US Pharmacopoeia Drug Information text. However, licensing has advantages that this kind of additional information cannot offer. First, information on licensed products is easily available on the data sheet for both professionals and patients and approved by regulatory bodies. Second, the availability of proper pediatric formulations will be guaranteed. Third, denial of reimbursement as a result of a lack of labeling will not be a problem anymore.1 Moreover, for ethical reasons, standards of drugs efficacy and safety should apply equally in adults and in children.1 Therefore, efforts to improve pediatric labeling are important and need full support. The present results can be used to focus these efforts. In view of the vulnerability of young children, it is unfortunate that of all risk factors presented in this paper, young age (0–1 year) is the most important one. It seems justified, therefore, to give priority to this age group.
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FOOTNOTES |
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Received for publication Apr 1, 2002; Accepted Aug 5, 2002.
Reprint requests to (H.T.) University of Groningen, Medical Sciences and Pharmacy, Department of Social Pharmacy, Pharmacotherapy and Pharmacoepidemiology, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands. Email: h.tobi{at}farm.rug.nl
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