Comparative Assessment of Off-label and Unlicensed Drug Prescriptions in Children: FDA Versus ANSM Guidelines
Introduction
The majority of drugs used in children are either not licensed for use (unlicensed [UL]) or are prescribed outside the terms of the product license (off-label [OL] prescribing),1, 2 a policy which increases the potential for medication errors and is a risk factor for adverse drug reactions.3 OL and UL prescribing has been prevalent because of the lack of assessment during the drug development process of the use of drugs in children.4
Prescribing UL or OL drugs has been described in studies conducted in North and South America, Australia, and Europe.5, 6, 7 These studies reported the frequency of prescribing OL and UL medications, in neonatal intensive care units, pediatric intensive care units, surgical intensive care units, general pediatric care, and emergency, cardiology, gastroenterology, oncology, psychiatry, and surgical units. The reported incidence of OL-UL use in children ranges from 36% to 100%.8 These studies show that the situation varies by country, due to differences in the process of authorization of medicinal products, and in clinical practice. Therefore, although the results are not directly comparable, they do provide a general idea about the subject in question.
The most prescribed OL drugs in this population were corticoids and salbutamol,9, 10, 11, 12 and caffeine was reported as the most common UL drug prescribed in the neonatal wards.13 Few studies examined OL and/or UL drug prescriptions in the Middle East,12, 14, 15 where prescribing habits of health professionals may be different with respect to the pediatric population. In Lebanon, local manufacturing of drugs concerns generic products only. Registered drugs are imported mainly from Europe countries and from the United States. Two main regulations may be followed by the physician when prescribing a medication: the US Food and Drug Administration (FDA) or the French Medical Regulatory Authority (ANSM) official regulations.16, 17 This specific situation makes it more difficult to analyze the prevalence of OL or UL prescriptions, but conversely, it offers a unique opportunity to compare both regulations and to specifically pinpoint the divergences in classifying a pediatric drug use as OL or UL depending on which regulation is used as reference.
The primary end points of this study were defining the incidence of OL and/or UL (OL-UL) prescriptions in a sample of Lebanese pediatric patients according to each regulation separately (FDA or ANSM) and analyzing the divergences between the results. Secondary end points were to identify to which anatomic therapeutic chemical group most commonly administered OL-UL belong, as well as the presence of an alternative to each UL medicine prescribed.
Section snippets
Study Design and Patients
This study was a retrospective analysis conducted in a Lebanese University hospital between October 1, 2013, and July 30, 2014. The study involved 3 pediatric wards at Hôtel-Dieu de France hospital: chronic diseases, acute diseases, and pediatric intensive care unit (which includes the neonatal intensive care unit). All patient files were first examined for the presence of hospital drug prescriptions, and those files with no prescribed drugs were excluded. An explicit review of each patient’s
Results
A total of 580 files were reviewed, and 500 included (the remaining files did not contain any drug prescription). Of the 500 patients, 53% were male. Patient ages ranged from 1 day to 16 years (median, 3.5 years).
Age, pediatric ward, and presenting symptom of included patients, as well as number of patients receiving at least 1 OF or UL prescription (according to FDA or according to ANSM regulations), are summarized in Table I.
The frequency of OL-UL drug prescribing was significantly different
Discussion
The pediatric population has been systematically insufficiently represented in clinical trials conducted to evaluate safety and efficacy of drugs. This oversight is the main reason behind the widespread use of OL-UL drugs in children, both in primary and hospital care.18
Most studies examining OL-UL prescriptions in children were conducted in hospital wards or intensive care units in Europe, America, Asia, and Oceania,18 with very few studies performed in the Middle East and, to the best of our
Conclusions
In Lebanon and worldwide, physician’s freedom to prescribe drugs OL-UL offers patients earlier access to potentially valuable medications. It is and should be a legal practice because it allows physicians to take good care of patients and offer them therapeutic options when approved treatments have failed. Our results revealed a percentage of OL-UL prescribing that is consistent with what was described in the literature in various European countries, the United States, and Israel30, 31; this
Conflicts of Interest
The authors have indicated that they have no conflicts of interest regarding the content of this article.
Acknowledgments
The authors thank Tatiana Papazian and Ramzi Namek for English editing of the manuscript. S. Berdkan collected the data, L. Rabbaa, A. Hajj, L. Karam and B. Eid contributed to data collection and analysis, H. Jabbour and N. El Osta performed statistical analysis, Lydia Rabbaa Khabbaz supervised data collection and analysis and wrote the manuscript. All authors read and approved the manuscript.
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