Elsevier

Clinical Therapeutics

Volume 38, Issue 8, August 2016, Pages 1833-1844
Clinical Therapeutics

Comparative Assessment of Off-label and Unlicensed Drug Prescriptions in Children: FDA Versus ANSM Guidelines

https://doi.org/10.1016/j.clinthera.2016.06.009Get rights and content

Abstract

Purpose

The main objectives of this study were to assess the incidence of off-label (OL) and/or unlicensed (UL) prescriptions in a sample of pediatric Lebanese patients by using US Food and Drug Administration (FDA) and the French Medical Regulatory Authority (ANSM) regulations. The goal was to analyze the divergences between regulations and to identify those drugs most commonly involved in OL-UL utilization.

Methods

This study was a retrospective analysis (500 pediatric files) conducted in a Lebanese University hospital in 3 pediatric wards (chronic diseases, acute diseases, and the pediatric intensive care unit).

Findings

The frequency of OL-UL drug use was significantly different between pediatric wards (P < 0.001), with the highest incidence occurring in the intensive care unit. The most frequent OL-UL prescriptions occurred with cancer (oncology) admissions. Age was significantly related to OL-UL frequency (highest incidence in children aged between 0 and 1 year). The number of drugs prescribed per patient ranged between 1 and 20 (mean [SD], 4.13 [2.6]). The incidence of OL-UL prescriptions was significantly higher in patients treated with a greater number of medicines (P < 0.001). Overall, 58.9% of drug prescriptions were authorized according to ANSM and 50.7% according to FDA regulations; 11.1% (ANSM) and 15.8% (FDA) were UL, and 30.2% (ANSM) and 33.5% (FDA), respectively, were OL use (where OL for the indication were the most common). The highest percentage of OL-UL prescriptions was seen with the following groups: blood and blood-forming organs, genitourinary system, and sex hormones. Divergence between FDA and ANSM was mainly observed for OL medicines. UL prescriptions assessed according to both regulations showed similar results.

Implications

This study highlights the need for prescribers to continuously examine updates to official regulations to avoid using an OL-UL drug whenever possible. It also calls for better harmonization between worldwide official guidelines concerning drugs used in children to reduce risk factors for adverse drug reactions.

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.

References (31)

  • L. Cuzzolin et al.

    Off-label and unlicensed prescribing for newborns and children in different settings: a review of the literature and a consideration about drug safety

    Expert Opin Drug Saf

    (2006)
  • D. McD Taylor et al.

    Off-label and unlicenced medicine administration to paediatric emergency department patients

    Emergency medicine Australasia: EMA

    (2015)
  • S. Conroy et al.

    Survey of unlicensed and off label drug use in paediatric wards in European countries. European Network for Drug Investigation in Children

    BMJ

    (2000)
  • C. Pandolfini et al.

    Off-label use of drugs in Italy: a prospective, observational and multicentre study

    Acta Paediatr

    (2002)
  • M.R. Khdour et al.

    Extent and nature of unlicensed and off-label medicine use in hospitalised children in Palestine

    International journal of clinical pharmacy

    (2011)
  • Cited by (9)

    • Off-label use and manipulations of antiepileptic drugs in children: Analysis of the outpatient prescriptions in a tertiary center

      2018, Epilepsy and Behavior
      Citation Excerpt :

      The off-label definition in our study depends on French Medical Regulatory Authority (ANSM) regulations. However, a recent study showed that the incidences of off-label and/or unlicensed prescriptions, according to the US Food and Drug Administration (FDA) or ANSM regulations, were close [28]. Manipulations might be underestimated as we did not explore the method of drug administration (e.g., crushing pills, opening capsules, and/or administering the drug in a milk or juice bottle) by parents and caregivers [19].

    • Off-label and unlicensed drug use in children population

      2018, Therapie
      Citation Excerpt :

      A search of papers published in Medline® database from January 2013 to May 2017 was performed using the terms: ((off-label*[Title]) OR off-label*[Title]) OR unlicensed*[Title] Filters: Publication date from 2013/01/01 to 2017/05/28; English; Child: birth-18 year. Out of the 106 articles selected, 27 studies were finally included in this review [5–7,9,21–43]. Definition of OL or UL drugs varied widely across studies.

    View all citing articles on Scopus
    View full text