Off-Label, but on-Evidence? A Review of the Level of Evidence for Pediatric Pharmacotherapy

Tjitske M. van der Zanden*, Nori J. L. Smeets, Marika de Hoop-Sommen, Michiel F. T. Schwerzel, Hui Jun Huang, Lieke J. C. Barten, Joyce E. M. van der Heijden, Jolien J. M. Freriksen, Akira A. L. Horstink, Inge H. G. Holsappel, Miriam G. Mooij, Matthijs de Hoog, Saskia N. de Wildt

*Corresponding author for this work

Research output: Contribution to journalReview articleAcademicpeer-review

21 Citations (Scopus)
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Abstract

Many drugs are still prescribed off-label to the pediatric population. Although off-label drug use not supported by high level of evidence is potentially harmful, a comprehensive overview of the quality of the evidence pertaining off-label drug use in children is lacking. The Dutch Pediatric Formulary (DPF) provides best evidence-based dosing guidelines for drugs used in children. For each drug-indication-age group combination-together compiling one record-we scored the highest available level of evidence: labeled use, systematic review or meta-analysis, randomized controlled trial (RCT), comparative research, noncomparative research, or consensus-based expert opinions. For records based on selected guidelines, the original sources were not reviewed. These records were scored as guideline. A total of 774 drugs were analyzed comprising a total of 6,426 records. Of all off-label records (n = 2,718), 14% were supported by high quality evidence (4% meta-analysis or systematic reviews, 10% RCTs of high quality), 20% by comparative research, 14% by noncomparative research, 37% by consensus-based expert opinions, and 15% by selected guidelines. Fifty-eight percent of all records were authorized, increasing with age from 30% in preterm neonates (n = 110) up to 64% in adolescents (n = 1,630). Many have advocated that off-label use is only justified when supported by a high level of evidence. We show that this prerequisite would seriously limit available drug treatment for children as the underlying evidence is low across ages and drug classes. Our data identify the drugs and therapeutic areas for which evidence is clearly missing and could drive the global research agenda.

Original languageEnglish
Pages (from-to)1243-1253
Number of pages11
JournalClinical Pharmacology & Therapeutics
Volume112
Issue number6
Early online date25 Sept 2022
DOIs
Publication statusPublished - Dec 2022

Bibliographical note

Funding Information:
The Dutch Pediatric Formulary has been developed by Dutch Knowledge Center Pharmacotherapy for Children which is funded by a government grant by the Dutch Ministry of Health. This research was performed independent from the government grant.

Funding Information:
The Dutch Pediatric Formulary has been developed by Dutch Knowledge Center Pharmacotherapy for Children which is funded by a government grant by the Dutch Ministry of Health. This research was performed independent from the government grant. This work was performed in close collaboration with the Dutch Knowledge Center Pharmacotherapy for Children, who shared their benefit–risk analysis documents for review of the level of evidence.

Publisher Copyright:
© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

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