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

4 Citations (Scopus)
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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
Issue number6
Publication statusE-pub ahead of print - 25 Sep 2022

Bibliographical note

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


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