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

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.

Figure 1

Example of the number of records per drug, taking metoprolol as an example.

Figure 2

Scoring system of the level of evidence of records. Jadad classification adapted from Jadad et al. DPF, Dutch Pediatric Formulary.

Figure 3

Highest level of evidence available per record. X‐axis: Group size (i.e., number of records) is indicated by the width of the bars and reported per age group (between brackets). Y‐axis: Level of evidence: A0: Authorized use; A1: systematic review or meta‐analysis with at least two studies of level A2; A2: randomized controlled trial with at least 4 points on the Jadad‐scale; B: comparative research with a maximum of 3 on the Jadad‐scale; C: noncomparative research; D: consensus or expert opinion; X: Selected guidelines (HIV, oncology, and metabolic diseases). Blue bars represent high level of evidence (level A1 and A2). Orange bars represent low level of evidence (B, C, and D). RCT, randomized controlled trial.

Figure 4

The level of evidence available regardless of age in each ATC level 1 group. The number of records for each ATC group is listed between brackets; ATC level 1: A: Alimentary tract and metabolism; B: Blood and blood forming organs; C: Cardiovascular system; D: Dermatologicals; G: Genito‐urinary system and sex hormones; H: Systemic hormonal preparations, excluding sex hormones and insulins; J: Anti‐infectives for systemic use; L: Antineoplastic and immunomodulating agents; M: Musculoskeletal system; N: Nervous system; P: Antiparasitic products, insecticides and repellents; R: Respiratory system; S: Sensory organs; V: Various. Y‐axis: Level of evidence: A0: Authorized use; A1: systematic review or meta‐analysis with at least two studies of level A2; A2: randomized controlled trial with at least 4 points on the Jadad scale; B: comparative research with a maximum of 3 on the Jadad scale; C: noncomparative research; D: consensus or expert opinion; X: Selected guidelines (HIV, oncology, and metabolic diseases). Blue bars represent high level of evidence (level A1 and A2). Orange bars represent low level of evidence (B, C, and D). ATC, Anatomical Therapeutic Chemical; RCT, randomized controlled trial.