The Use of Off-Label Medications in Newborn Infants Despite an Approved Alternative Being Available-Results of a National Survey.

Alex Veldman,Eva Richter,Doris Fischer,Christian Hacker

doi:10.3390/pharmacy10010019

Abstract

Neonates continue to be treated with off-label or unlicensed drugs while in hospital. However, some medications that have previously been used in adults underwent clinical testing and licensure for use with a different indication in the neonatal and pediatric population. Almost always, the marketing of these newly approved substances in a niche indication is accompanied by a steep increase in the price of the compound. We investigated the use of the approved formulation or the cheaper off-label alternative of Ibuprofen (Pedea®), Propanolol (Hemangiol®) and Caffeine Citrate (Peyona®) in neonatal clinical practice by conducting a National Survey of 214 Perinatal Centers in Germany. We also assessed price differences between on- and off-label alternatives and the extend of the clinical development program of the on-label medication in the neonatal population. On-label medication was more frequently used than the off-label alternative in all indications (PDA: on-label to off-label ratio 1:0.26, Apnea: 1:0.56, Hemangioma 1:0.76). All sponsors did conduct placebo-controlled Phase III trials with efficacy and safety endpoints in the target population and the number of participants in the target population varied between 82 and 497. Costs for the three drugs in their approved and marketed formulations increased in median 405-fold compared with the corresponding off-label alternative. Overall, about one out of three neonatologists prescribed an off-label or non-approved drug to patients despite an alternative medication that is approved for the indication in the target population being available.

Highlights

The robust and vigorous testing of the efficacy and safety of new drugs in the relevant population prior to approval by regulatory authorities and entry into market is regarded as one of the key achievements in safe prescription practice, yet, less than 50% of the drugs commonly prescribed in neonatal medicine have market approval for use in this age group or have ever been pre-clinically or clinically investigated for safety or efficacy in this population [1]
It is essential to differentiate between offlabel use versus unlicensed drugs versus compassionate-use
Two of the drugs investigated in this study have been converted from off-label to on-label use in neonates, while the other has previously been used in the form of a magisterial preparation, and as such, has converted from unlicensed to approved

Summary

Introduction

The robust and vigorous testing of the efficacy and safety of new drugs in the relevant population prior to approval by regulatory authorities and entry into market is regarded as one of the key achievements in safe prescription practice, yet, less than 50% of the drugs commonly prescribed in neonatal medicine have market approval for use in this age group or have ever been pre-clinically or clinically investigated for safety or efficacy in this population [1] This results in about 80% of all patients admitted to neonatal intensive care units (NICUs) being treated with at least one off-label/unlicensed medication during their stay in hospital [2]. We analyze the European Medicines Agency (EMA) public assessment reports (EPAR) on the clinical development programs of these drugs to understand to what extend additional clinical and non-clinical studies have been conducted by the respective sponsors to achieve market authorization in the neonatal indications

Survey of Clinical Practice in German Perinatal Centers

Analysis of EMA’s EPARs

Drug Price Comparison

Findings

Discussion