BackgroundsAs many drugs in paediatrics are used of off-label, prescribers across Europe face a lack of evidence-based dosing guidelines. The Dutch Paediatric Formulary (DPF) was developed to provide dosing guidelines based on best available evidence from registration data, investigator-initiated research, clinical experience and consensus (1). The DPF has recently joined forces with Germany, Norway and Austria aiming to develop multi-language, parallel, paediatric drug formularies based on the DPF.MethodsThe DPF database and ICT framework were extended to a duplicate database for Germany. The dosing guidelines were translated to German and reviewed for fit with German practice. Relevant drugs and dosing recommendations were selected and country-specific information was added to address country-specific needs. Work-sharing on content development was studied in a small pilot.ResultsThe German Pediatric Formulary (www.kinderformularium.de) was launched on 1 October 2018 within a German paediatric medication safety project (KiDSafe). At that time 119 of 769 drugs were reviewed and published in the German formulary.The dosing recommendations of the DPF show a good fit with German practice; i.e. adaptations were needed in less than 10% of the cases caused by differences in licensing status, national guidelines or availability of formulations. There were no differences in interpretation of evidence. Nine drugs - highly relevant for German practice, but not listed in the DPF, were added to the German formulary based on SmPC. The content work sharing was piloted by the development of a new monograph and the periodic revision of a monograph complying to the Dutch standard operating procedure by Germany. This pilot has shown the feasibility of work-sharing in developing and updating drug monographs.ConclusionThe Dutch framework has successfully been extended to the German situation. Work-sharing on the development of dosing recommendations is feasible. Similar extension to Norwegian and Austrian nation-wide formularies has started.Referencesvan der Zanden T, De Wildt S, Liem T, Offringa M, de Hoog M. Developing a pediatric formulary for the netherlands. Arch Dis Child 2017;Apr;102(4):357–61.Disclosure(s)Tjitske van der Zanden is managing director of the Dutch Paediatric Pharmacotherapy Expertise Network; Saskia de Wildt is medical director of Dutch Paediatric Pharmacotherapy Expertise Network. The other authors have no financial disclosures relevant to this article.
BackgroundMany drugs are used off-label in term and preterm neonates, and dosing recommendations for many drugs are lacking in the Dutch Paediatric Formulary (DPF). This results in widely varying dosing regimens used across neonatal intensive care units (NICUs) in the Netherlands. The Neodose pilot project aimed to develop best-evidence national dosing recommendations for (pre)term neonates. Because scientific evidence is scarce, a consensus-based approach was used.MethodsA priority drug list, containing the most frequently used drugs for neonates, was drafted. From this list 22 drugs were selected for further research within the Neodose pilot project. The pilot utilized a two-step approach: First, consensus was established with all Dutch NICUs for neonatal dosing recommendations. Local treatment protocols were retrieved, compared and discussed, leading to consensus-based dosing recommendations. Secondly, we aimed to develop best-evidence dosing recommendations for the following five drugs: acyclovir, ganciclovir, ibuprofen, hydrocortisone and dexamethasone.ResultsFor 21 of 22 drugs, local dosing guidelines differed significantly. Mostly concerning total daily dose, dosing frequency and route of administration. Little or no distinction is made between treatment of preterm and term neonates. Approximately half of the consensus-based dosing recommendations (45%) differ in some degree from all local protocols. Comparing the consensus-based dosing recommendations with the available evidence, almost half of the consensus doses were adjusted. The grounds on which dosing recommendations were adjusted differed. Acyclovir-dosing adjustment was based on pharmacokinetics. Hydrocortisone-dosing was adjusted due to new insights after the evidence has been put together. For dexamethasone-dosing, the consensus dose was eventually chosen, because every available trial used a different dosing regimen.ConclusionThis pilot showed that, when evidence is inconclusive, consensus on dosing regimens in neonates can be obtained by comparing local regimens and analysing the available evidence. For more uniform use, these new recommendations will be published in the DPF.Disclosure(s)This project was funded by the federation of medical specialists for qualitative improvement (Stichting Kwaliteitsgelden Medisch Specialisten (SKMS).
BackgroundGuidelines for off-label prescribing are emerging.1–6 However, these guidelines do not provide practical guidance to assess the risk benefit balance and select the right paediatric dose We, therefore, aimed to develop a practical framework to guide paediatric healthcare professionals to assess the risks and benefits of off-label use.MethodsWe have reviewed available literature on the suggested criteria for appropriate off-label use and evaluated these criteria for relevance in paediatrics. For guidance on dose-selection we searched for regulatory guidance on paediatric drug development. Next, the literature was searched for strategies that can be applied to assess the risks and benefits of off-label use. Based on literature findings a framework was proposed to provide practical guidance to physicians for off-label prescribing. Finally, the framework was applied to a case.ResultsThe following conditions for appropriate off-label use were identified based on available literature: 1. Medical need for off-label use. 2. Off-label use is based on ‘high quality evidence’. As ‘high quality evidence’ in paediatrics is often lacking-, we propose to replace the need for high quality evidence by a positive risk-benefit assessment based on available evidence. 3. Parents and patients are informed. This is not feasible for every single drug prescribed off-label, we propose a graded approach 4. The outcomes of off-label use are followed up.The PROACT-URL framework7 for decision-making as well as the FDA paediatric decision tree8 seem helpful tools to guide decisions in real-life practice.ConclusionWe identified important aspects and tools to develop a framework (ARBOP-P) to guide healthcare professionals on how to systematically assess and balance the benefits and risks for off-label use, including dose selection, to ultimately optimize efficacy and safety of paediatric off-label prescribing.ReferencesFrattarelli DA, Galinkin JL, Green TP, et al. Off-label use of drugs in children. Pediatrics 2014;133:563–7Online.Dooms M, Killick J. Off-label use of medicines: The need for good practice guidelines. Int J Risk Saf Med. 2017;29:17–23Online.Gazarian M, Kelly M, McPhee JR, Graudins LV, Ward RL, Campbell TJ. Off-label use of medicines: consensus recommendations for evaluating appropriateness. Med J Aust 2006;185:544–8Online.Largent EA, Miller FG, Pearson SD. Going off-label without venturing off-course: evidence and ethical off-label prescribing. Arch Intern Med 2009;169:1745–7Online.Ansani N, Sirio C, Smitherman T, et al. Designing a strategy to promote safe, innovative off-label use of medications. Am J Med Qual 2006;21:255–61Online.Weda M, Hoebert J, Vervloet M, et al. Study on the off-label use of medicinal products in the European Union.: www.ec.europa.com 2017.Hammond J, Keeney R, Raiffa H. Smart Choices:A practical guide to making better decisions. Boston, MA.: Harvard Business School Press.; 2002.Dunne J, Rodriguez WJ, Murphy MD, et al. Extrapolation of adult data and other data in pediatric drug-development programs...
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