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Regulating pediatric off-label uses of medicines in the EU and USA: challenges and potential solutions

Comparative regulation framework of off label prescriptions in pediatrics: a review

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Abstract

Background Off-label uses of medicines are common in pediatrics. The literature reports that at least one-third of children in hospital and up to 90% of newborns in neonatal intensive care units receive off-label prescriptions. Moreover, the lack of data on safety and efficacy in the pediatric population may sometimes increase the risk of adverse drug reactions. Objective This paper aims to (a) map the main gaps in the existing EU and US regulatory frameworks for pediatric drug development and off-label use and (b) propose potential solutions for further discussion. Conclusion The selected jurisdictions aim to limit off-label prescribing, but implementation levels generally seem low, including in pediatric settings. Subject to further research, we propose potential concerted actions and initiatives of international cooperation to fill this gap. In particular, regulators and pediatric societies could strengthen manufacturers’ incentives to develop pediatric medicines, pediatricians’ information about off-label uses, and patients’ and parents’ awareness.

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References

  1. Lenk C. Off-label drug use in paediatrics: a world-wide problem. Curr Drug Targets. 2012;13(7):878–84.

    Article  CAS  Google Scholar 

  2. Russo C, Stout L, House T, Santana VM. Barriers and facilitators of clinical trial enrollment in a network of community-based pediatric oncology clinics. Pediatr Blood Cancer. 2020;67(4):e28023.

    Article  Google Scholar 

  3. Schiavone S, Neri M, Pomara C, Riezzo I, Trabace L, Turillazzi E. Personalized medicine in the paediatric population: the balance between pharmacogenetic progress and bioethics. Curr Pharm Biotechnol. 2017;18(3):253–62.

    Article  CAS  Google Scholar 

  4. European Commission. Study on off-label use of medicinal products in the European Union.

  5. Bruxelles. 2017. Available online: https://ec.europa.eu/health/sites/health/files/files/documents/2017_02_28_final_study_report_on_of-label_use_.pdf.

  6. Carpenter D, Gonzalez D, Retsch-Bogart G, Sleath B, Wilfond B. Methodological and ethical issues in pediatric medication safety research. Pediatrics. 2017;140(3):e20170195.

    Article  Google Scholar 

  7. Allen HC, Garbe MC, Lees J, Aziz N, Chaaban H, Miller JL, et al. Off-label medication use in children, more common than we think: a systematic review of the literature. J Okla State Med Assoc. 2018;111(8):776–83.

    PubMed  PubMed Central  Google Scholar 

  8. Hoon D, Taylor MT, Kapadia P, Gerhard T, Strom BL, Horton DB. Trends in off-label drug use in ambulatory settings: 2006–2015. Pediatrics. 2019;144(4):e20190896.

    Article  Google Scholar 

  9. Cuzzolin L, Atzei A, Fanos V. Off-label and unlicensed prescribing for newborns and children in different settings: a review of the literature and a consideration about drug safety. Exp Opin Drug Saf. 2006;5(5):703–18.

    Article  Google Scholar 

  10. Court of Justice of the EU, 11th June 2015, case T-452/14, Laboratoires CTRS v Commission, EU:T:2015:373, para 79.

  11. Einbinder F. Mass torts: dispute resolution in France and the United States: the Vioxx and mediator cases compared. Wash L Rev. 2020;29(3):575–647.

    Google Scholar 

  12. Laude A, Mathieu B, Tabuteau D. Droit de la santé. PUF, 2007, n. 410.

  13. Durrieu G, Jacquot J, Baudrin D, Mège M, Rousseau V, Bagheri H, et al. Apport de la visite d’assistants de recherche clinique aux cabinets de médecins généralistes sur la notification des effets indésirables médicamenteux [Improving adverse drug reaction reporting by general practitioners through clinical research assistants visits]. Therapie. 2017;72(3):351–5.

    Article  Google Scholar 

  14. Guidi B, Nocco, L. The debate concerning the off-label prescriptions of drugs: a comparison between Italian and US law. Op. J, 2011, 1. Available from: http://www.opiniojurisincomparatione.org/opinio/article/view/43.

  15. Ferrajolo C, Capuano A, Trifirò G, Moretti U, Rossi F, Santuccio C. Pediatric drug safety surveillance in Italian pharmacovigilance network: an overview of adverse drug reactions in the years 2001–2012. Exp Opin Drug Saf. 2014;13(Suppl 1):S9-20.

    Article  Google Scholar 

  16. Corny J, Lebel D, Bailey B, Bussières JF. Unlicensed and off-label drug use in children before and after pediatric governmental initiatives. J Pediatr Pharmacol Ther. 2015;20(4):316–28.

    PubMed  PubMed Central  Google Scholar 

  17. Ausness RC. There’s danger here, cherie: liability for the promotion and marketing of drugs and medical devices for off-label uses. Brook L Rev. 2008;73:1253–326.

    Google Scholar 

  18. Liability and off-label prescriptions. Psychiatry (Edgmont). 2009; 6(2):43–4.

  19. Mithani Z. Informed consent for off-label use of prescription medications. Virtual Mentor. 2012;14(7):576–81.

    PubMed  Google Scholar 

  20. McNary A. Consent to treatment of minors. Innov Clin Neurosci. 2014;11(3–4):43–5.

    PubMed  PubMed Central  Google Scholar 

  21. Czaja AS, Reiter PD, Schultz ML, Valuck RJ. Patterns of off-label prescribing in the pediatric intensive care unit and prioritizing future research. J Pediatr Pharmacol Ther. 2015;20(3):186–96.

    PubMed  PubMed Central  Google Scholar 

  22. Hazell L, Shakir SA. Under-reporting of adverse drug reactions: a systematic review. Drug Saf. 2006;29(5):385–96.

    Article  Google Scholar 

  23. Park JJH, Siden E, Zoratti MJ, Dron L, Harari O, Singer J, et al. Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols. Trials. 2019;20(1):572.

    Article  Google Scholar 

  24. European Commission, Inception Impact Assessment, https://ec.europa.eu/info/law/better-regulation/have-your-say/initiatives/12767-Medicines-for-children-&-rare-diseases-updated-rules_en.

  25. Donato Bonifazi: CVBF as EPTRI Coordinator, 06 January 2021, https://ec.europa.eu/info/law/better-regulation/have-your-say/initiatives/12767-Medicines-for-children-&-rare-diseases-updated-rules/F1411106_en.

  26. Christine Dawson: European Social Insurance Platform: ESIP, 06 January 2021, https://ec.europa.eu/info/law/better-regulation/have-your-say/initiatives/12767-Medicines-for-children-&-rare-diseases-updated-rules/F1408716_en.

  27. Schrier L, Hadjipanayis A, Stiris T, Ross-Russell RI, Valiulis A, Turner MA, et al. Off-label use of medicines in neonates, infants, children, and adolescents: a joint policy statement by the European academy of paediatrics and the European society for developmental perinatal and pediatric pharmacology. Eur J Pediatr. 2020;179(5):839–47.

    Article  Google Scholar 

  28. Marika V. FRANCE: Secrétariat général des Affaires européennes, 06 January 2021 https://ec.europa.eu/info/law/better-regulation/have-your-say/initiatives/12767-Medicines-for-children-&-rare-diseases-updated-rules/F1407901_en.

  29. Rita K. Prescrire, 2021. https://ec.europa.eu/info/law/better-regulation/have-your-say/initiatives/12767-Medicines-for-children-&-rare-diseases-updated-rules/F1403036_en.

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Acknowledgements

The Authors are grateful to the anonymous reviewers for their helpful remarks.

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No specific funding was received.

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Author notes

  1. Benedetta Guidi and Andrea Parziale have contributed equally to this work.

Authors and Affiliations

  1. Clinical and Traslational Science Research Department, University of Pisa, Via Roma 55 1, 56124, Pisa, Italy

    Benedetta Guidi

  2. Eurac Research, Bolzano, Italy

    Andrea Parziale

  3. Sant’Anna School of Advanced Studies, Pisa, Italy

    Luca Nocco

  4. Legal Medicine Section, University of Pisa, Pisa, Italy

    Aniello Maiese, Marco Di Paolo & Emanuela Turillazzi

  5. University of Rome La Sapienza, Rome, Italy

    Raffaele La Russa

Authors
  1. Benedetta Guidi
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  2. Andrea Parziale
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  3. Luca Nocco
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  4. Aniello Maiese
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  5. Raffaele La Russa
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  7. Emanuela Turillazzi
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Correspondence to Benedetta Guidi.

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Guidi, B., Parziale, A., Nocco, L. et al. Regulating pediatric off-label uses of medicines in the EU and USA: challenges and potential solutions. Int J Clin Pharm 44, 264–269 (2022). https://doi.org/10.1007/s11096-021-01303-5

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  • DOI: https://doi.org/10.1007/s11096-021-01303-5

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