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Juvenile Animal Studies (JAS) may be warranted to ensure the safe clinical use of medicines for children. The ICH S11 guideline was developed to guide the need for and design of JAS, and proposes a weight-of-evidence (WoE) approach. We evaluated how the introduction of the guideline shaped the non-clinical strategy for paediatric medicines in the European Union. Our review included Paediatric Investigation Plans (PIPs) for 127 products approved between 2020 and 2023, along with the associated regulatory assessment and final non-clinical plans. Although in 12 of selected PIPs a JAS was already ongoing or completed at the time of submission, in all other cases (115/127), the PIP was submitted before the initiation of JAS. In 75% (86/115) of these procedures the discussions based on the ICH S11 WoE approach led to an agreement on the proposed non-clinical strategy. In approximately a quarter of PIPs, there was disagreement on the outcome of the WoE analysis leading to the addition (3%), modification (10%), or removal (11%) of JAS. Our review indicates that the implementation of ICH S11 facilitates science-driven discussions about the necessity and design of JAS within the broader non-clinical strategy. A thorough consideration of developmental aspects of the product’s pharmacological target, the clinical relevance of notable toxicity findings, and the clinical context of the medicine’s use fosters effective dialogue and improves regulatory alignment. The WoE approach in ICH S11 ensures that relevant safety information is generated to support paediatric drug development while balancing the principles of non-clinical replacement, reduction and refinement (the 3Rs).

Twenty years of orphan regulation in Europe have now elapsed, with almost 2,400 orphan designated medicinal products and more than 190 orphan products authorised in the EU. Alongside the evolution in understanding of rare diseases, considerable regulatory knowledge has also been accumulated regarding the level of evidence that would support inclusion of products into the framework. This article reviews publications and regulatory documents pertaining to orphan medicinal product designation in the EU and discusses the general expectations in submitted applications as reflected in the current regulatory practise. Important elements to recommend granting a European orphan designation are the key considerations of orphan condition, medical plausibility, seriousness, and prevalence, while significant benefit is also assessed when there are authorised medicinal products for the sought indication. This review attempts to clarify the specific concepts currently used in that regard and discusses how the available data can be used to justify the criteria for designation. Moving away from theoretical expectations or assumptions, it stresses that the applications have to be complemented with nosological and epidemiological justifications pertaining to the proposed condition, as well as relevant data in specific non-clinical in vivo models or in affected patients to support inclusion into the orphan scheme.