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BackgroundChildren remain underrepresented in clinical research, despite regulatory frameworks like the EU Paediatric Regulation and Paediatric Investigation Plans (PIPs). The 2024 Declaration of Helsinki revision now recognises excluding vulnerable populations from research as a potential ethical concern. The Clinical Trial Regulation (EU) No 536/2014 aims to harmonise clinical trial application assessment procedures through a coordinated process involving a Reporting Member State (RMS) and Member States Concerned (MSCs).AimsTo determine if harmonisation is occurring, we conducted the first systematic analysis of Phase I/II paediatric trial application assessments across Member States (MS) in the European Union (EU) focusing on assessment variability, evidence requirements, PIP integration, and adolescent inclusion practices in adult trials.MethodsIn the context of a fellowship at the European Medicines Agency, non-public data of 160 paediatric Clinical Trial Applications (CTAs) submitted through the Clinical Trial Information System (January 2022-July 2024) were screened, with inclusion of 55 Phase I/II trials in the main analysis (selected for their focus on innovative treatments and complex risk-benefit assessments). For each CTA, requests for information (consisting of considerations stated by the RMS and MSCs), assessment reports, sponsor responses, and PIP documentation were reviewed. The number of considerations in the requests for information per MS was analysed with median values calculated. Also, considerations were systemically categorised and assessment patterns between RMS and MSC roles were compared. It was examined how PIPs were integrated into assessments and approaches to adolescent inclusion in adult trials was analysed through systematic review of MS considerations.ResultsOf the 160 paediatric CTAs screened, 145 received authorisation, 10 were not authorised, and 5 were withdrawn. Among the 145 authorised CTAs, 61 were Phase I/II trials, 55 of which were included in the main analysis. Analysis of these applications revealed significant heterogeneity in both the number and type of considerations raised across MS, with the median number of considerations per CTA ranging from 5.5 to 26 across MSs (p = 0.025), with particularly marked variation when MSs acted as MSCs compared to RMSs-where additional considerations ranged from zero to 25 per CTA on top of those raised by the RMS. In 36% (20/55), MSs raised concerns about insufficient (pre-)clinical evidence pointing to divergent interpretations of evidence requirements. The degree to which PIPs were integrated into CTA assessments varied considerably-ranging from strict adherence to PIP elements to minimal consideration. In 92% (11/12), MSs showed reluctance to include adolescents in adult Phase I/II trials.ConclusionsDespite the CTR's harmonisation goals, substantial variations persist in assessment practices across MSs, particularly regarding evidence requirements, PIP integration, and adolescent inclusion in adult trials. These variations directly impact equitable access to clinical trials for children across the EU. Urgent regulatory guidance is needed to align interpretation of evidence standards, clarify the role of PIPs in CTA evaluation, and support evidence-based approaches to adolescent inclusion in adult trials.
Detection of N-nitrosamines (NA) in pharmaceuticals became a point of interest due to the mutagenic and carcinogenic potential of some compounds of this class, and their identification as nitrosated forms of marketed drugs, otherwise known as NA Drug Substance-Related Impurities (NDSRIs). The Ames test is used to assess the mutagenic potential of drug impurities, including NAs. Concerns over the sensitivity of the Ames test, as recommended in Organization for Economic Co-operation and Development Test Guideline 471, in predicting the rodent carcinogenic potential of NAs has prompted optimization of several test parameters used for detecting the mutagenicity of NAs (e.g. methods used for metabolic activation and the selection of tester strains). In order to discuss optimal Ames test conditions for the evaluation of NAs, including NDSRIs, the Office of New Drugs in the US Food and Drug Administration's Center for Drug Evaluation and Research and the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee co-organized and co-sponsored a workshop entitled "Nitrosamines: Ames Data Review and Method Development Workshop". The workshop featured five sessions addressing charge questions pertinent to the Ames test conditions and performance through the presentation of data and panel discussions. This report outlines the key takeaway points from the workshop.
N-nitrosamines are DNA alkylating agents found in food, cosmetics, tobacco products and, more recently, drugs. Following Cytochrome P450 (CYP)-mediated metabolic activation, these compounds cause DNA damage and mutations. Unlike well-characterized compounds like N-nitrosodimethylamine (NDMA), data on the genotoxicity of nitrosamine drug substance-related impurities (NDSRIs) remain limited. Given their regulatory relevance, this study assessed the genotoxic potential of three NDSRIs —N-nitrosobetahistine (NBH), N-nitrosofluoxetine (NFluo), and N-nitrosonortriptyline (NNT) —compared to NDMA. The NDSRIs demonstrated distinct DNA methylating potential, confirmed by elevated levels of N7-methyl-deoxyguanosine (N7-MedG) and O6-methyl-deoxyguanosine (O6-MedG) in a DNA alkylation assay with metabolic activation. Recombinant CYP isoforms contributed differentially to the bioactivation of each NDSRI, highlighting enzyme-specific pathways of toxification. Subsequently, we demonstrated that all NDSRIs cause DNA methylation adducts (N7-MedG > O6-MedG) in primary rat hepatocytes, with generally higher levels than those caused by NDMA. Consistently, the NDSRIs generated more DNA strand breaks than NDMA, which followed the DNA adduct kinetics. Furthermore, all NDSRIs showed cytotoxicity after 24 h, whereas no cytotoxic effect was observed for NDMA. Taken together, our study provided evidence that the three NDSRIs are genotoxic in primary rat hepatocytes, which warrants further investigation with regard to their mutagenic potential.
Rectal insufflation of tobacco smoke was the most used resuscitation method for drowning accidents in the second half of the 18th century. Probably practised for centuries by the indigenous tribes of Canadian Acadia, knowledge of this form of treatment reached England from the New World already at the beginning of the 17th century. The East India Company's fleet surgeon, John Woodall, was the first to describe the method in his textbook, published in its second edition in 1639, entitled "The Surgeons Mate" and referred to it as "Enema fumosum". Within a few decades, this treatment spread throughout Europe, initially being used primarily to treat severe abdominal complaints. Then in 1740, at the behest of Louis XIV the French polymath René-Antoine Ferchault de Réaumur recommended tobacco smoke enemas as the most effective method of resuscitation for drowning victims. The rescue organisations that emerged shortly thereafter in many European countries, such as the Dutch "Maatschappij tot Redding van Drenkelingen", founded in 1767, adopted Réaumur's recommendation. Emergency literature of the time contains hundreds of examples of successful resuscitation after using this method. The first doubts about its effectiveness were expressed in 1776 by the famous English surgeon John Hunter, followed shortly afterwards by the physicians Charles Kite and James Curry. The method fell increasingly into disrepute. By the middle of the 19th century, it had been definitively replaced by Marshall Hall's "Ready Method" and other new resuscitation methods. What remains of it today are memories of a form of therapy that seems curious, but whose implementation undoubtedly saved the lives of a large number of people threatened with drowning as many reports on successful drowning resuscitations demonstrate.
Zusammenfassung Die Senatskommission zur gesundheitlichen Bewertung von Lebensmitteln (SKLM) der Deutschen Forschungsgemeinschaft (DFG) existiert seit den frühen 1950er‐Jahren und hat sich über Jahrzehnte kontinuierlich weiterentwickelt. Sie arbeitet in Themenauswahl und Prioritätensetzung in wissenschaftlicher Freiheit und ist im Bereich der Lebensmittelsicherheit in Deutschland eine verlässliche, mandats‐unabhängige wissenschaftsgetriebene Instanz. Das Ziel der Kommission ist es, offene wissenschaftliche Fragen zur Lebensmittelsicherheit systematisch zu analysieren, Bewertungskriterien weiterzuentwickeln und wissenschaftlich fundierte Empfehlungen für gesundheitliche Bewertungen abzuleiten. Dies schließt neue Lebensmittel, Zusatzstoffe, Prozesskontaminanten und Auswirkungen der Behandlungsverfahren auf Lebensmittel ein. Kontroverse Diskussionen über mögliche Risiken durch Lebensmittel begleiten die Arbeit der Lebensmittel‐ und Ernährungswissenschaften seit Jahrzehnten und kommen häufig dadurch zustande, dass für die Bewertung erforderliches Grundlagenwissen fehlt. Die Vorgehensweise der SKLM unterscheidet sich von jener offizieller öffentlicher Institutionen wie dem Bundesinstitut für Risikobewertung (BfR) oder der Europäischen Lebensmittelbehörde EFSA (European Food Safety Authority), da sie den Schwerpunkt auf das proaktive Schließen von Erkenntnislücken sowie die Entwicklung neuer Bewertungskonzepte und Sicherheitsstrategien legt. Ein Beispiel für den Mehrwert ist etwa die Diskussion der unterschiedlichen Richtwerte, die von Regulierungsbehörden zu Bisphenol A (BPA) herausgegeben wurden, und die Nutzung dieser Diskussion, um ein zukunftsorientiertes Konzept zur Verbesserung des Prozesses zu entwickeln. Die neu gegründete „International Commission on Food Safety“ (ICFS) wird solche Aufgaben künftig von der SKLM übernehmen.
