The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or European Medicines Evaluation Agency (EMEA).The EMA was set up in 1995, with funding from the European Union and the pharmaceutical industry, as well as indirect subsidy from member states, its stated intention to harmonise (but not replace) the work of existing national medicine regulatory bodies. The hope was that this plan would not only reduce the €350 million annual cost drug companies incurred by having to win separate approvals from each member state but also that it would eliminate the protectionist tendencies of sovereign states unwilling to approve new drugs that might compete with those already produced by domestic drug companies.The EMA was founded after more than seven years of negotiations among EU governments and replaced the Committee for Proprietary Medicinal Products and the Committee for Veterinary Medicinal Products, though both of these were reborn as the core scientific advisory committees. The agency was located in London prior to the United Kingdom's vote for withdrawal from the European Union, relocating to Amsterdam in March 2019.The EMA was founded after more than seven years of negotiations among EU governments and replaced the Committee for Proprietary Medicinal Products and the Committee for Veterinary Medicinal Products, though both of these were reborn as the core scientific advisory committees. The agency was located in London prior to the United Kingdom's vote for withdrawal from the European Union, relocating to Amsterdam in March 2019.
This report summarises the Clinical Endpoints Special Session held during the 62nd annual symposium of the International Society for Clinical Electrophysiology of Vision (ISCEV), convened at Tivoli Vredenburg, Utrecht, The Netherlands. The session brought together clinicians, regulators, industry representatives, and a patient voice to consider the state of clinical endpoints in trials for inherited retinal disorders (IRDs). Discussions covered the adequacy of current endpoints, challenges of disease heterogeneity, regulatory expectations, operational feasibility, and the perspectives of patients. The session highlighted the need to anchor emerging endpoints to clinically meaningful outcomes and to minimise assessment burdens.
OBJECTIVES:Few studies have examined sample size and consensus methods in Delphi studies, leaving limited knowledge in the field of biomedicine. We aimed to analyze these methodological aspects in published articles in which the Delphi method was used. STUDY DESIGN AND SETTING:This was a meta-research study. We analyzed open-access full-text articles in English, retrieved from PubMed, that reported results of primary studies that used a Delphi method. The analysis included the number of planned and conducted rounds, the planned sample size and justification for the sample size, the number of invited and included participants in each round, and the methods used to achieve consensus. RESULTS:Analysis included 1875 articles describing 1904 Delphi studies. The description of the study design was provided in most articles (N = 1157; 62%). The word Delphi was mentioned in the title of 636 articles (34%), and the word consensus appeared in the title of 502 articles (27%). Only 19% of studies reported planned sample size, ranging in the overall sample from 5 to 420 participants (median 19-25). The rationale for their size was described in only 16% of the studies. Invited participants were usually reported for the first round, ranging in the overall sample from 3 to 7468 (median 20-37). The number of participants included was also most often stated for the first round, and in the overall sample, it ranged from 3 to 2295 (median 14-27.5). For all other Delphi rounds used in the studies, a decreasing number of participants was reported. Likert point scales were used in most studies (66%), most often as a single five-point scale. A percentage threshold for consensus was used in most studies, with 80% being the most common. Other numerical definitions most often used were the median, mean, and importance ranking. CONCLUSION:Sample sizes and consensus methods vary significantly in studies using the Delphi method. Therefore, consensus guidelines on sample sizes and recommendations for consistent reporting of consensus criteria need to be developed. PLAIN LANGUAGE SUMMARY:Researchers often use the Delphi method to collect and combine opinions from experts, usually through several rounds of questionnaires, to reach agreement on important topics such as clinical guidelines or research priorities. However, there is little clear guidance on how many experts should take part in these studies or how consensus should be defined. In this study, we examined 1904 Delphi studies published in biomedical journals. We looked at how many participants the authors planned to include, how many they actually invited and retained in each round, and how they defined when experts had reached agreement. We found large differences between studies. Only about one in five studies reported how many participants they planned to include, and even fewer explained why they chose that number. The number of participants ranged from just a few to several hundred. Definitions of consensus also varied widely, with thresholds ranging from 50% to 100% agreement, most often 80%. These findings show that Delphi studies are conducted and reported in very different ways. To make Delphi research more transparent, comparable, and reliable, there is a need for consensus-based guidelines on how to plan, conduct, and report Delphi studies, including how to choose the number of participants and how to define consensus.
There is an unmet need for developing drugs for the treatment of gonorrhea due to rapidly evolving resistance of Neisseria gonorrhoeae against antimicrobial drugs used for empiric therapy, an increase in globally reported multidrug-resistant cases, and the limited available therapeutic options. Furthermore, few drugs are under development. Development of antimicrobials is hampered by challenges in clinical trial design, limitations of available diagnostics, changes in and varying standards of care, lack of robust animal models, and clinically relevant pharmacodynamic targets. On 23 April 2021, the US Food and Drug Administration, Centers for Disease Control and Prevention, and National Institute of Allergy and Infectious Diseases of the National Institutes of Health co-sponsored a workshop with stakeholders from academia, industry, and regulatory agencies to discuss the challenges and strategies, including potential collaborations and incentives, to facilitate the development of drugs for the treatment of gonorrhea. This article provides a summary of that workshop.
Combination vaccine formulations contain distinct components targeting multiple strains of a single pathogen or multiple pathogens. By minimizing the number of separate vaccine administrations required, combination vaccines have been critical in allowing the broad expansion of the number and range of diseases that can now be prevented by immunization. Recent advances in vaccine development and our understanding of the immune system now make it possible to envision how new combination vaccines could play a major role in helping immunization programs address a much wider range of emerging or still problematic pathogens. However, few combinations are currently in the pipeline, in part due to their inherently increased complexity and cost of development compared to standalone formulations. This complexity, in turn, is partly driven by the regulatory requirements surrounding the clinical study program for the combination vaccine, especially the primary clinical endpoints and the required degree of precision around those endpoints, as these ultimately determine the sample size, cost, and duration of the study. As part of a larger effort to facilitate combination vaccine development, vaccine experts at the World Health Organization and PATH coordinated a one-day meeting in March 2025 gathering current and former national regulatory agency staff from a dozen countries, together with vaccine developers, representatives from funding and procurement agencies, and public health and policy officials. The convened participants held spirited discussions on how multiple immune markers and controlled human infection models (CHIM) might contribute to the demonstration of vaccine efficacy. In addition, participants considered the possibility of relying on clinical endpoints when the vaccine components are directed against pathogens causing the same disease syndrome but etiological determination of each component's contribution is not feasible. Regulators welcomed scientifically sound, creative proposals for demonstration of efficacy, and agreed that the benefit-risk of the combination vaccine as a whole should be the primary focus.
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.
