Medicines Evaluation Board

Long-acting injectable medicinal products (LAIs) prolong drug release and thereby aim to enhance adherence and patient outcomes. European regulatory guidelines require the conduct of single- and multiple-dose trials to exclude differences in drug release between non-steady and steady state conditions. The complexity of these trials may however hamper the development of LAIs. This study aimed to examine whether drug release is different after single- and multiple-dose administration using clinical pharmacokinetic (PK) data of a sample of five regulatory-approved LAIs. Single- and multiple-dose data were extracted from an internal regulatory database. Population pharmacokinetic models with different absorption structures were developed using nonlinear mixed-effect modeling based on the single-dose data of every LAI. The best-fitting models were used to predict the pharmacokinetic profiles after multiple-dose administration. The absorption of LAIs after single-dose administration was best described with (parallel) first-order absorption structures (with and without lag-time). After multiple-dose administration, the mean model accuracy was 93% (minimum to maximum: 70%-122%), and 7 out of 10 observed pharmacokinetic variables (i.e., area under the plasma concentration-time curve, minimum and maximum concentration) met the pre-specified acceptance criteria. In conclusion, multiple-dose PK characteristics can be predicted using models developed from single-dose PK data, which indicates that drug release may not be very different between dosing conditions in this sample of regulatory-approved LAIs. Nevertheless, additional studies on other LAIs are required to test the generalizability of our findings and to increase our understanding of the limitations of the proposed model-based approach vis-à-vis the current evidentiary standard.

Abstract PRESORT is a research project funded by the Conference of European Directors of Roads (CEDR) through the CEDR Transnational Road Research Programme (Call 2022). The aim is to improve the use of third-party data by National Road Authorities (NRAs). NRAs are seeing increasing levels of digitisation and are open to the potential opportunities through the utilisation of third-party data – that is, data aggregated from multiple sources – to support them in the delivery of their core business services in traffic management, asset management, and construction. PRESORT will eventually deliver practical, implementable, easy to use online guide to support NRAs to make better decisions regarding HOW and WHEN to acquire and use third-party data, which will assist their core business activities. The initial phase of this project involved capturing the current state of third-party data use by NRAs. Part of this phase explored the challenges and barriers NRAs face regarding use of third-party data through a literature review and engagement with data providers and crucially, the NRA end-users. This paper reports on the results of this engagement.

BackgroundEpidermolysis bullosa (EB) comprises a heterogeneous group of rare, genetic blistering diseases. The wide variety in EB trial outcomes limits the comparability of outcomes and, consequently, the implementation of the best available treatment options. A core outcome set (COS) is a minimum set of outcomes that should be measured in all clinical trials, comprising what should be measured (i.e., outcome domains) and how it should be measured (i.e., outcome measurement instruments). This enables standardization of outcome measurement aiming at improving the comparability and quality of research.MethodsThe Core Outcome Set for Epidermolysis Bullosa (COSEB) initiative aims to develop COSs for use in clinical trials for the four major EB types: EB simplex, junctional EB, dystrophic EB, and Kindler EB. This protocol focuses on the development of core outcome domain sets — outlining what should be measured in EB clinical trials. Involved stakeholders are patients and patient representatives, clinicians, researchers, methodologists, industry representatives, regulators, health technology assessors, and payers. In the initial part, working groups are formed to define long lists of candidate outcome domains for the four major EB types. Potentially relevant outcome domains will be identified based on scoping literature reviews and qualitative studies. Following consultations with a stakeholder advisory panel, a short list of candidate outcome domains will be subject to voting in Delphi consensus procedures. Finally, the definitive core outcome domain sets for the four major EB types and, if indicated, any overarching core outcome domain sets, will be confirmed in consensus meetings. The project Has been prospectively registered in the COMET registry for COSs on 23 October 2017 (registration number 1033).DiscussionThis protocol provides guidance to ensure a systematic, transparent, and comprehensible approach of COSEB. The final core outcome domain sets are supposed to serve as the minimum sets of what to measure in future EB trials. This will provide the basis for the subsequent outcome measurement instrument selection. Particularly in this rare disease with inherently small-sized study cohorts, this will facilitate the incorporation of meaningful outcomes and pooling of data, ultimately enhancing optimal treatment for EB.Trial registrationThis study Has been prospectively registered in the COMET database on 23 October 2017 and updated on 24 January 2022 (registration number 1033 https://www.comet-initiative.org/studies/details/1033).Supplementary InformationThe online version contains supplementary material available at 10.1186/s13063-025-09052-w.

BackgroundSelective serotonin reuptake inhibitors (SSRIs) are the preferred pharmacological treatment for obsessive–compulsive disorder (OCD). However, insufficient response is common and it remains unclear whether specific patient-level factors influence the likelihood of treatment response.AimsTo determine the efficacy and acceptability of SSRIs in adult OCD, and to identify patient-level modifiers of efficacy.MethodsWe conducted an individual patient data meta-analysis (IPDMA) of industry-sponsored short-term, randomised, placebo-controlled SSRI trials submitted for approval to the Dutch regulatory agency to obtain marketing approval for treating OCD in adults. We performed a two-stage meta-analysis, using crude data of available trials. The primary outcome was the difference in Yale–Brown Obsessive–Compulsive Scale (YBOCS) change between active treatment and placebo. Secondary outcomes were differences in response (defined as the odds ratio of ≥35% YBOCS point reduction) and acceptability (defined as the odds ratio for all-cause discontinuation). We examined the modifying effect of baseline characteristics: age, gender, illness severity, depressive symptoms, weight, illness duration and history of antidepressant use.ResultsAfter excluding three trials because of missing data, we analysed results from 11 trials (79% of all submitted trials, n = 2372). The trial duration ranged from 10 to 13 weeks. Mean difference of SSRIs relative to placebo was 2.65 YBOCS points (95% CI 1.85–3.46, p < 0.0001), equalling a small effect size (0.33 Hedges’ g). The odds ratio for response was 2.21 in favour of active treatment (95% CI 1.72–2.83, p < 0.0001), with a number needed to treat of seven. Patient characteristics did not modify symptom change or response. Acceptability was comparable for SSRIs and placebo.ConclusionsOur IPDMA showed that SSRIs are well accepted and superior to placebo for treating OCD. The effects are modest and independent of baseline patient characteristics.

Introduction: Inherited ichthyosis comprises a group of rare keratinization disorders caused by abnormal epidermal barrier function. Ichthyosis is yet incurable and current treatments mainly focus on alleviating symptoms such as scaling, erythema and pruritus. Recent developments show promising results for interventions based on the immune-phenotype like biologicals or pathogenesis-based therapies such as gene therapy. However, the lack of uniform reporting and variety of treatment outcomes may complicate performing and comparing efficacy studies. The core outcome set for inherited ichthyosis (COSII) aims to develop a core outcome set (COS), i.e., the minimum of outcomes that should be measured and reported in observational and interventional studies, including a minimum set of baseline characteristics. Methods: The COSII project will follow the guidelines from the Core Outcome Measures in Effectiveness Trials (COMET) initiative, including the Core Outcome Set-Standards for Development (COS-STAD) recommendations and the Core Outcome Set Standardised Protocol (COS-STAP) checklist. The COS development methodology, including this protocol, follows the guidance of the CHORD COUSIN Collaboration ‘C3’. The first stage of this project involves identifying a possible list of outcomes through performing a scoping literature review and conducting interviews with patient(s) (representatives). This list will be presented to five different stakeholder groups: healthcare professionals, researchers, patient(s) (representatives), industry representatives, and regulators. All stakeholders will rate the importance of each outcome in a three-round eDelphi survey. Ultimately, a virtual consensus meeting will be convened to finalize the COS. Ethical approval was obtained prior to the start of this project from the Medical Ethics Committee Board at Maastricht University Medical Centre (METC 2022-3192). Informed consent will be asked prior to enrolment in the eDelphi. This study is registered with the COMET. The results will be distributed via a peer-reviewed journal, communicated to all relevant parties and showcased at national and international conferences. Conclusion: This will be the first COS for inherited ichthyosis research in accordance with the Core Outcome Measures in Effectiveness Trials initiative. The development of a COS aims to improve the consistency of reporting and the heterogeneity of outcomes in ichthyosis research.

Direct Healthcare Professional Communications (DHPCs) are an important risk minimisation measure. Their effect has been shown to be variable and has been measured using different outcomes and study populations. Depending on the content of the message, the optimal outcome to measure a direct effect of the DHPC can differ. This systematic review investigates whether the effects of DHPCs differ according to the use of proximal outcomes and the inclusion of the targeted population. EMBASE and MEDLINE were searched for European DHPC effectiveness studies performed up to April 6, 2022, evaluating the impact of DHPCs issued from 2008. Outcomes and their impact were extracted, together with a classification of the message. The outcomes were categorised as knowledge/awareness, self-reported behaviour (prescribing/monitoring), prescribing of medication (including dosage changes), monitoring, or adverse events/other health outcomes, including hospitalisation. The outcomes closest to the message of the DHPC were defined as proximal. Outcomes were coded 1 when effective and 0 if not. If multiple outcomes were reported in a study, a composite outcome was created ranging from 0 to 1. Chi-square or Fisher exact tests were performed. From 7063 (scientific) publications identified in our literature search, 60 publications evaluating 31 different DHPCs were selected for our review. As publications could study multiple messages with an outcome, from the 60 scientific publications, 103 outcomes were generated for the messages, of which 30 had a high impact on the composite outcome, with the proportion of analyses with a significant association between 0.75 and 1. When taking the target population into account, some messages were studied in more than one population, resulting in 115 outcomes, of which 33 had a high impact, that is, a composite outcome between 0.75 and 1. Neither the use of proximal outcomes nor the restriction of the analysis to the targeted population significantly influenced the impact observed of the DHPC. These results stress the need for improving drug safety communication.

Pancreatic cancer (PC) remains one of the most challenging malignancies to treat. Current therapeutic options are unsatisfactory, and there is an urgent need for more effective and less toxic drugs to improve the dismal prognosis of PC. In recent years, drug repurposing (DR) has emerged as an attractive strategy to identify novel treatments for PC by leveraging existing drugs approved for other indications. Through the use of electronic medical records, Artificial Intelligence, study of metabolic pathways, signalling pathways, and many other approaches, it has become much easier in recent years to identify potential novel uses for old drugs. Although policy, funding and research attention in this area are steadily growing, major challenges to efficient and effective patient-centric DR in PC need to be addressed. These include but are not limited to regulatory, financial and funding barriers and the lack of coordination and collaboration among several sectors and stakeholders. To explore the opportunities and challenges associated with DR in PC, a one-day multi-stakeholder meeting was held on 14th of November 2023 in Brussels, Belgium as part of the REMEDi4ALL project. This meeting provided a platform for researchers, clinicians, industry representatives, funders, regulatory experts, and patient advocates to discuss and propose actions to optimize and accelerate DR in PC. Insights from this meeting support the potential of DR to enhance PC treatment options while highlighting the importance of systemic and supportive changes in the regulatory, policy and funding landscapes, interdisciplinary collaboration, data sharing, and patient involvement in driving therapeutic innovation. This summary highlights key outcomes and recommendations from the meeting in informing future efforts to advance DR initiatives in the context of PC.