A Comprehensive Architecture for Federated Learning-Based Smart Advertising.

This paper introduces a cutting-edge data architecture designed for a smart advertising context, prioritizing efficient data flow and performance, robust security, while guaranteeing data privacy and integrity. At the core of this study lies the application of federated learning (FL) as the primary methodology, which emphasizes the authenticity and privacy of data while promptly discarding irrelevant or fraudulent information. Our innovative data model employs a semi-random role assignment strategy based on a variety of criteria to efficiently collect and amalgamate data. The architecture is composed of model nodes, data nodes, and validator nodes, where the role of each node is determined by factors such as computational capability, interconnection quality, and historical performance records. A key feature of our proposed system is the selective engagement of a subset of nodes for modeling and validation, optimizing resource use and minimizing data loss. The AROUND social network platform serves as a real-world case study, illustrating the efficacy of our data architecture in a practical setting. Both simulated and real implementations of our architecture showcase its potential to dramatically curtail network traffic and average CPU usage, while preserving the accuracy of the FL model. Remarkably, the system is capable of achieving over a 50% reduction in both network traffic and average CPU usage even when the user count escalates by twenty-fold. The click rate, user engagement, and other parameters have also been evaluated, proving that the proposed architecture's advantages do not affect the smart advertising accuracy. These findings highlight the proposed architecture's capacity to scale efficiently and maintain high performance in smart advertising environments, making it a valuable contribution to the evolving landscape of digital marketing and FL.

The effectiveness of the Escape Room as an educational methodology in the Infarction Code.

OBJECTIVE: To evaluate the efficacy of an educational intervention (escape room) in the acquisition and retention of knowledge in relation to the Infarction Code, and to compare the knowledge of other teaching methodologies related to the Infarction Code. METHODS: A pre-post study was designed without a control group. After one month of the master class on the Infarction Code given to master's degree (doctors and nurses), an educational intervention was carried out consisting of an Escape Room on the same content, with a questionnaire that collected various sociodemographic data, and a knowledge test on the Infarction Code, which was repeated immediately after the activity and at the end of 2 months after the activity, and a test of knowledge on the Infarction Code. immediately after the activity and 2 months after the master class. Likewise, after the activity, a gamified experience evaluation questionnaire (GAMEX) was completed. RESULTS: Thirty-two students received the educational intervention (12 physicians and 20 nurses), and differences were observed between medical and nursing professionals in terms of initial knowledge of simulation and gamification. After the activity, and based on the initial knowledge test, the score increased by 3.49 points, an increase that was also reflected in the test taken two months after the master class, where an increase of 2.08 points was maintained. The participants rated the experience positively, with no significant overall differences between the two professional groups. CONCLUSIONS: The nurses had greater knowledge and contact with clinical simulation, virtual reality and gamification. The escape room showed to be a valid method for the assimilation and retention of knowledge in master's degree students. Medical professionals experienced a greater degree of immersion in the activity.

Transcutaneous bilirubin reliability during and after phototherapy depending on skin color.

Measurement of transcutaneous bilirubin (TcB) is a non-invasive, widely used technique to estimate serum bilirubin (SB). However, its reliability in multiethnic populations during and after phototherapy is still controversial even in covered skin. The aim of this study was to determine the reliability of TcB in covered (cTcB) and exposed (eTcB) skin during and after phototherapy in a multiethnic population of term and preterm neonates according to Neomar's neonatal skin color scale. Prospective, observational study comparing SB and TcB. We determined SB when clinically indicated and, at the same time, measured cTcB under a photo-opaque patch and eTcB next to it with a jaundice meter (Dräger JM-105TM). All dyads TcB-SB were compared, both globally and according to skin color. We obtained data from 200 newborns (color1: 44, color2: 111, color3: 41, color4: 4) and compared 296 dyads TcB/SB. Correlation between cTcB and SB is strong during (0.74-0.83) and after (0.79-0.88) phototherapy, both globally and by color group. The SB-cTcB bias depends on gestational age during phototherapy and on skin color following phototherapy. The correlation between eTcB and SB during phototherapy is not strong (0.54), but becomes so 12 h after discontinuing phototherapy (0.78).  Conclusions: Our study supports the reliability of cTcB to assess SB during and after phototherapy, with differences among skin tones after the treatment. The use of cTcB and Neomar's scale during and mainly after phototherapy may help reduce the number of blood samples required. What is Known: • Controversies exist on the reliability of jaundice meters during and after phototherapy in covered skin. Only a few studies have analyzed their accuracy in multiethnic populations, but none has used a validated neonatal skin color scale. What is New: • We verified correlation between serum and transcutaneous bilirubin in covered skin in a multiethnic population depending on skin color based on our own validated neonatal skin color scale during and after phototherapy.

Integrated psychological intervention programme for frontline healthcare workers during the COVID-19 pandemic. A qualitative study.

INTRODUCTION: The outbreak of the COVID-19 pandemic put at risk the resilience of healthcare professionals by exposing them to high levels of stress. Our aim was to identify key elements for implementing the STEP  programme, a psychological support service for healthcare professionals. METHODS: qualitative design.  The study participants were hospital healthcare staff. Anonymous questionnaires and transcriptions  of group interventions and focus groups were used to  identify professionals' preferences to receiving psychological support, needs, concerns, resilience (STEP1.0); constrained emotions and associated thoughts (STEP1.5); perception of self-efficacy on managing emotions (STEP2.0); and the professionals' profile requiring individual therapy. RESULTS: Three hundred professionals participated in the study, 100.0% in STEP 1.0 , 27.3% in STEP 1.5, 2.7% in STEP 2.0, and 10.0% in individual interventions. Two hundred and three (67.7%) participants reflected in the survey that they would prefer access to a face-to-face psychological service during working hours. Three consecutive phases with specific needs and concerns were identified: The "cognitive" phase, at the beginning of the pandemic, when infection and self-efficacy were major concerns, the "ventilation" phase, when constrained emotions associated with several factors were expressed; and the "recovery" phase, when the clinical overload decreased and professionals were able to focus on emotion management training. Several personal characteristics associated with referral to individual therapy were identified.  Conclusions: The key characteristics of a psychological support service are proximity, face-to-face interaction during working shifts, and a chronological phase system adapted to different emerging needs.

Introducción: El estallido de la pandemia de la COVID-19 puso en riesgo la resiliencia de los profesionales sanitarios exponiéndolos a alto riesgo de estrés. Nuestro objetivo consistió en identificar elementos clave para implementar un servicio de apoyo psicológico para profesionales. Método: Diseño cualitativo. Participaron profesionales a nivel hospitalario. Se utilizaron cuestionarios anónimos, transcripciones de intervenciones grupales y grupo focal. Se consideraron las variables asociadas a las herramientas de intervención psicológica implementadas: STEP 1.0, necesidades, preocupaciones y resiliencia; STEP 1.5, emociones contenidas y pensamientos asociados; STEP 2.0, percepción de autoeficacia en gestión de emociones. Características de profesionales asociadas a terapia individual; así como el método elegido para recibir apoyo psicológico.  Resultados: Participaron 300 profesionales, 100.0% en STEP 1.0, 27.3% en STEP 1.5, 2.7% en STEP 2.0 y 10.0% en intervenciones individuales. En 203 cuestionarios los profesionales preferían un servicio psicológico presencial y durante las horas de trabajo. Se identificaron 3 fases consecutivas con necesidades y preocupaciones específicas: Fase "Cognitiva", inicial, cuando la infección y autoeficacia preocupaban más. Fase de "Ventilación" cuando se expresaron emociones contenidas asociadas a varios factores. Fase de "Recuperación", cuando los profesionales afrontaron la gestión de emociones. Se identificaron características asociadas a la derivación a terapia individual.  Conclusión: Las características clave de un servicio de apoyo psicológico son la proximidad, presencialidad, activarse en turnos laborales y seguir un sistema cronológico de fases adaptado a las distintas necesidades emergentes.

Implementation of a Community-Based Public Model for the Prevention and Control of Communicable Diseases in Migrant Communities in Catalonia.

In high-income countries, migrant populations have a greater epidemiological vulnerability: increased exposure to infectious diseases, difficulties in diagnosis, case follow-up and contact tracing, and obstacles following preventive measures related to cultural and administrative barriers. This study aims to describe the implementation of a community-based program to address these challenges. The target population is the migrant native population from North Africa, South Asia, Sub-Saharan Africa, Eastern Europe, and Latin America resident in Catalonia during 2023. Implementation phases include the identification of the perceived needs, search, recruitment and capacity building of 16 community health workers, and the development of a computer software. From January to June 2023, 117 community-based interventions have been implemented, reaching 677 people: 73 community case and contacts management interventions, 17 community in-situ screenings (reaching 247 people) and 27 culturally adapted health awareness and education actions (reaching 358 people). The program addresses the following infectious diseases: tuberculosis, Chagas disease, hepatitis C, typhoid, scabies, hepatitis B, mumps and tinea capitis. The implementation of a community-based model may be key to improving surveillance communicable diseases, promoting an equitable and comprehensive epidemiological surveillance system.

Recurring renal lithiasis due to Dent's disease.

Dent's disease is a rare cause of hypercalciuria and recurring urolithiasis. Patients with this disease have elevated bone resorption due to the presence of parathormone (PTH) in the urine. We describe the case of a 21-year-old male with hypercalciuria, elevated bone resorption and recurring bilateral urolithiasis that achieves radiological and clinical stability with percutaneous nephrolithotomy (PNL) and medical treatment with hydrochlorothiazide, potassium-citrate and phytate.

Identity and functional characterisation of the transporter supporting the Na+ -dependent high-affinity NO3 - uptake in Zostera marina L.

Zostera marina is a seagrass, a group of angiosperms that evolved from land to live submerged in seawater, an environment of high salinity, alkaline pH and usually very low NO3 - . In 2000, we reported the first physiological evidence for the Na+ -dependent high-affinity NO3 - uptake in this plant. Now, to determine the molecular identity of this process, we searched for NO3 - transporters common to other vascular plants encoded in Z. marina's genome. We cloned two candidates, ZosmaNPF6.3 and ZosmaNRT2 with its partner protein ZosmaNAR2. ZosmaNAR2 expression levels increase up to 4.5-fold in Z. marina leaves under NO3 - -deficiency, while ZosmaNRT2 and ZosmaNPF6.3 expressions were low and unaffected by NO3 - . NO3 - transport capacity, kinetic properties and H+ or Na+ -dependence were examined by heterologous expression in the Hansenula polymorpha high-affinity NO3 - transporter gene disrupted strain (∆ynt1). ZosmaNPF6.3 functions as a H+ -dependent NO3 - transporter, without functionality at alkaline pH and apparent dual kinetics (KM = 11.1 µM at NO3 - concentrations below 50 µM). ZosmaNRT2 transports NO3 - in a H+ -independent but Na+ -dependent manner (KM = 1 mM Na+ ), with low NO3 - affinity (KM = 30 µM). When ZosmaNRT2 and ZosmaNAR2 are co-expressed, a Na+ -dependent high-affinity NO3 - transport occurs (KM = 5.7 µM NO3 - ), mimicking the in vivo value. These results are discussed in the physiological context, providing evidence that ZosmaNRT2 is a Na+ -dependent high-affinity NO3 - transporter, the first of its kind to be functionally characterised in a vascular plant, that requires ZosmaNAR2 to achieve the necessary high-affinity for nitrate uptake from seawater.

Involvement of the European Medicines Agency in multi-stakeholder regulatory science research projects: experiences of staff members and project coordinators.

Background: The European Medicines Agency (EMA) interacts with many different stakeholders involved in the development of drugs, including academic researchers. In recent years, EMA has collaborated more closely with academia, inter alia by taking part in external research projects such as those set up under the Horizon 2020 program in general and the Innovative Medicines Initiative in particular. The aim of this study was to evaluate the perceived added value of EMA's involvement in these projects, both from the perspective of the Agency's participating Scientific Officers and of the coordinators of the consortia that undertook them. Methods: Semi-structured interviews were conducted with the coordinators of 21 ongoing or recently finalized projects in which EMA has participated, as well as with the Agency experts contributing to them. Results: In total, 40 individuals were interviewed, of whom 23 were project coordinators and 17 were EMA staff members. While most of the projects were reported to suffer from delays due to the SARS-CoV-2 pandemic, the consortia adapted to the circumstances and their members still expected to deliver on their objectives. EMA's input into the projects ranged from providing guidance by reviewing documents and attending meetings to creating project materials and disseminating them. The frequency of communication between EMA and the consortia varied widely. The projects generated a diverse set of outputs, which encompassed new or improved medicinal products, methodological standards, research infrastructures, and educational tools. All of the coordinators expressed that EMA's contributions to their projects had increased the scientific relevance of their consortium's work, and the EMA experts found that the knowledge and the deliverables produced by the projects were valuable, taking into consideration the time they had invested into them. In addition, interviewees highlighted some actions which could be taken to increase the regulatory significance of the project outcomes. Conclusion: EMA's engagement in external research projects benefits the consortia conducting them and supports the Agency's mission to foster scientific excellence and advance regulatory science.

CPT1A in AgRP neurons is required for sex-dependent regulation of feeding and thirst.

BACKGROUND: Fatty acid metabolism in the hypothalamus has an important role in food intake, but its specific role in AgRP neurons is poorly understood. Here, we examined whether carnitinea palmitoyltransferase 1A (CPT1A), a key enzyme in mitochondrial fatty acid oxidation, affects energy balance. METHODS: To obtain Cpt1aKO mice and their control littermates, Cpt1a(flox/flox) mice were crossed with tamoxifen-inducible AgRPCreERT2 mice. Food intake and body weight were analyzed weekly in both males and females. At 12 weeks of age, metabolic flexibility was determined by ghrelin-induced food intake and fasting-refeeding satiety tests. Energy expenditure was analyzed by calorimetric system and thermogenic activity of brown adipose tissue. To study fluid balance the analysis of urine and water intake volumes; osmolality of urine and plasma; as well as serum levels of angiotensin and components of RAAS (renin-angiotensin-aldosterone system) were measured. At the central level, changes in AgRP neurons were determined by: (1) analyzing specific AgRP gene expression in RiboTag-Cpt1aKO mice obtained by crossing Cpt1aKO mice with RiboTag mice; (2) measuring presynaptic terminal formation in the AgRP neurons with the injection of the AAV1-EF1a-DIO-synaptophysin-GFP in the arcuate nucleus of the hypothalamus; (3) analyzing AgRP neuronal viability and spine formations by the injection AAV9-EF1a-DIO-mCherry in the arcuate nucleus of the hypothalamus; (4) analyzing in situ the specific AgRP mitochondria in the ZsGreen-Cpt1aKO obtained by breeding ZsGreen mice with Cpt1aKO mice. Two-way ANOVA analyses were performed to determine the contributions of the effect of lack of CPT1A in AgRP neurons in the sex. RESULTS: Changes in food intake were just seen in male Cpt1aKO mice while only female Cpt1aKO mice increased energy expenditure. The lack of Cpt1a in the AgRP neurons enhanced brown adipose tissue activity, mainly in females, and induced a substantial reduction in fat deposits and body weight. Strikingly, both male and female Cpt1aKO mice showed polydipsia and polyuria, with more reduced serum vasopressin levels in females and without osmolality alterations, indicating a direct involvement of Cpt1a in AgRP neurons in fluid balance. AgRP neurons from Cpt1aKO mice showed a sex-dependent gene expression pattern, reduced mitochondria and decreased presynaptic innervation to the paraventricular nucleus, without neuronal viability alterations. CONCLUSIONS: Our results highlight that fatty acid metabolism and CPT1A in AgRP neurons show marked sex differences and play a relevant role in the neuronal processes necessary for the maintenance of whole-body fluid and energy balance.

Assessment of a serum calcification propensity test for the prediction of all-cause mortality among hemodialysis patients.

BACKGROUND: Vascular calcification is a major contributor to the high cardiac burden among hemodialysis patients. A novel in vitro T50-test, which determines calcification propensity of human serum, may identify patients at high risk for cardiovascular (CV) disease and mortality. We evaluated whether T50 predicts mortality and hospitalizations among an unselected cohort of hemodialysis patients. METHODS: This prospective clinical study included 776 incident and prevalent hemodialysis patients from 8 dialysis centers in Spain. T50 and fetuin-A were determined at Calciscon AG, all other clinical data were retrieved from the European Clinical Database. After their baseline T50 measurement, patients were followed for two years for the occurrence of all-cause mortality, CV-related mortality, all-cause and CV-related hospitalizations. Outcome assessment was performed with proportional subdistribution hazards regression modelling. RESULTS: Patients who died during follow-up had a significantly lower T50 at baseline as compared to those who survived (269.6 vs. 287.7 min, p = 0.001). A cross-validated model (mean c statistic: 0.5767) identified T50 as a linear predictor of all-cause-mortality (subdistribution hazard ratio (per min): 0.9957, 95% CI [0.9933;0.9981]). T50 remained significant after inclusion of known predictors. There was no evidence for prediction of CV-related outcomes, but for all-cause hospitalizations (mean c statistic: 0.5284). CONCLUSION: T50 was identified as an independent predictor of all-cause mortality among an unselected cohort of hemodialysis patients. However, the additional predictive value of T50 added to known mortality predictors was limited. Future studies are needed to assess the predictive value of T50 for CV-related events in unselected hemodialysis patients.

Nanomedicine targeting brain lipid metabolism as a feasible approach for controlling the energy balance.

Targeting brain lipid metabolism is a promising strategy to regulate the energy balance and fight metabolic diseases such as obesity. The development of stable platforms for selective delivery of drugs, particularly to the hypothalamus, is a challenge but a possible solution for these metabolic diseases. Attenuating fatty acid oxidation in the hypothalamus via CPT1A inhibition leads to satiety, but this target is difficult to reach in vivo with the current drugs. We propose using an advanced crosslinked polymeric micelle-type nanomedicine that can stably load the CPT1A inhibitor C75-CoA for in vivo control of the energy balance. Central administration of the nanomedicine induced a rapid attenuation of food intake and body weight in mice via regulation of appetite-related neuropeptides and neuronal activation of specific hypothalamic regions driving changes in the liver and adipose tissue. This nanomedicine targeting brain lipid metabolism was successful in the modulation of food intake and peripheral metabolism in mice.

Comparison of the analgesic effect of inhaled lavender vs vanilla essential oil for neonatal frenotomy: a randomized clinical trial (NCT04867824).

It is necessary to treat neonatal pain because it may have short- and long-term adverse effects. Frenotomy is a painful procedure where sucking, a common strategy to relieve pain, cannot be used because the technique is performed on the tongue. In a previous randomized clinical trial, we demonstrated that inhaled lavender essential oil (LEO) reduced the signs of pain during neonatal frenotomy. We aimed to find out whether inhaled vanilla essential oil (VEO) is more effective in reducing pain during frenotomy than LEO. Randomized clinical trial with neonates who underwent a frenotomy for type 3 tongue-ties between May and October 2021. Pain was assessed using pre and post-procedure heart rate (HR) and oxygen saturation (SatO2), crying time, and NIPS score. Neonates were randomized into "experimental" and "control" group. In both groups, we performed swaddling, administered oral sucrose, and let the newborn suck for 2 min. We placed a gauze pad with one drop of LEO (control group) or of VEO (experimental group) under the neonate's nose for 2 min prior to and during the frenotomy. We enrolled 142 neonates (71 per group). Both groups showed similar NIPS scores (2.02 vs 2.38) and crying times (15.3 vs 18.7 s). We observed no differences in HR increase or in SatO2 decrease between both groups. We observed no side effects in either of the groups. CONCLUSIONS: We observed no appreciable difference between LEO and VEO; therefore, we cannot conclude which of them was more effective in treating pain in neonates who underwent a frenotomy. TRIAL REGISTRATION:  This clinical trial is registered with www. CLINICALTRIALS: gov with NCT04867824. WHAT IS KNOWN: • Pain management is one of the most important goals of neonatal care as it can have long-term neurodevelopmental effects. • Lavender essential oil can help relieve pain due to its sedative, antispasmodic, and anticolic properties. WHAT IS NEW: • Lavender and vanilla essential oils are safe, beneficial, easy to use, and cheap in relieving pain in neonates who undergo a frenotomy for type 3 tongue-ties.

Safety and preliminary efficacy on cognitive performance and adaptive functionality of epigallocatechin gallate (EGCG) in children with Down syndrome. A randomized phase Ib clinical trial (PERSEUS study).

PURPOSE: Although some caregivers are using epigallocatechin gallate (EGCG) off label in hopes of improving cognition in young adults with Down syndrome (DS), nothing is known about its safety, tolerability, and efficacy in the DS pediatric population. We aimed to evaluate safety and tolerability of a dietary supplement containing EGCG and if EGCG improves cognitive and functional performance. METHODS: A total of 73 children with DS (aged 6-12 years) were randomized. Participants received 0.5% EGCG (10 mg/kg daily dose) or placebo for 6 months with 3 months follow up after treatment discontinuation. RESULTS: In total, 72 children were treated and 66 completed the study. A total of 38 participants were included in the EGCG group and 35 in the placebo group. Of 72 treated participants, 62 (86%) had 229 treatment-emergent adverse events (AEs). Of 37 participants in the EGCG group, 13 (35%) had 18 drug-related treatment-emergent AEs and 12 of 35 (34%) from the placebo group had 22 events. In the EGCG group, neither severe AEs nor increase in the incidence of AEs related to safety biomarkers were observed. Cognition and functionality were not improved compared with placebo. Secondary efficacy outcomes in girls point to a need for future work. CONCLUSION: The use of EGCG is safe and well-tolerated in children with DS, but efficacy results do not support its use in this population.

Biomarkers in Medicines Development-From Discovery to Regulatory Qualification and Beyond.

Biomarkers are important tools in medicines development and clinical practice. Besides their use in clinical trials, such as for enrichment of patients, monitoring safety or response to treatment, biomarkers are a cornerstone of precision medicine. The European Medicines Agency (EMA) emphasised the importance of the discovery, qualification, and use of biomarkers in their Regulatory Science Strategy to 2025, which included the recommendation to enhance early engagement with biomarker developers to facilitate regulatory qualification. This study explores the journey of biomarkers through the EU regulatory system and beyond, based on a review of interactions between developers and the EMA from 2008 to 2020, as well as the use of qualified biomarkers in clinical trials. Of applicants that used early interaction platforms such as the Innovation Task Force, less than half engaged in fee-related follow-up procedures. Results showed that, as compared to companies, consortia were more likely to opt for the Qualification of Novel Methodologies procedure and engage in follow-up procedures. Our results highlight the importance of early engagement with regulators for achieving biomarker qualification, including pre-submission discussions in the context of the qualification procedure. A review of clinical trials showed that all qualified biomarkers are used in practice, although not always according to the endorsed context of use. Overall, this study highlights important aspects of biomarker qualification, including opportunities to improve the seamless support for developers by EMA. The use of qualified biomarkers in clinical trials underlines the importance of regulatory qualification, which will further enable precision medicine for the benefit of patients.

Analgesic effect of inhaled lavender essential oil for frenotomy in healthy neonates: a randomized clinical trial.

BACKGROUND: Neonatal pain may affect long-term neurodevelopment and must be treated. Frenotomy is a painful procedure wherein a common strategy to relieve pain (sucking) cannot be used because the technique is performed on the tongue. Lavender essential oil (LEO) has sedative and antispasmodic properties and has been successfully used to treat pain during heel puncture and vaccination. Our aim was to demonstrate if the use of inhaled LEO is effective in reducing pain during frenotomy in healthy, full-term neonates. METHODS: We conducted a randomized clinical trial in neonates who underwent a frenotomy between August 2020 and April 2021. We assessed pain using pre and post-procedure heart rate and oxygen saturation, crying time and Neonatal Infant Pain Scale (NIPS) score. Patients with type 3 tongue tie were randomized into the "experimental group" and "control group". In both groups, we performed swaddling, administered oral sucrose, and let the newborn suck for two minutes. In the experimental group, we also placed a gauze pad with one drop of LEO under the neonate's nose for two minutes prior to and during the frenotomy. RESULTS: We enrolled 142 patients (71 per group). The experimental group showed significantly lower NIPS scores (1.88 vs 2.92) and cried almost half the amount of time (14.8 vs. 24.6 seconds, P = 0.006). Comparing with the control group, we observed no side effects in either of the groups. CONCLUSIONS: We observed a significant decrease in crying time and lower NIPS scores in the neonates who received inhaled LEO and underwent a frenotomy for type 3 tongue-ties. Thus, we recommend using inhaled LEO during neonatal frenotomies.

Biomarker Qualification at the European Medicines Agency: A Review of Biomarker Qualification Procedures From 2008 to 2020.

Regulatory qualification of biomarkers facilitates their harmonized use across drug developers, enabling more personalized medicine. This study reviews various aspects of the European Medicines Agency's (EMA's) biomarker qualification procedure, including frequency and outcome, common challenges, and biomarker characteristics. Our findings provide insights into the EMA's biomarker qualification process and will thereby support future applications. All biomarker-related "Qualification of Novel Methodologies for Medicine Development" procedures that started from 2008 to 2020 were included. Procedural data were extracted from relevant documents and analyzed descriptively. In total, 86 biomarker qualification procedures were identified, of which 13 resulted in qualified biomarkers. Whereas initially many biomarker qualification procedures were linked to a single company and specific drug development program, a shift was observed to qualification efforts by consortia. Most biomarkers were proposed (n = 45) and qualified (n = 9) for use in patient selection, stratification, and/or enrichment, followed by efficacy biomarkers (37 proposed, 4 qualified). Overall, many issues were raised during qualification procedures, mostly related to biomarker properties and assay validation (in 79% and 77% of all procedures, respectively). Issues related to the proposed context of use and rationale were least common yet were still raised in 54% of all procedures. While few qualified biomarkers are currently available, procedures focus increasingly on biomarkers for general use instead of those linked to specific drug compounds. The issues raised during qualification procedures illustrate the thorough discussions taking place between applicants and regulators-highlighting aspects that need careful consideration and underlining the importance of an appropriate validation strategy.

Exploring the opportunities for alignment of regulatory postauthorization requirements and data required for performance-based managed entry agreements.

Performance-based managed entry agreements (PB-MEAs) might allow patient access to new medicines, but practical hurdles make competent authorities for pricing and reimbursement (CAPR) reluctant to implement PB-MEAs. We explored if the feasibility of PB-MEAs might improve by better aligning regulatory postauthorization requirements with the data generation of PB-MEAs and by active collaboration and data sharing. Reviewers from seven CAPRs provided structured assessments of the information available at the European Medicines Agency (EMA) Web site on regulatory postauthorization requirements for fifteen recently authorized products. The reviewers judged to what extent regulatory postauthorization studies could help implement PB-MEAs by addressing uncertainty gaps. Study domains assessed were: patient population, intervention, comparators, outcomes, time horizon, anticipated data quality, and anticipated robustness of analysis. Reviewers shared general comments about PB-MEAs for each product and on cooperation with other CAPRs. Reviewers rated regulatory postauthorization requirements at least partly helpful for most products and across domains except the comparator domain. One quarter of responses indicated that public information provided by the EMA was insufficient to support the implementation of PB-MEAs. Few PB-MEAs were in place for these products, but the potential for implementation of PB-MEAs or collaboration across CAPRs was seen as more favorable. Responses helped delineate a set of conditions where PB-MEAs may help reduce uncertainty. In conclusion, PB-MEAs are not a preferred option for CAPRs, but we identified conditions where PB-MEAs might be worth considering. The complexities of implementing PB-MEAs remain a hurdle, but collaboration across silos and more transparency on postauthorization studies could help overcome some barriers.