Marketing Authorization Applications Made to the European Medicines Agency in 2018-2019:What was the Contribution of Real-World Evidence?

Information derived from routinely collected real-world data has for a long time been used to support regulatory decision making on the safety of drugs and has more recently been used to support marketing authorization submissions to regulators. There is a lack of detailed information on the use and types of this real-world evidence (RWE) as submitted to regulators. We used resources held by the European Medicines Agency (EMA) to describe the characteristics of RWE included in new marketing authorization applications (MAAs) and extensions of indication (EOIs) for already authorized products submitted to the EMA in 2018 and 2019. For MAAs, 63 of 158 products (39.9%) contained RWE with a total of 117 studies. For 31.7% of these products, the RWE submitted was derived from data collected before the planned authorization. The most common data sources were registries (60.3%) followed by hospital data (31.7%). RWE was mainly included to support safety (87.3%) and efficacy (49.2%) with cohort studies being the most frequently used study design (88.9%). For EOIs, 28 of 153 products (18.3%) contained RWE with a total of 36 studies. For 57.1% of these products, studies were conducted prior to the EOIs. RWE sources were mainly registries (35.6%) and hospital data (27.0%). RWE was typically used to support safety (82.1%) and efficacy (53.6%). Cohort studies were the most commonly used study design (87.6%). We conclude that there is widespread use of RWE to support evaluation of MAAs and EOIs submitted to the EMA and identify areas where further research is required

Modelo de crecimiento en longitud y anchura del rotífero Brachionus plicatilis (Müller 1786), en tres razas asiáticas

Scarce information in available on the growth and development of Brcahionus plicatilis. This pper presents a growth model for three asiatic strains of B. plictilis: Thailand-S, Yashima-S and Nagasaki-L. The eperiments were carried out under controlled laboratory conditions. The morphometric estimations were done at regular intervals of time, along 96 hours. The growth models were made for length and width for each strain, and the residuals analysis were done to determinte the model fidelity. The results indicte correlations which go from 0.714 to 0.97 for length, nd from 0.845 to 0.924 for width. The growth pattern of B. plicatilis indicate differences whe the individual reaches the maturity. The length of the individuls of the strains studied was proportional until they reaches 30 hours of life, where the length rate goes from 153.36 to 245.64 um, depending of the strin. The width shows higher discrepncy, since the growth pattern fluctuates from 24 to 48 hours, and the rate goes from 136.59 to 175.38 um. On the other hand, the graphic analysis of residuals also indicate differences when the rotifers reach the sexual maturity.La información relacionada con el crecimiento y desarrollo de la lorica de Brachionus plicatilis es escasa. En el presente trabajo se determina el modelo de crecimiento en longitud y anchura para tres razas asiáticas: Tailandia-Ch, Yashima-Ch y Nagasaki-G. Las tres razas fuero cultivadas bajo las mismas condiciones eperimentales. Se realizaron estimaciones morfométrica en intervalos de tiempos regulres durnte 96 horas, para estimas los valores de los parámetros del modelo de crecimiento en longitud y anchura de cada una de las razas del rotífero. El ajuste del modelo se determinó por medio del análisis de residules. Los resultdaos indican correlaciones que fluctún desde 0.714 hasta 0.97 en el caso de la longitud, mientrsa que el ancho fue de 0.845  0.94. El crecimeinto del rotífero indica diferencias a partir de que alcanza su madurez sexual, en donde la longitud de las tres razas es proporcionl hasta las 30 horas y el intervalo va de 153.36 a 245.64 um, dependiendo de la raza. El ancho de la lorica muestra mayor discrepnci, ya que el ritmo de crecimiento proporcional fluctúa entre las 24 y 48 horas y el intervalo va de 136.59 a 175.38 um. El análisis gráfico de residules indica diferencias a partir de que el rotífero madura sexualmente

Diagnóstico morfométrico del rotífero Brchionus plicatilis (Müller 1786), con variables indicadoras "dummy"

The use of living feed in quculture depends on severl fcators, one of them is the sie, wich determine its efficincy to be predated. If the prey size not correspond to predator needs, the probbility to be consumed is low, and the growth and survival rates of the predator will be affected. The aim of this work ws to get  potentil morphometric model, using dummy variables, relating the length and width of Brachionus plicatilis from different strains; Thailand-S, Yashima-S, Yashima-L nad Nagasaki-L. The eperimentl organisms were cultured under the same controlled environmental conditions. In order to demostrate the model usefulness, the trditionla model of length vs. width was done to select the best fit. The results indicate high correlations in both methods from 0.895 to 0.961 with the trdaitional way and 0.95 with the proposed wy. The grphic analysis of residuals demostrate the high fidelity of the model presented here. The use of this model is important because it works with one nominal variable and simplify the calculations without loss its precision.La utilización del alimento vivo en acuicultura está directamente relacionado con su tamaño, lo cual determina su eficiencia para ser consumido, ya que una talla inapropiada reduce la probabilidad de ser depredado por el organismo de interés, repercutiendo en su crecimiento y sobrevivencia. El presente trabajo, propone un modelo potencial (morfométrico), utiliando variables indicadoras "dummy", que relacionan la longitud y el ancho de la lorica de Brachionus plicatilis. Los organismos utilizados pertenecen a cuatro razas asiáticas (Tailandia-Ch, Yashima-Ch, Yashima-G y Ngsaki-G), los cuales fueron cultivados bajo las mismas condiciones controladas en laboratorio. Para mostrar la utilidad del modelo propuesto, se estimó el modelo tradicional (longitud versus ancho), para cada raza, contrastándolos con el modelo único generado con variables indicadoras. El instrumento metodológico para seleccionar el mejor ajuste (fidelidad), fue a través del análisis de residuales estandarizados. Los resultados indican altas correlaciones en ambos métodos, que fluctúan desde 0.895 hasta 0.961 en el caso de la forma tradicional, mientras que en el segundo caso fue de 0.952. El análisis gráfico de residules indica una gran fidelidad del modelo. La improtancia del modelo rdica en la integración de una variable nominal simplificando los cálculos sin perder su precisión

Exploring the Relationship between Spontaneous Sister Chromatid Exchange and Genome Instability in Two Cryptic Species of Non-Human Primates

There are extensive studies on chromosome morphology and karyotype diversity in primates, yet we still lack insight into genomic instability as a key factor underlying the enormous interspecies chromosomal variability and its potential contribution to evolutionary dynamics. In this sense, the assessment of spontaneous sister chromatid exchange (SCE) frequencies represents a powerfultool for evaluating genome stability. Here, we employed G-banding, fluorescence plus Giemsa (FPG), and chromosome orientation fluorescence in situ hybridization (CO-FISH) methodologies tocharacterize both chromosome-specific frequencies of spontaneously occurring SCE throughout the genome (G-SCE) and telomere-specific SCE (T-SCE).We analyzed primary fibroblast cultures from two male species of Ateles living in captivity: Ateles paniscus (APA) and Ateles chamek (ACH). High frequencies of G-SCEs were observed in both species. Interestingly, G-SCEs clustered on evolutionary relevant chromosome pairs: ACH chromosomes 1, 2, 3, 4, and 7, and APA chromosomes 1, 2, 3, 4/12, 7, and 10. Furthermore, a statistically significant difference between the observed and expected G-SCE frequencies, not correlated with chromosome size, was also detected. CO-FISH analyses revealed the presence of telomere-specific recombination events in both species, which included T-SCE, as well as interstitial telomere signals and telomere duplications, with APA chromosomes displaying higher frequencies, compared to ACH. Our analyses support the hypothesis that regions of Ateles chromosomes susceptible to recombination events are fragile sites and evolutionary hot spots. Thus, we propose SCE analyses as a valuable indicator of genome instability in non-human primates.Fil: Nieves, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Puntieri, Fiona. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ecología, Genética y Evolución. Grupo de Investigación de Biología Evolutiva; ArgentinaFil: Bailey, Susan M.. Colorado State University; Estados UnidosFil: Mudry, Marta Dolores. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ecología, Genética y Evolución. Grupo de Investigación de Biología Evolutiva; ArgentinaFil: Marañon, David G.. Colorado State University; Estados Unido

Comparative study of the complement-activating and specific IgE-binding properties of ragweed pollen allergen

Previous reports have defined the capacity of ragweed pollen extract (RWA) to activate human complement (C) in fluid phase through the classical pathway and have ascertained a strong correlation between the extent of complement activation and the severity of symptoms of allergic rhinoconjunctivitis during the ragweed blooming season. In the present study the complement-activating and specific IgE-binding capacities of various ragweed allergen preparations were compared. Elimination of physically adsorbed (flavonoid) pigments from the allergenic proteins had no significant effect on their complement-consuming capacity, although the process strongly diminished specific IgE binding. Removal of an IgE-binding trypsin inhibitor from RWA significantly enhanced RWA-induced complement activation, whereas it did not change IgE binding. These findings indicate that neither the physically adsorbed pigments nor the trypsin inhibitor are involved in complement activation by ragweed pollen allergens, and suggest that complement activation and specific IgE binding are distinct molecular properties of ragweed pollen allergen