Guía metodológica para la evaluación de la eficacia y la seguridad de nuevos fármacos: implementación de las recomendaciones de EUnetHTA / Methodological guideline for the efficacy and safety assessment of new pharmaceuticals: implementation of EUnetHTA's recommendations

La colaboración European Network for Health Technology Assessment (EUnetHTA) es la red colaborativa de agencias y organismos públicos de evaluación de tecnologías sanitarias de la Unión Europea. En este marco se han elaborado guías metodológicas y procedimientos comunes que han dado lugar al denominado HTA Core Model®. La Agencia de Evaluación de Tecnologías Sanitarias de Andalucía (AETSA), miembro de la Red Española de Agencias de Evaluación de Tecnologías Sanitarias y Prestaciones del Sistema Nacional de Salud, y de la colaboración EUnetHTA, participa en la recién iniciada Tercera Acción Conjunta (Joint Action 3) de EUnetHTA (2016-2019). Adicionalmente, la AETSA cuenta con una línea de evaluación de medicamentos. Parte del trabajo se integra en la elaboración de informes de posicionamiento terapéutico (IPT) sobre fármacos que han recibido recientemente la autorización de comercialización, que coordina la Agencia Española de Medicamentos y Productos Sanitarios. Como apoyo a este trabajo, la AETSA elabora «Informes de síntesis de evidencia: medicamentos», en los que se realiza una evaluación comparada de la eficacia y la seguridad de los fármacos de los que va a elaborarse un IPT. La AETSA ha diseñado un proceso para la elaboración de dichos informes, basado en el HTA Core Model® y en las guías metodológicas de EUnetHTA. En este trabajo se describe la metodología empleada en la elaboración de la guía realizada por la AETSA para la elaboración de estos informes y se presentan los distintos apartados en los que esta se estructura (AU)

The European network for Health Technology Assessment (EUnetHTA) is the network of public health technology assessment (HTA) agencies and entities from across the EU. In this context, the HTA Core Model®, has been developed. The Andalusian Agency for Health Technology Assessment (AETSA) is a member of the Spanish HTA Network and EUnetHTA collaboration In addition, AETSA participates in the new EUnetHTA Joint Action 3 (JA, 2016–2019). Furthermore, AETSA works on pharmaceutical assessments. Part of this work involves drafting therapeutic positioning reports (TPRs) on drugs that have recently been granted marketing authorisation, which is overseen by the Spanish Agency of Medicines and Medical Devices (AEMPS). AETSA contributes by drafting ‘Evidence synthesis reports: pharmaceuticals’ in which a rapid comparative efficacy and safety assessment is performed for drugs for which a TPR will be created. To create this type of report, AETSA follows its own methodological guideline based on EUnetHTA guidelines and the HTA Core Model®. In this paper, the methodology that AETSA has developed to create the guideline for ‘Evidence synthesis reports: pharmaceuticals’ is described. The structure of the report itself is also presented (AU)

Tratamiento del cáncer de laringe avanzado y calidad de vida. Revisión sistemática / Treatment of advanced laryngeal cancer and quality of life. Systematic review

Introducción y objetivos: El objetivo fue comparar la calidad de vida de los pacientes con cáncer de laringe en estadio avanzado tratados con preservación de órgano respecto a aquellos tratados quirúrgicamente. Métodos: Se realizó una revisión sistemática consultando MedLine, EMBASE, y PubMed (1991-2014) y Web of Science (2012-2014). Los términos de búsqueda fueron: cáncer de laringe, preservación de órgano, quimioterapia, laringectomía, resultados de tratamiento y calidad de vida. Se incluyeron revisiones sistemáticas, metaanálisis, informes de evaluación de tecnologías sanitarias y estudios comparativos con grupo control, publicados en idioma español, francés o inglés. La selección y evaluación de la calidad fue realizada por dos investigadores. Se usaron los criterios de la Colaboración Cochrane para evaluar el riesgo de sesgo y los del Scottish Intercollegiate Guidelines Network (SIGN) para el nivel de evidencia. Resultados: De los 208 estudios identificados en la búsqueda se incluyeron tres: un ensayo clínico y dos estudios observacionales, con un total de 211 pacientes. Su calidad y nivel de evidencia fueron bajos. Los resultados fueron contradictorios, en algunas ocasiones favorables a la cirugía y en otras, a la combinación de radioterapia y quimioterapia, pero en general, sin diferencias significativas entre los tratamientos. Se trataba de estudios heterogéneos, con metodología diferente, tamaño insuficiente, limitaciones en su calidad, con importante riesgo de sesgo y utilización de escalas de medida distintas. Conclusiones: Carecemos de estudios de calidad suficiente para establecer si la calidad de vida en los pacientes con cáncer de laringe en estadio avanzado es diferente en función del tratamiento recibido (AU)

Introduction and objectives: The objective was the comparison of the quality of life in patients with advanced laryngeal cancer treated with organ preservation versus surgical treatment. Methods: We performed a systematic review in the databases MedLine, EMBASE, and PubMed (2014 1991) and Web of Science (2012 - 2014). The search terms were: Laryngeal cancer, organ preservation, chemotherapy, laryngectomy, treatment outcomes and quality of life. Systematic reviews, meta-analysis, reports of health technology assessment and comparative studies with control group, published in Spanish, French or English were included. The selection and quality assessment was made by two researchers. The criteria of the Cochrane Collaboration were used to assess the risk of bias and Scottish Intercollegiate Guidelines Network (SIGN) for the level of evidence. Results: Of the 208 studies identified in the search, three were included a clinical trial and two observational studies, with a total of 211 patients. Quality and level of evidence was low. The results were contradictory, on occasion they favoured surgery, and on other occasions chemotherapy, but in general there were no statistical differences between the treatments. The studies were heterogeneous, with different methodology, undersized, limitations in quality with high risk of bias and use of different measurement scales. Conclusions: There are not enough studies of quality to establish differences in the quality of life in patients with advanced laryngeal cancer according to the treatment received (AU)

Treatment of advanced laryngeal cancer and quality of life. Systematic review. / Tratamiento del cáncer de laringe avanzado y calidad de vida. Revisión sistemática.

INTRODUCTION AND OBJECTIVES: The objective was the comparison of the quality of life in patients with advanced laryngeal cancer treated with organ preservation versus surgical treatment. METHODS: We performed a systematic review in the databases MedLine, EMBASE, and PubMed (2014 1991) and Web of Science (2012 - 2014). The search terms were: Laryngeal cancer, organ preservation, chemotherapy, laryngectomy, treatment outcomes and quality of life. Systematic reviews, meta-analysis, reports of health technology assessment and comparative studies with control group, published in Spanish, French or English were included. The selection and quality assessment was made by two researchers. The criteria of the Cochrane Collaboration were used to assess the risk of bias and Scottish Intercollegiate Guidelines Network (SIGN) for the level of evidence. RESULTS: Of the 208 studies identified in the search, three were included a clinical trial and two observational studies, with a total of 211 patients. Quality and level of evidence was low. The results were contradictory, on occasion they favoured surgery, and on other occasions chemotherapy, but in general there were no statistical differences between the treatments. The studies were heterogeneous, with different methodology, undersized, limitations in quality with high risk of bias and use of different measurement scales. CONCLUSIONS: There are not enough studies of quality to establish differences in the quality of life in patients with advanced laryngeal cancer according to the treatment received.

[Methodological guideline for the efficacy and safety assessment of new pharmaceuticals: implementation of EUnetHTA's recommendations]. / Guía metodológica para la evaluación de la eficacia y la seguridad de nuevos fármacos: implementación de las recomendaciones de EUnetHTA.

The European network for Health Technology Assessment (EUnetHTA) is the network of public health technology assessment (HTA) agencies and entities from across the EU. In this context, the HTA Core Model®, has been developed. The Andalusian Agency for Health Technology Assessment (AETSA) is a member of the Spanish HTA Network and EUnetHTA collaboration In addition, AETSA participates in the new EUnetHTA Joint Action 3 (JA, 2016-2019). Furthermore, AETSA works on pharmaceutical assessments. Part of this work involves drafting therapeutic positioning reports (TPRs) on drugs that have recently been granted marketing authorisation, which is overseen by the Spanish Agency of Medicines and Medical Devices (AEMPS). AETSA contributes by drafting "Evidence synthesis reports: pharmaceuticals" in which a rapid comparative efficacy and safety assessment is performed for drugs for which a TPR will be created. To create this type of report, AETSA follows its own methodological guideline based on EUnetHTA guidelines and the HTA Core Model®. In this paper, the methodology that AETSA has developed to create the guideline for "Evidence synthesis reports: pharmaceuticals" is described. The structure of the report itself is also presented.

Grado de control de la anticoagulación en pacientes con fibrilación auricular en España: necesidad de minimizar sesgos y contextualizar resultados / Degree of anticoagulation control in patients with atrial fibrillation in Spain: need to minimize biases and contextualize results

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Interplay between iron homeostasis and the osmotic stress response in the halophilic bacterium Chromohalobacter salexigens.

In this study, the connection between iron homeostasis and the osmostress response in the halophile Chromohalobacter salexigens was investigated. A decrease in the requirement for both iron and histidine and a lower level of siderophore synthesis were observed at high salinity, and these findings were correlated with a lower protein content in salt-stressed cells. A six-gene operon (cfuABC-fur-hisI-orf6 operon) located downstream of the ectABC ectoine synthesis genes was characterized. A fur strain (in which the ferric iron uptake regulator Fur was affected) had the Mn resistance phenotype typical of fur mutants, was deregulated for siderophore production, and displayed delayed growth under iron limitation conditions, indicating that fur encodes a functional iron regulator. hisI was essential for histidine synthesis, which in turn was necessary for siderophore production. Fur boxes were found in the promoters of the cfuABC-fur-hisI-orf6 and ectABC operons, suggesting that Fur directly interacts with DNA in these regions. Fur mediated the osmoregulated inhibition of cfuABC-fur-hisI-orf6 operon expression by iron and functioned as a positive regulator of the ectABC genes under high-salinity conditions, linking the salt stress response with iron homeostasis. Excess iron led to a higher cytoplasmic hydroxyectoine content, suggesting that hydroxyectoine protects against the oxidative stress caused by iron better than ectoine. This study provides the first evidence of involvement of the iron homeostasis regulator Fur as part of the complex circuit that controls the response to osmotic stress in halophilic bacteria.

Calidad de las recomendaciones farmacoterapéuticas de los procesos asistenciales integrados en Andalucía / Quality of the pharmacotherapeutic recommendations for the integrated care procedures in Andalusia

Objetivos: Evaluar, a través del diseño y la validación de una herramienta, la calidad de las recomendaciones farmacoterapéuticas incluidas en los Procesos Asistenciales Integrados (PAI) de la Consejería de Salud de la Junta de Andalucía, publicados hasta marzo de 2008. Métodos: La herramienta de evaluación se diseñó a partir de instrumentos similares, fundamentalmente el Appraisal of Guidelines for Research and Evaluation. Otros criterios incluidos provenían de diversas fuentes bibliográficas o fueron de elaboración propia. Previamente a su utilización, la herramienta fue validada. Tras la aplicación a todos los PAI, se analizó el grado de cumplimiento de estos criterios farmacoterapéuticos globalmente y por subgrupos de PAI. Resultados: La herramienta elaborada consiste en un cuestionario de 20 ítems dividido en 4 bloques. El primer bloque corresponde a criterios esenciales, el resto hace referencia a criterios más específicos y considerados no esenciales: definición del nivel de evidencia, exhaustividad de la información y definición de indicadores. De los 60 PAI, 4 no contienen ningún tipo de recomendación terapéutica. Ningún PAI cumple el total de ítems recogidos en la herramienta; no obstante, un 70 % de ellos cumple los criterios esenciales de calidad establecidos. Conclusiones: Hay una gran variabilidad en cuanto al contenido de recomendaciones farmacoterapéuticas de cada PAI. Una vez demostrada la validez de la herramienta diseñada, podría utilizarse para valorar la calidad de las recomendaciones terapéuticas en guías de práctica clínica (AU)

Objectives: To evaluate the quality of the pharmacotherapeutic recommendations included in the Integrated Care Procedures (PAIs regarding its initials in Spanish) of the Andalusian Ministry of Health, published up to March 2008, through the design and validation of a tool. Methods: The assessment tool was designed based on similar instruments, specifically the AGREE. Other criteria included were taken from various literature sources or were devised by ourselves. The tool was validated prior to being used. After applying it to all the PAIs, we examined the degree of compliance with these pharmacotherapeutic criteria, both as a whole and by PAIs subgroups. Results: The developed tool is a questionnaire of 20 items, divided into 4 sections. The first section consists of the essential criteria, and the rest make reference to more specific, non essential criteria: definition of the level of evidence, thoroughness of information and definition of indicators. It was found that 4 of the 60 PAIs do not contain any type of therapeutic recommendation. No PAI fulfils all the items listed in the tool, however, 70 % of them fulfil the essential quality criteria established. Conclusions: There is a great variability in the content of pharmacotherapeutic recommendations for each PAI. Once the validity of the tool has been proved, it could be used to assess the quality of the therapeutic recommendations in clinical practice guidelines (AU)

The ectD gene, which is involved in the synthesis of the compatible solute hydroxyectoine, is essential for thermoprotection of the halophilic bacterium Chromohalobacter salexigens.

The halophilic bacterium Chromohalobacter salexigens synthesizes and accumulates compatible solutes in response to salt and temperature stress. (13)C-nuclear magnetic resonance analysis of cells grown in minimal medium at the limiting temperature of 45 degrees C revealed the presence of hydroxyectoine, ectoine, glutamate, trehalose (not present in cells grown at 37 degrees C), and the ectoine precursor, Ngamma-acetyldiaminobutyric acid. High-performance liquid chromatography analyses showed that the levels of ectoine and hydroxyectoine were maximal during the stationary phase of growth. Accumulation of hydroxyectoine was up-regulated by salinity and temperature, whereas accumulation of ectoine was up-regulated by salinity and down-regulated by temperature. The ectD gene, which is involved in the conversion of ectoine to hydroxyectoine, was isolated as part of a DNA region that also contains a gene whose product belongs to the AraC-XylS family of transcriptional activators. Orthologs of ectD were found within the sequenced genomes of members of the proteobacteria, firmicutes, and actinobacteria, and their products were grouped into the ectoine hydroxylase subfamily, which was shown to belong to the superfamily of Fe(II)- and 2-oxoglutarate-dependent oxygenases. Analysis of the ectoine and hydroxyectoine contents of an ectABC ectD mutant strain fed with 1 mM ectoine or hydroxyectoine demonstrated that ectD is required for the main ectoine hydroxylase activity in C. salexigens. Although in minimal medium at 37 degrees C the wild-type strain grew with 0.5 to 3.0 M NaCl, with optimal growth at 1.5 M NaCl, at 45 degrees C it could not cope with the lowest (0.75 M NaCl) or the highest (3.0 M NaCl) salinity, and it grew optimally at 2.5 M NaCl. The ectD mutation caused a growth defect at 45 degrees C in minimal medium with 1.5 to 2.5 M NaCl, but it did not affect growth at 37 degrees C at any salinity tested. With 2.5 M NaCl, the ectD mutant synthesized 38% (at 37 degrees C) and 15% (at 45 degrees C) of the hydroxyectoine produced by the wild-type strain. All of these data reveal that hydroxyectoine synthesis mediated by the ectD gene is thermoregulated and essential for thermoprotection of C. salexigens.

Osmoprotection of Salmonella enterica serovar Typhimurium by Ngamma-acetyldiaminobutyrate, the precursor of the compatible solute ectoine.

N(gamma)-acetyl-2,4-diaminobutyrate (NADA), the precursor of the compatible solute ectoine, was shown to function as an osmoprotectant for the non-halophilic bacterium Salmonella enterica serovar Typhimurium. The addition of NADA-containing extracts of an ectoine synthase mutant of the broad salt-growing halophile Chromohalobacter salexigens DSM 3043(T) could alleviate the inhibitory effects of high salinity in S. enterica, which lacks the ectoine biosynthetic pathway. NADA, purified from extracts of the mutant, protected S. enterica against salinity stress. This osmoprotective effect was slightly lower than that of ectoine, but more potent than that of hydroxyectoine. Accumulation of purified NADA by S. enterica was demonstrated by (13)C-NMR spectroscopy and HPLC analysis. In addition, it was shown that NADA was taken up by S. enterica via the ProP and ProU transport systems, which are known to transport glycine betaine and proline. This finding provides evidence that these permeases can recognize a diaminoacid that carries an unsubstituted alpha-amino group. This is the first time that NADA has been connected with osmoprotective functions in non-halophilic bacteria.