How innovation can be defined, evaluated and rewarded in health technology assessment

This study has received support from researchproject PID2019.105597RA.I00 financed by the Spanish Ministry of Science and Innovation/National Research Agency MCIN/AEI/10.13039/501100011033. The funders had no role in the study.Background: What constitutes innovation in health technologies can be defined and measured in a number of ways and it has been widely researched and published about. However, while many countries mention it as a criterion for pricing or reimbursement of health technologies, countries differ widely in how they define and operationalise it. Methods: We performed a literature review, using a snowballing search. In this paper, we explore how innovation has been defined in the literature in relation to health technology assessment. We also describe how a selection of countries (England, France, Italy, Spain and Japan) take account of innovation in their health technology assessment frameworks and explore the key methodologies that can capture it as a dimension of value in a new health technology. We propose a way of coming to, and incorporating into health technology assessment systems, a definition of innovation for health technologies that is independent of other dimensions of value that they already account for in their systems, such as clinical benefit. We use Spain as an illustrative example of how innovation might be operationalised as a criterion for decision making in health technology assessment. Results: The countries analysed here can be divided into 2 groups with respect to how they define innovation. France, Japan and Italy use features such as severity, unmet need and therapeutic added value as indicators of the degree of innovation of a health technology, while England, Spain consider the degree of innovation as a separate and additional criterion from others. In the case of Spain, a notion of innovation might be constructed around concepts of `step-change’, `convenience’, `strength of evidence base’ and `impact on future research & development’. Conclusions: If innovation is to be used as operational criteria for adoption, pricing and reimbursement of health technologies, the concept must be clearly defined, and it ought to be independent from other value dimensions already captured in their health technology assessment systems.Spanish Ministry of Science and Innovation/National Research Agency PID2019.105597RA.I00MCIN/AEI/10.13039/50110001103

Patterns of ROS Accumulation in the Stigmas of Angiosperms and Visions into Their Multi-Functionality in Plant Reproduction

Accumulation of reactive oxygen species (ROS) in the stigma of several plant species has been investigated. Four developmental stages (unopened flower buds, recently opened flowers, dehiscent anthers, and flowers after fertilization) were analyzed by confocal laser scanning microscopy using the ROS-specific probe DCFH2-DA. In all plants scrutinized, the presence of ROS in the stigmas was detected at higher levels during those developmental phases considered “receptive” to pollen interaction. In addition, these molecules were also present at early (unopened flower) or later (post-fertilization) stages, by following differential patterns depending on the different species. The biological significance of the presence ROS may differ between these stages, including defense functions, signaling and senescence. Pollen-stigma signaling is likely involved in the different mechanisms of self-incompatibility in these plants. The study also register a general decrease in the presence of ROS in the stigmas upon pollination, when NO is supposedly produced in an active manner by pollen grains. Finally, the distribution of ROS in primitive Angiosperms of the genus Magnolia was determined. The production of such chemical species in these plants was several orders of magnitude higher than in the remaining species evoking a massive displacement toward the defense function. This might indicate that signaling functions of ROS/NO in the stigma evolved later, as fine tune likely involved in specialized interactions like self-incompatibility.This study was supported by the following European Regional Development Fund co-financed grants: MCINN BFU2011-22779, RTC-2015-4181-2, CSIC-201540E065, CICE (Junta de Andalucía) P2010-CVI15767, P2010-AGR6274, P2011-CVI-7487, and the MINECO/CSIC agreement RECUPERA 2020.Peer reviewedPeer Reviewe

Pricing and reimbursement mechanisms for advanced therapy medicinal products in 20 countries

Introduction: Advanced Therapy Medicinal Products are a type of therapies that, in some cases, hold great potential for patients without an effective current therapeutic approach but they also present multiple challenges to payers. While there are many theoretical papers on pricing and reimbursement (P&R) options, original empirical research is very scarce. This paper aims to provide a comprehensive international review of regulatory and P&R decisions taken for all ATMPs with centralized European marketing authorization in March 2022. Methods: A survey was distributed in July 2022 to representatives of 46 countries. Results: Responses were received from 20 countries out of 46 (43.5%). 14 countries reimbursed at least one ATMP. Six countries in this survey reimbursed no ATMPs. Conclusion: Access to ATMPs is uneven across the countries included in this study. This arises from regulatory differences, commercial decisions by marketing authorization holders, and the divergent assessment processes and criteria applied by payers. Moving towards greater equality of access will require cooperation between countries and stakeholders, for example, through the WHO Regional Office for Europe’s Access to Novel Medicines Platform.Project PID 2019.105597RA.I00 financed by the Spanish Ministry of Science and Innovation/National Research Agency MCIN/AEI/10.13039/ 50110001103

Análisis del proteoma del exudado estigmático

Comunicaciones a congreso

Synthesis and in vitro antiprotozoal activity of some 2- amino-4-phenyloxazole derivatives

Purpose: To prepare some 2-amino-4-(p-substituted phenyl)-oxazole derivatives and to evaluate their in vitro antiprotozoal activity against Giardia lamblia and Trichomonas vaginalis.Methods: The 2-amino-4-(p-substituted phenyl)-oxazoles (a-g) were synthesized by microwave (MW) irradiation of mixtures of p-substituted 2-bromoacetophenones and urea in dimethylformamide (DMF). All compounds were identified by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy and lowand high-resolution mass spectrometry (HRMS). NMR assignments were made based on heteronuclear single quantum coherence (HSQC) and heteronuclear multiple bond correlation (HMBC) experiments. Each synthesized compound’s melting point was determined. Antiprotozoal activity against Giardia intestinalis and Trichomonas vaginalis was quantified using a rigorous and sensitive subculture method. The commercial drug, metronidazole, was used as positive control. The 50 % inhibitory concentration (IC50) of the antiprotozoal agents for each protozoa was determined.Results: Seven 2-amino-4-(p-substituted phenyl)-oxazoles (a-g) were synthesized. The most active compounds against G. lamblia was 2-amino-4-(p-benzoyloxyphenyl)-oxazole (3d) with an IC50 of 1.17 μM, while compound 3e (2-amino-4-(p-bromophenyl)-oxazole) showed the highest anti-trichomonal activity (IC50, 1.89 μM).Conclusion: The in vitro antigiardial activity of 2-amino-4-(p-benzoyloxyphenyl) oxazole was higher than that exhibited by metronidazole; however, it is necessary increase the number of synthetic derivatives in order to be able to determine their structure-activity relationship.Keywords: Antiprotozoal, 2-Amino-4-phenyl-oxazoles, Giardia lamblia, Trichomonas vaginali

In search of an evidence-based strategy for quality assessment of human tissue samples: report of the tissue Biospecimen Research Working Group of the Spanish Biobank Network

The purpose of the present work is to underline the importance of obtaining a standardized procedure to ensure and evaluate both clinical and research usability of human tissue samples. The study, which was carried out by the Biospecimen Science Working Group of the Spanish Biobank Network, is based on a general overview of the current situation about quality assurance in human tissue biospecimens. It was conducted an exhaustive review of the analytical techniques used to evaluate the quality of human tissue samples over the past 30 years, as well as their reference values if they were published, and classified them according to the biomolecules evaluated: (i) DNA, (ii) RNA, and (iii) soluble or/and fixed proteins for immunochemistry. More than 130 publications released between 1989 and 2019 were analysed, most of them reporting results focused on the analysis of tumour and biopsy samples. A quality assessment proposal with an algorithm has been developed for both frozen tissue samples and formalin-fixed paraffin-embedded (FFPE) samples, according to the expected quality of sample based on the available pre-analytical information and the experience of the participants in the Working Group. The high heterogeneity of human tissue samples and the wide number of pre-analytic factors associated to quality of samples makes it very difficult to harmonize the quality criteria. However, the proposed method to assess human tissue sample integrity and antigenicity will not only help to evaluate whether stored human tissue samples fit for the purpose of biomarker development, but will also allow to perform further studies, such as assessing the impact of different pre-analytical factors on very well characterized samples or evaluating the readjustment of tissue sample collection, processing and storing procedures. By ensuring the quality of the samples used on research, the reproducibility of scientific results will be guaranteed.This work was funded by the Ministerio de Ciencia, Innovacion y Universidades of Spain and Instituto de Salud Carlos III (PI16/00528, PI16/00946, PI16/01207 and PI16/01276), co-funded by the Spanish Biobank Network (PT13/0010/0030, PT17/0015/0001, PT17/0015/0021, PT17/0015/0049, PT17/0015/0018, PT17/0015/0002, PT17/0015/0016, PT17/0015/0038, PT17/0015/0027, PT17/0015/0004, PT17/0015/0047, PT17/0015/0014, PT17/0015/0041, and PT17/0015/0006), European Regional Development Fund (FEDER) "A way to make Europe" and granted by Conselleria d'Innovacio, Recerca i Turisme del Govern de les Illes Balears (TEC/002/2017).S

Biología reproductiva del olivo (BRO-EEZ-CSIC)

Trabajo presentado a las III Jornadas Nacionales del grupo de Horticultura de la SECH, celebradas en Sevilla el 6 y 7 de octubre de 2011.Peer reviewe

Microscopy to study plant sexual reproduction

This work has been supported by numerous research projects. Currently active projects include EFDF confunded grants BFU2011-22779 (Ministerio de Economía y Competitividad), P2010-CVI5767, P2010-AGR6274 and P2011-CVI7487 (Junta de Andalucía), and PEOPLE-PIOF-GA-2011-301550 (European Research Council)Peer reviewe

Proyecto FIDO: La Educación STEAM en las aulas del Grado de Educación Primaria. (ESTeam)

Este proyecto persigue el objetivo principal de introducir la educación STEAM en el alumnado de Educación Primaria. La educación STEAM supone un enfoque en el cual se trabajan conjuntamente Ciencias, Tecnología, Ingeniería, Arte y Matemáticas. Los trabajos del futuro cada vez están más unidos a la tecnología. Además, tienen una visión holística donde las distintas disciplinas tienen un aporte que encaja como un engranaje. La metodología usada en este proyecto es el Aprendizaje Basado en Proyectos (ABP) (Barrows, 1986). En este tipo de aprendizaje el alumno tiene un rol activo y el docente lo guía. Además, en el proyecto inicial se propuso conformar un “MakerSpace”. En este sentido, hay que indicar que nos tuvimos que adaptar a las condiciones impuestas con la pandemia del COVID-19 y procedimos como explicaremos a continuación. Este proyecto implementó en la asignatura de Ciencias Experimentales y su Transversalidad (CET en adelante). Se dedicaron varios seminarios al desarrollo de las actividades propuestas. Cuando se hizo la propuesta del proyecto, no se conocía cómo iba a ser la actividad docente debido a la situación sanitaria derivada del Covid-19, así que se pensó en presencial. Como esto no fue posible, el desarrollo de la primera actividad introductoria fue la siguiente: El profesor Rafael Gómez desarrolló una actividad (Escapada del planeta Gorogoa, reconstruyendo nuestro robot Joan Carlo, (ANEXO Ia y Ib donde se adjuntan guión y vídeos) donde el alumnado tenía que usar un robot tipo Mbot para desarrollar la actividad. El alumnado entregó un pequeño informe donde mostraba cómo había desarrollado esta tarea. Además, se invitaron a dos profesores que dieron dos charlas por videoconferencia. La primera conferencia llamada “El enfoque educativo STEM: un gran desconocido en boca de todos” (presentación en ANEXO IIa) la realizó el profesor experto en STEAM David Aguilera Morales, coautor, junto con F. Javier Perales Palacios, del artículo “Ciencia-Tecnología-Sociedad vs. STEM: ¿evolución, revolución o disyunción? “ (Perales Palacios y Aguilera, 2020). En esta charla el alumnado pudo conocer qué es STEAM e interactuar con el conferenciante. La segunda charla impartida fue “Docencia en STEAMs: Mi experiencia como ingeniera y profesora de ingeniería”, por la profesora de la Escuela de Informática y Telecomunicaciones de la Universidad de Granada Luz García Martínez (Presentación en ANEXO IIb). La segunda actividad que tuvieron que realizar los alumnos fue la elaboración de un proyecto con enfoque STEAM. Para ello se les dieron unas directrices (se adjunta guion en ANEXO III) y se les ofrecieron dos tipos de kits de robótica educativa: Makey Makey y Microbit. (Inicialmente en el presupuesto se incluía una partida para conferenciantes invitados y pósteres. Al pasar la docencia a virtual, este dinero se gastó en más material, para que el alumnado se lo pudiera llevar a casa y pudieran trabajar en grupos más pequeños, intentando así facilitar el trabajo online del alumnado). Como producto, cada grupo entregó un informe de su proyecto e hizo una presentación virtual del mismo. This project pursues the main objective of introducing STEAM education in Primary Education students. STEAM education is an approach in which Science, Technology, Engineering, Art and Mathematics work together. The jobs of the future are increasingly linked to technology. In addition, they have a holistic vision where the different disciplines have a contribution that fits like a gear. The methodology used in this project is Project Based Learning (PBL) (Barrows, 1986). In this type of learning the student has an active role and the teacher guides him/her. In addition, in the initial project it was proposed to create a “MakerSpace”. In this sense, it should be noted that we had to adapt to the conditions imposed with the COVID-19 pandemic and we proceeded as we will explain below. This project was implemented in the subject of Experimental Sciences and its Transversality (CET). Several seminars were devoted to the development of the proposed activities. When the project proposal was made, it was not known what the teaching activity was going to be like, so it was thought in person. As this was not possible, the development of the first introductory activity was as follows: Professor Rafael Gómez developed an activity (Getaway from the planet Gorogoa, rebuilding our Joan Carlo robot, (ANNEX Ia and Ib where script and videos are attached) where the students had to use an Mbot-type robot to develop the activity. The students gave a small report showing how they had developed this task. In addition, two teachers were invited to give two talks by videoconference. The first conference called "The STEM educational approach: a great unknown on everyone's lips" (presentation in ANNEX IIa) was held the expert professor in STEAM David Aguilera Morales, co-author, together with F. Javier Perales Palacios, of the article “Science-Technology-Society vs. STEM: evolution, revolution or disjunction?” (Perales Palacios and Aguilera, 2020). The second talk given was "Teaching in STEAMs: My experience as an engineer and engineering teacher", by the Professor at the School of Informatics and Telecommunications of the University of Granada Luz García Martínez (Presentation in ANNEX IIb). The second activity, that the students had to carry out, was the elaboration of a project with a STEAM approach. For this, they were given guidelines (script is attached in ANNEX III) and two types of educational robotics kits were offered: Makey Makey and Microbit. (Initially, the budget included an item for invited speakers and posters. When teaching went virtual, this money was spent on more material, so that students could take it home and they could work in smaller groups, thus trying to facilitate students' online work). As a product, each group delivered a report on their project and made a virtual presentation of it.Universidad de Granad

Improved clinical investigation and evaluation of high-risk medical devices: the rationale and objectives of CORE-MD (Coordinating Research and Evidence for Medical Devices)

: In the European Union (EU) the delivery of health services is a national responsibility but there are concerted actions between member states to protect public health. Approval of pharmaceutical products is the responsibility of the European Medicines Agency, whereas authorizing the placing on the market of medical devices is decentralized to independent 'conformity assessment' organizations called notified bodies. The first legal basis for an EU system of evaluating medical devices and approving their market access was the medical device directives, from the 1990s. Uncertainties about clinical evidence requirements, among other reasons, led to the EU Medical Device Regulation (2017/745) that has applied since May 2021. It provides general principles for clinical investigations but few methodological details-which challenges responsible authorities to set appropriate balances between regulation and innovation, pre- and post-market studies, and clinical trials and real-world evidence. Scientific experts should advise on methods and standards for assessing and approving new high-risk devices, and safety, efficacy, and transparency of evidence should be paramount. The European Commission recently awarded a Horizon 2020 grant to a consortium led by the European Society of Cardiology and the European Federation of National Associations of Orthopaedics and Traumatology, that will review methodologies of clinical investigations, advise on study designs, and develop recommendations for aggregating clinical data from registries and other real-world sources. The CORE-MD project (Coordinating Research and Evidence for Medical Devices) will run until March 2024; here we describe how it may contribute to the development of regulatory science in Europe