The Early Preclinical Development Program for Locally Administered Investigational Medicinal Products in Ophthalmology: Preclinical Data Required for Starting a First-in-Human Clinical Trial in Europe-Basic Considerations and 2 Case Studies.

BACKGROUND: Although regulatory guidance defines which preclinical data are required in general before proceeding to first-in-human clinical trials, a certain level of flexibility exists in the actual planning, timing, and design of a drug development program. Developing an ophthalmic medicinal product adds additional challenges, since the eye is a complex organ with unique features and specialized ophthalmic guidance documents are sparse. METHODS: We analyzed the preclinical guidelines with a focus on European Union legislation and guidance documents provided by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). We elaborated the particularities specific to ophthalmic drug developments and deduced the preclinical knowledge needed to safely enter a first-in-human trial program. Two hypothetical medicinal products for ophthalmic indications were chosen and specificities for ophthalmic preclinical tests were elaborated. RESULTS AND CONCLUSION: We conclude that the preclinical program of ophthalmic medicines is flexible and differs, based on the intended use and the nature of the active substance.

The healthcare system and the provision of oral healthcare in European Union member states. Part 9: Sweden.

Equally accessible and affordable dental services for all population groups have been a political goal in Sweden for almost a century. All political parties have shared the idea that a person's social background should not have consequences for his or her dental status. Strategic tools to achieve this ambitious goal have been the wide use of publicly provided oral healthcare services, covering even sparsely populated areas, focusing on preventive care and significant subsidies for necessary treatments. Besides free care for children and young adults, oral healthcare is reimbursed from public funds. The public subsidy was particularly generous in 1975-1999 when a 'full clearance' of adults' dentitions was undertaken both by the public and private providers under fixed prices and high reimbursement levels for all treatment measures. Today, preventive oral healthcare for the elderly is given higher priority as most Swedes have been able to keep their natural teeth.

The healthcare system and the provision of oral healthcare in European Union member states. Part 8: Italy.

In Italy healthcare is provided for all Italian citizens and residents and it is delivered mainly by public providers, with some private or private-public entities. Italy's public healthcare system - the Servizio Sanitario Nazionale (SSN) - is organised by the Ministry of Health and administered on a devolved regional basis. It is financed by general taxation that provides universal coverage, largely free of charge at the point of service. The central government establishes the basic national health benefits package, which must be uniformly provided throughout the country, through services guaranteed under the NHS provision called LEA - (Livelli Essenziali di Assistenza [Essential Level of Assistance]) and allocates national funds to the regions. The regions, through their regional health departments, are responsible for organising, administering and delivering primary, secondary and tertiary healthcare services as well as preventive and health promotion services. Regions are allowed a large degree of autonomy in how they perform this role and regarding decisions about the local structure of the system. Complementary and supplementary private health insurance is also available. However, as in most other Mediterranean European countries, in Italy oral healthcare is mainly provided under private arrangements. The public healthcare system provides only 5-8% of oral healthcare services and this percentage varies from region to region. Oral healthcare is included in the Legislation on Essential levels of care (LEAs) for specific populations such as children, vulnerable people (medically compromised and those on low income) and individuals who need oral healthcare in some urgent/emergency cases. For other people, oral healthcare is generally not covered. Apart from the national benefits package, regions may also carry out their own initiatives autonomously, but must finance these themselves. The number of dentists working in Italy has grown rapidly in the last few years. In December 2014, there were 59,324 practicing dentists with a ratio of one dentist every 1025 inhabitants, about 90,000 dental chair-side assistants, about 26,000 dental technicians and about 4000 dental hygienists. To enrol in an Italian dental school a student must pass a competitive national entrance examination after obtaining a high school leaving certificate. For entry in the 2015-2016 cycle, there were 792 places for dentistry. In comparison with dental schools in other EU member states, the number of dental students per school is low with an average of 20 students per year, per school and a range of 10 to 60. The aims of this paper are to give a brief description of the organisation of healthcare in Italy, to outline the system for the provision of oral healthcare in Italy and to explain and discuss the latest changes.

Assessing herbal products with health claims.

Herbs, herbal extracts, or phytochemicals are broadly used as foods, drugs, and as traditional medicines. These are well regulated in Europe, with thorough controls on both safety and efficacy or validity of health claims. However, the distinction between medicines and foods with health claims is not always clear. In addition, there are several cases of herbal products that claim benefits that are not scientifically demonstrated. This review details the European Union (EU) legislative framework that regulates the approval and marketing of herbal products bearing health claims as well as the scientific evidence that is needed to support such claims. To illustrate the latter, we focus on phytoecdysteroid (PE)-containing preparations, generally sold to sportsmen and bodybuilders. We review the limited published scientific evidence that supports claims for these products in humans. In addition, we model the in silico binding between different PEs and human nuclear receptors and discuss the implications of these putative bindings in terms of the mechanism of action of this family of compounds. We call for additional research to validate the safety and health-promoting properties of PEs and other herbal compounds, for the benefit of all consumers.

Evolution of European Union legislation of herbal medicinal products and its transposition to national legislation in 1965-2007: case Finland.

OBJECTIVES: The study aim was to explore the progress of legislation relating to herbal medicinal products in the European Union and compare it with the corresponding progress of the legislation in Finland in 1965-2007. METHODS: The study was carried out using content analysis. Data were searched from publicly available European Union directives and national acts. All definitions and safety-related requirements for herbal medicinal products were identified. The transposition of safety-related requirements into the national legislation was studied. RESULTS: Medicinal products from plant origins have been part of the European Union legislation since 1965. Most plant-based products have not initially been regarded as medicinal products but rather as some kind of medicine-like products. The official definition of herbal medicinal products was introduced in Directive 2004/24/EC and implemented into the Finnish legislation with the terminology to recognise herbal medicinal products as part of medicinal products. The current safety-related requirements of medicinal products concern analogously herbal medicinal products. CONCLUSIONS: Herbal medicinal products have had different definitions in pharmaceutical legislation over the study period in the European Union and Finland. The current definition places herbal medicinal products more clearly under the medicinal products' legislation. Safety-related requirements are now practically identical for all medicinal products. Transposition of the European Union legislation into the national legislation in Finland is apparent.

δ 18O of ethanol in wine and spirits for authentication purposes.

Since 1986 the European Union has established official isotopic analysis methods for detecting the illegal addition of sugar and water to wine and to enable geographical traceability. In this paper we investigate the possibility of using analysis of the 18O/16O stable isotope ratio (expressed as δ 18O) of ethanol to improve detection of the watering of wine and to determine the origin of ethanol. Sixty-nine authentic wine samples from all over Italy, 59 spirits from fruit and cereals, 5 chemically synthesized ethanols, one concentrated and rectified must, one beet and one cane sugar, one fresh must, and 6 waters with increasing δ 18O values were considered. Ethanol was recovered by distillation, using a Cadiot spinning band column, following the official OIV methods. The residual water was trapped by storing the distillate for at least 24 h on a molecular sieve. The 18O/16O ratio was measured using a pyrolyser interfaced with an isotope ratio mass spectrometer. The δ (-18)O of ethanol is significantly related to the δ 18O of the fermentation water and can be considered as a reliable internal reference. The values ranged from +24‰ to +36‰ in wine (years 2008 to 2012), +10‰ to +26‰ in fruit and cereal distillates, and from -2‰ to +12‰ in synthetic ethanol. The method was shown to be effective in improving detection of the watering of wine and determining the origin of ethanol (from grapes, other fruit, or synthesis), but not in detecting the addition of cane or beet sugar to wine.

Oceans and Human Health (OHH): a European perspective from the Marine Board of the European Science Foundation (Marine Board-ESF).

The oceans and coastal seas provide mankind with many benefits including food for around a third of the global population, the air that we breathe and our climate system which enables habitation of much of the planet. However, the converse is that generation of natural events (such as hurricanes, severe storms and tsunamis) can have devastating impacts on coastal populations, while pollution of the seas by pathogens and toxic waste can cause illness and death in humans and animals. Harmful effects from biogenic toxins produced by algal blooms (HABs) and from the pathogens associated with microbial pollution are also a health hazard in seafood and from direct contact with water. The overall global burden of human disease caused by sewage pollution of coastal waters has been estimated at 4 million lost person-years annually. Finally, the impacts of all of these issues will be exacerbated by climate change. A holistic systems approach is needed. It must consider whole ecosystems, and their sustainability, such as integrated coastal zone management, is necessary to address the highly interconnected scientific challenges of increased human population pressure, pollution and over-exploitation of food (and other) resources as drivers of adverse ecological, social and economic impacts. There is also an urgent and critical requirement for effective and integrated public health solutions to be developed through the formulation of politically and environmentally meaningful policies. The research community required to address "Oceans & Human Health" in Europe is currently very fragmented, and recognition by policy makers of some of the problems, outlined in the list of challenges above, is limited. Nevertheless, relevant key policy issues for governments worldwide include the reduction of the burden of disease (including the early detection of emerging pathogens and other threats) and improving the quality of the global environment. Failure to effectively address these issues will impact adversely on efforts to alleviate poverty, sustain the availability of environmental goods and services and improve health and social and economic stability; and thus, will impinge on many policy decisions, both nationally and internationally. Knowledge exchange (KE) will be a key element of any ensuing research. KE will facilitate the integration of biological, medical, epidemiological, social and economic disciplines, as well as the emergence of synergies between seemingly unconnected areas of science and socio-economic issues, and will help to leverage knowledge transfer across the European Union (EU) and beyond. An integrated interdisciplinary systems approach is an effective way to bring together the appropriate groups of scientists, social scientists, economists, industry and other stakeholders with the policy formulators in order to address the complexities of interfacial problems in the area of environment and human health. The Marine Board of the European Science Foundation Working Group on "Oceans and Human Health" has been charged with developing a position paper on this topic with a view to identifying the scientific, social and economic challenges and making recommendations to the EU on policy-relevant research and development activities in this arena. This paper includes the background to health-related issues linked to the coastal environment and highlights the main arguments for an ecosystem-based whole systems approach.

[Interpretation of Guidelines on Good Pharmacovigilance Practices for European Union].

Due to the limitations of pre-authorization clinical trials, the safety information obtained from them is relatively limited. Therefore, it is very necessary to carry out pharmacovigilance activities on drugs post-marketing. In order to promote the specific implementation of the new pharmacovigilance regulations, the European medicines agency (EMA) developed the Guideline on Good Pharmacovigilance Practices (GVP), as the new criteria for pharmacovigilance in the European Union (EU). Compared with the previously published, Guidelines on Pharmacovigilance for Medicinal Products for Human Use (2007), the GVP proposed more comprehensive and systematic provisions of pharmacovigilance systems, quality control systems, judgements, pharmacovigilance inspections and audits. In addition, it set more specific and comprehensive requirements on risk management systems, the management and reporting of adverse reactions to medicinal products, periodic safety update reports, post-authorization safety studies, signal management, and so on. Interpreting the basic principles, working mechanisms, key technologies and methods of the GVP provides a useful reference for us to carry out pharmacovigilance (especially regarding safety monitoring of parenterally administered Chinese medicine).

[Dissection of differences and similarities of botanical drugs in European Union, US and Canada].

Because of the unique nature and treatment concept of traditional Chinese medicines (TCMs), TCMs have been respected again since 70s of last century. The regulatory agencies of some developed countries (the FDA, EMA and Health Canada etc) have published new guidance/guidelines/directives in recent years, such as the botanical drug product guidance of the FDA, the evidence for quality of finished natural health products guidance of the Health Canada and the guideline on quality of herbal medicinal products/ traditional herbal medicinal products of the EMA etc. All of the regulatory agencies are willing to scientifically evaluate the herbal medicines and accept it as therapeutic product. This paper analyzed the history of herbal medicine regulation and the similarities and differences of the regulatory requirements of the European Union, the United States and Canada, proposed possible future direction of the international development of Chinese medicine from the perspective of global regulatory affairs.

The impact of European Union law on public health.

The previous articles on the European Union and health law have looked at the effect of EU law on the practitioner and on the patient. This article considers the impact on public health. This is a broad concept, and the impact of EU law is equally broadly felt. There is a general recognition of the importance of health issues, reflected in Article 152 (1) EC, A high level of human health protection shall be ensured in the definition and implementation of all Community policies and activities. This article focuses particularly on the impact of Article 152 on public health within individual member states.

[The regulatory framework for complementary and alternative medicines in Europe]. / Europäische Gesetzgebung zu besonderen Therapierichtungen.

Medicinal products from complementary and alternative medicine are in Germany a regular part of the health care system. Herbal, homeopathic, anthroposophic and traditional medicinal products are highly accepted by the population. The German Medicines Act obliged the competent authorities to consider the particular characteristics of complementary and alternative medicines. The European regulatory framework defined the status of herbal medicinal products, traditional herbal medicinal products and homeopathic medicinal products within the directive 2001/83/EC. The committee for herbal medicinal products (HMPC) was established at the European Medicines Agency in London (EMEA); for homeopathic medicinal products there is a specific working group established by the Heads of Medicines Agencies. Harmonisation of medicinal products from complementary and alternative and traditional medicine in Europe was enforced by implementation of directive 2001/83/EC in national legislations of member states. The provisions of this directive will substantially influence the development of the European market during the forthcoming years.

Issues, and the questions they inspire, when one considers the development of European higher education for health care professionals.

This paper highlights various aspects of an emerging European health strategy and the potential consequences this may bring. The various directives of the European Commission, ratified by the European Parliament and each of the Parliaments of the member states, are gently and progressively forging integration of systems and processes. These systems and processes are concerned with governance and regulation and are aimed at establishing equivalence and standards of activity across the Union. The European Union is not a federated state. However, in order for it to work effectively as a trading block, the establishment of these standards into social, educational and new health care processes is seen as essential. Therefore, various directives from the European Commission are being laundered to expedite this. These directives are often opposed by the member states and the ensuring debate generates many talking points. This paper raises some of these talking points in the area of Higher Education and health care strategy. The conclusion of the paper suggests what further debate needs to occur within the European Union if integration is to succeed.

Authenticating production origin of gilthead sea bream (Sparus aurata) by chemical and isotopic fingerprinting.

Recent EU legislation (EC/2065/2001) requires that fish products, of wild and farmed origin, must provide consumer information that describes geographical origin and production method. The aim of the present study was to establish methods that could reliably differentiate between wild and farmed European gilthead sea bream (Sparus aurata). The methods that were chosen were based on chemical and stable isotopic analysis of the readily accessible lipid fraction. This study examined fatty acid profiles by capillary gas chromatography and the isotopic composition of fish oil (delta(13)C, delta(18)O), phospholipid choline nitrogen (delta(15)N) and compound specific analysis of fatty acids (delta(13)C) by isotope ratio mass spectroscopy as parameters that could reliably discriminate samples of wild and farmed sea bream. The sample set comprised of 15 farmed and 15 wild gilthead sea bream (Sparus aurata), obtained from Greece and Spain, respectively. Discrimination was achieved using fatty acid compositions, with linoleic acid (18:2n-6), arachidonic acid (20:4n-6), stearic acid (18:0), vaccenic acid (18:1n-7) and docosapentaenoic acid (22:5n-3) providing the highest contributions for discrimination. Principle components analysis of the data set highlighted good discrimination between wild and farmed fish. Factor 1 and 2 accounted for >70% of the variation in the data. The variables contributing to this discrimination were: the fatty acids 14:0, 16:0, 18:0, 18:1n-9, 18:1n-7, 22:1n-11, 18:2n-6 and 22:5n-3; delta(13)C of the fatty acids 16:0, 18:0, 16:1n-7, 18:1n-9, 20:5n-3 and 22:6n-3; Bulk oil fraction delta(13)C; glycerol/choline fraction bulk delta(13)C; delta(15)N; % N; % lipid.

Enhancing IHE XDS for federated clinical affinity domain support.

One of the key problems in healthcare informatics is the inability to share patient records across enterprises. To address this problem, an important industry initiative called "integrating the healthcare enterprise (IHE)" specified the "cross enterprise document sharing (XDS)" profile. In the IHE XDS, healthcare enterprises that agree to work together form a "clinical affinity domain" and store healthcare documents in an ebXML registry/repository architecture to facilitate their sharing. The affinity domains also agree on a common set of policies such as coding lists to be used to annotate clinical documents in the registry/repository and the common schemes for patient identification. However, since patients expect their records to follow them as they move from one clinical affinity domain to another, there is a need for affinity domains to be federated to enable information exchange. In this paper, we describe how IHE XDS can be enhanced to support federated clinical affinity domains. We demonstrate that federation of affinity domains are facilitated when ontologies, rather than coding term lists, are used to annotate clinical documents. Furthermore, we describe a patient identification protocol that eliminates the need to keep a master patient index file for the federation.

[Integrated approach to the promotion of young academics in vision research at a European level]. / Integrativer Ansatz zur Nachwuchsförderung in der Sehforschung auf europäischer Ebene.

The European Commission predicts a dramatic dearth of researchers and doctors in the near future. At the same time, highly qualified and motivated human resources form the only guarantee for further development of scientific knowledge for research and clinical application. This situation calls for an integrated approach to the promotion of young academics in vision research at a European level. The Marie Curie Program of the European Union is an ideal tool, which can be used particularly efficiently in vision research to promote international networking and dedicated advancement of young academics. The exemplary chances and opportunities of this strategy can be demonstrated by six specific measures of the University Eye Hospital in Tübingen. In particular, strictly defined medical areas will need to fully exploit their innovation potential in the future in order to secure their position in the global research area or even to expand it. New organizational concepts and long-term career options as well as a clear commitment to cutting-edge performance are the prerequisites for effective promotion of young academics.

La protección de datos en la práctica privada / Data protection in private practice

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