Avis juridique important

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31983H0571

83/571/EEC: Council Recommendation of 26 October 1983 concerning tests relating to the placing on the market of proprietary medicinal products

Official Journal L 332 , 28/11/1983 P. 0011 - 0032 Spanish special edition: Chapter 13 Volume 14 P. 0215  Portuguese special edition Chapter 13 Volume 14 P. 0215

COUNCIL RECOMMENDATION of 26 October 1983 concerning tests relating to the placing on the market of proprietary medicinal products (83/571/EEC)  THE COUNCIL OF THE EUROPEAN COMMUNITIES,  Having regard to the Treaty establishing the European Economic Community, and in particular Article 235 thereof,  Having regard to the proposal from the Commission,  Having regard to the opinion of the European Parliament (1),  Having regard to the opinion of the Economic and Social Committee (2),  Whereas Council Directive 65/65/EEC of 26 January 1965 (3) led to the approximation of provisions laid down by law, regulation or administrative action relating to proprietary medicinal products in the Member States ; whereas Directives 75/318/EEC (4) and 75/319/EEC of 20 May 1975 (5) continued. this approximation and developed the principles set out in Directive 65/65/EEC;  Whereas, in particular, Council Directive 75/318/EEC lays down a general framework for the testing of proprietary medicinal products, lists the various types of tests to be conducted and defines certain principles to be followed in the examination of applications for authorizations to place a proprietary medicinal product on the market;  Whereas experience has shown that the conduct and content of these tests should be defined more precisely so as to make possible an identical implementation of the Community Directives when such tests are carried out and when applications are examined by national authorities;  Whereas Notes for guidance are therefore necessary in order to prevent differences of interpretation in the implementation of the standards and protocols referred to in Directive 75/318/EEC whereas this will help to promote the free movement of proprietary medicinal products;  Whereas tests designed to evaluate the quality, safety and efficacy of proprietary medicinal products must be constantly adapted to take account of the latest scientific and technical knowledge without, however, giving rise either to a waste of resources or to the more than necessary use of laboratory animals;  Whereas it is therefore highly desirable that the Notes for guidance be periodically revised to take account of the state of the art and that new Notes for guidance be drawn up as and when required, in agreement with the national authorities;  Whereas such progress in harmonization, essential at Community level, will also promote international recognition of tests on medicinal products conducted in accordance with these Notes and will therefore tend to render unnecessary the repetition of tests on products intended for export to third countries;  Whereas the Pharmaceutical Committee and the Committee for Proprietary Medicinal Products have been consulted on the measures contained in this recommendation,  HEREBY RECOMMENDS THE MEMBER STATES TO:     1. Ensure that, in the conduct of tests and in the presentation of results, applicants for authorization to place proprietary medicinal products on the market comply with the principles and adhere to the methodology set out in the Notes for guidance annexed hereto.       2. Examine and evaluate, in accordance with the Notes for guidance, all applications for marketing authorization.   Done at Luxembourg, 26 October 1983.  For the Council  The President  G. MORAITIS  (1) OJ No C 287, 9.11.1981, p. 127. (2) OJ No C 189, 30.7.1981, p. 39. (3) OJ No 22, 9.2.1965, p. 369/65. (4) OJ No L 147, 9.6.1975, p. 1. (5) OJ No L 147, 9.6.1975, p. 13.    ANNEX I REPEATED DOSE TOXICITY Note for guidance concerning the application of chapter I (B) (2) of part 2 of the Annex to Directive 75/318/EEC, with a view to the granting of a marketing authorization for a new drug      1. INTRODUCTION  The purpose of these studies is to obtain information on the toxicity of a product when repeated exposure to this medicinal product is anticipated, in order that an assessment may be made of the risk resulting from therapeutic administration of the product, taking into account the products of biotransformation.  The duration of these studies will be determined by the proposed use in man or by the intended duration of human exposure. The following periods of administration are suggested as a guidance to correlate the duration of the repeated dose toxicity studies with the proposed duration of human exposure to the drug: >PIC FILE= "T0025437">   When human exposure is likely to be longer term, for example when frequent discontinuous administration results in a total period of exposure of one month or more in a period of one year, or when retention in the body of a single dose of the drug is prolonged, then the duration of the repeated dose toxicity studies will be six months.  When it is necessary to conduct toxicity studies of three or six months duration, a subacute toxicity study of two or four weeks duration may be designed and carried out in such a manner that it acts as a range-finding study for the longer term investigation (see 2.5).  The reason is that administration of too high a dose would leave too few animals alive at the end of the study lasting three months or more ; administration of too low a dose would prevent the development of toxic changes.        1.1. General specifications with regard to the repeated dose toxicity study  In the Annex to Directive 75/318/EEC, part 2 concerning toxicological and pharmacological tests states that these tests should show inter alia the toxicity thresholds:  "Repeated dose toxicity tests are intended to reveal any physiological and/or pathological changes induced by repeated administration of the active substance or combination of active substances under examination, and to determine how these changes are related to dosage.  Generally it is desirable that two tests be performed : one short-term, lasting two to four weeks, the other long-term. The duration of the latter shall depend on the conditions of clinical use. Its purpose shall be to determine by experiment the non-toxic dose range of the product".  As these thresholds can only be determined when they have been crossed the repeated dose toxicity study must be conceived in such a way as to demonstrate signs of toxicity. This implies that:   1.1.1. In the selection of species for long-term studies prior to marketing, it is desirable that, with regard to the metabolism and the pharmacokinetics of the drug, the species should be as closely similar to man as is possible within the usual spectrum of laboratory animals used for repeated dose studies. If there are significant differences in metabolism these should be taken into account in evaluating the results.  1.1.2. It is desirable that the pharmacological target organs and the pharmacological effects of the product in the species used should be the same as those involved in the therapeutic effect envisaged for man where this is known and is practical.  1.1.3. The dosage, the route and the frequency of administration should be planned so as to promote a loading of the animal organism with the product and its metabolites sufficient to demonstrate the target organ(s) in terms of harmful secondary effects. In designing the protocol, account will be taken of the pharmacokinetics of the drug.  By continuous administration of a drug in sufficiently high doses the following principal stages may be reached:          (a) the load of the drug in the organism builds up until a steady state is reached;                   (b) adaptation of the organism to the load with regard to the pharmacological target organs or the biotransformation enzymes or the excretory mechanisms;                   (c) in some cases a second metabolic pathway may be activated due to an overloading of the primary detoxication pathway ; as a result a new toxic metabolite may be formed;                   (d) a phase of manifestation of target organ toxicity manifested by failure of physiological functions and ultimately by pathological changes.                     Administration of the product in the repeated dose toxicity studies should be sufficient with regard to dosage and duration to reach this final stage (d) so that the type of toxicity produced by an excessive dose and the multiple of the therapeutic dose producing toxicity may be assessed. Not all drugs can be practically administered in dosages that produce target organ toxicity. Under such circumstances, evidence should be produced that the highest possible dose has been given and that the drug has been systemically absorbed.                      2. SPECIFICATIONS WITH REGARD TO THE DRUG AND ITS ADMINISTRATION        2.1. Drug quality  The active substance should present the same pattern of impurities as the product to be marketed, when possible. Should drug substance in the final dosage form be shown to have impurities significantly different either in quantity or quality from those in the test batch then further steps should be taken to ascertain their possible toxicity. When the drug is given orally its physical characteristics such as particle size may be important ; therefore the physical characteristics and stability of the material used in the repeated dose toxicity studies should be stated in each case. Whenever more than one batch of active substance is used in repeated dose toxicity studies this must be stated and each batch identified. The batch or batches used in the repeated dose toxicity studies should not be of a higher degree of purity than those intended for the final product. When the drug is given in the diet or the drinking water it should be established that it is stable in that medium.  When a new excipient is used for the first time, it should be tested in accordance with the same criteria as a new active substance.               2.2. Duration of administration  The duration of these studies should be related to the duration of the proposed therapeutic use in man (see 1).                2.3. Route of administration  Whenever this is technically feasible, the product should be administered by the route intended for use in man and it is desirable that the pharmacological effect is demonstrable by this route. When this cannot be shown, the use of other routes should be considered. (Administration by inhalation is discussed in the Appendix.) The quantity of drug absorbed from the proposed site of administration should be known from pharmacokinetic studies. When the product is administered in the food or the drinking water, the applicant must give assurance that a reasonable and known amount of the drug ingested is absorbed. Dosing by incorporation of the test substance in the diet or drinking water requires regular adjustment of the amount of drug in the diet or drinking water to compensate for growth and changing consumption.  In addition to systemic toxicity the possibility of local toxicity at the site of application should be given due attention, for example in the case of application to the skin, intravaginal application, intravenous, intramuscular, rectal, subcutaneous, intra-articular, intrathecal, conjunctival, intranasal and aural application, or when the drug is given by inhalation.               2.4. Frequency of administration  The steady state of the loading of the organism with some products is reached only when they are administered for seven days a week. Usually the administration of a drug to animals should be conducted on this basis. If this is not possible the reason should be given. When the rate of elimination is slow, less frequent administration may be acceptable. A rapid rite of elimination or gastric intolerance may make it necessary to administer the products more than once a day.               2.5. Dose levels  The treatment should include:          (a) a high dose, selected for the purpose of causing target organ toxicity whenever possible or, failing this, other non-specific toxicity, or until limited by volume of dose;  For a toxicity study of three or six months duration this dose should be derived from a subacute toxicity test of two or four weeks duration, designed and carried out as a dose range-finding study;                   (b) a low dose, sufficient to produce a pharmacodynamic effect or the desired therapeutic effect, or to produce blood levels comparable to those expected to produce these effects in man;                   (c) an intermediate dose, such as the geometric mean between the high dose and the low one;                   (d) The study should include appropriate control group(s) ; in special cases a positive control group may be necessary.                     However, the above considerations do not apply when the pharmacodynamic effect by itself will cause toxicity ; hypoglycaemia by antidiabetic agents serves as an example.  The investigator should indicate the rationale on which the dose levels were selected.               2.6. Pro-drugs  When the product administered is a pro-drug, its conversion to an active drug should be demonstrated in the species under study.                          3. SPECIFICATIONS PERTAINING TO THE EXPERIMENTAL ANIMAL      3.1. Animal species : choice and characterizations  As far as possible, the species should be chosen on the basis of their similarity to man with regard to the pharmacokinetics including the biotransformation of the product (see 1.1.1).  The pharmacodynamic effect of the drug should, if possible, be demonstrated in at least one of the species, so as to provide information about the margin between therapeutic and toxic effects.  The investigator should justify the choice of the species and strain. Use of SPF animals usually increases the value of the study.           3.2. Sexes  Normally, equal numbers of male and female animals should be used.           3.3. Size of treatment groups  When the size of the treatment groups is being considered, attention should be given to the following:        (a) the size of the treatment groups should be such that all toxicologically important effects due to treatment will be revealed;               (b) the size of the treatment groups should be large enough to permit the sacrifice of animals at intervals before the end of the study without interfering with the final statistical analysis;               (c) the size of the treatment groups should be large enough to allow some animals to be retained at the completion of the period of dosing so that the reversibility of toxic changes at the end of the treatment may be evaluated;               (d) background knowledge concerning the ranges of variables to be studied in the species and strains used is also relevant to consideration of group size.                 However, the size of control and treatment groups will always be limited for practical and financial reasons and for humane considerations.           3.4. Number of species  The purpose of the repeated dose toxicity studies is to provide an animal model for the repeated administration of the product to man. The value of the model for extrapolation to man depends to a large extent on the qualitative similarity between the animal model and man ; this is usually unknown. To reduce the risk of error in extrapolation, due to effects or lack of effects, which are peculiar to one species, at least two species should be used, one being a non-rodent. The choice of species should be justified (see 1.1.1).                  4. ANIMAL HUSBANDRY  A high level of animal husbandry is required and the environmental conditions should be controlled and the diet should be of known constant composition throughout. Measures taken to obtain these conditions should be recorded in the report.       5. OBSERVATIONS      5.1. Pre-treatment and control values  Control data from the colony are necessary for small mammals for all morphological, biochemical and physiological variables. In the case of larger animals, pre-treatment values should be obtained from the animals used in the study.            5.2. Monitoring during the study        5.2.1. General monitoring  General monitoring should be carried out during the study and should include food intake, body weight, haematology, clinical chemistry, urinanalysis, ophthalmology, ECG and general behaviour. The selection of techniques used and the choice of other tests should be appropriate to the current state of knowledge and to the animal species being used. In rodents, if ECG and ophthalmological or other specialized examinations are required, it is acceptable that these are conducted in a limited number of animals at each dose level.               5.2.2. Frequency of monitoring  The frequency of monitoring in addition to pre-treatment studies and final monitoring should be adapted to the manifestations of toxicity and also to the pharmacokinetics of the drug. The tests performed (including the collection of blood samples) during the monitoring should also be performed on the controls, and should not affect the experimental animals in a way which would influence the final interpretation of the toxicity test results.               5.2.3. Food intake  When products are administered in the food, particular attention should be given to the effect of the product on food consumption. Allowance should be made for consequent effects on drug intake.                          5.3. Terminal monitoring  Terminal observations should be as complete as possible. Autopsy must be conducted on all animals. Histopathology should be performed on all organs and tissues of the high dose and the control groups listed in the table. In rodents the examination of the lower dosed groups may be restricted to those organs and tissues showing pathological changes at autopsy. In other species where small numbers of animals are used, histopathology on those tissues listed should be conducted in all animals at all doses.  If organs are not examined microscopically, wax blocks or slides should be prepared and conserved for five years from the date of marketing for examination if required. Peculiarities in the distribution of the drug may necessitate further histopathological studies.                  6. IMMUNO-INTERFERENCE  The expansive growth of immunology and the recognition of its importance has made it necessary to pay attention to interference with the immunologic system by drugs even when this does not belong to their intended activity. Such an interference may cause undesired side effects (interference with infection ; carcinoma). Therefore it is particularly important to examine the spleen, the thymus and some lymph nodes macroscopically and microscopically at the termination of the toxicity study. These should indicate any effect on the immune system and thus the need for further tests.  Since our present knowledge in this field is rapidly increasing, any test used to investigate the immunological effects of a drug should rely on the state of the scientific knowledge at that moment.       7. CONCLUSIONS  Conclusions should be drawn from these studies by the investigator.    Appendix A List of tissues to be studied histologically in a repeated dose toxicity study      - Gross lesions           - Tissue masses or tumors (including regional lymph nodes)           - Blood smears (in case of anaemia, enlarged thymus, lymphadenopathy)           - Lymph nodes           - Mammary glands           - Salivary glands           - Sternebrae, femur or vertebrae (including bone marrow)           - Pituitary           - Thymus           - Trachea           - Lungs           - Heart           - Thyroid           - Oesophagus           - Stomach           - Small intestine (Swiss roll method)           - Colon           - Liver           - Gall-bladder           - Pancreas           - Spleen           - Kidneys           - Adrenals           - Bladder           - Prostate           - Testes           - Ovaries           - Uterus           - Brain (coronal sections at three levels)           - Eyes           - Spinal cord  Appendix B Conduct of toxicity studies by inhalation      1. INTRODUCTION  Medicinal products intended for administration to humans by inhalation may either be aerosols containing the pharmacologically active substance in solid or liquid state or they may be vapors or gases. The latter mentioned products are used as inhalation anaesthetics while aerosols in general contain a drug material in the form of particles delivered in a propellant which in principle ought to be biologically inactive.  Toxicological studies conducted by inhalation are necessary where:        (a) pharmacokinetics after administration by inhalation may differ qualitatively or quantitatively from the pattern after other routes of administration ; or               (b) drug and propellant may interact in the body ; or               (c) the inhaled product may have a local effect in the airways, either a short-term effect (effect on ciliary function or other signs of local irritation) or a long term effect (emphysema, bronchitis, malignancy).                 Aerosols are used for the administration of drugs either (i) to obtain a local effect in the respiratory system, or (ii) for the purpose of obtaining systemic effects by using the lining of the airways for absorption of the active compound or (iii) for circumventing the alteration of drugs in the gastro-intestinal tract.  In some circumstances toxicological studies on the drug may have been performed using other routes of administration, therefore extensive toxicological investigation by other routes of administration may already have been performed when inhalational studies are planned. In other cases, for example, locally acting compounds, such as mucolytic agents, toxicological investigation by other routes of administration may be non-existent or of little relevance. Planning of the toxicology studies by inhalation should take into consideration any already existing toxicological or pharmacological knowledge of the substance.           2. PHYSICO-CHEMICAL PROPERTIES  The information of the active substance's physico-chemical properties should be provided in the same way as for any other toxicological study. Additional information should be provided on the characteristics of the aerosol, which should include the distribution of the particle or droplet size of the active substance and the physico-chemical specification of the substance or substances used as the propellant.  The propellant system used in these studies should be that proposed for the final product. If a novel propellant system is used, this should itself be investigated to the same standard as a new active substance.           3. DOSING SCHEDULES        3.1. Administration  The method of administration depends on the nature of the substance and the intended use in man. In acute studies it may be reasonable to administer the substance directly into the airways via a nasotracheal tube or through a tracheotomy. In this way the quantity administered can be determined directly.  In the case of long-term exposure studies it will usually be necessary to use either "head only" or "nose only" exposure chambers or masks for inhalation. If whole body exposure is used,  deposition of the drug on the skin, in the pelt, in the upper airways and the amount swallowed should be taken into account in determining the dose of substance administered.  It should be demonstrated that the method of administration ensures that the substance reaches the desired site.               3.2. Dose levels  In these studies, normally three dose levels and one or more control groups as appropriate should be used in both single dose and repeated dose studies. Different levels of drug exposure can be achieved by alteration of concentration of substance inhaled or by alteration of the duration of exposure. In the selection of dose levels the same principles should apply, as far as is possible to those used for toxicity studies by other routes.  The reasons for selecting particular dose levels should be given.               3.3. Duration of study  The duration of the study should be related, at least to some extent, to the proposed human exposure.                          4. PHARMACOKINETICS AND METABOLISM  The metabolic pattern of the drug administered by inhalation may differ from the pattern observed following other routes of administration. The investigator should determine whether there are any pharmacokinetic or metabolic differences of relevance for the interpretation of the toxicological studies conducted by the inhalation route.  When biotransformation occurs in the lung itself, the possibility of enzyme induction of this process should be taken into consideration.           5. ANIMALS  The experimental animals used in these studies should be free of pulmonary infection and have a low incidence of other pulmonary pathology.  The number of experimental animals to be used in each group should be adequate for statistical analysis and will be determined by the duration of the experiment and by the number of observations, measurements and interim sacrifices to be made during the exposure periods. At least one rodent and one non-rodent species should be used for all repeated exposure studies.           6. OBSERVATIONS  Interim monitoring and terminal studies should be conducted as indicated for other toxicity studies. Particular attention should be paid to any local effects. If the drug is to be administered repeatedly, special studies of ciliary function and on the microflora may be necessary.  Blood-level monitoring of drug and propellant or other methods of assessing absorption of drug and propellant should be performed at intervals during repeated dose studies.  Terminal examination  At the conclusion of the study all animals should be subjected to autopsy and examination of tissues should be conducted as with other toxicological studies.  In studies conducted by the inhalational route the lungs should be weighed in all animals and histopathological examination conducted on tissues taken from all exposed levels of the respiratory tract and from associated lymphoid tissue.           7. PRESENTATION OF RESULTS AND CONCLUSIONS  These should be drawn up in the same manner as in other toxicity studies and the investigator should draw appropriate conclusions from the study.              ANNEX II  REPRODUCTION STUDIES  Note for guidance concerning the application of chapter I (C) and (D) of part 2 of the Annex to Directive 75/318/EEC, with a view to the granting of a marketing authorization for a new drug   GENERAL STATEMENT  The study of drug effects on reproduction should be conducted on all new drugs in such a manner as would reveal the presence of any effect on mating behaviour and of any effect which might result in fetal loss, fetal abnormality and damage to the offspring in later life, e.g.:      (i) changes in fertility or in the production of abnormal young due to damage to the male and/or female gametes;           (ii) interference with preimplantation and implantation stages in the development of the conceptus;           (iii) toxic effects on the embryo;           (iv) toxic effects on the fetus;           (v) changes in maternal physiology producing secondary effects on embryo or fetus;        (vi) effects on uterine or placental growth or development;               (vii) interference with parturition;               (viii) effects on postnatal development and suckling of the progeny, and on maternal lactation;   (ix) late effects on the progeny.                  SPECIFIC GUIDELINES  In the interpretation of the following notes for guidance it must be appreciated that they are not rigid requirements and may not be universally applicable. Interpretation should therefore be flexible and related to the proposed use of the drug ; justification for choice of studies must be given.      1. SELECTION OF SPECIES  Embryotoxicity studies should normally be conducted on two mammalian species one of which should be other than a rodent. Fertility and perinatal studies should be conducted in at least one species. Where metabolism of a drug in a particular species is known to be similar to that in man, it is desirable to include this species. It is desirable that one of the species is the same as in the long term toxicity studies. Studies in a third species may be helpful if conflicting results are obtained in the initital two species. The species and strains used in the studies should be specified.           2. DOSAGE  Dosing should normally be conducted at three dose levels. The high dose usually should be such that evidence of some maternal toxicity is produced, for example decrease in body weight gain. The low dose should be sufficient to produce a pharmacodynamic effect similar to the desired therapeutic effect, or to produce blood levels comparable to those required to produce the effect (this does not apply if the pharmacodynamic effect by itself will cause toxicity). The intermediate dose should be the geometric mean of the high and low doses.  Dosing should be conducted by the proposed route or routes of clinical administration.   Dosing schedules for investigation of drug effects on reproduction should normally include:        (a) embryotoxicity studies ; dosing throughout the period of embryogenesis (organogenesis) in two species one of which should be other than a rodent;               (b) a fertility study which should be conducted in at least one species ; dosing should commence in male and female animals at a sufficient time before the proposed mating so that any effects of the drug on gametogenesis could be revealed. Dosed animals may be mated with dosed partners but in the event of positive findings of a reproductive defect then the study should be repeated using dosed animals mated with undosed partners. After mating, the dosed females should continue to be dosed throughout pregnancy.  Half the females should be killed during gestation, preferably some days before the expected date of parturition, and the fetuses removed by Caesarean Section and examined. The remainder of the females should be allowed to litter normally and rear their progeny.               (c) Perinatal studies which should be conducted in at least one species ; dosing should cover the period of gestation from the end of organogenesis parturition and should extend throughout the period of lactation up to weaning.                          3. NUMBERS OF ANIMALS  An adequate number of animals should be used at each dose level to enable valid assessments to be made. With the exception of primates, the following minimum numbers per dose level are suggested:        (a) embryotoxicity studies : 20 pregnant females in rodents, 12 pregnant females in non-rodents;               (b) fertility studies : 24 females and 24 males;               (c) perinatal studies : 12 pregnant females.                 Where a third species is used it is suggested that adequate numbers of dosed animals should be used together with controls to allow a clear conclusion to be drawn from the study.           4. HOUSING AND DIET  Full details of the housing and caging conditions of the animals must be given. The full specification of the diet (including additives) must be provided.           5. PHARMACOKINETICS  In the conduct of reproduction studies, account should be taken of the pharmacokinetics of the drug in the pregnant animal. The level of exposure of the fetus to the drug should have been determined as far as this is technically possible.           6. EVALUATIONS        (a) Examinations should be made of the fetuses from the animals dosed during the period of embryogenesis. Animals should be killed and the fetuses removed by Caesarean Section. In these animals the numbers of corpora lutea, implantation sites (visible and those determined by special techniques e.g. by the Salewsky method), resorptions, the weight and sex of their individual fetuses should be recorded. The individual fetuses should be examined for external abnormalities and adequate examination of the skeleton or viscera or both made on all fetuses. Where obvious abnormalities are found further appropriate examination should be conducted. Special attention should be paid to abnormally high numbers of resorptions as this might indicate the need for further studies for teratogenic effects in the early stages of pregnancy.                (b) In the fertility study, females killed during the period of gestation should have their fetuses delivered by Caesarean Section and the following information should be recorded : number of corpora lutea, implantation sites, resorptions, weight and sex of individual fetuses. All individual fetuses should be examined for either skeletal and/or visceral abnormalities.  From animals dosed during the fertility study and allowed to litter normally and rear their progeny to the stage of weaning, a large enough number of progeny to allow for the subsequent investigations should be allowed to live and reach maturity. Late effects of the drug on the progeny in terms of auditory, visual and behavioural impairment should be assessed. Reproductive function should be determined in the progeny by allowing at least one male and one female from each litter of dosed animals to breed and produce one litter (brother/sister mating is not envisaged).               (c) The females dosed through the pre- and post-natal period should be allowed to litter spontaneously and the progeny examined at weaning. All animals killed at the end of lactation should be subjected to a thorough autopsy examination. Under certain circumstances some of the progeny may be allowed to live and reach maturity so that their reproductive capacity could be assessed, and other late effects of the drug on the progeny in terms of behavioural, visual and auditory impairment determined.                          7. CONCLUSIONS  The investigator is required to draw overall conclusions from the results of these studies indicating either:        (a) there is no evidence of adverse effects of the drug on reproductive function ; or               (b) there is evidence of adverse effects on reproductive function(s) to be specified ; or               (c) the data are inadequate to draw conclusions.                 If particular studies have been omitted the investigator should justify the omission.               Appendix Duration of gametogenesis  In rodent studies, dosing of the male should be for a minimum of 60 days and the female for a minimum of 14 days prior to mating. Animals should be about 40 days of age at the commencement of dosing. In the present stage of knowledge these times would be regarded as acceptable.     ANNEX III CARCINOGENIC POTENTIAL  Note for guidance concerning the application of chapter I (E) of part 2 of the Annex to Directive 75/318/EEC, with a view to the granting of a marketing authorization for a new drug  The strongest evidence that a compound is a carcinogenic hazard for man is epidemiological although most known human carcinogens are found to be carcinogenic for experimental animals. There is no evidence that all substances which are carcinogenic for animals are also carcinogenic for man, but it is difficult to declare any compound as being non-carcinogenic for man when it has been shown to be carcinogenic in animal studies.  Extrapolation to man is a difficult, sometimes arbitrary, procedure, and the ideal would be to analyze the mechanisms involved in increasing the incidence of the experimental tumours and to determine whether such mechanisms involving specific biochemical pathways and the formation of the proximate carcinogen would be applicable to man. The criteria on which extrapolation is based may vary with the agent under consideration, its projected use, dosage and mode of administration on the one hand, and the species, sites, incidence of tumours and required test dosage, on the other.  The likelihood of carcinogenic risk in man is increased if there is a high yield of malignant tumours involving a specific tissue when the test animal is given the test substance by the route to be used in man and at a dosage equal to or lower than that which induces minimal toxicity. However, since there is no good evidence of a threshold level, an increase in yield of benign tumours, or malignant tumours at higher dosage, or reduction of latency should be interpreted as constituting a possible risk for man. In such circumstances ; the agent is generally regarded as less potent and the risk may more easily be reconciled with benefits associated with the therapeutic use of the compound.      1. REQUIREMENTS FOR CARCINOGENICITY STUDIES  Carcinogenicity studies will usually be required in the following circumstances:        (a) when the medicine is likely to be administered regularly over a substantial period of life (continuously during a minimum period of six months, or frequently in an intermittent manner so that the total exposure is similar) ; or               (b) where a substance has a chemical structure that suggests a carcinogenic potential ; or               (c) where a substance causes concern due to:          (i) some specific aspects of its biological action (e.g. a therapeutic class of which several members have produced positive carcinogenic results);                   (ii) its pattern of toxicity or long-term retention (of drug or metabolites) detected in previous studies; (iii) the findings in mutagenicity tests and/or short-term carcinogenicity tests.                     Carcinogenicity testing may not be regarded as necessary where the substance in question will be used only in patients with a life expectancy shorter than that in which a chemical might reveal any carcinogenic hazard in man. If circumstances alter and a drug of the latter variety were used in less serious conditions then carcinogenicity testing would become necessary. Insoluble substances which are not absorbed may not require formal carcinogenicity studies.                           2. SPECIES AND STRAIN SELECTION  Where carcinogenicity studies are required, they should normally be conducted on two species. The metabolic handling of the drug should be known in the species used and should preferably show similarities to the metabolism in man. Cognizance should be taken of known species and strain responses with similar chemicals. Species and strains with a high incidence of spontaneous tumour formation should normally be avoided. Those undertaking the study should select species and strains known to be sensitive to one or more carcinogens. Positive controls will not be required routinely but the spontaneous tumour incidence of the strains used should be recorded.           3. DOSAGE        (a) Route and frequency of dosing  Where possible, dosing should be conducted by the proposed clinical route of administration. Where relevant, evidence of absorption should be provided. The frequency of dosing normally will be daily.               (b) Dose levels  Carcinogenicity testing should normally be conducted at three dose levels. The top dose should produce a minimum toxic effect, for example a 10 % weight loss or failure of growth, or minimal target organ toxicity. Target organ toxicity will be demonstrated by failure of physiological functions and ultimately by pathological changes. The lowest dose should be of the order of two to three times the maximum human therapeutic dose or the dose that produces a pharmacological effect in animals. The middle dose should be the geometric mean of the high and low dose.  Exceptions to these principles may occur, for example where the toxic dose of the drug is a high multiple of the therapeutic dose ; in these circumstances it is acceptable if the top dose is set at approximately 100 times the human therapeutic dose, where technically feasible.                          4. PRACTICAL FEATURES  Animals should be in good general health initially and this should be maintained throughout the study. High standards of animal husbandry are essential. Special precautions are necessary when inhalational or volatile carcinogens are being tested.  The pharmaceutical quality of the batch(es) used should be clearly characterized.        (a) Age of animals at commencement of study  Carcinogenicity studies should commence as soon as possible after weaning ; i.e. as soon as the animals are accustomed to their diet and surroundings.               (b) Duration of studies  The currently recommended practice is to conduct studies for 24 months in the rat and 18 months in the mouse and hamster. Where the survival rate is high there may be advantages in extending studies for 30 months in the rat and 24 months in the mouse, or for the lifespan of the animals ; i.e. to 20 % survival in the controls.               (c) Number of animals per group  For routine tests with mice, rats and hamsters it is suggested that for each sex there should be 50 animals per treated group, and two control groups of 50 for each sex dosed with the vehicle by the same route (in most cases the drug will be administered in the diet).                (d) Composition of diet  Commercial diets are variable and steps should be taken to provide as uniform a diet as possible throughout the duration of the carcinogenicity study. Full specification of the diet should be given.                          5. ADDITIONAL MONITORING  Carcinogenicity studies should be designed to obtain the maximum amount of information from the animals used but any investigations undertaken to elicit additional toxicological data should not prejudice the prime purpose of evaluating a drug's carcinogenic potential. Information on absorption, distribution and metabolism of the drug and on whether the drug accumulated or was an enzyme inducer should have been determined during other toxicity studies.           6. STATISTICAL DESIGN OF STUDY  An appropriate experimental design should be selected and in particular:        (i) the cages containing the animals in the treatment and control groups should be distributed within the animal house so as to eliminate bias due to the effects of any local environmental factor;               (ii) animals should be allocated at random to the various experimental units (e.g. cages) and the method used to achieve this randomization should be clearly stated;               (iii) if for practical reasons of handling such large numbers of animals it is decided to stagger the start of the study it is desirable that all groups should be represented at each start in equal numbers. If the study is conducted using a staggered start the times at which the various batches of animals enter the study must be stated.                          7. TERMINAL INVESTIGATIONS        7.1. Autopsy  A full autopsy should be made on all animals dying during the study or killed because of their poor condition.  At the conclusion of the study all surviving animals should be sacrificed and a full autopsy conducted on each animal. Previously demonstrated toxic effects may indicate particular topics for investigation. Haematological and biochemical investigations may be helpful in the interpretation of any lesions found.               7.2. Histopathology          7.2.1. Carcinogenicity screening            (i) Microscopical examination should be carried out on all listed tissues and organs from all high-dose animals and from all controls ; and                       (ii) tissues from any animal in any group in which macroscopical lesions of any kind are found at autopsy.  If the results from (i) indicate that tumours occur in one or more organs or tissues, then:                       (iii) those tissues and organs should be examined in the mid- and low-dose groups even when macroscopically normal.  All listed tissues should be microscopically examined from all animals dying or killed during the course of the study.                                           7.2.2. Toxicity screening  Previously demonstrated toxic effects may indicate particular aspects for investigation.  Haematological and biochemical investigations may be helpful in the interpretation of any lesion found. Particular attention should be paid to the site of application if the drug is administered other than by the oral route.                                           8. PRINCIPLES OF REPORTING ON CARCINOGENICITY STUDIES      8.1. Definitions  A neoplasm (tumour) is regarded as a population of abnormal cells with uncontrolled and usually increased proliferative activity and other less well-defined morphological and functional features.  A malignant neoplasm is one which invades surrounding tissues or metastasises. In general terms, the tumour is considered to be benign or malignant on the basis of its histopathological appearances and the correlation by the pathologist of such charges with biological behaviour known from previous experience to occur in tumours displaying comparable characteristics.  Tumours should be described in conventional histopathological terms according to welldefined classifications (e.g. WHO).           8.2. Presentation of the data  In the first instance the findings should be summarized for each treatment group and each control group separately, keeping the sexes separate, in terms of:        1. number of animals examined and their individual gross and microscopic examination;               2. numbers (and percentages) of animals with tumours of each identified type in a specified tissue, distinguishing malignant from benign tumours, wherever possible;               3. a frequency distribution of the total number of tumours found in an animal with one or more tumours of the same or different types ; and another of the total number of malignant tumours found in the animal. If the tumours cannot be enumerated some grading of multiplicity of tumours should be used instead;               4. time to each interim death;               5. time of appearance of any mass (starting from clinical palpation) and its progress, as well as its eventual histopathology.                                 9. ANALYSIS OF THE DATA  The form of the analysis and the tests of statistical significance used should be appropriate to the type of data and to the basic experimental design. The statistical procedures used should be clearly stated.  The responses should be assessed in the following ways:      (i) the total incidence of tumour bearing animals;           (ii) the total incidence of tumours;           (iii) the incidence of tumours involving a specific tissue;           (iv) the incidence of tumours judged to be malignant;           (v) the latent period to tumour appearance (using actuarial approaches).              The analysis should be directed towards:      (a) the assessment of the presence of any effect of the substance under study, as shown by the contrast between the response in the three treatment groups, as a set, and the response in the two control groups, as a set;           (b) the assessment of whether any effect is dose-related, as shown by a trend in the responses in the low-, mid- and high-dose groups. This assessment is statistically independent of that in (a).             Professional statistical advice should be available in order to assess the influence of other factors, such as death of test animals because of other diseases, and premature killing of animals because of clinical detection of tumours. The particular tests of statistical significance which should be used in assessing the presence of an effect or a dose-relationship are intentionally not specified. The data in one experiment may require a different approach from the data in another.  The test substance should be regarded as having the potential to increase the risk of neoplastic change if any of the above responses is materially increased (or the latent period is materially decreased). The compound may be regarded as possessing more powerful activity for the animal if several of the above responses are affected and if there is evidence of a dose-response as well as the presence of the effect. A raised incidence of tumours in treated as compared with control animals is of significance whatever the mechanism postulated or defined for the development of such tumours, but any particular circumstances should be identified or remarked. Examples include known pathways which may be peculiar to one species (griseofulvin and porphyrin metabolism in the mouse), severe stimulation of endocrine glands (especially in the dog), or the development of physical features peculiar only to the test species (vesical calculi in the rat).  Different circumstances may result in:      (i) an increased incidence or reduced latency of malignant tumours;           (ii) an increased incidence of benign tumours;           (iii) local induction of tumours at the site of injection.                  10. USE OF SHORT-TERM CARCINOGENICITY STUDIES  Evaluation of new compounds in a mutagenicity screen is desirable. However, available techniques involving short-term testing of chemicals for mutagenicity/carcinogenicity are not capable of replacing formal carcinogenicity testing in animals as a means of evaluating a drug's carcinogenic potential. Short-term studies giving positive results will always indicate the need for formal carcinogenicity studies if the drug is to be developed further ; those giving negative results do not preclude the need for formal studies when these are advisable for the reasons given in paragraph 1.       11. CONCLUSIONS  Conclusions from these studies should be drawn by the investigator.            Appendix List of tissues to be studied histologically in a carcinogenicity study    - Gross lesions       - Tissue masses or tumors (including regional lymph nodes)       - Blood smears (in case of anaemia, enlarged thymus, lymphadenopathy)       - Lymph nodes       - Mammary glands       - Salivary glands       - Sternebrae, femur or vertebrae (including bone marrow)       - Pituitary       - Thymus       - Trachea       - Lungs       - Heart       - Thyroid       - Oesophagus       - Stomach       - Small intestine (Swiss roll method)       - Colon       - Liver       - Gall-bladder       - Pancreas       - Spleen       - Kidneys       - Adrenals       - Bladder       - Prostate       - Testes       - Ovaries       - Uterus       - Brain (coronal sections at three levels)       - Eyes       - Spinal cord          ANNEX IV PHARMACOKINETICS AND METABOLIC STUDIES IN THE SAFETY EVALUATION OF NEW DRUGS IN ANIMALS Note for guidance concerning the application of chapter I (F) and (G) of part 2 of the Annex to Directive 75/318/EEC, with a view to the granting of a marketing authorization for a new drug    1. INTRODUCTION  These notes are concerned with the time course of the absorption, distribution and excretion of new drugs and with their metabolism in relation to their safety. For many steps in the evaluation of a drug such data are essential, for example:      (a) to assess the levels of the drug and of its metabolites and their kinetics in blood, body fluids and organs;           (b) to obtain information on the relationship between target organ toxicity and the blood, body fluids and organ concentrations of the drug;           (c) to assess the possibility of enzyme induction and of cumulation of the drug with repeated administration;           (d) to choose where possible the animal species to be used in toxicological studies on the basis of their similarity to man in handling the drug, and to determine the relevance of these toxicity studies to man.                  2. DRUG SPECIFICATION  Specification of the physical and chemical properties of the drug substance must be given and the stability of the preparation should be provided.  When a labelled drug is used the position of the label in the molecule and the specific activity of the material must be stated. Consideration should be given when selecting the position of the label to its likely metabolic fate.       3. METHODS  Data on the levels of drug and metabolites in blood, body fluids, organs and in the excreta can be obtained by physical, chemical or biological methods. The investigator should justify the details of the methods used, their validity and reproducibility, including the specificity, precision and accuracy. (The study of the time course of its pharmacodynamic effects may provide useful additional information.)  When using labelled drugs attention must be given to the fact that the measured label in body fluids may not correspond to that of the unmodified drug, but may include labelled metabolites and conjugates. Attention should be given to the possibility of isotope exchange with endogenous compounds.       4. SPECIES  The animal species in these studies usually should be those normally used in the laboratory for pharmacological and toxicological investigations. The reasons for selection of any other species should be given.   A preliminary study of kinetics and metabolism of the drug in a few human subjects could provide useful information in choosing the animal species to be used in repeated dose toxicity studies.       5. DRUG ADMINISTRATION  Doses and routes of drug administration should be related, when possible, to the proposed clinical use of the drug. One of the routes selected should ensure the absorption of the drug if this is relevant to human usage.       6. PRESENTATION OF RESULTS  Information should be presented on the following items:      (i) absorption (fractional absorption, kinetics);           (ii) distribution in the principal organs and tissues and the time course in body fluids;           (iii) blood, plasma or serum half-life;           (iv) plasma protein binding;           (v) characterization of the pattern of metabolites in excreta, and where practicable, identification of major metabolites;        (vi) route and time course of excretion of drug and metabolites;               (vii) if biliary excretion is a major route of elimination, then the possibility of enterohepatic recycling should be investigated;               (viii) a quantitative account of the fate of the administered dose should be attempted;   (ix) possibilities of enzyme induction should be investigated. If enzyme induction is found its relevance in the context of the proposed use of the drug should be examined.                   7. CONCLUSIONS  Appropriate conclusions should be drawn from these studies in the context of the objectives indicated in paragraph 1.   ANNEX V FIXED-COMBINATION PRODUCTS Note for guidance concerning the application of chapter II (C) (2) of part 3 of the Annex to Directive 75/318/EEC, with a view to the granting of a marketing authorization for a new drug      1. JUSTIFICATION  Applicants will be required to justify the particular combination of active ingredients proposed. Fixed combination products will only be considered acceptable if the proposed combination is based on valid therapeutic principles.  For any individual fixed combination it will be necessary to assess the potential advantages in the clinical situation against possible disadvantages, in order to determine whether the product meets the requirements of the standards and protocols with respect to efficacy and safety.  Potential advantages of fixed combinations include:    1. an improvement in the therapeutic : toxic ratio, e.g. as a result of the potentiation of the therapeutic effect;           2. simplification of therapy, resulting in improved patient compliance.  Disadvantages of fixed combinations include:        1. the fact that even a combination which meets the need of the average patient is unlikely to be ideally formulated for the needs of the individual;               2. accumulation of adverse reactions.                 Combinations, in principle, may not be considered rational if the half-life and/or the duration of action of the components differ significantly, but this may not necessarily apply where it can be shown that the combination is clinically valid despite differences in this respect, e.g. if one component is intended to enhance absorption of the other or where the components are intended to exert their effects successively.  The inclusion of an ingredient to counteract an adverse effect of one of the other components may be considered justified, but only if the adverse reaction is a commonly occurring one.  The inclusion of a component intended to produce unpleasant side-effects as a means of preventing abuse is undesirable.  Substances having a critical dosage range or a narrow therapeutic index are unlikely to be suitable for inclusion in fixed combinations.    2. INDICATIONS  The indications claimed for a fixed-combination product should be such that the presence of each component is justified for each indication. The product should be formulated so that the dose and proportion of each component present is appropriate to all the recommended uses.  Clearly, an "indication" must be a well-recognized disease state, dysfunctional state, syndrome or pathological entity. The individual components of a fixed combination may be intended to relieve simultaneously different symptoms of such a disease state, but it will not be proper to regard each individual symptom as an indication for the fixed combination, since it may also occur in other diseases and for treating this symptom alone the other constituents may be irrelevant.            3. SAFETY AND EFFICACY  It is permissible to distinguish between the extent of the studies required in the case of those fixed combinations which correspond closely to combinations which are already in widespread use provided these are thoroughly and reliably documented, and those studies required in the case of those combinations which are essentially new (either because the drugs involved are not usually combined, because the quantitative composition is unusual, or because one of the components is entirely new).  Safety studies in animals with fixed combinations should, as a general rule, have been performed with the active ingredients in the proportions present in the product. Such studies will not be required where all the components have been extensively and safely used in humans in identical or very similar combinations for a long period and the safety of such combinations is well-documented.  Both the efficacy and the safety of a fixed-combination product should have been investigated in man. For well-recognized combinations well-founded bibliographical data will be acceptable in some cases. It will be necessary to test a new combination clinically against one or more of the components in order to define the role played by each in the total.           4. INTERACTIONS  The possibility of interactions between the components should always be considered. Where a pharmaceutical, pharmacokinetic or pharmacodynamic interaction appears possible, the applicant should submit data either to establish that such interaction does not occur, or that it is clearly recognized and defined.           5. ADVERSE EFFECTS  Where there are grounds to expect that a fixed-combination product may be substantially more harmful or give rise to much more frequent adverse effects than any individual components given alone, the applicant should provide evidence that this does not occur in therapeutic use, or that the advantages of the combination, e.g. increased efficacy, outweigh such disadvantages.           6. DOSAGE  The combination product must be safe and effective throughout the whole of the recommended dosage range.           7. COMBINATION PACKS  The principles applicable to fixed-combination products will also be applied in the assessment of preparations consisting of different medicinal products in combination packs where the products are intended for simultaneous or sequential administration.           8. CHEMICAL COMBINATIONS AND COMPLEXES  Substances of this type which dissociate prior to absorption into two or more active components may be regarded for the application of the above provisions as fixed combinations of these substances rather than as chemical entities.


Avis juridique important

|

31996Y0318(01)

Council recommendation of 4 March 1996 relating to local consular cooperation regarding visas

Official Journal C 080 , 18/03/1996 P. 0001 - 0001

COUNCIL RECOMMENDATIONof 4 March 1996relating to local  consular cooperation regarding visas(96/C 80/01)THE COUNCIL OF THE EUROPEAN  UNION, Having regard to the Treaty on European Union, and in particular Article K.1 (3) thereof, Whereas it is advisable to prepare for greater harmonization in the policy and practice of the  issue of visas; Whereas the issue of visas, pending the possible preparation of joint instructions on the matter,  is governed by each Member State's national legislation; Whereas each Member State, when issuing its own visas, should have the necessary information to  take account of the interests of the other Member States, in particular the protection of national  security and public order and the prevention of clandestine immigration, HEREBY RECOMMENDS THAT THE GOVERNMENTS OF THE MEMBER STATES: in so far as the practical need is felt, take the measures necessary to  facilitate that: 1. the Member States' consular services should maintain local cooperation on visas, involving an  exchange of information on the criteria for issuing visas and an exchange of information on risks  to national security and public order or the risk of clandestine immigration; 2. the Heads of their consular services and their assistants in visa matters should hold meetings  for the purposes of exchanging the information referred to in paragraph 1; 3. their consular services should organize mutual visits of officials responsible for issuing visas  in order to improve the exchange of information and reciprocal knowledge; 4. at the request of the Council, their consular services should draw up joint reports on local  visa issues which are likely to be relevant to the Council's discussions; 5. their consular services should adopt any appropriate joint measures to establish the existence  of simultaneous visa applications or a series of applications, and, if need be, to ascertain any  earlier visa refusal by another Member State; 6. their consular services should exchange information to help to determine the good faith of visa  applicants and their reputation, it being understood that the fact that the applicant has obtained  a visa for another Member State does not exempt the authorities of the other Member States from  their responsibility to examine individually the visa application and perform the verification  required for purposes of security, public order and clandestine immigration control. The exchange of information provided for in this recommendation must take the relevant data  protection rules into account. Done at Brussels, 4 March 1996. For the CouncilThe PresidentP. BARATTA


title: 2011/856/EU: Commission Recommendation of 15 December 2011 regarding relief for double taxation of inheritances

text:
               20.12.2011

               EN

               Official Journal of the European Union

               L 336/81

         COMMISSION RECOMMENDATION
   of 15 December 2011
   regarding relief for double taxation of inheritances
   (2011/856/EU)
   THE EUROPEAN COMMISSION,
   Having regard to the Treaty on the Functioning of the European Union, and in particular Article 292 thereof,
   Whereas:

               (1)

               Most Member States apply taxes upon the death of a person, notably inheritance and estate taxes while some Member States may tax inheritances and estates under other tax headings, such as income. All taxes applied upon the death of a person are hereafter called inheritance taxes.

               (2)

               Most Member States that apply inheritance taxes also apply taxes to gifts between living persons.

               (3)

               Member States may tax inheritances on the basis of varying ‘connecting’ factors. They may do so on the basis of a personal link such as the residence, domicile or nationality of the deceased, or the residence, domicile or nationality of the heir, or both. Some Member States may apply more than one of these factors or may apply anti-abuse measures that entail an extended concept of domicile or residence for tax purposes.

               (4)

               In addition to taxing on the basis of a personal link, Member States may apply inheritance tax to assets located in their jurisdictions. Tax may be applied on this basis even if neither the deceased nor the heir has a personal link with the country of location.

               (5)

               Increasing numbers of citizens of the Union are moving during their lifetimes from one country to another within the Union to live, study, work and retire, and are purchasing property and investing in assets in countries other than their home countries.

               (6)

               If these cases result in inheritances across borders upon the death of an individual, more than one Member State may have the right to apply inheritance taxes to those bequests.

               (7)

               Member States have few bilateral conventions to relieve double or multiple taxation of inheritances.

               (8)

               Most Member States provide, through legislation or administrative practices adopted unilaterally at national level, for double taxation relief for foreign inheritance taxes.

               (9)

               However, those national systems of relief for foreign inheritance tax generally have limitations. In particular they may have a limited scope as regards the taxes and persons covered. They may not allow credit for previously paid gift taxes on the same inheritance or for taxes applied at local or regional rather than national level, or for all taxes levied by other countries upon death. They may only grant relief for foreign taxes paid on certain foreign property. They may not grant relief in respect of foreign tax on a property situated in a country other than that of the heir or deceased. They may exclude foreign tax on assets located within the territory of the Member State granting relief. The national systems of relief may also fail because they do not have regard to mismatches with inheritance tax rules in other Member States, particularly regarding what is to be considered as a local compared to a foreign asset, and regarding the timing of the transfer of assets and the date when tax is due. Finally, tax relief may be subject to the discretion of the competent authority and may not, therefore, be guaranteed.

               (10)

               The absence of appropriate ways of relieving cumulative taxation of inheritances may lead to overall levels of taxation that are appreciably higher than those applicable in situations that are purely internal to one or other of the Member States involved.

               (11)

               This may hinder EU citizens from benefiting fully from their right to move and operate freely across borders within the Union. It may also create difficulties for the transfer of small businesses on the death of owners.

               (12)

               While revenues from inheritance taxes represent a relatively low share of the overall tax revenue of Member States, and cross-border cases alone account for far less, double taxation of inheritances may have a major impact on the individuals affected.

               (13)

               Double taxation of inheritances is not currently being resolved comprehensively at national or bilateral level, or on the basis of Union law. In order to ensure the smooth functioning of the internal market a more comprehensive system for granting relief for double inheritance tax in cross-border cases should be encouraged.

               (14)

               An order of priority of taxing rights or, conversely, of granting relief should be provided in cases where two or more Member States apply inheritance taxes to the same inheritance.

               (15)

               As a general rule, and in line with the practice predominantly followed at international level, Member States in which immovable property and business property of a permanent establishment is situated should, as the State with the closest link, have the primary right to apply inheritance tax to such property.

               (16)

               Since movable property that is not the business property of a permanent establishment can easily shift location, its link to the Member State where it happens to be located at the time of death is, in general, considerably less close than the personal links that the deceased or the heir may have with another Member State. The Member State where such movable property is situated should, therefore, exempt the property from its inheritance taxation if such taxation is applied by the Member State with which the deceased and/or the heir has a personal link.

               (17)

               Inheritances have often been accumulated over the lifetime of the deceased. Moreover, the assets contained in an inheritance are more likely to be located in the Member State to which the deceased has personal links than in the Member State to which the heir has such links, if different. When taxing inheritances on the basis of personal links to their territory, a majority of Member States refers to the links of the deceased rather than to those of the heir, albeit several also or only tax if the heir has a personal link to their territory. Because of the said nature and importance of the personal links of the deceased as well as for practical reasons, double taxation due to the fact that the deceased and the heir have personal links to different Member States should be relieved by the Member State to which the heir has personal links.

               (18)

               Conflicts of personal links to several Member States could be solved on the basis of a mutual agreement procedure involving tie-breaker rules to determine the closest personal link.

               (19)

               Since the timing for the application of inheritance tax may differ in the Member States involved and cases with cross-border elements may take significantly longer to be resolved compared to domestic inheritance tax cases due to the necessity of dealing with more than one legal and/or tax system, Member States should allow claims for tax relief for a reasonable period of time.

               (20)

               This Recommendation promotes the fundamental rights recognised in particular by the Charter of Fundamental Rights of the European Union, such as the right to property (Article 17), which specifically guarantees the right to bequeath lawfully acquired possession, freedom to conduct business (Article 16) and EU citizens’ freedom to move freely within the EU (Article 45),

         HAS ADOPTED THIS RECOMMENDATION:
   1.   Subject matter
   1.1.   This Recommendation sets out how Member States can apply measures, or improve existing measures, to relieve double or multiple taxation caused by the application of inheritance taxes by two or more Member States (hereinafter ‘double taxation’).
   1.2.   This Recommendation relates by analogy to gift taxes, where gifts are taxed under the same or similar rules as inheritances.
   2.   Definitions
   For the purpose of this Recommendation the following definitions apply:

               (a)

               ‘inheritance tax’ means any tax levied at national, federal, regional, or local level upon death, irrespective of the name of the tax, of the manner in which the tax is levied and of the person to whom the tax is applied, including in particular estate tax, inheritance tax, transfer tax, transfer duty, stamp duty, income and capital gains tax;

               (b)

               ‘tax relief’ means a provision contained in legislation and/or general administrative instructions or guidance whereby a Member State grants relief for inheritance tax paid in another Member State, by crediting the foreign tax against tax due in that Member State, by exempting the inheritance or parts of it from taxation in that Member State in recognition of the foreign tax paid or by otherwise refraining from the imposition of inheritance tax;

               (c)

               ‘assets’ means any movable and/or immovable property and/or rights that are subject to inheritance tax;

               (d)

               ‘personal link’ refers to the link of a deceased or heir with a Member State, which may be based on domicile, residence, permanent home, centre of vital interests, habitual abode, nationality or centre of effective management;

         For the purposes of point (a) previously paid gift tax on the same asset is considered as inheritance tax for the purposes of granting tax credit.
   The terms ‘permanent establishment’, ‘immovable property’, ‘movable property’, ‘resident’, ‘domicile/domiciled’, ‘national/nationality’, ‘‘habitual abode’, and ‘permanent home’ have the meaning applicable under the domestic law of the Member State applying the term.
   3.   General objective
   The recommended measures aim at resolving cases of double taxation, so that the overall level of tax on a given inheritance is no higher than the level that would apply if only the Member State with the highest tax level among the Member States involved had tax jurisdiction over the inheritance in all its parts.
   4.   Provision of tax relief
   When applying inheritance taxes, Member States should grant tax relief in accordance with points 4.1 to 4.4.
   4.1.   Tax relief in respect of immovable property and movable property of a permanent establishment
   When applying inheritance taxes, a Member State should allow tax relief for inheritance tax applied by another Member State on the following assets:

               (a)

               immovable property situated in that other Member State;

               (b)

               movable property which is the business property of a permanent establishment situated in that other Member State.

         4.2.   Tax relief in respect of other kinds of movable property
   In respect of movable property other than business property as referred to in paragraph 4.1(b), a Member State with which neither the deceased nor the heir has a personal link should refrain from applying inheritance tax provided that such tax is applied by another Member State by reason of the personal link of the deceased and/or the heir to that other Member State.
   4.3.   Tax relief in cases where the deceased had a personal link to a Member State other than that to which the heir has a personal link
   Subject to paragraph 4.1, in cases where more than one Member State can apply taxation to an inheritance on the basis that a deceased had personal links with one Member State and the heir has personal links with another Member State, then the second Member State should give tax relief for the tax paid on the inheritance in the Member State with which the deceased had personal links.
   4.4.   Tax relief in cases of multiple personal links of a single person
   Where, on the basis of provisions of different Member States, a person is deemed to have a personal link with more than one taxing Member State, then the competent authorities of the Member States concerned should determine through mutual agreement, in accordance with the procedure set out in point 6 or otherwise, the Member State that should grant tax relief if inheritance tax is applied in a State with which the person has a closer personal link.

               4.4.1.

               A closer personal link of an individual could be determined as follows:

                           (a)

                           he could be deemed to have a closer personal link with the Member State in which he has a permanent home available to him;

                           (b)

                           if the Member State referred to in (a) does not tax or if the individual has a permanent home available to him in more than one Member State, he could be deemed to have a closer personal link with the Member State with which his personal and economic relations are closer (centre of vital interests);

                           (c)

                           if the Member State referred to in (b) does not tax or if the Member State in which the individual has his centre of vital interests cannot be determined, or if he has not a permanent home available to him in any Member State, he could be deemed to have a closer personal link with the Member State in which he has an habitual abode.

                           (d)

                           if the Member State referred to in (c) does not tax or if the individual has an habitual abode in more than one Member State or in no Member State, he could be deemed to have a closer personal link with the Member State of which he is a national.

               4.4.2.

               In the case of a person other than an individual, such as a charity, its closer personal link could be deemed to be with the Member State in which its place of effective management is situated.

         5.   Timing of application of the tax relief
   Member States should allow tax relief for a reasonable period of time, e.g. 10 years from the time limit by which inheritance taxes that they apply have to be paid.
   6.   Mutual agreement procedure
   Where necessary in order for the general objective set out in point 3 to be attained, Member States should operate a mutual agreement procedure to deal with any disputes connected with double taxation, including conflicting definitions of movable and immovable property or of the location of assets or the determination of the Member State which should provide tax relief in a given case.
   7.   Follow-up
   7.1.   Member States should continue working on possible ways to improve the cooperation of tax authorities, including at local and regional level, in order to assist taxpayers who are subject to double taxation.
   7.2.   Member States should also adopt a coordinated position in discussions at the Organisation for Economic Cooperation and Development (OECD) on inheritance taxes.
   7.3.   The Commission will follow up on the Recommendation with Member States and publish a report on the state of play of cross-border relief for inheritance taxes within the Union three years after the adoption of the Recommendation.
   8.   Addressees
   This Recommendation is addressed to the Member States.

      Done at Brussels, 15 December 2011.

            For the Commission

         Algirdas ŠEMETA

            Member of the Commission


title: 2013/637/EU: Commission Recommendation of 4 November 2013 amending Recommendation 2006/576/EC as regards T-2 and HT-2 toxin in compound feed for cats  Text with EEA relevance

text:
               6.11.2013

               EN

               Official Journal of the European Union

               L 294/44

         COMMISSION RECOMMENDATION
   of 4 November 2013
   amending Recommendation 2006/576/EC as regards T-2 and HT-2 toxin in compound feed for cats
   (Text with EEA relevance)
   (2013/637/EU)
   THE EUROPEAN COMMISSION,
   Having regard to the Treaty on the Functioning of the European Union, and in particular Article 292 thereof,
   Whereas:

               (1)

               T-2 toxin and HT-2 toxin are mycotoxins produced by various Fusarium species. T-2 toxin is rapidly metabolised to a large number of products, HT-2 toxin being a major metabolite.

               (2)

               The Scientific Panel on Contaminants in the Food Chain (CONTAM panel) of the European Food Safety Authority (EFSA) adopted an opinion on a request from the Commission related to the risks for animal and public health related to the presence of T-2 and HT-2 toxin in food and feed (1).

               (3)

               As regards the animal health risk, the CONTAM panel concluded that for ruminants, rabbits and fish, the current estimated exposure to T-2 and HT-2 toxin is considered unlikely to be a health concern. For pigs, poultry, horses and dogs, the estimates of exposure to T-2 and HT-2 toxin indicate that the risk of adverse health effects is low. Cats are amongst the most sensitive animal species. Due to the limited data and the severe adverse health effects at low dose levels, no No Observed Adverse Effect Level (NOAEL) or Lowest Observed Adverse Effect Level (LOAEL) could be established.

               (4)

               Taking into account the conclusions of the scientific opinion, investigations have to be undertaken in order to collect information on the factors resulting in relative high levels of T2 and HT-2 toxin in cereals and cereal products and on the effects of feed and food processing. Therefore, Commission Recommendation 2013/165/EU (2) was adopted to recommend carrying out these investigations.

               (5)

               Given the toxicity of T-2 and HT-2 toxin for cats it is appropriate to establish in addition a guidance value for the sum of T-2 and HT-2 toxin in cat feed to be applied for judging the acceptability of cat feed as regards the presence of T-2 and HT-2 toxin. Commission Recommendation 2006/576/EC (3) should therefore be amended,

         HAS ADOPTED THIS RECOMMENDATION:
   In the Annex of Recommendation 2006/576/EC, the following entry is added after the entry on Fumonisin B1 + B2:

                  ‘Mycotoxin

                  Products intended for animal feed

                  Guidance value in mg/kg (ppm) relative to a feedingstuff with a moisture content of 12 %

                  T-2 + HT-2 toxin

                  Compound feed for cats

                  0,05’

      Done at Brussels, 4 November 2013.

            For the Commission

         Tonio BORG

            Member of the Commission

      (1)  EFSA Panel on Contaminants in the Food Chain (CONTAM); Scientific Opinion on risks for animal and public health related to the presence of T-2 and HT-2 toxin in food and feed, EFSA Journal 2011; 9(12):2481. [187 pp.] doi:10.2903/j.efsa.2011.2481. Available online: www.efsa.europa.eu/efsajournal

      (2)  Commission Recommendation 2013/165/EU of 27 March 2013 on the presence of T-2 and HT-2 toxin in cereals and cereal products (OJ L 91, 3.4.2013, p. 12).

      (3)  Commission Recommendation 2006/576/EC of 17 August 2006 on the presence of deoxynivalenol, zearalenone, ochratoxin A, T-2 and HT-2 and fumonisins in products intended for animal feeding (OJ L 229, 23.8.2006, p. 7).


Important legal notice

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52006SC1135

Recommendation from the Commission to the Council on the participation of the European Community in negotiations on international rules and procedures in the field of liability and redress for damage resulting from transboundary movements of Living Modified Organisms (LMOs) under the Cartagena Protocol on Biosafety  /* SEC/2006/1135 final */

	[pic] | COMMISSION OF THE EUROPEAN COMMUNITIES |Brussels, 15.09.2006SEC(2006) 1135 finalRECOMMENDATION FROM THE COMMISSION TO THE COUNCILon the participation of the European Community in negotiations on international rules and procedures in the field of liability and redress for damage resulting from transboundary movements of Living Modified Organisms (LMOs) under the Cartagena Protocol on BiosafetyA. EXPLANATORY MEMORANDUM1. The Cartagena Protocol on Biosafety to the Convention on Biological Diversity entered into force on 11 September 2003. The Protocol provides a framework, based on the precautionary principle, for the safe transfer, handling and use of living modified organisms (LMOs) resulting from modern biotechnology that may have adverse effects on the conservation and sustainable use of biological diversity, or pose risks to human health. The Protocol focuses specifically on transboundary movements.2. The Council adopted a Decision on the conclusion, on behalf of the European Community, of the Protocol on 25 June 2002. The instrument for Community ratification was deposited on 27 August 2002.3. According to Article 27 of the Protocol, the Conference of the Parties serving as the Meeting of the Parties to the Protocol (COP/MOP) shall, at its first meeting, adopt a process with respect to the appropriate elaboration of international rules and procedures in the field of liability and redress for damage resulting from transboundary movements of living modified organisms, analysing and taking due account of the ongoing processes in international law on these matters, and shall endeavour to complete this process within four years. The COP/MOP established at its first meeting in 2004 an Open-ended Ad Hoc Working Group of Legal and Technical Experts on Liability and Redress to fulfil Article 27.4. The mandate of this group is to examine information and analyse general issues relating to liability and redress for damage resulting from transboundary movements of LMOs and to elaborate options for elements of rules and procedures on liability and redress. The Ad Hoc Group on Liability and Redress met twice,from 25 to 27 May 2005 and from 20 to 24 February 2006 in Montreal, Canada. After the review of information and analysis of general issues, the Group has moved to the elaboration of operational text for the various elements of the rules and procedures on liability and redress. The third, fourth and fifth meeting of the Group will take place in 2007 and to 2008 in order for it be able to present its final report together with the proposed international rules and procedures in the field of liability and redress to COP/MOP4 scheduled for 2008 in Germany.5. According to Article 174.1 of the EC Treaty, one of the objectives of Community environment policy is the promotion of measures at international level to deal with regional or worldwide environmental problems. To achieve this objective, the Community may conclude agreements with third parties in accordance with Articles 175 and 300.6. According to the Article 300.1 of the EC Treaty, for the conclusion of agreements between the Community and one or more States or international organisations, the Commission shall make recommendations to the Council, which shall authorise the Commission to open the necessary negotiations. The Commission shall conduct these negotiations in consultation with special committees appointed by the Council to assist it in this task and within the framework of such directives as the Council may issue to it. In exercising the powers conferred upon it by this paragraph, the Council shall act by a qualified majority, except in the cases where the first subparagraph of paragraph 2 provides that the Council shall act unanimously.7. The text of the international rules and procedures on liability and redress that will be presented to COP/MOP4 for adoption in 2008 will be negotiated in the next three meetings of Ad Hoc Working Group of Legal and Technical Experts on Liability and Redress. These rules and procedures concern environmental protection and will constitute an agreement in the sense of Article 300.1 of the EC Treaty. A number of EC legislative instruments[1] cover liability and redress for damage resulting from transboundary movements of LMOs. Member States cannot take on obligations outside the framework of Community legislation which might affect Community rules or alter their scope.8. Therefore, it is necessary for the Commission to make recommendations to the Council, which shall authorise the Commission to open the necessary negotiations on this issue at the next meetings of the Open-ended Ad Hoc Working Group of Legal and Technical Experts on Liability and Redress in 2007 and 2008 and at COP/MOP4 in 2008.B. RECOMMENDATIONIn the light of the above, the Commission recommends that:1.  the Council authorises the Commission to participate, on behalf of the European Community, as regards matters falling under Community competence, in the negotiations on international rules and procedures in the field of liability and redress for damage resulting from transboundary movements of LMOs under the Cartagena Protocol on Biosafety at the third, fourth and fifth meeting of the Open-ended Ad Hoc Working Group of Legal and Technical Experts on Liability and Redress and at the fourth meeting of the Conference of the Parties serving as the Meeting of the Parties to the Protocol.2.  the Commission conducts these negotiations on behalf of the European Community, as regards matters falling within Community competence, in consultation with a special committee of representatives of Member States in accordance with the appended negotiating directives;3.  when the rules and procedures deal with matters falling within the shared competence of the Community and of the Member States, the Commission and the Member States should cooperate closely during the negotiation process, with a view to aiming for unity in the international representation of the European Community;4.  the Council issues the appended negotiating directives.ANNEXNEGOTIATING DIRECTIVES1. The Commission shall ensure that the international rules and procedures in the field of liability and redress for damage resulting from transboundary movements of LMOs to be adopted under the Cartagena Protocol on Biosafety are consistent with relevant Community legislation and that the capacities of developing countries are taken into account during the negotiations of these rules and procedures.2. The Commission shall ensure that, should the rules and procedure or parts thereof take the form of a legally binding agreement, the latter contains appropriate provisions allowing the Community to become a Party thereto.3. The Commission shall report to the Council on the outcome of the negotiations and, where appropriate, on any problem that may arise during the negotiations. [1] Inter alia , Directive 2004/35/CE on environmental liability with regard to the prevention and remedying of environmental damage, OJ L 143, 21.4.2004, p.56; Directive 85/374/EEC on the approximation of the laws, regulations and administrative provisions of the Member States concerning liability for defective products, OJ L 210, 7.8.1985, p.29, as later amended; Regulation (EC) 44/2001 on jurisdiction and the recognition and enforcement of judgments in civil and commercial matters, OJ L 12, 22.12.2000, p.1.