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31990L0658

Council Directive 90/658/EEC of 4 December 1990 amending certain Directives on the recognition of professional qualifications consequent upon the unification of Germany

Official Journal L 353 , 17/12/1990 P. 0073 - 0076 Finnish special edition: Chapter 6 Volume 3 P. 0079  Swedish special edition: Chapter 6 Volume 3 P. 0079

COUNCIL DIRECTIVE  of 4 December 1990  amending certain Directives on the recognition of professional qualifications consequent upon the unification of Germany (90/658/EEC) THE COUNCIL OF THE EUROPEAN COMMUNITIES,    Having regard to the Treaty establishing the European Economic Community, and in particular Article 49, Article 57 (1) and (2), first and third sentences, and Article 66 thereof,    Having regard to the proposal from the Commission(1),    In cooperation with the European Parliament(2),    Having regard to the opinion of the Economic and Social Committee(3),    Whereas, by reason of the unification of Germany, certain amendments should be made to Directives 75/362/EEC(4), 77/452/EEC(5), 78/686/EEC(6), 78/1026/EEC(7) and 80/154/EEC(8), as last amended by Directive 89/594/EEC(9) and Directive 89/595/EEC(10)  concerning the mutual recognition of diplomas, certificates and other evidence of formal qualifications as doctors, nurses responsible for general care, dental practitioners, veterinary surgeons and midwives respectively, and to Directive  85/433/EEC(11), as amended by Directive 85/584/EEC(12), and Directive 85/384/EEC(13), as last amended by Directive 86/17/EEC(14), concerning the mutual recognition of diplomas, certificates and other evidence of formal qualifications in the field of  pharmacy and architecture respectively and to Directive 75/363/EEC(15), as last amended by Directive 89/594/EEC, concerning the coordination of provisions laid down by law, regulation or administrative action relating to the activities of doctors;     () () Whereas from the date of German unification Community law will be fully applicable to the territory of the former German Democratic Republic;    Whereas it is necessary to make changes to the said Directives to take account of the specific situation in the said territory;    Whereas, in accordance with the principle of acquired rights, the diplomas, certificates or other evidence of formal qualifications held by German nationals in that territory who are pursuing their professional activities on the basis of training  which began before unification and does not conform to Community rules on training should be granted recognition under similar conditions to those applied to other nationals of Member States at the time of the adoption of the said Directives or  accessions to the Community;    Whereas it is necessary to protect at Community level the rights acquired by the holders of former qualifications which are no longer awarded as a result of changes which have taken place in the rules of the Member States which awarded the  qualification to them; whereas such a provision was introduced by Directive 89/594/EEC into most Directives on the mutual recognition of diplomas, certificates and other evidence of formal qualifications; whereas it could also be applied, unamended, to  German nationals from the territory of the former German Democratic Republic; whereas a similar provision should also be incorporated into Directive 85/433/EEC relating to the mutual recognition of diplomas, certificates and other evidence of formal  qualifications in pharmacy;    Whereas most of the specific provisions relating to the recognition of diplomas, certificates or other evidence of formal qualifications awarded by the former German Democratic Republic cease to be relevant as a result of German unification; whereas  they should be repealed,   HAS ADOPTED THIS DIRECTIVE:      Article 1  Directive 75/362/EEC is hereby amended as follows:    1.In Article 3 (a), point 3, 'in Germany' shall be deleted.    2.The following Article shall be inserted:    'Article 9a   1.  In the case of nationals of Member States whose diplomas, certificates and other evidence of formal qualifications in medicine attest to training received on the territory of the former German Democratic Republic which does not satisfy all the  minimum training requirements laid down in Article 1 of Directive 75/363/EEC, Member States other than Germany shall recognize those diplomas, certificates and other evidence of formal qualifications as being sufficient proof if:    they attest to training commenced before German unification,    they entitle the holder to pursue the activities of a doctor throughout the territory of Germany under the same conditions as the qualifications awarded by the competent German authorities and referred to in points 1 and 2 of Article 3 (a), and   they are accompanied by a certificate issued by the competent German authorities stating that those nationals have effectively and lawfully been engaged in the activities in question in Germany for at least three consecutive years during the five  years prior to the date of issue of the certificate.    2.  In the case of nationals of Member States whose diplomas, certificates and other evidence of formal qualifications in specialized medicine attest to training received on the territory of the former German Democratic Republic which does not satisfy  the minimum training requirements laid down in Articles 2 to 5 of Directive 75/363/EEC, Member States other than Germany shall recognize those diplomas, certificates and other evidence of formal qualifications as being sufficient proof if:    they attest to training commenced before the expiry of the time limit laid down in Article 9 (1), second subparagraph, of Directive 75/363/EEC, and   they permit the pursuit, as a specialist, of the activity in question throughout the territory of Germany under the same conditions as the qualifications awarded by the competent German authorities and referred to in Articles 5 and 7.    They may, however, require that these diplomas, certificates or other evidence of formal qualifications be accompanied by a certificate issued by the competent German authorities or bodies stating that the holders have, as specialists, been engaged in  the activity in question for a period equivalent to twice the difference between the period of specialized training received on German territory and the minimum duration of training laid down in Directive 75/363/EEC, where they do not satisfy the  minimum requirements regarding the duration of training laid down in Articles 4 and 5 of Directive 75/363/EEC.'    Article 2  The following second subparagraph is hereby added to Article 9 (1) of Directive 75/363/EEC:    'For the territory of the former German Democratic Republic, however, Germany shall take the measures necessary to comply with Articles 2 to 5 within 18 months of unification.'    Article 3  Directive 77/452/EEC is hereby amended as follows:    1.In Article 3 (a), the second indent, 'in Germany' shall be deleted;    2.The following Article shall be inserted:    'Article 4a   In the case of nationals of Member States whose diplomas, certificates and other evidence of formal qualifications as nurses responsible for general care attest to training received on the territory of the former German Democratic Republic which does  not satisfy all the minimum training requirements laid down in Article 1 of Directive 77/453/EEC, Member States other than Germany shall recognize those diplomas, certificates and other evidence of former qualifications as being sufficient proof if:  they attest to training commenced before German unification,  they entitle the holder to pursue the activities of a nurse responsible for general care throughout the territory of Germany under the same conditions as the qualifications awarded by the competent German authorities and referred to in Article 3 (a),  and   they are accompanied by a certificate issued by the competent German authorities stating that those nationals have effectively and lawfully been engaged in the activities of nurse responsible for general care in Germany for at least three years during  the five years prior to the date of issue of the certificate. These activities must have included taking full responsibility for the planning, organization and carrying-out of the nursing care of the patient.'    Article 4  Directive 78/686/EEC is hereby amended as follows:    1.In Article 3 (a), 'in Germany', the following shall be deleted:    presentation in the form of two numbered points,    the text of point 2;    2.The following Article shall be inserted:    'Article 7 a   1.  In the case of nationals of Member States whose diplomas, certificates and other evidence of formal qualifications as dental practitioner attest to training received on the territory of the former German Democratic Republic which does not satisfy  all the minimum training requirements laid down in Article 1 of Directive 78/687/EEC, Member States other than Germany shall recognize those diplomas, certificates and other evidence of formal qualifications as being sufficient proof if:    they attest to training commenced before German unification,    they entitle the holder to pursue the activities of a dental practitioner throughout the territory of Germany under the same conditions as the qualifications awarded by the competent German authorities and referred to in Article 3 (a), and   they are accompanied by a certificate issued by the competent German authorities stating that those nationals have effectively and lawfully been engaged in the activities in question in Germany for at least three consecutive years during the five  years prior to the date of issue of the certificate.    2.  In the case of nationals of Member States whose diplomas, certificates and other evidence of formal qualifications as specialist dental practitioners attest to training received in the territory of the former German Democratic Republic which does  not satisfy the minimum training requirements laid down in Articles 2 and 3 of Directive 78/687/EEC, Member States other than Germany shall recognize those diplomas, certificates and other evidence of formal qualifications as being sufficient proof if:     they attest to training commenced before German unification, and   they entitle the holder to pursue, as a specialist dental practitioner, the activity in question throughout the territory of Germany under the same conditions as the qualifications awarded by the competent German authorities and referred to in Article  5 (1) and (2).    They may, however, require that these diplomas, certificates or other evidence of formal qualifications be accompanied by a certificate issued by the competent German authorities or bodies stating that the holder has, as a specialist dental  practitioner, been engaged in the activity in question for a period equivalent to twice the difference between the period of specialized training received on German territory and the minimum duration of training laid down in Directive 78/687/EEC, where  they do not satisfy the minimum requirements regarding the duration of training laid down in Article 2 of Directive 78/687/EEC.' Article  Article 5  Directive 78/1026/EEC is hereby amended as follows:    1.In Article 3 (a), 'in Germany', the following shall be deleted:    presentation in the form of two numbered points,    the text of point 2.    2.The following Article shall be inserted:    'Article 4a   In the case of nationals of Member States whose diplomas, certificates and other evidence of formal qualifications as veterinary surgeons attest to training received in the territory of the former German Democratic Republic which does not satisfy all  the minimum training requirements laid down in Article 1 of Directive 78/1027/EEC, Member States other than Germany shall recognize those diplomas, certificates and other evidence of formal qualifications, as being sufficient proof if:    they attest to training commenced before German unification;    they entitle the holder to pursue the activities of a veterinary surgeon throughout the territory of Germany under the same conditions as the qualifications awarded by the competent German authorities and referred to in Article 3 (a), and   they are accompanied by a certificate issued by the competent German authorities stating that those nationals have effectively and lawfully been engaged in the activities in question in Germany for at least three consecutive years during the five  years prior to the date of issue of the certificate.' Article  Article 6  Directive 80/154/EEC is hereby amended as follows:    1.In Article 3 (a) 'in Germany' the following shall be deleted:    presentation in the form of two indents,    the text of the second indent.    2.the following Article shall be added:    'Article 5a   1.  In the case of Member States whose diplomas, certificates and other evidence of formal qualifications as midwife attest to training received on the territory of the former German Democratic Republic which does not satisfy all the minimum training  requirements laid down in Article 1 of Directive 80/155/EEC, Member States other than Germany shall recognize those diplomas, certificates and other evidence of formal qualifications as being sufficient proof if:    they attest to training commenced before German unification;    they entitle the holder to pursue the activities of a midwife throughout the territory of Germany under the same conditions as the qualifications awarded by the competent German authorities and referred to in Article 3 (a), and   they are accompanied by a certificate issued by the competent German authorities stating that those nationals have effectively and lawfully been engaged in the activities in question in Germany for at least three years during the five years prior to  the date of issue of the certificate.    2.  In the case of nationals of Member States whose diplomas, certificates and other evidence of formal qualifications as midwives attest to training received in the territory of the former German Democratic Republic which satisfies all the minimum  training requirements laid down in Article 1 of Directive 80/155/EEC but which, pursuant to Article 2, has to be recognized only if it is complemented by the professional practice referred to in Article 4, Member States other than Germany shall  recognize those diplomas, certificates and other evidence of formal qualifications as being sufficient proof if:    they attest to training commenced before German unification, and   they are accompanied by a certificate stating that those nationals have effectively and lawfully been engaged in the activities in question in Germany for at least two years during the five years prior to the date of issue of the certificate.'    Article 7  Directive 85/433/EEC is hereby amended as follows:    1.In Article 4 (a), 'in Germany', the following shall be deleted:    presentation in the form of two numbered points,    the text of point 2.    2.In Article 6:    the present text becomes paragraph 1,    the following paragraph 2 shall be added:   '2.  Diplomas, certificates and other university or equivalent qualifications in pharmacy which were awarded to nationals of Member States by Member States and which satisfy all the minimum training requirements laid down in Article 2 of Directive  85/432/EEC but which do not conform to the designations set out in Article 4 shall be treated, for the purposes of the Directive, as the diplomas set out in that Article if they are accompanied by a certificate stating that they attest to training  conforming to the provisions of Directive 85/432/EEC referred to in Article 2 of this Directive and shall be treated by the Member States which awarded them as those designations are set out in Article 4 of this Directive.'   3.The following Article shall be inserted:    'Article 6a   Diplomas, certificates and other university or equivalent qualifications in pharmacy which attest to training received by nationals of the Member States on the territory of the former German Democratic Republic and which do not satisfy all the minimum  training requirements laid down in Article 2 of Directive 85/432/EEC shall be treated as diplomas satisfying these requirements if:    they attest to training commenced before German unification,    they entitle the holder to pursue the activities of pharmacist throughout the territory of Germany under the same conditions as the qualifications awarded by the competent German authorities and referred to in Article 4 (c), and   they are accompanied by a certificate stating that their holders have effectively and lawfully been engaged in Germany in one of the activities referred to in Article 1 (2) of Directive 85/432/EEC for at least three consecutive years during the five  years prior to the date of issue of the certificate, provided that such activity is regulated in the Member State in question.'    Article 8  Article 6 of Directive 85/384/EEC is hereby deleted.    Article 9  Member States shall take the necessary measures to comply with this Directive by 1 July 1991. They shall forthwith inform the Commission thereof.    When Member States take these measures, they shall contain a reference to this Directive or shall be accompanied by such reference on the occasion of their official publication. The methods of making such a reference shall be laid down by the Member  States.   Article 10  This Directive is addressed to the Member States.    Done at Brussels, 4 December 1990.  For the CouncilThe PresidentG. DE MICHELIS   (1)OJ No L 266, 28. 9. 1990, p. 12, as amended on 28 November 1990.  (2) Opinion delivered on 24 October 1990 (not yet published in the Official Journal) and Decision of 21 November 1990 (not yet published in the Official Journal).  (3) Opinion delivered on 20 November 1990 (not yet published in the Official Journal).  (4)OJ No L 167, 30. 6. 1975, p. 1.  (5) OJ No L 176, 15. 7. 1977, p. 1.  (6) OJ No L 233, 24. 8. 1978, p. 1.  (7) OJ No L 362, 23. 12. 1978, p. 1.  (8) OJ No L 33, 11. 2. 1980, p. 1.  (9) OJ No L 341, 23. 11. 1989, p. 19.  (10)OJ No L 341, 23. 11. 1989, p. 30.  (11) OJ No L 253, 24. 9. 1985, p. 37.  (12) OJ No L 372, 31. 12. 1985, p. 42.  (13) OJ No L 223, 21. 8. 1985, p. 15.  (14) OJ No L 27, 1. 2. 1986, p. 71.  (15) OJ No L 167, 30. 6. 1975, p. 14.


Avis juridique important

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31975L0318

Council Directive 75/318/EEC of 20 May 1975 on the approximation of the laws of Member States relating to analytical, pharmaco-toxicological and clinical standards and protocols in respect of the testing of proprietary medicinal products

Official Journal L 147 , 09/06/1975 P. 0001 - 0012 Finnish special edition: Chapter 13 Volume 4 P. 0086  Greek special edition: Chapter 13 Volume 3 P. 0054  Swedish special edition: Chapter 13 Volume 4 P. 0086  Spanish special edition: Chapter 13 Volume 4 P. 0080  Portuguese special edition Chapter 13 Volume 4 P. 0080

COUNCIL DIRECTIVE  of 20 May 1975  on the approximation of the laws of Member States relating to analytical, pharmaco-toxicological and clinical standards and protocols in respect of the testing of proprietary medicinal products  (75/318/EEC)  THE COUNCIL OF THE EUROPEAN COMMUNITIES,  Having regard to the Treaty establishing the European Economic Community, and in particular Article 100 thereof;  Having regard to the proposal from the Commission;  Whereas the approximation begun by Council Directive 65/65/EEC (1) of 26 January 1965 on the approximation of provisions laid down by law, regulation or administrative action relating to proprietary medicinal products should be continued and the implementation of the principles laid down in that Directive should be ensured;  Whereas among existing disparities those relating to the control of proprietary medicinal products are of fundamental importance and point 8 of Article 4, second paragraph of the said Directive requires that applications for authorization to place a proprietary medicinal product on the market should be accompanied by particulars and documents relating to the results of tests and trials carried out on the product concerned;  Whereas standards and protocols for the performance of tests and trials on proprietary medicinal products are an effective means of control of these products and hence of protecting public health and can facilitate the movement of these products by laying down uniform rules applicable to tests and trials, the compilation of dossiers and the examination of applications;  Whereas the adoption of the same standards and protocols by all the Member States will enable the competent authorities to arrive at their decisions on the basis of uniform tests and by reference to uniform criteria and will therefore help to avoid differences in evaluation;  Whereas the physico-chemical, biological or microbiological tests provided for in point 8 of Article 4, second paragraph, of Directive 65/65/EEC are closely related to points 3, 4, 6 and 7 of the same paragraph and it is therefore necessary to specify the data to be provided pursuant to these points;  Whereas the quality of the tests is the essential consideration ; whereas therefore tests carried out in accordance with these provisions must be taken into consideration irrespective of the nationality of the experts who perform them or the country in which they are carried out;  Whereas the concepts of "harmfulness" and "therapeutic efficacy" referred to in Article 5 of Directive 65/65/EEC can only be examined in relation to each other and have only a relative significance depending on the progress of scientific knowledge and the use for which the proprietary medicinal product is  (1)OJ No 22, 9.2.1965, p. 369/65.   intended ; whereas the particulars and documents which must accompany an application for authorization to place a proprietary medicinal product on the market demonstrate that potential risks are outweighed by the therapeutic efficacy of the product ; whereas failing such demonstration, the application must be rejected;  Whereas the evaluation of "harmfulness" and "therapeutic efficacy" may be modified in the light of new discoveries and standards and protocols must be amended periodically to take account of scientific progress,  HAS ADOPTED THIS DIRECTIVE:    Article 1 Member States shall take all appropriate measures to ensure that the particulars and documents which must accompany applications for authorization to place a proprietary medicinal product on the market (marketing authorization), pursuant to points 3, 4, 6, 7 and 8 of Article 4, second paragraph, of Directive 65/65/EEC, are submitted by the persons concerned in accordance with the Annex to this Directive.  Where, pursuant to point 8 (a) and (b) of Article 4, second paragraph, of the abovementioned Directive, references to published data are submitted, the provisions of this Directive shall apply in like manner.   Article 2 Notwithstanding the provisions of other Directives on proprietary medicinal products, Member States shall take all appropriate measures to ensure that the competent authorities examine the particulars and documents submitted in support of applications for marketing authorization in accordance with the criteria of the Annex to this Directive.   Article 3 Member States shall bring into force the provisions needed in order to comply with this Directive within 18 months of its notification and shall forthwith inform the Commission thereof.  Member States shall ensure that they communicate to the Commission the text of the main provisions of national law which they adopt in the field covered by this Directive.   Article 4 This Directive is addressed to the Member States.     Done at Brussels, 20 May 1975.  For the Council  The President  R. RYAN     ANNEX   PART 1 PHYSICO-CHEMICAL, BIOLOGICAL OR MICROBIOLOGICAL TESTS OF PROPRIETARY MEDICINAL PRODUCTS  A. QUALITATIVE AND QUANTITATIVE PARTICULARS OF THE CONSTITUENTS  The particulars and documents which must accompany applications for marketing authorization, pursuant to point 3 of Article 4, second paragraph, of Directive 65/65/EEC shall be submitted in accordance with the following requirements.    1. "Qualitative particulars" of all the constituents of the proprietary medicinal product shall mean the designation or description of:      - the active ingredient(s);           - the constituent(s) of the excipients, whatever their nature or the quantity used, including colouring matter, preservatives, stabilizers, thickeners, emulsifiers, flavouring and aromatic substances, etc.;           - the constituents, intended to be ingested or otherwise administered to the patient, of the outer covering of the proprietary medicinal products - capsules, gelatine capsules, cachet shells, rectal capsules, etc.             These particulars shall be supplemented by any relevant data concerning the container and, where appropriate, its manner of closure.       2. The "usual terminology", to be used in describing the constituents of proprietary medicinal products, shall mean, notwithstanding the application of the other provisions of point 3 of Article 4, second paragraph, of Directive 65/65/EEC:      - in respect of substances which appear in the European Pharmacopoeia or, failing this, in the national pharmacopoeia of one of the Member States, the main title at the head of the monograph in question, with reference to the pharmacopoeia concerned;           - in respect of other substances, the international non-proprietary name recommended by the World Health Organization, which may be accompanied by another non-proprietary name, or, failing these, the exact scientific designation ; substances not having an international non-proprietary name or an exact scientific designation shall be described by a statement of how and from what they were prepared, supplemented, where appropriate, by any other relevant details;           - in respect of colouring matter, designation by the "E" code assigned to them in a future Council Directive on the approximation of the rules of the Member States concerning the colouring matters authorized for use in proprietary medicinal products.                  3. In order to give "quantitative particulars" of the active constituents of the proprietary medicinal products, it is necessary, depending on the pharmaceutical form concerned, to specify the weight, or the number of international units, either per dosage-unit or per unit of weight or volume, of each active ingredient.  This information shall be supplemented:    - in respect of injectable preparations, by the weight of each active ingredient in the unit container, taking into account the usable volume of the product;       - in respect of proprietary medicinal products to be administered by drops, by the weight of each active ingredient contained in the number of drops corresponding to an average dose;       - in respect of syrups, emulsions, granular preparations and other pharmaceutical forms to be administered in measured quantities, by the weight of each active ingredient per measured quantity.         Active ingredients present in the form of compounds or derivatives shall be described quantitatively by their total weight, and if necessary or relevant, by the weight of the active moiety or moieties of the molecule (in the case of chloramphenicol palmitate, for example, the weight of the ester and that of the corresponding chloramphenicol shall be given).  The biological units of activity of substances which have not been defined chemically, and on which there is insufficient bibliographical information, shall be expressed in such a way as to provide unambiguous information on the activity of the substances.  B. DESCRIPTION OF METHOD OF PREPARATION  The "brief description of the method of preparation" accompanying the application for marketing authorization pursuant to point 4 of Article 4, second paragraph, of Directive 65/65/EEC, shall be drafted in such a way as to give an adequate synopsis of the nature of the operations employed.   For this purpose it shall include at least:    - mention of the various stages of manufacture, so that an assessment can be made of whether the processes employed in producing the pharmaceutical form might have produced an adverse change in the constituents;       - in the case of continuous manufacture, full details concerning precautions taken to ensure the homogeneity of the final product;       - the actual manufacturing formula, with the quantitative particulars of all the substances used, the quantities of excipients, however, being given in approximate terms in so far as the pharmaceutical form makes this necessary ; mention shall be made of any substances that may disappear in the course of manufacture;       - a statement of the stages of manufacture at which sampling is carried out for in-process control tests, where other data in the documents supporting the application show such texts to be necessary for the quality control of the proprietary medicinal product.         C. CONTROL OF STARTING MATERIALS  For the puposes of this paragraph, "starting materials" shall mean all the constituents of the proprietary medicinal product and, if necessary, of its container, as referred to in paragraph A point 1, above.  The particulars and documents accompanying the application for marketing authorization pursuant to points 7 and 8 of Article 4, second paragraph, of Directive 65/65/EEC shall include the results of the tests relating to quality control of all the constituents used. These shall be submitted in accordance with the following provisions.  1. Starting materials listed in pharmacopoeias  The monographs of the European Pharmacopoeia shall be applicable to all substances appearing in it.  In respect of other substances, each Member State may require observance of its own national pharmacopoeia with regard to products manufactured in its territory.  Constituents fulfilling the requirements of the European Pharmacopoeia or the pharmacopoeia of one of the Member States shall be deemed to comply sufficiently with point 7 of Article 4, second paragraph, of Directive 65/65/EEC. In this case the description of the analytical methods may be replaced by a detailed reference to the pharmacopoeia in question.  However, where a starting material in the European Pharmacopoeia or in the pharmacopoeia of a Member State has been prepared by a method liable to leave impurities not mentioned in the pharmacopoeia monograph these impurities and their maximum tolerance levels must be declared and a suitable test method advanced.  Reference to pharmacopoeias of third countries may be permitted in cases where the substance is described neither in the European Pharmacopoeia nor in the national pharmacopoeia concerned ; in that case the monograph shall be submitted, accompanied where necessary by a translation for which the applicant will be responsible.  Colouring matter shall, in all cases, satisfy the requirements of a future Council Directive on the approximation of the rules of the Member States concerning the colouring matters authorized for use in proprietary medicinal products.  For routine tests on each batch of starting material, only that part of the pharmacopoeia relating to control tests (purity and strengths) shall be mandatory ; the full range of identity tests need not necessarily be performed where those that have been performed permit an unambiguous characterization. In this case, the reference to the monograph of the pharmacopoeia mentioned above shall include details relating to this aspect.  In cases where a specification contained in a monograph of the European Pharmacopoeia or in the national pharmacopoeia of a Member State might be insufficient to ensure the quality of the substance, the competent authorities may request more appropriate specifications from the person responsible for placing the product on the market.  2. Starting materials not in a pharmacopoeia  Constituents which are not given in any pharmacopoeia shall be described in the form of a monograph under the following headings:    (a) The name of the substance, meeting the requirements of paragraph A, point 2, shall be supplemented by any trade or scientific synonyms;       (b) the description of the substance, set down in a form similar to that used in a descriptive item in the European Pharmacopoeia, shall be accompanied by any necessary explanatory evidence, especially concerning the molecular structure where appropriate ; it must in such a case be accompanied by a brief indication of the method of synthetic preparation. Where substances can only be described by their method of preparation, the description should be sufficiently detailed to characterize a substance which is constant both in its composition and in its effects;       (c) methods of indentification may be described in the form of complete techniques as used for production of the substance, and in the form of tests which ought to be carried out as a routine matter;       (d) purity tests shall be described in relation to the sum total of predictable impurities, especially those which may have a harmful effect, and, if necessary, those which, having regard to the combination of substances to which the application refers, might adversely affect the stability of the proprietary medicinal product or distort analytical results;        (e) the assay technique(s) must be described in sufficiently precise detail so as to be reproducible in control tests, carried out at the request of the competent authority ; any special apparatus and equipment which may be used shall be described in adequate detail, possibly accompanied by a diagram. The formulae of the laboratory reagents shall be supplemented, if necessary, by the method of preparation.  The standard error of the method, its reliability and the acceptability limits of the results shall be specified and, if necessary, explained.  With regard to complex substances of plant or animal origin, a distinction must be made between the case where multiple pharmacological effects render chemical, physical or biological control of the principal constituents necessary, and the case of substances containing one or more groups of principles having similar activity, in respect of which an overall method of assay may be accepted;  (f) any special precautions that may be necessary during storage of the starting material and, if necessary, its storage life shall be given.  D. CONTROL TESTS CARRIED OUT AT AN INTERMEDIATE STAGE OF THE MANUFACTURING PROCESS  The particulars and documents accompanying an application for marketing authorization ; pursuant to points 7 and 8 of Article 4, second paragraph, of Directive 65/65/EEC, shall include particulars relating to the product control tests that may be carried out at an intermediate stage of the manufacturing process, with a view to ensuring the consistency of the technical characteristics and the production process.  These tests are essential for checking the conformity of the proprietary medicinal product with the formula when, exceptionally, an applicant proposes an analytical technique for testing the finished product which does not include the assay of all the active ingredients (or of all the excipient constituents subject to the same requirements as the active ingredients).  The same applies where the quality control of the finished product depends on in-process control tests, particularly if the substance is essentially defined by its method of preparation.  E. CONTROL TESTS ON THE FINISHED PRODUCT  The particulars and documents accompanying the application for marketing authorization pursuant to points 7 and 8 of Article 4, second paragraph, of Directive 65/65/EEC, shall include particulars relating to control tests on the finished product. They shall be submitted in accordance with the following requirements.   1. General characteristics of the various pharmaceutical forms  Certain tests of the general characteristics of a product which can be carried out in the course of the manufacturing process shall always be included among the tests on the finished product.  As a guideline, and subject to the possible future requirements of the European Pharmacopoeia or the national pharmacopoeias of Member States, the general characteristics which are to be verified for various pharmaceutical forms are given at point 5 below.  These tests shall, wherever applicable, relate to the control of average weights and maximum deviations, to mechanical, physical, or microbiological tests, organoleptic characteristics, such as clarity, colour, taste, physical characteristics such as density, pH, refractive index, etc. For each of these characteristics, standards and tolerances must be specified by the applicant in each particular case.  2. Identification and assay of active ingredient(s)  The description of the techniques for analyzing the finished product shall set out in sufficiently precise detail, so that they can be reproduced readily, the methods used for identification and assay of the active ingredient(s) either in a representative sample from the production batch or in a number of dosage-units analyzed individually.  In every case, the methods must correspond to the state of scientific progress at the time and give details and explanations of the standard errors and reliability of the analytical method and also of maximum acceptable deviations.  In certain exceptional cases of particularly complex mixtures, where assay of active ingredients which are very numerous or present in very low amounts would necessitate an intricate investigation difficult to carry out in respect of each production batch, the assay of one or more active ingredients in the finished product may be omitted, on the express condition that such assays are made at intermediate stages in the production process. This relaxation may not be extended to the characterization of the substances concerned. This simplified technique shall be supplemented by a method of quantitative evaluation, enabling the competent authority to have the conformity of the proprietary medicinal product with its formula verified after it has been placed on the market.  An assay of biological activity shall be obligatory when physico-chemical methods cannot provide adequate information on the quality of the product.  Where the particulars given in paragraph B show that a significant overage of an active ingredient was employed in the manufacture of the proprietary medicinal product, the description of the control tests on the finished product shall include, where appropriate, the chemical and, if necessary, the toxico-pharmacological investigation of the changes that this substance has undergone, and possibly the characterization or assay of the degradation products.   3. Identification and assay of excipient constituents  In so far as is necessary, the constituents of the excipient shall be subject at least to characterization tests.  The method proposed for identifying colouring matters must enable a verification to be made that such matters appear in the list to be annexed to a future Council Directive on the approximation of the rules of the Member States concerning the colouring matters authorized for use in proprietary medicinal products.  An upper limit test shall be obligatory in respect of excipient constituents which are subject to rules relating to toxic substances or which are being used as preservatives, while an assay shall be obligatory in respect of constituents liable to affect physiological functions.  4. Safety tests  Apart from the toxico-pharmacological tests submitted with the application for marketing authorization, particulars of safety tests (abnormal toxicity) or local tolerance in animals shall be included in the analytical particulars wherever such tests must be undertaken as a matter of routine in order to verify the quality of the product.  5. General characteristics of finished products to be verified systematically, depending on the pharmaceutical form of each product  The following requirements are given as an indication and without prejudice to any future requirements of the European Pharmacopoeia or national pharmacopoeias of Member States ; for example, microbiological control tests of preparations for oral administration shall be performed in accordance with the requirements of the European Pharmacopoeia.  Tablets and pills : colour, weight and acceptable variations in unit weight ; if necessary, disintegration time with the method used to determine this.  Coated tablets : colour, disintegration time with the method used to determine this ; weight of finished tablet ; weight of core and acceptable variations in unit weight.  Capsules and gelatine capsules : colour, disintegration time with the method used to determine this ; appearance and weight of content with acceptable variations in unit weight.  Enteric-coated preparations (tablets, capsules, gelatine capsules, granular preparations) : in addition to the requirements of the particular pharmaceutical form, resistance time in an artificial gastric medium, with the method used to determine this ; disintegration time in an artificial intestinal medium, with the method used to determine this.  Preparations with special protective coating (tablets, capsules, gelatine capsules, granular preparations) : in addition to the requirements of the particular pharmaceutical form, verification of the effectiveness of the coating for the desired purpose.  Preparations with gradual release of the active principle : in addition to the requirements of the particular pharmaceutical form, requirements relating to gradual release, with the method used to determine this.  Cachets, packets and sachets : nature and weight of contents and acceptable variations in unit weight.  Injectable preparations : colour, volume of contents and acceptable variations of this volume ; pH, clarity of solution, size limit of particulate matter in the case of suspensions ; sterility tests, with description of test methods ; except in special cases, in respect of preparations to be administered in single doses of 10 ml or more, a pyrogen test with description of method.  Ampoules with solid content : quantity of product per ampoule and permitted variations in weight ; sterility requirements and tests.  Ampoules to be taken orally : colour, appearance, volume of content and acceptable variations.  Ointments, creams, etc. : colour and consistency ; weight and acceptable margin of variation ; nature of container ; in certain cases microbiological control tests.  Suspensions : colour ; where settlement occurs, the ease of re-suspendability.  Emulsions : colour, type, stability.  Suppositories and pessaries : colour, weight and acceptable variations in unit weight ; melting temperature or disintegration time, with the methods used to determine these.  Aerosols : description of container and valve with details of output ; particle size-limit, where the product is intended to be inhaled.  Collyria, eye ointments, eye lotions : colour, appearance, sterility controls, with description of the method used ; where appropriate, clarity and size limit of particulate matter in the case of suspensions, pH determination.  Syrups, solutions, etc : colour, appearance.  F. STABILITY TESTS  The particulars and documents accompanying the application for marketing authorization pursuant to points 6 and 7 of Article 4, second paragraph, of Directive 65/65/EEC shall be submitted in accordance with the following requirements:  A description shall be given of the investigations by which the shelf life proposed by the applicant has been determined.  Where a finished product is liable to give rise to toxic degradation products the applicant must declare these and indicate characterization and assay methods.  The conclusions shall contain the results of analyses, justifying the proposed shelf life under normal, or, where appropriate, under special storage conditions.  A study of the interaction between product and container shall be submitted wherever the risk of such interaction is regarded as possible, especially where injectable preparations or aerosols for internal use are concerned.    PART 2 TOXICOLOGICAL AND PHARMACOLOGICAL TESTS  The particulars and documents accompanying the application for marketing authorization pursuant to point 8 of Article 4, second paragraph, of Directive 65/65/EEC shall be given in accordance with the requirements of Chapters I and II below.  CHAPTER I PERFORMANCE OF TESTS  A. INTRODUCTION  The toxicological and pharmacological tests must show:    1. the potential toxicity of the product and any dangerous or undesirable toxic effects that may occur under the proposed conditions of use in human beings ; these should be evaluated in relation to the gravity of the pathological condition concerned;       2. the pharmacological properties of the product, in both qualitative and quantitative relationship to the proposed use in human beings. All results must be reliable and of general applicability. Whenever appropriate, mathematical and statistical procedures shall be used in designing the experimental methods and in evaluating the results.         Additionally, it is necessary for clinicians to be given information about the therapeutic potential of the product.  B. TOXICITY 1. Single dose toxicity (acute toxicity)  Acute toxicity test means a qualitative and quantitative study of the toxic reactions which may result from a single administration of the active substance or substances contained in the proprietary medicinal product, in the proportions in which they are present in the actual product.  Wherever practicable, the product in its actual pharmaceutical form shall be subjected to an acute toxicity test.  This study will cover the symptoms observed, including local reactions. Where possible, the LD50 value with its fiducial limits (95 %) will be determined. The period during which the test animals are oberserved shall be fixed by the investigator and shall not be less than one week.  The acute toxicity test must be carried out on at least two mammalian species of known strain, and at least two different routes of administration shall normally be used : one being indentical with or similar to that proposed for use in human beings and the other ensuring systemic absorption of the substance. This determination must be carried out on equal numbers of male and female animals.  In the case of active substances in combination, the study must be carried out in such a way as to check whether or not potentiation or novel toxic effects occur.  2. Repeated dose toxicity (sub-acute or chronic toxicity)  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 and normally it shall last three to six months.  In respect of proprietary medicinal products to be administered once only to humans, a single test lasting two to four weeks shall be performed.  If, however, having regard to the proposed duration of use in human beings, the investigator sees fit to carry out experiments of greater or lesser duration than indicated above, he must give adequate reasons for doing so.  Reasons should also be given for the dosages chosen.  Repeated dose toxicity tests shall be carried out on two species of mammals one of which must be a non-rodent. The choice of route(s) of administration employed shall  depend on the intended therapeutic use and the possibilities of systemic absorption. The method and frequency of dosage shall be clearly stated.  The maximum dose should be chosen so as to bring harmful effects to light. The lower doses will then enable the animal's tolerance of the product to be determined.  Wherever possible, and always in experiments on small rodents, the design of the experiment and the control procedures must be suited to the scale of the problem being tackled and enable fiducial limits to be determined.  The evaluation of the toxic effects shall be based on observation of behaviour, growth, haematological and biochemical tests, especially those relating to the excretory mechanism, and also on autopsy reports and accompanying histological data. The choice and range of each group of tests will depend on the species of animal used and the state of scientific knowledge at the time.  In the case of new combinations of known substances that have been investigated in accordance with the provisions of this Directive, the long-term tests may, except where acute and subacute toxicity tests have demonstrated potentiation or novel toxic effects, be suitably modified by the investigator who shall submit his reasons for such modification. Substances that have been shown to be safe by wide usage over at least three years in clinical treatment of human beings, and by the result of controlled trials shall be treated in the same way as known substances which have already been investigated in accordance with these standards and protocols.  An excipient used for the first time in the pharmaceutical field shall be treated like an active ingredient.  C. FOETAL TOXICITY  This investigation comprises a demonstration of the toxic and especially the teratogenic effects observed in the issue of conception when the substance under investigation has been administered to the female during pregnancy.  Although up to the present these tests have had only a limited predictive value in regard to the application of the results to human beings, they are thought to provide important information where the results show effects such as resorptions and other anomalies.  Omission of these tests, either because the proprietary medicinal product will not normally be used by women capable of childbearing or for other reasons, must be adequately justified.  The tests in question shall be carried out on at least two animal species : a breed of rabbits sensitive to known teratogenic substances and rats or mice (specifying the strain) or, if appropriate, in some other animal species.  The details of the test (number of animals, amounts administered, timing of administration and criteria for evaluation of results) shall depend on the state of scientific knowledge at the time when the application is lodged, and the level of statistical significance that the results must attain.  D. EXAMINATION OF REPRODUCTIVE FUNCTION  If the results of other tests reveal anything suggesting harmful effects on progeny or impairment of male or female reproductive function, this shall be investigated by appropriate tests.  E. CARCINOGENICITY  Tests to reveal carcinogenic effects shall be essential:    1. in respect of substances having a close chemical analogy with known carcinogenic or cocarcinogenic compounds;       2. in respect of substances which have given rise to suspicious changes during the long term toxicological tests.         Such tests may also be required in respect of substances to be included in proprietary medicinal products likely to be administered regularly over a prolonged period of a patient's life.  F. PHARMACODYNAMICS  This heading covers the variations caused by the substance in the functions of the physiological systems, whether these functions are normal or experimentally modified.  This study shall follow two distinct lines of approach.  Firstly, the actions on which the recommended application in therapeutic practice is based shall be adequately described. The results shall be expressed in quantitative terms using, for example, dose-effect curves, time-effect curves etc., and wherever possible, compared with data relating to a substance whose activity is known. Where a higher therapeutic potency is being claimed for a substance, the difference shall be demonstrated and shown to be statistically significant.  Secondly, the investigator shall provide a general pharmacological characterization of the substance, with special reference to collateral effects. In general, the main functions of the physiological systems should be investigated. The depth of this investigation must be increased as the doses liable to produce side-effects approach those producing the main effect for which the substance is being proposed.  The experimental techniques, unless they are standard procedures, must be described in such detail as to allow them to be reproduced, and the investigator must  establish their validity. The experimental results shall be set out clearly and, when relevant to the test, their statistical significance quoted.  Unless good reasons are given to the contrary, any quantitative modification of responses resulting from repeated administration of the substance shall be investigated.  Tests on combinations of active substances may be promoted either by pharmacological premises or by indications of therapeutic effect.  In the first case, the pharmacodynamic study shall demonstrate those interactions which might make the combination of value in therapeutic use.  In the second case, where scientific justification for the combination is sought through therapeutic experimentation, the investigation shall determine whether the effects expected from the combination can be demonstrated in animals, and the importance of any collateral effects shall at least be investigated.  If a combination includes a novel active substance, the latter must previously have been studied in depth.  G. PHARMACOKINETICS  Pharmacokinetics means the study of the fate of the active substance within the organism, and covers the study of the absorption, distribution, biotransformation and elimination of the substance.  The study of these different phases may be carried out both by means of physical, chemical or biological methods, and by observation of the actual pharmacodynamic activity of the substance itself.  Information on distribution and elimination shall be necessary in all cases where such data are indispensable to determine the dosage for humans, and in respect of chemotherapeutic substances (antibiotics, etc.) and substances whose use depends on their non-pharmacodynamic effects (e.g. numerous diagnostic agents etc.)  Pharmacokinetic investigation of pharmacologically active substances is desirable.  In the case of new combinations of known substances which have been investigated in accordance with the provisions of this Directive pharmacokinetic studies shall not be required, if the toxicity tests and therapeutic experimentation justify their omission. The same applies to substances that have been shown to be efficaceous and safe by wide usage over a period of at least three years in the clinical treatment of human beings and by controlled trials.  H. PRODUCTS FOR TOPICAL USE  Where a proprietary medicinal product is intended for topical use systemic absorption must be investigated, due account also being taken of the possible use of the product on broken skin. Only if it is proved that systemic absorption under these conditions is negligible may repeated dose systemic toxicity tests, foetal toxicity tests and studies of reproductive function be omitted.  If, however, systemic absorption is demonstrated during therapeutic experimentation, toxicity tests shall be carried out on animals, and where necessary, foetal toxicity tests.  In all cases tests of local tolerance after repeated application shall be carried out with particular care and include histological examinations ; the possibility of sensitization shall be investigated and any carcinogenic potential investigated in the cases referred to in paragraph E.  CHAPTER II PRESENTATION OF PARTICULARS AND DOCUMENTS  As in all scientific work, the dossier of toxicological and pharmacological tests shall be arranged as follows:    (a) an introduction defining the subject accompanied possibly by references to published data;       (b) a detailed experimental protocol giving a description of the methods, apparatus and materials used, details of the species, and the breed and strain of animals, where they were obtained, their number and the conditions under which they were housed and fed, stating, inter alia, whether they were specific pathogen-free (SPF) or not ; omission of any of the tests listed above shall be explained;       (c) all the important results obtained, whether favourable or unfavourable. The original data should be described in sufficient detail to allow the results to be critically evaluated independently of their interpretation by the author. By way of explanation and illustration, the results may be accompanied by reproductions of kymographic charts, microphotographs, etc.;       (d) a statistical analysis of the results, where such is called for by the test programme, and variance within the data;       (e) an objective discussion of the results obtained, leading to conclusions on the toxicological and pharmacological properties of the substance, on its safety margins in the animal and its possible side-effects, on its fields of application, on its active dose levels and any possible incompatibilities;       (f) all information necessary to acquaint the clinician as fully as possible with the potential of the proposed proprietary medicinal product. The discussion shall be supplemented by suggestions as to possible treatment for acute toxic reactions and any side-effects that may occur in human beings;       (g) a summary together with precise references to published data.             PART 3 CLINICAL TRIALS  The particulars and documents accompanying applications for marketing authorizations pursuant to point 8 of Article 4, second paragraph, of Directive 65/65/EEC shall be submitted in accordance with the provisions of Chapters I and II below.  CHAPTER I  CONDUCT OF TRIALS    1. Clinical trials must always be preceded by adequate pharmacological and toxicological tests, carried out on animals in accordance with the requirements of this Directive relevant to such tests. The clinician must acquaint himself with the conclusions drawn from the pharmacological and toxicological studies and hence the applicant must provide him with the complete pharmacological and toxicological reports.       2. Clinical trials must be carried out in the form of "controlled clinical trials". The design of the trials will vary from case to case and also will depend on ethical considerations ; thus it may, in some instances, be more pertinent to compare the therapeutic effect of a new proprietary medicinal product with that of an established medicinal product of proven therapeutic value rather than with the effect of a placebo.       3. As far as possible, and particularly in trials where the effect of the product cannot be objectively measured, the "double blind" method of controlled study should be used.       4. If statistical methods are necessary to determine the therapeutic effect, the criteria upon which the trial is based must be sufficiently precise to permit a statistical analysis to be undertaken. Inclusion of a large number of patients in a trial must not be regarded as an adequate substitute for a properly controlled trial.         CHAPTER II PRESENTATION OF PARTICULARS AND DOCUMENTS    1. The clinical particulars to be provided pursuant to point 8 of Article 4, second paragraph, of Directive 65/65/EEC must enable a sufficiently well-founded and scientifically valid opinion to be formed as to whether the proprietary medicinal product satisfies the criteria governing the granting of a marketing authorization. Consequently, an essential requirement is that the results of all clinical trials should be communicated, both favourable and unfavourable.       2. The results of the trials shall be presented in accordance with the following scheme:   A. PHARMACOLOGICAL PARTICULARS  (Clinical pharmacology)        1. Wherever possible particulars shall be-given of the results of:          (a) tests demonstrating pharmacological actions;                   (b) tests demonstrating the pharmacodynamic mechanisms underlying the therapeutic effect;                   (c) tests demonstrating biotransformation and the main pharmacokinetic processes.                     Total or partial omission of these data must be explained.  Should unexpected results occur during the course of the tests, further preliminary toxicological and pharmacological tests on animals must be undertaken and reviewed.               2. If the proprietary medicinal product is intended for long-term administration, particulars shall be given of any modification of the pharmacological action following repeated administration.               3. If the product is normally to be administered concomitantly with other medicinal products, particulars shall be given of joint administration tests performed to demonstrate possible modification of the pharmacological action.               4. All side-effects noted during the tests shall be described individually.                  B. CLINICAL PARTICULARS  1. Individual case histories - Clinical records  Particulars of clinical trials must contain sufficient detail to allow an objective judgment to be made. As a general rule, these trials should be carried out in a medical care establishment.   The aim of the trials shall be stated, together with the criteria, both favourable and unfavourable, for evaluating the results.  Each investigator shall give his name, address, appointments, university qualifications and clinical duties, state where the trial was carried out and assemble the following information in respect of each patient individually:        1. identification of the patient (e.g., by reference to the number of his medical file);               2. criteria determining admission of the patient to the trials;               3. patient's age;               4. patient's sex;               5. diagnosis and indication for which the product was administered and the patient's history ; relevant particulars of any previous illnesses shall be given;               6. dosage and method of administration of the product;               7. frequency of administration and any precautions taken at the time of administration;               8. duration of treatment and of the subsequent observation period;               9. details of medicinal products administered previously or concomitantly, i.e. at any time during the period covered by the investigation;               10. dietary regime, if pertinent;               11. all results of the clinical trials (including unfavourable or negative results) with a full statement of clinical observations and results of clinical investigations (such as X-rays, electroencephalograms, electrocardiograms, laboratory analyses, physiological tests etc.), required to evaluate the application. The techniques used must be specified, and the significance of any variations in the results explained (for example, variance in method, variance between individuals or the effects of treatment);               12. all particulars of the observed side-effects, whether harmful or not, and any measures taken in consequence. Relation of cause and effect must be investigated with the same care normally accorded to identifying therapeutic action;               13. an opinion concerning each individual case.                Omission of one or more of items 1 to 13 must be explained.  The information referred to above must be forwarded to the competent authorities.  The competent authorities may waive this requirement in whole or in part if the documentation is very extensive or if there are other adequate reasons of the same order, subject, however, to there being no doubt as to the sound basis of the summary and conclusions referred to in point 2 below.  The person responsible for placing the proprietary medicinal product on the market must make arrangements to ensure that the original documents which formed the basis of the data supplied, including the codes for associating those documents with the patients in question, are kept for at least five years following transmission of the dossier to the competent authority.  2. Summary and conclusions        1. The clinical observations referred to in items 1 to 13 of paragraph 1 above, shall be summarized in a synopsis of the trials and their results, indicating:          (a) the number and sex of patients treated;                   (b) the selection and age-distribution of the groups of patients being investigated and the control groups;                   (c) the number of patients withdrawn prematurely from the trials and the reasons for such withdrawal;                   (d) where controlled trials were carried out under the above conditions, whether the control group:            - received no treatment,                       - received a placebo,                       - received another medicinal product of known effect;                                          (e) the frequency of observed side-effects;                   (f) details concerning patients who may be at increased risk, e.g. elderly people, children, women during pregnancy or menstruation, or whose physiological or pathological condition requires special consideration;                   (g) a statistical evaluation of the results when this is called for by the design of the trials and the variable factors involved.                                  2. Finally the investigator shall, in the general conclusions on the experimental evidence, express an opinion on the safety of the product under normal conditions of use, its compatibility, its therapeutic efficacy and any useful information relating to indications and contraindications, dosage and average duration of treatment as well as any special precautions to be taken during treatment and the clinical symptoms of overdosage.                 C. GENERAL CONSIDERATIONS     1. The clinician shall always indicate his observations on:      (a) any signs of habituation, addiction or difficulty in weaning patients from the medicinal product;            (b) any interactions that have been observed with other medicinal products administered concomitantly;           (c) the criteria determining exclusion of certain patients from the trials.                  2. Particulars concerning a new combination of medicinal substances must be identical to those required for new medicinal products and must substantiate the safety and therapeutic efficacy of the combination.  CHAPTER III EXAMINATION OF APPLICATIONS FOR AUTHORIZATION TO PLACE A PROPRIETARY MEDICINAL PRODUCT ON THE MARKET  In examining any application submitted pursuant to Article 4 of Directive 65/65/EEC, the competent authorities of Member States shall apply the following principles.      1. Evaluation of the application for marketing authorization shall be based on clinical trials or clinical pharmacological experiments designed to determine the therapeutic efficacy and safety of the product under normal conditions of use, having regard to the therapeutic indications for use in human beings. Therapeutic advantages must outweigh potential risks.           2. Clinical statements concerning the therapeutic efficacy or safety of a proprietary medicinal product under normal conditions of use which are not scientifically substantiated cannot be accepted as valid evidence.           3. Demonstration of pharmacodynamic effects in human beings shall not in itself be sufficient to justify conclusions regarding any particular potential therapeutic effect.           4. The value of data on the therapeutic efficacy and safety of a proprietary medicinal product under normal conditions of use will be very greatly enhanced if such data come from several competent investigators working independently.           5. When, in respect of particular therapeutic indications, the applicant can show that he is unable to provide comprehensive data on therapeutic efficacy and safety under normal conditions of use, because:      (a) the indications for which the product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence, or           (b) in the present state of scientific knowledge comprehensive information cannot be provided, or           (c) it would be contrary to generally accepted principles of medical ethics to collect such information,            marketing authorization may be granted on the following conditions:      (a) the proprietary medicinal product in question may be supplied on medical prescription only and may in certain cases be administered only under strict medical supervision, possibly in a hospital;           (b) the package leaflet and any medical information shall draw the attention of the medical practitioner to the fact that the particulars available concerning the proprietary medicinal product in question is as yet inadequate in certain specified respects.


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31991L0336

Commission Directive 91/336/EEC of 10 June 1991 amending the Annexes to Council Directive 70/524/EEC concerning additives in feedingstuffs

Official Journal L 185 , 11/07/1991 P. 0031 - 0031 Finnish special edition: Chapter 3 Volume 38 P. 0051  Swedish special edition: Chapter 3 Volume 38 P. 0051

COMMISSION DIRECTIVE  of 10 June 1991  amending the Annexes to Council Directive 70/524/EEC concerning additives in feedingstuffs  (91/336/EEC) THE COMMISSION OF THE EUROPEAN COMMUNITIES,  Having regard to the Treaty establishing the European Economic Community,  Having regard to Council Directive 70/524/EEC of 23 November 1970 concerning additives in feedingstuffs (1), as last amended by Commission Directive 91/249/EEC (2), and in particular Article 7 thereof,  Whereas Directive 70/524/EEC provides for regular amendment of the content of its Annexes to take account of advances in scientifc and technical knowledge;  Whereas the preservative 'Propane-1,2-diol' no longer appears to meet all the requirements necessary for its maintenance in the list of additives authorized throughout the Community as far as it is used as an additive in feedingstuffs for cats;  Whereas, therefore, the use of this substance in feedingstuffs for cats should prohibited;  Whereas the measures provided for in this Directive are in accordance with the opinion of the Standing Committee for Feedingstuffs,  HAS ADOPTED THIS DIRECTIVE:  Article 1  Annex I to Directive 70/524/EEC is hereby amended as set out in the Annex hereto.  Article 2  The Member States shall bring into force the laws, regulations and administrative provisions necessary to comply with the provisions of Article 1 by 30 November 1991 at the latest. They shall immediately inform the Commission thereof.  When Member States adopt the measures referred to in paragraph 1, they shall contain a reference to this Directive or shall be accompanied by such reference on the occasion of their official publication. The methods of marking such a reference shall be  laid down by the Member States.  Article 3  This Directive is addressed to the Member States. Done at Brussels, 10 June 1991. For the Commission  Ray MAC SHARRY  Member of the Commission  (1) OJ No L 270, 14. 12. 1970, p. 1. (2) OJ No L 124, 18. 5. 1991, p. 43.    ANNEX  Under part G 'Preservatives' under E 490 'Propane-1,2-diol', the indication 'Cats' in the column 'Species of animal' and the figure 75 000 in the column 'Maximum content' as well as any other indication referring to feedingstuffs  for cats are delted.


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32002L0041

Commission Directive 2002/41/EC of 17 May 2002 adapting to technical progress Directive 95/1/EC of the European Parliament and of the Council on the maximum design speed, maximum torque and maximum net engine power of two- or three-wheel motor vehicles

Official Journal L 133 , 18/05/2002 P. 0017 - 0020

Commission Directive 2002/41/ECof 17 May 2002adapting to technical progress Directive 95/1/EC of the European Parliament and of the Council on the maximum design speed, maximum torque and maximum net engine power of two- or three-wheel motor vehiclesTHE COMMISSION OF THE EUROPEAN COMMUNITIES,Having regard to the Treaty establishing the European Community,Having regard to Council Directive 92/61/EEC of 30 June 1992 relating to the type-approval of two- or three-wheel motor vehicles(1), as last amended by European Parliament and Council Directive 2000/7/EC(2) and in particular Article 16 thereof,Having regard to Directive 95/1/EC of the European Parliament and of the Council of 2 February 1995 on the maximum design speed, maximum torque and maximum net engine power of two- or three-wheel motor vehicles(3), and in particular Article 4 thereof,Whereas:(1) Directive 95/1/EC is one of the separate directives under the Community type-approval procedure introduced by Directive 92/61/EEC. The provisions of Directive 92/61/EEC relating to systems, components and separate technical units for vehicles therefore apply to Directive 95/1/EC.(2) In order to enable the full type-approval system to function properly, it is necessary to clarify or supplement certain requirements of Directive 95/1/EC.(3) To that end, it is necessary to specify the values to be entered in the test report to ensure the consistent application of Directive 95/1/EC in the case of mopeds, motorcycles and tricycles with spark-ignition engines and two- or three-wheel motor vehicles with compression-ignition engines.(4) Directive 95/1/EC should therefore be amended accordingly.(5) The measures provided for in this Directive are in accordance with the opinion of the Committee for Adaptation to Technical Progress set up under Article 13 of Council Directive 70/156/EEC(4), as last amended by Commission Directive 2001/116/EC(5),HAS ADOPTED THIS DIRECTIVE:Article 1The Annexes to Directive 95/1/EC are amended in accordance with the Annex to this Directive.Article 21. With effect from 1 July 2003, Member States may not, on grounds relating to the maximum design speed, maximum torque and maximum net engine power:- refuse to grant EC type-approval for a type of two- or three-wheel motor vehicle, or- prohibit the registration, sale or entry into service of two- or three-wheel motor vehicles;if the maximum design speed, maximum torque and maximum net engine power of the vehicles comply with the requirements of Directive 95/1/EC, as amended by this Directive.2. With effect from 1 January 2004, Member States shall refuse to grant EC type-approval for any new type of two- or three-wheel motor vehicle on grounds relating to the maximum design speed, maximum torque and maximum net engine power if the requirements of Directive 95/1/EC, as amended by this Directive, are not fulfilled.Article 31. Member States shall bring into force the laws, regulations and administrative provisions necessary to comply with this Directive by 30 June 2003 at the latest. They shall forthwith inform the Commission thereof.When Member States adopt those provisions, they shall contain a reference to this Directive or be accompanied by such a reference on the occasion of their official publication. Member States shall determine how such reference is to be made.2. Member States shall communicate to the Commission the main provisions of national law that they adopt in the field covered by this Directive.Article 4This Directive shall enter into force on the 20th day following its publication in the Official Journal of the European Communities.Article 5This Directive is addressed to the Member States.Done at Brussels, 17 May 2002.For the CommissionErkki LiikanenMember of the Commission(1) OJ L 225, 10.8.1992, p. 72.(2) OJ L 106, 3.5.2000, p. 1.(3) OJ L 52, 8.3.1995, p. 1.(4) OJ L 42, 23.2.1970, p. 1.(5) OJ L 18, 21.1.2002, p. 1.ANNEXThe Annexes to Directive 95/1/EC are amended as follows:1. Annex I is amended as follows:(a) in point 5 the second line is replaced by the following: "Atmospheric pressure: 97 +- 10 kPa."(b) in point 5 the fifth line is replaced by the following: "Average wind speed, measured 1 m above the ground: <  3 m/s, permitting gusts <  5 m/s."2. Annex II is amended as follows:(a) in Appendix 1, point 3.1.2, Table 1, the first sentence of note (3) is replaced by the following: "The radiator, fan, fan nozzle, water pump and thermostat must, on the test bench, occupy as far as possible the same position relative to each other as if they were on the vehicle. If the radiator, fan, fan nozzle, water pump and/or thermostat have a position on the test bench which is different from that on the vehicle, the position on the test bench shall be described and noted on the test report."(b) in Appendix 1, point 4.1 is replaced by the following: "4.1. Definition of factors á1 and á2Factors by which the torque and power measured are to be multiplied in order to determine the torque and power of an engine, taking account of the efficiency of the transmission (factor á2) used during the tests and in order to bring that torque and that power within the reference atmospheric conditions specified in 4.2.1 (factor á1).The power correction formula is as follows:>REFERENCE TO A GRAPHIC>where:P0 = the corrected power (i.e. the power under the reference conditions at the end of the crankshaft)α1 = the correction factor for reference atmospheric conditionsα2 = the correction factor for the efficiency of the transmissionP = the power measured (power observed)."(c) in Appendix 1, point 4.3 is replaced by the following: "4.3. Determination of the correction factors4.3.1. Determination of the factor α2- Where the measuring point is the crankshaft output side this factor is equal to 1.- Where the measuring point is not the output side of the crankshaft this factor is calculated via the formula:>PIC FILE= "L_2002133EN.001802.TIF">where nt is the efficiency of the transmission located between the crankshaft and measuring point.This transmission efficiency nt is determined via the product (multiplication) of efficiency nj of each of the components of the transmission:>REFERENCE TO A GRAPHIC>Efficiency nj of each of the components of the transmission is shown in the following table.>TABLE>4.3.2. Determination of factor α1(1)4.3.2.1. Definition of characteristics T, Ps for correction factors α1T = the absolute temperature of the ingested airPs = the dry atmospheric pressure in kilopascals (kPa) i.e. the total barometric pressure minus the water vapour pressure.4.3.2.2. Factor α1Correction factor α1 is obtained from the following>PIC FILE= "L_2002133EN.001901.TIF">That formula only applies if:>REFERENCE TO A GRAPHIC>If the limit values are exceeded the corrected value obtained must be stated and the test conditions (temperature and pressure) stated exactly in the test report."(d) in Appendix 1, points 4.4 and 4.5 are deleted;(e) in Appendix 1, point 6.1, "1,5 %" is replaced by "3 %";(f) in Appendix 2, point 3.1.2, Table 1, the first sentence of Note (3) is replaced by the following: "The radiator, fan, fan nozzle, water pump and thermostat must, on the test bench, occupy as far as possible the same position relative to each other as if they were on the vehicle. If the radiator, fan, fan nozzle, water pump and/or thermostat have a position on the test bench which is different from that on the vehicle, the position on the test bench shall be described and noted on the test report."(g) in Appendix 2, point 4.1 is replaced by the following: "4.1. Definition of factors α1 and α2Factors by which the torque and power measured are to be multiplied in order to determine the torque and power of an engine, taking account of the efficiency of the transmission (factor α2) used during the tests and in order to bring that torque and that power within the reference atmospheric conditions specified in 4.2.1 (factor α1).The power correction formula is as follows:>REFERENCE TO A GRAPHIC>where:P0 = the corrected power (i.e. the power under the reference conditions at the end of the crankshaft)α1 = the correction factor for reference atmospheric conditionsα2 = the correction factor for the efficiency of the transmissionP = the power measured (power observed)."(h) in Appendix 3, point 3.1.3, Table 1, the first sentence of note (5) is replaced by the following: "The radiator, fan, fan nozzle, water pump and thermostat must, on the test bench, occupy as far as possible the same position relative to each other as if they were on the vehicle. If the radiator, fan, fan nozzle, water pump and/or thermostat have a position on the test bench which is different from that on the vehicle, the position on the test bench shall be described and noted on the test report."(i) in Appendix 3, point 4.1 is replaced by the following: "4.1. Definition of factors αd and α2Factors by which the torque and power measured are to be multiplied in order to determine the torque and power of an engine, taking account of the efficiency of the transmission (factor α2) used during the tests and in order to bring that torque and that power within the reference atmospheric conditions specified in 4.2.1 (factor αd).The power correction formula is as follows:>REFERENCE TO A GRAPHIC>where:P0 = the corrected power (i.e. the power under the reference conditions at the end of the crankshaft)αd = the correction factor for reference atmospheric conditionsα2 = the correction factor for the efficiency of the transmission (see Appendix 2, point 4.3.1)P = the power measured (power observed)."(j) in Appendix 3, point 4.4, the heading is replaced by the following: "4.4. Determination of correction factor αd (1)".(1) The test may be carried out in temperature-controlled test chambers where the atmospheric conditions may be controlled.


title: Commission Directive 2010/14/EU of 3 March 2010 amending Council Directive 91/414/EEC to include heptamaloxyloglucan as active substance (Text with EEA relevance)

text:
               4.3.2010

               EN

               Official Journal of the European Union

               L 53/7

         COMMISSION DIRECTIVE 2010/14/EU
   of 3 March 2010
   amending Council Directive 91/414/EEC to include heptamaloxyloglucan as active substance
   (Text with EEA relevance)
   THE EUROPEAN COMMISSION,
   Having regard to the Treaty on the Functioning of the European Union,
   Having regard to Council Directive 91/414/EEC of 15 July 1991 concerning the placing of plant protection products on the market (1), and in particular Article 6(1) thereof,
   Whereas:

               (1)

               In accordance with Article 6(2) of Directive 91/414/EEC France received on 9 May 2006 an application from Elicityl SA for the inclusion of the active substance heptamaloxyloglucan in Annex I to Directive 91/414/EEC. Commission Decision 2007/560/EC (2) confirmed that the dossier was ‘complete’ in the sense that it could be considered as satisfying, in principle, the data and information requirements of Annexes II and III to Directive 91/414/EEC.

               (2)

               For that active substance, the effects on human health and the environment have been assessed, in accordance with the provisions of Article 6(2) and (4) of Directive 91/414/EEC, for the uses proposed by the applicant. The designated rapporteur Member State submitted a draft assessment report on 26 July 2007.

               (3)

               The assessment report was peer reviewed by the Member States and the EFSA and presented to the Commission in the format of the EFSA Scientific Report for heptamaloxyloglucan on 17 July 2009 (3). This report was reviewed by the Member States and the Commission within the Standing Committee on the Food Chain and Animal Health and finalised on 27 November 2009 in the format of the Commission review report for heptamaloxyloglucan.

               (4)

               It has appeared from the various examinations made that plant protection products containing heptamaloxyloglucan may be expected to satisfy, in general, the requirements laid down in Article 5(1)(a) and (b) and Article 5(3) of Directive 91/414/EEC, in particular with regard to the uses which were examined and detailed in the Commission review report. It is therefore appropriate to include heptamaloxyloglucan in Annex I to that Directive, in order to ensure that in all Member States the authorisations of plant protection products containing this active substance may be granted in accordance with the provisions of that Directive.

               (5)

               Without prejudice to the obligations defined by Directive 91/414/EEC as a consequence of including an active substance in Annex I, Member States should be allowed a period of six months after inclusion to review existing provisional authorisations of plant protection products containing heptamaloxyloglucan to ensure that the requirements laid down by Directive 91/414/EEC, in particular in its Article 13 and the relevant conditions set out in Annex I, are satisfied. Member States should transform existing provisional authorisations into full authorisations, amend them or withdraw them in accordance with the provisions of Directive 91/414/EEC. By derogation from the above deadline, a longer period should be provided for the submission and assessment of the complete Annex III dossier of each plant protection product for each intended use in accordance with the uniform principles laid down in Directive 91/414/EEC.

               (6)

               It is therefore appropriate to amend Directive 91/414/EEC accordingly.

               (7)

               The measures provided for in this Directive are in accordance with the opinion of the Standing Committee on the Food Chain and Animal Health,

         HAS ADOPTED THIS DIRECTIVE:
   Article 1
   Annex I to Directive 91/414/EEC is amended as set out in the Annex to this Directive.
   Article 2
   Member States shall adopt and publish by 30 November 2010 at the latest the laws, regulations and administrative provisions necessary to comply with this Directive. They shall forthwith communicate to the Commission the text of those provisions and a correlation table between those provisions and this Directive.
   They shall apply those provisions from 1 December 2010.
   When Member States adopt those provisions, they shall contain a reference to this Directive or shall be accompanied by such a reference on the occasion of their official publication. Member States shall determine how such reference is to be made.
   Article 3
   1.   Member States shall in accordance with Directive 91/414/EEC, where necessary, amend or withdraw existing authorisations for plant protection products containing heptamaloxyloglucan as active substance by 30 November 2010. By that date, they shall in particular verify that the conditions in Annex I to that Directive relating to heptamaloxyloglucan are met, with the exception of those identified in part B of the entry concerning the active substance, and that the holder of the authorisation has, or has access to, a dossier satisfying the requirements of Annex II to that Directive in accordance with the conditions of Article 13(2) of that Directive.
   2.   By way of derogation from paragraph 1, for each authorised plant protection product containing heptamaloxyloglucan as either the only active substance or as one of several active substances all of which were listed in Annex I to Directive 91/414/EEC by 31 May 2010 at the latest, Member States shall re-evaluate the product in accordance with the uniform principles provided for in Annex VI to Directive 91/414/EEC, on the basis of a dossier satisfying the requirements of Annex III to that Directive and taking into account part B of the entry in Annex I to that Directive concerning heptamaloxyloglucan. On the basis of that evaluation, they shall determine whether the product satisfies the conditions set out in Article 4(1)(b), (c), (d) and (e) of Directive 91/414/EEC.
   Following that determination Member States shall:

               (a)

               in the case of a product containing heptamaloxyloglucan as the only active substance, where necessary, amend or withdraw the authorisation by 30 November 2011 at the latest; or

               (b)

               in the case of a product containing heptamaloxyloglucan as one of several active substances, where necessary, amend or withdraw the authorisation by 30 November 2011 or by the date fixed for such an amendment or withdrawal in the respective Directive or Directives which added the relevant substance or substances to Annex I to Directive 91/414/EEC, whichever is the latest.

         Article 4
   This Directive shall enter into force on 1 June 2010.
   Article 5
   This Directive is addressed to the Member States.

      Done at Brussels, 3 March 2010.

            For the Commission

            The President

         José Manuel BARROSO

      (1)  OJ L 230, 19.8.1991, p. 1.

      (2)  OJ L 213, 15.8.2007, p. 29.

      (3)  EFSA Scientific Report (2009) 334, 1-52, Conclusion regarding the peer review of the pesticide risk assessment of the active substance heptamaloxyloglucan (finalised: 17 July 2009).

      ANNEX
      In Annex I to Directive 91/414/EEC, the following entry is added at the end of the table:

                  No

                  Common name, Identification numbers

                  IUPAC name

                  Purity (2)

                  Entry into force

                  Expiration of inclusion

                  Specific provisions

                  ‘304

                  Heptamaloxyloglucan
                  CAS No
                  870721-81-6
                  CIPAC No
                  Not available

                  Full IUPAC name in footnote (1)

                              Xyl p: xylopyranosyl

                              Glc p: glucopyranosyl

                              Fuc p: fucopyranosyl

                              Gal p: galactopyranosyl

                              Glc-ol: glucitol

                  ≥ 780 g/kg
                  The impurity Patulin must not exceed 50 μg/kg in the technical material.

                  1 June 2010

                  31 May 2020

                  PART A
                  Only uses as plant growth regulator may be authorised.
                  PART B
                  For the implementation of the uniform principles of Annex VI, the conclusions of the review report on heptamaloxyloglucan, and in particular Appendices I and II thereof, as finalised in the Standing Committee on the Food Chain and Animal Health on 27 November 2009 shall be taken into account.

         (1)  ’

         (2)  Further details on identity and specification of active substances are provided in the review report.