THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION, Having regard to the Treaty establishing the European Community, and in particular Article 95 thereof, Having regard to the proposal from the Commission; Having regard to the opinion of the Economic and Social Committee(1), Acting in accordance with the procedure laid down in Article 251 of the Treaty(2), Whereas: (1) Council Directive 65/65/EEC of 26 January 1965 on the approximation of provisions laid down by law, regulation or administrative action relating to medicinal products(3), 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(4), Council Directive 75/319/EEC of 20 May 1975 on the approximation of provisions laid down by law, regulation or administrative action relating to proprietary medicinal products(5), Council Directive 89/342/EEC of 3 May 1989 extending the scope of Directives 65/65/EEC and 75/319/EEC and laying down additional provisions for immunological medicinal products consisting of vaccines, toxins or serums and allergens(6), Council Directive 89/343/EEC of 3 May 1989 extending the scope of Directives 65/65/EEC and 75/319/EEC and laying down additional provisions for radiopharmaceuticals(7), Council Directive 89/381/EEC of 14 June 1989 extending the scope of Directives 65/65/EEC and 75/319/EEC on the approximation of provisions laid down by law, regulation or administrative action relating to medicinal products and laying down special provisions for proprietary medicinal products derived from human blood or human plasma(8), Council Directive 92/25/EEC of 31 March 1992 on the wholesale distribution of medicinal products for human use(9), Council Directive 92/26/EEC of 31 March 1992 concerning the classification for the supply of medicinal products for human use(10), Council Directive 92/27/EEC of 31 March 1992 on the labelling of medicinal products for human use and on package leaflets(11), Council Directive 92/28/EEC of 31 March 1992 on the advertising of medicinal products for human use(12), Council Directive 92/73/EEC of 22 September 1992 widening the scope of Directives 65/65/EEC and 75/319/EEC on the approximation of provisions laid down by law, regulation or administrative action relating to medicinal products and laying down additional provisions on homeopathic medicinal products(13) have been frequently and substantially amended. In the interests of clarity and rationality, the said Directives should therefore be codified by assembling them in a single text. (2) The essential aim of any rules governing the production, distribution and use of medicinal products must be to safeguard public health. (3) However, this objective must be attained by means which will not hinder the development of the pharmaceutical industry or trade in medicinal products within the Community. (4) Trade in medicinal products within the Community is hindered by disparities between certain national provisions, in particular between provisions relating to medicinal products (excluding substances or combinations of substances which are foods, animal feeding-stuffs or toilet preparations), and such disparities directly affect the functioning of the internal market. (5) Such hindrances must accordingly be removed; whereas this entails approximation of the relevant provisions. (6) In order to reduce the disparities which remain, rules should be laid down on the control of medicinal products and the duties incumbent upon the Member States' competent authorities should be specified with a view to ensuring compliance with legal requirements. (7) The concepts of harmfulness and therapeutic efficacy 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 medicinal product is intended. The particulars and documents which must accompany an application for marketing authorization for a medicinal product demonstrate that potential risks are outweighed by the therapeutic efficacy of the product. (8) Standards and protocols for the performance of tests and trials on 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. (9) Experience has shown that it is advisable to stipulate more precisely the cases in which the results of toxicological and pharmacological tests or clinical trials do not have to be provided with a view to obtaining authorization for a medicinal product which is essentially similar to an authorized product, while ensuring that innovative firms are not placed at a disadvantage. (10) However, there are reasons of public policy for not conducting repetitive tests on humans or animals without over-riding cause. (11) 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. (12) With the exception of those medicinal products which are subject to the centralized Community authorization procedure established by Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products(14) a marketing authorization for a medicinal product granted by a competent authority in one Member State ought to be recognized by the competent authorities of the other Member States unless there are serious grounds for supposing that the authorization of the medicinal product concerned may present a risk to public health. In the event of a disagreement between Member States about the quality, the safety or the efficacy of a medicinal product, a scientific evaluation of the matter should be undertaken according to a Community standard, leading to a single decision on the area of disagreement binding on the Member States concerned. Whereas this decision should be adopted by a rapid procedure ensuring close cooperation between the Commission and the Member States. (13) For this purpose, a Committee for Proprietary Medicinal Products should be set up attached to the European Agency for the Evaluation of Medicinal Products established in the abovementioned Regulation (EEC) No 2309/93. (14) This Directive represents an important step towards achievement of the objective of the free movement of medicinal products. Further measures may abolish any remaining barriers to the free movement of proprietary medicinal products will be necessary in the light of experience gained, particularly in the abovementioned Committee for Proprietary Medicinal Products. (15) In order better to protect public health and avoid any unnecessary duplication of effort during the examination of application for a marketing authorization for medicinal products, Member States should systematically prepare assessment reports in respect of each medicinal product which is authorized by them, and exchange the reports upon request. Furthermore, a Member State should be able to suspend the examination of an application for authorization to place a medicinal product on the market which is currently under active consideration in another Member State with a view to recognizing the decision reached by the latter Member State. (16) Following the establishment of the internal market, specific controls to guarantee the quality of medicinal products imported from third countries can be waived only if appropriate arrangements have been made by the Community to ensure that the necessary controls are carried out in the exporting country. (17) It is necessary to adopt specific provisions for immunological medicinal products, homeopathic medicinal products, radiopharmaceuticals, and medicinal products based on human blood or human plasma. (18) Any rules governing radiopharmaceuticals must take into account the provisions of Council Directive 84/466/Euratom of 3 September 1984 laying down basic measures for the radiation protection of persons undergoing medical examination or treatment(15). Account should also be taken of Council Directive 80/836/Euratom of 15 July 1980 amending the Directives laying down the basic safety standards for the health protection of the general public and workers against the dangers of ionizing radiation(16), the objective of which is to prevent the exposure of workers or patients to excessive or unnecessarily high levels of ionizing radiation, and in particular of Article 5c thereof, which requires prior authorization for the addition of radioactive substances to medicinal products as well as for the importation of such medicinal products. (19) The Community entirely supports the efforts of the Council of Europe to promote voluntary unpaid blood and plasma donation to attain self-sufficiency throughout the Community in the supply of blood products, and to ensure respect for ethical principles in trade in therapeutic substances of human origin. (20) The rules designed to guarantee the quality, safety and efficacy of medicinal products derived from human blood or human plasma must be applied in the same manner to both public and private establishments, and to blood and plasma imported from third countries. (21) Having regard to the particular characteristics of these homeopathic medicinal products, such as the very low level of active principles they contain and the difficulty of applying to them the conventional statistical methods relating to clinical trials, it is desirable to provide a special, simplified registration procedure for those homeopathic medicinal products which are placed on the market without therapeutic indications in a pharmaceutical form and dosage which do not present a risk for the patient. (22) The anthroposophic medicinal products described in an official pharmacopoeia and prepared by a homeopathic method are to be treated, as regards registration and marketing authorization, in the same way as homeopathic medicinal products. (23) It is desirable in the first instance to provide users of these homeopathic medicinal products with a very clear indication of their homeopathic character and with sufficient guarantees of their quality and safety. (24) The rules relating to the manufacture, control and inspection of homeopathic medicinal products must be harmonized to permit the circulation throughout the Community of medicinal products which are safe and of good quality. (25) The usual rules governing the authorization to market medicinal products should be applied to homeopathic medicinal products placed on the market with therapeutic indications or in a form which may present risks which must be balanced against the desired therapeutic effect. In particular, those Member States which have a homeopathic tradition should be able to apply particular rules for the evaluation of the results of tests and trials intended to establish the safety and efficacy of these medicinal products provided that they notify them to the Commission. (26) In order to facilitate the movement of medicinal products and to prevent the controls carried out in one Member State from being repeated in another, minimum requirements should be laid down for manufacture and imports coming from third countries and for the grant of the authorization relating thereto. (27) It should be ensured that, in the Member States, the supervision and control of the manufacture of medicinal products is carried out by a person who fulfils minimum conditions of qualification. (28) Before an authorization to market an immunological medicinal product or derived from human blood or human plasma can be granted, the manufacturer must demonstrate his ability to attain batch-to-batch consistency. Before an authorization to market a medicinal product derived from human blood or human plasma can be granted, the manufacturer must also demonstrate the absence of specific viral contamination, to the extent that the state of technology permits. (29) The conditions governing the supply of medicinal products to the public should be harmonized. (30) In this connection persons moving around within the Community have the right to carry a reasonable quantity of medicinal products lawfully obtained for their personal use. It must also be possible for a person established in one Member State to receive from another Member State a reasonable quantity of medicinal products intended for his personal use. (31) In addition, by virtue of Regulation (EC) No 2309/93, certain medicinal products are the subject of a Community marketing authorization. In this context, the classification for the supply of medicinal products covered by a Community marketing authorization needs to be established. It is therefore important to set the criteria on the basis of which Community decisions will be taken. (32) It is therefore appropriate, as an initial step, to harmonize the basic principles applicable to the classification for the supply of medicinal products in the Community or in the Member State concerned, while taking as a starting point the principles already established on this subject by the Council of Europe as well as the work of harmonization completed within the framework of the United Nations, concerning narcotic and psychotropic substances. (33) The provisions dealing with the classification of medicinal products for the purpose of supply do not infringe the national social security arrangements for reimbursement or payment for medicinal products on prescription. (34) Many operations involving the wholesale distribution of medicinal products for human use may cover several Member States simultaneously. (35) It is necessary to exercise control over the entire chain of distribution of medicinal products, from their manufacture or import into the Community through to supply to the public, so as to guarantee that such products are stored, transported and handled in suitable conditions. The requirements which must be adopted for this purpose will considerably facilitate the withdrawal of defective products from the market and allow more effective efforts against counterfeit products. (36) Any person involved in the wholesale distribution of medicinal products should be in possession of a special authorization. Pharmacists and persons authorized to supply medicinal products to the public, and who confine themselves to this activity, should be exempt from obtaining this authorization. It is however necessary, in order to control the complete chain of distribution of medicinal products, that pharmacists and persons authorized to supply medicinal products to the public keep records showing transactions in products received. (37) Authorization must be subject to certain essential conditions and it is the responsibility of the Member State concerned to ensure that such conditions are met; whereas each Member State must recognize authorizations granted by other Member States. (38) Certain Member States impose on wholesalers who supply medicinal products to pharmacists and on persons authorized to supply medicinal products to the public certain public service obligations. Those Member States must be able to continue to impose those obligations on wholesalers established within their territory. They must also be able to impose them on wholesalers in other Member States on condition that they do not impose any obligation more stringent than those which they impose on their own wholesalers and provided that such obligations may be regarded as warranted on grounds of public health protection and are proportionate in relation to the objective of such protection. (39) Rules should be laid down as to how the labelling and package leaflets are to be presented. (40) The provisions governing the information supplied to users should provide a high degree of consumer protection, in order that medicinal products may be used correctly on the basis of full and comprehensible information. (41) The marketing of medicinal products whose labelling and package leaflets comply with this Directive should not be prohibited or impeded on grounds connected with the labelling or package leaflet. (42) This Directive is without prejudice to the application of measures adopted pursuant to Council Directive 84/450/EEC of 10 September 1984 relating to the approximation of the laws, regulations and administrative provisions of the Member States concerning misleading advertising(17). (43) All Member States have adopted further specific measures concerning the advertising of medicinal products. There are disparities between these measures. These disparities are likely to have an impact on the functioning of the internal market, since advertising disseminated in one Member State is likely to have effects in other Member States. (44) Council Directive 89/552/EEC of 3 October 1989 on the coordination of certain provisions laid down by law, regulation or administrative action in Member States concerning the pursuit of television broadcasting activities(18) prohibits the television advertising of medicinal products which are available only on medical prescription in the Member State within whose jurisdiction the television broadcaster is located. This principle should be made of general application by extending it to other media. (45) Advertising to the general public, even of non-prescription medicinal products, could affect public health, were it to be excessive and ill-considered. Advertising of medicinal products to the general public, where it is permitted, ought therefore to satisfy certain essential criteria which ought to be defined. (46) Furthermore, distribution of samples free of charge to the general public for promotional ends must be prohibited. (47) The advertising of medicinal products to persons qualified to prescribe or supply them contributes to the information available to such persons. Nevertheless, this advertising should be subject to strict conditions and effective monitoring, referring in particular to the work carried out within the framework of the Council of Europe. (48) Advertising of medicinal products should be subject to effective, adequate monitoring. Reference in this regard should be made to the monitoring mechanisms set up by Directive 84/450/EEC. (49) Medical sales representatives have an important role in the promotion of medicinal products. Therefore, certain obligations should be imposed upon them, in particular the obligation to supply the person visited with a summary of product characteristics. (50) Persons qualified to prescribe medicinal products must be able to carry out these functions objectively without being influenced by direct or indirect financial inducements. (51) It should be possible within certain restrictive conditions to provide samples of medicinal products free of charge to persons qualified to prescribe or supply them so that they can familiarize themselves with new products and acquire experience in dealing with them. (52) Persons qualified to prescribe or supply medicinal products must have access to a neutral, objective source of information about products available on the market. Whereas it is nevertheless for the Member States to take all measures necessary to this end, in the light of their own particular situation. (53) Each undertaking which manufactures or imports medicinal products should set up a mechanism to ensure that all information supplied about a medicinal product conforms with the approved conditions of use. (54) In order to ensure the continued safety of medicinal products in use, it is necessary to ensure that pharmacovigilance systems in the Community are continually adapted to take account of scientific and technical progress. (55) It is necessary to take account of changes arising as a result of international harmonisation of definitions, terminology and technological developments in the field of pharmacovigilance. (56) The increasing use of electronic networks for communication of information on adverse reactions to medicinal products marketed in the Community is intended to allow competent authorities to share the information at the same time. (57) It is the interest of the Community to ensure that the pharmacovigilance systems for centrally authorised medicinal products and those authorised by other procedures are consistent. (58) Holders of marketing authorisations should be proactively responsible for on-going pharmacovigilance of the medicinal products they place on the market. (59) The measures necessary for the implementation of this Directive should be adopted in accordance with Council Decision 1999/468/EC of 28 June 1999 laying down the procedures for the exercise of implementing powers conferred on the Commission(19). (60) The Commission should be empowered to adopt any necessary changes to Annex I in order to take into account scientific and technical progress. (61) This Directive should be without prejudice to the obligations of the Member States concerning the time-limits for transposition of the Directives set out in Annex II, Part B. HAVE ADOPTED THIS DIRECTIVE: TITLE I DEFINITIONS Article 1 For the purposes of this Directive, the following terms shall bear the following meanings: 1. Proprietary medicinal product: Any ready-prepared medicinal product placed on the market under a special name and in a special pack. 2. Medicinal product: Any substance or combination of substances presented for treating or preventing disease in human beings. Any substance or combination of substances which may be administered to human beings with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in human beings is likewise considered a medicinal product. 3. Substance: Any matter irrespective of origin which may be: - human, e.g. human blood and human blood products; - animal, e.g. micro-organisms, whole animals, parts of organs, animal secretions, toxins, extracts, blood products; - vegetable, e.g. micro-organisms, plants, parts of plants, vegetable secretions, extracts; - chemical, e.g. elements, naturally occurring chemical materials and chemical products obtained by chemical change or synthesis. 4. Immunological medicinal product: Any medicinal product consisting of vaccines, toxins, serums or allergen products: (a) vaccines, toxins and serums shall cover in particular: (i) agents used to produce active immunity, such as cholera vaccine, BCG, polio vaccines, smallpox vaccine; (ii) agents used to diagnose the state of immunity, including in particular tuberculin and tuberculin PPD, toxins for the Schick and Dick Tests, brucellin; (iii) agents used to produce passive immunity, such as diphtheria antitoxin, anti-smallpox globulin, antilymphocytic globulin; (b) "allergen product" shall mean any medicinal product which is intended to identify or induce a specific acquired alteration in the immunological response to an allergizing agent. 5. Homeopathic medicinal product: Any medicinal product prepared from products, substances or compositions called homeopathic stocks in accordance with a homeopathic manufacturing procedure described by the European Pharmacopoeia or, in absence thereof, by the pharmacopoeias currently used officially in the Member States. A homeopathic medicinal product may also contain a number of principles. 6. Radiopharmaceutical: Any medicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose. 7. Radionuclide generator: Any system incorporating a fixed parent radionuclide from which is produced a daughter radionuclide which is to be obtained by elution or by any other method and used in a radiopharmaceutical. 8. Radionuclide kit: Any preparation to be reconsitituted or combined with radionuclides in the final radiopharmaceutical, usually prior to its administration. 9. Radionuclide precursor: Any other radionuclide produced for the radio-labelling of another substance prior to administration. 10. Medicinal products derived from human blood or human plasma: Medicinal products based on blood constitutents which are prepared industrially by public or private establishments, such medicinal products including, in particular, albumin, coagulating factors and immunoglobulins of human origin. 11. Adverse reaction: A response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, correction or modification of physiological function. 12. Serious adverse reaction: An adverse reaction which results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect. 13. Unexpected adverse reaction: An adverse reaction, the nature, severity or outcome of which is not consistent with the summary of product characteristics. 14. Periodic safety update reports: The periodical reports containing the records referred to in Article 104. 15. Post-authorisation safety study: A pharmacoepidemiological study or a clinical trial carried out in accordance with the terms of the marketing authorisation, conducted with the aim of identifying or quantifying a safety hazard relating to an authorised medicinal product. 16. Abuse of medicinal products: Persistent or sporadic, intentional excessive use of medicinal products which is accompanied by harmful physical or psychological effets. 17. Wholesale distribution of medicinal products: All activities consisting of procuring, holding, supplying or exporting medicinal products, apart from supplying medicinal products to the public. Such activities are carried out with manufacturers or their depositories, importers, other wholesale distributors or with pharmacists and persons authorized or entitled to supply medicinal products to the public in the Member State concerned. 18. Public service obligation: The obligation placed on wholesalers to guarantee permanently an adequate range of medicinal products to meet the requirements of a specific geographical area and to deliver the supplies requested within a very short time over the whole of the area in question. 19. Medicinal Prescription: Any medicinal prescription issued by a professional person qualified to do so. 20. Name of the medicinal product: The name given to a medicinal product, which may be either an invented name or a common or scientific name, together with a trade mark or the name of the manufacturer; the invented name shall not be liable to confusion with the common name. 21. Common name: The international non-proprietary name recommended by the World Health Organization, or, if one does not exist, the usual common name. 22. Strength of the medicinal product: The content of the active substances expressed quantitatively per dosage unit, per unit of volume or weight according to the dosage form. 23. Immediate packaging: The container or other form of packaging immediately in contact with the medicinal product. 24. Outer packaging: The packaging into which is placed the immediate packaging. 25. Labelling: Information on the immediate or outer packaging. 26. Package leaflet: A leaflet containing information for the user which accompanies the medicinal product. 27. Agency: The European Agency for the Evaluation of Medicinal Products established by Regulation (EEC) No 2309/93. 28. Risk to public health: All risks with regard to the quality, safety and efficacy of the medicinal product. TITLE II SCOPE Article 2 The provisions of this Directive shall apply to industrially produced medicinal products for human use intended to be placed on the market in Member States. Article 3 This Directive shall not apply to: 1. Any medicinal product prepared in a pharmacy in accordance with a medical prescription for an individual patient (commonly known as the magistral formula). 2. Any medicinal product which is prepared in a pharmacy in accordance with the prescriptions of a pharmacopoeia and is intended to be supplied directly to the patients served by the pharmacy in question (commonly known as the official formula). 3. Medicinal products intended for research and development trials. 4. Intermediate products intended for further processing by an authorized manufacturer. 5. Any radionuclides in the form of sealed sources. 6. Whole blood, plasma or blood cells of human origin. Article 4 1. Nothing in this Directive shall in any way derogate from the Community rules for the radiation protection of persons undergoing medical examination or treatment, or from the Community rules laying down the basic safety standards for the health protection of the general public and workers against the dangers of ionizing radiation. 2. This Directive shall be without prejudice to Council Decision 86/346/EEC of 25 June 1986 accepting on behalf of the Community the European Agreement on the Exchange of Therapeutic Substances of Human Origin(20). 3. The provisions of this Directive shall not affect the powers of the Member States' authorities either as regards the setting of prices for medicinal products or their inclusion in the scope of national health insurance schemes, on the basis of health, economic and social conditions. 4. This Directive shall not affect the application of national legislation prohibiting or restricting the sale, supply or use of medicinal products as contraceptives or abortifacients. The Member States shall communicate the national legislation concerned to the Commission. Article 5 A Member State may, in accordance with legislation in force and to fulfil special needs, exclude from the provisions of this Directive medicinal products supplied in response to a bona fide unsolicited order, formulated in accordance with the specifications of an authorized health care professional and for use by his individual patients on his direct personal responsibility. TITLE III PLACING ON THE MARKET CHAPTER 1 Marketing authorization Article 6 1. No medicinal product may be placed on the market of a Member State unless a marketing authorization has been issued by the competent authorities of that Member State in accordance with this Directive or an authorization has been granted in accordance with Regulation (EEC) No 2309/93. 2. The authorisation referred to in paragraph 1 shall also be required for radionuclide generators, radionuclide kits, radionuclide precursor radiopharmaceuticals and industrially prepared radiopharmaceuticals. Article 7 A marketing authorization shall not be required for a radiopharmaceutical prepared at the time of use by a person or by an establishment authorized, according to national legislation, to use such medicinal products in an approved health care establishment exclusively from authorized radionuclide generators, radionuclide kits or radionuclide precursors in accordance with the manufacturer's instructions. Article 8 1. In order to obtain an authorization to place a medicinal product on the market regardless of the procedure established by Regulation (EEC) No 2309/93, an application shall be made to the competent authority of the Member State concerned. 2. A marketing authorization may only be granted to an applicant established in the Community. 3. The application shall be accompanied by the following particulars and documents, submitted in accordance with Annex I: (a) Name or corporate name and permanent address of the applicant and, where applicable, of the manufacturer. (b) Name of the medicinal product. (c) Qualitative and quantitative particulars of all the constituents of the medicinal product in usual terminology, but excluding empirical chemical formulae, with mention of the international non-proprietary name recommended by the World Health Organization where such name exists. (d) Description of the manufacturing method. (e) Therapeutic indications, contra-indications and adverse reactions. (f) Posology, pharmaceutical form, method and route of administration and expected shelf life. (g) If applicable, reasons for any precautionary and safety measures to be taken for the storage of the medicinal product, its administration to patients and for the disposal of waste products, together with an indication of any potential risks presented by the medicinal product for the environment. (h) Description of the control methods employed by the manufacturer (qualitative and quantitative analysis of the constituents and of the finished product, special tests, e.g. sterility tests, tests for the presence of pyrogenic substances, the presence of heavy metals, stability tests, biological and toxicity tests, controls carried out at an intermediate stage of the manufacturing process). (i) Results of: - physico-chemical, biological or microbiological tests, - toxicological and pharmacological tests, - clinical trials. (j) A summary, in accordance with Article 11, of the product characteristics, one or more specimens or mock-ups of the outer packaging and the immediate packaging of the medicinal product, together with a package leaflet. (k) A document showing that the manufacturer is authorised in his own country to produce medicinal products. (l) Copies of any authorisation obtained in another Member State or in a third country to place the medicinal product on the market, together with a list of those Member States in which an application for authorisation submitted in accordance with this Directive is under examination. Copies of the summary of the product characteristics proposed by the applicant in accordance with Article 11 or approved by the competent authorities of the Member State in accordance with Article 21. Copies of the package leaflet proposed in accordance with Article 59 or approved by the competent authorities of the Member State in accordance with Article 61. Details of any decision to refuse authorization, whether in the Community or in a third country, and the reasons for such a decision. This information shall be updated on a regular basis. Article 9 In addition to the requirements set out in Articles 8 and 10(1), an application for authorization to market a radionuclide generator shall also contain the following information and particulars: - a general description of the system together with a detailed description of the components of the system which may affect the composition or quality of the daughter nucleid preparation, - qualitative and quantitative particulars of the eluate or the sublimate. Article 10 1. In derogation of Article 8(3)(i), and without prejudice to the law relating to the protection of industrial and commercial property: (a) The applicant shall not be required to provide the results of toxicological and pharmacological tests or the results of clinical trials if he can demonstrate: (i) either that the medicinal product is essentially similar to a medicinal product authorized in the Member State concerned by the application and that the holder of the marketing authorization for the original medicinal product has consented to the toxicological, pharmacological and/or clinical references contained in the file on the original medicinal product being used for the purpose of examining the application in question; (ii) or that the constituent or constituents of the medicinal product have a well established medicinal use, with recognized efficacy and an acceptable level of safety, by means of a detailed scientific bibliography; (iii) or that the medicinal product is essentially similar to a medicinal product which has been authorized within the Community, in accordance with Community provisions in force, for not less than six years and is marketed in the Member State for which the application is made. This period shall be extended to 10 years in the case of high-technology medicinal products having been authorised according to the procedure laid down in Article 2(5) of Council Directive 87/22/EEC(21). Furthermore, a Member State may also extend this period to 10 years by a single Decision covering all the medicinal products marketed on its territory where it considers this necessary in the interest of public health. Member States are at liberty not to apply the six-year period beyond the date of expiry of a patent protecting the original medicinal product. However, where the medicinal product is intended for a different therapeutic use from that of the other medicinal products marketed or is to be administered by different routes or in different doses, the results of appropriate toxicological and pharmacological tests and/or of appropriate clinical trials must be provided. (b) In the case of new medicinal products containing known constituents not hitherto used in combination for therapeutic purposes, the results of toxicological and pharmacological tests and of clinical trials relating to that combination must be provided, but it shall not be necessary to provide references relating to each individual constituent. 2. Annex I shall apply by analogy where, pursuant to point (ii) of paragraph 1, (a), bibliographic references to published data are submitted. Article 11 The summary of the product characteristics shall contain the following information: 1. Name of the medicinal product. 2. Qualitative and quantitative composition in terms of the active substances and constituents of the excipient, knowledge of which is essential for proper administration of the medicinal product. The usual common name or chemical description shall be used. 3. Pharmaceutical form. 4. Pharmacological properties and, in so far as this information is useful for therapeutic purposes, pharmacokinetic particulars. 5. Clinical particulars: 5.1. therapeutic indications, 5.2. contra-indications, 5.3. adverse reactions (frequency and seriousness), 5.4. special precautions for use and, in the case of immunological medicinal products, any special precautions to be taken by persons handling such products and administering them to patients, together with any precautions to be taken by the patient, 5.5. use during pregnancy and lactation, 5.6. interaction with other medicaments and other forms of interaction, 5.7. posology and method of administration for adults and, where necessary, for children, 5.8. overdose (symptoms, emergency procedures, antidotes), 5.9. special warnings, 5.10. effects on ability to drive and to use machines. 6. Pharmaceutical particulars: 6.1. major incompatibilities, 6.2. shelf life, when necessary after reconstitution of the medicinal product or when the immediate packaging is opened for the first time, 6.3. special precautions for storage, 6.4. nature and contents of the immediate packaging, 6.5. special precautions for disposal of unused medicinal products or waste materials derived from such medicinal products, if appropriate. 7. Name or corporate name and permanent address of the marketing authorization holder. 8. For radiopharmaceuticals, full details of internal radiation dosimetry. 9. For radiopharmaceuticals, additional detailed instructions for extemporaneous preparation and quality control of such preparation and, where appropriate, maximum storage time during which any intermediate preparation such as an eluate or the ready-to-use pharmaceutical will conform with its specifications. Article 12 1. Member States shall take all appropriate measures to ensure that the documents and particulars listed in Article 8(3)(h) and (i), and Article 10(1)(a)(ii) are drawn up by experts with the necessary technical or professional qualifications before they are submitted to the competent authorities. These documents and particulars shall be signed by the experts. 2. The duties of the experts according to their respective qualifications shall be: (a) to perform tasks falling within their respective disciplines (analysis, pharmacology and similar experimental sciences, clinical trials) and to describe objectively the results obtained (qualitatively and quantitatively); (b) to describe their observations in accordance with Annex I, and to state, in particular: - in the case of the analyst, whether the medicinal product is consistent with the declared composition, giving any substantiation of the control methods employed by the manufacturer; - in the case of the pharmacologist or the specialist with similar experimental competence, the toxicity of the medicinal product and the pharmacological properties observed; - in the case of the clinician, whether he has been able to ascertain effects on persons treated with the medicinal product which correspond to the particulars given by the applicant in accordance with Articles 8 and 10, whether the patient tolerates the medicinal product well, the posology the clinician advises and any contra-indications and adverse reactions; (c) where applicable, to state the grounds for using the bibliography mentioned in point (a)(ii) of Article 10(1). 3. Detailed reports by the experts shall form part of the particulars accompanying the application which the applicant submits to the competent authorities. CHAPTER 2 Specific provisions applicable to homeopathic medicinal products Article 13 1. Member States shall ensure that homeopathic medicinal products manufactured and placed on the market within the Community are registered or authorized in accordance with Articles 14, 15 and 16, except where the products are covered by a registration or authorization which was granted under national law on or before 31 December 1993 (and whether or not that registration or authorization has been renewed after that date). Each Member State shall take due account of registrations and authorizations previously granted by another Member State. 2. A Member State may refrain from establishing a special, simplified registration procedure for the homeopathic medicinal products referred to in Article 14. A Member State shall inform the Commission accordingly. The Member State concerned shall allow the use in its territory of homeopathic medicinal products registered by other Member States in accordance with Articles 14 and 15. Article 14 1. Only homeopathic medicinal products which satisfy all of the following conditions may be subject to a special, simplified registration procedure: - they are administered orally or externally, - no specific therapeutic indication appears on the labelling of the medicinal product or in any information relating thereto, - there is a sufficient degree of dilution to guarantee the safety of the medicinal product; in particular, the medicinal product may not contain either more than one part per 10000 of the mother tincture or more than 1/100th of the smallest dose used in allopathy with regard to active substances whose presence in an allopathic medicinal product results in the obligation to submit a doctor's prescription. At the time of registration, Member States shall determine the classification for the dispensing of the medicinal product. 2. The criteria and rules of procedure provided for in Article 4(4), Article 17(1) and Articles 22 to 26, 112, 116 and 125 shall apply by analogy to the special, simplified registration procedure for homeopathic medicinal products, with the exception of the proof of therapeutic efficacy. 3. The proof of therapeutic efficacy shall not be required for homeopathic medicinal products registered in accordance with paragraph 1 of this Article, or, where appropriate, admitted in accordance with Article 13(2). Article 15 An application for special, simplified registration may cover a series of medicinal products derived from the same homeopathic stock or stocks. The following documents shall be included with the application in order to demonstrate, in particular, the pharmaceutical quality and the batch-to-batch homogeneity of the products concerned: - scientific name or other name given in a pharmacopoeia of the homeopathic stock or stocks, together with a statement of the various routes of administration, pharmaceutical forms and degree of dilution to be registered, - dossier describing how the homeopathic stock or stocks is/are obtained and controlled, and justifying its/their homeopathic nature, on the basis of an adequate bibliography, - manufacturing and control file for each pharmaceutical form and a description of the method of dilution and potentization, - manufacturing authorization for the medicinal product concerned, - copies of any registrations or authorizations obtained for the same medicinal product in other Member States, - one or more specimens or mock-ups of the outer packaging and the immediate packaging of the medicinal products to be registered, - data concerning the stability of the medicinal product. Article 16 1. Homeopathic medicinal products other than those referred to in Article 14(1) shall be authorized and labelled in accordance with Articles 8, 10 and 11. 2. A Member State may introduce or retain in its territory specific rules for the toxicological and pharmacological tests and clinical trials of homeopathic medicinal products other than those referred to in Article 14(1) in accordance with the principles and characteristics of homeopathy as practised in that Member State. In this case, the Member State concerned shall notify the Commission of the specific rules in force. 3. Title IX shall apply to homeopathic medicinal products, with the exception of those referred to in Article 14(1). CHAPTER 3 Procedures relevant to the marketing authorization Article 17 1. Member States shall take all appropriate measures to ensure that the procedure for granting an authorization to place a medicinal product on the market is completed within 210 days of the submission of a valid application. 2. Where a Member State notes that an application for authorization is already under active examination in another Member State in respect of that medicinal product, the Member State concerned may decide to suspend the detailed examination of the application in order to await the assessment report prepared by the other Member State in accordance with Article 21(4). The Member State concerned shall inform the other Member State and the applicant of its decision to suspend detailed examination of the application in question. As soon as it has completed the examination of the application and reached a decision, the other Member State shall forward a copy of its assessment report to the Member State concerned. Article 18 Where a Member State is informed in accordance with Article 8(3)(l) that another Member State has authorized a medicinal product which is the subject of an application for authorization in the Member State concerned, that Member State shall forthwith request the authorities of the Member State which has granted the authorization to forward to it the assessment report referred to in Article 21(4). Within 90 days of the receipt of the assessment report, the Member State concerned shall either recognize the decision of the first Member State and the summary of the product characteristics as approved by it or, if it considers that there are grounds for supposing that the authorization of the medicinal product concerned may present a risk to public health, it shall apply the procedures set out in Articles 29 to 34. Article 19 In order to examine the application submitted in accordance with Articles 8 and 10(1), the competent authority of the Member State: 1. must verify whether the particulars submitted in support of the application comply with the said Articles 8 and 10(1) and examine whether the conditions for issuing an authorization to place medicinal products on the market (marketing authorization) are complied with. 2. may submit the medicinal product, its starting materials and, if need be, its intermediate products or other constituent materials, for testing by a State laboratory or by a laboratory designated for that purpose in order to ensure that the control methods employed by the manufacturer and described in the particulars accompanying the application in accordance with Article 8(3)(h) are satisfactory. 3. may, where appropriate, require the applicant to supplement the particulars accompanying the application in respect of the items listed in the Articles 8(3) and 10(1). Where the competent authority avails itself of this option, the time limits laid down in Article 17 shall be suspended until such time as the supplementary information required has been provided. Likewise, these time limits shall be suspended for the time allowed the applicant, where appropriate, for giving oral or written explanation. Article 20 Member States shall take all appropriate measures to ensure that: (a) the competent authorities verify that manufacturers and importers of medicinal products coming from third countries are able to carry out manufacture in compliance with the particulars supplied pursuant to Article 8(3)(d), and/or to carry out controls according to the methods described in the particulars accompanying the application in accordance with Article 8(3)(h); (b) the competent authorities may allow manufacturers and importers of medicinal products coming from third countries, in exceptional and justifiable cases, to have certain stages of manufacture and/or certain of the controls referred to in (a) carried out by third parties; in such cases, the verifications by the competent authorities shall also be made in the establishment designated. Article 21 1. When the marketing authorization is issued, the holder shall be informed, by the competent authorities of the Member State concerned, of the summary of the product characteristics as approved by it. 2. The competent authorities shall take all necessary measures to ensure that the information given in the summary is in conformity with that accepted when the marketing authorization is issued or subsequently. 3. The competent authorities shall forward to the Agency a copy of the authorization together with the summary of the product characteristics. 4. The competent authorities shall draw up an assessment report and comments on the dossier as regards the results of the analytical and pharmacotoxicological tests and the clinical trials of the medicinal product concerned. The assessment report shall be updated whenever new information becomes available which is of importance for the evaluation of the quality, safety or efficacy of the medicinal product concerned. Article 22 In exceptional circumstances, and following consultation with the applicant, an authorization may be granted subject to certain specific obligations, including: - the carrying out of further studies following the granting of authorization, - the notification of adverse reactions to the medicinal product. These exceptional decisions may be adopted only for objective and verifiable reasons and shall be based on one of the causes referred to in Part 4 (G) of Annex I. Article 23 After an authorization has been issued, the authorization holder must, in respect of the methods of manufacture and control provided for in Article 8(3)(d) and (h), take account of scientific and technical progress and introduce any changes that may be required to enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods. These changes shall be subject to the approval of the competent authority of the Member State concerned. Article 24 Authorization shall be valid for five years and shall be renewable for five-year periods, on application by the holder at least three months before the expiry date and after consideration by the competent authority of a dossier containing in particular details of the data on pharmacovigilance and other information relevant to the monitoring of the medicinal product. Article 25 Authorization shall not affect the civil and criminal liability of the manufacturer and, where applicable, of the marketing authorization holder. Article 26 The marketing authorisation shall be refused if, after verification of the particulars and documents listed in Articles 8 and 10(1), it proves that: (a) the medicinal product is harmful in the normal conditions of use, or (b) that its therapeutic efficacy is lacking or is insufficiently substantiated by the applicant, or (c) that its qualitative and quantitative composition is not as declared. Authorisation shall likewise be refused if the particulars and documents submitted in support of the application do not comply with Articles 8 and 10(1). CHAPTER 4 Mutual recognition of authorizations Article 27 1. In order to facilitate the adoption of common decisions by Member States on the authorization of medicinal products on the basis of the scientific criteria of quality, safety and efficacy, and to achieve thereby the free movement of medicinal products within the Community, a Committee for Proprietary Medicinal Products, hereinafter referred to as "the Committee", is hereby set up. The Committee shall be part of the Agency. 2. In addition to the other responsibilities conferred upon it by Community law, the Committee shall examine any question relating to the granting, variation, suspension or withdrawal of marketing authorization which is submitted to it in accordance with this Directive. 3. The Committee shall draw up its own Rules of Prodecure. Article 28 1. Before submitting the application for recognition of a marketing authorization, the holder of the authorization shall inform the Member State which granted the authorization on which the application is based (hereinafter "reference Member State"), that an application is to be made in accordance with this Directive and shall notify it of any additions to the original dossier; that Member State may require the applicant to provide it with all the particulars and documents necessary to enable it to check that the dossiers filed are identical. In addition the holder of the authorization shall request the reference Member State to prepare an assessment report in respect of the medicinal product concerned, or, if necessary, to update any existing assessment report. That Member State shall prepare the assessment report, or update it, within 90 days of the receipt of the request. At the same time as the application is submitted in accordance with paragraph 2, the reference Member State shall forward the assessment report to the Member State or Member States concerned by the application. 2. In order to obtain the recognition according to the procedures laid down in this Chapter in one or more of the Member States of a marketing authorization issued by a Member State, the holder of the authorization shall submit an application to the competent authorities of the Member State or Member States concerned, together with the information and particulars referred to in Articles 8, 10(1) and 11. He shall testify that the dossier is identical to that accepted by the reference Member State, or shall identify any additions or amendments it may contain. In the latter case, he shall certify that the summary of the product characteristics proposed by him in accordance with Article 11 is identical to that accepted by the reference Member State in accordance with Article 21. Moreover, he shall certify that all the dossiers filed as part of the procedure are identical. 3. The holder of the marketing authorization shall communicate the application to the Agency, inform it of the Member States concerned and of the dates of submission of the application and send it a copy of the authorization granted by the reference Member State. He shall also send the Agency copies of any such authorization which may have been granted by the other Member States in respect of the medicinal product concerned, and shall indicate whether any application for authorization is currently under consideration in any Member State. 4. Save in the exceptional case provided for in Article 29(1), each Member State shall recognize the marketing authorization granted by the reference Member State within 90 days of receipt of the application and the assessment report. It shall inform the reference Member State which granted the initial authorization, the other Member States concerned by the application, the Agency, and the marketing authorization holder. Article 29 1. Where a Member State considers that there are grounds for supposing that the marketing authorization of the medicinal product concerned may present a risk to public health, it shall forthwith inform the applicant, the reference Member State which granted the initial authorization, any other Member States concerned by the application and the Agency. The Member State shall state its reasons in detail and shall indicate what action may be necessary to correct any defect in the application. 2. All the Member States concerned shall use their best endeavours to reach agreement on the action to be taken in respect of the application. They shall provide the applicant with the opportunity to make his point of view known orally or in writing. However, if the Member States have not reached agreement within the time limit referred to in Article 28(4) they shall forthwith refer the matter to the Agency with regard to the Committee's reference for the application of the procedure laid down in Article 32. 3. Within the time limit referred to in Article 28(4), the Member States concerned shall provide the Committee with a detailed statement of the matters on which they have been unable to reach agreement and the reasons for their disagreement. The applicant shall be provided with a copy of this information. 4. As soon as he is informed that the matter has been referred to the Committee, the applicant shall forthwith forward to the Committee a copy of the information and particulars referred to in Article 28(2). Article 30 If several applications submitted in accordance with Articles 8, 10(1) and Article 11 have been made for marketing authorization for a particular medicinal product, and Member States have adopted divergent decisions concerning the authorization of the medicinal product or its suspension or withdrawal, a Member State, or the Commission, or the marketing authorization holder may refer the matter to the Committee for application of the procedure laid down in Article 32. The Member State concerned, the marketing authorization holder or the Commission shall clearly identify the question which is referred to the Committee for consideration and, where appropriate, shall inform the holder. The Member State and the marketing authorization holder shall forward to the Committee all available information relating to the matter in question. Article 31 The Member States or the Commission or the applicant or holder of the marketing authorization may, in specific cases where the interests of the Community are involved, refer the matter to the Committee for the application of the procedure laid down in Article 32 before reaching a decision on a request for a marketing authorization or on the suspension or withdrawal of an authorization, or on any other variation to the terms of a marketing authorization which appears necessary, in particular to take account of the information collected in accordance with Title IX. The Member State concerned or the Commission shall clearly identify the question which is referred to the Committee for consideration and shall inform the marketing authorization holder. The Member States and the marketing authorization holder shall forward to the Committee all available information relating to the matter in question. Article 32 1. When reference is made to the procedure described in this Article, the Committee shall consider the matter concerned and issue a reasoned opinion within 90 days of the date on which the matter was referred to it. However, in cases submitted to the Committee in accordance with Articles 30 and 31, this period may be extended by 90 days. In case of urgency, on a proposal from its Chairman, the Committee may agree to a shorter deadline. 2. In order to consider the matter, the Committee may appoint one of its members to act as rapporteur. The Committee may also appoint individual experts to advise it on specific questions. When appointing experts, the Committee shall define their tasks and specify the time-limit for the completion of these tasks. 3. In the cases referred to in Articles 29 and 30, before issuing its opinion, the Committee shall provide the marketing authorization holder with an opportunity to present written or oral explanations. In the case referred to in Article 31, the marketing authorization holder may be asked to explain himself orally or in writing. If it considers it appropriate, the Committee may invite any other person to provide information relating to the matter before it. The Committee may suspend the time limit referred to in paragraph 1 in order to allow the marketing authorization holder to prepare explanations. 4. The Agency shall forthwith inform the marketing authorization holder where the opinion of the Committee is that: - the application does not satisfy the criteria for authorization, or - the summary of the product characteristics proposed by the applicant in accordance with Article 11 should be amended, or - the authorization should be granted subject to conditions, with regard to conditions considered essential for the safe and effective use of the medicinal product including pharmacovigilance, or - a marketing authorization should be suspended, varied or withdrawn. Within 15 days of the receipt of the opinion, the marketing authorization holder may notify the Agency in writing of his intention to appeal. In that case, he shall forward the detailed grounds for appeal to the Agency within 60 days of receipt of the opinion. Within 60 days of receipt of the grounds for appeal, the Committee shall consider whether its opinion should be revised, and the conclusions reached on the appeal shall be annexed to the assessment report referred to in paragraph 5. 5. Within 30 days of its adoption, the Agency shall forward the final opinion of the Committee to the Member States, the Commission and the marketing authorization holder together with a report describing the assessment of the medicinal product and stating the reasons for its conclusions. In the event of an opinion in favour of granting or maintaining an authorization to place the medicinal product concerned on the market, the following documents shal