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.
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.
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.
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.
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.
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.
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
