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1.3. 1.3.1.

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5.2.7. Part II: Specific marketing authorisation dossiers and requirements 1 2 3 4 5 6 7. Part III: Particular medicinal products 1.

1.1. 1.2 2.

2.1. 2.2 3 4

5. Part IV: Advanced therapy medicinal products 1. Introduction 2. Definitions 2.1. Gene therapy medicinal product 2.2. Somatic cell therapy medicinal product 3. Specific requirements regarding Module 3 3.1. Specific requirements for all advanced therapy medicinal products 3.2. Specific requirements for gene therapy medicinal products 3.2.1. Introduction: finished product, active substance and starting materials 3.2.1.1. Gene therapy medicinal product containing recombinant nucleic acid sequence(s) or genetically modified microorganism(s) or virus(es) 3.2.1.2. Gene therapy medicinal product containing genetically modified cells 3.2.1.3.

3.2.1.4. 3.2.1.5.

3.2.2. Specific requirements 3.3. Specific requirements for somatic cell therapy medicinal products and tissue engineered products 3.3.1. Introduction: finished product, active substance and starting materials 3.3.2. Specific requirements 3.3.2.1. Starting materials 3.3.2.2. Manufacturing process 3.3.2.3. Characterisation and control strategy 3.3.2.4. Excipients 3.3.2.5. Developmental studies 3.3.2.6. Reference materials 3.4. Specific requirements for advanced therapy medicinal products containing devices 3.4.1. Advanced therapy medicinal product containing devices as referred to in Article 7 of Regulation (EC) No 1394/2007 3.4.2. Combined advanced therapy medicinal products as defined in Article 2(1)(d) of Regulation (EC) No 1394/2007 4. Specific requirements regarding module 4 4.1. Specific requirements for all advanced therapy medicinal products 4.2. Specific requirements for gene therapy medicinal products 4.2.1. Pharmacology 4.2.2. Pharmacokinetics 4.2.3. Toxicology 4.3. Specific requirements for somatic cell therapy medicinal products and tissue engineered products 4.3.1. Pharmacology 4.3.2. Pharmacokinetics 4.3.3. Toxicology 5. Specific requirements regarding module 5 5.1. Specific requirements for all advanced therapy medicinal products 5.2. Specific requirements for gene therapy medicinal products 5.2.1. Human pharmacokinetic studies 5.2.2. Human pharmacodynamic studies 5.2.3. Safety studies 5.3. Specific requirements for somatic cell therapy medicinal products 5.3.1. Somatic cell therapy medicinal products where the mode of action is based on the production of defined active biomolecule(s) 5.3.2. Biodistribution, persistence and long-term engraftment of the somatic cell therapy medicinal product components 5.3.3. Safety studies 5.4. Specific requirements for tissue engineered products 5.4.1. Pharmacokinetic studies 5.4.2. Pharmacodynamic studies 5.4.3. Safety studies

Introduction and general principles (1) The particulars and documents accompanying an application for marketing authorisation pursuant to Articles 8 and 10 (1) shall be presented in accordance with the requirements set out in this Annex and shall follow the guidance published by the Commission in The rules governing medicinal products in the European Community, Volume 2 B, Notice to applicants, Medicinal products for human use, Presentation and content of the dossier, Common Technical Document (CTD).

(2) The particulars and documents shall be presented as five modules: Module 1 provides European Community specific administrative data; Module 2 provides quality, non-clinical and clinical summaries, Module 3 provides chemical, pharmaceutical and biological information, Module 4 provides non-clinical reports and Module 5 provides clinical study reports. This presentation implements a common format for all ICH () regions (European Community, United States of America, Japan). These five Modules shall be presented in strict accordance with the format, content and numbering system delineated in details in Volume 2 B of the Notice to Applicants referred to above.

(3) The European Community-CTD-presentation is applicable for all types of marketing authorisation applications irrespective of the procedure to be applied (i.e. centralised, mutual recognition or national) and of whether they are based on a full or abridged application. It is also applicable for all types of products including new chemical entities (NCE), radio-pharmaceuticals, plasma derivatives, vaccines, herbal medicinal products, etc.

(4) In assembling the dossier for application for marketing authorisation, applicants shall also take into account the scientific guidelines relating to the quality, safety and efficacy of medicinal products for human use as adopted by the Committee for Proprietary Medicinal Products (CPMP) and published by the European Medicine Evaluation Agency (EMEA) and the other pharmaceutical Community guidelines published by the Commission in the different volumes of The rules governing medicinal products in the European Community.

(5) With respect to the quality part (chemical, pharmaceutical and biological) of the dossier, all monographs including general monographs and general chapters of the European Pharmacopoeia are applicable.

(6) The manufacturing process shall comply with the requirements of Commission Directive 91/356/EEC laying down the principles and guidelines of Good Manufacturing Practice (GMP) for medicinal products for human use () and with the principles and guidelines on GMP, published by the Commission in The rules governing medicinal products in the European Community, Volume 4.

(7) All information, which is relevant to the evaluation of the medicinal product concerned, shall be included in the application, whether favourable or unfavourable to the product. In particular, all relevant details shall be given of any incomplete or abandoned pharmaco-toxicological or clinical test or trial relating to the medicinal product and/or completed trials concerning therapeutic indications not covered by the application.

(8) All clinical trials, conducted within the European Community, must comply with the requirements of Directive 2001/20/EC of the European Parliament and of the Council on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use (). To be taken into account during the assessment of an application, clinical trials, conducted outside the European Community, which relate to medicinal products intended to be used in the European Community, shall be designed, implemented and reported on what good clinical practice and ethical principles are concerned, on the basis of principles, which are equivalent to the provisions of Directive 2001/20/EC. They shall be carried out in accordance with the ethical principles that are reflected, for example, in the Declaration of Helsinki.

(9) Non-clinical (pharmaco-toxicological) studies shall be carried out in conformity with the provisions related to Good Laboratory Practice laid down in Council Directives 87/18/EEC on the harmonisation of regulations and administrative provisions relating to the application of the principles of good laboratory practice and the verification of their application for tests in chemical substances () and 88/320/EEC on the inspection and verification of good laboratory practice (GLP) ().

(10) Member States shall also ensure that all tests on animals are conducted in accordance with Council Directive 86/609/EEC of 24 November 1986 on the approximation of laws, regulation and administrative provisions of the Member States regarding the protection of animals for experimental and other scientific purposes.

(11) In order to monitor the benefit/risk assessment, any new information not in the original application and all pharmaco-vigilance information shall be submitted to the competent authority. After marketing authorisation has been granted, any change to the data in the dossier shall be submitted to the competent authorities in accordance with the requirements of Commission Regulations (EC) No 1084/2003 () and (EC) No 1085/2003 () of the Commission or, if relevant, in accordance with national provisions, as well as the requirements in Volume 9 of Commission publication The rules governing medicinal products in the European Community. This Annex is divided in four different parts:

— Part I describes the application format, the summary of product characteristics, the labelling, the leaflet and presentation requirements for standard applications (Modules 1 to 5).

— Part II provides derogation for ‘Specific applications’, i.e. well-established medicinal use, essentially similar products, fixed combinations, similar biological products, exceptional circumstances and mixed applications (part bibliographic and part own studies).

— Part III deals with ‘Particular application requirements’ for biological medicinal products (Plasma Master File; Vaccine Antigen Master File), radio-pharmaceuticals, homeopathic medicinal products, herbal medicinal products and orphan medicinal products.

— Part IV deals with ‘Advanced therapy medicinal products’ and concerns specific requirements for gene therapy medicinal products (using human autologous or allogeneic system, or xenogeneic system) and cell therapy medicinal products both of human or animal origin and xenogeneic transplantation medicinal products.

1. MODULE 1: ADMINISTRATIVE INFORMATION 1.1. Table of contents A comprehensive table of contents of Modules 1 to 5 of the dossier submitted for marketing authorisation application shall be presented.

1.2. Application form The medicinal product, which is the subject of the application, shall be identified by name and name of the active substance(s), together with the pharmaceutical form, the route of administration, the strength and the final presentation, including packaging. The name and address of the applicant shall be given, together with the name and address of the manufacturers and the sites involved in the different stages of the manufacture (including the manufacturer of the finished product and the manufacturer(s) of the active substance(s)), and where relevant the name and address of the importer. The applicant shall identify the type of application and indicate what samples, if any, are also provided.

Annexed to the administrative data shall be copies of the manufacturing authorisation as defined in Article 40, together with a list of countries in which authorisation has been granted, copies of all the summaries of product characteristics in accordance with Article 11 as approved by Member States and a list of countries in which an application has been submitted. As outlined in the application form, the applicants shall provide, inter alia, details of the medicinal product subject of the application, the legal basis of the application, the proposed marketing authorisation holder and manufacture(s), information on orphan medicinal product status, scientific advice and paediatric development program.

1.3. Summary of product characteristics, labelling and package leaflet 1.3.1. Summary of product characteristics The applicant shall propose a summary of the product characteristics, in accordance with Article 11.

1.3.2. Labelling and package leaflet