Changes from plenary report to adopted text

AddedWith respect to the elucidation of the structure and other characteristics of the herbal substance, information on the botanical, macroscopical, microscopical, phyto-chemical characterisation, and biological activity if necessary, shall be provided.

AddedWith respect to the elucidation of the structure and other characteristics of the herbal preparation, information on the phyto- and physicochemical characterisation, and biological activity if necessary, shall be provided.

AddedThe specifications for the herbal substance(s) and herbal preparation(s) where applicable shall be provided.

AddedThe analytical procedures used for testing the herbal substance(s) and herbal preparation(s) where applicable shall be provided.

AddedWith respect to the validation of analytical procedures, analytical validation information, including experimental data for the analytical procedures used for testing the herbal substance(s) and herbal preparation(s) where applicable shall be provided.

AddedWith respect to batch analyses, description of batches and results of batch analyses for the herbal substance(s) and herbal preparation(s) where applicable shall be provided, including those for pharmacopoeial substances.

AddedJustification for the specifications of the herbal substance(s) and herbal preparation(s) where applicable shall be provided.

AddedInformation on the reference standards or reference materials used for testing of the herbal substance(s) and herbal preparation(s) where applicable shall be provided.

AddedWhere the herbal substance or the herbal preparation is the subject of a monograph, the applicant can apply for a certificate of suitability that was granted by the European Directorate for the Quality of Medicines.

Added(2) H e r b a l M e d i c i n a l P r o d u c t s

AddedWith respect to the formulation development, a brief summary describing the development of the herbal medicinal product should be provided, taking into consideration the proposed route of administration and usage. Results comparing the phyto-chemical composition of the products used in supporting bibliographic data and the herbal medicinal product applied for shall be discussed, where appropriate.

Added5. ORPHAN MEDICINAL PRODUCTS

Added— In the case of an orphan medicinal product in the meaning of Regulation (EC) No 141/2000, general provisions of Part II-6 (exceptional circumstances) can be applied. The applicant shall then justify in the non-clinical and clinical summaries the reasons for which it is not possible to provide the complete information and shall provide a justification of the benefit/risk balance for the orphan medicinal product concerned.

Added— When an applicant for an marketing authorisation for an orphan medicinal product invokes the provisions of Article 10 (1)(a)(ii) and Part II-1 of this Annex (well-established medicinal use), the systematic and documented use of the concerned substance can refer — as way of derogation — to the use of that substance in accordance with the provisions of Article 5 of this Directive.

AddedPART IV

AddedADVANCED THERAPY MEDICINAL PRODUCTS

Added1. INTRODUCTION

AddedMarketing authorisation applications for advanced therapy medicinal products, as defined in point (a) of Article 2(1) of Regulation (EC) No 1394/2007, shall follow the format requirements (Modules 1, 2, 3, 4 and 5) described in Part I of this Annex.

AddedThe technical requirements for Modules 3, 4 and 5 for biological medicinal products, as described in Part I of this Annex, shall apply. The specific requirements for advanced therapy medicinal products described in sections 3, 4 and 5 of this part explain how the requirements in Part I apply to advanced therapy medicinal products. In addition, where appropriate and taking into account the specificities of advanced therapy medicinal products, additional requirements have been set.

AddedDue to the specific nature of advanced therapy medicinal products, a risk-based approach may be applied to determine the extent of quality, non-clinical and clinical data to be included in the marketing authorisation application, in accordance with the scientific guidelines relating to the quality, safety and efficacy of medicinal products referred to in point 4 of the ‘Introduction and general principles’.

AddedThe risk analysis may cover the entire development. Risk factors that may be considered include: the origin of the cells (autologous, allogeneic, xenogeneic), the ability to proliferate and/or differentiate and to initiate an immune response, the level of cell manipulation, the combination of cells with bioactive molecules or structural materials, the nature of the gene therapy medicinal products, the extent of replication competence of viruses or micro-organisms used in vivo, the level of integration of nucleic acids sequences or genes into the genome, the long time functionality, the risk of oncogenicity and the mode of administration or use.

AddedRelevant available non-clinical and clinical data or experience with other, related advanced therapy medicinal products may also be considered in the risk analysis.

AddedAny deviation from the requirements of this Annex shall be scientifically justified in Module 2 of the application dossier. The risk analysis described above, when applied, shall also be included and described in Module 2. In this case, the methodology followed, the nature of the identified risks and the implications of the risk based approach for the development and evaluation program shall be discussed and any deviations from the requirements of this Annex resulting from the risk analysis shall be described.

Added2. DEFINITIONS

AddedFor the purposes of this Annex, in addition to the definitions laid down in Regulation (EC) No 1394/2007, the definitions set out in sections 2.1 and 2.2 shall apply.

Added2.1. Gene therapy medicinal product

AddedGene therapy medicinal product means a biological medicinal product which has the following characteristics:

Added(a) it contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence;

Added(b) its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.

AddedGene therapy medicinal products shall not include vaccines against infectious diseases.

Added2.2. Somatic cell therapy medicinal product

AddedSomatic cell therapy medicinal product means a biological medicinal product which has the following characteristics:

Added(a) contains or consists of cells or tissues that have been subject to substantial manipulation so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered, or of cells or tissues that are not intended to be used for the same essential function(s) in the recipient and the donor;

Added(b) is presented as having properties for, or is used in or administered to human beings with a view to treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of its cells or tissues.

AddedFor the purposes of point (a), the manipulations listed in Annex I to Regulation (EC) No 1394/2007, in particular, shall not be considered as substantial manipulations.

Added3. SPECIFIC REQUIREMENTS REGARDING MODULE 3

Added3.1. Specific requirements for all advanced therapy medicinal products

AddedA description of the traceability system that the marketing authorisation holder intends to establish and maintain to ensure that the individual product and its starting and raw materials, including all substances coming into contact with the cells or tissues it may contain, can be traced through the sourcing, manufacturing, packaging, storage, transport and delivery to the hospital, institution or private practice where the product is used, shall be provided.

AddedThe traceability system shall be complementary to, and compatible with, the requirements established in Directive 2004/23/EC of the European Parliament and of the Council (), as regards human cells and tissues other than blood cells, and Directive 2002/98/EC, as regards human blood cells.

Added3.2. Specific requirements for gene therapy medicinal products

Added3.2.1. Introduction: finished product, active substance and starting materials

Added3.2.1.1. Gene therapy medicinal product containing recombinant nucleic acid sequence(s) or genetically modified microorganism(s) or virus(es)

AddedThe finished medicinal product shall consist of nucleic acid sequence(s) or genetically modified microorganism(s) or virus(es) formulated in their final immediate container for the intended medical use. The finished medicinal product may be combined with a medical device or active implantable medical device.

AddedThe active substance shall consist of nucleic acid sequence(s) or genetically modified microorganism(s) or virus(es).

Added3.2.1.2. Gene therapy medicinal product containing genetically modified cells

AddedThe finished medicinal product shall consist of genetically modified cells formulated in the final immediate container for the intended medical use. The finished medicinal product may be combined with a medical device or active implantable medical device.

AddedThe active substance shall consist of cells genetically modified by one of the products described in section 3.2.1.1 above.

Added3.2.1.3. In the case of products consisting of viruses or viral vectors, the starting materials shall be the components from which the viral vector is obtained, i.e. the master virus vector seed or the plasmids used to transfect the packaging cells and the master cell bank of the packaging cell line.

Added3.2.1.4. In the case of products consisting of plasmids, non-viral vectors and genetically modified microorganism(s) other than viruses or viral vectors, the starting materials shall be the components used to generate the producing cell, i.e. the plasmid, the host bacteria and the master cell bank of recombinant microbial cells.

Added3.2.1.5. In the case of genetically modified cells, the starting materials shall be the components used to obtain the genetically modified cells, i.e. the starting materials to produce the vector, the vector and the human or animal cells. The principles of good manufacturing practice shall apply from the bank system used to produce the vector onwards.

Added3.2.2. Specific requirements

AddedIn addition to the requirements set out in sections 3.2.1 and 3.2.2 of Part I of this Annex, the following requirements shall apply:

Added(a) information shall be provided on all the starting materials used for the manufacture of the active substance, including the products necessary for the genetic modification of human or animal cells and, as applicable, subsequent culture and preservation of the genetically modified cells, taking into consideration the possible absence of purification steps;

Added(b) for products containing a microorganism or a virus, data on the genetic modification, sequence analysis, attenuation of virulence, tropism for specific tissues and cell types, cell cycle dependence of the microorganism or virus, pathogenicity and characteristics of the parental strain shall be provided;

Added(c) process-related impurities and product-related impurities shall be described in the relevant sections of the dossier, and in particular replication competent virus contaminants if the vector is designed to be replication incompetent;

Added(d) for plasmids, quantification of the different plasmid forms shall be undertaken throughout the shelf life of the product;

Added(e) for genetically modified cells, the characteristics of the cells before and after the genetic modification, as well as before and after any subsequent freezing/storage procedures, shall be tested.

AddedFor genetically modified cells, in addition to the specific requirements for gene therapy medicinal products, the quality requirements for somatic cell therapy medicinal products and tissue engineered products (see section 3.3) shall apply.

Added3.3. Specific requirements for somatic cell therapy medicinal products and tissue engineered products

Added3.3.1. Introduction: finished product, active substance and starting materials