Changes from plenary report to adopted text

Added(d) Genotoxicity shall be studied. However, standard genotoxicity studies shall only be conducted when they are necessary for testing a specific impurity or a component of the delivery system.

Added(e) Carcinogenicity shall be studied. Standard lifetime rodent carcinogenicity studies shall not be required. However, depending on the type of product, the tumourigenic potential shall be evaluated in relevant in vivo/in vitro models.

Added(f) Reproductive and developmental toxicity: Studies on the effects on fertility and general reproductive function shall be provided. Embryo-foetal and perinatal toxicity studies and germline transmission studies shall be provided, unless otherwise duly justified in the application on the basis of the type of product concerned.

Added(g) Additional toxicity studies

Added— Integration studies: integration studies shall be provided for any gene therapy medicinal product, unless the lack of these studies is scientifically justified, e.g. because nucleic acid sequences will not enter into the cell nucleus. For gene therapy medicinal products not expected to be capable of integration, integration studies shall be performed, if biodistribution data indicate a risk for germline transmission.

Added— Immunogenicity and immunotoxicity: potential immunogenic and immunotoxic effects shall be studied.

Added4.3. Specific requirements for somatic cell therapy medicinal products and tissue engineered products

Added4.3.1. Pharmacology

Added(a) The primary pharmacological studies shall be adequate to demonstrate the proof of concept. The interaction of the cell-based products with the surrounding tissue shall be studied.

Added(b) The amount of product needed to achieve the desired effect/the effective dose, and, depending on the type of product, the frequency of dosing shall be determined.

Added(c) Secondary pharmacological studies shall be taken into account to evaluate potential physiological effects that are not related to the desired therapeutic effect of the somatic cell therapy medicinal product, of the tissue engineered product or of additional substances, as biologically active molecules besides the protein(s) of interest might be secreted or the protein(s) of interest could have unwanted target sites.

Added4.3.2. Pharmacokinetics

Added(a) Conventional pharmacokinetic studies to investigate absorption, distribution, metabolism and excretion shall not be required. However, parameters such as viability, longevity, distribution, growth, differentiation and migration shall be investigated, unless otherwise duly justified in the application on the basis of the type of product concerned.

Added(b) For somatic cell therapy medicinal products and tissue engineered products, producing systemically active biomolecules, the distribution, duration and amount of expression of these molecules shall be studied.

Added4.3.3. Toxicology

Added(a) The toxicity of the finished product shall be assessed. Individual testing of active substance(s), excipients, additional substances and any process-related impurities shall be taken into consideration.

Added(b) The duration of observations may be longer than in standard toxicity studies and the anticipated lifespan of the medicinal product, together with its pharmacodynamic and pharmacokinetic profile, shall be taken into consideration. A justification of the duration shall be provided.

Added(c) Conventional carcinogenicity and genotoxicity studies shall not be required, except with regard to the tumourigenic potential of the product.

Added(d) Potential immunogenic and immunotoxic effects shall be studied.

Added(e) In the case of cell-based products containing animal cells, the associated specific safety concerns such as transmission to humans of xenogeneic pathogens shall be addressed.

Added5. SPECIFIC REQUIREMENTS REGARDING MODULE 5

Added5.1. Specific requirements for all advanced therapy medicinal products

Added5.1.1. The specific requirements in this section of Part IV are additional requirements to those set in Module 5 in Part I of this Annex.

Added5.1.2. Where the clinical application of advanced therapy medicinal products requires specific concomitant therapy and involve surgical procedures, the therapeutic procedure as a whole shall be investigated and described. Information on the standardisation and optimisation of those procedures during clinical development shall be provided.

AddedWhere medical devices used during the surgical procedures for application, implantation or administration of the advanced therapy medicinal product may have an impact on the efficacy or safety of the advanced therapy product, information on these devices shall be provided.

AddedSpecific expertise required to carry out the application, implantation, administration or follow-up activities shall be defined. Where necessary, the training plan of health care professionals on the use, application, implantation or administration procedures of these products shall be provided.

Added5.1.3. Given that, due to the nature of advanced therapy medicinal products, their manufacturing process may change during clinical development, additional studies to demonstrate comparability may be required.

Added5.1.4. During clinical development, risks arising from potential infectious agents or the use of material derived from animal sources and measures taken to reduce such risk shall be addressed.

Added5.1.5. Dose selection and schedule of use shall be defined by dose-finding studies.

Added5.1.6. The efficacy of the proposed indications shall be supported by relevant results from clinical studies using clinically meaningful endpoints for the intended use. In certain clinical conditions, evidence of long-term efficacy may be required. The strategy to evaluate long-term efficacy shall be provided.

Added5.1.7. A strategy for the long-term follow-up of safety and efficacy shall be included in the risk management plan.

Added5.1.8. For combined advanced therapy medicinal products, the safety and efficacy studies shall be designed for and performed on the combined product as a whole.

Added5.2. Specific requirements for gene therapy medicinal products

Added5.2.1. Human pharmacokinetic studies

AddedHuman pharmacokinetic studies shall include the following aspects:

Added(a) shedding studies to address the excretion of the gene therapy medicinal products;

Added(b) biodistribution studies;

Added(c) pharmacokinetic studies of the medicinal product and the gene expression moieties (e.g. expressed proteins or genomic signatures).

Added5.2.2. Human pharmacodynamic studies

AddedHuman pharmacodynamic studies shall address the expression and function of the nucleic acid sequence following administration of the gene therapy medicinal product.

Added5.2.3. Safety studies

AddedSafety studies shall address the following aspects:

Added(a) emergence of replication competent vector;

Added(b) emergence of new strains;

Added(c) reassortment of existing genomic sequences;

Added(d) neoplastic proliferation due to insertional mutagenicity.

Added5.3. Specific requirements for somatic cell therapy medicinal products

Added5.3.1. Somatic cell therapy medicinal products where the mode of action is based on the production of defined active biomolecule(s)

AddedFor somatic cell therapy medicinal products where the mode of action is based on the production of defined active biomolecule(s), the pharmacokinetic profile (in particular distribution, duration and amount of expression) of those molecules shall be addressed, if feasible.

Added5.3.2. Biodistribution, persistence and long-term engraftment of the somatic cell therapy medicinal product components

AddedThe biodistribution, persistence and long-term engraftment of the somatic cell therapy medicinal product components shall be addressed during the clinical development.

Added5.3.3. Safety studies

AddedSafety studies shall address the following aspects:

Added(a) distribution and engrafting following administration;

Added(b) ectopic engraftment;

Added(c) oncogenic transformation and cell/tissue lineage fidelity.

Added5.4. Specific requirements for tissue engineered products

Added5.4.1. Pharmacokinetic studies

AddedWhere conventional pharmacokinetic studies are not relevant for tissue engineered products, the biodistribution, persistence and degradation of the tissue engineered product components shall be addressed during the clinical development.

Added5.4.2. Pharmacodynamic studies