Directive 2001/83/EC of the European Parliament and of the CouncilShow full title

[F1 [F2 4. SPECIFIC REQUIREMENTS REGARDING MODULE 4 U.K.

4.1. Specific requirements for all advanced therapy medicinal products U.K.

The requirements of Part I, Module 4 of this Annex on the pharmacological and toxicological testing of medicinal products may not always be appropriate due to unique and diverse structural and biological properties of advanced therapy medicinal products. The technical requirements in sections 4.1, 4.2 and 4.3 below explain how the requirements in Part I of this Annex apply to advanced therapy medicinal products. Where appropriate and taking into account the specificities of advanced therapy medicinal products, additional requirements have been set.

The rationale for the non-clinical development and the criteria used to choose the relevant species and models ( in vitro and in vivo ) shall be discussed and justified in the non-clinical overview. The chosen animal model(s) may include immuno-compromised, knockout, humanised or transgenic animals. The use of homologous models (e.g. mouse cells analysed in mice) or disease mimicking models shall be considered, especially for immunogenicity and immunotoxicity studies.

In addition to the requirements of Part I, the safety, suitability and biocompatibility of all structural components (such as matrices, scaffolds and devices) and any additional substances (such as cellular products, biomolecules, biomaterials, and chemical substances), which are present in the finished product, shall be provided. Their physical, mechanical, chemical and biological properties shall be taken into account.

4.2. Specific requirements for gene therapy medicinal products U.K.

In order to determine the extent and type of non-clinical studies necessary to determine the appropriate level of non-clinical safety data, the design and type of the gene therapy medicinal product shall be taken into account.

4.2.1. Pharmacology U.K.

(a)

In vitro and in vivo studies of actions relating to the proposed therapeutic use (i.e. pharmacodynamic ‘ proof of concept ’ studies) shall be provided using models and relevant animal species designed to show that the nucleic acid sequence reaches its intended target (target organ or cells) and provides its intended function (level of expression and functional activity). The duration of the nucleic acid sequence function and the proposed dosing regimen in the clinical studies shall be provided.

(b)

Target selectivity: When the gene therapy medicinal product is intended to have a selective or target-restricted functionality, studies to confirm the specificity and duration of functionality and activity in target cells and tissues shall be provided.

4.2.2. Pharmacokinetics U.K.

(a)

Biodistribution studies shall include investigations on persistence, clearance and mobilisation. Biodistribution studies shall additionally address the risk of germline transmission.

(b)

Investigations of shedding and risk of transmission to third parties shall be provided with the environmental risk assessment, unless otherwise duly justified in the application on the basis of the type of product concerned.

4.2.3. Toxicology U.K.

(a)

Toxicity of the finished gene therapy medicinal product shall be assessed. In addition, depending on the type of product, individual testing of active substance and excipients shall be taken into consideration, the in vivo effect of expressed nucleic acid sequence-related products which are not intended for the physiological function shall be evaluated.

(b)

Single-dose toxicity studies may be combined with safety pharmacology and pharmacokinetic studies, e.g. to investigate persistence.

(c)

Repeated dose toxicity studies shall be provided when multiple dosing of human subjects is intended. The mode and scheme of administration shall closely reflect the planned clinical dosing. For those cases where single dosing may result in prolonged functionality of the nucleic acid sequence in humans, repeated toxicity studies shall be considered. The duration of the studies may be longer than in standard toxicity studies depending on the persistence of the gene therapy medicinal product and the anticipated potential risks. A justification for the duration shall be provided.

(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.

(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.

(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.

(g)

Additional toxicity studies

• 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.

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

4.3. Specific requirements for somatic cell therapy medicinal products and tissue engineered products U.K.

4.3.1. Pharmacology U.K.

(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.

(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.

(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.

4.3.2. Pharmacokinetics U.K.

(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.

(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.

4.3.3. Toxicology U.K.

(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.

(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.

(c)

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

(d)

Potential immunogenic and immunotoxic effects shall be studied.

(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.] ]

Textual Amendments

F1 Substituted by Commission directive 2003/63/EC of 25 June 2003 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use (Text with EEA relevance).

F2 Substituted by Commission Directive 2009/120/EC of 14 September 2009 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products (Text with EEA relevance).