General principles of the regulation on advanced therapy medicinal products

Regulation (EC) No 1394/2007 on advanced therapy medicinal products specifically governs gene therapy medicinal products, somatic cell therapy medicinal products and tissue engineered products. The Regulation supplements the general provisions of EU law governing medicinal products for human use as provided by Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use and Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use.
This regulation introduces specific rules for tissue engineered products. The requirements for gene therapy medicinal products and somatic cell therapy products as established by Directive 2001/83/EC and Regulation No 726/2007 are only affected by the Regulation to a minor degree.

What is a tissue engineered product?

The regulation defines a tissue engineered product as a product that contains or consists of engineered cells or tissues, and is presented as having properties for, or is used in or administered to human beings with a view to regenerating, repairing or replacing a human tissue.
A tissue engineered product may contain cells or tissues of human or animal origin, or both. The cells or tissues may be viable or non-viable. It may also contain additional substances, such as cellular products, bio-molecules, biomaterials, chemical substances, scaffolds or matrices.
Products containing or consisting exclusively of non-viable human or animal cells and/or tissues, which do not contain any viable cells or tissues and which do not act principally by pharmacological, immunological or metabolic action, shall be excluded from the above definition.
Cells or tissues shall be considered engineered if they fulfil at least one of the following conditions:

• the cells or tissues have been subject to substantial manipulation, so that biological characteristics, physiological functions or structural properties relevant for the intended regeneration, repair or replacement are achieved.
• the cells or tissues are not intended to be used for the same essential function or functions in the recipient as in the donor.

The culturing (i.e. expansion) of cells, e.g. chondrocytes to reconstruct cartilage, is in this connection considered as substantial manipulation, so it will be within the new regulation.

Requirement for centralised marketing authorisation

The regulation extends the requirement of the mandatory centralised authorisation procedure to tissue engineered products. Up to now, the central procedure was only mandatory for gene therapy medicinal products and somatic cell therapy medicinal products. In future, it will therefore only be legal to market an advanced therapy product in the EU if the EU Commission has issued a marketing authorisation for the medicinal product concerned based on a scientific evaluation carried out by the European Medicines Agency (EMEA). A new scientific committee will in the future assist the EMEA in the review process of applications for marketing authorisations for advanced therapy medicinal products.

Donation, procurement and testing of human tissues and cells

Human cells and tissues that are a constituent of an advanced therapy medicinal product must comply with the requirements for donation, procurement and testing as established by Directive 2004/23/EC on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells. The Directive has been implemented in Danish law by the Danish Act on the Quality and Safety of Handling Human Tissue and Cells (the Danish Tissue Act).

Recommendation on advanced therapy classification

The regulation gives companies developing a product based on genes, cells or tissues the opportunity to request a scientific recommendation of the EMEA with a view to determining whether the referred product falls, on scientific grounds, within the definition of an advanced therapy medicinal product.

Certification of data

According to the regulation, small and medium-sized companies developing an advanced therapy medicinal product may submit to the EMEA all relevant quality and non-clinical data to obtain a scientific evaluation and certification.

Reduction of application fee

Where the applicant for a marketing authorisation is a hospital or a small or medium-sized company, the fee for marketing authorisation will be reduced for a defined period if the applicant can prove that there is a particular public health interest in the Community for the advanced therapy medicinal product concerned.

Transitional period and entry into force

The regulation on advanced therapy medicinal products entered into force on 30 December 2007, and it applies from 30 December 2008, but it contains transitional rules for medicinal products marketed legally in the EU on 30 December 2008.

This means that gene therapy medicinal products and somatic cell therapy medicinal products on the market on 30 December 2008 must comply with the regulation no later than 30 December 2011. Tissue engineered products must comply with the rules of the regulation no later than 30 December 2012.

Danish Medicines Agency, updated 4 November 2008