BRUSSELS, Belgium - The European Union (EU) is tightening rules on marketing authorizations for biotechnology medicines.

Three years after establishment of the drug registration system, through which the European Medicines Evaluation Agency in London acts on behalf of all 15 member states for centralized approvals, the European Commission (EC) has decided it needs to clarify the ground rules defining the products that must go through the system.

In particular, from now on it will be less flexible about the definition of DNA-derived products, gene therapy and cell therapy.

Under the 1993 regulation setting up the system, which came into effect in 1995, certain products must be authorized via the centralized system. These include medicinal products derived from biotechnological processes; recombinant DNA technology; controlled expression of genes coded for biologically active proteins in prokaryotes and eukaryotes, including transformed mammalian cells; and hybridoma and monoclonal antibody methods.

In a 1994 communication, the EC gave practical examples of the medicinal products for which the centralized procedure was required: gene therapies; vaccines developed from recombinant DNA technology, including gene deletion; and any medicinal product for which a monoclonal antibody is used at any stage in the manufacturing process.

Part of the EC's current clarification efforts relate to what it means by “medicinal product developed by means of recombinant DNA technology,“ since, it said, “questions continue to arise“ about the scope of this terminology.

The EC has decided the mandatory procedure should apply to “any medicinal product in the composition of which there is a proteinaceous constituent obtained by means of recombinant DNA technology,“ irrespective of whether or not the constituent is an active substance of the medicinal product.

To arrive at this determination, the EC has opted for the definition in the European Pharmacopoeia monograph of products of recombinant DNA technology (No. 1997,784), which already is in effect as part of the EU's pharmaceutical legislation.

“It is particularly important to determine which categories of substances developed by means of recombinant DNA technology represent, when used as constituents of medicinal products, an essential element of a medicinal product to be considered in the choice of the procedure to be followed,“ the EC said.

The EC also has clarified what it means by “products intended for gene therapy.“ It said, “Gene therapy corresponds to a set of processes aimed at the transfer of a gene, basically a piece of DNA, to human tissues and its subsequent expression in vivo.

“The systems for therapeutic gene transfer and expression involve a therapeutic gene and an expression system that is contained in a delivery system, known as a vector,“ the EC said. “The delivery system can use either viral vectors (retroviral or adenoviral vectors, for example), as well as nonviral vectors (such as cationic liposomes or molecular conjugates). The vectors themselves, regardless of their physical nature, have to be considered as part of the 'product intended for gene therapy,' which is a medicinal product in the meaning of the [EU] pharmaceutical legislation. Indeed, the vectors represent an intrinsic part of this product endowed with a therapeutic effect.“

Cell therapy also receives a more precise definition from the EC. It is defined as “the administration to humans of autologous living cells [emanating from the patient himself] or allogeneic cells [coming from another human being], or even xenogeneic cells [coming from an animal]. To some extent, these selected cells may have been manipulated or processed to change their biological characteristics prior to their administration.

“This definition,“ the EC said, “includes the expansion and activation of autologous cell populations ex vivo and the use of allogeneic or xenogeneic cells contained in microcapsules for protein drug replacement.“

Cell therapy products must be considered medicinal products, requiring a marketing authorization, if they are industrially manufactured, the EC added. If cell therapy products are the result of any of the biotechnological processes outlined in the 1993 regulation, they will have to be authorized via the centralized procedure.

“It is essential to have clear criteria,“ the EC said in its just-published official communication, titled “The Community marketing authorisation procedures for medicinal products.“

The clarification is a response to developments in the world of biotechnology. There has been a change in perception of the role of biotech in drug production since the 1993 regulation was framed.

“Initially biotechnology was seen as an opportunity to develop new medicinal products which would otherwise not be possible. Now, however, biotechnology techniques can also be incorporated into the manufacture of existing medicinal products in order to enhance yields, improve quality or reduce environmental impact,“ the EC observed. *

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