Companies who are currently conducting, or plan to conduct clinical trials for "tissue engineered products" - including medical devices containing such products - need to examine the EU's new law carefully. Beginning on December 30, 2008, authorization of tissue engineered products falling within the definition “advanced therapies” will be governed by the EU legislation on the approval of medicinal products. EU legislation on the approval of medicinal products differs substantially from that on medical devices. One effect of the new Regulation could be that companies who have designed, or are currently conducting, clinical trials to satisfy the requirements of the EU medical device provisions may end up with results that will not satisfy the requirements that will ultimately apply to the approval of their products.
Three types of advanced therapy fall within the Advanced Therapies Regulation. These are gene therapy, somatic cell therapy and tissue engineered products. Gene therapy and somatic cell therapy have already been classified as products falling within the application of the EU law on approval of medicinal products for a number of years, so the new Regulation will not directly impact the current authorization procedure for these products to the same extent as tissue-engineered products. The most significant change under the new Regulation, however, is the extension of the application of the medicinal product framework to tissue engineered products. These are defined as products containing or consisting of engineered cells or tissues and presented as having properties for, or used in or administered to human beings with a view to regenerating, repairing or replacing a human tissue. This definition could include tissue engineered skin, wound healing matrices, cartilage, any biologically derived matrix containing viable cells (and possibly non-viable cells, as discussed below), and possibly the future in vitro development of organs.
Cells or tissues are not considered to have been engineered if they have undergone any of the treatments listed in Annex I to the Regulation. These treatments include cutting, grinding, shaping, soaking in antibiotic or antimicrobial solutions, sterilization, irradiation, cell separation/concentration/purification, filtering, freezing, cryopreservation and vitrification.
A tissue engineered product may contain cells or tissues of human origin, of animal origin, or of both. The cells or tissues may be viable or non-viable. However, products that contain or consist 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 do not fall within the definition of a tissue engineered product and thus within the application of the Regulation. Thus, if the product contains non-viable cells, but acts principally by pharmacological, immunological or metabolic action (i.e., through a medicinal product mechanism of action), the product will be subject to the Regulation. Tissue engineered products may also contain additional substances, such as cellular products, bio-molecules, biomaterials, chemical substances, scaffolds or matrices.
Products that consist of both an advanced therapy and a medical device are specifically addressed in the Regulation and defined as a “combined advanced therapy medicinal product”. The device element of such products must respect EU provisions governing medical devices including, where relevant, the results of the assessment by a notified body. However, irrespective of the role of the device element, for tissue engineered products the medicinal product mechanism of action of the cells or tissues will be considered to be the principal mode of action of the combination product. As such, for purposes of authorization the product is classified as a medicinal product irrespective of the prior regulation of the device component under the Medical Device Directive. It must, therefore, be authorized through the EU’s centralized authorization procedure for medicinal products. This involves a single scientific evaluation by the European Medicines Agency (EMEA) of the quality, safety and efficacy of the product and authorization by the European Commission.
Products prepared by doctors or hospitals for use within a common facility, commonly referred to as "home brews", that fall within the definition of advanced therapies (not to be confused with "home brew" or laboratory developed diagnostic tests) will fall within the application and obligations of the Regulation. The only exception to this will be for custom-made products that are prepared on a non-routine basis according to particular quality standards and used within the same Member State in a hospital in accordance with an individual prescription for an individual patient and under the exclusive professional responsibility of a medical practitioner.
The Regulation includes provisions permitting requests for a scientific recommendation by the EMEA concerning borderline products and advice concerning pharmacovigilance obligations. The Regulation also introduces stringent obligations as regards traceability of the patient and of the product and its starting materials.
Specific obligations as regards Summary of product Characteristics (SmpC), packaging, labeling and the package leaflet of advanced therapy products are also introduced.
The law also creates some ambiguities that may require regulatory clarification. For example, where a combination product is defined as a medicinal product due to the presence of an advanced therapy but also contains a previously authorized medicinal product, the question arises as to who should be the MAH (marketing authorization holder) for the product as approved; the company that developed the advanced therapy or the company that holds the MA (marketing authorization) for the medicinal product. Furthermore, reclassification of products from a medical device to a medicinal product may have consequences for their pricing and reimbursement position in some EU Member States.
The Regulation will apply from December 30, 2008. However, it provides two transition periods for existing products. Gene therapy and somatic cell products legally on the EU market on December 30, 2008 must comply with the Regulation by December 30, 2011. Tissue engineered products legally on the EU market on December 30, 2008, must comply with the Regulation no later than December 30, 2012.