European regulation tackles tissue engineering

To the editor:

The EP, whose Strasbourg headquarters are shown here, recently adopted a new regulatory framework covering gene therapy, somatic cell therapy and TEPs for human use. Credit: Gerard Cerles/AFP/Getty Images

The lack of a harmonized, pan-European regulatory framework for tissue-engineering products (TEPs) has led to divergent regulatory oversight by member states and uncertainty among manufacturers as to the optimal path for creating and commercializing such products. In April, the European Parliament (EP; Strasbourg, France) adopted, after intense discussion and consultation, a first-reading opinion on the Regulation on Advanced Therapy Medicinal Products, a new regulatory framework covering gene therapy, somatic cell therapy and TEPs for human use¹. The following month, the EU Health Ministers (Council) also approved the new regulation. For the regulation to be formally adopted most likely by the end of this year, all that remains is for it to be translated into the different EU languages.

The term 'Advanced Therapy Medicinal Products' (ATMPs) was first introduced in Part IV of Annex I to Directive 2001/83/EC as amended by Directive 2003/63/EC on the European Community code relating to medicinal products for human use^2,3. Whereas gene therapy and somatic cell therapy medicinal products have already been classified as ATMPs under this framework, the new legislation also defines tissue-engineered products (TEPs) as a third group of ATMPs^4,5, providing a unified legal instrument for overseeing these biologic products. The integration of TEPs as medicinal products was suggested on the basis of a 2005 study, conducted by the Institute for Prospective Technology Studies from the Joint Research Centre of the European Commission (JRC-IPTS), which indicated that the lack of European-wide legislation for TEPs has led to divergent national procedures⁶. Today, certain European Union (EU; Brussels) member states classify TEPs as medicinal products, whereas others classify them as medical devices, resulting in prohibitive inconsistency and uncertainty among manufacturers and legislative bodies on how TEPs should be treated, commercialized and placed on the European market.

The rationale for merging gene, cell and tissue engineering therapies into one regulation is based on several shared key characteristics. First, they are based on complex, highly innovative manufacturing processes and are usually developed by small and medium-sized enterprises (SMEs) or university units. Second, scientifically it might be difficult to classify cell-based products and to draw a line between somatic cell medicinal products and TEPs. Third, specific regulatory and scientific expertise for the evaluation is not fully established in EU member states and has to be pooled at the European Community level. And fourth, adequate provisions for post-authorization follow-up of efficacy/adverse reactions and for risk management and traceability systems have yet to be developed and implemented.

Medicinal products are generally defined to be either presented as having properties for treating or preventing diseases in humans or used in or administered to human beings with a view to restoring, correcting or modifying physiological functions by exerting principally a pharmacological, immunological or metabolic action². The Annex to Regulation (EC)726/2004 outlines that for all medicinal products derived from biotechnological processes involving recombinant DNA technology, controlled expression of genes encoding biologically active proteins and hybridomas/monoclonal antibodies, as well as for medicinal products containing a new active substance for the treatment of AIDS, cancer, neurodegenerative disorders or diabetes, a centralized authorization procedure is compulsory⁷.

The assessment of medicinal products for which a centralized marketing authorization application has to be filed is conducted by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA; London). The CHMP is supported by several working parties including the Biologics Working Party (BWP), the Gene Therapy Working Party (GTWP) and the Cell-based Product Working Party (CPWP). Apart from giving recommendations to the CHMP on issues related to gene and cell therapy medicinal products, these working parties are also responsible for the preparation of guidelines on quality, safety and efficacy testing requirements and are involved in scientific advice and protocol assistance in liaison with the Scientific Advice Working Party (SAWP) of the CHMP.

Within this overarching legislative and organizational background, the new Regulation on ATMPs aims to create a compulsory centralized marketing-authorization procedure and direct harmonized access to the European Community market for all ATMPs, which are either prepared industrially or manufactured by a method involving an industrial process and irrespective of whether the cells within the product are of autologous or allogeneic origin. Nevertheless, Article 28 (1) will exclude those ATMPs from the scope that are prepared on a non-routine basis and used within the same member state in a hospital under the exclusive responsibility of a medicinal practitioner to comply with an individual medical prescription for a custom-made product for an individual patient.

The EP vote took place after intense discussion, especially on ethical issues. The new Regulation focuses mainly on technical issues and will not interfere with national ethical decisions on the acceptance of the use of specific cell types, such as human embryonic or fetal cells, primordial germ cells or cells derived from those cells. This means that each member state remains free to enact its own legislation that forbids the use of some cell types or therapies on its national territory on the basis of ethical objections. The present regulation reaffirms the general principles of voluntary and unpaid donation of cells/tissues and anonymity of donors and recipients throughout the European Community (as laid down in Directive 2004/23/EC)⁸.

Realizing the complex nature of the ATMPs, the EP agreed on the proposal's suggestion to set up a special Committee for Advanced Therapies (CAT) within the EMEA. The CAT will formulate a draft opinion on the quality, safety and efficacy of a given ATMP for final approval by the CHMP and should also have a prominent role in the provision of scientific expertise.

To encourage SMEs to develop ATMPs, grant fee reductions have been provided (90% for SMEs and up to 65% for other companies). Moreover, a reduction of 50% of the marketing authorization fee can be granted for SMEs during the transitional period if the applicant can prove a particular public health interest in the European Community in the product. ATMPs already on the market at the time of application of the Regulation (which is one year after entry into force) are granted a further transitional period (three years for gene and cell therapies and four years for TEPs). Therefore, TEPs will only have to comply with the new provisions five years after the Regulation has entered into force. Compared with the original proposal from the European Commission, this is a significant extension of the transitional period. In addition, the exemption from the scope in Article 28 (1) provides equal opportunities for small-scale operators, hospitals and SMEs.

Apart from these incentives for product development, the new Regulation also provides clear guidance on the quality of manufacturing expected from the field. Even ATMPs manufactured on a non-routine/ad hoc basis must comply with recognized quality standards equivalent to those for ATMPs requiring a manufacturing authorization. Reflecting the specific nature of ATMPs, the regulation also points out that guidelines in line with the principles of good manufacturing practice and good clinical practice but specific to ATMPs will be drawn up by the European Commission.

In this context, the CPWP and BWP have recently developed a guideline on quality, nonclinical and clinical aspects of cell-based medicinal products⁹. The main guideline text covers risk analysis, quality and manufacturing aspects as well as core aspects for nonclinical and clinical development. Quality and manufacturing aspects of the guideline include characterization of starting and raw materials, quality control, validation of the manufacturing process, development pharmaceutics, traceability, biovigilance and comparability. The objectives of the nonclinical studies are to demonstrate proof of principle and to define pharmacological and toxicological effects predictive of the human response. The clinical development should include pharmacodynamic and pharmacokinetic studies, mechanism-of-action and dose-finding studies and studies to demonstrate safety and efficacy. Later this month, an open workshop will be convened to discuss the external comments on the draft guideline as well as other scientific aspects.

The Regulation defines a TEP 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 TEP may contain cells or tissues of human or animal origin, or both. It may also contain additional substances, such as cellular products, bio-molecules, bio-materials, chemical substances, scaffolds or matrices.” These combined ATMPs have to fulfill the following conditions: they must incorporate, as an integral part of the product, one or more medical devices within the meaning of Article 1(2)(a) of Directive 93/42/EEC or one or more active implantable medical devices within the meaning of Article 1(2)(c) of Directive 90/385/EEC, and their cellular or tissue part must contain viable cells or tissues; or their cellular or tissue part containing nonviable cells or tissues must be liable to act upon the human body with action that can be considered as primary to that of the referred devices^10,11. In any case, where a product contains viable cells or tissues, the pharmacological, immunological or metabolic action of those cells or tissues shall be considered as the principal mode of action of the product, assigning it to the pharmaceutical legislation. Thus, the problem of delineation of the medicinal product legislation from the legislation of medical devices regarding TEPs has been overcome.

'Engineered' cells or tissues are defined in the Regulation as cells or tissues that fulfill at least one of the following points: first, 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 (a list of nonsubstantial manipulations is provided in Annex I); and second, the cells or tissues are not intended to be used for the same essential function or functions in the recipient as in the donor. It should be emphasized that this is the definition as currently amended by the Council Working Party and the EP.

Despite the lack of an EU-wide classification of TEPs so far, quality and safety standards for the handling of human tissues and cells intended for human application already exist. Directive 2004/23/EC lays down standards for donation, procurement, testing, processing, preservation, storage and distribution of cells and tissues and products derived from these⁷. Notably, these standards are only valid for tissues and cells of human origin. Blood and blood products are regulated under EU law in Directive 2002/98/EC¹². Implementing 2004/23/EC, technical requirements for the donation, procurement and testing of human tissues and cells are laid down in Directive 2006/17/EC, whereas technical requirements for coding, processing, preservation, storage, distribution and traceability as well as notification of serious adverse reactions and events are implemented by Directive 2006/86/EC^13,14. Directives 2006/17/EC, 2004/23/EC and 2006/86/EC were stipulated to be transformed into national law by November 2006, April 2007 and last month, respectively (needless to say, not all member states have enacted the legislation as yet).

The other two categories of biologic products are defined in Directive 2003/63/EC. Somatic cell therapy is described as “the use in humans of autologous, allogeneic or xenogeneic somatic living cells, the biological characteristics of which have been substantially altered as a result of their manipulation to obtain a therapeutic, diagnostic or preventive effect through metabolic, pharmacological and immunological means.” This manipulation includes the expansion or activation of autologous cell populations ex vivo (e.g., adoptive immunotherapy) or the use of allogeneic and xenogeneic cells associated with medical devices ex vivo or in vivo (e.g., microcapsules, intrinsic matrix scaffolds, biodegradable or not).

Somatic cell therapy medicinal products include a variety of cell types: first, cells manipulated to modify their immunological, metabolic or other functional properties in qualitative or quantitative aspects; second, cells sorted, selected and manipulated and subsequently undergoing a manufacturing process to obtain the finished medicinal product; third, cells manipulated and combined with noncellular components (e.g., biological or inert matrices or medical devices) and exerting the principal intended action in the finished product; fourth, autologous cell derivatives expressed in vitro under specific culture conditions; and fifth, cells genetically modified or otherwise manipulated to express previously unexpressed homologous or nonhomologous functional properties. As definitions are overlapping, it can be expected that in some cases it might be difficult to draw a line between somatic cell therapy medicinal products and TEPs. This problem was addressed in the Regulation by including solutions for borderline products.

The last category of biologic, gene therapy medicinal products, is defined in Directive 2003/63/EC as “a product obtained through a set of manufacturing processes aimed at the transfer, to be performed either in vivo or ex vivo, of a prophylactic, diagnostic or therapeutic gene (that is, a piece of nucleic acid), to human/animal cells and its subsequent expression in vivo. The gene transfer involves an expression system contained in a delivery system known as a vector, which can be of viral, as well as nonviral origin. The vector can also be included in a human or animal cell.” In summary, the transgene can be transferred to the patient either as naked DNA, by viral vectors or nonviral vectors or by administration of ex vivo genetically modified cells. Again, the boundaries between the different ATMPs are not easy to define. In general, the classification of genetically modified cells as a gene therapy or as a cell therapy product/TEP mainly depends on the properties of the transgene. In gene therapy products, the transferred gene has to fulfill a prophylactic, diagnostic or therapeutic function, whereas the transferred gene in a cell-based medicinal product does not serve any of these functions but may have been introduced for manufacturing purposes. A product that may fall within the definition of a cell-based and a gene therapy medicinal product shall be considered as a gene therapy medicinal product. The CHMP is currently considering public comments on a Concept Paper on the development of a guideline on the quality, preclinical and clinical aspects of medicinal products containing genetically modified cells¹⁵.

Although no ATMP has so far obtained community marketing authorization, several products are on their way. In line with the rapidly evolving scientific and medical progression in the area of innovative products, the EU is establishing a framework that will harmonize the Regulation on ATMPs. Although the centralized marketing authorization procedure is still challenging for small-scale operators like hospitals or SMEs that often develop experimental therapies such as TEPs, we nevertheless anticipate that access to the EU market through the centralized procedure and the promotion of the pharmaceutical development of innovative medicines will have a positive impact on the availability of advanced therapies in the near future.