Regulatory Requirements for Stem Cell-based Therapies
This article was originally published in SRA
Executive Summary
In Part 2 of a three part series Jens Schletter, Manfred Ruediger and Sybille Esser consider regulation of stem cell-based therapies in the EU, Germany and the UK.
In Part 2 of a three part series Jens Schletter, Manfred Ruediger and Sybille Esser consider regulation of stem cell-based therapies in the EU, Germany and the UK.
Jens Schletter is Director of Regulatory Affairs, Manfred Ruediger, Chief Scientific Officer and Sybille Esser Project Manager (stem cell therapies) with Cardion AG, Erkrath, Germany.
In this series of papers on stem cell-based therapies, Part 1 covers basic considerations, regulatory challenges and requirements in the US [RAJ Pharma, 14 (3)];Part 2 in this issue covers classification and regulatory requirements in the EU, Germany and UK; Part 3 will consider regulatory requirements during product development [RAJ Pharma, 14 (5)].
Classification of stem cell-based therapies in the EU
Compared to the USA, in the European Union the manner in which stem cell-based therapies will be regulated is far less well established. Possible scenarios for regulation ranging from 'medicinal product’ to 'medical device’ to 'regulated differently from existing options’ are being considered. To a large extent this is due to the uncertainties and ongoing nature of discussions about the regulation of cell- and tissue-based products in general. In the EU, Directive 2001/83/EC, defines medicinal products as:
Substance is defined as any matter irrespective of origin including, for example, human blood or animal organ parts1. A medical device is distinguished from a medicinal product basically by what it does not do, namely '...not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means...2’ As a general rule a product is regulated either as medical device or as medicinal product3. The method by which the principal intended action is achieved is crucial in the definition of a medical device. Typically the medical device function is fulfilled predominantly by physical means. It could be argued that certain specialised cell- and tissue-based therapies (e.g. skin cells for transient coverage of injured skin surfaces) should be classified as devices rather than as medicinal products. However, until now the respective legislation in the EU has not been unequivocal: products incorporating human cells are specifically excluded from the Medical Device Directive 93/42/EEC as well as Directive 98/79/EC on in vitro diagnostic medical devices. Directive 2000/70/EC widens the scope of Directive 93/42/EEC to include medical devices incorporating substances derived from human blood or plasma, but substances derived from human tissues remain excluded.
In the European Community the Treaty of Amsterdam, in particular Article 152(4)(a), provides the legal basis for regulation of human cell-based products: 'The Council? shall contribute to the achievement of the objectives referred to in this Article through adopting? measures setting high standards of quality and safety of organs and substances of human origin?4’ The need for the generation of Community legislation as soon as possible in this field has been highlighted5. However, at the moment, the EU has not implemented a specific regulation. In practice, this absence of EU classification regulation leads to substantial inconsistencies amongst the regulatory bodies of EU member states. For example, the regulation of human tissue products spans from 'not regulated’ in Italy to dedicated national regulation as 'transplants’ in France to 'medicinal products’ in Germany6. The European Medical Technology Industry Association, Eucomed has emphasised the urgent need for the regulation of such products at European level and pointed out that this situation 'if not resolved? will result in further discouragement of European R&D investment and deny patients access to benefits, many of which are life-saving, provided by these products.'7
The EU Commission has clarified that cell therapy under certain conditions would fall under the authority of the principal pharmaceutical directives. In Commission Communication 98/C229/03 cell therapy is defined as:
The Commission clearly states that cell therapy products have to be considered as medicinal products needing a marketing authorisation 'if they are industrially manufactured’. This term has been explained in more detail by the Biotechnology Working Party of the CPMP in its guideline on human cell therapy products:
Consequently in the EU, as in the US, a pre-market approval would be required for products with more than minimal manipulation. The centralised community procedure (as described in Council Regulation 2309/93 ) for the authorisation of medicinal products is compulsory for products that are the result of the following biotechnological processes:
- recombinant DNA technology;
- controlled expression of genes coding for biologically active proteins in prokaryotes and eukaryotes including transformed mammalian cells; and
- hybridoma and monoclonal antibody methods10.
In its Communication Paper 94/C82/04 the EU Commission clarified that gene therapy products are covered by this definition11. Thus, an allogeneic cell-based therapy using genetically engineered cells would clearly fall under the scope of the biotechnological processes listed in Part A of the Annex to Regulation 2309/93/EEC. For this type of therapy, the Community's centralised procedure for the authorisation of medicinal products would be mandatory. This means a single application, scientific evaluation by the EMEA and the granting of a central marketing authorisation allowing direct access to the Community market.
Current approaches: to an EU regulatory system
Currently, several approaches are underway at EU level to improve the regulatory environment for cell- and tissue-based products:
Proposed directive - quality and safety standards
The EU Commission's DG SANCO has issued a proposal for a directive on quality and safety standards for the donation, procurement, testing, processing, storage and distribution of human tissues and cells12. The directive proposal does not make any comment on the type of legislation to be applied to cell therapy products. However, it clarifies that certain quality/safety standards would be required for all (allogeneic) cell therapy products irrespective of their final legal status:
Autologous cells are excluded from the scope of the directive 'if they are to be used for the manufacturing of medicinal products’.
Legislative framework - tissue engineering
A consultation document has been generated by the DG Enterprise of the European Commission highlighting the need for a legislative framework covering human tissue engineering and tissue-engineered products13. It is considered necessary to introduce a demarcation between tissue engineered products, medical devices and pharmaceutical products. Implicitly it is stated that cell therapy products, since they 'carry risks of the same type as are associated with pharmaceuticals’ should be grouped together with pharmaceuticals. Consequently, the framework to be developed should cover 'organs, tissues and cells? that have been substantially modified by treatments and that do NOT exert their effect through metabolic, pharmacological or immunological means.’ Cell therapy and stem cells are considered as borderline products in this regard.
Dossier content - Annex I, Directive 2001/83/EC
Annex I to Directive 2001/83/EC (former Directive 75/318/EEC ) sets out format and content of the application dossier for marketing authorisation of medicinal products for human use. DG Enterprise has published a working document on future revision of Annex I14. As the explanatory note to this document states15, enhancement of the flexibility to deal with new therapies was one of the main reasons for the proposed revision. The working document contains a dedicated chapter on advanced therapy medicinal products including cell therapies. Somatic cell therapies are defined as 'administration to humans of autologous, allogeneic or xenogeneic cells the biological characteristics of which have been altered to obtain a therapeutic effect through metabolic, pharmacological and immunological means.’ It clarifies that 'this category of medicinal products falls within the scope of Part A of the Annex to Council Regulation (EEC) No 2309/93.’
As a result of the latter two of the above approaches, a classification of stem cell-based therapies could be performed according to the mode of action (i.e. effect exerted/not exerted through metabolic, pharmacological and immunological means). For the majority of the currently envisaged stem cell-based therapies (see also part one of this article series), this would mean classification as medicinal product. However, as already mentioned, therapies using genetically altered allogeneic cells would underlie the requirements of Regulation 2309/93 in every case.
Regulating R&D of stem cell-based therapies
Regarding a possible approval process for stem cell-based therapies there has been, until now, no limitation to grant an EU marketing authorisation according to the source from which the product has been derived. However, the European Union has no authority over the research and development of medicinal products. Article 3 of Directive 2001/83/EC clearly states that the regulations do not apply to 'medicinal products intended for research and development trials’. Thus, the responsibility for regulation of stem cell-based research rests at the national level of the member states.
An important potential supranational influence on member states’ decisions in this matter could derive from the European Convention on Human Rights and Biomedicine. In the EU Directive 98/79/EC mentions that:
Some experts even argue, that according to this Convention, embryonic stem (ES) cell-based products should be regulated differently from medicinal products or medical devices16. Article 18 of this Convention states:
Reflecting the disparate views, up to now not all member states have signed the convention, and only the signatories are bound by it. Furthermore, in the Council of Europe's Explanatory Report to the Convention it is clarified, that 'the article does not take a stand about the admissibility of the principle of research on in vitro embryos18.
Research on embryos must not be mixed up with research on embryonic cell lines. In the case of stem cell-based therapies the Convention applies only to the step of embryonic stem cell line generation, since the cell line itself is no longer totipotent (and hence has neither the properties nor falls under the definition of an embryo). So the Convention should not pose an obstacle for the development of ES cell line-derived therapeutics, provided the stem cell lines used were generated under appropriately controlled conditions e.g. those listed in the Naational Institues of Health registry in the US.
The diversity of regulation of stem cell-based research in the different EU member states reflects the pluralism in ethical, religious and political opinions. As indicated in Table 4, in many countries embryonic stem cell research and use is not regulated as such at the national level or it is disputed whether the existing regulations concerning embryos should apply to embryonic stem cells as well. This is understandable, as the scientific area concerned is a relatively new one. In some countries, such as Germany or Denmark, research is allowed under certain controlled conditions. In the EU member states of Sweden or the United Kingdom it is even allowed to generate new human embryonic stem cell lines; not surprisingly, these are the countries with the most advanced scientific research activities i.e. with the most pressing need for such regulation. However the status compiled in Table 4 constitutes only a snap-shot in a rapidly changing regulatory area; in almost all member states new regulations are being discussed or are already underway.
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Source: compiled from a survey on respective national regulations in the EU member states 19 | |
Type of regulation/legislation | |
EU member states | |
Research on existing cell lines: | |
| Belgium, Greece, Italy, Luxembourg, Portugal |
| Austria, Ireland, Spain |
| Denmark, Germany, Finland, France |
Research on existing cell lines and creation of new cell lines permitted | The Netherlands, Sweden, United Kingdom |
The need for the development of a harmonised supranational (i.e. European) regulatory framework for stem cell-based therapies has been recognised. The establishment of clear cut rules for the development, but also for testing and approving, stem cell therapies is regarded as an essential foundation underpinning a safe, efficient and responsible development of the technology. The EU Commission is in the process of examining separate regulations20.
Quality requirements
Medicinal products have to be produced according to the principles and guidelines of good manufacturing practice. The EU GMP regulations comprise basic requirements applying to all medicinal products as well as annexes with detailed requirements for special types of products21. Most likely to be of particular relevance to stem cell-based products are:
- Annex 1: Manufacture of Sterile Medicinal Products;
- Annex 2: Manufacture of Biological Medicinal Products for Human Use; and
- Annex 13: Manufacture of Investigational Medicinal Products.
However it is clear that for stem cell-based products additional specialised standards and regulations will have to be developed.
In the recently proposed revision of Annex 1 of EU Directive 2001/83/EC a dedicated chapter on advanced therapy medicinal products was included, also comprising particular requirements for the quality documentation to be submitted as part of a marketing authorisation application for a cell therapy medicinal product (for overview see Table 5) 14.
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For the quality documentation accompanying applications for marketing authorisation of a cell therapy product, special attention should be granted to the following items: | General information on active substance(s) |
| Information related to the starting materials of active substance(s) |
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Information on the manufacturing process | |||
Characterisation of active substance | |||
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Pharmaceutical development of finished medicinal product | |||
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Traceability | |||
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Specific requirements for xenogeneic cell therapy medicinal products |
Extra requirements connected with xenotransplantation
As in the US, the issue of xenotransplantation would meet additional regulatory hurdles in the EU. To date there is no EU-wide legislation on xenotransplantation and hence not even a uniform definition of respective therapies. In a concept paper of the EMEA's Biotechnology Working Party, xenogeneic cell therapy is explained as 'live cells or tissues from a non-human animal source administered to a human recipient'22. This definition was enlarged upon by the Scientific Committee on Medicinal Products and Medical Devices of the European Commission to:
This is very much consistent with the definition given in the USA by the respective Public Health Service guideline and would mean that also in the EU stem cell-based therapies using animal feeder cells would be considered to constitute xenotransplantation. Compared with the USA, the regulatory situation for xenotransplantation in the EU is even more stringent. The Council of Europe considered xenotransplantation of whole organs, cells and tissues in 1997 and recommended the establishment of mechanisms for the registration and regulation of xenotransplantation24.
In 1999, the Parliamentary Assembly of the Council of Europe called for the rapid introduction of a legally-binding moratorium on all clinical xenotransplants in all member states, and encouraged steps to make this moratorium a worldwide legal agreement25. However, European Community-wide legislative or regulatory frameworks have not yet followed these decisions. Despite this unfavourable environment, several clinical trials using xenotransplantation have been performed or are ongoing26. In view of the risks, considered to be on an international scale, it was proposed that the European Commission should establish a centralised regulatory body to oversee the process and minimise the risk23.
Recognising the regulatory need, the CPMP Biotechnology Working Party has scheduled the development and finalisation of a 'points to consider’ document (CPMP/BWP/1700/01 ) on xenogeneic cell therapy in their work program for 2002/0327. In its concept paper on the development of such a guideline it highlights that a xenogeneic cell therapy product can be classified as a medicinal product22. The main considerations covered by the guideline very much resemble those dealt with in the respective US PHS and FDA guidelines.28,29
Recently, a draft Points to consider on xenogeneic cell therapy medicinal products (CPMP/1199/02) has been released for consultation30. It comprises particular requirements for sourcing, manufacturing, non-clinical and clinical testing as well as special pharmacovigilance and surveillance issues. However, it is highlighted that often general principles are given rather than detailed guidance, and that for each type of therapy a case-by-case decision has to be taken.
In summary, a stem cell-based therapy would have to meet the following requirements:
- follow national regulations concerning embryonic stem cell sourcing;
- follow national regulations concerning research and development;
- GMP and Good Tissue Practice (GTP) requirements;
- institutional ethics committee and regulatory authority approval for clinical trials in accordance with Clinical Trials Directive 2001/20/EC; and
- approval process using the centralised procedure, with marketing authorisation applications submitted to the EMEA.
Regulatory requirements in Germany
Regulation of stem cell-based research
In Germany, the main legal framework for human embryonic stem cell research is the Embryo Protection Law (Embryonenschutzgesetz ) of 199031. It forbids the creation or even handling of embryos for any other purpose than procreation (§2), effectively preventing the generation of new embryonal stem cell lines. However, the Embryo Protection Law does not forbid work on existing cell lines imported from abroad. On 30 January 2002 the German Bundestag decided to allow the import of embryonal stem cells for research purposes under tightly regulated conditions; these regulations were specified in the German Stem Cell Law which became effective on 1 July 200232:
- import restricted to stem cell lines generated before 1 January 2002;
- outstanding importance of the intended research project;
- previously conducted work on animal cells or in vitro experiments;
- no promising cell alternatives available;
- informed consent of the parents (of the embryo used for the generation of the cell line) is available; informed consent must not have been achieved using financial inducements; and
- embryo used for the generation of the cell line was originally generated for procreation, but has not been implanted for reasons not connected to the embryo itself.
The ethical evaluation of submitted research projects will be performed by a Central Ethics Committee33. A control agency located at the Robert-Koch-Institute in Berlin will supervise compliance to these terms and will issue permits. In addition, this agency has established and will manage a national public registry listing details of the individual applications and the cell lines covered in the permits. To date, two import permits have been granted.
In contrast to embryonic stem cells, the use of foetal and adult stem cells/stem cell lines is not limited by separate regulations in Germany.
Regulation of stem cell-based therapies
Stem cell-based therapeutic products will be regulated under the scope of the German Drug Law 34. The German Drug Law (§2) defines medicinal products as:
substances? intended to:
According to §3, the term substance also includes human or animal body parts or body components. So, stem cell-based products would clearly be regulated as medicinal products. This implies several requirements:
- a manufacturing licence is necessary for manufacturers who intend to commercially manufacture the drug (§13); this is issued by the local authority of the respective Federal State (the requirements for obtaining a manufacturing licence are detailed further in §14 and §15, including the availability of Qualified Persons for manufacturing and quality control and of adequate manufacturing facilities);
- notification of the competent authority of the Federal State before development, manufacture, testing, packaging or commencing clinical trials (§67);
- evaluation by a local ethics committee before initiation of a clinical trial (§40); and
- since the approach would consist of an off-the-shelf ready-to-use product manufactured and packaged in advance, it would be classified as a finished medicinal product (§4) requiring regulatory approval before marketing; however, this approval process would not be performed by the national regulatory authority but the respective product would fall under the scope of European Council Regulation 2309/93 leading to a centralised approval procedure10.
Good Manufacturing Process is generally required for the manufacture of medicinal products for human use. The German Drug Law (§54) provides the legal basis for the issuance of decrees to ensure adequate quality of medicinal products. Following from this the Operation Decree for Pharmaceutical Enterprises (Betriebsverordnung für pharmazeutische Unternehmer ) details the respective GMP requirements and has to be followed. Of course, the existing EU GMP regulations must be considered (see above).
As this article focuses on allogeneic products i.e. ready-to-use products manufactured in advance and intended for the treatment of many different patients, the above classification and requirements apply specifically to this case. For an autologous cell product the situation is different: the therapeutic product would only be produced upon demand, on a single patient basis. Thus the product would still be classified as a medicinal product according to German Drug Law (§2), requiring for example a manufacturing licence, but would not constitute a finished medicinal product according to §4; for these kinds of product no marketing approval is necessary.
Additional requirements connected with the genetic alteration of cells
If the stem cells are genetically manipulated, then at least some of the development aspects (generation of genetically modified cells, research as well as manufacturing) fall under the scope of the German Gene Technology Law (GTL ). This implies approval of research facilities (more precisely, the particular laboratories concerned) and notification of the competent authority of the Federal State when working with such genetically modified cells. However, applications for clinical trials (GTL §3) as well as use in humans in general (GTL §2) are specifically excluded from regulation by the Gene Technology Law.
In contrast to other medicinal products, besides the positive opinion of the local ethics committee a positive appraisal of clinical studies by the Central Commission for Somatic Gene Therapy of the German Medical Association (Kommission Somatische Gentherapie, der Bundesärztekammer ) is required for clinical trials.
Regulatory requirements in the UK
Regulation of stem cell-based research
There is a clear difference in the regulation of stem cell-based research in the UK, as compared to Germany, in particular with regard to research using embryonic stem cells. The UK is particularly advanced with regard to stem cell science, research infrastructure and regulation. Unlike many other countries the UK has nearly 20 years’ experience with a comprehensive control system on assisted conception and embryo research. After successive UK governments have agreed that properly controlled embryo research is in the public interest and fast developing national science made clear regulations imperative, the UK has created a legal framework under which such research and development of stem-cell therapies can be carried out.
Unlike in Germany and most other EU countries, it is not only permitted to conduct research on existing embryonic stem cell lines in the UK, but furthermore even to generate new embryonic cell lines. The generation of such new cell lines falls under the surveillance of the Human Fertilisation and Embryology Authority (HFEA), where - in contrast to the US - no distinction is made between publicly and privately funded research. The HFEA has its legal base in the 1990 established Human Fertilisation and Embryology Act 35. Following recommendations made by the Human Genetics Advisory Commission and the HFEA in 1998, and the Chief Medical Officer's Expert Group in 2000, new Human Fertilisation and Embryology (Research Purposes) Regulations 36 were introduced in 2001. These regulations permit the HFEA to license research aimed at increasing knowledge about serious diseases, such as Parkinson's disease, diabetes or cancer.
Different UK agencies are working closely together to establish the necessary regulations for stem cell research. The British Medical Research Council (MRC) cooperates with the regulatory agencies to develop standard donor information leaflets and consent forms as well as guidelines to help stem cell researchers identify which licences and accreditations they need to obtain.
To ensure that stem cell therapy is developed in an appropriate framework of quality and safety the MRC was also charged with establishing a stem cell bank. This bank, which will provide storage for embryonic as well as foetal and adult stem cell lines, was established to offer a resource centre to support the advance in stem cell research and will supply cell lines for both research and potential clinical applications. Hosted at the National Institute for Biological Standards and Control (NIBSC) and jointly funded by the MRC and Biotechnology and Biological Sciences Research Council (BBRSC), the UK Stem Cell Bank is the first national stem cell bank to be established worldwide. It will assure that cell lines which could provide the basis for clinical treatment are appropriately characterised and also handled and stored under properly controlled conditions. Additional tasks will be the provision of scientific training courses, the definition of safety characteristics and the establishment of standardised protocols. The bank will have a non-GMP arm for basic research and a GMP arm for research leading to clinical applications. The licences granted by the HFEA under the 2001 regulations include the pre-requisite that all newly generated lines have to be deposited in the Stem Cell Bank. Any party wishing to use cell lines generated in human embryo research must then apply to the Stem Cell Bank since researchers are not allowed to pass on generated cell lines directly to third parties. The deposited cells will be available to academia and industry in the UK and other countries. However, non-UK users will have to present equivalent authorisation before gaining access to the cell lines.
In the development of stem cell-based therapies, good practice standards will have to be followed for example in the selection of donors, testing, processing or storage, as outlined in the Code of Practice for the Production of Human-derived Therapeutic Products 37.
Regulation of clinical development and stem cell-based therapies
In contrast to the above described, well covered, cell line generation and first research steps, the regulation and classification of stem cell-based therapies and its clinical development is far less clear. The above mentioned Code of Practice for the Production of Human-derived Therapeutic Products consequently puts emphasis on the point that it is not intended for use in classifying products. In particular for stem cell technologies leading to therapeutic products or other treatments 'regulatory guidance should be obtained from the medicinal authorities'37.
The House of Lords’ Select Committee report on stem cell research pointed out that 'ES cell lines? are a human tissue and need to be treated on a similar basis to other human tissues used for research', however 'ES cells are not embryos and the HFEA is not responsible under the 1990 Act for ES cell lines. There is consequently considerable urgency in deciding how these lines should be maintained and what degree of regulation, if any, they require.'38
In the government response to this report, it was clarified that in the case where cell therapy medicinal products are developed from stem cells, 'these will be regulated at the clinical trials or licensing stage by the Medicines Control Agency (MCA) under the current legislation'39. In line with this, the Medicines Commission has cautiously stated, that 'certain stem cell therapy products will fall within the definition of a medicinal product and will be regulated? by the MCA.'40 However, at the moment the Commission considers it 'too early for the MCA to become deeply engaged in the regulatory aspects of stem cell research'; MCA and HFEA should 'maintain close communications’.
Final remarks
Different national regulations of stem cell-based research reflect the diversity in cultural, historical and religious backgrounds of the EU member states. The need for general regulations and classification on a European level has been recognised; several approaches and working documents are discussed to improve this situation. The generation of a clear regulatory framework will be of utmost importance for companies developing stem cell-based products to allow the definition of an appropriate regulatory strategy and to remove impediments in development planning.
Acknowledgements: the authors thank Bruno M Giannetti (Verigen AG), Anwaltskanzlei Sträter (in particular Markus Ambrosius) and Thomas Moll for helpful discussions and critical review of the manuscript.
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