Advanced Therapy Medicinal Products in the EU: Navigating the Regulatory Maze
This article was originally published in SRA
Ralf D Hess explains the complex regulatory framework that manufacturers need to consider when seeking marketing authorisation of ATMPs in Europe.
Enormous scientific progress not only in cellular and molecular biotechnology but also in developmental biology and advanced in vitro methodologies has ultimately led to the production of advanced therapy medicinal products. These therapies, such as gene therapy, somatic cell therapy and tissue engineering offer new ways of treating or even curing otherwise non-treatable life-threatening diseases or dysfunctions of the human body.
Regulation (EC) No 1394/2007 (the ATMP Regulation1) is the “lex specialis” on advanced therapy medicinal products. It amended Directive 2001/83/EC on human medicines and Regulation (EC) No 726/2004 on the community procedures on authorisation and supervision of medicinal products, and became effective on 30 December 2008. The regulation, which made the centralised procedure mandatory for ATMPs, applies to therapies that are industrially produced and intended to be placed on the market in European Union member states. It primarily lays down provisions on the manufacture, pharmacovigilance and traceability for these products and on the implementation of the CAT (Committee for Advanced Therapies) within the European Medicines Agency. Most notably, the ATMP Regulation has finally closed the regulatory gap for tissue-engineered products, allowing previously “unmet medical needs” to be addressed.
The regulation, however, cannot be applied in a vacuum. As such, this article aims to explain its provisions as well as the other existing and applicable directives and regulations that make up the basic regulatory framework for ATMPs, as shown in Figure 1. The article also discusses areas of ongoing regulatory uncertainty such as personalised medicine and combination products, as well as ethical considerations.
Additionally applicable and already existing directives and regulations, relevant guidance documents and points to consider are detailed in Table 1 at the end of this article, illustrating the complexity of the regulatory framework ATMP manufacturers are faced with. For example, despite the fact that quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution requirements of human tissues and cells are regulated under the overarching Directive 2004/23/EC, the quality, safety and efficacy requirements for gene therapy medicinal products and somatic cell therapy medicinal products are laid down in Directive 2001/83/EC Part IV to Annex I. This directive covers genetic medicinal products and somatic cell therapy medicinal products and was only recently amended by the Directive 2009/120/EC2 to include provisions for tissue-engineered products and updated definitions for gene therapy products and somatic cell therapy products.
Furthermore, ATMP manufacturers should be aware of Directives 2006/86/EC and 2006/17/EC, which regulate traceability requirements, notification of serious adverse reactions and events, and also certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells. The directives also regulate technical aspects for donation procurement and testing as well as distribution of human tissues and cells as cross referenced in Directive 2004/23/EC.
Directive 2004/23/EC applies to haematopoietic peripheral blood, umbilical cord blood, bone marrow stem cells, reproductive cells, foetal tissue and cells, adult stem cells, cornea and bone, but does not regulate blood and blood products, human organs, organ tissues and cells of animal origin, tissues and cells used for in vitro research. The ATMP Regulation additionally bridges the regulatory gaps with respect to human medicinal products as cells or tissues (as defined in Part IV to Annex I of Directive 2001/83/EC, as amended).
Other implementation, interpretation and application issues have included the installation and operation of the CAT, which has held 11 meetings since it started working in January 2009. The committee focuses on scientific recommendation, evaluation, classification and drafting market authorisation opinions for ATMPs. It also considers borderline products and is responsible for the certification of small and medium-sized enterprises.
Personalised medicine (PM) aims to deliver individual and patient-tailored medical care and promises three key benefits: improved diagnostics; efficient drug development; and effective therapeutics. It thus takes into account the patient’s individual genetic background, but also considers the current stage of disease. Often, personalised patient care therapeutics are meant to bridge the gap of “unmet medical need” diseases – or in other words – attempts to cure otherwise non-treatable disorders. Again, a hallmark of PM is patient-tailored medical care.
A good example is the attempt to induce and stimulate a patient’s immune response towards otherwise chemotherapy-resistant tumours, which is referred to as adoptive immunotherapy or adoptive T cell therapy. This approach takes peripheral blood lymphocytes (PBL) from an individual tumour patient. Either the transfection of a human immunostimulatory gene (eg human interleukin-2) of these PBLs in vitro or the in vitro conditioning of these PBLs in the presence of tumour antigens and cytokines is aimed at generating polyclonal T cell in vitro activations and expansion, and either “boosting” (stimulate to proliferation) and “priming” (acquire antigen-specificity) PBLs for re-infusion into the patient. Thus, these medicinal products fall within the definitions of gene therapy medicinal products or somatic cell therapy medicinal products and, as such, Regulation (EC) No 1394/2007 is applicable. Interestingly, manufacturing – according to Article 28(2) (“hospital exemption”) of the regulation – of custom-made ATMPs prepared to specific quality standards on a non-routine basis and used within the same member state in a hospital under the exclusive professional responsibility of a medical practitioner shall be authorised by the competent authority of the member state.
In spite of these definitions, it still remains difficult to classify products made of non-viable cells, since existing national legislation is applicable and some European member states may favour classifying non-viable cells as medical devices. As with other medical devices, it strictly depends on the “intended use” and whether or not the products act principally by pharmacological, immunological or metabolic action. This example underscores the necessity of the CAT, which, as mentioned, is tasked with providing recommendations on ATMP classifications. Figure 2 provides an illustration of the increasing number of clinical trial applications in the EU that are indication-dependent, supporting the necessity of the implementation of harmonised regulations for ATMPs, especially tissue-engineered products.
Combined advanced therapy medicinal products consist of an ATMP plus a medical device and thus manufacturers of these products must address the regulatory provisions as defined in the respective medical device directives. For the purpose of a market authorisation of a combined ATMP, such a product is considered an ATMP and not medical device and falls within the ATMP Regulation. Since the EMA aims to be a “one-stop-shop”, it takes into account the results from the assessments of the medical device, as provided by notified bodies if available. If not, the EMA may commission a notified body for the medical device part of the assessment. This is one prominent remit of the CAT. The quality assessment procedure could be facilitated by the availability of a “Device Master Record”, a document that the US Food and Drug Administration requires under its medical device quality system regulations3. The device master record, though, is not part of the accepted European quality management systems standard for medical device manufacturers (DIN/EN/ISO 13485:2007), although technical dossiers are mandatory for CE marking. The technical documentation required under the EU standard includes elements of both the device master record and the design history files.
As provided for in the ATMP Regulation, clinical trials of ATMPs should be conducted in accordance with the general principles and the ethical requirements provided in Directive 2001/20/EC (the Clinical Trials Directive), although more specific requirements are still needed. With regards to donation, procurement and testing of human cells or tissues, Directive 2004/23/EC stipulates that principles such as the anonymity of both donor and recipient, altruism of the donor and solidarity between donor and recipient should be respected. As a matter of principle, human cells or tissues contained in ATMPs should be procured from voluntary and unpaid donation. Additional national legislation, such as the German Transplantation Act (TPG, Transplantationsgesetz), is applicable and requires the information and consent of donors or their relatives. Furthermore, heart valves and bones are subject to a trade embargo under the German law. Organ transplantation, such as kidney transplants, is not covered by the ATMP Regulation, meaning it falls within the European member states’ national legislation.
The complexity of the medicinal product influences the ethical conduct of clinical trials, while the value and the validity of the trial, the risk:benefit ratio and the protection of the trial participant needs to be considered5. In addition, human embryonic stem cells do not fall under the ATMP Regulation. The legislation of embryo-derived therapeutic products is subject to the EU member states’ national legislation and decisions on the availability of such products are left with the member state itself. The European Commission in 2003 provided a description of the status, at the time, for the scientific, ethical, legal, social and economic issues related to human stem cell research and human embryonic stem cell research, but it has not been updated6.
Guidance and updates still needed
The introduction of Regulation (EC) No 1394/2007 is an important step in regulating ATMP-associated activities leading up to first-in-man studies. It also necessitates updates or amendments to a number of existing guidelines, directives and national legislation. Many regulatory aspects such as the requirements for good manufacturing practice as laid down in Directive 2003/94/EC, or requirements for clinical trials, need to be established specifically for ATMPs. Also, Regulation (EC) No 726/2004 needs to be amended with regard to the ATMP Regulation. Neither existing GMP guidance nor the Clinical Trials Directive currently adequately address tissue-engineered product clinical trials set up and tissue-engineering manufacturing processes.
Details of an extensive implementation plan for the coming months and years can be found in the EMA’s ATMP Regulation implementation plan dated December 20077. The plan acknowledges that detailed guidelines on good clinical practice specific to ATMPs need to be to be drawn up by the commission. Although a draft version for public consultation has been issued, which defines the standard template for the Clinical Trial Application form8, it is still necessary to amend this form in order to incorporate the changes entailed by the ATMP Regulation. To that end, the commission published a draft document for public consultation, the comment deadline for which was 15 October 20089. Guidance will come with an emphasis on traceability and defining responsibilities, plus patient follow-up after completion of clinical trials for safety and data collection.
GMP guidelines specific to ATMPs also need to be prepared by the commission and as a consequence Annex 2 to its GMP guide on medicinal products, which covers the manufacture of biologics, has to be revised and amended accordingly.
Guidelines relating to traceability of ATMP and post-marketing follow-up are now in place and Parts I and II of Eudralex Volume 9A are directly affected by the new guideline. Traceability requirements in this context need to be consistent with those laid down in Directives 2004/23/EC (human tissue and cells) and 2002/98/EC (blood products).
In addition to the CAT, exemptions (eg hospital exemption) and technical requirements according to Annex I are addressed by the EMA and its scientific committee, the CHMP, as well as other agency working parties (eg the biologics, gene therapy and cell-based products working parties). Existing dossier requirements for gene therapy products and somatic cell therapy products need to be revised and adapted to include tissue-engineered products.
It is important to note that the regulation of ATMPs at EU level should not interfere with decisions made by individual member states on whether to allow the use of any specific type of human cells, such as embryonic stem cells, or animal cells. Nor should it affect the application of national legislation prohibiting or restricting the sale, supply or use of medicinal products containing, consisting of or derived from the above mentioned cells.
A list of guidance documents under development and all final and draft guidelines are published on the EMA’s advanced therapies web page10. In summary, neither technical issues such as analytical methods used for characterisation of ATMPs nor precise expectations on the quality part of the expected small batch sizes with variable shelf life is given in the regulation. In addition, ATMP-specific GCP and GMP guidance is still needed.
1. Regulation EC (No) 1394/2007, OJ, 10 December 2007, L324, 121-137, http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-1/reg_2007_1394/reg_2007_1394_en.pdf
2. Directive 2009/120/EC, OJ, 15 September 2009, L242, 3-12, http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2009:242:0003:0012:EN:PDF
3. US Code of Federal Regulations, 21 CFR 820.181, www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=820.181
4. Personal communication, Dr Christa Schroeder, Paul-Ehrlich-Institute, ATMP workshop, Munich, Germany, 11 April 11 2008
5. Trommelmanns H, Ethical reflections on clinical trials with human tissue engineered products, J Med Ethics, 2008, 34:e1; doi:10.1136/jme.2007.022913
6. European Commission, Staff working paper report on human embryonic stem cell research, Brussels, 3 April 2003, http://ec.europa.eu/research/press/2003/pdf/sec2003-441report_en.pdf
7. European Medicines Agency, Advanced Therapy Medicinal Products (ATMP) Regulation Implementation Plan, 11 December 2007
8. European Commission, Draft Amendments to the Clinical Trial Application Form as regards Advanced Therapy Medicinal Products, Public Consultation Paper, 22 July 2008, http://ec.europa.eu/enterprise/pharmaceuticals/advtherapies/docs/consultation_paper-2008-07-22.pdf
9. European Commission, Draft Detailed Guideline on Good Clinical Practice Specific to Advanced Therapy Medicinal Products, 2 July 2008, http://ec.europa.eu/enterprise/pharmaceuticals/advtherapies/docs/2008_07/Consultation%20paper-NR-2008-07-02.pdf
10. European Medicines Agency, Medicines and Emerging Science: Advanced Therapies, www.emea.europa.eu/htms/human/mes/advancedtherapies.htm
The author would like to acknowledge the contributions of Henrike Bergmann and Dr Siegfried Schmitt (PAREXEL International) in the preparation of this article.
Ralf D Hess is a principal consultant at PAREXEL based in Freiburg, Germany.