Abstract
Over the last two decades, clinical trials using gene therapy medicinal products (GTMPs) have been carried out for a large number of rare, inherited monogeneic disorders as well as common multigeneic diseases such as cancer, cardiovascular and infectious diseases including AIDS. Despite some early difficulties and setbacks, the gene therapy field has slowly progressed and, nowadays, offers the promise of novel treatments for a growing number of diseases. On the other hand, gene therapy approaches are often associated with additional risks due to limited clinical experience with a given gene transfer system, long-lasting effects of the therapeutic gene, and/or a complex mode of action. As a result, specific regulations and guidelines have been introduced within the EU to help address these uncertainties. This article summarises the legislative framework and will provide an overview on the regulatory requirements for clinical trials and marketing authorisation applications.
Zusammenfassung
In den vergangenen 20 Jahren wurde eine zunehmende Zahl gentherapeutischer Arzneimittel (GTMPs) in klinischen Studien getestet. Die Indikationen reichten dabei von seltenen, monogenischen Erbkrankheiten über multifaktorielle Krankheiten wie Krebs oder kardiovaskuläre Erkrankungen bis hin zu Infektionserkrankungen, wie zum Beispiel AIDS. Trotz anfänglicher Schwierigkeiten und Rückschläge eröffnet die Gentherapie mittlerweile eine vielversprechende Behandlungsoption für zahlreiche Krankheiten. Andererseits sind natürlich Behandlungen mit diesen Therapieformen aufgrund (i) geringer klinischer Erfahrung mit den entsprechenden Gentransfersystemen, (ii) der Langzeitwirkung der transferierten Gene und (iii) der oftmals komplexen Wirkungsweise der Arzneimittel mit zusätzlichen Risiken verbunden. Deshalb wurden in der EU zahlreiche Verordnungen und Leitfäden zu dieser Thematik veröffentlicht. Dieser Übersichtsartikel bietet einen Überblick über die regulatorischen Anforderungen an die Durchführung von klinischen Prüfungen mit und die Marktzulassung von Gentherapeutika und stellt die grundlegenden gesetzlichen Rahmenbedingungen dafür dar.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
(n a) (2001) 2001/83/EC, The European Parliament and the Council of the European Union. Off J Eur Comm L311:67–126. http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-1/dir_2001_83_cons/dir2001_83_cons_20081230_en.pdf
(2009) 2009/120/EC, The Commission of the European communities. Off J Eur Comm L 242 15(9)2009, p. 3–12. http://www.ec.europa.eu/enterprise/pharmaceuticals/endralex/vol-1/dir_2009_120/dir_2009_120_en.pdf
(n a) (2004) 726/2004, The European Parliament and the Council of the European Union. Off J Eur Comm L136:1–33. http://eur-lex.europa.eu/LexUriServ/site/en/oj/2004/l_136/l_13620040430en00010033.pdf
(n a) (2003) 2003/63/EC, The Commission of the European Communities. Off J Eur Comm L159:46–94. http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol1/dir_2003_63/dir_2003_63_en.pdf
(n a) (2003) 2003/94/EC, Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use (Official Journal L262:22–26). http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-1/dir_2003_94/dir_2003_94_en.pdf
(n a) (2007) 1394/2007, Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (Note: shall apply from 30 December 2008) (Official Journal L324:121–137). http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-1/reg_2007_1394/reg_2007_1394_en.pdf
European Pharmacopeia, 6th edn, Supplement 6.3. Chapter 5.14. Gene transfer medicinal products for human use. 01/2008:54100, correct 6.0
Committee for Proprietary Medicinal Products (CPMP) (2001) Note for guidance on the quality, preclinical and clinical aspects of gene transfer medicinal products. Doc. ref. CPMP/BWP/3088/99 (EMEA, London). http://www.emea.europa.eu/pdfs/human/bwp/308899en.pdf
European Pharmacopeia, 6th edn, Supplement 6.3. Chapter 5.2.3. Cell substrates for production of vaccines for human use. 01/2008:50203
ICH Topic Q 5 D (1998) Quality of biotechnological products: derivation and characterisation of cell substrates used for production of biotechnological/biological products. Doc. Ref. CPMP/ICH/294/95 (EMEA, London). http://www.emea.europa.eu/pdfs/human/ich/029495en.pdf
(n a) (2004) 2004/23/EC, The European Parliament and the Council of the European Union. Off J Eur Comm L102:48–58. http://europa.eu/eur-lex/pri/en/oj/dat/2004/l_102/l_10220040407en00480058.pdf
(n a) (2006) 2006/17/EC, The Commission of the European Communities. Off J Eur Comm L38:40–52. http://eur-lex.europa.eu/LexUriServ/site/en/oj/2006/l_038/l_03820060209en00400052.pdf
(n a) (2006) 2006/86/EC, The Commission of the European Communities. Off J Eur Comm L294:32–50. http://eurlex.europa.eu/LexUriServ/site/en/oj/2006/l_294/l_29420061025en00320050.pdf
(n a) (2001) 2001/18/EC, Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EEC (Official Journal L106:1–39). http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-1/dir_2001_18/dir_2001_18_en.pdf
(n a) (2002) 2002/623/EC, Commission Decision 2002/623/EC establishing guidance notes supplementing Annex II to Directive 2001/18/EC of the European Parliament and of the Council on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EEC.24 July 2002. Official Journal L200:22–33. http://faolex.fao.org/docs/pdf/eur37457.pdf
Committee for the Medicinal Product for Human Use (CHMP) (2008) Guideline on scientific requirements for the environmental risk assessment of gene therapy medicinal products. Doc. Ref. EMEA/CHMP/GTWP/125491/2006. EMEA, London, http://www.emea.europa.eu/pdfs/human/genetherapy/12549106enfin.pdf
ICH considerations on the general principles to address virus and vector shedding – dated 11 June 2009. http://www.ich.org/LOB/media/MEDIA5521.pdf
Committee for Medicinal Products for Human Use (CHMP) (2006) Guideline on non-clinical testing for inadvertent germline transmission of gene transfer vectors. Doc. Ref. EMEA/273974/2005. EMEA, London, http://www.emea.europa.eu/pdfs/human/swp/27397405enfin.pdf
Committee for Proprietary Medicinal Products CPMP/EWP/2330/99 (2001) Points to consider on application with 1. meta-analyses; 2. one pivotal study. EMEA, London. http://www.emea.europa.eu/pdfs/human/ewp/233099fen.pdf
Committee for Medicinal Products for Human Use CHMP/GTWP/60436/07 (2008) Follow-up of patients administered with gene therapy medicinal products (Draft). EMEA, London. http://www.emea.europa.eu/pdfs/human/genetherapy/6043607endraft.pdf
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Schüle, S., Renner, M., Longhurst, S. et al. Regulatory requirements for clinical trial and marketing authorisation application for gene therapy medicinal products. Bundesgesundheitsbl. 53, 30–37 (2010). https://doi.org/10.1007/s00103-009-0988-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00103-009-0988-0