Regulatorischer Rahmen für neuartige Therapien

Vom Labor zur klinischen Prüfung
  • C. Walter
  • B. Rohde
  • D.C. Wicke
  • C. Pohler
  • A. Lührmann
  • H. von der Leyen
Leitthema

Zusammenfassung

Arzneimittel für neuartige Therapien wie Zell- und Gentherapeutika oder Gewebeersatz werden in den europäischen Richtlinien unter dem Begriff „Advanced Therapy Medicinal Products“ (ATMPs) zusammengefasst. ATMPs sind in ihrer Zusammensetzung und ihren Eigenschaften hoch komplex und unterliegen sich ständig weiterentwickelnden regulatorischen Rahmenbedingungen. Die vielversprechenden Ergebnisse der Grundlagenforschung wecken hohe Erwartungen an das therapeutische Potenzial dieser Produkte. Es besteht aber das Risiko, dass sie nicht die therapeutischen Effekte zeigen, die anfangs auf Basis theoretischer Überlegungen postuliert wurden. Umso wichtiger ist daher ein effizienter präklinischer und klinischer Entwicklungsplan, um den Übergang vom Labor in die erste klinische Anwendung erfolgreich zu gestalten. Aufgrund der Komplexität der ATMPs sollte dieser Entwicklungsplan frühzeitig mit den Regulierungsbehörden abgestimmt werden, um die Besonderheiten und Herausforderungen des individuellen Produktes zu definieren. Bei der Planung und Durchführung der ersten klinischen Prüfung sind – ebenfalls aufgrund der Eigenschaften der ATMPs – besondere Anforderungen zu beachten, die in diesem Beitrag diskutiert werden.

Schlüsselwörter

ATMP Gentherapie Somatische Zelltherapie Gewebeersatz Neuartige Therapien 

Regulatory framework of innovative therapies

From bench to bedside

Abstract

Novel therapies, e.g., cell and gene therapy or tissue engineering, are summarized in the European Union as advanced therapy medicinal products (ATMPs). In terms of composition and product properties, ATMPs are highly complex, and given their multiple potential actions they are subject to continuously developing regulatory requirements. Due to promising basic research findings, there are high expectations by the society toward the therapeutic potential of ATMPs. It is of utmost importance to develop a scientifically sound preclinical and clinical development plan before entering into the first clinical trial. Due to the complex features of ATMPs, this development plan should be discussed early with the regulatory authorities to define the specifics and challenges of each individual product. For planning as well as operational realization of the initial clinical trial involving ATMPs, specific requirements that need to be addressed are discussed in this paper.

Keywords

ATMP Gene therapy Somatic cell therapy Tissue engineering Advanced therapies 

Literatur

  1. 1.
    Sabado RL, Bhardwaj N (2010) Directing dendritic cell immunotherapy towards successful cancer treatment. Immunotherapy 2:37–56PubMedCrossRefGoogle Scholar
  2. 2.
    Leyen H von der, Mügge A, Hanefeld C et al (2010) REGENT1 – a prospective single-blind multicenter dose escalation study of intracoronary iNOS lipoplex (CAR-MP583) gene therapy for the prevention of restenosis in patients with de novo or restenotic coronary artery lesion. Hum Gene Ther Feb 26 [Epub ahead of print]Google Scholar
  3. 3.
    Boztug K, Schmidt M, Schwarzer A et al (2010) Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med 363:1918–1927PubMedCrossRefGoogle Scholar
  4. 4.
    Hacein-Bey-Abina S, Hauer J, Lim A et al (2010) Efficacy of gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 363:355–364PubMedCrossRefGoogle Scholar
  5. 5.
    Cappelli B, Aiuti A (2010) Gene therapy for adenosine deaminase deficiency. Immunol Allergy Clin North Am 30:249–260PubMedCrossRefGoogle Scholar
  6. 6.
    Kang EM, Choi U, Theobald N et al (2010) Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils. Blood 115:783–791PubMedCrossRefGoogle Scholar
  7. 7.
    Palmer DH, Young LS, Mautner V (2006) Cancer gene-therapy: clinical trials. Trends Biotechnol 24:76–82PubMedCrossRefGoogle Scholar
  8. 8.
    (2001) Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. OJ L311:67–126Google Scholar
  9. 9.
    (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. OJ L324:121–137Google Scholar
  10. 10.
    (2009) Commission Directive 2009/120/EC of 14 September 2009 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products,. OJ L242:3–12Google Scholar
  11. 11.
    Voelkel C, Lührmann A, Baum C, Leyen HE von der (2009) Retrovirus mediated hematopoietic gene therapy: A European regulatory perspective with special focus on the situation in Germany. Cell Ther Transplant 1 (4):e.000044.01Google Scholar
  12. 12.
    (1993) Council Directive 93/42/EEC of 14 June 1993 concerning medical devices. OJ L 169:1–43Google Scholar
  13. 13.
    (1990) Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the member states relating to active implantable medical devices. OJ L 189:17–36Google Scholar
  14. 14.
    (2007) Directive 2007/47/EC of the European Parliament and of the Council of 5 September 2007 amending Council Directive 90/385/EEC on the approximation of the laws of the member states relating to active implantable medical devices, Council Directive 93/42/EEC concerning medical devices and Directive 98/8/EC concerning the placing of biocidal products on the market. OJ L 247:21–55Google Scholar
  15. 15.
    Schneider CK, Celis P (2010) Challenges with advanced therapy medicinal products and how to meet them. Nat Reviews – Drug Discovery 9:195–201Google Scholar
  16. 16.
    Hacein-Bey-Abina S, Garrigue A, Wang GP et al (2008) Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest 118:3132–3142PubMedCrossRefGoogle Scholar
  17. 17.
    Howe SJ, Mansour MR, Schwarzwaelder K et al (2008) Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Invest 118:3143–3150PubMedCrossRefGoogle Scholar
  18. 18.
    Cavagnaro JA (2002) Preclinical safety evaluation of biotechnology-derived pharmaceuticals. Nat Reviews Drug Discov 1:469–475CrossRefGoogle Scholar
  19. 19.
    Dejas-Eckertz P, Schäffner G (2005) Scientific advice by the nationally competent authority and by the EMEA on the conduct of clinical trials. Bundesgesundheitsbl Gesundheitsforsch Gesundheitsschutz 48:423–428CrossRefGoogle Scholar
  20. 20.
    Krafft H, Cichutek K (2005) Approval of clinical trials of immunobiological medicinal products at the Paul Ehrlich Institute. Bundesgesundheitsbl Gesundheitsforsch Gesundheitsschutz 48:168–172CrossRefGoogle Scholar
  21. 21.
    (2009) Commission Regulation (EC) No 668/2009 of 24 July 2009 implementing Regulation (EC) No 1394/2007 of the European Parliament and of the Council with regard to the evaluation and certification of quality and non-clinical data relating to advanced therapy medicinal products developed by micro, small and medium-sized enterprises. OJ L 194:7–10Google Scholar
  22. 22.
    (2010) Guideline on the minimum quality and non-clinical data for certification of advanced therapy medicinal products. EMA/CAT/486831/2008/corrGoogle Scholar
  23. 23.
    (2007) Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products. Doc RefEMEA/CHMP/SWP/28367/07Google Scholar
  24. 24.
    (2010) EudraLex, Volume 4, EU Guidelines for good manufacturing practice for medicinal products for human and veterinary use, Draft Annex 2: Manufacture of biological medicinal substances and products for human use. ENTR/C/8/SF D(2010) 380334Google Scholar
  25. 25.
    (2001) Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the member states relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. OJ L121:34–44Google Scholar
  26. 26.
    (2005) Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products. OJ L 91:13–19Google Scholar
  27. 27.
    (2009) Detailed guidelines on good clinical practice specific to advanced therapy medicinal products. ENTR/F/2/SF/dn D(2009) 35810Google Scholar
  28. 28.
    Schächinger V, Erbs S, Elsässer A et al (2006) Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 355:1210–1221PubMedCrossRefGoogle Scholar
  29. 29.
    Meyer GP, Wollert KC, Lotz J et al (2009) Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial. Eur Heart J 30:2978–2984PubMedCrossRefGoogle Scholar
  30. 30.
    Yousef M, Schannwell CM, Köstering M et al (2009) The BALANCE Study: clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction. J Am Coll Cardiol 53:2262–2269PubMedCrossRefGoogle Scholar
  31. 31.
    Strauer BE, Yousef M, Schannwell CM (2010) The acute and long-term effects of intracoronary Stem cell Transplantation in 191 patients with chronic heARt failure: the STAR-heart study. Eur J Heart Fail 12:721–729PubMedCrossRefGoogle Scholar
  32. 32.
    Strauer BE, Brehm M, Zeus T et al (2001) Intracoronary, human autologous stem cell transplantation for myocardial regeneration following myocardial infarction. Dtsch Med Wochenschr 126:932–938PubMedCrossRefGoogle Scholar
  33. 33.
    Janssens S, Dubois C, Bogaert J et al (2006) Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 367:113–121PubMedCrossRefGoogle Scholar
  34. 34.
    (2010) Concerns over unregulated medicinal products containing stem cells. EMA/763463/2009Google Scholar
  35. 35.
    Gerok W (1990) Die gefährdete Balance zwischen Chaos und Ordnung im menschlichen Körper. In: von Ditfurth H, Fischer EP (Hrsg) Mannheimer Forum 89/90. Ein Panorama der Naturwissenschaften. Pieper & Co. KG, München, S. 137–181Google Scholar

Copyright information

© Springer Medizin Verlag 2011

Authors and Affiliations

  • C. Walter
    • 1
  • B. Rohde
    • 1
  • D.C. Wicke
    • 1
  • C. Pohler
    • 1
  • A. Lührmann
    • 1
  • H. von der Leyen
    • 1
  1. 1.Hannover Clinical Trial Center GmbHCampus Medizinische Hochschule HannoverHannoverDeutschland

Personalised recommendations