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Regulatory Focus™ > News Articles > 2020 > 7 > Regulation of advanced therapy medicinal products in the EU

Regulation of advanced therapy medicinal products in the EU

Posted 16 July 2020 | By Siegfried Schmitt, PhD 

Regulation of advanced therapy medicinal products in the EU

This article explains some of the terminology relating to advanced therapy medicinal products (ATMPs), including gene and cell-based therapies, tissue-engineered products, and combined ATMPs. The author explains the key EU regulations and guidance documents for each therapy type and discusses marketing authorization, accelerated regulatory pathways, and market access. He advises companies navigating this complex regulatory environment to engage with the regulatory agencies early and often during the approval process and to seek external regulatory support if in-house resources are limited.
 
Introduction
Advanced therapy medicinal products include cell therapies, gene therapies, and tissue-engineered products. These highly complex treatments differ from traditional medicines, both in how they are made and administered and in the type of benefits they may provide. These are products for which regulations were established relatively recently and that present challenges for regulatory agencies on how to best they should be regulated within the existing regulatory framework.
 
Terminology
Gene therapies
Gene therapies treat disease by replacing, inactivating, or introducing genes into the body (see Figure 1). They deliver a corrected copy of a faulty or missing gene, typically using a vector or carrier molecule. The new gene allows cells to function correctly, alleviating all, or some, disease symptoms and potentially offering a long-term cure.
 
Gene therapy medicinal product refers to a biologic medicinal product, which has the following characteristics:
  • It has an active substance containing or consisting of a recombinant nucleic acid that is used in, or administered to, human beings with a view to regulating, repairing, replacing, adding, or deleting a genetic sequence.
  • Its therapeutic, prophylactic, or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.  
Gene therapy medicinal products do not include vaccines against infectious diseases.

Schmitt_ATMPs_Figure-1-(1).png
Cell-based therapies
Cell-based therapies involve transplanting substantially manipulated cells or cellular material into a patient. In some cases, the genetic material in the cells may be genetically modified. Cell therapy restores or alters certain cells to deliver therapy. Cells are first modified outside of the body.

Cells may be from the patient (autologous) or from a donor (allogeneic). Autologous therapies are manufactured using cells taken from a patient, which are then re-administered to the same patient. Therefore, each batch is unique and irreplaceable. Allogenic products are those in which batches are manufactured using material from a single donor and then administered to different patients.
 
Somatic cell therapy medicinal product refers to a biological medicinal product, which has the following characteristics:
  • It contains or consists of cells or tissues that have been subject to substantial manipulation so that biological characteristics, physiological functions, or structural properties relevant for the intended clinical use have been altered; or of cells or tissues that are not intended to be used for the same essential function(s) in the recipient and the donor.
  • It is presented as having properties for, or is used in or administered to, human beings with a view to treating, preventing, or diagnosing a disease through the pharmacologic, immunologic, or metabolic action of its cells or tissues.  
Tissue-engineered products
Tissue-engineered products are cells or tissues that have been specially engineered ex vivo to regenerate, maintain, repair, or replace damaged human tissue. For example, cartilage cells taken from patients with osteoarthritis can be grown and expanded on special scaffolds and used to repair painful cartilage defects. Engineered tissue or cells may be used as a standalone ATMP or be integrated into a biodegradable matrix or other medical device, creating what is known as a combined therapy medicinal product.
 
Products containing or consisting exclusively of nonviable human or animal cells and/or tissues are excluded from this definition if they do not contain any viable cells or tissues and do not act principally by pharmacologic, immunologic, or metabolic action.
 
Combined ATMPs1
“Combined advanced therapy medicinal product” refers to an advanced therapy medicinal product that fulfils the following conditions:
  • It 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,
  • Its cellular or tissue part must contain viable cells or tissues, or
  • Its cellular or tissue part containing nonviable cells or tissues must be liable to act on the human body with action that can be considered as primary to that of the devices referred to.  
The regulations
Medicinal products are governed by EU Directive 2001/83/EC.2 Article 5 of Regulation (EC) No 1394/20073 mandated the European Commission to draw up guidelines on good manufacturing practice (GMP) specific to ATMPs. Until then, ATMPs had to comply with the GMP regulations as detailed in EudraLex Volume 4 (see Figure 2).4 The many differences of ATMPs compared with traditional medicinal products necessitated this change and amendment to the regulations. Since May 2018, the new Part IV, GMP requirements for ATMPs, is in force. It is worth noting that the rest of Volume 4 does not apply to ATMPs.

Schmitt_ATMPs_Figure-2.png

Guidance documents
The European Medicines Agency (EMA) provides several guidance documents and operates a specific help desk email address (advancedtherapeis@ema.europe.com):
  • Clinical aspects related to tissue-engineered products5
  • EMA advanced therapy medicinal products and ATMP regulation6
  • Dossier requirements for centrally authorised products7
  • Questions and answers on the use of out-of-specification batches of authorised cell/tissue-based ATMPs8
  • Questions and answers on comparability considerations for ATMPs9  
Guidelines on cell-based products10
  • ATMPs and support to developers6
  • CAT considerations for minimally manipulated ATMPs and the use of RBA for such products11
  • Reflection paper on stem cell-based medicinal products12
  • Reflection paper on in vitro cultured chondrocyte containing products for cartilage repair of the knee13
  • Guideline on quality, nonclinical, and clinical aspects of medicinal products containing genetically modified cells14
  • Guideline on potency testing of cell-based immunotherapy medicinal products for the treatment of cancer15
  • Guideline on quality, nonclinical, and clinical requirements for investigational ATMPs in clinical trials16
  • Guideline on safety and efficacy follow-up and risk management of ATMPs17  
Guidelines on gene therapy and tissue-engineered products18
  • Guideline on development and manufacture of lentiviral vectors19
  • Design modifications of gene therapy medicinal products during development20
  • Guideline on quality, nonclinical and clinical aspects of medicinal products containing genetically modified cells14
  • 2006 guideline on scientific requirements for the environmental risk assessment of gene therapy medicinal products21
  • Follow-up of patients administered with gene therapy medicinal products22
  • Management of clinical risks deriving from insertional mutagenesis23
  • Nonclinical studies required before first clinical use of gene therapy medicinal products24
  • Nonclinical testing for inadvertent germline transmission of gene transfer vectors25
  • Quality, nonclinical and clinical issues relating specifically to recombinant adeno-associated viral vectors26  
Marketing authorization
The marketing authorization procedures for ATMPs in the EU are listed on the EMA website.27 The agency's Committee for Advanced Therapies (CAT) has a central role in the scientific assessment of advanced therapy medicines. It provides the expertise that is needed to evaluate advanced therapy medicines.
 
During the assessment procedure, the CAT prepares a draft opinion on the quality, safety, and efficacy of the advanced therapy medicine. It sends this to the Committee for Medicinal Products for Human Use (CHMP). Based on the CAT opinion, the CHMP adopts an opinion recommending, or not recommending, the authorization of the medicine by the European Commission. The commission makes its final decision based on the CHMP opinion.28
 
The initial (full) marketing authorization application assessment timetables for an ATMP can be found on the EMA website.29
 
Because ATMPs are such a complex group of products, companies can consult the EMA to determine whether a medicine they are developing is an advanced therapy medicinal product (ATMP). The procedure allows them to receive confirmation that a medicine, which is based on genes, cells, or tissues, meets the scientific criteria for defining an ATMP.30 The ATMP classification procedure can take up to 60 days to complete, but is often shorter, and it is free.
 
CAT provides a certification procedure for ATMPs under development by micro- or small- and medium-sized enterprises (SMEs). This is an opportunity for SMEs to get an assessment of the data they have generated and to check they are on the right track for successful development.31 This is a 90-day procedure. If positive, EMA issues a certificate.
 
Accelerated regulatory pathways
EMA offers several accelerated approval pathways, not limited to, but including ATMPs. Table 1 provides a summary view. Figure 3 provides a graphical representation of the regular and accelerated marketing authorization pathways for ATMPs.32

Schmitt_ATMPs_Table-1-(1).png
 

FIGURE 3 Marketing authorization pathways for ATMPs Reprinted with permission (Detela & Lodge)32
Schmitt_ATMPs_Figure-3a.png
 
Market access
As of May 2020, 10 ATMPs have been granted marketing authorization in Europe ‒ seven gene therapies, one cell therapy, and two tissue-engineered products ‒ targeting several diseases in different therapeutic areas. An additional five approved ATMPs were removed from the market for commercial reasons. At the time, marketing authorizations for five gene therapies were pending.38 The high number of approved, but not marketed, products can be explained at least partially by the cost of ATMPs. It is, however, important to note the fundamental differences between conventional therapies and ATMPs (see Table 2).

Schmitt_ATMPs_Table-2.png
Outlook
Navigating this complex regulatory environment means companies need to engage with the regulatory agencies early and often throughout the approval process. Many of these therapies are developed by scientific institutions and medical research groups with typically limited regulatory resources in-house, so it is advisable to seek external regulatory support. This exciting field, with hundreds of products currently tested in clinical trials,39 should yield many new therapies with enormous benefits. Something to look forward to, particularly in a time of a global pandemic crisis.
 
Abbreviations
ATMP, advanced therapy medicinal product; CAT, Committee for Advanced Therapies; CHMP, Committee for Medicinal Products for Human Use; EMA, European Medicines Agency; EU, European Union; GMP, good manufacturing practice; SMEs, small- and medium-sized enterprises.
 
References [All references accessed 16 July 2020]
  1. Official Journal of the European Union. 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. https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32007R1394&from=EN. Dated 12 October 2007.
  2. European Medicines Agency. 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. https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/directive-2001/83/ec-european-parliament-council-6-november-2001-community-code-relating-medicinal-products-human-use_en.pdf. Dated 28 November 2004.
  3. 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 - https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32007R1394&from=EN.
  4. European Commission. EudraLex - Volume 4 - Good Manufacturing Practice (GMP) guidelines. https://ec.europa.eu/health/documents/eudralex/vol-4_en. Last updated 6 July 2020.
  5. European Medicines Agency. Clinical aspects related to tissue-engineered products. https://www.ema.europa.eu/en/clinical-aspects-related-tissue-engineered-products. Last updated 11 December 2014.
  6. Celis P. Advanced therapy medicinal products (ATMPs) and ATMP Regulation. https://www.ema.europa.eu/en/documents/presentation/presentation-module-4-advanced-therapy-medicinal-products-atmps_en.pdf. Presentation at: 2nd International Awareness Session – The EU medicines regulatory system and the European Medicines Agency; 8 March 2018.
  7. European Medicines Agency. Dossier requirements for centrally authorised products (CAPs). EMA/497021/2012 Rev. 24. http://www.ema.europa.eu/docs/en GB/document library/Regulatory and procedural guideline/2009/10/WC500003980.pdf. Dated 20 February 2017.
  8. European Medicines Agency. Questions and answers on the use of out-of-specification batches of authorised cell/tissue-based advanced therapy medicinal products. EMA/CAT/224381/2019. https://www.ema.europa.eu/en/documents/other/questions-answers-use-out-specification-batches-authorised-cell-tissue-based-advanced-therapy_en.pdf. Dated 24 April 2019.
  9. European Medicines Agency. Questions and answers on comparability considerations for advanced therapy medicinal products (ATMP). https://www.ema.europa.eu/en/questions-answers-comparability-considerations-advanced-therapy-medicinal-products-atmp . Published 13 December 2019.
  10. European Medicines Agency. Multidisciplinary: Cell therapy and tissue engineering. https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/multidisciplinary/multidisciplinary-cell-therapy-tissue-engineering. Last updated 2019.
  11. Lipnik-Štangelj M. CAT considerations for minimally manipulated ATMPs and the use of RBA for such products. Presentation at : EMA – EuropaBio Information Day; 15 October 2015. CAT Member - https://www.ema.europa.eu/en/documents/presentation/presentation-committee-advanced-therapies-cat-considerations-minimally-manipulated-advanced-therapy_en.pdf.
  12. European Medicines Agency. Reflection paper on stem cell-based medicinal products.   EMA/CAT/571134/2009. https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-stem-cell-based-medicinal-products_en.pdf. Dated 14 January 2011.
  13. European Medicines Agency. Reflection paper on in-vitro cultured chondrocyte containing products for cartilage repair of the knee. EMA/CAT/CPWP/568181/2009. https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-vitro-cultured-chondrocyte-containing-products-cartilage-repair-knee_en.pdf. Dated 8 April 2010.
  14. European Medicines Agency. Guideline on quality, nonclinical and clinical aspects of medicinal products containing genetically modified cells, EMA/CAT/GTWP/671639/2008 Rev. 1 - https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-non-clinical-clinical-aspects-medicinal-products-containing-genetically_en.pdf. Dated 26 July 2018
  15. European Medicines Agency. Guideline on potency testing of cell-based immunotherapy medicinal products for the treatment of cancer. EMA/CHMP/BWP/271475/2006 rev.1. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-potency-testing-cell-based-immunotherapy-medicinal-products-treatment-cancer-revision-1_en.pdf. Dated 21 July 2016.
  16. European Medicines Agency. Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials. https://www.ema.europa.eu/en/guideline-quality-non-clinical-clinical-requirements-investigational-advanced-therapy-medicinal. Published 21 February 2020.
  17. European Medicines Agency. Guideline on safety and efficacy follow-up and risk management of advanced therapy medicinal products. https://www.ema.europa.eu/en/guideline-safety-efficacy-follow-risk-management-advanced-therapy-medicinal-products. Last updated 21 November 2008.
  18. European Medicines Agency. Multidisciplinary: Gene therapy. https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/multidisciplinary/multidisciplinary-gene-therapy. Last updated 2019.
  19. European Medicines Agency. Guideline on development and manufacture of lentiviral vectors. CHMP/BWP/2458/03. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-development-manufacture-lentiviral-vectors_en.pdf. Dated 26 May 2005.
  20. European Medicines Agency. Design modifications of gene therapy medicinal products during development. https://www.ema.europa.eu/en/design-modifications-gene-therapy-medicinal-products-during-development. Last updated 9 February 2012.
  21. European Medicines Agency. Guideline on scientific requirements for the environmental risk assessment of gene therapy medicinal products. EMEA/CHMP/GTWP/125491/2006. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-scientific-requirements-environmental-risk-assessment-gene-therapy-medicinal-products_en.pdf. Dated 30 May 2008.
  22. European Medicines Agency. Follow-up of patients administered with gene therapy medicinal products. https://www.ema.europa.eu/en/follow-patients-administered-gene-therapy-medicinal-products. Last updated 13 November 2009.
  23. European Medicines Agency. Management of clinical risks deriving from insertional mutagenesis. https://www.ema.europa.eu/en/management-clinical-risks-deriving-insertional-mutagenesis. Last updated 1 August 2013.
  24. European Medicines Agency. Non-clinical studies required before first clinical use of gene therapy medicinal products. https://www.ema.europa.eu/en/non-clinical-studies-required-first-clinical-use-gene-therapy-medicinal-products. Last updated 30 May 2008.
  25. European Medicines Agency. Non-clinical testing for inadvertent germline transmission of gene transfer vectors. https://www.ema.europa.eu/en/non-clinical-testing-inadvertent-germline-transmission-gene-transfer-vectors. Last updated 16 November 2008.
  26. European Medicines Agency. Quality, non-clinical and clinical issues relating specifically to recombinant adeno-associated viral vectors. https://www.ema.europa.eu/en/quality-non-clinical-clinical-issues-relating-specifically-recombinant-adeno-associated-viral. Last updated 8 July 2010.  
  27. European Medicines Agency. Marketing-authorisation procedures for advanced-therapy medicinal products. https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/advanced-therapies/marketing-authorisation-procedures-advanced-therapy-medicinal-products. Last update January 2018.
  28. European Medicines Agency. Advanced therapy medicinal products: Overview. https://www.ema.europa.eu/en/human-regulatory/overview/advanced-therapy-medicinal-products-overview#advanced-therapies-in-the-product-lifecycle-section. Last update April 2020.
  29. European Medicines Agency. Initial (Full) Marketing Authorisation application assessment timetables Advanced therapy medicinal product (ATMP). EMA/824993/2015 Rev.2. https://www.ema.europa.eu/en/documents/other/timetable-initial-full-marketing-authorisation-application-atmp_en.pdf. Dated 31 October 2017.
  30. European Medicines Agency. Advanced therapy classification. https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/advanced-therapies/advanced-therapy-classification. Last updated 2014.
  31. European Medicines Agency. Certification procedures for micro-, small- and medium-sized enterprises (SMEs). https://www.ema.europa.eu/en/human-regulatory/research-development/advanced-therapies/advanced-therapy-development/certification-procedures-micro-small-medium-sized-enterprises-smes. Last updated 2016.
  32. Detela G, Lodge A. EU regulatory pathways for ATMPs: Standard, accelerated and adaptive pathways to marketing authorisation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378853/. Mol Ther Methods Clin Dev. 2019;13:205-32.
  33. European Medicines Agency. PRIME: priority medicines. https://www.ema.europa.eu/en/human-regulatory/research-development/prime-priority-medicines. Last updated 1 July 2020.
  34. European Medicines Agency. Conditional marketing authorisation. https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/conditional-marketing-authorisation. Last updated 2017.
  35. European Medicines Agency. Exceptional circumstances. https://www.ema.europa.eu/en/glossary/exceptional-circumstances. Not dated.
  36. European Medicines Agency. Accelerated assessment. https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/accelerated-assessment.
  37. European Medicines Agency. Compassionate use. https://www.ema.europa.eu/en/human-regulatory/research-development/compassionate-use. Last updated 2010.
  38. Verband Forschender Arzneimittelhersteller e.V., Medizinische Biotechnologie in Deutschland 2020. https://www.vfa-bio.de/vb-de/vb-presse/vb-publikationen.  
  39. Alliance for Regenerative Medicine. Advancing gene, cell, & tissue-based therapies – ARM annual report & sector year in review: 2019. https://alliancerm.org/sector-data/2019-annual-report-europe/.  
About the authors
Siegfried Schmitt, PhD, is vice president, technical at Parexel International, providing strategic compliance and consulting services to the regulated healthcare industries. Before joining Parexel, he worked for major pharmaceutical and medical device companies, and for engineering and compliance consulting firms. Schmitt is member of the editorial advisory committee for Regulatory Focus. He can be reached at siegfried.schmitt@parexel.com.
 
Citation Schmitt S. Advanced therapy medicinal products regulations in the EU. Regulatory Focus. July 2020. Regulatory Affairs Professionals Society.

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