All modern biotechnology medicinal products currently regulated at EU level are subject to a centralised marketing authorisation procedure, involving a single scientific evaluation of the quality, safety and efficacy of the product, which is carried out to the highest possible standard by the EMA. The ATMP Regulation that came into force in the EU on 30 December 2008 was set up as a lex specialis introducing particular
66European Medicines Agency: Advanced therapies. Available at:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000294.jsp&mid
=WC0b01ac05800241e0. Accessed 21 June 2016. European Union (2004) Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells. European Union Commission Directive 2006/17/EC of 8 February 2006 implementing Directive 2004/23/EC of the European Parliament and of the Council as regards certain technical requirements for the donation, procurement and testing of human tissues and cells.
67 European Union (2004) Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells. European Union Commission Directive 2006/17/EC of 8 February 2006 implementing Directive 2004/23/EC of the European Parliament and of the Council as regards certain technical requirements for the donation, procurement and testing of human tissues and cells. European Union Commission Directive 2006/86/EC of 24 October 2006 implementing Directive 2004/23/EC of the European Parliament and of the Council as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells.
68 Pirnay, et al., supra note 22, 526. See also Mansnérus, supra note 22, 428. The drafting history of the EUCTDs has been discussed in Research Article IV and will be discussed in further detail in Section 6.1 of
this study.
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provisions to the existing pharmaceutical legislation in respect of authorisation, supervision and pharmacovigilance of ATMPs to ensure that they are safe and effective.69 The ATMP Regulation encompasses the following categories of medicinal products for human use: GTMPs, CTMPs and TEPs. They have been described as a
“complex, heterogeneous class of innovative therapies that combine features of medicine, cell biology, science and engineering to regenerate, repair or replace damaged tissues or cells”.70
Table 3. Definitions of the ATMP subcategories71
ATMP subcategory
Definition
GTMP GTMP means a biological medicinal product which has the following characteristics: it contains an active substance which contains or consists of a recombinant nucleic acid 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.
CTMP CTMP means a biological medicinal product which has the following characteristics: 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 pharmacological, immunological or metabolic action of its cells or tissues.
TEP TEP means a biological medicinal product containing or consisting of engineered cells or tissues. It is presented as having properties for, or is used in or administered to human beings with a view to regenerating, repairing or replacing a human tissue.
Combined ATMPs These are medicines that contain one or more medical devices as an integral part of the medicine. An example of this is cells embedded in a biodegradable matrix or scaffold.
69 See for instance Celis, P. CAT – The new committee for advanced therapies at the European Medicines Agency. Bundesgesundheitsbl 2010;53:9–13. European Union 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. Official Journal of the European Union L311:67–128. See also Mansnérus, supra note 22, 428.
70 European Medicines Agency. European Medicines Agency. Reflection paper on classification of advanced therapy medicinal products, dated 21 May 2015. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/06/WC500187744.pd f. Accessed 21 June 2016.
71 These definitions are adapted from the European Medicines Agency. Reflection paper on classification of advanced therapy medicinal products, op.cit. Please note that official legal definitions are provided for a GTMP in Part IV of Annex I to Directive 2001/83/EC; for a CTMP in Part IV of Annex I to Directive 2001/83/EC and for TEP in Article 2.1.b. of the ATMP Regulation.
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The investigation whether a product under development falls within any of these categories may require profound scientific analysis. Especially, the aspect whether a manipulation of a living material should be considered as “substantial” may be very challenging to answer. Article 2 1.c. of the ATMP Regulation defines ATMPs as
‘engineered’products that contain or consist of cells or tissues that have been subject to substantial manipulation, so that “biological characteristics, physiological functions or structural properties relevant for the intended regeneration, repair or replacement are achieved” or/and “the cells or tissues are not intended to be used for the same essential function or functions in the recipient as in the donor.”72
Before adoption of the ATMP Regulation, Directive 2003/63/EC amending Directive 2001/83/EC had introduced the definition of ATMPs in 2003, characterising them as products GTMPs and CTMPs.73 TEPs were previously considered as an unregulated class of medicinal products and the absence of an unambiguous legal and regulatory framework at the EU level had resulted in divergent national approaches for the authorisation of TEPs. Some Member States authorised them as medicinal products, others as medical devices or as tissue products, whereas some had issued particular national guidelines to regulate ATMPs.74 As reported, this remarkable discrepancy in national regulatory approaches not only established real obstacles to the free movement of TEPs but it could also limit availability these new therapies.75 It was noted that the unclear legal status of TEPs that had resulted in the fragmentation of the market within the EU, constituting a disadvantage for European companies and academia developing these innovative products.76
The current ATMP Regulation provides tailored regulatory principles for evaluation, for the mandatory centralised marketing authorisation procedure for ATMPs, for post-authorisation follow-up and for traceability.77 As noted, the new
72 European Union Regulation (EC) No. 1394/2007 of the European Parliament and Council of 13 November 2007 on Advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004. Official Journal of the European Union L324:121–137. It should be noted that this study does not aim at providing any specific guidance regarding scientific classification of any particular pharmaceutical product. For further details, please refer to “Reflection paper on classification of advanced therapy medicinal products” issued by the EMA. It provides further guidance regarding classification of ATMPs. It also provides “decision trees” that may facilitate classification of ATMPs.
73 European Union Commission Directive 2003/63/EC of 25 June 2003 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code related to medicinal products for human use. Official Journal of the European Union L159:46–94. See also for instance Celis, supra note 69.
74 Bock, A-K., Rodriguez-Cerezo, E., Hüsing, B. et al. Human tissue-engineered products: Potential socio-economic impacts of a new European regulatory framework for authorisation, supervision and vigilance. Synthesis report Eur 21838 EN, Institute for Prospective Technology Studies, (Seville), 2005,1–58. Available at: http://ftp.jrc.es/EURdoc/eur21838en.pdf. Accessed 21 June 2016. See also Mansnérus, supra note 22, 429. See also for instance Celis, supra note 66.
75 Bock, et al., op. cit., 13. See also Mansnérus, supra note 22, 429.
76 Pirnay, et al., supra note 22, 539. See also Mansnérus, ibid. The drafting history of the ATMP Regulation, will be discussed in further detail in Section 6.2. of this study.
77 European Medicines Agency. Reflection paper on classification of advanced therapy medicinal products, supra note 70. European Medicines Agency. EU Regulation on advanced therapies. Available at:http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000295.jsp&
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scientific committee at the EMA, the Committee for Advanced Therapies (CAT) was founded pursuant to the ATMP Regulation as a multidisciplinary body, with primary responsibility to assess the quality, safety and efficacy of ATMPs, and to follow scientific developments in the field. The CAT also provides an advisory service to innovators developing ATMPs. Since June 2009 the CAT has issued scientific recommendations on ATMPs classification.78 The legislation also provides incentives tailored to SMEs that develop ATMPs.79 Recently, some of these incentives have been extented to cover academia and non profit actors. 80
Since adoption of the ATMP Regulation, as presented in Table 1. of Appendix 1, only six marketing authorisations have been granted to ATMPs thus far and currently four of them are still on the market.81 The low number of marketing authorisations granted is despite the increasing amount of companies and investment in the field.82 A recent study by Hanna et al. reveals significant increases in clinical trials on ATMPs reported in the EudraCT, ClinicalTrials.gov, and ICTRP (International Clinical Trials Registry Platform of the World Health Organization) during the recent years (number of ATMPs in development increased from 12 trials in 2004 to 150 in 2014).
A study by Hanna et al. identified 939 clinical trials on ATMPs (85% ongoing, 15% completed) from 1999 to June 2015. The great majority of trials were in the early stages (Phase I, I/II: 64.3%, Phase II, II/III: 27.9%, Phase III: 6.9%). Per category of ATMP, 53.6% of trials involved CTMPs, 22.8%
TEPs, 22.4% GTMPs, and 1.2% combined ATMPs. Disease areas included cancer (24.8%), cardiovascular diseases (19.4%), musculoskeletal (10.5%), immune system and inflammation (11.5%), neurology (9.1%), and others. Of the trials, 47.2% enrolled less than 25 patients. To address particularities of ATMPs new clinical trial approaches are being considered (e.g., small sample size, non-randomised trials, single-arm trials, surrogate endpoints, integrated protocols, and adaptive designs). Therefore, Hanna et al. conclude that “evidence generation post-launch will become unavoidable to address payers’ expectations.” 83
mid=WC0b01ac058007f4bb. Accessed 21 January 2016. See also Bock, A-K., Ibarreta, D., Rodriguez-Cerezo, E. Human tissue engineered products. Today’s markets and future prospects. Synthesis report Eur 21000 EN, Institute for Prospective Technology Studies. (Seville), 2003;1–49. Available at:
http://ec.europa.eu/health/files/advtherapies/docs/memo-05-429_en.pdf. Accessed 21 June 2016.
78 European Medicines Agency, op.cit.
79 Bock, et al., supra note 74, 33. Sanzenbacher, R., Dwenger, A., Schuessler-Lenz, M., et al. European regulation tackles tissue engineering. Nat Biotechnol 2007;25:1089–1091. See also e.g. Celis, supra note 69.
80 These aspects of ATMP regulation has been discussed in Research Article IV and Section 7.7.2 of this study. Possible amendments improving the potential impact of to these incentives will be discussed in Section 8.1.1. of this study.
81 See Table 1. in Appendix 1. for further details.
82According to the Annual Report 2015 of the EMA, p. 50 over the past few years, there have been some signs of an increase in ATMP development. The number of medicine applications recommended by CAT to be classified as advanced therapies increased significantly (in 2015 compared to 2014, 61 versus 28).
European Medicines Agency. Annual Report 2015. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Annual_report/2016/05/WC500206482.pdf.
Accessed 21 June 2016.
83 Hanna, E., Remuzat, C., Auquier, P., Toumi, M. Advanced therapy medicinal products: current and future perspectives. J Mark Access Health Policy 2016;4.
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Furthermore, it has been reported by Barfoot et al. that the field of stem cell research has grown globally very rapidly over the past decade 84 According to Barfoot et al. the volume of research output and the number of publications as well as citation frequency has increased significantly in hESCs and iPSCs related topics.85 There is an evident need for a re-assessment of how the ATMP Regulation is being implemented, as commercialisation of these medicines appears to be very slow. Research Article IV and the Chapter 7 of this study analyse possible reasons for this by investigating why so few ATMPs have progressed through the clinical trials to commercialisation of these products. It is particularly investigated whether obstacles to a fully-fledged market entry of these medicines relate to ATMPs as such or whether something else in the innovation system is hindering their progress. The harmonisation attempts, notwithstanding some obstacles remain as the ATMP Regulation has been so divergently implemented across the Member States, which is against the initial purpose of the EU regulation that was supposed to guarantee regulatory uniformity. Therefore, there is a need to further streamline and clarify of the ATMP Regulation. However, more harmonisation should not result in making regulatory compliance an excessively resource-consuming activity for the developers and manufacturers of ATMPs and it should not divert resources from their innovative activities.86
Moreover, the ATMP Regulation allows hospitals to treat patients with ATMPs on a “non-routine basis” according to specific quality standards, and used within the same Member States in a hospital under the exclusive professional responsibility of a physician, under an individual medical prescription for a custom-made product for an individual patient. Hospital exemption necessitates the application of national requirements on quality, traceability, and pharmacovigilance similar to those required for authorised medicinal products. Some Member States have implemented this so-called “hospital exemption”, whereas others have utilised different definitions for the use of “non-routine”, and some have not defined it at all. Consequently, lack of a uniform definition has resulted in significant discrepancies in the national implementation of hospital exemption (as it has been reported in Research Article IV and further specified in Section 7.7.1 of this study). These findings suggest that there is a need for the European Commission to further clarify and streamline this definition.
84 Barfoot, J., Kemp, E., Doherty, K., Blackburn, C., Sengoku, S., van Servellen, A., Gavai, A., Karlssson A. “Trends and Perspectives on the Evolving International Landscape” (2013), 5. Available at:
http://www.eurostemcell.org/files/Stem-Cell-Report-Trends-and-Perspectives-on-the-Evolving-International-Landscape_Dec2013.pdf. Accessed 21 June 2016.
85 More specifically, it was reported that in terms of the number of the publications, there were 4402 publications in 1996, which represented 0.4% of global publications. Whilst the number increased to 21193 publications in 2012, representing 1% of global publications. Furthermore it was reported that during 2008-2012 stem cell publications demonstrated annual growth rate of 7.0% in comparison to the world average growth rate of 2.9% across all field of research. According to the report the hESC publications showed a growth rate of 5.1%. Whilst, the emerging field of iPSC research grew more rapidly representing an annual growth rate of 77%. According to the report stem cell publications, on average, were cited 50% more than the global average for all related disciplines.
86 Mansnérus, supra note 22, 460.
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