It appears that the clarity in the ATMP Regulation is impaired when its scope is further explored. The ATMP Regulation introduced a new mutual term of “advanced therapies”. However, the use of cells within its sphere of activity is also very often used for non-therapeutic purposes (e.g. as models for toxicology screenings or for an in vitro study of mechanisms of particular diseases).534 Broadly speaking, tissue engineering covers the use of cells and tissues to repair or replace existing malfunctions in components of the human body. Despite the term “tissue engineering” has been often used as an alternative to “regenerative medicine”, it appears that the latter has become synonymous with stem cells. It has been also reported by Barfoot et al. that nearly half
transferring personal data from the EU to the U.S. but also continue to adhere to the existing transfer mechanisms (such as the Standard Contractual Clauses and Binding Corporate Rules). There is no certainty whether the Privacy Shield will be greeted with satisfaction by the Article 29 Working Party, a body representing all EU data protection authorities, which is predicted to issue its opinion on the new arrangement shortly.
532 Pursuant to Article 15.1 the ATMP Regulation, the holder of a marketing authorisation for an shall establish and maintain a system ensuring that the individual product and its starting and raw materials, including all substances coming into contact with the cells or tissues it may contain, can be traced through the sourcing, manufacturing, packaging, storage, transport and delivery to the hospital, institution or private practice where the product is used. The marketing authorisation holder shall keep such data for a minimum of 30 years after the expiry date of the product, or longer if required by the European Commission as a term of the marketing authorisation (Article 15.4).
533Among other things following aspects need to be addressed: Are trial master files sufficiently safe if the company goes out of the business? If a site or contract research organisation closes down, who keeps information (e.g. informed consents)? If the contract research organisation closes who conducted the study goes out of business, how the access to all of the standard operating precedures can be ensured in such circumstances?
534Warren-Jones, supra note 36, 83.
Funding IP Materials Class GMP Trials MA Cost
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of all stem cell papers use keywords related to “drug development” or “regenerative medicine”.535 Currently “tissue engineering” is usually used to describe the creation of parts of the human body, covering even entire organs. As a consequence, “tissue engineering” that by using cells or tissue to create tissue or body parts or whole organs for transplantation is a term that intersects with three related forms of technology:
antisense technology (utilising RNA to interrupt a cell’s ordinary function, meaning a technology that interrupts the production of proteins, but cannot e.g. result in the production of a different protein), somatic gene therapy (utilising DNA to genetically alter an adult cell’s normal function) and stem cell technology (utilising a stem cell that divides and can be reprogrammed to a specific cellular function).536 As for application of these three forms of health technologies, tissue engineering overlaps with transplantation and therapy. When it comes to antisense technology, it is restricted to a form of therapy for its application. As for somatic gene therapy, it is evidently therapeutic, however the products used in the therapy can be used e.g. to manufacture bio-pharmaceuticals, or they can be utilised as models for toxicological screenings.
When it comes to the stem cell technology, it can be used in any of the applications described above. Furthermore, due to the rapid scientific advancements in the field, it is important to keep the definitions of ATMPs under continuous assessment. New innovative products, which are not explicitly covered by existing provisions (such as combination products that comprise of an ATMP and a medical device537), may emerge.
Consequently, the ATMP Regulation fails to be clearly accessible, due to the absence of standardised terminology and disregarding the standard terms when such exist. Despite these technologies are often referred to by using different terms, they are scientifically very closely related or even interlinked depending on their context of application. 538 This makes scientific classification and regulation of ATMPs a very difficult task for the regulators and especially for those applying for marketing authorisations. The rapid advances in the ATMP field, risks to resulting in a lack common scientific terminology, which may in turn result in fragmented use of these ATMP classifications. That may significantly hamper commercialisation of these innovative medicines.
535 Barfoot, et al supra note 84,5. According to Barfoot et al. 47% of stem cell publications used keywords related to regenerative medicine, whilst 2% used keywords referring to drug development.
536 Warren-Jones, supra note 36, 83.
537 Recital 18 of the ATMP Regulation notes that ATMPs may incorporate medical devices or active implantable medical devices. Those devices should meet the essential requirements laid down in Council Directive 93/42/EEC of 14 June 1993 concerning medical devices and 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, respectively, to ensure an appropriate level of quality and safety. Pursuant to the Recital 18 of the ATMP Regulation the results of the assessment of the medical device part or the active implantable medical device part by a notified body in accordance with those Directives should be recognised by the EMA in the evaluation of a combined ATMP carried out under the ATMP Regulation.
Please refer to Article 6, 7 and 9 of the ATMP Regulation for further details.
538 Warren-Jones, supra note 36, 83.
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There are some significant issues with the uneven practices of national competent authorities regarding ATMPs classifications despite the definitions of “CTMP” and
“GTMP“ are provided in Annex I to Medical Products Directive and “TEP” is defined in the ATMP Regulation, respectively. It appears paradoxical that even if a developer of an ATMP requests for a classification from the CAT, it is not legally binding, and national competent authorities of Member States frequently classify the same product differently. This concern has been also raised in a public consultation of the European Commission. It was reported by the European Commission that:
“the possibility that the same product may be subject to different requirements across the EU implies that the level of public health protection is different according to the place of residence of the patient. That the same product can be marketed under different regulatory regimes is not only undesirable from a public health standpoint but it also undermines the incentives to develop ATMPs. First, the uncertainty as to the market potential for a product discourages investments.
Secondly, divergent classification of the same product distorts competition between developers.
Finally, the application of different regulatory requirements across the EU hinders the free movement of these products.” 539
This constitutes a significant barrier to commercialisation of these medicines. For instance, ChondroCelect is already facing this problem in some Member States where academic and hospital facilities are permitted to produce an autologous chondrocyte preparation in direct competition with this licensed medicine.540 Another example is a case of three similar products comprising of human natural killer (NK) cells expanded and activated in ex vivo culture over many weeks as an anti-cancer immunotherapy. In France, these products were deemed “not substantially modified” and thus were not regulated as medicines, whereas Spain, Germany and Switzerland classified these products as ATMPs. The U.K. authorities classified a significantly less-manipulated NK cell product in which the cells were simply activated and not expanded as an ATMP. As for the future development of these products, those regulated as medicines could presumably follow a drug development trail to generate necessary data for a marketing authorisation application to the EMA, whereas in the case of the NK cell product that is perceived a ‘non-substantially modified’ preparation, it is unclear how this might be developed if the clinical trials were successful. This product does not appear commercially valuable, as it cannot follow a drug development pathway. In the absence of adequate efficacy trials that are systematically organised and controlled, these non-medicinal products cannot be provided to a wider group of patients.541
539 Report from the Commission to the European Parliament and the Council in accordance with Article 25 of Regulation (EC) No 1394/2007 of the European Parliament and of the Council on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 /*
COM/2014/0188 final, see section 4.3.2. Available at: http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A52014DC0188. Accessed 21 June 2016.
540Pearce, K.F., Hildebrandt, M., Greinix, H., Scheding, S., Koehl, U., et al.Regulation of advanced therapy medicinal products in Europe and the role of academia. Cytotherapy. 2014;Mar;16(3):289-97.
541 Op.cit., 294.
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Furthermore, the licensed NK cell medicine would not be legally protected from competing unlicensed products.
Notwithstanding, the issues relating to divergent classifications by national competent authorities, classification is helpful as such, because it provides the developers of ATMPs the possibility to share a preliminary understanding of particular issues applicable to their medicine in development (GMP and GCP requirements depend on the ATMP’s subclass).542 Yet, the national competent authorities cannot use the classification procedure when they face difficulties with classification of ATMPs.