Translational medicine is a rapidly growing discipline within biomedical and public health research intended to improve the health of individuals and the community by
‘translating’ its research findings into novel diagnostic tools, medicines, procedures and policies governing research, as well as education. It seeks especially to accelerate the discovery of new diagnostic tools and treatments by using an interdisciplinary, very collaborative ‘bench-to-bedside’ approach.132 Initially, translational medicine was described as "the marriage between new discoveries in basic science and clinical practice".133 The translational process can also be seen, as initially described by Marincola, as a two-way road; “from bench to bedside and back”. Discoveries from the bench may be translated into clinical application and/or the translation of clinical findings into the understanding of molecular mechanisms. 134
From a regulatory perspective, the translational approach could be characterised as a hybrid between basic research and clinical treatment.135 Regulating ‘hybrids’ has usually been seen to constitute a great challenge for legislators.136 The regulation of translational research is a hybrid sector that seemingly involves particular characteristics which research based on a traditional division of disciplines is powerless to address adequately.137 For regulation of translational hESC research especially, these
132 Woolf, S.H. The Meaning of Translational Research and Why It Matters. JAMA Jan 2008; 299(2):
3140–3148.
133 Geraghty, J. Adenomatous polyposis coli and translational medicine. Lancet 1996: 348(9025):422.
134 Minna, J.D., Gazdar, A.F. Translational research comes of age. Nat Med 1996;2(9):974-975.
Marincola, F.M.Translational medicine: a two-way road. J Transl Med 2003;1(1):1.
135 See, e.g., Hartlev, M. “Banks Repositories and Registries of Stem Cell Lines” in Hug, K., Hermerén, G. (eds.) Translational Stem Cell Research (New York, Dordrecht, Heidelberg, London: Springer), 2011, 252-264.
136 Brown, N., Faulkner, A., Kent, J., Michael, M. Regulating hybrids: “making mess” and “cleaning up”
in tissue engineeering and transspecies transplantation. Soc Theory Health 2006; 4:1-24. See also Hartlev, op. cit., 262.
137 See also Lahti, supra note 97,250. Lahti discusses the emergence of biolaw as a new discipline and he also raises the question of whether the object or context of regulation in this hybrid sector involves particular characteristics that research based on a traditional division of subjects is incapable of adequately addressing. He has expressed the view that medical law and biolaw “focuses on the legal issues of healthcare and those involving medical technology and other applications in an integrative way.” He perceives medical and biolaw as a new legal discipline which allows for structuring and
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regulatory challenges are numerous and multifaceted. The regulatory uncertainty in this area of translational research risks constituting a significant impediment for development and commercialisation of hESC-based advanced therapies, especially as ethical aspects of some types of hESC-research activity may compromise the legitimacy of such research. Hence, better regulatory clarity in this area is urgently needed. This not only requires analysis of the multilayered, variable and complex set of rules and regulations governing ATMPs in general (and hESC research in particular), but also necessitates a critical review of multiple ethical considerations underpinning the legislative framework. The scope and content of the undefined concept of human dignity and rights arising therefrom in particular constitute a core element for this ethical debate.
The Institute of Medicine's Clinical Research Roundtable has identified two major bottlenecks (i.e., specific areas in need of improvement) for efficient translation; the first translational block (T1) prevents basic research findings from being tested in a clinical setting, whereas the second translational block (T2) prevents proven interventions from becoming standard practice.138 It has been noted that blocks T1 and T2 face different challenges. T1 predominantly deals more with biological and biotechnological issues, clinical trial recruitment, and some regulatory concerns, whereas as T2 struggles more with human behaviour and organisational indolence, as well as research infrastructure and resource limitations. As a starting-point, the translational approach is strongly interdisciplinary. According to Woolf:
“[s]uccessful health interventions in hospitals, homes, and statehouses require the translation of other “basic sciences”—such as epidemiology, behavioural science, psychology, communication, cognition, social marketing, economics, political science—not only the translation of biotechnological insights and novel therapies.”
In my view, legal science should be also added to Woolf’s list of “basic sciences”
above. In addition, I would like to suggest legal and bioethical constraints preventing the efficient translation of research, access to therapies and commercialisation of novel therapeutics as a third significant translational block (T3). This study investigates the legal and ethical crossing points of translational research in terms of the development of ATMPs.
systematising the general principles and concepts contained in the legal regulation of healthcare and medicine “ into more consistent and coherent general doctrines of law than in case of the traditional division of subjects.”
138 Woolf, supra note 132. According to Woolf, the first roadblock (T1) has been perceived as “the transfer of new understandings of disease mechanisms gained in the laboratory into the development of new methods for diagnosis, therapy, and prevention and their first testing in humans,” whereas the second roadblock (T2) has been described as “the translation of results from clinical studies into everyday clinical practice and health decision making.” See also American Medical Association. Clinical Research Initiatives. Available at: http://www.ama-assn.org/ama/pub/about-ama/our-people/ama-councils/council-science-public-health/clinical-research.page? Accessed 21 June 2016.
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The main research questions of this regulatory study are:
1. What are the benefits and limitations of the ATMP Regulation for SMEs and academia developing ATMPs?
2. What kinds of amendment to the ATMP Regulation and related regulatory processes are needed to:
(i) accelerate translation of research into advanced therapies whilst ensuring the safety of the patients; and
(ii) facilitate commercialisation of ATMPs?
Despite the primary objective of this study is to analyse regulatory aspects affecting commercialisation of ATMPs, it would be wrong however to attribute the currently very low number of ATMPs solely and exclusively to the ATMP Regulation, as the ATMP landscape is influenced by a number of factors and other legislative instruments affecting the commercialisation prospects of these new products. Therefore, in addition to the above mentioned primary research questions there is a need to study what other roadblocks to commercialisation will developers of ATMPs encounter on their way from
‘bench to bedside’ and how will they meet these challenges. Yet, analysis of these aspects is limited to legal and ethical considerations pertaining to regulatory commercialisation process. In addition, hESC-based inventions will be discussed as example of products facing obstacles to market entry.
The objective of primary research questions this study is to evaluate the benefits and limitations of the ATMP Regulation for SMEs, research units in academia, and public tissue establishments developing ATMPs. This pragmatic study proposes practical amendments to the ATMP Regulation and related marketing authorisation processes to accelerate translation of research into advanced therapies and to facilitate commercialisation of ATMPs whilst ensuring patient safety. This study analyses the reasons for the low number of authorised ATMPs on the market, in particular by investigating why so few ATMPs have been granted marketing authorisations. Hence, the scope of research questions 1 and 2 is limited to aspects pertaining to the ATMP Regulation impeding market-entry of ATMPs undergoing development prior to a grant of marketing authorisation by the EMA via the mandatory centralised procedure. As only a small number of ATMPs have been granted marketing authorisations thus far (and currently only one is a stem cell product), this study will not only discuss regulatory challenges faced by developers of stem cell based products, but will more generally analyse commercialisation and the challenges SMEs and academia developing ATMPs usually face. Further aspects beyond commercialisation of ATMPs, such as pharmaceutical marketing of ATMPs to health care professionals, are beyond the scope of this study.
To provide a balanced overview of the multiple aspects influencing commercialisation of ATMPs, there is a need to investigate whether barriers to
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commercialisation relate to ATMPs as such or whether something else in the innovation system is impeding their market entry. These aspects investigated include among other things difficulties with the availability of primary materials, difficulties in obtaining authorisations for preclinical or clinical trials, as well as research funding, IP and reimbursement related issues. Yet, it should be noted that despite the relevance of these aspects, the primary scope of this study covers regulatory commercialisation obstacles directly associated with the ATMP Regulation. Hence, only some limited aspects of clinical trials pertaining to the developing quality management framework for ATMP manufacture and clinical trials are covered in this study. Further analysis of biomedical obstacles preventing basic research findings from being tested in a clinical setting, as well as human behaviour, organisational or research infrastructure related factors affecting ATMP market entry will be left outside the primary scope of this study.
Biomedical considerations and the particularities of clinical trial design have been discussed in a very limited sense only.
In addition, as an example of ATMPs under development, this study investigates what kinds of obstacles to market-entry developers of hESC-based products encounter in particular. The impact of EU funding policies moral patentability restrictions stemming from the Biotech Patent Directive will be discussed in this context. Relevant case law that aims at harmonising the European stem cell patenting practices has been discussed in Research Articles II and III. Study of patenting aspects is limited to assessing the implications of the moral patentability restrictions on hESC-based applications, as well as ethical assessment of some related emerging technologies such as iPSC-based inventions in regenerative medicine in the EU. Further analysis regarding the general patentability criteria (i.e., novelty139, the inventive step140 and industrial application141) are left out. The invention v. discovery dichotomy will not be studied either, despite being an important aspect affecting biotechnology patenting in general.Further ethical considerations beyond patenting and commercialisation of stem cell research will also be left out. There is also a need to discuss the European regulatory approaches to hESC research governance, as well as the European perception of the ambiguous notion of human dignity that influences the ethical landscape for stem cell patents in Europe. Yet, it should be noted that national law is not the object of this study. However, some references to national laws will be made to illustrate the fragmentation of the regulatory landscape for hESC research governance and commercialisation of hESC research. The role of the morality clause in the European unitary patent system and the forthcoming Unified Patent Court will not be discussed in detail. The new Trade Secrets Directive will not be discussed in detail. Neither licensing of biotechnological inventions nor further analysis of patenting aspects regarding commercialisation of university inventions are within the detailed scope of this study.
139 Article 54 of the EPC.
140 Article 56 of the EPC.
141 Article 57 of the EPC.
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