Regenerative medicine in Europe: political conflicts, economic biases, and legal loopholes Alex Faulkner Centre for Global Health Policy University of Sussex a. faulkner@sussex. ac. uk
Overview • Concepts • Classification, stakeholders, interests • From tissue/cell banking to healthcare commodities -The mode of action conflicts -The ‘ethical issues’ conflicts • What the new EU RM product Regulation accomplishes • How the new products regulatory system ‘performs’ – holes, loopholes and biases • Negotiating the system • Cartilage cell therapy • Patent nonsense? – stem cells and embryos between national law and the European Court of Justice
CEO of World's Leading Regenerative Medicine Company, Organogenesis, Gives Keynote Address at World Congress of Regenerative Medicine in Germany. 5 th annual World Stem Cells and Regenerative Medicine Conference 2010 Cloning and Regenerative Medicine News Reprogramming a patient's eye cells may herald new treatments against degenerative disease (10/25/2009)
The Bioeconomy e. g. OECD report UK’s Life Science strategy 2011
Social shaping of technology Regulatory politics -Regulation is innovative force -Regulatory classification -Interaction of materiality of RM and regulatory politics
Social shaping of technology Regulation – rules of engagement of ‘technological zones’ (A. Barry) What does societal regulation do? - Performativity of law
Regenerative Medicine as a sector or zone - Fragile Product or asset-based model for business? SMEs and hospitals, a few MNCs arriving Funding/venture capital uncertainties Unclear business models; failures Uncertain and evolving science – biology, engineering, craft - Novel modes of action – uncertainties for regulatory science - Ethical issues – starting materials; property - Autologous/allogeneic
Core question • how to maintain ‘regulatory connection’? - i. e. matching and linkage between a diversifying, innovative regulatable field and challenged set of regulatory frameworks and practices R. Brownsword (2008) ‘So what does the world need now: reflections on regulating technologies’, In: R. Brownsword and K. Yeung (eds. ). (2008) Regulating Technologies: Legal Futures, Regulatory Frames, and Technological Fixes.
Taxonomy - classification
Socioeconomic classification Three dimensions of socioeconomic classification: 1. confer identities on social actors (or objects), and imply social control 2. create social boundaries and signify social standing of actors (or objects) 3. involve political struggles between different interest groups; classification systems embody political power Zhao W. (2005). Understanding classifications: Empirical evidence from the American and French wine industries. POETICS , 33, 3 -4: 179 -200.
Classification - research sectors EC FP 7 - ‘Health’ - ‘Regenerative medicine clinical trials’
Regenerative medicine – material classifications and types • transplantation • Cell therapy -somatic/adult -h. ESCs -mesenchymal • Tissue engineering, tissue preparations • Gene therapy • [Combined therapy products] • Medical devices - decellularised products - non-manipulated cells
Classificatory politics of RM sectors E. g. ‘cells as medicines’: ‘Regen: the industry responsible for cellbased therapies… universally recognised as an emerging new healthcare sector…’ C. Mason Cell Therapy and RM Advisory Group
Europe ‘cell therapy industry’ survey (Martin et al 2009) 138 primary firms and 49 secondary firms at the start of 2009 All allogeneic products - US firms autologous products – all but one European. 50 firms adult stem cells, 20 h. ESCs 97 products - 88 skin, bone or cartilage.
Stakeholders, states and sectors European Commission Enterprise - Biotechnology - Pharmaceuticals - Medical devices Health & Consumers European Parliament and committees Council of Ministers (member states positions) Regulatory bodies Donors; Patients Medical professionals Cell/tissue banks Scientists – developmental biology etc; scientific societies Bio-engineers Hospitals, Charities Companies
EU regulation early-mid 2000 s • Medical devices directives (x 3) • Medicinal product directives & regulations • Annex 1 directive 2001/83/EC - cell therapy medicinal products • Blood & blood products directive • Guide on safety and quality assurance for organs, tissues and cells. Council of Europe July 2002 • Clinical trials directive • ? ? ? Organ transplantation • ? ? ? Xenotransplantation • ? ? ? ? ? h. ES cell therapy products
The xenotransplant debate • ‘for another day’ - MEP in ENVI committee
EU polity - plurality of interests • EU ENVI Committee & Health Working Group • EU Industry, Research & Energy (ITRE) • EU Legal Affairs (JURI) • EC DG Enterprise & Industry • EC DG SANCO • Council of Europe - Employment, Social Policy, Health and Consumer Affairs Council
EC Issues, early 2000 s • ‘Urgent need to regulate the conditions under which human tissues circulate in the European market’ • ‘Realpolitik dictates the exclusion of stem cells’ • ‘Most of the (European Parliament’s) proposals were thrown out because they concerned matters of ethics’ • ‘Localising the ethical problems will. . jeopardise the basic right of physical integrity’
Cell/tissue banking Human tissues and cells directive 2004 (TCD) –standards for quality & safety : supply, storage, processing, distribution. . -voluntary donation HFEA Human Tissue Authority in UK
Definitions: ‘Tissue engineering’ and cell therapy ‘regeneration of biological tissue through the use of cells, with the aid of supporting structures and/or biomolecules’ (EC SCMPMD, 2001)
Tissue engineering and cell therapy regulation early 2000 s Proposal 1
Risk-based regulatory model proposed Tissue/cell provenance: autologous: national regulation allogeneic: EU central regulation
Regulatory politics – classification and commensuration EC invents ‘coherent ensemble’ of ‘advanced therapy medicinal products’ by expanding existing pharmaceutical regime - aligns gene therapy, cell therapy, tissue engineered products (xeno included) (TE = ‘unconventional medicine’)
One form of classification: commensuration ‘the comparison of different entities according to a common metric’ (Espeland & Stevens 1998)
Commensuration – designing markets ‘…process of making goods measurable and comparable…standardization of product categories …is a socially embedded driver of market evolution’ (Kai) ‘how the destruction of one gas in one place is made commensurate with emissions of a different gas in a different place…’ (Mac. Kenzie – the ‘politics of market design’) -K. Kai, Arbitrage and Commensuration as Socially Embedded Performativity. Paper presented at the American Sociological Association Annual Meeting, San Francisco, CA, August 8 th, 2009. -D. Mackenzie (2009) Making things the same: Gases, emission rights and the politics of carbon markets. Accounting, Organizations and Society 34 (3/4): 440.
Enterprise and Industry Directorate-General European Commission BIO 2006 April 9 -12, 2006 Genes, Cells and Tissues: Commission proposal on Advanced Therapies Georgette LALIS Director, European Commission DG Enterprise & Industry georgette. lalis@cec. eu. int
Policy objectives Proposal adopted on 16. 11. 2005 • Guarantee a high level of health protection • Harmonise and facilitate market access • Foster competitiveness • Provide overall legal certainty
Ethical aspects The proposal does not affect the application of national legislation prohibiting or restricting the use of any specific type of human or animal cells, or the sale, supply or use of medicinal products containing, consisting of or derived from these cells. Ref. : Article 28 of the proposal and Art. 2(1) of Dir. 2001/83/EC
‘Shared characteristics’ commensuration strategy • “innovative manufacturing; • scarce scientific and industrial expertise; • the importance of traceability and risk management; • primary participation of small and mediumsized enterprises (SMEs), hospitals and tissue banks. ”
Tissue engineering and cell therapy regulation mid-2000 s Proposal 2. Legislation Medical Devices 93/42/EEC Medicinal Products Directive 2001/83/EC ? Advanced Therapies Medical Devices Tissue Engineering Cell Therapy Gene Therapy Biotech Chemicals
Advanced Therapies - EU political conflict • Embryonic stem cells • ‘hybrid’ technologies
Ethics and ‘Ethical issues’ HESCs and hybrids vs. Public health/medical advance
Mode of action “Cells or tissues shall be considered engineered if they fulfil at least one of the following conditions: • the cells or tissues 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. • the cells or tissues are not intended to be used for the same essential function or functions in the recipient as in the donor” (ATMP Regulation text - European Parliament and Council of the European Union, 2007).
‘Mode of action’ sectoral conflicts ‘… say a heart valve covered by cells. . . the main mode of action is…not the cells, it’s the valve itself. However the cells are there for a certain function but it might be secondary to the physical mode of action by the valve or by the artificial hip…’ (MHRA interview with medical device regulator, 2006).
Mode of action conflicts ‘what will be classed as an 'engineered' tissue, specifically the possibility that processes that have been traditionally applied to tissue allografts to render them safer, amenable to long term preservation or more biocompatible could be classed as 'engineering'’ (NBS Tissue Services–written response to EC Consultation, May 2005).
Mode of action politics ‘The Presidency has also suggested…all combined products containing viable cells or tissues should be considered ATMPs (…Members States’ positions on this): Support: Belgian, Estonian, Lithuanian, Hungarian, Portuguese and Slovenian delegations; Against: Danish, Spanish, French, Netherlands, Swedish and United Kingdom delegations hold that the principal mode of action should be decisive. (Health Council of Europe Working Party on Pharmaceuticals & Medical Devices, 2006)
Pharmaceutical regulatory regime ‘(Impossible) to re-open discussion on all those different balances on … responsibilities of member states, of the Commission, related to good manufacturing practices, to Good Clinical Practice, for clinical trial conduct, to pharmacovigilance, of post-authorisation safety follow up’ (interview with EMEA, 2007).
EU’s “Advanced Therapy Medicinal Products” (ATMP) Regulation 2007 (REG/1394/2007/EC)
Main features of the Advanced Therapies Medicinal Products Regulation • Liberal regarding cell materials incl h. ESC and xeno • scope of TE product defined • EC/EU centralised authorisation: A new authorisation Committee based in European Medicines Agency (CAT) • ‘Hospital exemption’ • Pre-certification of new products (new) • Fee-waiver incentives for SMEs • 30 year traceability; surveillance scheme • ‘technical requirements’ open-ended
Committee for Advanced Therapies’ work • Classification (60+) • Scientific advice • Certification SME (2) • Authorisation (recommendation) (2)
Example classifications ‘Suspension of allogeneic bone-marrow derived osteoblastic cells, intended for the treatment of non-union, delayed union or other fractures’ -Tissue engineered product, non-combined Encapsulated cell based delivery system engineered to deliver human ciliary neurotrophic factor (CNTF) intraocularly after implantation. (reducing photoreceptor loss associated with degeneration of the cells of the retina) -Gene therapy medicinal product, combined ATMP:
The law’s effects Stabilising a sector / zone? Harmonisation of states’ regulation ‘Loophole’ of hospital exemption? Lack of incentive for hospital/academic sector Complexity of regulatory system
Effects of the ATMP Regulation A woundcare cell/TE therapy ‘This life-saving technique - taking a sample of unaffected skin, placing it on a mesh, and allowing the cells to reproduce and expand - has been in use for more than 10 years now with extremely good safety and efficacy records’ ‘For us surgeons the use of human tissue engineered products has allowed us to give so many patients, over 8, 000 in the last 15 years, renewed hope for a better quality of life. For regulators, however, the question was whether these products were medical devices or medicinal products. . ’ Wound/Burns clinician, Italy, Feb. 2013
…contd. ‘it was decided to classify them under gene and cell therapy which essentially meant that the EMA would now be responsible for approving these products. The result: since that day in 2007 EMA gave more than 100 scientific advices, of which only 9 (!) resulted into a submission. Of these 9 submissions, only 2 (!) have been approved. And when it comes to my own practice, not a single one of the products that I have been using for decades with full satisfaction has been given approval. And moreover, since the 1 st of January of this year, these products can no longer be made available to patients because they have not been granted approval. ’ Wound/Burns surgeon, Italy, Feb. 2013 http: //www. medtecheurope. org/blogposts
Wound care technology- a regulatory cause célèbre
The identity of Apligraf -Viable human cells (keratinocytes and fibroblasts) cultured from neonatal foreskin on a bovine-based collagen matrix
The classification of Apligraf Regulation FDA – ‘medical device’ European Medicines Agency - ? ? ? ATMP
Effects of the ATMP Regulation Hospital exemption Hospital-based One-off Individually prescribed Non-standardised Non-industrial
Hospital exemption “hospitals might be able to avoid complying with the provisions of the regulation, whereas industrial manufacturers of similar products would bear the obligations of compliance. . , where hospitals are preparing products routinely, using an established process to create treatments for patients on a serial and routine basis, they too should have to comply with the provisions of the regulation” (Eucomed, 2006).
Stem cell ATMPs regulation EMA: “To date, no stem-cell medicinal products have received marketing authorisation within the EU. However, it is still possible to gain access to stemcell medicinal products under certain controlled conditions. These include taking part in clinical trials or compassionate-use programmes, or receiving a custom-made medicine as part of ‘hospital exemption”. (2010)
Stem cell ATMPs …“use of stem-cell medicinal products outside these controlled conditions may result not only in little or no benefit to patients, but could also be detrimental. This is because, outside these conditions, checks on the quality of these products may not have been carried out, and their safety and efficacy may not be properly assessed”. (EMA)
First ATMP through central authorisation • Chondro. Celect ‘characterised viable autologous cartilage-forming cells expanded ex vivo expressing specific marker proteins’ - classified as ‘tissue-engineered ATMP’ - Global cartilage/ACI industry
Framing the market/usership through regulatory science • ‘Recent …trials suggest that ACI techniques, which are indicated for young people with traumatic cartilage defects, could also be used in degenerative defects of elderly people with OA’
Regenerative device for cartilage repair Cell. Co. Tec - A revolutionary approach to cartilage repair
First gene therapy authorised in the West 2012 Glybera -Dutch biotechnology company Uniqure -treatment for lipoprotein lipase deficiency (prevents the breakdown of fat in food and causes severe pain and inflammation of the pancreas) - affects one to two people in every million -Orphan drug designation -€ 250, 000 a year for five years
Effects of ATMP – economic bias Problem: 60% of applicants to ATMP CAT committee are academic, hospital or charities – not SMEs Solution? - CAT Interested Parties (IP) (2009) ‘not-for-profits’ - ‘Hearings’ - closer interaction academic producers and EMA - meeting between CAT and national clinical trial authorities - EMA link to funding bodies - Scientific societies – CAT interaction - urge European Commission to allow certif for non-SMEs
Effects of ATMP: proliferating EMA forums • “CAT-IP Focus Group on Incentives for academia, hospitals, charities • CAT IP Focus Groups (2011) - ‘Focus Groups: a model for a fruitful interaction between CAT and its stakeholders’ (Conference, January 2012). ‘small group theory’ • EMA/CAT-Notified Body Collaboration Group • CAT- Scientific Society networking - European Society Gene & Cell Therapy workshop (2012)
Effects of the ATMP Regulation as legislative text/document Represents EU/EC/EP RM world-view: Legislative Articles and non-legislative rationale Textual analysis
RM in the text of the ATMP regulation - ‘ Industry’ – 1, undefined - Firms, hospitals? - ‘public confidence’ - Patients? Citizens?
Strategies in the EU regulatory system for tissue/cell products - Centralised ATMP route - Hospital exemption (national variation) - ‘Unlicensed medicines’ (‘Specials’ in UK) - Orphan designation - Compassionate use - ‘Medical device’ – decellularised/acellular product/process
Current public consultation on ATMP Regulation http: //ec. europa. eu/health/files/advtherapies/2012_12_12__ public_consultation. pdf -Application data requirements -Combined products (no applications to CAT) - Hospital exemption (‘a too large application of this exemption may discourage the application for marketing authorisations’). -Incentives
ATMP summary • Conflicts • Biases • Loopholes • Some harmonisation & standardisation
Human embryonic stem cells
Uneven regulations governing h. ESC research e. g: –Cannot derive but can import h. ESClines(DE, IT); –Allow procurement of h. ESC from supernumerary IVF embryos(CZ, DK, EL, FI, FR, NL, PT), and –Allow somatic cell nuclear transfer(BE, ES, SE, UK); –Embryo research legislation, not specifying h. ESC(HU, SI); –No specific h. ESC research regulation(BG, CY, EE, IE, LU, LV, PT, RO; AT, LT, MT, PL, SK). Source EGE Opinion 22
Stem cell therapy as commodities? - EU law ‘the politics of biotechnology at the EU was subordinated…to that of the member states. Basic questions about the acceptability of biotechnology’s products and the allowable forms of debate concerning them remained national in character’ (Jasanoff 2005: 280; cited in Kent, 2012)
Stem cell therapy as commodities? - EU law Biotechnology Directive 1998 If commercial exploitation offends ‘ordre public’ or morality – exclude from patentability: - Cloning human beings - Modifying germ line - Use of human embryos for industrial or commercial purposes
1999 -Extraction of neural precursor cells
Oliver Brüstle
Greenpeace vs. Brüstle Greenpeace challenge legality of patent 2004 -Sent to CJEU 2011, followed Btech Directive but - definition of ‘human embryo’? -EPO guidance prohibiting SCs from blastocytes - CJEU stem cells obtained at the blastocyst stage national decision -Nov 2012 federal court upheld CJEU but allowed Brüstle patent (revised) – cell lines/embryos not capable of development
Politics of patenting Letter of protest at Brustle case threat to stem cell funding in EU’s Horizon 2020 funding programme
Joint statement “To maintain its global edge in this area of research, Europe must ensure all avenues of stem cell research continue to be financially supported, including through Horizon 2020. Europe’s strengths in this field present valuable opportunities to attract skilled scientists, biopharmaceutical companies and international investment in stem cell research to Europe, to drive the translation of basic research towards clinical benefits, and to influence the international agenda”.
EU parliamentary politics – h. ESCs in Horizon 2020 Opposition continues Majority of Council remain in favour
Concluding: Regulatory connection Product regulation - ATMP biases, poorly aligned to sectoral interests Property/patent regulation - material definitions (in h. ESC) are evolving and re-classifiable
Identities, boundaries, politics (Zhao) Malleability and uncertainty of classification of RM materials, product definitions and modes of action Political, economic and ethical struggles over boundary definitions National and sectoral identities - With real implications for future medicine, healthcare and global bioeconomies!
Thank you! a. faulkner@sussex. ac. uk
Publications Book Faulkner A. (2009) Medical Technology into Healthcare and Society: a sociology of devices, innovation and governance, Basingstoke: Palgrave Macmillan. Journal Special Issue Editorships 1. ) Journal of Law and Society : Guest Editorship special issue: ‘Material Worlds: The Intersections of Law, Technology and Society’, (2012) vol 39 issue 1. (Also book by Wiley-Blackwell). 2. INNOVATION: the European Journal of Social Science Research : Guest-editorship special issue Steering Biomedicine: The Regulatory Dynamics of Therapeutic Technologies in Europe. October 2012. Articles/Chapters include: Faulkner A. (2012) Commensuration and Proliferation: Similarity and Divergence in Law’s Shaping of Medical Technology. Law, Innovation and Technology, 4(2): 165– 184. Faulkner A. (2012) Law’s performativities: shaping the emergence of regenerative medicine through European Union legislation. Social Studies of Science Faulkner, A. (2013). Medical Technology. In : Gabe J. , Monaghan L. (eds. ) Key Concepts in Medical Sociology, 2 nd ed. Sage Publications. Hogarth S, Hopkins M, Faulkner A. (2012) Personalized medicine: renewing the social science agenda. Personalized Medicine, 9, 2: 121 -126 Mahalatchimy A, Rial-Sebbag E, Tournay V, Faulkner A. (2012) The legal landscape for Advanced Therapies: material and institutional implementation of European Union rules in France and the UK, in: Journal of Law and Society vol 39 issue 1. 131 -149. Faulkner A, Lawless C, Lange B. (eds). Introduction: Material Worlds: intersections of law, science, technology and society. Journal of Law and Society, 39, 1:
Publications contd. Faulkner A. (2012) Tissue engineered technologies: regulatory pharmaceuticalisation in the European Union. In: Steering Biomedicine: regulatory dynamics of therapeutic technologies in Europe. Special Issue (ed. A. Faulkner) of INNOVATION: the European Journal of Social Science Research. Faulkner A. (2011). Resisting the screening imperative: patienthood, populations and politics in prostate cancer detection technologies for the UK. Sociology of Health and Illness, Special Issue on Screening. Salter B, Faulkner A. (2011). State strategies of governance in biomedical innovation: aligning conceptual approaches for understanding ‘Rising Powers’ in the global context. Globalization and Health, 7: 3. Faulkner, A. (2010) Trial, trial again: reconstructing the gold standard in the science of prostate cancer detection. In: Will, C. & Moreira T. (eds). Medical Proofs/Social Experiments: clinical trials in context. Ashgate. pp 136 -51. Faulkner A. (2009) Regulatory policy as innovation: constructing rules of engagement of a technological zone for tissue engineering in the European Union, Research Policy, 38(4): 637 -646. Faulkner A, Geesink I, Kent, J, Fitz. Patrick D (2008) Tissue-engineered technologies: scientific biomedicine, frames of risk and regulatory regime-building in Europe, Science as Culture, 17, 2, 195222. Faulkner A, Kent J, Geesink I, Fitzpatrick D. (2006). Purity and the dangers of regenerative medicine: regulatory innovation of human tissue engineered technology. Social Science & Medicine, 63, 2277 -88.
Publications contd. Brown, N. ; Faulkner, A. ; Kent, J; Michael, M. (2006). Regulating Hybrids: `Making a Mess' and `Cleaning Up' in Tissue Engineering and Transpecies Transplantation. Social Theory & Health, 4, 1, 124. Kent, J. , Faulkner, A. , Geesink, I. , & Fitz. Patrick, D. (2006). Towards Governance of Human Tissue Engineered Technologies in Europe: Framing the case for a new regulatory regime. Technological Forecasting and Social Change, 73, 41 -60. Kent J, Faulkner A. (2002). Regulating human implant technologies in Europe – understanding the new era in medical device regulation. Health, Risk & Society, 4, 2, 190 -209. Faulkner A, Kent J. (2001). Innovation and regulation in human implant technologies: developing comparative approaches, Social Science and Medicine, 53, 895– 913.
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