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Regenerative medicine in Europe: political conflicts, economic biases, and legal loopholes

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

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Regenerative medicine in Europe: political conflicts, economic biases, and legal loopholes

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  1. 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

  2. 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

  3. CEO of World's Leading Regenerative Medicine Company, Organogenesis, Gives Keynote Address at World Congress of Regenerative Medicine in Germany. 5th 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)

  4. The Bioeconomy e.g. OECD report UK’s Life Science strategy 2011

  5. Social shaping of technology Regulatory politics • Regulation is innovative force • Regulatory classification • Interaction of materiality of RM and regulatory politics

  6. Social shaping of technology Regulation – rules of engagement of ‘technological zones’ (A. Barry) What does societal regulation do? - Performativity of law

  7. 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

  8. 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.

  9. Taxonomy - classification

  10. 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. 

  11. Classification - research sectors EC FP7 - ‘Health’ - ‘Regenerative medicine clinical trials’

  12. Regenerative medicine – material classifications and types • transplantation • Cell therapy -somatic/adult -hESCs -mesenchymal • Tissue engineering, tissue preparations • Gene therapy • [Combined therapy products] • Medical devices - decellularised products - non-manipulated cells

  13. Classificatory politics of RM sectors E.g. ‘cells as medicines’: ‘Regen: the industry responsible for cell-based therapies… universally recognised as an emerging new healthcare sector…’ C.Mason Cell Therapy and RMAdvisory Group

  14. 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 hESCs 97 products - 88 skin, bone or cartilage.

  15. Stakeholders, states and sectors European CommissionEnterprise - Biotechnology - Pharmaceuticals - Medical devices Health & Consumers European Parliament and committees Council of Ministers (member states positions) Regulatory bodies Donors; PatientsMedical professionalsCell/tissue banksScientists – developmental biology etc; scientific societiesBio-engineersHospitals, CharitiesCompanies

  16. EU regulation early-mid 2000s • 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 • ?????????hES cell therapy products

  17. The xenotransplant debate • ‘for another day’ - MEP in ENVI committee

  18. 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

  19. EC Issues, early 2000s • ‘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’

  20. 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

  21. 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)

  22. Tissue engineering and cell therapy regulation early 2000s Proposal 1

  23. Risk-based regulatory model proposed Tissue/cell provenance: autologous: national regulation allogeneic: EU central regulation

  24. 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’)

  25. One form of classification: commensuration ‘the comparison of different entities according to a common metric’ (Espeland & Stevens 1998)

  26. 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…’ (MacKenzie – 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 8th, 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.

  27. European Commission Enterprise and IndustryDirectorate-General BIO 2006 April 9-12, 2006 Genes, Cells and Tissues: Commission proposalon Advanced Therapies Georgette LALISDirector, European CommissionDG Enterprise & Industrygeorgette.lalis@cec.eu.int

  28. 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

  29. 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

  30. ‘Shared characteristics’ -commensuration strategy • “innovative manufacturing; • scarce scientific and industrial expertise; • the importance of traceability and risk management; • primary participation of small and medium-sized enterprises (SMEs), hospitals and tissue banks.”

  31. Legislation Medical Devices 93/42/EEC Medicinal Products Directive 2001/83/EC ? Advanced Therapies CellTherapy Gene Therapy Biotech Chemicals Medical Devices Tissue Engineering Tissue engineering and cell therapy regulation mid-2000s Proposal 2.

  32. Advanced Therapies - EU political conflict • Embryonic stem cells • ‘hybrid’ technologies

  33. Ethics and ‘Ethical issues’ HESCs and hybrids vs. Public health/medical advance

  34. 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).

  35. ‘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).

  36. 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).

  37. 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 Kingdomdelegations hold that the principal mode of action should be decisive. (Health Council of Europe Working Party on Pharmaceuticals & Medical Devices, 2006)

  38. 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).

  39. EU’s “Advanced Therapy Medicinal Products” (ATMP) Regulation 2007 (REG/1394/2007/EC)

  40. Main features of the Advanced Therapies Medicinal Products Regulation • Liberal regarding cell materials incl hESC 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

  41. Committee for Advanced Therapies’ work • Classification (60+) • Scientific advice • Certification SME (2) • Authorisation (recommendation) (2)

  42. 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:

  43. 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

  44. 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

  45. …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 1st 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

  46. Wound care technology- a regulatory cause célèbre

  47. The identity of Apligraf • Viable human cells (keratinocytes and fibroblasts) cultured from neonatal foreskin on a bovine-based collagen matrix

  48. The classification of Apligraf Regulation FDA – ‘medical device’ European Medicines Agency - ??? ATMP

  49. Effects of the ATMP Regulation Hospital exemption Hospital-based One-off Individually prescribed Non-standardised Non-industrial

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