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.
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)
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 FP7
- ‘Health’
- ‘Regenerative medicine clinical
trials’
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
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 hESCs
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 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
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 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’
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 2000s
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…’
(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.
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-2000s
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 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
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 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
Wound care technologya 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
• ChondroCelect
‘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
CellCoTec - 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
hESC research e.g:
–Cannot derive but can import hESClines(DE, IT);
–Allow procurement of hESC 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 hESC(HU,
SI);
–No specific hESC 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
European Genetic Alliances' Network
Association of Medical Research Charities
European Institute of Women's Health
British Heart Foundation
European Medical Research Councils
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 –
hESCs 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 hESC) 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, 2nd 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, 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, FitzPatrick 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, 227788.
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., & FitzPatrick, 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.