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

1
Regenerative medicine in Europe political
conflicts, economic biases, and legal loopholes

• Alex Faulkner
• Centre for Global Health Policy
• University of Sussex
• a.faulkner_at_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
• UKs 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
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11
Socioeconomic classification

• Three dimensions of socioeconomic
  classification1. 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. 

12
Classification - research sectors

• EC FP7
• - Health
• - Regenerative medicine clinical trials

13
Regenerative medicine material classifications
and types

• transplantation
• Cell therapy -somatic/adult -hESCs -mesenchym
  al
• Tissue engineering, tissue preparations
• Gene therapy
• Combined therapy products
• Medical devices - decellularised products -
  non-manipulated cells

14
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
15
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.

16
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

17
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

18
The xenotransplant debate

• for another day - MEP in ENVI committee

19
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

20
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 Parliaments) proposals
  were thrown out because they concerned matters of
  ethics
• Localising the ethical problems will..
  jeopardise the basic right of physical integrity

21
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

22
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)

23
Tissue engineering and cell therapy regulation
early 2000s

• Proposal 1

24
Risk-based regulatory model proposed

• Tissue/cell provenance
• autologous national regulation
• allogeneic EU central regulation

25
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)

26
One form of classification commensuration
the comparison of different entities
according to a common metric (Espel
and Stevens 1998)
27
Commensuration designing markets
process of making goods measurable and
comparablestandardization 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.
28
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_at_cec.eu.int
29
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

30
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
31
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.

32
Tissue engineering and cell therapy regulation
mid-2000s Proposal 2.
33
Advanced Therapies - EU political conflict

• Embryonic stem cells
• hybrid technologies

34
Ethics and Ethical issues

• HESCs and hybrids
• vs.
• Public health/medical advance

35
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).

36
Mode of action sectoral conflicts

• say a heart valve covered by cells. .. the
  main mode of action isnot the cells, its 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).

37
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
  Serviceswritten response to EC Consultation, May
  2005).

38
Mode of action politics

• The Presidency has also suggestedall 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)

39
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).

40

EUs Advanced Therapy Medicinal Products (ATMP)
Regulation 2007 (REG/1394/2007/EC)
41

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

42
Committee for Advanced Therapies work

• Classification (60)
• Scientific advice
• Certification SME (2)
• Authorisation (recommendation) (2)

43
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

44
The laws effects

• Stabilising a sector / zone?
• Harmonisation of states regulation
• Loophole of hospital exemption?
• Lack of incentive for hospital/academic sector
• Complexity of regulatory system

45
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

46
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/b
  logposts

47
Wound care technology- a regulatory cause
célèbre

48
The identity of Apligraf

• Viable human cells (keratinocytes and
  fibroblasts) cultured from neonatal foreskin on a
  bovine-based collagen matrix

49
The classification of Apligraf

• Regulation
• FDA medical device
• European Medicines Agency - ??? ATMP

50
Effects of the ATMP Regulation

• Hospital exemption
• Hospital-based
• One-off
• Individually prescribed
• Non-standardised
• Non-industrial

51
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).

52
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
  stem-cell 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)

53
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)

54
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

55
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56
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

57
Regenerative device for cartilage repair
CellCoTec - A revolutionary approach to cartilage
repair
58
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

59
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

60
Effects of ATMPproliferating 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)

61
Effects of the ATMP Regulation as legislative
text/document

• Represents EU/EC/EP RM world-view
• Legislative Articles and non-legislative
  rationale
• Textual analysis

62
RM in the text of the ATMP regulation

• Industry 1, undefined
• Firms, hospitals?
• public confidence
• Patients? Citizens?

63
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

64
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

65
ATMP summary

• Conflicts
• Biases
• Loopholes
• Some harmonisation standardisation

66
Human embryonic stem cells
67
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68
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69
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
70
Stem cell therapy as commodities? - EU law

• the politics of biotechnology at the EU was
  subordinatedto that of the member states. Basic
  questions about the acceptability of
  biotechnologys products and the allowable forms
  of debate concerning them remained national in
  character (Jasanoff 2005
  280 cited in Kent,2012)

71
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

72
1999
-Extraction of neural precursor cells
73
Oliver Brüstle
74
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75
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

76
Politics of patenting

• Letter of protest at Brustle case threat to stem
  cell funding in EUs Horizon 2020 funding
  programme

77
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.Europes 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.

78
EU parliamentary politics hESCs in Horizon 2020

• Opposition continues
• Majority of Council remain in favour

79
Concluding Regulatory connection

• Product regulation - ATMP biases, poorly aligned
  to sectoral interests
• Property/patent regulation - material
  definitions (in hESC) are evolving and
  re-classifiable

80
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!

81
Thank you!

• a.faulkner_at_sussex.ac.uk

82
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 Laws
  Shaping of Medical Technology.Law, Innovation and
  Technology, 4(2) 165184.
• Faulkner A. (2012) Laws 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

83
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, 73.
• 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, 195-222.
• 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.

84
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, 1-24.
• 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, 895913.