Download Bone graft/Cartilage

Innovation and health technologies:
celling science?
Professor Andrew Webster,
Director SATSU, University of York and of UK SCI
KITE Seminar Series
February 4 2009
Outline
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The emergent tissue economy
Technology translation – an uneven story
The case of tissue engineering
Lessons and implications for innovation and
take-up of new TE/hESC therapies
• Conclusion
The emergent tissue economy
• Policy debates
– US OTA – Biotechnology in a Global Economy
(1991)
– UK BIGT ([Red] Biotechnology Innovation
and Growth Team) (2008)
– Australia – Innovation Review (2008)
• Globalisation of tissue production and
exchange (Waldby, 2006)
• Seen as driver for new biotech growth
The chain of economic biovalue creation
Primary
resources
Tissues
e.g. blood,
solid organs, skin,
bone, gametes
Extraction
& analysis
Tissue components,
stem cells &
cell lines
Engineering
Synthesis
Tissue engineering
Cell therapy
DNA, proteins
& other molecules
Protein engineering
Regen
Med
Gene sequencing
Gene therapy
Personal medical
data
Gene/ disease
associations
Molecular
diagnostics
Progress in the clinic
• Mixed progress in the clinical adoption of genomics and
biotechnology
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Therapeutic proteins
Monoclonal antibodies
Genetic tests (monogenic)
Cell therapies (non-stem cell)
Pharmacogenetics
Genetic tests (complex diseases)
Stem cell therapies (inc HSCs)
Therapeutic vaccines
Gene therapy
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(Martin and Morrison, ’Realising the Potential of Genomic
Medicine’ 2006)
Two possible explanations
• Failure to get new technologies into the clinic
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Genetic tests (complex diseases)
Therapeutic vaccines
Gene therapy
Stem cells
– Problems of proof of principle and safety
• Lack of uptake when new technologies reach
the clinic
• Cell-based therapies (non-stem cells)
• Pharmacogenetics (PGx)
– Relative utility?
Defining TE
“The application of principles and methods
of engineering and life sciences to develop
biological substitutes to restore, maintain,
or improve tissue function.” WTEC Panel, 2002
•
Core principle: Using engineering
principles and techniques to create
substitutes for organs and tissues
(i.e. replacing parts and functions)
Operationalising the definition (1)
• Two types of cell-based products
– Structural TE products/ applications
e.g. substitutes for skin, bone and cartilage;
– Metabolic TE products/ applications
e.g. functional substitutes of liver and pancreas
• Two generations of products
– First generation products based on non-stem
cell therapies, grafts and implants
– Second generation based on stem cells.
Operationalising the definition (2)
• Disease targets included
– Dermatology
– Opthalmic applications
– Aesthetic applications
– Bone and cartilage disorders
– Dental disorders
– Muscle disorders
– Cardiovascular disease
– Bladder and kidney disease
– Neurological disorders
– Metabolic disorders
Cell product/choice
All cell sources have different risks and
benefits concerning availability, immunogenicity,
pathogenicity, and quality. The choice of cells
will also influence product development time,
the regulatory framework to comply with and
marketing strategy
TE Firms by Country
Mesoblast, Melbourne
Australia, 3
Belgium, 1
Canada, 3
Denmark , 1
France , 4
Germany , 11
Israel, 2
Japan , 2
Norway , 1
S’gapore, 1
Slovenia , 1
South Korea , 1
Spain, 1
USA, 66
Sweden, 3
Switzerland, 2
UK, 11
Source: Martin, 2008
Growth of TE Firms by Year Founded
50
45
40
35
30
USA & Canada
25
Europe
Rest of World
20
15
10
5
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
1987
1986
≤1985
0
Primary Products by Disease Indication
2
1
Cartilage
Skin
Bone substitutes
Ophthalmic
13
8
Worldwide 2008: 2185 RCTs using cell-based techniques
Source: NIH: ClinicalTrials.gov
Cumulative Growth in Launched Products
8
7
6
5
Skin
4
Cartilage
Other
3
2
1
0
≤1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
Sales of skin & cartilage products
Product
Company
Sales (2007)
•Apligraf (‘medicine’)
Organogenesis
$60m p.a.
•Dermagraft (‘device’)
Smith & Nephew/now $15m in 2003;
Advanced Biohealing relaunched 2007
•Epicel
Genzyme
700 since 1987
•Carticel
Genzyme
<$28m p.a.
•Chondrotransplant
Co.don
1,350 since 1996
Skin
Bone graft/Cartilage
•INFUSE (for treatment of Medtronic
degenerative (disc) disease)
$700m (170k
patients)
Hyped market sales
Market
estimates for tissue-engineered products have been very
Dermagraft:
promising, ranging from 80 billion € for the USA alone
‘Skin replacement
million
dollar (Langer
(MedTech
Insight, 2000) opens
to 400 billion
€ worldwide
markets’,
Care Industry
July
1992 a
& Vacanti,
1993).Health
More moderate
estimates still
calculated
global market of 3.9 billion € by 2007 (Business
Communication Company, 1998) or of 270 million € by 2007
‘The firm's "conservative revenue model" predicted
for skin products alone (MedMarket Diligence, 2002).
first-year Dermagraft sales of $37 million and 1998
sales of $125 million. An aggressive model estimated
The reality provides much lower figures with world-wide
sales of $280 million by 1998.’
sales of tissue-engineered products probably not surpassing 60
million € in 2002.
Source: IPTS, 2003
Current world-wide sales
Total sales $1.3b
Source: M. LYSAGHT et.al. 2008 (TE, vol 14)
Japan Tissue Engineering Co., Ltd.
(J-TEC)
Est: February 1, 1999
Capitalization: 5,543.45 million
yen
Summary
• The number of firms has remained stable over the
last five years, but a high level of turnover
• Sub-sectoral structure is slowly changing following
shift to stem cells in early 2000s
• Geographically concentrated
• Relatively mature, but problem with firm growth
• Healthy number of products, but relatively poor
sales apart from a few dominant ones
• Narrow development pipeline
• Few collaborations with large firms
The Gartner Curve
Gartner ‘hype cycles’ are said to distinguish hype from
reality, so enabling firms to decide whether or not to enter
the market
Technology Push: Beginning the 2nd Half of the Gartner Curve?
Visibility
Trough of
Disillusionment
Peak of Inflated
Expectations
Slope of
Enlightment
Plateau of
Productivity
2001: 3000 jobs, 73 firms, mkt cap > $3B
2000 Time Magazine:
TE No. 1 job
2001 Ortec FDA approved
2001 TE blood vessel enters clinic
2001 Dermagraft FDA approved
2002 ISSCR founded
1999 Intercytex founded
1999 TE bladders in clinic
1999 First TE product FDA
approved (Apligraf)
2001 Bush “partial ban” on HESCs
Synthetic Biology??
1998 Plan to build human heart in 10 years
1998 Human ESCs first derived
1997 Dolly the sheep
1997 First cell therapy
FDA approved (Carticel)
1992 Geron
founded
1988 SyStemix founded
1986 ATS & Organogenesis founded
1985 Term “TE” coined
1980 Early TE research (MIT)
2002 ATS + Organogenesis file
Chapter 11
Technology Trigger
2003 UK Stem Cell Bank set up
2005 CIRM founded
2006 Carticel - 10,000 patients
2006 hESCs derived without harming embryo
2006 Batten’s Disease trial
2006 Reneuron file IND for stroke trial
2007 Apligraf - 200,000 patient therapies
2007 Mouse fibroblast to mESCs
2007 Intercytex start Phase 3 ICX-PRO
2007 Osiris Named Biotech Co. of the Year
2008 Geron expected to file IND - spinal cord
Stage of Development
(Source: Paul Martin)
hESCs and investment
Exploitation of hESCs
hESCs:
- currently (in short to medium term) hESCs
used in drugs testing and medicines development:
as disease models to explore pathology of
disease; as drug screens for toxicity or efficacy
e.g Roslin Cells Centre, (Edin); ES Cell
International (Singapore); Cellartis (Gothenburg);
Invitrogen (California); HemoGenix (Sydney)
Patenting activity in hESC
• Patent applicants are going via national offices
such as the UKIPO to file and secure patents on
pluripotent lines, short-circuiting the EPO in
Munich which conflates toti and pluri potent lines
• So, ironically, it is much easier to obtain patent
protection on hESCs in the US than in Europe.
• Most recent data on stem cell patents reveals a
dramatic growth in the number of stem cell patent
applications suggesting the field is ripe for the
emergence of a stem cells ‘patent thicket’ and
blocking monopolies
Patents in hESC domain
Private sector
Public sector
Globally
69%
31%
UK
53%
47%
USA
75%
25%
• ‘The technical content of the patent landscape is
highly complex. Stem cell lines and preparations,
stem cell culture methods and growth factors show
the most intense patenting activity but also have
the most potential for causing bottlenecks, with
component technologies expected to show high
degrees of interdependence while being widely
needed for downstream innovation in stem cell
applications.’ (Source Bergman and Graff, Nature
biotech 2007)
Key questions
• What were/are the difficulties faced by TE
innovation?
• What sort of business model: e.g. ‘product’
or ‘service’
to ‘cryovial
Different
businessbased
models:(akin
Allogeneic
products amendable to
large-scale
manufacturing
at single sites
products’
vs IVF clinic)
•Autologous
Allogeneic
vs autologous
therapies?
therapies
more of a service
industry, with a heavy
emphasis on local or regional cell banking.
Tissue engineering: allogeneic paradigm
Why slow adoption of TE?
• Multiple reasons
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High cost of manufacturing & distribution
Lack of evidence base – cost-effectiveness
No better than established alternatives and more costly
Wrong product (e.g. skin thickness, storage) & poor
choice of disease/ clinical target
– Problems fitting products into established routines
– Linked problems of storage and delivery on demand
• Central issue of clinical utility not being taken into
account in product specification and design
• Regulatory hurdles
Regulatory issues
Scale-up via automation a key issue:
•consistency in bio-processing and in therapeutic
results (GMP as basis for stable product)
•a scale-up that works – automation (mix of mass and
customised products?), and delivery system which
has regulatory approval
•measures of cost effectiveness
•‘regulatory intelligence’: e.g. assignment to specific
classification categories will funnel products into
varying regimes of risk and functionality – eg are TE
products a ‘device’ vs ‘medicine’?
Lack of user-producer links
• Data on development of first generation
products suggests lack of interaction between
developers and users
• Small science-based firms adopted rather
linear model – poor understanding of user
needs
• Success of Apligraf (Organogenesis) only
after changed specification based on user
feedback because of changed business model
Clinical utility
• Acceptance only possible if new technology
demonstrates clear benefit over current
practice
• Utility is framed by context: e.g
administration of the cell product (compare
diabetes with spinal injury)
• Utility constructed within existing work
practices, routines, infrastructures and
constrained by resources
Need to understand two things:
• clinical relevance (what would make
something worthwhile having?)
• clinical practice (what organisational and
cultural factors influence this?)
Factors determining clinical relevance of TE products (source:
Laboratoire D’Organogenese Experimental, Canada, 2007)
The nature of clinical practice
• Medical work is deeply embedded in entrenched
socio-technical regimes shaped by:
– Management of complexity and uncertainty (about body
and disease)
– Established routines and interventions
– Existing technical infrastructures (therapies, diagnostics)
– Organisation of services and care
– Rationed access to resources
• Medical knowledge is much more than the appliance
of science
– Other forms of knowledge are key and are only produced in
particular clinical settings e.g. experience of disease,
routines and protocols, practice style, complementary
technologies, assessment of cost-benefit
Addressing market failure
• Reimagining the innovation process in therapeutics
– Key role of public research in early stage clinical
development – major source of innovation even in
pharmaceuticals (see PUBLIN project – I.Miles)
– Translational research as complex two-way flow of
knowledge between bench and bedside
– Better understanding of clinical need and delivery
• New division of labour between public/ private
sector
– Change in policy focus – underwriting risk, cost &
benefit sharing, greater steering to maximise public
health gains?
– Creating public sector innovation infrastructure
‘Celling science’: lessons for stem
cells
• Successful embedding for both products and
therapies (whether hESC-based) will require:
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Overcoming major technical problems
Good product specification & design (user input)
Careful choice of clinical target (user input)
Scale manufacturing
Investment from pharma/ device companies
Evidence base (cost-effectiveness) – also key
issue for reimbursement and insurance
– Integration into existing practices & institutions
Conclusion
• Challenges and opportunities of regen med defined
differently across globe; ethical and practical concerns
express different priorities and shape innovation patterns
• Considerable scientific and clinical work needed to be
done to produce robust, workable therapies
• Commercial interest in cells been cautious in ‘west’,
expanding in ‘east’ – but iPS likely to change this
• Need to recognise role of public sector in innovation
• Some regulatory convergence in Europe but still highly
sensitive and politicised issue
Acknowledgements
• Paul Martin, Institute for Innovation,
University of Nottingham
• SCI network (www.york.ac.uk/res/sci)