innovation and health technologies: celling science - newcastle
TRANSCRIPT
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
• 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
Primary resources
Extraction & analysis
Engineering Synthesis
Tissues e.g. blood,
solid organs, skin,bone, gametes
Gene sequencing
Tissue components,stem cells &
cell lines
Cell therapy
DNA, proteins& other molecules Protein engineering
Tissue engineering
The chain of economic biovalue creation
Personal medicaldata
Gene/ disease associations
Molecular diagnostics
Gene therapy
Regen Med
Progress in the clinic• Mixed progress in the clinical adoption of genomics and
biotechnology– 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 -
(Martin and Morrison, ’Realising the Potential of Genomic Medicine’ 2006)
Two possible explanations
• Failure to get new technologies into the clinic• 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 andbenefits concerning availability, immunogenicity,pathogenicity, and quality. The choice of cellswill also influence product development time,the regulatory framework to comply with andmarketing strategy
TE Firms by Country
Norway , 1
S’gapore, 1Slovenia , 1
South Korea , 1
Spain, 1
Sweden, 3
Switzerland, 2
UK, 11
Japan , 2
Israel, 2
Germany , 11
Canada, 3Denmark , 1
France , 4
Belgium, 1
Australia, 3
USA, 66
Source: Martin, 2008
Mesoblast, Melbourne
Growth of TE Firms by Year Founded
0
5
10
15
20
25
30
35
40
45
50
≤198
5
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
USA & CanadaEuropeRest of World
138
21
CartilageSkinBone substitutesOphthalmic
Primary Products by Disease Indication
Worldwide 2008: 2185 RCTs using cell-based techniques
Source: NIH: ClinicalTrials.gov
Cumulative Growth in Launched Products
0
1
2
3
4
5
6
7
8
≤1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
SkinCartilageOther
Sales of skin & cartilage productsProduct Company Sales (2007)Skin•Apligraf (‘medicine’) Organogenesis $60m p.a.•Dermagraft (‘device’) Smith & Nephew/now
Advanced Biohealing $15m in 2003; relaunched 2007
•Epicel Genzyme 700 since 1987
Bone graft/Cartilage•Carticel Genzyme <$28m p.a.•Chondrotransplant Co.don 1,350 since 1996•INFUSE (for treatment of degenerative (disc) disease)
Medtronic $700m (170k patients)
Hyped market sales
Dermagraft:‘Skin replacement opens million dollar
markets’, Health Care Industry July 1992
‘The firm's "conservative revenue model" predicted first-year Dermagraft sales of $37 million and 1998 sales of $125 million. An aggressive model estimated sales of $280 million by 1998.’
Market estimates for tissue-engineered products have been very promising, ranging from 80 billion € for the USA alone (MedTech Insight, 2000) to 400 billion € worldwide (Langer& Vacanti, 1993). More moderate estimates still calculated a global market of 3.9 billion € by 2007 (Business Communication Company, 1998) or of 270 million € by 2007 for skin products alone (MedMarket Diligence, 2002).
The reality provides much lower figures with world-widesales 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?
Stage of Development
Visibility
Technology Trigger
Peak of Inflated Expectations
Trough of Disillusionment
Slope of Enlightment
Plateau of Productivity
1980 Early TE research (MIT)
1985 Term “TE” coined1986 ATS & Organogenesis founded
1988 SyStemix founded
1992 Geronfounded
1997 First cell therapyFDA approved (Carticel)
1997 Dolly the sheep1998 Human ESCs first derived
1998 Plan to build human heart in 10 years
1999 First TE product FDA approved (Apligraf)
1999 TE bladders in clinic
1999 Intercytex founded
2000 Time Magazine:TE No. 1 job
2001 Bush “partial ban” on HESCs
2001 Dermagraft FDA approved2001 TE blood vessel enters clinic
2001 Ortec FDA approved
2001: 3000 jobs, 73 firms, mkt cap > $3B
2002 ISSCR founded
2002 ATS + Organogenesis file Chapter 11
2003 UK Stem Cell Bank set up2005 CIRM founded2006 Carticel - 10,000 patients2006 hESCs derived without harming embryo2006 Batten’s Disease trial2006 Reneuron file IND for stroke trial2007 Apligraf - 200,000 patient therapies2007 Mouse fibroblast to mESCs2007 Intercytex start Phase 3 ICX-PRO2007 Osiris Named Biotech Co. of the Year2008 Geron expected to file IND - spinal cord
Synthetic Biology??
(Source: Paul Martin)
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)
hESCs and investmentExploitation of hESCs
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’ based (akin to ‘cryovial products’ vs IVF clinic)
• Allogeneic vs autologous therapies?
Different business models: Allogeneic products amendable to large-scale manufacturing at single sites
Autologous 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– 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 issuesScale-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:– 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)