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  • SLIDE Within the context of human ESCs biovalue as such is still highly prospective rather than real as embryonic-derived products are still, to use an appropriate phrase, in their infancy. Most as this slide shows relate to the use of hESCs as a source of tissue to test the toxicity of new pharmaceutical compounds, and indeed in the UK, the Medical Research Council and Department of health recently established the Stem Cells For Safer Medicine (SC4SM) programme to fund experimental work to do precisely this. I have listed some of the main centres internationally that are developing these sorts of techniques and products, including one just down the road in Redfern .
  • Within the context of hESC there have been some interesting developments. Here I make a number of important observations about patent activity we have found that reflects the intellectual property response of companies to the moral position taken by the EPO in Munich. The EPO does not make a distinction between embryonic cells as toti compared with pluri-potent. This means that cell lines are seen to be able to generate whole persons, not just specific organs. While in the US The United States Patent and Trademark Office (USPTO) has, to date, granted over 50 patents that claim human embryonic stem (hES) cells in their title and front pages. These include patents on culture methods, differentiated cells derived from hES cells and even hES cells per se . By contrast, the European Patent Office (EPO) has not granted a single patent that makes direct hES cell claims. This reflects the major constraints imposed by the European Patent Convention (EPC), which prohibits the patenting of the "human embryo" on moral grounds As I note here – despite the Federal constraint on hESC research in the US, ironically it is easier to get a patent there than in Europe. One other point to note is that we can see the emergence of patent thickets that serve to secure commercial monopolies in the area: WARF is trying t do this with new IPS cells.
  • This slide simply gives you an idea of patenting by private compared with public (university/research organisation) sectors, here a UK/US regional comparison. It is quite interesting to note that despite the long-standing complaint about British universities being entrepreneurially weak the proportion of patents they are filing is much higher than the US, though in absolute terms is still of a lower number of course.
  • SLIDE – Overall, as Bergman and Graff have recently argued, we can say that 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’. This complexity makes for real difficulties among firms trying to secure some niche in the market, especially smaller ones, who have to embark on a considerable amount of cross-licensing to be able to make any headway with their product.

Innovation and health technologies: celling science - Newcastle ... Presentation Transcript

  • 1. Innovation and health technologies: celling science? Professor Andrew Webster, Director SATSU, University of York and of UK SCI KITE Seminar Series February 4 2009
  • 2. 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
  • 3. 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
  • 4. 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 medical data Gene/ disease associations Molecular diagnostics Gene therapy Regen Med
  • 5. 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 )
  • 6. 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?
  • 7. 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)
  • 8. 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.
  • 9. 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
  • 10. 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
  • 11. TE Firms by Country Source: Martin, 2008 Mesoblast, Melbourne
  • 12. Growth of TE Firms by Year Founded
  • 13. Primary Products by Disease Indication
  • 14. Worldwide 2008: 2185 RCTs using cell-based techniques Source: NIH: ClinicalTrials.gov
  • 15. Cumulative Growth in Launched Products
  • 16. Sales of skin & cartilage products $700m (170k patients) Medtronic
    • INFUSE (for treatment of degenerative (disc) disease)
    1,350 since 1996 Co.don
    • Chondrotransplant
    <$28m p.a. Genzyme
    • Carticel
    Bone graft/Cartilage 700 since 1987 Genzyme
    • Epicel
    $15m in 2003; relaunched 2007 Smith & Nephew/now Advanced Biohealing
    • Dermagraft (‘device’)
    $60m p.a. Organogenesis
    • Apligraf (‘medicine’)
    Skin Sales (2007) Company Product
  • 17. Hyped market sales
    • Dermagraft:
    • ‘ Skin replacement opens million dollar markets’ , Health Care Industry July 1992
    ‘ The firm's &quot;conservative revenue model&quot; 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-wide sales of tissue-engineered products probably not surpassing 60 million € in 2002. Source: IPTS, 2003
  • 18. Current world-wide sales Total sales $1.3b Source: M. LYSAGHT et.al. 2008 (TE, vol 14)
  • 19. Japan Tissue Engineering Co., Ltd. (J-TEC) Est: February 1, 1999 Capitalization: 5,543.45 million yen
  • 20. 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
  • 21. 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
  • 22. Technology Push: Beginning the 2 nd 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” coined 1986 ATS & Organogenesis founded 1988 SyStemix founded 1992 Geron founded 1997 First cell therapy FDA approved (Carticel ) 1997 Dolly the sheep 1998 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 approved 2001 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 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 Synthetic Biology?? (Source: Paul Martin)
  • 23.
    • 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 investment Exploitation of hESCs
  • 24. 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
  • 25. Patents in hESC domain 25% 75% USA 47% 53% UK 31% 69% Globally Public sector Private sector
  • 26.
    • ‘ 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)
  • 27. 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.
  • 28. Tissue engineering: allogeneic paradigm
  • 29. 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
  • 30. 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’?
  • 31. 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
  • 32. 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
  • 33.
    • Need to understand two things:
    • clinical relevance (what would make something worthwhile having?)
    • clinical practice (what organisational and cultural factors influence this?)
  • 34. Factors determining clinical relevance of TE products (source: Laboratoire D’Organogenese Experimental, Canada, 2007)
  • 35. 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
  • 36. 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
  • 37. ‘ 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
  • 38. 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
  • 39. Acknowledgements
    • Paul Martin, Institute for Innovation, University of Nottingham
    • SCI network ( www.york.ac.uk/res/sci )