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Innovation and health technologies: celling science?

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Title: Innovation and health technologies: celling science?


1
Innovation and health technologies celling
science?
Professor Andrew Webster, Director SATSU,
University of York and of UK SCI
Australian Centre for Innovation and
International Competitiveness August 19 2008
2
Outline
  • The emergent bioeconomy
  • 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 bioeconomy
  • Policy debates
  • US OTA Biotechnology in a Global Economy (1991)
  • UK BIGT (Red Biotechnology Innovation and
    Growth Team) (2008)
  • Australia Innovation Review (2008)
  • Biotech as key part of knowledge economy
  • Potential for wealth creation through development
    of new high tech products, industries and jobs

4
The chain of economic biovalue creation
Primary resources
Extraction analysis
Engineering
Synthesis
Tissue engineering
Tissues e.g. blood, solid organs, skin, bone,
gametes
Tissue components, stem cells cell lines
Cell therapy
Regen Med
DNA, proteins other molecules
Protein engineering
Gene sequencing
Gene therapy
Personal medical data
Gene/ disease associations
Molecular diagnostics
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)
  • Why the lack of demand?

7
The engineering principle in biology
  • Long tradition of conceiving body in mechanical
    terms in which parts can be exchanged and
    replaced artificially
  • e.g. Prosthetics, mechanical organs, military
    cyborgs
  • Birth of tissue engineering (TE) in mid-1980s
  • Institutionalised in 1990s, but eclipsed by and
    integrated into regenerative medicine in 2000s

8
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)

9
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.

10
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

11
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

12
TE Firms by Country
Mesoblast, Melbourne
Source Martin, 2008
13
Growth of TE Firms by Year Founded
14
Primary Products by Disease Indication
15
Worldwide 2008 2185 RCTs using cell-based
techniques
Source NIH ClinicalTrials.gov
16
Cumulative Growth in Launched Products
17
Sales of skin cartilage products
Product 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 lt28m p.a.
Chondrotransplant Co.don 1,350 since 1996
INFUSE (for treatment of degenerative (disc) disease) Medtronic 700m (170k patients)
18
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.
19
Current world-wide sales
Total sales 1.3b
Source M. LYSAGHT et.al. 2008 (TE, vol 14)
20
Japan Tissue Engineering Co., Ltd. (J-TEC) Est
February 1, 1999 Capitalization 5,543.45 million
yen
21
A relatively mature industry
  • Large number (40) of primary firms founded more
    than 10 years ago, with 30 listed on public
    markets
  • Significant number have products on the market or
    in clinical development
  • But 90 are small with lt100 staff and only four
    companies are large with gt500 staff
  • High level of company failure

22
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

23
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
24
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 gt 3B
2000 Time MagazineTE 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 therapyFDA approved (Carticel)
1992 Geronfounded
2003 UK Stem Cell Bank set up 2005 CIRM
founded 2006 Carticel - 10,000 patients 2006
hESCs derived without harming embryo 2006
Battens 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
1988 SyStemix founded
1986 ATS Organogenesis founded
1985 Term TE coined
2002 ATS Organogenesis file Chapter 11
1980 Early TE research (MIT)
Technology Trigger
Stage of Development
25
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)

26
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

27
Patents in hESC domain
Private sector Public sector
Globally 69 31
UK 53 47
USA 75 25
28
  • 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)

29
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.
30
Tissue engineering allogeneic paradigm
31
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

32
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?

33
Lack of user-producer links
  • Preliminary 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

34
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

35
  • Need to understand two things
  • clinical relevance (what would make something
    worthwhile having?)
  • clinical practice (what organisational and
    cultural factors influence this?)

36
Factors determining clinical relevance of TE
products (source Laboratoire DOrganogenese
Experimental, Canada, 2007)
37
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

38
Australian Innovation review
  • Bio21 Cluster argues for
  • an innovative entity based on the highly
    successful Centre for Integration of Medicine and
    Innovative Technology (CIMIT, www.cimit.org) in
    Boston, USA. CIMITs mission is to improve
    patient care by bringing scientists, engineers
    and clinicians together to catalyse development
    of innovative technology. They are interested in
    developing international affiliations and have
    recently worked with the North West of the UK to
    establish MIMIT in Manchester

39
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40
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

41
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

42
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/Australia
    but still highly sensitive and politicised issue

43
Acknowledgements
  • Paul Martin, Institute for Innovation, University
    of Nottingham
  • SCI network (www.york.ac.uk/res/sci)
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