Innovation and health technologies: celling science?

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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
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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

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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

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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
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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)

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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?

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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

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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)

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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.

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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

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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

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TE Firms by Country
Mesoblast, Melbourne
Source Martin, 2008
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Growth of TE Firms by Year Founded
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Primary Products by Disease Indication
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Worldwide 2008 2185 RCTs using cell-based
techniques
Source NIH ClinicalTrials.gov
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Cumulative Growth in Launched Products
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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)
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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.
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Current world-wide sales
Total sales 1.3b
Source M. LYSAGHT et.al. 2008 (TE, vol 14)
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Japan Tissue Engineering Co., Ltd. (J-TEC) Est
February 1, 1999 Capitalization 5,543.45 million
yen
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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

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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

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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
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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
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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)

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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

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

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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.
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Tissue engineering allogeneic paradigm
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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

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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?

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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

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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

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

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

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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

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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

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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

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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

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Acknowledgements

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