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Commercialisation of Biosensors
Anthony P F Turner Biosensors & Bioelectronics Centre
IFM-Linköping University
Biosensor Technology TFTB34, Linköping, Tuesday19 February 2013
Outline
• Commercialisation: ingredients and hurdles • Market pull • Technology push • Home blood glucose monitors • Continuous blood glucose monitoring (CBGM) • Non-invasive glucose monitoring • Future markets • Conclusions
Ingredients for Commercialisation
• Market need • Protectable technology • Clear ownership • Platform technology or • …marked improvement • Entrepreneurship of inventors or commercialisation team
Intellectual Property Protection
• PATENTS e.g. methods & apparatus • COPYRIGHTS e.g. text, pictures & software • TRADE SECRETS i.e. technical know-how • DATABASE RIGHTS • DESIGN RIGHTS
© Copyright APF Turner 2011
Regulation and Litigation • Regulatory bodies can drastically change the product landscape e.g.
FDA & the maltose problem with GDH which hit Abbott & Roche products
• The mature glucose biosensors field is currently typified by litigation by the four dominant players against each other and the medium sized companies threatening to take market share. A series of expensive suits have been filed, some being settled out of court by substantial payments and others going to high profile trials
• In 1999 in the USA, Biacore (now GE) successfully asserted its carboxymethylated dextran patent against Thermo. In 2005, Roche asserted its proprietary position in Cotrell Current amperometric biosensors against Apex/Hypoguard and the Roche patent was declared invalid; in 2008, Abbott asserted 4 of its glucose sensor patents against Roche, Bayer, Matsushita, BD and Nova; it lost all four cases! Roche then filed suit against its competitors based on its <1µl and <5 secs claims. Once again, the cases were lost, but the battles continue.
Lord Wolf, DSc Cranfield
Professional Uptake • Sometimes there has been slow uptake of novel
technologies caused by cautious or conservative attitudes amongst professionals. These attitudes may often be rooted in culture and education and can vary greatly from country to country.
• Near-patient monitoring was initially resisted heavily by clinical chemists concerned by quality control issue associated with a shift away from centralised facilities
• Effective communication to healthcare educators and the medical community in general of the benefits of novel technologies is always essential
• A highly self-educated community living with a chronic disease like diabetes mitigates against conservatism
The Climate for Investment • Bioscience & Healthcare is a fundamental sector for private equity venture funds; it is
also one of the most challenging due to complex scientific development intricacies, a politically influenced regulatory environment and the cyclical nature of clinical developments
• These sectors are a venture sector inherent with risk. Nevertheless, sectors including biotechnology, pharmaceuticals and medical devices are proving increasingly attractive to private equity investors given their potential to dislocate existing billion dollar markets
• Private equity funds focused on life sciences raised in excess of 17 billion (USD) in 2007 and 28 billion (USD) in 2008, but far less in 2009, largely as a consequence of market conditions affecting private equity fund managers’ ability to attract capital for their vehicles (Evolution LS Ltd.). Recovery is still slow.
Reimbursement • Reimbursement for new systems can be a major
challenge and a major disincentive in investing in R&D
• A new paradigm for glucose monitoring, for example, will face challenges in established reimbursement systems for lancing and measurement
• Reimbursement schemes currently vary widely from country to country, and patient access can even vary within a country
• Reimbursement prices may be forced down (eg. Germany) or new technology refused (eg. implantable defibrillators in France and Pelikan Technologies’ painless blood sampler)
Diabetes Diagnostics: A Special Case
Newman, J.D. and Turner, A.P.F. (2005). Home blood glucose biosensors: a commercial perspective. Biosensors and Bioelectronics 20, 2435-2453.
Diabetes Prevalence • Diabetes is an immense and growing public health issue:
• The fastest growing chronic disease in the World; expected to double in prevalence by 2030
• Afflicts around 2% of the world’s population & 6% of the adult population of the western world
• 170 m diabetics worldwide, 27 m diagnosed
• In the USA, 8% of all citizens and 18% of Senior Citizens afflicted
• Asia now has the bulk of cases with four of the world's five largest diabetic populations – India (33 m), China (23m), Indonesia (9m) and Japan (7m) cases
• There is no known cure
The Diabetes Health Care Space
IMS and EAC data - 2004
$0.35B
$5.6B
$12.1B
$5.2B
Insulin
Oral Anti-Diabetics
Blood Glucose Monitoring
Lancets and other paraphernalia
Source: Frost & Sullivan
Diabetes – Influential Studies - DCCT
• Intensive therapy (including frequent monitoring of glucose) can reduce the risk of complications by 60%
• Intensive therapy increases the risk of hypoglycaemia
• All diabetics should benefit in the longer term by improved monitoring and control of blood glucose
• Diabetes Control and Complications Trial. New England Journal of Medicine, 329(14),1993 http://diabetes.niddk.nih.gov/dm/pubs/control/
• American Clinical Diabetes Educators estimated that in 2009, 37% of their Type 1 patients are using CGM, compared to only 7% in 2008
• Growing acceptance and adoption of CGM is presumably fuelled by a large amount of clinical data that has been published in the past year (the NEJM published the JDRF trial October 2, 2008) underscoring the clinical utility of CGM
• If it was widely available and reimbursed (for the device and healthcare provider time), Educators would put the following patients on GCM:
Growing Acceptance of CGM
Annual AADE Survey, Close Concerns (2009)
YEAR TYPE 1 TYPE 2 2009 91% 58% 2008 69% 35% 2007 33% 0%
Biosensors: World Market Drivers
0
2000
4000
6000
8000
10000
12000
14000
1995 2000 2005 2010
Sal
es (
$ M
illio
n)
DCCT
CBGM & New Markets
A conventional enzyme electrode
16
The YSI Analyser
1500 Sport Analysers
17
Enzyme Electrode Reactions
Yellow Springs Instrument Company Inc (YSI)
Glucose Biosensor 1975
YSI, Ohio 1987
The original YSI serum-glucose biosensor for diabetes clinics 1975
Clark, LC & Lyons, C (1962). Annals New York Academy of Sciences 102, 29.
1987
2
A brief chronology of home testing for glucose
Urine testing using, for example, Clinitest Reagent Tablets (1941) followed by visually read paper test strips for urine (1956)
Visually read paper strip for blood glucose (1964)
Instrument to measure paper strip by reflectance of light (1969)
First electrochemical home blood glucose monitor (1987)
First devices to fill by capillary action: Medisense QID (1995); Bayer / KDK / Menarini (1996)
20
Ames Reflectance Meter Tom Clemens work led to the Ames Reflectance Meter. Ames was a division of Miles and is now part of Bayer. Work started in 1966, four years after Clark’s description of the glucose biosensor, but development of the reflectometer was much faster. A U.S. patent (no. 3,604,815) was granted on September 14, 1971, about two years after it went on the market. The original Meter was expensive, large and heavy, (approx 1 Kg) and required a prescription. Despite this, it was a success and eventually led to the Eyetone, then to the Ames Glucometer and eventually to the great variety of other products.
21
Mediated Enzyme Electrode
Cass, A.E.G., Davis, G., Francis, G.D., Hill, H.A.O., Aston, W.J., Higgins, I.J., Plotkin, E.V., Scott, L.D.L. and Turner, A.P.F. (1984) Ferrocene-mediated enzyme electrode for amperometric determination of glucose. Analytical Chemistry 56, 667-671.
Glucose oxidase or PQQ Glucose Dehydrogenase
22
Ferrocene-Mediated Amperometric Biosensors
1981 1983
1982
23
Mediated Amperometric Glucose Sensors
MediSense ExacTech™ 1987: Ferocene
Johnson & Johnson Lifescan FastTake™ 1998: Hexacyanoferrate
Roche Diagnostics
Lifescan
Bayer Diagnostics
Abbott
Nova biomedical
Others
China
Biosensors: $13b Market
Share
Beijing Yicheng JPS-5
Roche Accu-Check Aviva Nano
Lifescan OneTouch Ultra
Bayer Contour
Abbott FreeStyle Lite
The Market leaders in Glucose Biosensor Sales
Capillary-fill Biosensors 1996 et sequa
1995
Kyoto Daiichi, Japan (& made for Menarini, Italy and Bayer circa 1996)
Unilever, UK 1987 Kyoto Daiichi, Japan
Mass Production: Screen Printing
Mass Production: Sputtering & Lamination
Key Electrode Designs Classical top-fill design
Substrate: e.g. Mylar™ Polyethylene terephthalate (PET)
Conducting tracks: Silver & Carbon ink
Ag/AgCl reference/ counter electrode
Working electrode: Carbon, mediator, enzyme, binder (e.g PEO: polyethylene oxide) & surfactant
Dielectric (insulator)
CONTACTS
SAMPLE to meter
Key Electrode Designs Capillary-fill design
Substrate: e.g. Mylar™ Polyethylene terephthalate (PET)
Conducting tracks: Silver & Carbon ink
Ag/AgCl reference/ counter electrode
Working electrode: Carbon, enzyme, binder (e.g PEO: polyethylene oxide) & surfactant
Dielectric (insulator)
CONTACTS
SAMPLE to meter Spacer Soluble mediator
Key Electrode Designs
Auto on
Sample detect Fill detect
Automation and error correction
+ = haematocrit compensation via fill rate
More Sophisticated Designs
MediSense Precision QID with laminated sequence for ”wicking”
Bayer Breeze 2 screen-printed electrodes with hexacyanoferrate: sample detect, 1µl, 5 secs, no coding
Acencisia Contour laser ablated sputtered Pd electrodes with complex electrode sequence
The Fully-printed Glucose Sensing System
Turner, A.P.F. (2013) Biosensors: sense and sensibility. Chemical Society Reviews DOI:10.1039/C3CS35528D
Short Break
Outline
• Commercialisation: ingredients and hurdles • Market pull • Technology push • Home blood glucose monitors • Continuous blood glucose monitoring (CBGM) • Non-invasive glucose monitoring • Future markets • Conclusions
Unknown cause (34) Meter malfunction (11) False High Results (11)
Diabetic Ketoacidosis (8) Maltose/non-glucose interference (13)
Use on Critically Ill Patient (6) False Low results (6) Possible Medication Interference (5) Renal patient (2) Dehydration (1) Hyperosmolar Hyperglycemia (1) Feeding tube –glucose (1) Neonatal death (1)
1992-2009: 100 deaths associated with glucose meters reported
Adverse Events - Deaths
Source: C.C. Harper (FDA)
GDH-PQQ Problems GDH-PQQ (glucose dehydrogenase pyrroloquinoline quinone) Glucose Monitoring Technology Audience: Diabetes healthcare professionals, hospital risk managers, patients [Posted 08/13/2009] FDA notified healthcare professionals of the possibility of falsely elevated blood glucose results when using GDH-PQQ glucose test strips on patients who are receiving therapeutic products containing certain non-glucose sugars. These sugars can falsely elevate glucose results, which may mask significant hypoglycemia or prompt excessive insulin administration, leading to serious injury or death.
The specificity of GDH-FAD and GDH-PQQ
The Move to Integration
Ascensia® AUTODISC® loads the meter with 10 tests at a time
Accu-Check Compact – Preloaded drum of 17 strips
Hypoguard 100 test strips In disposable meter
Pelikan integrated 50 sensor cartridge and electronic lancing system
Roche Strip-free Glucose Sensing
Accu-Chek Compact Plus / Accu-Chek Mobile (2012) • Glucose meter system with no strips to handle and integrated lancing device. • Everything together: a test strip cartridge, no coding, a detachable lancing device, and easy,
one-handed operation. • 50 Strip-free tests on a continuous tape – no single strips to handle or dispose of • 6 lancets in a drum – no single lancets to see or touch
• Bayer’s DIDGET™ blood glucose meter plugs into a Nintendo DS™ or Nintendo DS™ Lite system
• This helps encourage consistent testing with reward points that children can use to buy items and unlock new game levels
The Importance of the User Interface
Blood Glucose: “We’ve got an App For That”
Lifescan popularised the iPhone route 2009
AgaMatrix Nugget iPhone
plug-in glucose meter gained FDA 510(k) 2011, marketted by Sanofi Aventis with iBGStar app, 2012.
Key Product Features
e.g. LifeScan’s One Touch Vario incorporating technology developed by Universal Biosensors (UBI) and manufactured in Rowville, Melbourne, Australia, launched in the Netherlands in January 2010: • 0.45µl • Side-loaded sample • No Code • Results in 5 seconds • Accurate to within ±15%
Current Paradigm of Blood Glucose Monitoring
Load lancet into launcher and
reassemble launcher
Prick finger or arm
Deposit blood drop on to test strip &
insert strip
Read test strip
Dispose of materials
1-2 Minutes
Burdensome and lengthy process is impediment to high compliance
Insulin Therapy
Diabetes Mellitus
Frequent Glucose
Monitoring
Good Metabolic
Control
Normal Life
Better Health
Painful Cumbersome Stigmatising
The Current Regimen
43
Pelikan Technologies Lancing System
Iron Core
Drive Coils
Guide Tube
Lancet
Iron Core
Drive Coils
Guide Tube
Lancet
The key component of the engine is a series of solenoids, which produce a strong, uniform and very controllable magnetic field inside a tube that houses a metal piston.
44
Pelikan Lancing Device
The Pelikan Sun went on the market in Australia, Germany and the USA from late 2007, but Pelikan Technologies (Palo Alto, USA) went into voluntray liquidation in 2011 and its asets were purchased by Sanofi.
45
Electronic Actuation Cam Driven Actuation Ballistic Actuation
Evolution of Lancet Actuation
Softclix® B-D PelikanSystems
Velocity
X
Velocity
X
Velocity
X
Skin Deformation
Exit Skin
Initial Penetration
Limit of Penetration
Skin Deformation
Exit Skin
Initial Penetration
Limit of Penetration
Skin Deformation
Exit Skin
Initial Penetration
Limit of Penetration
46
Integ LifeGuide – Minimally Invasive • Acquired by Inverness Medical Oct 2000 • Draws a tiny sample of interstial fluid (about 1 μl) from the outermost layers of the skin on the forearm in 8-10 secs • The unit then analyzes it for glucose in 30 secs • “Key” (white section) is disposable • Process avoids capillaries and nerve endings therefore is bloodless and eliminates pain associated with lancing a finger
The Case for Continuous Monitoring
Biostator-GCIIS (Circa 1981) Miles Laboratories in Elkhart, glucose-controlled insulin infusion system
Shichiri et al (1982) subcutaneous enzyme electrode with peroxide-based detection
The Origins of Continuous Glucose Monitoring (CGM)
49
Via Medical Inc Ex Vivo Glucose Sensor
Measurements taken every 5 Minutes for up to 72 hours
50
Micodialysis Micodialysis fibre
Fibre threaded through forearm (Mascini et al.)
The Arrival of Continuous Glucose Monitoring (CGM)
Medtronic Dexcom Abbott Freestyle Guardian STS Navigator Meter Kit $1,339 $800 $960-1,040 Sensors/m $350 (10x3day) $240 (4x7day) $360-390 (6x5 day) FDA Aug 2005 March 2006 March 2008 (CE June 07) approval Reading 1 per 5min (2h run in) 1 per 5min (2h) 1 per min (10h run in) Frequency Reading must be checked by finger-stick method before adjusting insulin
Sensor Augmented Pump
Real-time continuous glucose monitoring and the insulin pump have been combined into the Sensor-Augmented Pump system (Medtronic Diabetes, Northridge, CA). The first system was not widely released and it used a large transmitter, which was part of the original Guardian RT continuous glucose monitoring system. When the Minilink transmitter component of the Guardian RT monitor was approved in 2007, at that point the Medtronic Sensor Augmented Pump system was launched for marketing. Pilot studies have demonstrated improvements in mean glyceamia in users of this technology.
53
Futrex Inc 1992: Non-invasive glucose monitoring using NIR
The U.S. Securities and Exchange Commission charged Futrex with fraud, claiming that the Dream Beam never worked.
Minimally-Invasive and Non-Invasive Systems
Cygnus Glucowatch Biographer
Cygnus Inc. in Redwood City, California, has gone out of business and has stopped manufacturing its
meters. It sold essentially all of its assets to Animas Corp. (which makes insulin pumps) for $10 million.
Pendragon Pendra Pendra was CE approved in May 2003 and was available on the Dutch direct-to-consumer market. A post-marketing reliability study was performed in six type 1 diabetes patients. Mean absolute difference between Pendra glucose values and values obtained through self-monitoring of blood glucose was 52% and a Clarke error grid showed 4.3% of the Pendra readings in the potentially dangerous zone E. Pendragon now bankrupt.
Non-Invasive Monitoring: The Alarming Message To Date • Pendragon Pendra fails and Cygnus
Glucowatch stalls • Now 4 major failures in non-invasive sector • Alarming messages to investors
Yet, the push continues:
• Volatile analysis in skin & breath at Cranfield
“the science fiction you were speaking about is reality and being tested these days in Israel [by Cnoga]. The device is being in the middle of clinical tests … in the CARMEL hospital … it is been tested for CE …. the Device is not FDA approved yet. “ Samuel Payne / Dov Ben Asher. 22.10.08.
Non-invasive Monitoring
COMPANY TECHNOLOGY SITE
BioTex Inc, TX, USA Near-infrared Skin
Sensys Medical (Sensys GTS), AZ, USA Near-infrared Skin
Cascade Metrix Inc, IN, USA Mid-infrared/microfluid Skin
Light Touch Medical Inc, PA, USA Raman spectroscopy Finger
Integrity applications (GlucoTrack), Israel
Photoacoustic spectroscopy Ear lobe
VeraLight Inc (Scout DS), NM, USA Fluorescence spectroscopy Skin
Lein applied diagnostics, UK Optical Eye
Glucolight Corp (Sentris -100), PA, USA Optical coherence tomography Skin
Echo Therapeutics (Symphony tCGS, MA, USA
Sonophoresis Skin
Calisto Medical (Glucoband), TX, USA Bio-Electromagnetic Resonance Wrist
AiMedics (HypoMon), Australia Electro-physiological Chest skin
Biosign technologies (UFIT TEN-20), Canada
Electro-physiological Wrist
Cnoga Inc. (SoftTouch), Israel Optical (cell colour distribution) Skin
EyeSense, Germany Bio-chemical/fluorescence Eye (ISF)
VivoMedical, CA, USA Sweat analysis Skin
A selection of the apparently most active from >95 companies identified. Bold = in clinical trials
Glucotrack: ultrasound + thermal and electromagnetic conductivity
GlucoLight
HypoMon: 4 electrodes; electrophys changes
“The science
fiction you were
speaking about is reality “
Cnoga
Generations of Glucose Monitoring C
onve
nie
nce
1965 1970 1975 1980 1985 1990 1995 2000 2005 2010
AMES First Test Strips (Wash)
Boehringer Mannheim Visual Test Strips (Wipe)
LifeScan Non-Wipe Test Strip
Boehringer Mannheim Fast (12 sec) Test Time
Bayer Small (5μl) Blood Volume
LifeScan/TheraSense/Amira
Alternate Site Testing
Roche/Bayer Multi-Strip Integration
MediSense First Electrochemical Test Strip
Minimed
Cygnus (off the market) Dexcom
TheraSense
Continuous Monitoring
1st generation
2nd generation
3rd generation?
Pelikan Technologies Fully-integrated “One-Step” Approach
Defining Events 1962 - 1990
• 1962 First description of a biosensor: an amperometric enzyme electrode for glucose (Clark & Lyons)
• 1969 Ames Reflectance Meter launched • 1973-75 First commercial biosensor: Yellow Springs Instrument’s
electrochemical laboratory glucose biosensor • 1976 Miles Biostator: first bedside artificial pancreas • 1976 La Roche Lactate Analyser LA 640 using soluble mediators • 1981 1st Medisense electrochemical glucose sensor patent filed EP 0078363 • 1984 Shanks et al., capillary-fill Patent filed EP 0170375 • 1984 Publication of mediated amperometric glucose biosensor: ferrocene
used with glucose oxidase for the detection of glucose (Cass et. al.) • 1987 Launch of the MediSense™ ExacTech™ pen-shaped ferrocene-
mediated electrochemical home blood glucose biosensor • 1989 Launch of the MediSense™ credit card calculator-shaped ExacTech™
blood glucose biosensor
Defining Events 1990 - 2012 • 1992 Accucheck Advantage™ launched by Boehringer Mannheim • 1993 DCCT published; a major clinical study begun in 1983 which proved
the value of intensive control in reducing the complications of diabetes • 1995 Precision QID™ launched by Medisense with capillary-fill by “wicking” • 1996 Widespread introduction of capillary-fill devices by Bayer (Glucometer
Elite™), the manufacturer Kyoto Daiichi Kagaku (DIC Glucocard) and Menarini Diagnostics (Glucocard Memory)
• 1996 Abbott acquired Medisense for $867 million • 1998 Launch of LifeScan FastTake™ capillary-fill blood glucose biosensor
manufactured by Inverness Medical • 1998 Merger of Roche and Boehringer Mannheim to form Roche
Diagnostics • 2001 LifeScan purchased Inverness Medical’s capillary-fill glucose testing
business for $1.3 billion • 2004 Abbott acquires TheraSense (capillary-fill coulometry) for $1.2 billion • 2005 Medtronic Guardian introduced for continuous monitoring • 2006 Dexcom STS 7-day continuous sensor • 2012 Medtronic gained approval in Europé for automatic insulin shut off
Market Sizes in Diagnostics
• Biosensors - currently worth just under US$13 billion
• In Vitro Diagnostics (IVDs) – currently worth around US$40 billion
• Theranostics (companion diagnostics) – IVDs potentially worth US$72 billion Systems combining diagnosis, therapy and monitoring e.g. a test that qualifies a patient for treatment with a particular drug. Most common e.g. the HER-2/neu assay (Human epidermal growth factor receptor) required prior to treatment with Herceptin (humanised Mab) to determine 25% of breast cancer cases where receptors overexpressed. Also presence of KRAS mutation results in no benefit from Vectibix (Mab) for colorectal cancer. Numerous diagnostic/pharma alliances now being formed.
What Can Biosensors Contribute? The integration of diagnostics and therapy offers new funding paradigms • Convenient tests for polymorphisms • Metabolic assessments prior to and during treatment • Monitoring and control of drug administration • Outcome assessment including results of vaccination • Antibiotic resistance tests (current cost to EU ~$1.5b)
• Drug discovery and pharamacokinetic research • Alternatives to animal testing • Array-based single-cell investigation
“For every single Pharma product … the biomarker research and the
development of potentially companion diagnostics is a standard part of the development process” (Severin Schwan, CEO Roche, June 2007)
Conclusions
• Mediated amperometric glucose biosensors continue to dominate the home diabetes diagnostics market
• Peroxide based amperometric glucose biosensors predominate in the decentralised and in vivo markets
• The sector is typified by companies seeking to acquire a full set of technologies and pursuing high levels of integration (multi-sensors + multi-lancing &/or insulin injection) and sophisticated data treatment, displays and transmission
• Implantable sensors are in the market and home-use automated systems coupled to insulin infusion have been announced
• Non-invasive techniques have obvious attractions, but are meeting serious (insurmountable?) technical hurdles
Conclusions
63
Web Sites www.mendosa.com/diabetes.htm www.mendosa.com/faq.htm www.ysilifesciences.com/ www.minimed.com/products/guardian/ www.viamedical.com/bgm.html www.pelikantechnologies.com http://echotx.com/ www.smartholograms.com www.glucodr.com (video) www.accu-chek.com.au/au/products/metersystems/advantage.html www.bayerdiabetes.com/sections/ourproducts/meters/breeze2 www.lifescan.com/ www.abbottdiabetescare.com/index.htm www.ifm.liu.se/biosensors
www.ifm.liu.se/biosensors
5.602
2011
Turner, A.P.F. (2013). Biosensors: sense and sensibility. Chemical Society Reviews DOI:10.1039/C3CS35528D Newman, J.D. and Turner, A.P.F. (2008). Historical perspective of biosensor and biochip development. In: Handbook of Biosensors and Biochips (Eds R. Marks, D. Cullen, I. Karube, C. Lowe and H. Weetall) John Wiley & Sons. ISBN 978-0-470-01905-4 www.wiley.com/go/biosensors Newman, J.D. and Turner, A.P.F. (2005). Home blood glucose biosensors: a commercial perspective. Biosensors and Bioelectronics 20, 2435-2453.