BBI Contributing Editor

DUSSELDORF, Germany — The Medica 2001 exhibition, held here in late November, has historically been the largest gathering of medical product companies in the world. In spite of the global slowdown that has reduced attendance at other medical conferences, attendance at Medica was up as compared to last year, with total attendance of 127,500 trade visitors, an increase of 1,500. A total of 3,637 exhibitors from 58 countries took part in the exhibition, up by 121 companies from 2000. While representation at Medica for some segments of the market, such as laboratory products, has been declining over recent years, other sectors, such as medical informatics and products for performing tests outside of the hospital laboratory, have shown an increasing presence. The Medica exhibition also is perhaps the best forum in the world for companies seeking to establish new distribution relationships or marketing alliances. A particularly noteworthy trend is the growing presence of Asian manufacturers in the European market, including a number of new suppliers from Korea and mainland China.

Overall, the European diagnostics market remains healthy, with growth projected at 6.2% through 2005, as shown in Table 1. While the hospital segment of the market is mature in most respects, there is some growth in the market for point-of-care testing products for use in the hospital setting. In addition, there is attractive growth in the markets for home and self-testing products, particularly for products used in diabetes management, as well as in products for use in physician's office testing and for testing in alternate sites such as clinics and surgery centers.

Table 1
European In Vitro Diagnostics
Market Trend

Year Sales Growth
2000 $7.34 billion
2001 $7.79 billion 6.5%
2002 $8.27 billion 6.1%
2003 $8.79 billion 6.3%
2004 $9.32 billion 6.0%
2005 $9.88 billion 6.1%
CAGR,
2000-2005
6.2%

Source: Diagnostics & Imaging Update

Another expanding segment of the market is cellular analysis reagents and equipment, led by rapid growth in the use of the HER 2 cancer test, but also growing to include a variety of other cellular testing products. New technologies exhibited at the Medica venue promise to open up a number of new applications for cellular analysis. Finally, molecular diagnostics remains a high-growth segment of the European market, with overall growth projected at 26.6% per year through 2005. A key area of development in that segment is automated systems to allow labs to meet the growing demand for molecular testing in the areas of infectious disease, oncology and genetic testing.

POC product offerings expanding

One of the most important new products introduced at Medica for point-of-care testing in the hospital environment is the OPTI Plus from Roche Diagnostics (Mannheim, Germany). The new system combines the original OPTI blood gas/electrolyte technology with the AccuChek Advantage glucose meter and the CoaguChek Pro POC coagulation testing system. In addition, the system will have the capability to interface with the Roche Cardiac Reader, which is now on the market for performing POC cardiac marker testing using the Roche Troponin T and the Cardiac M myoglobin assays, as well as the Cardiac D-Dimer assay. In terms of the analytical parameters offered, the system bears some similarity to the MobilCare system that Roche and AVL Medical had under development prior to the acquisition of AVL by Roche in June 2000. However, the new OPTI Plus is considerably more compact and offers features such as the SNAP PAK module which allows multiple (25) tests to be performed using a single cartridge, and wireless data transmission. The system will compete with analyzers from suppliers such as i-STAT (Princeton, New Jersey) and Instrumentation Laboratory (Lexington, Massachusetts) that also offer combined blood gas/electrolyte/coagulation/glucose testing at the point of care, with cardiac marker tests planned for addition to the i-STAT menu in the future.

Another new competitor in the cardiac marker segment is Genzyme Diagnostics (Cambridge, Massachusetts). Genzyme is developing a quantitative cardiac marker testing system with a menu that will include Troponin I, CK-MB, and myoglobin. The system will consist of a reader and disposable test cartridges, with Troponin I available on one cartridge and a second cartridge offering CK-MB and myoglobin. Kalibrant Ltd. (Loughborough, UK) also is developing a new POC testing system, the Jetstream, that will offer cardiac markers and other tests performed using a new multiplexed fluorescence detection technology and the company's proprietary flow-driven automation technology. The highly compact system will also have applications in central lab testing as well as in drug discovery, proteomics, and industrial testing. A high-throughput version of the Jetstream will be capable of performing 200 immunoassay tests per hour. Kalibrant does not plan to market the system directly but is actively seeking commercial partners to bring the product to market.

A number of other new POC testing systems that will likely enter the European market within the next one to two years were described at the Medica exhibition. Table 2 presents an overview of some of the key new products recently introduced or under development. Additional cardiac marker testing systems for use in the hospital chest pain clinic are under development by the Jaeger (Hoechberg, Germany) unit of Viasys (Conshohocken, Pennsylvania), Cardimac GmbH (Ludersdorf, Germany) and Boditech (Gangwondo, Korean). The Jaeger system uses technology developed at the Institut fur Chemo- und Biosensorik (Munster, Germany). While cardiac markers are an important target for the initial system menu for most new POC systems for hospital use, the new systems will also offer POC assays for analytes such as prostate specific antigen (PSA), C-Reactive Protein (CRP) and markers for sepsis such as procalcitonin. Another new marker under development by 8sens.biognostic.AG (Berlin, Germany) is heart type Fatty Acid Binding Protein (FABP), a low molecular weight marker that appears in the blood up to two hours before markers such as troponin and returns to normal within 24 hours. FABP is believed to be more sensitive than myoglobin, the traditional marker for early myocardial infarct detection, because of its much lower normal levels (20-fold less) and its higher concentration in cardiac muscle (5-fold greater). The company has developed a simple visually read card test using colloidal gold labeled antibodies that requires only two drops of whole blood and that could be used in both the hospital emergency room as well as in alternate sites such as the physician's office. Blood/serum separation is performed on a special membrane included in the card. 8sens.biognostic.AG plans to introduce the test in late 2Q02 in Europe, with a target price of 25 Euro in Germany. The company plans to market the test through pharmacies and other outlets.

Table 2
New Point-of-Care Testing Products for the European Market
Company Product Key Features and Status
77 Elektronika Kft (Budapest, Hungary) POC PSA test and reader Immunochromatography strip, single test format. No CE mark or FDA clearance.

8sens.biognostic AG (Berlin, Germany) CardioDetect1-check Card Qualitative test for MI using Fatty Acid Binding Protein as early marker. Data indicates ability to detect MI two hours earlier vs. Troponin or CK-MB.

Boditech (Gangwondo, Korea) BodiTech Fluorescence Assay Reader and Immunosensors Fluorescence-sensor based system provides results in under 15 minutes with sensitivity to 50 pg/ml. Cardiac markers and cancer diagnostic assays under development. 3 to 4 months from market.

Brahms Diagnostica GmbH
(Henningsdorf, Germany)
LUMItest PCT Semi-quantitative visually read test for procalcitonin as an early marker for sepsis. 9 Euro per test.

Cardimac GmbH (Ludersdorf, Germany) Cardimac Controller Analyzer; Multilab-LP Hand-held Lipid Panel/ Glucose System Immunochromatography test strip readers. Strip test for PSA available now; CRP, Troponin I and myoglobin in development. $880 for Controller; $2.13/test (PSA).

Genzyme Diagnostics (Cambridge, Massachusetts) POC Cardiac Marker System Menu to include Troponin I, CK-MB, myoglobin. Available 2Q02.

Incomat Medizinische Gerate GmbH (Glasshutten, Germany) FORM Free oxygen radical monitor. Six-minute enzymatic test. Free radical damage has recently been shown to occur in children from families with early heart disease as early as age six.

Jaeger/Vyasis Healthcare (Hoechberg, Germany) MultiCheck System. Menu to include PSA, cardiac markers,
high sensitivity CRP (<0.001mg/L)
Quantitative POC analyzer using fluorescence immunosensor technology; can measure up to 10 analytes simultaneously. Target launch 2Q02.

Kalibrant Ltd. (Loughborough, UK) Jetstream POC cardiac marker system; multiplexed fluorescence sensor technology. 2 to 3 years from market introduction.

Polymedco (Courtlandt Manor, New York) Ultra-Sensitive CRP test kit
(0.1 mg/L or better sensitivity)
For use on ATAC 8000 physician's office chemistry system and various central lab analyzers.

Roche Diagnostics
(Mannheim, Germany)
OPTI Plus blood gas/electrolyte/
glucose/coagulation/cardiac marker test system
Combines OPTI blood gas/electrolyte technology with CoaguChek Pro coagulation system, AccuChek Advantage, and Cardiac Reader. Available in Europe this year.


Source: Diagnostics & Imaging Update

Radiometer Medical A/S (Copenhagen, Denmark) introduced the Ultegra POC platelet function testing system in Europe in October 2001, a product added to the company's line via the $10 million acquisition of Accumetrics (San Diego, California), a transaction announced in July 2001. The Ultegra positions Radiometer to enter a new segment of the hospital-based POC testing market in Europe, with products for use in the cardiac catheterization laboratory to monitor patients treated with GPIIb/IIIa inhibitors in combination with an angioplasty or coronary stent procedure. The company also markets the ABL 77 POC blood gas/electrolyte analyzer in Europe but has so far found that most hospitals prefer its larger models, such as the ABL 700 Series or the ABL 5, for use in near-patient testing. As a result, Radiometer is continuing to upgrade the capabilities of the ABL 700, with the most recent addition being a bilirubin test that will increase the attractiveness of the system for users in neonatal units.

The new PCT test from Brahms Diagnostika GmbH (Henningsdorf, Germany) addresses a potentially significant market in the hospital for tests to detect the development of sepsis. There are about 500,000 cases of septic shock annually in North America alone, resulting in 215,000 deaths, thus creating a large potential market opportunity since many more patients would likely be screened in the hospital during periods when they are at high risk. Another positive factor creating demand for new tests for sepsis is the impending introduction of new drugs to treat the condition. For example, Eli Lilly and Co. (Indianapolis, Indiana) recently received FDA approval for Xigris, a genetically engineered drug that is the first to be approved for treatment of sepsis, addressing a market opportunity in excess of $1 billion. Spectral Diagnostics (Toronto, Ontario) also is developing a POC test for the detection of sepsis. The Brahms test will require a 200 microliter serum or plasma sample, and will require about 30 minutes to perform.

Table 3
European Whole Blood Glucose Testing Products Market

Year Sales Growth
2000 $1.24 billion
2001 $1.41 billion 13.7%
2002 $1.60 billion 13.4%
2003 $1.81 billion 13.0%
2004 $2.04 billion 12.9%
2005 $2.32 billion 13.5%
CAGR,
2000-2005
13.3%

Source: Diagnostics & Imaging Update

While there is clearly a considerable level of investment in development of new products for the hospital POC segment, there may be an even greater interest in new products for the home and self-testing market. Glucose testing is one area of continued focus for many companies, because of the large and still growing global market opportunity for such products. As shown in Table 3, there is a substantial market for whole blood glucose testing products in Europe, representing an estimated 37% of the global market. While the capillary blood glucose market is dominated by large suppliers including Roche Diagnostics, the LifeScan (Milpitas, California) unit of Johnson & Johnson, Bayer Diagnostics (Tarrytown, New York) and Abbott Diagnostics (Abbott Park, Illinois), there are a number of smaller existing and emerging suppliers in Europe vying for a share of the market. Asian suppliers are active in Europe, including Apex Biotechnology (Taipei, Taiwan) with the GlucoSmart meter, as are Europe-based companies, including A. Menarini Diagnostics (Florence, Italy), B. Braun Petzold GmbH (Melsungen, Germany) and 77 Elektronika (Budapest, Hungary).

In addition to its GlucoMen glucose meter, Menarini also is developing a new continuous glucose monitor, similar to the one introduced in the U.S. by the MiniMed (Northridge, California) unit of Medtronic (Minneapolis, Minnesota). The Menarini GlucoDay monitor features a microfiber that is used to sample glucose in subcutaneous tissue, a micro-pump (similar in size to a insulin infusion pump), a microdialysis membrane and a glucose biosensor. After insertion of the microfiber under the skin and priming of the sampling fluid circuit, the system records glucose readings every three minutes for up to 48 hours. The sensor must be calibrated with a fingerstick glucose reading at the start of the monitoring period and every 120 minutes thereafter. As with the MiniMed device, the system is used to characterize trends in a patient's glucose level over time, allowing the physician to determine the optimal times for performing capillary glucose measurements on an on-going basis. Launch of the GlucoDay system in Europe is planned for this year. Clinical trials are now under way in Italy and Germany.

Another POC testing product for use in the management of diabetes was exhibited at the Medica meeting by Callegari (Parma, Italy). The Callegari DBScreen is a compact, automated, whole blood analyzer for use in the physician's office, with a menu including glucose, glycated hemoglobin, creatinine, triglycerides, total/ HDL cholesterol and hematocrit. A fructosamine assay is under development. Other companies developing glucose sensors in Europe include Inventus Biotec (Munster, Germany), SensLab (Leipzig, Germany), DiaSys Diagnostic Systems (Holzheim, Germany) and GlukoMediTech AG (Witten, Germany), an affiliate of Sangui BioTech International (Santa Ana, California). DiaSys also has developed a lactate biosensor for its Super GL ambulance system, a portable analyzer for use in the physician's office. Roche, the leading supplier of whole blood glucose testing products worldwide, exhibited the AccuLink Modem for use by patients in transmitting their glucose records to their physician. An evaluation project is now under way in Germany, the TEDDI project, involving 200 patients to determine the impact on patient outcome of regular tracking of glucose levels. The AccuLink system is now being used by about 500 diabetics in Germany for tracking of glucose levels.

New products for the physician's office lab (POL) sector are being introduced at a rapid rate in the European market. For example, Quidel (San Diego, California) exhibited the UrinQuick 2000, a new urine chemistry strip reader that will compete with systems available from suppliers such as Bayer Diagnostics and Roche Diagnostics. The reader can process over 360 strips per hour and provides self-calibration and stat/interrupt capability. The reader will be available in Germany next month and will be priced at about DM 10,000 (about $5,000). The product should enhance Quidel's increasingly strong position in the POL market. Alfa Wassermann BV (Woerden, the Netherlands) exhibited the OC-SENSOR , a new automated fecal occult blood analyzer for the quantitative analysis of human specific fecal hemoglobin. The analyzer can perform 80 tests per hour at a cost of about 2 Euro each, and will be priced at about 15,000 Euro. A CE mark is expected in March. Alfa Wassermann is a leading supplier of POL chemistry analyzers, and the new OC-SENSOR may prove attractive in that market segment because of the lack of sample exposure for the test technician. Another supplier, Acon Laboratories (San Diego, California), also has developed a new fecal occult blood test that offers a five-minute turnaround time.

TECO Medical Instruments (Neufahm, Germany) is developing a new hand-held coagulation analyzer, the Coatron M1, for physician's office and intensive care use. The analyzer should be available in about two years and will be priced at about $700. The test menu will include PT, APTT, TT, fibrinogen, Intrinsic Factor and Extrinsic Factor. Cost per test is expected to range from as low as 0.1 Euro up to 15 Euro, depending on the test. The TECO device requires a 25 ul blood sample. Another new POC coagulation testing system was exhibited by SEAC Radim Group (Florence, Italy). The SEAC Clot 2S is a semiautomatic analyzer for use in ambulatory care or the central lab, and not only offers a standard menu of coagulation assays, but also can perform a platelet aggregation test.

START Diagnostics (Viernheim, Germany) is developing a new chemistry/immunochemistry analyzer for the physician's office and small specialty laboratories that will provide a highly self-contained format along with a broad menu of about 90 tests including lipid panels with direct LDL, a high-sensitivity CRP assay, procalcitonin, PSA, hemoglobin A1C, CEA and D-Dimer. Development of the system originally began at SCIL Diagnostics (Martinsried, Germany), but the technology has since been acquired by its inventor, the founder of START Diagnostics. The system will offer similar capabilities to those of the CareSide analyzer, marketed in the U.S. by CareSide (Culver City, California), but will offer a broader menu at lower cost per test, according to START. The company plans to launch the product late in 2Q02 in Europe.

Another important emerging application in diagnostics is testing for neurological disorders. Alzheimer's disease represents a large and growing public health problem in most developed countries, and so far there are few effective tests for the disease, particularly tests that can be used at the point of care. A new test exhibited at Medica, Nexus Dx, is manufactured by Princeton BioMeditech (Princeton, New Jersey). The test, configured as a visually read card, measures glutamine synthetase as an aid in the diagnosis of Alzheimer's disease. The test uses a whole blood sample and provides results in 15 minutes. Preliminary clinical data show that the marker is elevated in Alzheimer's disease with a 100% sensitivity and 93% specificity, and that it also is highly sensitive (100%) and specific (94%) in differentiating patients with Alzheimer's from those with other dementias.

Cellular analysis, cancer diagnosis

Cellular analysis is another segment of the European clinical diagnostics market that is attracting increased interest from suppliers. Emerging companies in the equipment segment include CellaVision AB (Lund, Sweden) and ChromaVision Medical Systems (San Juan Capistrano, California), while key suppliers of reagents for cellular assays include Dako A/S (Glostrup, Denmark); Vysis (Downers Grove, Illinois), acquired recently by Abbott; and Cytocell Ltd. (Oxfordshire, UK). In addition, new cellular analysis technologies are under development that promise to expand the field to include fundamentally new types of tests for use in the clinical lab. Researchers at the Heinrich Heine Universtat Dusseldorf and Result Medizinische Analyseverfahren GmbH (Erkrath, Germany) are developing a new cell function assay technology with applications in neural diagnosis. The technique involves growth of human neuronal cells in vitro on a microfabricated electrode network containing an array of 60 points. The array allows measurement of the electrical activity of the cells before and after exposure to various agents. The results have been shown to correlate with the biological effects of neurotoxins, and the response is rapid (about 10 seconds). Potential applications include diagnosis of neurological disease such as multiple sclerosis — although no feasibility studies have yet been done in that area — and detection of the presence of neurotoxins in patients' blood. The company is seeking partners to commercialize the technology. Another group, led by Dr. Marlon Hinner at the Max Planck Institut fur Biochemie (Martinsried, Germany), is developing silicon neurosensor chips that allow neuronal cells to be cultured in defined positions created by microfabricated cages. The cells can be electrically stimulated to study their behavior during directed growth. Applications include studies of memory processes and learning behavior.

The existing clinical market for cellular analysis products is dominated by products for flow cytometry analysis, as well as reagents for use in immunohistochemistry and in situ hybridization procedures. Dako is the leading supplier of immunohistochemistry reagents, dominating the market for products such as HercepTest, an assay now being performed on an increasing percentage of breast cancer patients to determine if they should be treated with Herceptin, a targeted bioengineered drug developed by Genentech (South San Francisco, California). More recently, labs also have been using molecular techniques, namely the PathVysion assay from Vysis, for HER-2/neu analysis. As a result, Vysis' sales for the first nine months of 2001 increased 47% over the prior year to $19.8 million, including an 80% increase in sales of clinical and analyte specific reagent products. Abbott acquired Vysis in late November for approximately $355 million.

As the use of advanced cellular analysis techniques expands in the clinical laboratory, suppliers of automated imaging systems for use in clinical diagnostics are expected to experience increased demand for their products. CellaVision, for example, has recently consummated an agreement with Sysmex Europe, a subsidiary of Sysmex (Kobe, Japan), for distribution of the CellaVision DiffMaster in the German market. DiffMaster is a system used to perform differential white cell counts and assessment of red cell morphology. The first placement of the system was achieved in April 2001. Another supplier of cellular imaging systems, ChromaVision, reported revenues of $3.1 million for the first nine months of 2001 vs. revenues of under $1 million for the prior-year period. ChromaVision now has installed its ACIS cell imaging system in more than 130 sites. Most recently, the company announced promising results of studies using the ACIS system to detect micrometastases and tumor cells in sentinel nodes in breast cancer patients.

Molecular analysis is expected to become increasingly important in cellular testing as additional targeted drugs are developed for treating cancer and other diseases. The growing interest in molecular testing in cancer diagnostics in Europe is indicated by expanding use of tests such as BRCA1/2 analysis in breast and ovarian cancer. bioscientia Institut fur Laboruntersuchungen Ingelheim GmbH (Ingelheim, Germany), one of the largest reference laboratories in Europe, began offering BRCA1/2 testing in December, after forming an exclusive collaboration with Myriad Genetics (Salt Lake City, Utah) to offer the test in Germany, Switzerland and Austria, as well as in countries in the Middle East. The test has proven to be a powerful predictor of breast and ovarian cancer risk, allowing women who test positive to undergo more intensive surveillance, chemopreventative therapy with drugs such as tamoxifen, or prophylactic surgery.

Lab automation trends in Europe

Automation in cellular analysis is only one example of the trend toward increased use of automation in all sectors of clinical diagnostics in the European market. Another major trend is automation of molecular testing, which at present is focused primarily in the infectious disease segment. Automation of conventional growth-based testing methods in the infectious disease laboratory is also a key trend. In molecular testing, Roche Diagnostics is the leading supplier, with semi-automated systems now available for performing nucleic acid amplification (pcr), as well as systems for sample preparation and detection. The Roche MagnaPure LC is now widely used for performing sample preparation tasks such as extraction in many research labs and also is used in some clinical labs for automation of some of the initial processes for molecular testing. However, Roche also manufactures the AmpliPrep system, which can be used to prepare samples for pcr analysis, followed by readout using the Roche Amplicor system. In the future, molecular assays from Roche probably will be offered on the TaqMan system, an analyzer designed for routine use in labs performing amplification and detection. The company eventually plans to combine its AmpliPrep system for sample preparation with the Cobas Taqman system for performing real-time pcr amplification and detection, reducing the hands-on time now required for molecular assays as well as the time required to obtain a result.

Microarray-based products are likely to play an increasingly important role in the molecular diagnostic laboratory in Europe over the next few years. Companies active in the market include GeneScan Europe AG (Freiburg, Germany), providing BioChip technology for use in targeted drug development, with longer-term plans to develop pharmacogenomic profiling tests using the Pharm-O-Kin Chip. The GeneScan analyzer is priced at 72,100 Euro, and a typical chip for performing pharmacogenomic analysis is priced at 800 Euro. Nanogen (San Diego, California) also has established a European unit to market its microarray products in that region. Another supplier of microengineered devices, STEAG microParts GmbH (Dortmund, Germany) is developing the Lilliput chip in partnership with Merlin Diagnostika (Bornheim, Germany), which will be used to automate and miniaturize conventional microbiology assays, as well as providing significant improvements in turnaround time because of the ability to detect bacterial growth at an earlier stage in the miniaturized wells used in the device.