BBI Contributing Editor

DUSSELDORF, Germany – The clinical diagnostics market in Europe, which represents the second-largest market worldwide for diagnostic products, has, like the economies of most European countries, exhibited only modest growth recently.

As shown in Table 3, the market for in vitro diagnostic products totaled almost $7 billion in 1999 and is forecast to grow to almost $9.5 billion by 2005. The market is comprised of a number of slow-growing, and in some cases declining segments, including clinical chemistry, urinalysis and laboratory-based coagulation testing products; moderate growth segments such as immunodiagnostics and hematology; plus higher growth segments including whole blood glucose testing products and molecular diagnostics.

One area of emphasis for suppliers in Europe is new systems for bedside testing in both hospital and non-hospital settings for analytes, including blood gases and electrolytes, coagulation parameters and drugs of abuse. In particular, point-of-care (POC) coagulation testing has already achieved a reasonable degree of acceptance in Germany, and now new suppliers, as well as existing suppliers, are introducing new products in an attempt to grow the market. POC drugs of abuse testing is another segment that is attracting interest in the European market, with inroads being made in home testing, for example, and a number of companies are beginning to try to open up the market for hospital-based POC drugs of abuse test kits in Europe. Glucose monitoring products continue to be a growth segment in Europe, and one special session at Medica focused on ongoing efforts to develop less-invasive and noninvasive technologies for glucose testing.

Molecular diagnostics is a strong growth area in Europe, as in the U.S. and the rest of the world. Screening of the blood supply using amplified nucleic acid diagnostic tests is well on the way to full-scale implementation in most European countries, and the use of molecular diagnostics in infectious disease diagnosis in the hospital is now well established. As enabling technologies for molecular diagnostics advance, the stage is set for expansion into areas such as pharmacogenomic testing, molecular diagnostic cancer testing, testing for genetic predisposition in coagulation disorders and drug resistance testing in patients with viral infections, including HIV and hepatitis C. Certain companies that have in the past focused on research products for molecular testing are now beginning to implement initiatives to expand into the clinical market in Europe, altering the competitive landscape in one of the fastest-growing segments of the clinical diagnostics market.

There is continued interest within the European diagnostics community in new cell-based cancer tests. The HercepTest, an immunohistochemistry assay marketed by Dako A/S (Glostrup, Denmark) in Europe, and used to select patients for treatment with Herceptin, a breast cancer drug manufactured by Genentech (South San Francisco, California), is widely used, but utilization is hampered somewhat by reimbursement levels that, at least in Germany, are less than half the patient charge of 100 DM. A new cell-based assay for use in managing cervical cancer is under development by MTM Laboratories AG (Heidelberg, Germany), targeting the CINtec (P16) marker. The company was founded by scientists and clinicians of the University of Heidelberg (Heidelberg, Germany) and the German Cancer Research Center, and is focused on the development of molecular tools to improve early cancer detection. While MTM has not yet registered the P16 test for diagnostic use in either Europe or the U.S., clinical trials are underway, and the company plans to introduce a research-use version of the assay during 1Q01. In comparison with the conventional pap test for cervical cancer detection, the MTM assay exhibits fewer false positives (none have been detected in studies to date). The marker, which indicates the presence of dysplastic cells, may also be present in other types of cancers, according to MTM.

Another important trend in Europe that is expected to impact the structure of the clinical diagnostics market is the emergence of e-health and telemedicine. A number of e-health and e-commerce companies are now in the market in Europe, although so far they have established only a minor presence. An example is Medical.net AG (Bonn, Germany), which provides networking and electronic medical records for physicians' offices, laboratories and hospitals in Australia, Germany and Switzerland. The Medical.net Med Connect system can process 500 lab reports in 90 seconds and costs about one-10th the amount per transaction as regular mail. The company has contracts with 160 hospitals in Australia, and with 70% of the clinical labs in that country. Since its start-up in Germany in July 2000, the company had established contracts with 30 clinics, 30 hospitals and two clinical labs as of November. Internet-based and other types of information technology companies are expected to have a growing impact on the conduct of in vitro diagnostic testing in Europe, altering the way in which suppliers conduct internal operations as well as the way in which tests are ordered, reported and archived.

Suppliers push POC, alternate-site tests

A number of suppliers introduced new products at Medica for use in bedside and alternate site testing. In the point-of-care blood gas/electrolyte segment, adoption of systems such as the i-STAT Analyzer from i-STAT (Princeton, New Jersey) and the IRMA SL from Diametrics (St. Paul, Minnesota) has been slow in part because essentially all intensive care areas in Europe already are equipped with conventional bench-top analyzers capable of handling between 80 and 200 samples per day from suppliers such as Radiometer A/S (Copenhagen, Denmark). Such systems allow critical care tests to be performed rapidly by technicians working in satellite testing locations. However, at Medica, Radiometer launched its ABL77 in the European market, a true bedside blood gas/electrolyte testing system developed by SenDx Medical (San Diego, California), a company acquired by Radiometer in 1998 for $27 million. The system, priced at DM 22,900 and DM 12 per test, will be targeted at users in cardiac surgery and dialysis, where test volume requirements are lower. Another supplier of POC systems, IL Sensor Systems (Ann Arbor, Michigan), a unit of Instrumentation Laboratory SpA (Milan, Italy), also is targeting placement of its GEM Premier Plus POC blood gas monitoring system in such sites in Europe. Roche Diagnostics (Mannheim, Germany), the leader in the global clinical diagnostics market, also is offering a variety of POC testing products in Europe, including the AVL Opti R and Opti CCA bedside testing systems using fluorescence sensor technology to measure blood gases and electrolytes, as well as sensors for glucose and urea; the MobilCare system for integration of POC blood gas/electrolyte, glucose, and coagulation testing; POC systems for coagulation and glucose testing; and the Cardiac Reader, a portable meter for performing rapid cardiac tests including Troponin T and myoglobin. The Cardiac Reader will soon be launched in the U.S. market, according to Roche, and provides 12-minute turnaround time for the Troponin T assay at a cost of DM 17 per test (about $8.50). The meter is priced at DM 5000 in Germany.

Another portable system for performing rapid (less than 10-minute) quantitative cardiac marker tests, the Drylab Plus, will be launched this year by Audit Diagnostics (Cork, Ireland). The Drylab menu includes Troponin I, CK-MB, and myoglobin for cardiac testing, and a prostate-specific antigen test cartridge also is available. Drugs-of-abuse tests are under development. ANI Biotech Oy (Helsinki, Finland) exhibited a qualitative Troponin I test, the Biocard Troponin I, at Medica that provides a result in 10 to 15 minutes using only four drops of whole blood. Although pricing for the Biocard test is not yet established, preliminary indications are that the test will be priced well under the level of existing tests from Roche and others, such as Biosite Diagnostics (San Diego, California), but its qualitative design may be a drawback for some users.

POC coagulation testing is attracting increased attention in the diagnostics market in Europe. In Germany, the health system has provided 100% reimbursement for POC coagulation testing since 1992, resulting in widespread use of such testing by patients. Roche launched a new system, CoaguChek S, in January 2000 in Germany. The new meter provides prothrombin time or international normalized ratio (INR) readings from 10 uL of blood in about 1.5 minutes at a cost of DM 6 per strip. The meter is priced at DM 1,800. Another company developing POC coagulation test systems is Teco Medical Instruments (Neufam, Germany). Teco's Coatron M1, to be launched in about one year, will perform prothrombin time, activated partial thromboplastin time, D-dimer, thrombin time, fibrinogen, and intrinsic and extrinsic factor measurements using a hand-held meter on 25 uL of whole blood. Up to 200 test results can be stored on-board. Another supplier in the POC coagulation testing segment in Europe is Avocet Medical (San Jose, California), maker of the AvoSure PT POC prothrombin time testing system. The AvoSure PT is distributed in Europe by Menarini Diagnostics (Florence, Italy) and is intended for use by patients for self-testing.

Many suppliers are also introducing D-dimer tests as part of their POC hemostasis testing product lines. In addition to Teco, Roche now is offering a D-dimer assay on the CoaguCheck system. Axis-Shield PoC AS (Oslo, Norway) introduced its NycoCard D-dimer assay and reader at the Medica exhibition, which performs a two-minute D-dimer assay at the point of care using 50 uL of platelet-free plasma. Elevated levels of D-dimer indicate the presence of deep vein thrombosis, pulmonary embolism and disseminated intravascular coagulation disorders.

Drugs-of-abuse testing products have historically been in demand mainly in the U.S., where screening of prospective employees and of transportation workers is common. Recently, however, some suppliers have witnessed increased use of such tests in other countries. For example, SureScreen Diagnostics (Derby, England) has marketed the At Home Drug Test in Europe for about one year, and continues to achieve growing sales. The test requires phone counseling for home users, sells for 19 in the United Kingdom and uses a urine sample. The test kit automatically checks for specimen adulteration and also has a confirmatory test built in. Roche also is a participant in the drugs-of- abuse testing market in Europe with its OnSite TestCup and TestCup Pro urine testing products. A third supplier is Ultimed Products GmbH (Ahrensburg, Germany), offering the DrugScreen test cards and panel tests for commonly abused drugs detected in urine.

Another drug-of-abuse testing product was exhibited at Medica by LifePoint (Ontario, California). The LifePoint test system uses a saliva sample to test for a panel of abused drugs including marijuana, cocaine, opiates, PCP, amphetamine/methamphetamine and ethanol. The company believes its product is the only device using a saliva sample that can simultaneously measure alcohol and drugs of abuse. LifePoint believes that its technology can ultimately allow measurement of up to 10 analytes using a single device. Results are obtained in under five minutes, and the target price per test is about $25. A portable, table-top instrument also is required, costing about $5,000. The product has not yet been introduced, but clinical trials are planned for early this year. The company is seeking distributors for the product in Europe. According to LifePoint, studies have shown that drug abuse is a more common cause of driving under the influence in Europe than is alcohol consumption. Consequently, a combination drug/alcohol testing device would meet with ready acceptance in Europe, according to LifePoint, particularly one using a readily-obtainable saliva sample. LifePoint is assessing the development of a hand-held unit to replace the table-top analyzer for on-site testing. The LifePoint sensor is based on flow immunosensor technology licensed exclusively from the U.S. Navy. The company believes additional applications can be developed for cardiac marker testing, osteoporosis screening and measurement of other critical analytes in an emergency room setting.

Glucose monitoring products continue to comprise the largest segment by far of the POC testing market in Europe and worldwide. Although glucose meters and test strips are manufactured by a large number of suppliers, the market is dominated by four major companies, including the LifeScan (Milpitas, California) unit of Johnson & Johnson; Roche Diagnostics; Bayer Diagnostics (Leverkusen, Germany); and Abbott Diagnostics (Abbott Park, Illinois). The European market for whole blood glucose monitoring products is estimated at $1.3 billion for 2000, as shown in Table 4. A continuing effort is being directed at development of less invasive and, ultimately, non-invasive glucose monitoring devices by the major suppliers in the market as well as by numerous small ventures. A special session at Medica described the current status of research in new glucose monitoring technologies. Among the new technologies described was a fiber-optic monitor using diffuse infrared reflectance spectroscopy of the inner lip, under evaluation by Dr. H.M. Heise at Dortmund; and a near-infrared absorbance system under development by Instrumentation Metrics (Tempe, Arizona). The Instrumentation Metrics system has demonstrated reasonable accuracy when calibrated to an individual user, and a pivotal trial was expected to begin last month.

The consensus of a panel that discussed glucose monitoring at the Medica session was that introduction of completely noninvasive glucose testing is not on the foreseeable horizon and that new developments will more likely come from continued improvements in existing technologies. Another approach that has attracted considerable investment is sampling of glucose levels in the interstitial fluid. A system from Cygnus (Redwood City, California), the GlucoWatch, already approved by the FDA, intermittently monitors glucose levels in interstitial fluid, and another system for continuous monitoring was described at Medica by Rosch AG Medizintechnik (Berlin, Germany). The Rosch system uses a suction device that creates a very small blister on the skin surface filled with interstitial fluid. A small opening is automatically created in the blister, allowing interstitial fluid to flow to a biosensor chip that measures the glucose level in the fluid. The integration of a glucose sensor into the sampling unit results in rapid response times, providing good correlation of the reading with blood glucose, according to the company.

The large size and high growth rate of the glucose monitoring market continues to attract investment in new measurement technologies and also attracts new suppliers of more conventional technologies. Smaller suppliers attempting to penetrate the glucose monitoring products market in Europe with miniaturized meters and glucose biosensor technologies include Apex Biotechnology Group (Hsinchu, Taiwan), Tyson Bioresearch (Hsin-Chu, Taiwan), Yeongdong Pharmaceutical (Seoul, South Korea), A. Menarini Diagnostics (Florence, Italy), and Medpro GmbH (Ludersdorf, Germany). The Tyson Bioresearch EZ Scan system, with a 3 uL sample volume requirement, offers sampling from either the finger or the forearm, similar to systems from Amira and TheraSense. The Apex Bio MultiSure system also requires only 3 uL of blood and includes the capability to measure uric acid levels using a separate strip.

Molecular diagnostics revolutionizes market

While the glucose monitoring market offers a significant growth opportunity for suppliers, molecular diagnostics may ultimately be the largest growth market in clinical diagnostics in Europe. Molecular diagnostics already have had a major impact in infectious disease testing. For example, more than 90% of the blood supply in Germany now is being screened using nucleic acid testing methods, and nucleic acid testing of all donated blood in France began last month. In addition, there is widespread use of nucleic acid diagnostics for infectious disease testing in Europe, using systems such as the Amplicor analyzer from Roche Molecular Diagnostics to detect the presence of infectious organisms (e.g., chlamydia and Neisseria gonorrhea) in clinical specimens. A number of new molecular diagnostic products were described at Medica that will drive further expansion of the market in Europe. As shown in Table 5, the market for clinical molecular diagnostic products in Europe reached almost $270 million in 2000 and is continuing to grow at in excess of 20% annually. Roche Diagnostics is the dominant supplier in the European molecular diagnostics market, based on the widespread use of its PCR technology, including test kits for HIV viral load measurement. Other important suppliers in the European market include Bayer Diagnostics, Innogenetics (Zwijnaarde, Belgium), Digene (Silver Springs, Maryland), Gen-Probe (San Diego, California), Vysis (Downers Grove, Illinois) and Abbott Diagnostics.

Another new device based on miniaturization technology was exhibited at Medica by GeneScan Europe AG (Freiburg, Germany). The GeneScan BioChip technology is under development for applications in infectious disease diagnosis and genetic disease testing. Although the microscope slide-size chip can accommodate up to 10,000 sites on its surface, it is fabricated using low-cost Top Spot printing technology rather than semiconductor processing techniques. The initial version of the BioChip will be a microarray for performing multiplex analysis of specimens post-amplification. Applications that have been demonstrated include an HLA-Chip for HLA typing and a Gaucher chip for screening for five of the most frequent mutations associated with Gaucher disease. Other chips are under development for diagnosis of Duchenne muscular dystrophy, hemachromatosis, HIV/Hepatitis and sepsis. The BioChip also has applications in SNP analysis and gene expression studies. GeneScan has also developed the BioDetect system that includes a laser-based fluorescence imaging reader with CCD detector, a computer, and Signalyse software. The GeneScan products are being marketed by Scil Diagnostics GmbH (Martinsried, Germany).

Adnagen GmbH (Hanover-Langenhagen, Germany) demonstrated its recently launched Hepargnost test kit for detection of glutathion-S-transferase M1/T1 (GSTM1/T1) gene deletions, which indicate susceptibility to xenobiotic agents because of decreased activity of genes involved in detoxification. Clinical studies have also shown that a GSTM1 and or GSTT1 gene deletion and the resulting accumulation of xenobiotics in fat tissues correlates with increased risk of developing cancer and chronic bronchitis. About 40% to 50% of European caucasians show a deleted GSTM1 genotype, and about 25% show a deletion of the GSTT1 gene. The test is based on pcr analysis and detection by capillary electrophoresis or gel electrophoresis, and is priced at DM 1000 for a 25-test kit.

Another emerging player in the molecular diagnostics market is Applera (Norwalk, Connecticut), the new name for the company comprised of PE Corp./ Applied Biosystems and Celera Genomics. Applied Biosystems is not currently selling reagents or equipment for clinical use, although some hospitals in Europe are using its products for genetic profiling and assessment of genetic disease risk in patients on a research basis. The Applied Biosystems Prism 3100 Genetic Analyzer is being used with the ViroSeq HIV-1 Genotyping System for analyzing drug-resistant mutations in AIDS. Celera Genomics is the leading company in the genomic and related medical information field. The former PE Corp. has restructured to focus on the life science market, and may eventually assume a more central role in clinical diagnostics as medically relevant genomics information is developed by Celera.

Although the use of molecular diagnostics for infectious disease testing, genetic disease diagnosis and cancer-related testing is expanding rapidly in Europe, development of alternative technologies for infectious disease diagnosis is continuing to attract investment. An automated BioChip system, called Lilliput, was described at Medica by Merlin Gesselschaft fur mikrobiologische Diagnostika mbH (Bornheim-Hersel, Germany). It performs microbiology testing using a microfluidics platform developed by Steag microParts GmbH (Dortmund, Germany). The Lilliput biochip is a miniaturized microplate that integrates 96 wells, four sample reservoirs and five additional ports for chemicals on an area that is smaller than a thumb (20x38x3 mm3). The small dimensions of the device result in an acceleration in the rate of reactions and biochemical processes, and it is possible to detect growth of organisms in the wells earlier because of their small dimensions. The biochip is formed using the LIGA micromolding process, a form of micromachining. A spectrophotometric analyzer, the Lilliput Analyzer, has been developed to provide rapid readout of the biochips. Merlin already markets the Micronaut analyzer for bacterial identification and antibiotic susceptibility testing and will introduce the Lilliput as its next-generation product. Merlin also is developing the DyNAmid device for genetic analysis of bacteria. However, the company projects that genetic analysis will capture only 10% to 15% of the market for microbial identification and susceptibility testing products.

Another system that may compete with molecular diagnostic methods in the infectious disease testing segment was introduced at Medica by Osmetech plc (Crewe, United Kingdom). Osmetech has developed an electronic system for detection of infectious agents that uses digital sensing of the metabolites emitted by growing bacteria. The system uses semiconducting polymer sensors in an array, forming an electronic nose that can differentiate bacteria based on their metabolic signatures. The sensor can be implemented as an automated system for the laboratory or in a POC device for the physician's office. Results are available within 15 minutes at a cost of $5 to $10 per sample. Organisms that have been studied include E. coli, Pseudomonas, S. aureus, Proteus and yeasts. FDA approval is targeted for May.