BBI Contributing Editor
DUSSELDORF, Germany The European market for medical devices used in disease screening, as well as the market for point-of-care testing products, has historically lagged behind the market in the U.S., mainly because of the characteristically lower level of healthcare spending as a percentage of gross domestic product in European countries. For example, about 60 million Pap smear tests are performed annually in the U.S. vs. 35 million to 40 million in Europe, even though the population in Western Europe alone is larger than that of the U.S. and cervical cancer incidence rates are slightly higher. Point-of-care (POC) testing products also have been adopted quite slowly in Europe as compared to the U.S.
At the 2004 MEDICA exhibition, the world's largest showcase for medical devices and supplies held here last November, a number of products for use in disease screening and point-of-care testing were introduced. Cellular analysis, including applications in cancer screening, is one market segment that is attracting considerable investment in Europe, along with a variety of non-invasive imaging and sensing technologies that show promise for early disease detection. POC testing, while continuing to represent a smaller market opportunity in Europe than in the U.S., is an expanding market segment, and is attracting a number of new suppliers to the European market.
Expansion of POC testing
The European market for POC testing products, including products sold for hospital, alternate site, and self-testing, totaled more than $2.8 billion in 2003 as shown in Table 1, and is estimated to have reached $3.3 billion in 2004. High-growth segments of the market include whole blood glucose testing products for both personal and professional use, POC cardiac marker test kits and systems and POC coagulation monitoring systems. The overall market is expected to grow at about 13% annually through 2009. A number of suppliers in the European market are focusing on products for POC testing for drugs and infectious agents. For example, Cozart (Oxfordshire, UK) markets the RapiScan oral fluid drug test in Europe, which uses an oral collection pad inserted under the tongue to collect a saliva sample, which is then applied to a test cartridge and analyzed using a handheld instrument. Two different five-drug test panels are available one for cannabinoids, amphetamine, cocaine, opiates and benzodiazepines, and a second that substitutes methadone for cannabinoids. The company also sells dual-analyte drug testing kits for opiates, methadone, and cocaine. Cozart's POC kits are being used by the criminal justice system in the UK. for testing of individuals after they are charged with drug-related crimes.
BamburghMarsh (Vancouver, Washington) is another player in the POC drug testing market in Europe with its line of saliva testing products, including the VersiSAL split sample oral fluid collection device, which is used to collect a saliva sample and automatically split it into two aliquots, one that can be tested immediately and a second that can be mailed to a laboratory for confirmatory testing. The company also sells the VerOFy I/II sample collection device, which is used with the SaliChek handheld reader and an immunochromatographic test strip to measure drug levels on-site. The SaliChek can transmit test results wirelessly to a companion printer to provide a hard copy, which is important for applications in law enforcement.
Additional applications of the technology may include infectious disease testing, such as screening for HIV infection. The meter is priced at $50 to $75, while the collection device costs between $2.50 and $3. A typical drug panel test is priced at $25. Although BamburghMarsh has focused so far on law enforcement testing, the company believes there is a significant opportunity for its products in workplace testing because of the greater ease of sample collection as compared to urine. In addition, saliva drug levels are more closely correlated with sensory impairment than are urine levels, and it is more difficult to adulterate saliva samples than urine samples, according to the company.
Other companies exhibiting at MEDICA that are targeting expansion into the European POC drugs of abuse and infectious disease testing market include Calypte Biomedical (Rockville, Maryland), Branan Medical (Irvine, California), LifePoint (Ontario, California) and Varian (Cary, North Carolina). Calypte has licensed technology for POC HIV-1/2 oral fluid testing from the Centers for Disease Control and Prevention (CDC; Atlanta) that allows a test result to be obtained in 20 minutes with a simple, three-step procedure. The company also has developed versions of the test that can be used with whole blood, serum, plasma, and urine samples. The current versions of the test are not sold in the U.S. due to patent issues, but Calypte is developing a new test format that will circumvent the patents and allow the test to be marketed in the U.S. as well as Europe.
In the U.S., the Calypte test will compete with the OraQuick Advance Rapid HIV-1/2 Antibody Test, a CLIA-waived POC test from OraSure Technologies (Bethlehem, Pennsylvania) that also can use whole blood, plasma or oral fluid specimens, which was launched in the U.S. late last year. Branan Medical is marketing the Oratect drug test in Europe, a single-step, oral-fluid drug-screening test that can be used both for POC testing and for collection of a specimen for testing by a central lab. The Branan Oratect test has short (six-minute) turnaround time and can detect the six major drugs of abuse in one assay in both oral fluid and urine. The Oratect test can be read visually by a clinician without the need for an electronic reader, lowering the barrier to product adoption.
LifePoint exhibited the Impact Test System at MEDICA, an on-site saliva-based drug and alcohol testing system that performs a test panel consisting of up to 10 drugs and alcohol in five minutes. The system is targeted at law enforcement, emergency medical and workplace testing applications. Varian is a new entrant in the POC drugs of abuse testing arena as a direct marketer of products, having acquired the marketing rights to the On-Site drug testing product line of Roche Diagnostics (Indianapolis), a line that is manufactured by Varian.
One of the most rapidly growing segments of the POC testing products market in Europe is products for sepsis detection, particularly a new procalcitonin POC test from Brahms Aktiengesselschaft (Henningsdorf, Germany). Brahms sells both POC and laboratory versions of its procalcitonin test, PCT-Q and PCT, for use in sepsis detection. The PCT-Q test is a semi-quantitative immunochromatographic assay with a 30-minute turnaround time, while the PCT laboratory version is an immunoluminescence assay that runs on the Kryptor immunoassay analyzer and requires 90 minutes. According to Brahms, 43% of the hospitals in Germany are using procalcitonin for sepsis diagnosis, and a similar or higher proportion of hospitals are using the test in France, Austria and Switzerland. Sales of the company's procalcitonin tests are growing 30% annually.
In January, Brahms received FDA 510(k) clearance in the U.S. to market the PCT test for use in conjunction with other laboratory and clinical assessments as an aid in assessing the risk of progression to severe sepsis and septic shock for critically ill patients on their first day in the ICU. According to Brahms, international thought leaders in sepsis management now are recommending use of the PCT test for monitoring critically ill patients. Clinical studies have shown a sensitivity of more than 98% for severe sepsis detection, vs. a sensitivity for the primary competing method, blood culture testing, of about 40%. In part, that difference stems from the fact that the PCT test becomes positive within six hours of entry of bacteria into the bloodstream, vs. about three days for blood culture. In addition to applications in initial detection of sepsis, the PCT test can be used to monitor the results of interventions, possibly helping to reduce the need for antibiotics, thus helping to address the growing concern about antibiotic-resistant infections. In hospitals that have adopted the PCT test, it is typically performed once per day for at-risk patients in the ICU.
Another growing segment of the POC testing market in Europe is products for blood lipid analysis, used in the assessment of cardiovascular disease risk. AccuTech (Vista, California) is a supplier of personal-use blood lipid tests, and is marketing a $25 cholesterol test in Europe. The company believes the trend for patients to take increasing control of their own health management will favor adoption of its products in Europe. AccuTech is developing a direct LDL cholesterol test to expand its offering of cardiac risk assessment products. Another supplier, DiaGlobal (Berlin, Germany) introduced POC tests for total cholesterol, HDL cholesterol and triglycerides at the MEDICA exhibition. The tests are performed in individual tubes and read on a spectrophotometer.
Other suppliers of POC lipid testing products in Europe include Cholestech (Hayward, California), Abaxis (Union City, California) and Roche Diagnostics. Abaxis launched its new Lipid Panel Plus test cartridge at the MEDICA exhibition, which provides results for cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glucose, ALT, AST and VLDL in less than 15 minutes at the point of care.
Qualigen (Carlsbad, California) exhibited the FastPack System at MEDICA, which performs point-of-care testing for prostate-specific antigen (PSA), free PSA and testosterone in 11 minutes using a 100 ul serum sample. The Qualigen system uses chemiluminescence immunoassay technology and is targeted primarily at the physician's office laboratory market segment. The product has both a CE Mark and FDA 510(k) clearance. The instrument is priced at EUR 5,980 in Europe and tests for total PSA cost EUR 3, while free PSA and testosterone are priced at EUR 6 to EUR 8. More than 500 systems have been placed worldwide, including 250 in Germany, 200 to 250 in the U.S. and about 100 in Asia. An average user performs between 50 and 150 tests per month, at a patient charge of EUR 21 for total PSA in Germany.
The largest segment of the POC testing market in Europe by far is whole blood glucose testing, estimated at $2.5 billion in 2004 including both professional and personal-use products, and continuing to expand at double-digit rates. The market has attracted numerous suppliers from the U.S., Europe and Asia, including a number of companies from China, Taiwan and Korea. A new development in the market is the introduction of combination glucose and blood pressure monitors, such as the EZ2 Check Combo from Tyson Bioresearch (Chu Nan, Taiwan). The Tyson device is worn on the wrist, and performs an oscillometric blood pressure reading and pulse rate determination, displaying the result and storing it in an internal memory. The user also can insert a biosensor test strip into the device to obtain a glucose reading in 10 seconds using a 1.5 ul whole blood sample. The $25 device is targeted at the growing number of individuals who are afflicted with both cardiovascular disease and diabetes.
Another combination glucose/blood pressure meter, the Clever Chek, was introduced by Taidoc Technology (Taipei, Taiwan). The Clever Chek provides a blood pressure and pulse rate reading in 20 seconds, and also performs glucose testing using a separate test strip that requires a 1.8 ul blood sample. A new test strip to be introduced shortly will have a reduced sample volume requirement of less than 1 ul, presumably enabling alternative-site testing (AST) to be performed. The Clever Chek also has the capability to wirelessly transmit test data to a PC, and can store up to 350 glucose test results.
A second type of product combining whole blood glucose testing with other analytical capabilities is the multiCare system from Biochemical Systems International (Arezzo, Italy). The multiCare is a new self-testing device that can measure both cholesterol and triglycerides in addition to glucose. A similar product, the AccuTrend GCT, is available from Roche Diagnostics. The multiCare meter is priced at EUR 60, and distributor pricing for glucose test strips is EUR 6.50 for a box of 50. Cholesterol and triglyceride strips are priced at EUR 13 each. A 3 ul blood sample is required for each test, using individual strips for each analyte, and test time is 20 seconds for glucose and one minute for other analytes. The multiCare is targeted for use by patients who have both cardiovascular disease and diabetes who require both blood lipid and glucose monitoring.
Hypoguard (Edina, Minnesota), a subsidiary of Medisys (London), exhibited at MEDICA the Advance Express, a unique glucose test system that consists of a disposable meter containing 100 test strips. The product is sold in the U.S. as the NewTek glucose meter by Wal-Mart (Bentonville, Arkansas). The integrated design of the Advance Express addresses accuracy and precision issues that arise due to sample and test strip handling. The test strip requires a 3 ul blood sample. Hypoguard is awaiting receipt of a CE mark for the product in order to launch in Europe. The Advance Express will be priced at $55.
Aviara Biotech (Carlsbad, California) exhibited the new Glucose Vision, which is available in the European market and will be introduced in the U.S. (as the Glucose Pilot) following receipt of FDA clearance. The Vision requires only a 1 ul blood sample, allowing testing to be performed from alternative body sites such as the arm and thigh as well as the fingertip. Test time is five seconds, and the meter's memory holds up to 300 results. Aviara also has developed the For Sure Glucose Test, a complete glucose testing system contained in a disposable plastic cassette. The device is not intended for use in routine daily monitoring, but rather for occasional screening. The test requires about 15 minutes using a 40 ul blood sample, but does not require a separate meter. Instead, the user visually compares the cassette to a chart to read the glucose value.
Another unique blood glucose testing system was exhibited by ABT (Radeberg, Germany). The ABT Glukometer 3000 uses a single reusable sensor chip that can be used for 30 days or 1,000 whole blood glucose tests. It uses a thick film electrode on a ceramic substrate. A 5 ul blood sample, which is collected in a capillary supplied by ABT as part of the test kit, is required. The capillary is then inserted into the sensor chip, and an amperometric determination of glucose is completed in less than 20 seconds. The highly cost-effective system has a specified accuracy of 10% or better up to 550 mg/dL, and an imprecision of less than 5%. Up to 1,000 patient results can be stored in the system memory.
A large number of other suppliers exhibited glucose self-testing products at MEDICA, including Science Technology (Taipei, Taiwan), a company that recently entered the market in mainland China and sold 15,000 glucose meters in the first nine months after product launch. The company plans to introduce a new meter in 2005 that will offer a 1 microliter sample volume. Two other suppliers, YD Diagnostics (Seoul, Korea) and 77 Elektronika (Budapest, Hungary), have introduced systems having submicroliter (0.5 ul) blood sample volume requirements.
A key trend in the whole blood glucose monitoring market is the conversion of the market to devices with alternate-site testing capability, typically with blood sample volume requirements of 1 ul or less, since that feature allows users to test from sites other than the fingertip and thus reduce the pain associated with testing. While many diabetics who purchase meters with AST capability do not routinely perform testing from sites other than the fingertip, sales trends in the whole blood glucose market clearly demonstrate that products with AST capability are increasingly favored. An analysis of sales of glucose meters sold in the U.S. self-testing market over the past three years demonstrates that, without exception, products with AST capability have exhibited above-market growth rates, while those without AST capability have exhibited either minimal growth rates or declining sales, with some showing a precipitous drop.
Table 2 presents estimates of sales trends in the worldwide whole blood glucose testing products market over the 2001-2009 interval, demonstrating that almost half of the market was attributable to AST products in 2004. Over the 2004-2009 interval, the compound annual growth in AST product sales is projected to be more than double that of the total market, with the AST segment accounting for 82% of the market by 2009. The trend in the whole blood glucose testing market reflects a more general trend in the medical device market toward increased preference for less-invasive technologies.
New developments in disease screening
Another developing segment of the medical device market in Europe is products for disease screening, including cancer-screening. Audit Diagnostics (Cork, Ireland) manufactures for the European market the Cell Slide system, a thin-layer cytology system used to prepare Pap slides. The Cell Slide is sold in Europe by Menarini Diagnostics (Florence, Italy), which has so far placed about 50 systems. Utilization of thin-layer cytology for Pap smears has become widespread in the U.S. as a result of the strong acceptance of the ThinPrep system sold by Cytyc (Marlborough, Massachusetts). The ThinPrep technology has been shown to provide improved detection of cervical cancer (high-grade squamous intraepithelial and more severe lesions) in Pap smears because of its ability to remove debris from the slide and provide a more representative specimen for analysis. In Europe, however, adoption of the technology has been slow, primarily, according to suppliers, because of cost issues. Cytyc, for example, reported that only about 12% of its sales of diagnostic products in 2004 were realized outside the U.S., although the U.S. accounts for less than half of the Pap smears performed worldwide.
According to Menarini, which markets the competing Cell Slide system, pathologists in Europe have not wholeheartedly endorsed liquid-based cytology, as is used in the Cell Slide and in the ThinPrep. Penetration of liquid cytology in Europe ranges from 5% to between 25% and 30% depending on the country, with penetration highest in the Benelux nations at about 50%, and in France and the UK at 25% to 30%. Penetration is much lower in Italy and Germany, with the low penetration in Germany resulting in low overall penetration in Europe of 15% to 20% because of the large size of the German market (6 million to 7 million Pap smears vs. 35 million to 40 million in all of Europe). Budget issues in many European countries are slowing adoption, even though studies have now shown that the use of liquid cytology actually saves money in the long term by reducing recall rates and improving patient management. Suppliers believe that liquid cytology eventually will reach a level of penetration in Europe equivalent to the U.S.
Another important advance in cell analysis technologies expected to have an impact on the European diagnostics market is digital imaging. Carl Zeiss (Oberkochen, Germany) is developing a new system called the MIRAX Scan, a digital histopathology system that may replace conventional visual microscopy in medium and large hospital laboratories. While digital imaging technology for cell analysis has been available for decades, its acceptance in routine clinical pathology laboratories has been slow because image quality has not equaled that of visual microscopy, while costs are higher. But with the latest advances in digital imaging, including advances in high-resolution display technology, pathologists can now realize performance that is equivalent to if not better than that of conventional visual microscopy, while also reaping the advantages of computer storage and processing of image data.
The new Zeiss system employs a digital scanner and virtual slides to provide increased flexibility and reliability as compared to visual microscopy, and also allows more rapid access to the images to be analyzed. Carl Zeiss has established a collaboration with IBM (Armonk, New York) in information technology to develop a total solution for pathology imaging. The MIRAX system includes an automated slide scanner that acquires a high-resolution image of the tissues on each slide, and a specialized 9.2 megapixel monitor from IBM that provides an image to the user that is the equivalent of eight conventional monitors combined. The system is priced at EUR 130,000 and so far has been placed primarily in research sites. Zeiss is continuing to develop the technology to add automated image analysis and interpretation capabilities.
The next advance in pathology imaging promises to move pathology practice out of the laboratory and into the operating room. Pentax (Tokyo) exhibited its new endomicroscopy system at MEDICA, a product launched in January. The Pentax endomicroscope consists of a miniaturized fluorescence microscope mounted on the tip of an endoscope. It provides a 250-micron depth of view and can be adjusted to focus through a tissue in seven-micron steps. Dyes that are the same as those used in eye exams are infused into the region under examination to elucidate tissue characteristics, and in the future dyes to identify specific targets such as H. pylori are to be developed. The endomicroscope uses suction to ensure approximation of the tissue to the surface of the scope, and also uses confocal imaging techniques to provide improved image clarity and to allow optical sectioning of the tissue.
Initial applications under development include early detection of colon cancer, incorporating the mic-roscope into a colonoscope, to be followed by development of applications in lung cancer detection. The device can in principle be employed in any application where an endoscope is used, and is priced at EUR 130,000 in Germany. According to clinicians who have assessed the technology, endomicroscopy has the potential to become the standard method for gastroenterological examination and could in theory replace 100% of the endoscopic biopsy and laboratory-based histology exams performed today.
Advances in drug delivery technology
Another growing segment of the medical device market in Europe is drug delivery products, including infusion pumps for use both in the hospital and in ambulatory therapy. The market also includes insulin infusion pumps used by Type 1 diabetics for improved control of glucose levels. As shown in Table 3, the market for drug delivery devices exceeds $1 billion worldwide and is growing at double-digit rates. As a result, it is attracting a number of new suppliers. Q-Core (Ramat Gan, Israel) introduced a new electromagnetic pump technology at MEDICA with applications in both hospital and ambulatory drug delivery that promises reduced costs, improved safety and increased user-friendliness as compared to existing ambulatory drug infusion devices. The Q-Core pumps use Electromagnetic Flow Control technology, which allows the pump to perform any linear or non-linear flow profile, with no restrictions on the physical orientation of the pump. Applications include patient-controlled analgesia, enteral feeding and both continuous and intermittent drug infusion. Q-Core is in the process of obtaining a CE mark for the pump, and will then introduce the product in Europe through distributors. An important characteristic of the EFC technology for ambulatory applications is its low power consumption, which allows the pump to operate up to 25 hours with a typical flow rate of 125 ml/hr on one battery charge. The high flow accuracy afforded by EFC technology also makes the pump suitable for hospital use. As a result, the Q-Core pump can bridge the gap between hospital and ambulatory care.