BBI Contributing Editor

ORLANDO, Florida — A major area of new product development activity in clinical diagnostics is automated lab systems, particularly systems for automation of chemistry and immunochemistry testing. While automated laboratory systems, including systems that automate all phases of the testing process, have been available for some time, new products continue to be introduced that provide additional options addressing a wider range of laboratories, as seen at the late-July annual meeting of the American Association for Clinical Chemistry (AACC; Washington).

Ortho Clinical Diagnostics (Raritan, New Jersey), for example, described its evolving Fusion series of chemistry/ immunochemistry analyzers that features a combination of dry chemistry slide and microvolume wet chemistry technologies to perform a wide range of assays on an integrated platform. The first system, the 5.1FS, will be ready for shipment starting in 2003, and will eventually accommodate up to 80 different chemistry and special chemistry assays. Throughput will exceed that of any of the available Vitros analyzers, or more than 900 tests per hour. Ortho also reported the development of the 5.2FS high-volume immunoassay system; and the 5.3FS that will offer combined high-volume chemistry/immunochemistry capabilities. Another system, the 3.1FS, will be targeted at labs requiring medium-volume chemistry testing capabilities, and the 3.2FS will be designed for medium volume immunochemistry testing. The 3.3FS will be a combined chemistry/immunochemistry system targeted at smaller or mid-sized labs.

While Ortho historically has relied on the advantages of its Ektachem dry slide chemistry technology, which employs a separation layer that typically excludes many interfering substances, to maintain a position among the market leaders in the global clinical chemistry segment, recent trends have demanded more advanced capabilities. The MicroTip technology was introduced in response to those demands, and Ortho is counting on the combination of technologies, along with enhanced chemiluminescence immunoassay technology in the future, to remain competitive. The Ortho systems feature a workstation philosophy that focuses on maximizing the efficiency and cost-effectiveness of specific segments of lab testing, rather than on attempting to integrate and automate all processes in the clinical lab.

Bayer Diagnostics (Tarrytown, New York) also is investing aggressively to enhance its product offerings for lab automation. Bayer's Advia 1650 clinical chemistry system has been well received in the market place so far. For example, Bayer recently announced a contract with Novation (Irving, Texas), a major supply company serving 7,700 members of three purchasing organizations including VHA Inc., University HealthSystem Consortium and HealthCare Purchasing Partners International, to supply immunoassay and lab automation products. More than 500 Advia 1650 instruments are in clinical use worldwide, including more than 50 in the U.S. The 1650 can be interfaced to Bayer's high-throughput Centaur immunochemistry system to provide an integrated workstation (the Advia Workcell), an approach that many labs are adopting in the face of worsening shortages of lab technologists. By using a high-throughput system such as the Centaur, with a stat turnaround time of 19 minutes and a test throughput of 240 tests per hour, labs can eliminate batch processing of samples, running all specimens as they are received and lowering average turnaround time. For example, the laboratory at 325-bed Swedish Covenant Hospital (Chicago, Illinois) installed the Advia 1650 and Centaur workstation configuration and reduced turnaround time for tests requested by the ICU by 47 minutes, and turnaround time for routine tests was reduced to 95 minutes.

Even some larger labs, such as one at the 805-bed Wake Forest University Medical Center (Winston-Salem, North Carolina) performing 3 million tests per year, have found that the workstation approach can be attractive compared to total lab automation because of the extended return on investment (typically over three years), complexity, long implementation time and laboratory information system (LIS) interface issues associated with total automation. The Wake Forest lab succeeded in eliminating two full-time equivalent (FTE) positions in the chemistry/ immunochemistry section, reduced stat immunoassay turnaround time from 60 minutes to 40 minutes (for Troponin I), and reduced stat glucose turnaround time from 45 minutes to 34 minutes by installing an Advia 1650/Centaur workstation consisting of two linked 1650/Centaur systems. Total workstations were reduced from 4.5 to one. A new Advia model, the 2400, has just been added to the Bayer line that offers higher throughput for chemistry testing.

Other leading suppliers of chemistry/immunochemistry/hematology automated workstation products include Abbott Diagnostics (Abbott Park, Illinois), Beckman Coulter (Brea, California), Roche Diagnostics (Indianapolis, Indiana), Dade Behring (Deerfield, Illinois) and Olympus Clinical Instruments (Tokyo). Abbott is developing the Architect instrument line, with the i2000 immunoassay instrument now available and the c8000 chemistry analyzer having just received FDA clearance. Abbott next will focus on developing a linked workstation (the ci8200) comprised of the i2000 and c8000 instruments, providing a throughput of 1,400 tests per hour. Beckman Coulter's Synchron LXi 725 is the company's newest offering, allowing chemistry and immunochemistry testing to be performed from the same primary sample tube. The LXi 725 offers closed tube sampling and automatic specimen aliquotting. Throughput is quoted at 1,440 chemistry and 100 immunochemistry tests per hour, with a menu of 146 tests. Other products that compete in the workstation/lab automation segment include the Modular Analytics, Roche/Hitachi and Roche/Sysmex lines from Roche Diagnostics; Dade Behring's StreamLab, and the OLA 1500, OLA 2500 and OLA 4000 systems from Olympus.

The advancement of lab automation in the clinical diagnostics industry is continuing to expand as more suppliers enter the market with expanded automation options, and as shortages of lab personnel and increases in test volume in the industry require labs to perform more tests with fewer technologists. As shown in Table 1, there are only about 300 labs worldwide that have installed total lab automation systems capable of handling all aspects of the testing process, from loading of the specimen tube to result generation for all the major lab disciplines (chemistry, immunochemistry, and hematology), while a number of others have automated one or more sections of the lab. The trend toward increased use of automation is expected to continue, with most of the growth in workstation-based automation rather than total lab automation. Based on information presented at the AACC conference by a number of labs that have adopted the workstation approach, most facilities can expect to reduce the number of instruments in chemistry and immunochemistry by a factor of two, and to reduce FTEs by a similar factor.

POC testing, physician's office segments

Clinical diagnostics market sectors that continue to attract investment by suppliers include the hospital-based point-of-care (POC) market, self-testing products and products for the physician's office laboratory (POL). The POC hemostasis testing products segment is advancing on two fronts. There is growing interest in platelet function testing at the point of care, as well as in tests that can help identify patients who are at risk for conditions such as heparin-induced thrombocytopenia, a condition affecting patients who have had prior surgery and which can lead to life-threatening disorders such as pulmonary embolism, gangrene and thromboembolism. In addition, coagulation self-testing is expected to increase in popularity later this year as reimbursement becomes available through Medicare for heart valve patients.

As discussed by Paula Santrach, MD, of the Mayo Clinic (Rochester, Minnesota) at the AACC gathering, up to half of all cardiac surgery patients may have antibodies to heparin as a result of a prior treatment, and in 1% to 2% of those patients thrombocytopenia occurs due to formation of immune complexes when they receive another heparin dose. About 51% of patients experiencing heparin-induced thrombocytopenia develop thromboembolism, and 37% die. To prevent such adverse events, Santrach uses the Ecarin Clotting Time (ECT) assay manufactured by Pharmanetics (Morrisville, North Carolina) and marketed exclusively by Bayer Diagnostics on the RapidPoint Coag POC testing system. The test is approved under humanitarian device exemption regulations, and thus must be provided under institutional review board control and informed consent. However, it can play an important role in avoiding adverse events in cardiac surgery patients who are typically at high risk. When a patient scheduled for cardiac surgery tests positive with the ECT assay, the physician can either delay the procedure until the antibodies disappear (typically requiring 50 to 85 days from the initial rise in titer) or switch to an alternative anticoagulant.

Platelet function testing is gaining increased importance as a result of the growing use of anti-platelet agents such as clopidogrel, ticlopidine, aspirin, and GP IIb/IIIa inhibitors in cardiology. As discussed by Steven Steinhubl, MD, of the University of North Carolina (Chapel Hill, North Carolina) during the AACC meeting in the sprawling Orange County Convention Center, there is a high degree of variability among patients in their response to such agents, but most are treated with a standardized dose, at present. Systems now available for platelet function testing include the PFA-100 from Dade Behring, the Ultegra from Radiometer Medical (Copenhagen, Denmark) and the Plateletworks from Helena Laboratories (Beaumont, Texas). By using POC platelet function testing to optimize the dose of anti-platelet agents, physicians can minimize concerns that arise, for example, when patients from the cath lab must undergo emergency CABG procedures. Since an increasing number of patients undergoing angioplasty and stent procedures are being treated with anti-platelet agents, particularly clopidogrel, those who are high responders are at risk of excessive bleeding if they must be switched to surgical treatment and have received a standardized dose. Tests are now available for POC use on systems such as the Ultegra, for example, to monitor not only anti-platelet agents such as abciximab but also aspirin and other agents to ensure that the dosage is optimized for each patient.

The market for coagulation self-testing products is likely to be stimulated later this year by the availability of reimbursement, as well as by the introduction of additional products tailored for that application. Reimbursement under Medicare will be available in three categories, including 1) a physician reimbursement for training of patients in the use of the test system; 2) an additional reimbursement to physicians for oversight of ongoing testing (paid in four-test increments); and 3) reimbursement for the cost of the test. Reimbursement is being provided under a Diagnostic Service Model, with payment made to the agency that is managing the patient. At least one private insurer, Aetna (Hartford, Connecticut), has indicated that coverage will be added, according to LifeScan (Milpitas, California), although a different reimbursement model will be used.

The primary existing supplier of home prothrombin monitoring devices is the International Technidyne (Edison, New Jersey) division of Thoratec (Pleasanton, California). Other systems cleared by the FDA for home use include the Roche CoaguChek PST and the Harmony INR system from LifeScan/Johnson & Johnson. A system from Avocet Medical (San Jose, California) was cleared in late 1998 but is no longer actively marketed. Roche also announced that it was discontinuing marketing of its product for home testing.

However, as reimbursement becomes available in October of this year, there may be renewed interest in the market. The LifeScan Harmony system will be available for shipment at the end of the year, with pricing for the instrument expected to be between $1,295 and $1,500. There is potentially a large market for home prothrombin time or INR testing. As shown in Table 2, data from the Center for Medicare & Medicaid Services (Baltimore, Maryland) indicates that there are more than 1 million patients in the U.S. alone who have conditions such as atrial fibrillation or who have suffered a stroke who could benefit from anti-coagulation therapy but do not receive it, and that for 80% of the patients who are receiving therapy the frequency of testing is probably too low, as indicated by increased rates of adverse events. Home testing, now employed by less than 5% of all patients, is a potential solution to the problem of underutilization of therapy and of testing, since physicians are often reluctant to subject patients, particularly older ones, to a potentially dangerous treatment with adverse event rates in excess of 15%. Since home monitoring has been shown to provide the lowest adverse event rates, it may become the preferred method in the future, and could also result in increased utilization of anticoagulation therapy.

Additional new products for POC testing were shown on the Orange County Convention Center exhibit floor by Clinical Analysis Corp. (Doylestown, Pennsylvania), LifeSign (Somerset, New Jersey), Quidel (San Diego, California), Orion Diagnostica (Espoo, Finland), Polymer Technology Systems (Indianapolis, Indiana), Otsuka Electronics Co. Ltd. (Osaka, Japan) and Stanbio Laboratory (Boerne, Texas). Clinical Analysis introduced the Bio-Chem Analyzer 1, a hand-held analyzer employing disposable test strips that use planar sensor technology and three different electrochemical analysis methods (potentiometric, amperometric, and conductometric) to perform various routine chemistry tests on a 60 uL whole blood sample. The test menu includes sodium, potassium, calcium, hematocrit, hemoglobin and chloride, with additional tests under development including BUN, glucose, blood gases and creatinine. The color-coded test cards include bar code labels for positive test identification, and the system also has an integrated bar code reader allowing the patient's wristband to be scanned at the bedside. The test strips use dry reagents, providing a one-year shelf life at room temperature. Three different data ports are included for interface to a laboratory information system, and a built-in thermal printer also is included. The system will be introduced in the first half of 2003, following completion of clinical studies that are about to begin. The company's goal is to obtain CLIA-waived status for all tests. Polymer Technology Systems' CardioChek and CardioChek PA instruments also provide POC chemistry testing capabilities, but the menu is focused on lipid, glucose and creatinine testing rather than critical care analysis.

LifeSign introduced new POC cardiac marker tests at the AACC exhibition. The company has manufactured similar products for Spectral Diagnostics (White Stones, Virginia) and has now begun marketing the devices under its own label. Tests are available for Troponin I, CK-MB and myoglobin. A reader also is under development. LifeSign also has introduced the Alzheimer's Dementia Assay, which detects high levels of glutamine synthetase in whole blood, plasma or serum, as an aid in the early diagnosis of Alzheimer's dementia. The test was developed by SynX Pharma (Toronto, Ontario) and is manufactured by Princeton BioMediTech (Princeton, New Jersey).

Quidel introduced the UrinQuick automated urine analyzer, a product that was launched in Europe at last November's MEDICA exhibition. The technology was acquired from Dade Behring and provides the capability to store results for 500 patients in a benchtop analyzer priced at $8,000 to $10,000. The company will compete with major entrenched suppliers in the urinalysis segment, including Bayer and Roche Diagnostics, but believes its strong position in the POL segment coupled with a distribution alliance with Allegiance Healthcare (McGaw Park, Illinois) will enable it to penetrate the market. Long-term, Quidel is investing to develop a new and expanded family of POL testing products based on its Layered Thin Film (LTF) analytical technology. The first product to be introduced in that line is a test for bacterial vaginosis that provides a result at the point of care in less than two minutes, and replaces a set of three exams including a microscopy test. Other applications that will use the LTF technology are planned in the areas of tumor markers and semi-quantitative cardiac marker tests.

Orion Diagnostica previewed its new QuikRead CRP assay at AACC. The test is performed using disposable reagent caps in the QuikRead reader. The system already is available in Europe at a price of Euro 800, with disposables priced at about $2 each. U.S. launch is planned for early next year pending FDA clearance. CRP testing is used to distinguish bacterial from viral infections, to monitor and control post-operative infections, and to monitor antimicrobial therapy. High-sensitivity versions of the CRP tests are rapidly gaining in popularity as a result of recent studies showing the value of hs-CRP as an independent risk factor for cardiovascular disease.

Meretek (Nashville, Tennessee) exhibited a new device, the DiaScan, manufactured by Otsuka Electronics (Osaka, Japan), for reading qualitative test strips at the point of care. The battery-powered device is intended primarily for use in the POL to provide a rapid, objective analysis of reflectance test strips used to perform pregnancy and infectious disease tests, and will be launched in the near future. Stanbio Laboratory demonstrated a new POC hemoglobin test system, the STAT-Site M Hgb that will compete with the Hemocue hemoglobin analyzer now used in thousands of POLs and clinics worldwide. The STAT-Site analyzer is priced at $167, and test cartridges cost $1 each. A single test requires 10 uL to 12 uL of whole blood, with results available in a few seconds.