BBI Contributing Editor

LOS ANGELES – New developments in the clinical diagnostics market have historically been technology driven, stimulated by the discovery of new biochemical markers, advances in detection technologies and the introduction of automated systems that have allowed labs to generate test results in increasingly high volume while continuing to improve operational efficiency. As discussed by presenters at the annual meeting of the American Association for Clinical Chemistry (AACC; Washington) here this summer, advances in sensor technology are one of the factors expected to drive new developments in clinical diagnostics in the future, particularly in the area of point-of-care testing. Presenters at the AACC conference discussed trends in the field of nanotechnology that are expected to result in the development of new sensors with applications in clinical diagnostics.

Noting the major revolution in technologies for diagnostic testing that has occurred in the past 20 years, experts presenting at the conference predicted an accelerated pace of technological change over the next 20 years. In addition to advances in sensor technology, informatics also is expected to play an increasingly important role in driving technological change in the industry.

Informatics is, in fact, expected to play a pervasive role in the healthcare system of the future, having impacts in the areas of genomics, medical records, remote medicine and connectivity among the diverse providers of healthcare services. Informatics will also enable a major transformation in the rapidity of disease diagnosis, leading to "turbocharged" diagnosis, with significant reductions in the time needed to pinpoint the factors responsible for a patient's pathophysiology and to identify the most effective personalized treatment. Experts presenting at AACC, among them Jeff Goldsmith, PhD, of Health Futures (Charlottesville, Virginia), predict that the U.S. healthcare system will go electronic over the next 10 years, at a cost of $100 billion to $200 billion. That transformation will be enabled in part because patient data is rapidly becoming digitized, eliminating the bottleneck of data transcription that has hindered the implementation of electronic medical records in the past. Goldsmith envisions the development of a computerized navigation system for the medical field, which will manage a patient's transition through an episode of illness, and provide follow-up monitoring using remote sensors, intelligent devices and automated notification when physician interaction is needed.

At present, remote diagnostics and monitoring is at an early stage of development, providing data on parameters such as patient motion, location, temperature, oxygen saturation and basic ECG data. In the future, capabilities will expand to include features such as breath analysis (for noninvasive diagnosis), blood counts, visual acuity and remote viewing of internal organs via personal ultrasound devices.

The field of remote patient monitoring is now comprised of a number of small (and some large) companies developing monitors for one or a few parameters, each using its own base station and data interface. Eventually, consolidation is likely, and the need will emerge for a care organization that can supervise the comprehensive monitoring process. That organization could well be the clinical lab, since it already is the entity that is responsible for generating most of the data used in making patient management decisions.

New analyzers for central lab automation

To enable the transformation of clinical diagnostics that will be required by the healthcare system of the future, suppliers of testing equipment already have begun to introduce next-generation automated chemistry analyzers for both centralized and remote testing. These developments are part of a market that totals some $5 billion, with an annual growth rate estimated at nearly 3% annually for the remainder of the decade (see Table 1).

Bayer Diagnostics (Tarrytown, New York) exhibited the RapidLab 1265, a new bench-top critical care analyzer employing the same multi-test cartridge technology as the company's RapidLab 400, and which includes automated tracking of reagents via an RFID chip contained in each cartridge, automated detection of blood clots, electronic signature capability and a 28-day cartridge life. The 1265 will be available early in 2005. Bayer also introduced the IMS analyzer, combining clinical chemistry and immunoassay capabilities in a single, compact platform. The system offers a modular design to provide flexible expansion of throughput from the level of 400 tests per hour for clinical chemistry (700 per hour including ISE-based tests) and 100 tests per hour for immunoassay provided in the basic system. The IMS is based on a next-generation version of the analytical technology first introduced in the Chem 1 analyzer, as well as chemiluminescence immunoassay technology, with $300 million invested in the development program.

Bayer also exhibited a new hematology analyzer at the AACC gathering, the Advia 2120, launched this spring in the U.S., which provides a five-part differential at a throughput of 120 samples per hour and will include the capability to automatically prepare slides for differential testing using the AutoSlide integrated stainer, scheduled for launch in 2005. One of the leading suppliers in the urinalysis market, Bayer also announced the launch of the Atlas high-volume urinalysis system, which can be interfaced to the UF-100 automated urine cell analyzer from Sysmex (Kobe, Japan) to provide a complete high-speed urinalysis workstation for the central lab.

Abbott Diagnostics (Abbott Park, Illinois) described the development of a new family of hematology analyzers, which will include the Pearl, Ruby and Sapphire systems. The Sapphire is a next-generation version of the CellDyn 4000 that uses fluorescence and MAPSS technology for high-speed cell analysis, while the Ruby will use the optics of the CD3200 flow cytometer as its base technology and add new features. The Pearl will offer optical laser technology for performing white cell differential analysis. Introduction of the new analyzers is targeted for sometime next year.

Dade Behring (Deerfield, Illinois) described a wide range of new products for clinical chemistry and immunoassay, which are being developed as part of the company's ongoing strategy to increase its penetration of the clinical chemistry market and expand its market-leading position in the integrated chemistry/ immunoassay analyzer segment. The company now claims a 10% share of the chemistry/immunochemistry market, as well as a 37% share in coagulation testing, a 32% share in microbiology and a 17% share in the infectious disease testing products market. Dade Behring's Dimension family of chemistry analyzers had the largest number of new placements in clinical chemistry of any supplier according to an independent survey, and its Dimension RxL has the largest U.S. installed base of any integrated chemistry/ immunoassay analyzer.

Dade is expanding its offerings in the chemistry/ immunoassay segment via a partnership with Diagnostic Products Corp. (DPC, Los Angeles) that provides connectivity between the highly successful Immulite series immunoassay systems from DPC and the Dade Dimension in the StreamLab system. DPC is continuing to enhance its Immulite line with the addition of the Immulite 2500, a high-throughput (200 test per hour) analyzer that offers a 15-minute turnaround time for high-priority tests such as cardiac markers. The DPC partnership allows Dade to offer integrated chemistry/immunochemistry testing for a wider range of immunoassay tests, including some that require the highest level of sensitivity. Dade Behring's next-generation system in the integrated analyzer segment, the Dimension VISTA, will offer an even higher level of integration by adding on-board nephelometry as well as new assays employing the company's LOCI immunoassay technology. The system is targeted for full commercialization in 2006.

Another area of rapid technology development within the clinical lab is the use of mass spectrometry for performing clinical analysis of proteins. Mass spectrometry, when coupled with various specimen preparation methods that provide an initial separation of the components of interest, is proving to be a very powerful tool for the analysis of complex mixtures of proteins. According to one of the leading suppliers of mass spectrometry equipment, Thermo Electron (Waltham, Massachusetts), many clinical laboratories are replacing certain radioimmunoassay procedures with mass spectrometry-based assays, since mass spectrometry can achieve the high sensitivity needed without the use of hazardous radioisotope labels. A key limitation of mass spec that has prevented its use for many applications in protein analysis is its qualitative nature, a major drawback for clinical testing. However, a number of techniques have recently been developed to provide quantitative analysis, and Thermo Electron plans to unveil a technology within about a year that will offer a relatively inexpensive method for protein quantitation, based on ion trap detection.

While mass spectrometry has historically been used only for a limited number of applications in the clinical lab until now, mainly in the area of toxicology and nutrition, the potential exists for the technology to evolve to become a routinely used modality for the measurement of a wide range of protein analytes, particularly as the proteomics field matures. One telling sign of the growing importance of mass spectrometry in the clinical lab was evident on the AACC exhibit floor. All of the major vendors of mass spectrometry equipment exhibited at this year's show, whereas five years ago they were largely absent.

Small technology, advanced sensors

An emerging field that may become an important driver of the clinical diagnostics market in the future is small technology. As discussed by Rick Snyder of Ardesta (Ann Arbor, Michigan) at an AACC plenary session, small technology encompasses the areas of micro-electro-mechanical systems (MEMS), nanotechnology, mechatronics and microfluidics. Nanotechnology, which involves structures having dimensions of 100 nanometers or less, is attracting considerable attention at present, as it is thought to provide an avenue to the development of fundamentally faster and less-expensive devices for applications in electronics, mechanics, materials fabrication and chemical/ biochemical sensing. Snyder quoted data showing that venture capital investment in nanotechnology has increased from $85 million in 1991, representing between 0.5% and 1% of all venture investment, to $1 billion in 2003, representing 4% of venture investments. In addition, Snyder said he expects four to six initial public offerings to be completed this year by companies developing small or nanotechnologies.

Key development sectors in small technology include tools for materials analysis, engineered materials and smart devices including biochemical sensors. About 1,500 companies are involved in the small technology field, including about 170 in the life sciences. There already are numerous examples of small technology-based devices that have succeeded in the commercial markets, including micro-mirror devices used in digital projectors, ink jet printer heads and imaging devices employed in medical and life science applications.

One development predicted by Snyder that could impact clinical diagnostics is direct detection of small numbers of target molecules, vs. existing approaches employing technologies such as nucleic acid amplification. Small technology also may allow expansion of the number of analytes that can be measured at the point of care, and ultimately could enable the development of implantable sensors for detecting, and perhaps controlling, events such as seizures or for managing chronic diseases such as diabetes. However, numerous barriers to acceptance exist, according to Snyder, including manufacturability, FDA approval, reimbursement issues and the need for considerable additional investment in order to achieve commercialization.

Significant progress already is evident, however, in the development of applications of small technology in areas that will impact clinical diagnostics. As shown in Table 2 below, a number of companies and institutions have described new sensors, microfluidic devices, and microsampling devices that address important applications in diagnostic testing. Chempaq (Copenhagen, Denmark), for example, has developed a system consisting of a miniaturized cartridge containing micro-impedance sensors for performing a complete blood count (CBC) at the point of care using a small, handheld analyzer. The Chempaq XBC analyzer provides results in less than three minutes, including a three-part differential, platelet count, and hemoglobin level.

Magna Biosciences (San Diego) has developed a new magnetic sensing technology that provides detection sensitivity equivalent to that available with existing fluorescence-based immunoassay systems, and which provides improved quantitation compared to optical detection methods. A key advantage of Magna's magnetic detection technology is that it detects label distributed throughout a chromatographic test strip, whereas optical methods only detect molecules in the vicinity of the surface of the strip. Colloidal iron particles with diameters ranging from 60 microns to 300 microns are used as labels, and detection is accomplished using an oscillating magnetic field that allows sensing of the number of particles trapped in a magnetic field zone. In a demonstration project for the U.S. Navy, Magna developed an assay for Staph enterotoxin B that was 10 to 1,000 times more sensitive than lateral flow immunoassay devices using visual detection. Costs are said to be lower than for comparable assays using chemiluminescence labels.

Another promising area of application for small technology is cell-based sensors. As described by Albert Van Den Berg, PhD, of the University of Twente (Bilthoven, the Netherlands) and the MESA Institute for Nanotechnology, nanometer-size probes are being used for analysis of biochemical events in single cells, allowing, for example, assessment of oxidative stress at the cellular level. Helene Andersson, PhD, of Silex Microsystems (Jarfalla, Sweden), described microchip sensors that use cells as the active component, which can be used to assess drug effects or apoptosis when cells are exposed to varying environmental conditions. A number of other new sensor technologies are under development that show promise for applications in non-invasive monitoring of glucose and other analytes, and for point-of-care immunoassays for blood lipids, cardiac markers and markers of liver and renal disorders, as shown in Table 2.

Advances in point-of-care testing

New sensor technologies are expected to play a particularly important role in expanding the use of point-of-care (POC) testing in clinical diagnostics, a segment that already comprises close to one-third of the diagnostics market, according to some experts. A number of new POC testing products were described at the AACC conference that will help drive continued growth in the market. Biosite (San Diego), now the leading supplier of point-of-care products used in cardiac marker testing, exhibited its new Shortness of Breath panel, the Triage Profiler S.O.B., a quantitative point-of-care test that simultaneously provides quantitative measurement of D-dimer, BNP, Troponin I, CK-MB and Myoglobin. Indications for use include diagnosis of acute myocardial infarction, risk stratification of acute coronary syndrome patients, diagnosis of congestive heart failure (CHF), assessment of disease severity of CHF and evaluation of suspected pulmonary embolism. Turnaround time for the test is about 15 minutes. The target patient population for the test is the 10 million individuals who visit emergency departments annually in the U.S. with shortness-of-breath, dyspnea and chest pain. The test can help physicians make a more accurate and rapid diagnosis, allowing timely patient triage to speed treatment when needed and to improve efficiency in the ED.

Another supplier of point-of-care cardiac marker tests, LifeSign (Somerset, New Jersey), described a new cartridge-based quantitative POC CHF test that will run on the company's new compact bench-top reader. The LifeSign Myoglobin/Troponin I/CK-MB test also will be available on the reader, along with infectious disease and drugs of abuse tests.

Axis-Shield PoC (Oslo, Norway) announced a new POC system, the Afinion, which will be launched next month at the MEDICA exhibition in Dusseldorf, Germany, with tests for HbA1c and CRP, to be followed by additional tests for PT-INR, hsCRP, homocysteine and ACR. The Afinion is a compact desktop analyzer that provides results in three to five minutes using a 1 L to 15 L capillary whole blood sample, and is a next-generation system to follow the company's existing NycoCard POC instrument. Axis-Shield is a growing player in the POC testing products market, and has more than 12,000 NycoCard POC instruments installed worldwide. Sales for the NycoCard line increased 15.7% in 2003 to about $21.6 million. The company has not yet established distribution agreements for the Afinion in the U.S. market, and may elect to set up a new direct sales unit.

Another supplier of POC cardiac tests, AccuTech (Vista, California), which now markets visually read quantitative test cards for total cholesterol and HDL cholesterol, also will introduce a new hs-CRP test in about one year which will be designed in the company's AccuMeter format, and will have a sensitivity of 3 mg/L.

As shown in Table 3 below, the worldwide market for professional-use POC testing products totaled almost $1.5 billion in 2003, and is forecast to grow at a 9.6% compound annual rate over the next five years. The market estimates do not include home and self-testing products, such as whole blood glucose test strips and meters for personal use. Segments that are expected to exhibit particularly strong growth include professional-use whole blood chemistry products (primarily whole blood glucose testing products) and POC cardiac marker testing products, including POC tests for BNP, TnI, CK-MB and myoglobin, as well as new tests that are expected to enter the market later in the period such as stroke markers and new tests for cardiac ischemia. The POC cardiac marker segment grew almost 70% in 2003, mainly due to rapid growth in sales of BNP testing products by Biosite.

The coagulation monitoring products segment also is continuing to expand, due to growth in the number of patients treated for cardiovascular disease. For example, sales for the International Technidyne (ITC; Edison, New Jersey) division of ventricular-assist device manufacturer Thoratec (Pleasanton, California) increased almost 20% in 2003 to $55.5 million. That increase was due in part to increased sales in the coagulation self-testing segment, which is not included in the figures shown in Table 3, a segment that has entered a rapid growth phase and in which ITC now claims the leadership position in the U.S. International Technidyne estimates that there are only about 6,000 to 8,000 patients in the U.S. performing self-testing, but the number is growing rapidly. In Europe, about 100,000 patients are performing coagulation self-testing, including 50,000 to 70,000 in Germany. At the AACC exhibition, ITC discussed plans to develop a next-generation version of its ProTime instrument which will provide increased connectivity and data management features. Longer-term, the company is evaluating development of a new system that will combine its coagulation testing technology with the blood gas/electrolyte/chemistry technology acquired last year from Diametrics Medical (St. Paul, Minnesota). ITC also exhibited its Hgb Pro professional hemoglobin testing system, a CLIA-waived, hand-held analyzer priced at $200 that provides POC determinations of hemoglobin level using a $1.00 disposable test cartridge. The system requires a 15 L whole blood sample and provides results in 30 seconds or less.

Another growing segment of the professional-use POC testing products market is systems for hematology analysis. The Chempaq XBC point-of-care CBC device is an example of trends in the POC hematology segment which reflect an increasing demand for blood counts and related tests in point-of-care settings. Established suppliers in the hematology segment also are pursuing the POC market opportunity, as indicated by the development of a new POC hematology analyzer by Sysmex, the pocH-100i, for the physicians' office lab market. The new system provides a three-part differential and CBC using a 15 L sample in two minutes, offers cap-piercing capability, and is priced at $13,500. Digital Biotechnology (Seoul, Korea) exhibited a new device for performing cell counts, the iN CYTO microchip hemocytometer. The system consists of a disposable plastic chip containing a Neubauer grid pattern with integrated injection ports, and an automated image analyzer, the C-Reader, with a CCD camera detector. Applications include white and red cell counting, counting of somatic cells, and counting of bacteria, as well as assessment of cell viability.

A number of new POC infectious disease testing products were described at the AACC conference. Trinity Biotech (St. Louis) showed its Uni-Gold Recombigen HIV test, a new rapid (10 minute) test for HIV-1 antibody in whole blood, serum or plasma. The company recently received notification of CLIA- waived status for the Uni-Gold HIV test, which is priced at $11 to $15 depending on quantity. BRAHMS (Hennigsdorf, Germany) exhibited its Procalcitonin test for detection of sepsis, currently under investigational use status in the U.S., which is available in Europe in a rapid (30-minute) semi-quantitative format, or as a quantitative immunoassay for the central lab.

Hema Diagnostic Systems (North Bay Village, Florida) is developing a new rapid POC testing platform that incorporates a novel housing to help avoid cross-contamination. The first test under development is a rapid HIV test, and additional tests may include assays for West Nile virus as well as cardiac markers and CRP. The company also is developing a broad range of additional POC infectious disease tests, including tests for tuberculosis, hepatitis B and sexually transmitted disease, which are not yet cleared for marketing in the U.S. The POC infectious disease testing market accounts for most of the sales in the POC immunoassay segment shown in Table 3, and exceeded $250 million worldwide in 2003, growing at 7% to 8% per year. Continued expansion is likely as new infectious agents emerge and as new tests for conditions such as sepsis become more widely accepted in the marketplace.

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