BBI Contributing Editor

SAN DIEGO, California Point-of-care (POC) testing has been one of the growth segments within the clinical diagnostics industry for more than a decade, driven by new developments in sensor technology and demands from healthcare providers and patients for more rapid and convenient testing to improve efficiency and outcomes. POC testing is now applied in the management of a wide range of diseases and in a broad spectrum of sites both within and outside of the hospital. As shown in Table 1, the global market for POC in vitro diagnostics testing products of all types approached $6.9 billion at the product supplier level in 2002, comprising about 30% of the total IVD products market of $22.8 billion. Furthermore, the market for POC testing products is growing more rapidly than the overall IVD market. As Table 1 indicates, growth in the POC segment is forecast to average 9.1% over the 2003-2009 period, vs. expected growth for the total market of only 5% to 7% per year.

Point-of-care (POC) testing is now widely used in hospitals in the U.S. and is considered the standard of care, especially for critically ill patients. The advantages include improved clinical decision-making and faster therapeutic turnaround time, as well as reduced blood volume requirements. Gerald Kost, MD, PhD, of the University of California-Davis Medical Center (Davis, California), said during the September annual meeting of the College of American Pathologists (CAP; Northfield, Illinois) that POC testing is beginning to be adopted more widely outside the U.S. He predicted that utilization would become worldwide within this decade.

A major factor driving the growth in POC testing has been the expansion in the range of analytes that can be measured on a single bedside testing platform. Systems such as the i-STAT System from i-STAT (East Windsor, New Jersey), for example, allow up to 13 different tests to be performed using a hand-held analyzer at the patient's bedside. Kost said he expects more expansion of the range of analytes available on a single platform in the future.

POC cardiac markers and POC coagulation testing products are showing rapid growth. Some emerging applications likely to represent attractive opportunities include glycated hemoglobin testing products for improving the management of diabetes, and tests for the detection of sepsis for use in the hospital critical care department. A product for POC sepsis testing, for example, was just approved for use in Europe, addressing a very large patient population. Sepsis is a major clinical challenge in the hospital setting. In the U.S., more than 750,000 people develop severe sepsis each year, mostly in the critical care environment, and mortality rates range from 28% to 50%, according to data presented by Kost.

The economic impact of sepsis is estimated at $16.7 billion per year in the U.S., and age shifts in the population are projected to increase the incidence of severe sepsis by 1.5% per year. Sepsis often develops rapidly in hospitalized patients, creating a significant need for tests that can detect the condition as quickly as possible.

Spectral Diagnostics (Toronto, Ontario) reported in September that it had received the CE mark for its Endotoxin Activity Assay (EAA), a new test that can be used to risk-stratify sepsis patients. The test is the first to provide physicians with a tool that can detect a broad spectrum of sepsis cases. Other products now in development are expected to play an important role in improving the ability of physicians to identify and treat sepsis in the critical care setting. A rapid POC molecular diagnostic test using target amplification technology for sepsis detection is under development by Aridia, a joint venture between Cepheid (Sunnyvale, California) and Infectio Diagnostic (Sainte-Foy, Quebec). Such tests will eventually allow clinicians to identify the best antibiotic to use in the treatment of sepsis, and to determine the optimum dose.

Studies have shown that patients who receive adequate antibiotic treatment for sepsis have a survival rate almost twice that for patients having inadequate therapy. The initial test from Aridia will run on a laboratory analyzer, but the second-generation test will be performed on a POC system near the patient in order to achieve the most rapid turnaround time. Kost said rapid diagnosis and treatment of sepsis could potentially improve patient survival by 50% if physicians know which organism is present.

New POC tests for use in the management of cardiac patients in the critical care unit, the emergency department, and the chest pain clinic also are proving valuable for clinicians. Critical care physicians are convinced that immediate results are needed for such tests, and that a delay of 30 minutes, as is targeted by many hospitals seeking to meet guidelines for turnaround time, is unacceptably long. Instead, they have implemented tests such as the Biosite (San Diego, California) Cardiac Triage that provides results in about 15 minutes.

A new marker being studied by Kost is POC lactate, a test that is available on the i-STAT system, among others, and is particularly useful in managing patients undergoing congenital heart surgery. A major drop in mortality among neonates and infants has been observed in pilot studies where serial measurements of lactate were performed at the point-of-care.

New cardiac markers, including a new cardiac-specific myoglobin from Spectral Diagnostics and the Biosite BNP test for congestive heart failure, are important examples of POC tests that will help to improve the ability of clinicians to rapidly and accurately diagnose patients and implement treatment without the delay and discontinuity associated with central lab testing.

A study of turnaround time for POC testing in the emergency department vs. testing in the central lab was described at the CAP conference by Kent Lewandrowski, MD, of Massachusetts General Hospital (Boston, Massachusetts). The study assessed a variety of test types that can be performed either at the point-of-care or in the central lab using existing technologies. As shown in Table 2, there was a highly significant drop in turnaround time for POC testing of more than 51 minutes, or 87% for all test types combined. The reduction in turnaround time ranged from 60% for glucose testing to 94% for pregnancy testing. Importantly, the study also found that the length of stay in the ED dropped by an average of 41 minutes after POC testing was implemented, from 389 minutes to 347 minutes.

While the overall impact on length of stay was relatively small, the implementation of POC testing solved a major bottleneck in the emergency department at Massachusetts General. In fiscal 1999, prior to the implementation of POC testing, the hospital recorded a total of 436 hours when the ED was filled to capacity and was forced to divert incoming patients to another hospital. In the hospital's 2003 fiscal year, following the implementation of POC testing, divert hours dropped by almost half to 222, and the number of diverts dropped by 13.3%.

Diabetes management and POC testing

There is little dispute about the benefits of POC testing in diabetes management, which represents by far the largest application of the technology. Recent studies have shown that more intensive self-monitoring, even for those patients who test multiple times per day, can provide added benefits in reducing complication rates. Products used for whole blood glucose self-testing now comprise one of the largest segments of the IVD products market.

Recently, there has been progress in the development of continuous glucose monitoring technologies, with two products now approved by the FDA. One, the CGMS from Medtronic MiniMed (Northridge, California), uses an electrochemical sensor that is implanted subcutaneously to track glucose levels in interstitial fluid at five-minute intervals over a three-day period. The patient's doctor then downloads the trend data to determine how well glucose levels are being controlled. Studies with the device have shown that conventional fingerstick blood glucose testing misses many clinically significant excursions.

A second device, the GlucoWatch from Cygnus (Redwood City, California), monitors interstitial fluid glucose through the skin using reverse iontophoresis. While so far only a small percentage of diabetics have adopted continuous monitoring, the existing technology represents only the first generation, and a wide range of additional devices are now in active development, as shown in Table 3 below.

Development of an accurate, completely noninvasive blood glucose monitor would have a major impact on market dynamics, and on market share in this key sector. Numerous companies have claimed to have promising noninvasive glucose monitoring technologies, but so far none have proven to be a substitute for conventional fingerstick testing. At least one device, the Pendra from Pendragon Medical (Zurich, Switzerland), is targeted for market launch in Europe next year.

While continuous monitoring devices, and particularly noninvasive monitors, clearly have their largest opportunity for use by individual diabetics, the technology also will have value in monitoring patients in the hospital, since whole blood glucose testing is by far the highest-volume POC test performed at the hospital bedside.

Recent studies have shown major benefits in outcome for diabetics undergoing cardiac surgery when tight glucose control is maintained in the ICU following surgery using intensive insulin therapy to maintain glucose in the 80 to 110 mg/dL range, vs. a range of 120 to 200 mg/dL that has historically been targeted. However, implementation of tight glucose control is problematic using fingerstick sampling because of the considerable added workload for nurses who are already in short supply in the ICU, and because of the imprecision that is typical for today's hand-held glucose meters.

A continuous glucose monitor, and particularly a noninvasive monitor, that could not only eliminate the added labor but also could detect transitions in glucose level often not revealed by intermittent testing and provide improved accuracy, could not only make tight glucose control practical in the ICU but also more effective.

The use of POC testing in diabetes management is not limited to whole blood glucose measurement, however. There has been a considerable level of new product development activity over the past two to three years in POC hemoglobin A1c measurement, for example. Hemoglobin A1c is used as an indicator of long-term glycemic control, since its level in blood is indicative of the average glucose level over the preceding three months. There now are about 100 million hemoglobin A1c measurements performed worldwide each year, according to product suppliers, and test volume is continuing to grow due to rapid increases in diabetes prevalence and growing awareness of the utility of testing in minimizing the adverse outcomes of diabetes.

As discussed by UC Davis' Kost, a recent development is the introduction of a new home-use testing device for hemoglobin A1c measurement. The A1cNow, developed by Metrika (Sunnyvale, California), is an electronic disposable hemoglobin A1c testing device that is sold with a doctor's prescription in retail pharmacies at a price of $21.99 and provides results using a fingerstick blood sample in eight minutes. The CLIA-waived product was cleared for marketing in the U.S. in January and also is marketed in Europe and Asia. Some physicians' office labs in the U.S. already have adopted the device for POC testing.

The A1cNow joins POC hemoglobin A1c testing products from a number of other suppliers in the IVD market, including Bayer Diagnostics (Tarrytown, New York), Bio-Rad Laboratories (Hercules, California), Cholestech (Hayward, California), Axis-Shield (Dundee, UK), BD (Franklin Lakes, New Jersey) and SpectRx (Norcross, Georgia). Most of those suppliers have launched their products only within the past two to three years, although the Bayer DCA 2000 has been on the market for more than a decade. The recent expansion in suppliers in the market is indicative of the growing demand for POC hemoglobin A1c testing, as well as of the large potential market for the devices.

Suppliers such as Metrika, Axis-Shield and Cholestech are developing additional POC testing products that are expected to drive further expansion in the range of analytes that can be measured at the point-of-care. For example, Metrika is developing the MicroalbuminNow Creatinine Monitor, a disposable single-use device that can test for microalbuminuria using an unprocessed urine sample in less than 10 minutes. Microalbuminuria is indicative of renal dysfunction, a condition that is often associated with diabetes, as well as with hypertension.

Metrika will further expand its offerings with the LipidNow Profile Monitor, a development-stage, single-use device that will provide a lipid profile in less than 10 minutes using a whole blood sample.

Another POC test targeted by suppliers including Axis-Shield and Cholestech is high-sensitivity CRP, a test that is attracting increasing attention as an independent risk marker for cardiovascular disease. Axis-Shield is developing a new POC testing platform, the COLIBRI system, that it plans to introduce in 2004, which allows a wide range of chronic disease tests, including tests for diabetes, cardiovascular disease, and cancer to be performed in the physician's office or other POC sites.

Future trends in POC testing

The growing array of products available for point-of-care testing exemplifies one of the megatrends in the sector, namely test menu expansion, that have characterized the field since the mid-1990s. As discussed by Lewandrowski, other major trends in POC testing include improved testing technology, consolidated instrumentation, a product line approach to the market by vendors, improved data management, improved organizational management and increasing utilization. With regard to menu expansion, other POC tests that Lewandrowski will add at Massachusetts General in the future include HIV, continuous blood gas analysis, drugs of abuse, thromboelastography, BNP and D-dimer.

Utilization of POC testing also is expected to grow in part as a result of menu expansion. At present, POC tests now comprise 8% of all tests performed at Massachusetts General, according to Lewandrowski, and some who are bullish predict that POC tests will comprise 70% of all IVD testing in five years.

Others, who consider POC testing too expensive and difficult to manage, believe it will remain a minor aspect of in vitro diagnostics. The truth may lie somewhere between those extremes, with the ultimate level of utilization depending on whether patient outcomes are improved as well as on advances in technology that will determine the range of tests that can be cost-effectively performed at the point-of-care.

Another important trend is the rapid proliferation of CLIA-waived tests in the POC marketplace. There are now slightly less than 100 CLIA-waived tests on the market in the U.S., vs. only about a dozen when the CLIA regulations were first implemented. The expanding range of available waived tests has helped to drive growth in the number of labs that perform only CLIA-waived testing and expanded the POC testing market. Between 2002 and 2003, the number of CLIA-waived labs increased from 93,129 to 98,193, accounting for most of the growth in the total number of CLIA-registered labs, which increased from 174,504 to 179,638. In July 1997, there were only 74,735 waived labs, demonstrating the rapid growth in waived testing in the U.S.

One of the most notable new waived tests is the OraQuick Rapid HIV-1 Antibody Test from OraSure Technologies (Bethlehem, Pennsylvania), cleared for marketing in January. The OraQuick version now cleared for marketing in the U.S. uses a fingerstick blood sample, but a version that uses a saliva sample has been developed, and OraSure has applied for marketing clearance for that product also.

A number of other infectious disease tests have also recently been granted waived status, including the Immuno/Strep A Detector from Immunostics (Ocean, New Jersey) and the QuStick Strep A test from Stanbio (Boerne, Texas).

The proliferation of waived tests, particularly for analytes such as HIV, have not been welcomed by some clinical laboratorians, in part due to concerns about accuracy and result interpretation but also because of the potential for reduced demand for testing in the central lab. However, agencies such as the Centers for Disease Control and Prevention (Atlanta, Georgia) have promoted the development of waived tests as a means to increase the rate of detection of diseases such as AIDS that represent major public health problems.

An additional trend enabled by the development of a wider range of waived tests is the increase in home testing. The range of home tests now available includes blood glucose, pregnancy, ovulation testing, cholesterol, drugs of abuse, HIV, coagulation, occult blood and hemoglobin A1c, and the global market for products used in home and self-testing exceeds $5 billion.

Another trend, although not one that is based on the use of POC testing technology, is the growing use of direct-access testing. Direct-access testing allows patients to order lab tests and receive results without the need for physician involvement. Tests can be ordered via the Internet, and for complex tests that must be performed in a laboratory, a consumer can either send in a specimen using a special collection kit or visit a specimen drawing center. In the U.S., 20 states now have laws that do not prohibit direct access testing, while another 12 states have laws that allow some types of direct testing. Laws in 18 states still prohibit such testing, although the trend is in the direction of wider availability.

A wide range of tests is available at prices that typically are lower than the cost of visiting a physician to have the test performed and with shorter turnaround time. Leading providers of direct-access testing services include Quest Diagnostics (Teterboro, New Jersey), Health Tests Direct (Costa Mesa, California), Nova (Conroe, Texas) and a number of companies now offering genetic testing services directly to the public.

So far, the proportion of lab tests being performed through direct-access services remains small. Quest Diagnostics, for example, estimates that 2% to 5% of its total requisition volume is attributable to tests ordered directly by patients, but such tests account for 5% to 10% of the company's total revenues.

The trend toward increased use of direct-access testing is not expected to be detrimental to labs, and in fact benefits most hospital labs that already are struggling to keep pace with growing test volume in the face of shortages of lab technologists. In the future, direct-access testing is expected to become available nationwide, and patient-directed testing is expected to become integrated into care plans.

Technology advances will continue to play a key role in expanding the use of POC testing, according to presenters at the CAP conference. A miniaturized, hand-held device for performing polymerase chain reaction (PCR)-based nucleic acid tests, the Bio-Seeq Analyzer, has been developed by Smiths Detection (Warren, New Jersey). It allows high-sensitivity detection of viral and bacterial pathogens in as little as 20 minutes. While the device is currently intended for use in biowarfare agent detection, it demonstrates the possibilities for future development in the POC in vitro diagnostics testing arena, such as in the early detection of sepsis.

Advances in areas such as microfluidics and microdetection are also playing an important role. The new Colibri system under development by Axis-Shield, for example, employs a microfluidic chip and camera to allow a wide range of complex test procedures to be performed on a single, low-cost platform. Other technologies that are expected to prove important include sensors for in vivo and ex vivo monitoring, which not only eliminate the need for reagents but also improve the ability to detect sudden or transient changes in patient condition, adaptive systems technologies that can minimize errors in diagnosis and integrated systems that combine monitoring and therapy for improved efficiency.

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