Biomedical Business &Technology Contributing Editor

Personalized medicine, decentralization, changing regulations, new healthcare IT systems are altering, expanding the testing/screening landscape

SAN DIEGO — The annual meeting of the American Association for Clinical Chemistry (AACC; Washington) and Clinical Lab Expo, held here in mid-July, highlighted the major strategic changes among leading suppliers in the diagnostics market as well as the shifting demands on laboratories resulting from key trends in this sector. These key trends include: personalized medicine, decentralization of diagnostic testing, and changing requirements for management of healthcare information.

New developments that will suppliers in the diagnostics market were described in a diverse range of application areas, including pharmacogenomic testing and molecular diagnostics; point-of-care testing; proteomics and immunoassay technology; and information technology. In addition, emerging trends in the integration of diagnostic imaging and laboratory diagnostics were described that may lead to a major restructuring of diagnostics market, including significant changes in the competitive structure of the in vitro diagnostics industry.

Sector an investment magnet

The diagnostics industry is becoming increasingly attractive for investment as growth in the market has accelerated. As shown in Table 1, the global in vitro diagnostics market totaled an estimated $33.7 billion in 2006 and is forecast to grow at a 6.5% compound annual rate to more than $46 billion by 2011. High-growth segments of the market include molecular diagnostics, forecast to expand at a 9% compound annual rate, and whole blood glucose testing, expected to grow at a double-digit rate (included within the Chemistry segment in Table 1).

As discussed by Eugenio Zabaleta, PhD, of the MedCentral Health System Laboratory (Mansfield, Ohio), at an AACC session sponsored by Siemens Medical Solutions Diagnostics (Tarrytown, New York), it is recognized that 60% to 70% of the data used to make clinical decisions is generated by the laboratory, but the percentage increases to 90% if diagnostic imaging data is added. Consequently, the convergence of diagnostic imaging and in vitro diagnostics, combined with advanced information technology to collect, interpret, and distribute information throughout the healthcare system, will enable the emergence of integrated suppliers addressing almost all of the factors involved in patient management.

While that transition is expected to occur slowly among suppliers of diagnostic products, some academic medical centers are already moving in that direction, and soliciting vendor assistance in establishing such programs.

(For IVD R&D Spending in 2006, see Table 2.)

Integrating in vitro diagnostics, imaging

The acquisitions of Bayer Diagnostics and Diagnostic Products Corp. (Los Angeles) by Siemens, both completed in 2006, represented the first concrete step among suppliers to integrate imaging and laboratory testing within a single entity, with information technology (IT) serving to link the modalities from a functional perspective. Another such combination, which would have integrated the core laboratory diagnostics business of Abbott Laboratories (Abbott Park, Illinois) with the imaging business of GE Healthcare (Chalfont St. Giles, UK), was abandoned this summer, but expectations within the industry are that additional mergers or acquisitions combining imaging and in vitro diagnostics companies are quite possible.

Examples already are emerging that demonstrate the potential benefits of such integration.

At an AACC symposium addressing the integration of imaging, biomarkers and interventional therapy for coronary artery disease, Allan Jaffe, MD, of the Mayo Clinic (Rochester, Minnesota), described recent experience using high-sensitivity cardiac troponin assays to detect micro-infarcts that are not detected by imaging methods. Slight troponin elevations, which have only become detectable using the latest-generation assays, have generally not been considered to be significant, but Jaffe has found that they are highly prognostic.

He said it may be possible to use markers such as high-sensitivity troponin along with others, including NT-proBNP and high-sensitivity CRP in combination with imaging modalities such as MRI, CT and intravascular ultrasound to identify vulnerable plaque, demonstrating the benefits of combining in vitro and in vivo diagnostics.

As discussed by Kristin Newby, MD, of Duke University Medical Center (Durham, North Carolina), the goal in cardiac diagnosis is to combine biomarkers and imaging in the mix that is least costly and most effective, using the two modalities in a synergistic manner.

Biomarkers have an obvious role in diagnosis of acute coronary artery disease by indicating if tissue injury has occurred and helping to determine prognosis, whereas in stable disease their role is to determine the risk posed by any plaque that is detected. In cancer management, molecular imaging is an important focus of development, ideally employing the same markers for imaging as are used in in vitro diagnostics. High-sensitivity markers can provide early detection of cancer, before a lesion becomes visible by imaging.

In the future, those same markers can be targeted with imaging agents once disease is detected to help localize a tumor and guide therapy. Conversely, imaging can be used in a highly selective manner to guide biopsy of a lesion to help ensure that subsequent molecular analysis of tissue in the lab uses tissue that is representative of the culprit lesion. Another approach that combines in vitro diagnostics with imaging, described by King Li, MD, of The Methodist Hospital (Houston) at the AACC conference, is the use of fiber-optic imaging probes with immunochemical staining to perform in vivo immunohistochemical analysis of tumor tissue.

IT an integrating enabler

An important enabler of the integration of in vitro and in vivo diagnostic modalities is information technology.

As discussed by Emery Stephens, president of Enterprise Analysis Corp. (Stamford, Connecticut), at a special symposium on integrating laboratory diagnostics and diagnostic imaging in an IT-driven environment held at the conference, implementation of new integrated approaches to medical practice is difficult without the use of sophisticated IT on an enterprise-wide foundation. One of the key drivers for expansion of IT in healthcare consequently is trends such as integration of diagnostics and others such as personalized medicine, which require the collection of data from a wide range of sources often not in close physical proximity, and integrating the data in a structured manner that allows it to be used effectively.

Siemens' IT portfolio, which was a focus for the company at this year's AACC exhibition, is an example of an advanced information management platform designed to meet the requirements for integrated applications.

The Siemens Advia CentraLink provides integration of various instruments within the central lab, while the RapidCom system captures data from the company's near-patient and point-of-care testing analyzers which are typically distributed throughout the hospital. Both Advia CentraLink and RapidCom link to the Novius Lab information system, which employs client server architecture.

In addition, the company provides a Positive Patient Identification system for identification of patient samples at the bedside via the BD.id Patient Identification System acquired in March 2007.

The Novius radiology information system is used to manage in vivo imaging data, and like Novius Lab, interfaces to the Soarian clinical information system to provide integrated patient data from both imaging and lab modalities. Almost 150 Soarian systems are installed worldwide. Siemens also featured the Real-Time Solutions product, acquired through the purchase of Diagnostic Products, which provides a real-time proactive maintenance for laboratory instruments via a remote electronic interface from the customer's lab instruments to Siemens.

Point-of-care testing gets IT-assist

Advanced IT systems also are playing an increasingly important role in point-of-care (POC) testing, by helping to make test results generated at the patient bedside, or by patients themselves, rapidly available to clinical information systems and electronic patient records, without burdening POC test system operators with time-consuming data upload requirements.

For example, the LifeScan (Milpitas, California) unit of Johnson & Johnson (New Brunswick, New Jersey) now markets the OneTouch Data Link Wireless system for use in POC test data management in the hospital setting. The system is used to capture data from bedside whole blood glucose tests performed by nurses, in many cases in conjunction with tight glycemic control (TGC) protocols in hospitals.

As described by Beverly Robertson of the University of North Carolina Health Care System (UNC; Chapel Hill, North Carolina) at an AACC press conference, the wireless connectivity provided by OneTouch Data Link Wireless has allowed bedside whole blood glucose test data to be made available not only on the UNC lab information system but also to a wide range of portable data devices such as PDAs and Apple i-Phones within two minutes of performing a test.

Previously, when docking stations placed throughout the hospital were used for data upload, data was transmitted only once every 24 hours. The system can be programmed to generate alerts in real time, significantly improving the ability of clinicians to implement TGC in the hospital.

The market for whole blood glucose testing products for use at the hospital bedside is exhibiting strong growth, due to the expanding use of TGC protocols in hospitals worldwide. LifeScan, the No. 2 supplier of whole blood glucose testing products worldwide in 2006, presented results of a 2006-2007 survey of U.S. hospitals that assessed utilization trends for TGC.

As shown in Table 3, 77% of LifeScan hospitals have implemented a TGC program, and an additional 20% are planning to implement such programs, indicating that TGC will soon be used in essentially all U.S. hospitals.

While adoption rates for TGC are lower outside the U.S., there nevertheless is continued growth in TGC utilization in hospitals worldwide. An important trend is the expansion in use of TGC outside of the Intensive Care Unit and Cardiac Care Unit, where it was first implemented.

As shown in Table 3, 85% of the hospitals surveyed by LifeScan have plans to implement TGC in additional departments of the hospital. Medical-Surgical units account for the largest percentage of new programs, followed by the Operating Room, the Telemetry unit, the ICU and the CCU.

Patient outcomes improving

The key driver of increased TGC adoption, as discussed by Steve Edelman, MD, of the University of California San Diego, at an AACC press conference, is improved patient outcome. Data from patient outcome studies not only shows a short-term improvement in mortality for patients managed with TGC, but the outcome benefits extend to four years post-hospitalization.

Four-year follow-up of the 970 cardiac surgery patients managed with TGC in the landmark study conducted by Van den Berghe et al. shows an 18% reduction in mortality for the cohort having a three-day ICU stay, and a 47% reduction for those patients having a five-day ICU stay. Edelman said that many additional studies of TGC correlate and validate the Van den Berghe study data.

POC outpacing clinical diagnostics

The worldwide market for point-of-care in vitro diagnostic testing products exceeded $11.3 billion in 2006, as shown in Table 4. The POC testing market includes products used in self-testing, physician's office laboratory/professional testing products and hospital bedside testing.

The POC testing products market is continuing to grow more rapidly than the overall clinical diagnostics market, due primarily to growth in self-testing products, which mainly consist of whole blood glucose testing products used by diabetics. However, other segments of the POC testing products market are expected to exhibit strong growth, including the POC cardiac marker segment as well as some newer applications.

Biosite (San Diego), the leader in the POC cardiac marker segment, described two development-stage POC testing products at the conference that promise to drive continued market expansion. Biosite is the process of being acquired by Inverness Medical Innovations (Waltham, Massachusetts), which is rapidly becoming a dominant player in the POC market excluding diabetes testing products. At an AACC workshop sponsored by Biosite, speakers described POC testing products under development for applications including sepsis testing and testing for acute kidney injury.

Emanuel Rivers, MD, of Henry Ford Health System (Detroit), discussed a three-marker panel for sepsis diagnosis that can be performed in 15 to 20 minutes at the hospital bedside. Rivers noted that while the availability of POC cardiac marker tests such as the Biosite Triage Cardiac Panel now allow myocardial infarction patients to be routed to the cath lab within 10 minutes of arrival in the Emergency Department, sepsis patients do not have that advantage. Some rapid sepsis tests are beginning to become available, including markers such as procalcitonin, C-reactive protein and lactate.

The new Biosite sepsis panel was developed through an extensive screening program that evaluated about 150 potential markers not only for their ability to detect sepsis but also for their capability to risk-stratify sepsis patients.

As discussed by Rivers, the Biosite panel allows discrimination of patients with community-acquired sepsis into high-risk and low-risk groups. The new sepsis panel exhibits a higher predictive power than existing sepsis markers, primarily because it includes markers that relate to multiple metabolic pathways, consistent with the fact that sepsis is a complex, multi-faceted syndrome.

The markers used in the Biosite panel include macrophage inflammatory protein-3 (MIP-3), C-reactive protein and neutrophil gelantinase-associated lipocalin (NGAL). The Biosite test addresses a significant market opportunity, since 2.9% of the more than 36 million hospital admissions in the U.S. each year are for severe sepsis and septic shock.

Sepsis testing opportunity

An additional market opportunity may exist for sepsis testing of hospital inpatients, but that application has not yet been evaluated for the Biosite assay. A validation study for community-acquired sepsis, the MINDSET trial, is planned for the U.S., and additional studies including the ENCOMPASS trial are planned in Europe.

A second test under development by Biosite uses NGAL, one of the markers included in the sepsis panel, for diagnosis of acute kidney injury. Acute kidney injury, or AKI, is a common problem present in 5% of all hospitalized patients, and in up to 50% of patients in ICUs. Incidence is increasing globally, and 4 million patients die annually of AKI. AKI requiring dialysis is one of the most important independent predictors of death in ICU patients.

At present, the diagnosis of AKI often is delayed, since it is based on measurement of serum creatinine levels, which vary considerably among individual patients and require several days to reach a new steady state. An early marker for AKI could enable more timely therapy, which could be very beneficial since early forms of AKI are often reversible. For example, patients undergoing cytotoxic chemotherapy are at risk for AKI, but often are treated as outpatients and thus are not monitored intensively to detect kidney damage. A POC test for AKI could potentially be used to detect the development of AKI in its initial stages, allowing corrective measures to be taken instead of allowing the patient to progress to acute renal failure.

NGAL could potentially serve as an early marker of AKI, and is one of a number of emerging AKI markers, as shown in Table 5. According to Prasad Devarajan, MD, of Cincinnati Children's Hospital Medical Center, who discussed AKI at a Biosite-sponsored workshop at the AACC conference, NGAL becomes elevated within two hours of the onset of kidney injury.

The marker exhibits high sensitivity and specificity of 93% and 88% respectively, since it becomes elevated by 10-fold to 15-fold in AKI. Biosite is developing an NGAL POC test based on its Triage format that will provide results in 20 minutes using whole blood or plasma samples. An opportunity also may exist to develop a POC urine NGAL test, which will eliminate the need to draw a blood sample at the point of care. A laboratory test for NGAL in urine is under development by Abbott Diagnostics (Abbott Park, Illinois).

POC making 'micro' and 'nano' bigger

New micro and nanotechnologies are expected to play an increasingly important role in POC testing in the future.

As discussed by Catherine Klapperich, PhD, of Boston University at an AACC symposium, emerging nanotechnologies are enabling more sensitive and accurate POC testing platforms to be developed, and are also allowing molecular diagnostics to move to the point-of-care, at least for some applications. Klapperich described a platform based on magnetic nanoparticles for performing nucleic acid assays at the point of care, including one that integrates a microsampling needle with the sensor chip to allow combined blood sampling and testing using a single device.

Two companies exhibited nanoparticle-based systems for use in POC testing applications at the conference, including MagniSense (Rosny-sous-Bois, France) and Magna Bio Sciences (San Diego), a unit of Quantum Design (San Diego).

MagniSense, working in collaboration with Indicia Biotechnology (Oullins, France), its contract R&D partner, is developing the MIAtek biosensor technology which uses nanometer-size superparamagnetic particles as labels for POC immunoassays. The company has developed a readout method that takes advantage of the non-linear response of the particles to a magnetic field, eliminating background and stray field effects and enhancing sensitivity.

The technology enables quantitative detection for assays that are currently limited to qualitative readout, and has demonstrated a sensitivity advantage in certain applications. A portable reader has been developed that can be operated from mobile power sources. Feasibility has been demonstrated with assays for avian flu virus, Legionella, a high-sensitivity prion assay, and POC immunoassays for Listeria and hepatitis B virus.

The MIAtek technology is particularly advantageous for tests that are targeted at non-professional users, since the effects of conditions such as sample hemolysis do not affect the readout as they do for optical methods.

Magna Bio Sciences is developing the MICT technology employing magnetic detection for applications in POC cardiac marker testing, thyroid and pregnancy testing, and POC infectious disease testing including POC tests for HIV 1/2, hepatitis B, and hepatitis C. At present, the company's products are for investigational use only, but plans call for development of in vitro diagnostic kits both for point-of-care and laboratory use.

Oxonica (Oxfordshire, UK) is another company developing POC testing products based on nanotechnology. Oxonica has a broad technology base encompassing applications in security, energy, materials and healthcare. The company's healthcare unit has developed nanoparticles that have been used in in vivo imaging, histopathology, laboratory diagnostics and POC testing systems. The nanoparticles are used as labels in a variety of prototype immunoassays as well as molecular diagnostic assays.

The key differentiating feature of the nanoparticle labels, known as SERS nanotags, is their ability to provide high sensitivity assays based on surface-enhanced Raman scattering. The SERS technology allows high-sensitivity immunoassays and molecular tests to be performed using a low cost portable reader with minimal sample preparation.

All reagents to perform an assay are contained in a single tube, and assay times of between two and 30 minutes are achievable compared to over five hours for conventional immunoassays for the same analytes. For cardiac markers such as Troponin I, Oxonica has demonstrated 40 pg/mL sensitivity, and for bacterial assays such as detection of E. coli strains, a sensitivity of 500 to 1,000 colony forming units has been demonstrated. Oxonica's strategy is to partner with established companies in the in vitro diagnostics market to commercialize assays employing the SERS nanotag technology.

POC growing into critical care

Two new POC critical-care testing products were exhibited at the AACC conference — the GEM Premier 4000 from Instrumentation Laboratory (Lexington, Massachusetts) and the Epoc blood analysis system from Epocal (Ottawa). The GEM Premier 4000 was first introduced in December 2006, but was marketed in a limited release until now. The 4000 performs critical care (blood gas/electrolyte/glu-cose/ lactate) testing at the hospital bedside, and adds co-oximetry to the menu available on the previous-generation GEM Premier 3000. In addition, the new system provides a direct bi-directional link to a server via the GEMweb Plus connectivity software for data management and remote system interface.

The Epoc system consists of a compact card reader that is placed at bedside locations throughout the hospital and communicates via a wireless interface to a PDA carried by the physician or nurse. Blood gas, electrolyte and hematocrit assays can be performed using low-cost test cards that allow up to 14 different tests to be performed on a single card. Cost for the test card is about 70% less than for equivalent test cartridges for the i-STAT bedside critical care testing system from Abbott Diagnostics. In addition, test cards can be stored at room temperature, significantly enhancing ease of use.

Although the Epoc system received FDA clearance in late 2006, the product still remains in limited release while the company installs high-volume manufacturing, with full market launch anticipated in 2008.

Alfa Wassermann (West Caldwell, New Jersey) previewed a new system, the S40, for the physician's office lab segment. The S40 is a compact clinical chemistry/immunochemistry analyzer that features a very simple user interface, random-access testing using individual bar-coded test cartridges, and test throughput of about 120 per hour. The analyzer is manufactured by Hitachi Medical Systems (Tokyo), and when development is complete will offer a menu of about 100 tests. The system is not yet on the market pending FDA clearance.

Emerging uses for molecular diagnostics

New developments in molecular diagnostics were described at the conference that demonstrate a trend toward increased levels of automation, as well as expansion of applications beyond the area of infectious disease testing, which at present accounts for over 90% of the market. Emerging applications include pharmacogenomic testing, cancer testing, and genetic testing including prenatal testing.

A promising new application highlighted in a special session at the conference is the use of circulating nucleic acids as an analytical target for a number of applications including testing for genetic defects and early detection of cancer.

Dennis Lo, MD, of Chinese University of Hong Kong, described an application in prenatal testing that involves detection of circulating nucleic acids in maternal plasma for prenatal detection of Rhesus D positivity of the fetus. In a mother who is Rhesus D-negative, detection of a the Rhesus D genotype in circulating nucleic acid is a definitive indication of an Rh-positive fetus. In labs that have adopted the assay, the test has replaced more invasive methods to check Rh status, and Lo believes the test is now beginning to gain acceptance in the U.S.

Testing of circulating nucleic acids can also potentially be used to detect a number of genetic defects, including congenital adrenal hyperplasia and muscular dystrophy, again without the need for an invasive sampling procedure. Another version of the test involves analysis of circulating fetal RNA using markers that are only present in the placenta.

That technique, which employs selective pcr amplification to isolate the desired nucleic acids, has been used successfully for prenatal detection of Down's syndrome, a more demanding application since it requires precise quantitation of the amount of fetal DNA present. In labs that have adopted circulating nucleic acid testing for prenatal diagnosis of genetic defects, the amniocentesis rate has been cut in half, according to Lo.

Circulating nucleic acid testing

Circulating nucleic acid analysis also has numerous potential applications in cancer testing, including applications in disease staging, detection of relapse, prediction and monitoring of response to therapy, assessment of occult disease, and identification of patients who are low risk of recurrence and therefore will not benefit from additional treatment.

At present, as discussed by Bret Taback of Columbia University Medical Center (New York) at the AACC symposium, the use of circulating nucleic acids is hampered by issues of low sensitivity, due in part to the low yield of the sampling process; lack of standardization of assays; variability of results due to the timing of sampling; and a lack of understanding of the source of circulating nucleic acids.

For example, the sensitivity of circulating DNA testing for detection of late-stage (grade III/IV) ovarian cancer is 95%, according to Taback, but detection of disease at an earlier stage is needed if the test is to be clinically useful in changing patient outcome.

New molecular diagnostics platforms

New products for molecular diagnostics were exhibited at the conference by a number of suppliers.

Both Roche Diagnostics (Indianapolis) and Abbott Molecular (Des Plaines, Illinois) have recently received FDA clearance for initial assays on their newest molecular diagnostic platforms, with Roche introducing the fully automated COBAS AmpliPrep/COBAS TaqMan System, and Abbott introducing the m2000 system, both with FDA-cleared HIV-1 viral load assays.

The Roche system requires samples to be pipetted from the primary specimen tube to a sample tube on the instrument, but after that initial step all other aspects of the assay are automated, including transfers from the AmpliPrep sample extraction and processing system to the TaqMan real-time PCR system. Roche next will add tests for hepatitis C virus, hepatitis B virus and cytomegalovirus to the COBAS AmpliPrep/COBAS TaqMan automated platform in the U.S. Roche has sold 5.1 million hepatitis B nucleic acid tests in the past two years alone, indicating the expansion of the infectious disease nucleic acid testing market.

The Abbott HIV assay is unique in its ability to detect all known subtypes of HIV. The test targets a different region of the HIV genome than the Roche HIV assay, and also employs a unique PCR assay design that makes it tolerant to a small number of mismatches between the target and probe, which is advantageous for detection of multiple subtypes.

Another leading supplier of molecular diagnostic products, Siemens Medical Solutions (Malvern, Pennsylvania), exhibited the Versant 440 system, which provides full automation for molecular viral load assays using the Siemens bDNA technology. The system was approved for clinical use in Canada in May 2007, and is pending FDA clearance in the U.S. The Versant 440 automates the nucleic acid extraction step, an advance over the company's previous system. The bDNA technology used in the 440 system provides high-precision viral load test results, and will remain the technology of choice for viral load assays developed by Siemens, although the company also is developing another new analyzer employing kinetic PCR for other types of molecular tests, due out in 2009.

Siemens said it expects to receive FDA clearance for an HCV viral load assay on the Versant 440 platform by the end of the year and is targeting introduction of an HIV viral load assay on the platform in 2008. The company said it believes it now has a 90% to 95% share of the global market for HCV molecular diagnostic products. The Versant 440 is complemented by the Trugene HIV-1 genotyping system, providing a package that enables laboratories to perform the complete range of molecular tests needed for AIDS patient management.

A new automated molecular diagnostics system, the Jaguar, is under development by HandyLab (Ann Arbor, Michigan) that will provide automation of nucleic acid extraction coupled with real-time PCR analysis. The system employs a 12-sample microfluidic cartridge and will be priced at between $60,000 and $70,000. The test menu will focus on infectious disease tests including detection of bacterial and viral pathogens.

Emphasis on detection, rapid and quick

Another development-stage molecular diagnostics system was exhibited at the AACC conference by Osmetech Molecular Diagnostics (Pasadena, California).

The eSensor XT-8 System is based on sensor technology acquired from Motorola (Schaumburg, Illinois), and provides random access testing using microarray cartridges. It does not automate the initial sample extraction and preparation steps, but performs rapid PCR and fluorescence detection, with most assays completed in less than 45 minutes. Osmetech is currently seeking distributors for the e-Sensor XT-8 in Europe, and plans to introduce the system there in early 2008, followed by U.S. regulatory approval and market launch.

Future developments in molecular diagnostics are expected to include rapid POC systems for nucleic acid testing. Iquum (Marlborough, Massachusetts) is developing the Liat Analyzer, a compact, portable analyzer that will perform nucleic acid tests on whole blood samples in 30 to 60 minutes using a simple three-step procedure. The initial test menu for the Liat will include nucleic acid tests for influenza A and B as well as an avian flu virus (influenza A H5N1) assay. The company recently received ISO certification, and is developing the POC avian flu molecular test with funding from the Centers for Disease Control and Prevention (Atlanta).

Roche Molecular also is developing a POC molecular diagnostics system called Quicklab. The Quicklab, now in the concept stage, employs a single test card that contains all reagents needed for a test, and requires a 40 microliter sample. The system includes a portable meter for read-out of the test cartridge, and will provide results in 60 minutes. The primary applications being targeted by Roche for the Quicklab are in disease screening and risk assessment for chronic diseases at the point of care.