Originally Published in IVD Technology October 2003
This Year in IVDs
In the face of outbreaks of social unrest, a new disease, and economic challenges, IVD manufacturers offered aid by developing new technologies.
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| bioMerieux: The Vidas D-dimer New assay has a reportable range that extends to 10,000 ng/ml, allowing for the detection of high levels of D-dimer indicative of conditions such as disseminated intravascular coagulation. |
In spite of, and often in response to, multiple international crises this
past year, IVD manufacturers stepped up to the plate and turned out an
impressive portfolio of new and improved products. The world took notice.
Along with the news of mounting infections and casualties due to the new and
virulent severe acute respiratory syndrome (SARS), headlines alerted the public
to IVD manufacturers’ development of SARS tests. When countries were
threatened with biological warfare and terrorism, the public took solace in the
news of the development of environmental tests that could detect biothreat
agents. As government-based surveys reported a shortage of skilled laboratory
personnel, manufacturers responded with systems offering higher levels of
automation. In addition, in an effort to combat one of the world’s most
widespread diseases, U.S. president George Bush pledged $15 billion towards
fighting HIV, much of which will take the form of HIV testing.
Indeed, the IVD industry made great strides this year, and is receiving acknowledgment for its crucial role in national protection and effective healthcare. During the annual meeting of the Medical Device Manufacturers Association (Washington, DC), FDA commissioner Mark McClellan spoke of the importance of the IVD industry’s role in the rapid response to the outbreak of SARS. Referring to the industry’s ability to develop effective individualized diagnostics, McClellan said, “This is the way we are going to deliver on the promise of getting the right treatment to the right patient at the right time.” In addition, late last year, IVDs received their own office in FDA’s Center for Devices and Radiological Health. The Office of In Vitro Diagnostic Device Evaluation and Safety was formed in order to consolidate all regulatory activities for IVDs.
All of this support has proved to be a positive development for the IVD
sector. In light of a weakened economy that has yet to recover from the damage
done by the war in Iraq, and the pressure of wrestling with reimbursement
challenges, IVD manufacturers have released ever-faster, more effective,
smaller, and better tests and systems. This article examines some of the key
segments of the IVD industry. It highlights new product launches, product
updates, and trends in each area.
Immunoassays
As IVD manufacturers developed improved techniques for diagnosing
established medical conditions such as coronary diseases and cancer, they faced
a new challenge this year.
The continued spread of infectious diseases such as HIV, the return of
particularly virulent diseases such as West Nile Virus (WNV), and emergence of
the new SARS virus presented IVD manufacturers with the daunting task of rapidly
developing accurate immunoassays for these diseases. IVD manufacturers were able
to overcome this obstacle with the support of regulatory institutions and to
create effective diagnostics in a remarkably brief amount of time.
Cardiovascular Tests. One new cardiovascular test on the market this
year detects a novel cardiac marker. The Mayo Clinic (Jacksonville, FL), Mayo
Medical Laboratories (Rochester, MN), and diaDexus (San Francisco)
joined forces to develop the test, which detects a new marker for coronary heart
disease (CHD). The test, called the PLAC test, received FDA approval in July. It
screens for Lp-PLA2, an enzyme that accompanies low-density lipoprotein (LDL) in
blood circulation.
Concentrations of traditional laboratory markers for CHD (e.g., total
cholesterol, LDL cholesterol, and triglyceride) are in the normal range for at
least one-third of Americans who experience coronary events. However, high
concentrations of Lp-PLA2 indicate heightened atherosclerotic plaque production,
which raises CHD risk. Therefore, Lp-PLA2 serves as an independent marker for
heightened risk of the disease. The PLAC test will initially be made available
through large reference laboratories, and may eventually be used to monitor CHD
therapy.
Similar to heightened plaque production, the presence of homocysteine serves as
a risk factor for cardiovascular and other diseases. The A/C Diagnostics unit
of AntiCancer (San Diego) received FDA approval for its enzymatic
homocysteine assay. By developing and marketing the relatively inexpensive
assay, the company hopes to fill the need for more-affordable widespread testing
for homocysteine.
In 2001, the Access AccuTnI troponin I assay by Beckman Coulter
(Fullerton, CA) received FDA approval to be used for diagnosing and monitoring
treatment of patients exhibiting symptoms of myocardial infarction. This past
year, FDA gave the company clearance to expand the applications of the AccuTnI
test. It can now be used to aid in risk stratification for patients who have an
elevated chance of suffering myocardial infarction.
The test provides results within 12 minutes, and has a minimal response to blood
sample contents that traditionally interfere with assays for troponin I
including heterophile interferences, human antimouse antibodies, and rheumatoid
factor. The test uses antibodies that bind to the stable nondegraded region of
the troponin molecule, so it can detect both intact and degraded forms of
troponin I.
Last year, a study published in the New England Journal of Medicine validated
the effectiveness of b-type natriuretic peptide (BNP) for establishing or
excluding the diagnosis of congestive heart failure in patients with breathing
difficulty. Since release of the study results, several major IVD companies have
added BNP assays to their cardiac test menus.
One such company is Bayer Diagnostics (Tarrytown, NY), which received FDA
clearance for its automated BNP assay. The assay is designed for use as part of
the company’s cardiovascular panel, which is run on the Advia Centaur
immunoassay system. Results are reported in as few as 18 minutes. The assay has
a greater than 99% negative predictive value in ruling out heart failure, with
total precision of 3–5 percent across the dynamic range.
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| American Diagnostica: The Acticlot Protein S Activity assay features reconstituted reagent stability and dating and a rapid test turnaround time. |
Another BNP test is being redesigned through a joint effort by Beckman
Coulter and Biosite (San Diego). The test will be based on Biosite’s BNP
assay and will be designed for use on Beckman’s immunoassay systems.
Biosite’s test has heretofore been available only on the company’s Triage
Cardio MeterPlus testing platform.
Once adapted for use on Beckman Coulter’s instruments, the test will be
available on the Access and Access 2 immunoassay systems, the Synchron Lxi 725
chemistry and immunoassay workstation, and the UniCel DxI 800 Access immunoassay
system. The assay will produce results within 15 minutes and will be used to
diagnose and assess the severity of heart failure and also for risk
stratification of patients with acute coronary syndromes. The companies expect
to place the new test on the market during the first quarter of 2004.
Although endogenous BNP can indicate heart disease, synthetic BNP is a treatment
for heart failure. For patients receiving this treatment, BNP tests do not allow
practitioners to differentiate between elevated BNP levels due to drug treatment
and those due to ventricular dysfunction. An alternate cardiac marker,
N-terminal prohormone brain natriuretic peptide (NT-proBNP), can aid in the
diagnosis of congestive heart failure (CHF) and correlates with the severity of
CHF. The measurement of NT-proBNP levels can aid in the diagnosis of left-ventricular
dysfunction, thereby allowing physicians to distinguish between CHF and lung
disorders that present in a similar manner. In November, 2002, Roche Diagnostics
(Basel, Switzerland) received FDA clearance for its Elecys proBNP assay, which
is the first fully automated proBNP test on the market. The test generates
results within 18 minutes. In February, the company’s proBNP assay technology
was licensed, on a nonexclusive basis, to Dade Behring (Deerfield,
IL).
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| Beckman Coulter: The Access OV monitor detects cancer antigen 125 levels, which are most consistently elevated in patients with ovarian cancer, in human serum and plasma. |
In addition to new menu offerings, some well-established assays for
myocardial damage were revamped over the past year. Beckman Coulter
reformulated two assays in its Access cardiac panel. The Access CK-MB and Access
Myoglobin assays now reduce interference from substances such as rheumatoid
factor and heterophile antibodies, and provide results within 15 minutes. The
Access CK-MB test features an analytical sensitivity of less than 0.1 ng/ml and
no hook effect up to levels of 20,000 ng/ml. The test has an analytical
sensitivity of less than 1 ng/ml and gender-specific reference ranges to
compensate for the differences in male and female muscle mass.
D-dimer tests, which detect increased fibrin formation and lysis, indicate the
presence of a blood clot. As an aid in ruling out deep-vein thrombosis (DVT) and
diagnosing pulmonary embolism (PE), bioMerieux (Marcy L’Etoile, France)
received clearance for its extended-range D-dimer assay, Vidas D-dimer New. This
improved version of the assay increases its reportable range from 1000 ng/ml to
10,000 ng/ml. This greater range allows for the detection of high levels of D-dimer
indicative of other conditions such as disseminated intravascular coagulation.
According to bioMerieux, the assay is 99% effective in ruling out DVT, as
compared to other FDA-approved tests that are 95% effective. Results are
obtained within 60 minutes.
For patients in acute care settings, Dade Behring developed a rapid D-dimer test to help practitioners distinguish between pulmonary embolism and other causes of chest pains. The test can be run on the company’s Stratus CS instrument in central laboratories or near the patient in the emergency room. The turnaround time for this test, including onboard sample centrifugation, is approximately 14 minutes. With D-dimer, troponin I, myoglobin, mass CK-MB, and the bhCG test available on the Stratus CS, a panel incorporating all of these tests can be performed on one whole citrated or heparinized blood sample.
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| Chemicon: The SARS OligoDetect assay identifies genetic material specific to the SARS virus and produces results within 90 minutes postamplification. |
Ischemia Technologies (Denver) received FDA clearance to market its Albumin
Cobalt Binding (ACB) test for the detection of Ischemia Modified Albumin (IMA). In the ACB test, cobalt is added to a serum sample. Cobalt binds to
normal albumin, but not to IMA. The ACB test measures unbound cobalt. Higher
levels of unbound cobalt indicate greater concentrations of IMA.
Although the test has not yet received approval for marketing, Metabometrix
(London) has employed a technique called metabonomics to develop a test for
heart disease. The platform uses high-frequency radio waves to measure the
magnetic properties of the components of a blood sample in a nuclear magnetic
resonance spectrometer. The properties are then scanned for the presence of
abnormal patterns associated with heart disease. Clinical trials are underway at
Papworth Hospital (Cambridge, UK).
To aid in the development of anti-platelet pharmacological drugs and improve
real-time treatment of cardiovascular disease, Immunocor (Norcross, GA), Bio-Tek
Instruments (Winooski, VT), and the University of Vermont
(Burlington, VT) have teamed up to develop an IVD that measures markers of
platelet activity. The assay will be useful in determining the risk associated
with increased platelet activity (e.g., thrombic occlusion of vessels) which can
lead to a myocardial infarction, and decreased reactivity, which can lead to
excess bleeding.
As an addition to its selection of special coagulation test kits, American
Diagnostica (Greenwich, CT) introduced its Anticlot Protein S Activity
assay. The assay measures the activity of protein S in citrated plasma, and can
be automated on a variety of coagulation instruments.
Cancer Tests. In March, FDA approved the expanded use of the hcHigh-Risk
HPV DNA laboratory test by Digene (Gaithersburg, MD) to detect human
papillomavirus (HPV). Initially, FDA approved use of the Digene Hybrid Capture 2
High-Risk HPV DNA test for determining whether women with abnormal pap smears
should receive further examination. The new indications allow the test to be
used for screening women over 30 for HPV infection, when used in conjunction
with the pap test. This screening, along with consideration of medical history
and risk factors, will allow physicians to detect and treat early cell
changes.
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| Beckman Coulter: The Synchron LXi 725 clinical system consolidates chemistry and immunoassay tests on a single platform and features closed-tube sampling and closed-tube aliquotting technology. |
In patients with ovarian cancer, cancer antigen 125 (CA 125) levels in serum and plasma may rise consistently as the disease progresses. Decreasing CA 125 levels may indicate a positive response to therapy. In order to provide a tool with which practitioners can monitor CA 125 levels, thereby evaluating disease progression and response to therapy, Beckman Coulter developed the Access OV monitor. The FDA-cleared test reports levels of CA 125 within 20 minutes, and uses 25 µl of sample. The assay is available on the company’s Access, Access 2, Synchron Lxi 725, and UniCel DxI systems.
In some breast cancer patients, persistently rising HER-2/neu oncoprotein
levels may indicate aggressive cancer and a poor response to therapy, while
decreasing levels of the oncoprotein may suggest that therapy has been
effective. Bayer Diagnostics has made its serum HER-2/neu oncoprotein assay
available on the Avida Centaur immunoassay system. Automation of the test on a
platform that uses a serum sample rather than the tissue sample required of
traditional HER-2/neu testing provides a less invasive, real-time diagnostic
that may be used to monitor a woman’s HER-2/neu levels over the course of the
disease.
Targeted Diagnostics & Therapeutics (Westchester, PA) received FDA clearance
to market its GCC-B1 blood test. The test detects recurrent colorectal cancer by
screening for the presence of guanylyl cyclase C, which is expressed on the
surface of metastatic colorectal cancer cells.
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| Nova Biomedical: The Stat Profile Critical Care Xpress can measure blood gases, electrolytes, chemistry, and hematology with onboard CO-Oximetry in an integrated and compact instrument. |
Molecular Diagnostics (MDI; Chicago) is working to bring Diagnocure’s
(Quebec, Canada) ImmunoCyt molecular assay for the detection of bladder cancer
to MDI’s InPath slide-based test’s automated microscopy platform. The
ImmunoCyt biomolecular assay is an immunocytofluorescent assay for the detection
of bladder cells in urine samples. The test is based on a cocktail of three
monoclonal antibodies, and is designed to complement cytology and cytoscopies in
bladder-cancer-monitoring programs.
A line of assays developed for the detection of biomarkers associated with
hepatocellular carcinoma (HCC) has been developed by Xeptagen (Pozzuoli,
Italy). The Hepa-Ab kit uses immunohistochemistry to detect HCC in liver
biopsies. The company is developing the Hepa-Lisa, an enzyme-linked
immunosorbent assay kit that will be used to diagnose HCC from sera.
Infectious Diseases. West Nile virus (WNV) spread across the United
States in 2002, and has returned in 2003. The disease is transmitted by
mosquitoes, blood transfusions, and organ donations. Manufacturers have been
working to develop assays that can effectively test the donated blood supply,
patients, and other animals (as reported in the January/ February and May issues
of IVD Technology).
The first FDA-cleared test for use in the clinical laboratory diagnosis of WNV
infection is the WNV IgM Capture ELISA by PanBio ( Brisbane, Australia).
Although the test is useful as an aid in diagnosing WNV, FDA points out that
since the detection of antibody is not always specific in acute viral
infections, test results are considered presumptive. In addition, due to
similarities with other viruses in the same family, there is a need to confirm
positive results via an additional test or by using current CDC guidelines for
diagnosis of WNV.
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| Beckman Coulter: The LH 1500–series hematology automation system is designed to manage the entire hematology testing process, from preanalytical sorting to postanalytical storage. |
To document the spread of WNV among wildlife, Response Biomedical (Burnaby, BC, Canada) developed a WNV test for its RAMP system, a portable fluorescent reader that processes single-use disposable test cartridges. The test is a high-sensitivity rapid on-site assay that can detect low levels of the virus in mosquitoes and crows.
Roche has developed a nucleic acid
amplification based test (NAT) that can be used to screen donated blood for WNV.
The company’s TaqScreen WNV test is a fully automated test that can screen
whole blood for WNV as well as other forms of encephalitis. The assay can screen
for St. Louis, Japanese, and Murray Valley strains of the encephalitis virus.
The assay is designed run on the COBAS AmpliPrep Taqman analyzer. It is
currently being evaluated at blood testing sites in the United States under an
investigational new drug application and under a similar regulatory process in
Canada.
Gen-Probe (San Diego) and Chiron (Emeryville, CA) have joined
forces to develop a NAT for WNV. The test is based on Gen-Probe’s
transcription-mediated amplification technology (TMA) and is run on Chiron’s
Procleix semiautomated instrumentation. The test has been launched and is being
used on an investigational-use-only basis.
With the unexpected appearance of the SARS virus this past winter, FDA has
renewed its effort to eradicate emerging diseases as they are first detected. In
light of this support, several companies are developing tests for SARS. Serologicals’
Chemicon International (Atlanta) developed an assay on its OligoDetect light
diagnostics platform that can be used to detect SARS. The NAT-based assay uses a
postamplification-based technology to provide qualitative detection of SARS
single-stranded RNA. The assay is available as an analyte specific reagent
(ASR). When including the time needed for sample extraction and amplification,
results are available in less than 3 hours.
Other companies in the United States are also working to develop SARS tests. Abbott
Laboratories (Abbott Park, IL) and artus GmbH (Hamburg, Germany) have
developed a PCR-based test for use on Applied Biosystems’ (Foster City,
CA) ABI Prism 7000 sequence detection system. The test, called the RealArt HPA
Coronavirus test, has received the CE mark and is awaiting FDA approval.
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| Becton Dickinson: The FACS Sample Prep Assistant provides fully automated sample preparation of up to 40 sample tubes in one run for the company’s FACSCalibur flow cytometer. |
Roche has also developed a test for detecting SARS in donated blood, based on
its PCR technology and run on its LightCycler system. The company has performed
preliminary studies with the research-use-only test and plans additional studies
at various sites in Asia, Europe, and Canada.
Genaco Biomedical Products (Huntsville, AL) has developed a SARS test
called the Multiplex Analysis System for Acute Respiratory Infections. The test
was billed as the “first test to provide differential diagnosis.” The test
simultaneously screens for SARS and nine other common respiratory diseases, and
takes 3 hours to complete. It can detect the viruses in nasal swabs, saliva,
serum, or stool, and is currently available in the Chinese market for research
purposes only.
Another and more well-established virus that manufacturers developing tests for
is HIV. Bio-Rad Laboratories (Hercules, CA) received FDA clearance to
market its HIV-1/HIV-2 Plus O EIA test kit. The kit can be used detect
antibodies to HIV-1 (groups M and O) and HIV-2 in blood and blood products. The
test is the first kit to be sold in the United States that combines testing for
HIV-1, HIV-2, and group O.
Bayer Diagnostics has made its HIV 1/O/2 assay available on its Avida Centaur
immunoassay system. The assay aids physicians in the diagnosis of patients
infected with the human immunodeficiency virus (HIV) types 1 and 2 by performing
the qualitative determination of antibodies to HIV 1 and 2. The test is only
available for sale outside of the United States.
Bayer Diagnostics also received both expedited review and FDA approval for its
hepatitis C viral-load assay, Versant HCV RNA 3.0 Assay (bDNA), for use on its
Versant automated immunoassay platform, the Bayer System 340 bDNA Analyzer.
Bayer’s Versant HCV viral-load assay is the first FDA-approved quantitative
test to measure HCV viral-load levels. The test will be useful for guiding
therapeutic decisions early in treatment.
In addition, Gen-Probe employed its proprietary TMA technology to develop an
assay for qualitative detection of hepatitis C. This Versant HCV qualitative
assay is a nucleic acid–probe diagnostic assay that can detect HCV RNA in
patients infected with the virus. A study published in the American Journal of
Gastroenterology reported that the use of TMA results in higher sensitivity than
that of conventional PCR-based assays when detecting residual HCV RNA in the
serum of patients who have completed treatment. The assay will be marketed and
sold to clinical laboratories in the United States by Bayer Diagnostics.
Tests for other forms of hepatitis have received FDA approval as well. Bayer
Diagnostics released four hepatitis B assays, all of which are
available outside the United States on its automated immunoassay platform, Advia Centaur. The company’s
HbsAg and HBc Total assays are used to diagnose acute and chronic infections.
The Anti-HBc IgM is used to aid in the diagnosis of acute hepatitis B and may
aid in the differentiation of acute and chronic HBV infections.
The disappearance of HbsAg and the appearance of Anti-HBs indicate recovery. In
addition, Anti-HBs can be monitored following vaccination, to determine whether
protective immunity has been achieved. With the addition of the HBV assays,
Bayer moved closer to its goal of providing a comprehensive
infectious-disease-testing panel on one platform.
FDA approval for another hepatitis B test was received by Ortho-Clinical
Diagnostics (Raritan, NJ). The company’s biologics license application was
approved for its Ortho Antibody to HbsAg ELISA Test System 3, a qualitative
third-generation assay for the detection of hepatitis B surface antigen in serum
or plasma. The test is designed for screening donated blood prior to transfusion
and as an aid in diagnosing hepatitis B infection. The assay provides improved
sensitivity (0.10 ng/ml) and specificity (99.97%), and several enhancements to
its ease of use.
Thermo Electron Corp. (Waltham, MA) has developed a test that can detect
Neisseria gonorrhoeae (GC) in endocervical swab samples from females and urine
samples from males. The development of rapid diagnostic tests for GC has been a
challenge due to the difficulty of identifying single-protein targets that are
found only in GC, in all strains of GC, and not in other Neisseria species. The
GC OIA rapid test detects the L 7/L 12 ribosomal protein marker found within the
viral cells, enabling the company to provide a test that is truly specific for
GC.
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| Sysmex: The UF-50 automated urine cell analyzer’s fluorescent flow cytometry and cluster analysis provide automatic classification and identification of 10 types of formed elements. |
Not only have blood-sample-based tests been approved, but FDA has also cleared a test that can detect kidney and cardiovascular diseases from urine samples. AusAm Biotechnologies (Santa Monica, CA) received approval for its Microalbumin Plus test, which can detect an excess of albumin that may indicate the presence of a condition called microalbuminuria. The test was developed as an improvement to conventional tests that may miss as much as 10 percent of albumin in urine. By separating albumin from other compounds in urine, the test directly determines the true quantity of the protein.
In order to increase the safety of newborns, FDA cleared a new test for group
B streptococcus (GBS), a leading cause of sepsis, meningitis, and death among
newborn infants. The test, IDI-Strep B, is manufactured by Infectio
Diagnostic Inc. (Quebec, Canada) and distributed by Cepheid
(Sunnyvale, CA) in the United States. It is intended to be used to detect GBS in pregnant women at the
time they enter labor and during delivery. The test provides results within 30
minutes, and is the first FDA-cleared test that meets the performance criteria
for GBS detection in the latest CDC guidelines.
Other Medical Conditions. Beckman Coulter developed Total IgE, a
laboratory test designed to help physicians determine whether symptoms are due
to general allergic reactions. The assay generates a qualitative determination
of Immunoglobulin E (IgE) in human serum and plasma. Beckman’s assay features
a measurement range from 5 to 30,000 IU/ml and is available on the company’s
Immage immunochemistry system.
Beckman Coulter also released an improved version of its microparticle enhanced
C-reactive protein (CRP) assay for its Array 360 system. The CRP assay yields a
quantitative determination of CRP in human serum and plasma for the diagnosis of
automimmune and infectious disorders. The new version of the assay improved the
sensitivity of the serology panel on Array 360 systems. It features a dynamic
range of 0.1 to 54 mg/dl, can detect lower concentrations of CRP than its
predecessor, and reduces possible interference from triglyceride, bilirubin, and
hemoglobin.
Hycor Biomedical (Garden Grove, CA) received clearance to market its
Anti-Beta-2-Glycoprotein (beta-2-GPI) IgA autoimmune test in the United States.
The test complements the beta-2-GPI IgG and IgM tests cleared in January
2003.
Sysmex (Long Grove, IL) received FDA clearance for its hematopoietic
progenitor cell (HPC) parameter on the IMI channel, a test that is used as a
screen for the optimal presence of HPCs in peripheral blood and cord samples.
Test results can be used to predict the optimal time to harvest stem cells in
patients undergoing mobilization for autologous or allogeneic stem-cell
transplants. The test is run on the IMI channel of the company’s XE-2100
automated hematology analyzer.
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| LifeScan: The SureStep Flexx glucose monitor brings photometric technology commonly used in clinical laboratories to the point of care. |
Spectral Diagnostics (Toronto, ON, Canada) received FDA clearance to
market its endotoxin activity assay, which identifies patients at risk for
developing severe sepsis upon admission to the intensive care unit. The test was
cleared through FDA’s de novo process, a relatively new provision of the U.S.
Food, Drug and Cosmetic Act that allows new, unique, and low-risk medical
devices to be evaluated under 510(k) procedures.
Automation
In order to increase productivity, operator and patient safety, and to
decrease turnaround time and human error, laboratories are implementing higher
and higher levels of automation. A shortage of available skilled laboratory
personnel has also put pressure on laboratories to minimize the number of manual
steps required for testing samples.
In an attempt to satisfy the need for automated systems, Beckman Coulter has
launched the Synchron LXi 725 clinical system, combining the company’s
chemistry analysis technology with immunoassay testing, data management, and
automated sample handling. The system features 146 chemistry and immunoassay
tests as well as parallel processing technology, allowing immunoassay and
chemical testing to be performed simultaneously. As a result, a basic metabolic
panel can be run in less than 2 minutes and a critical troponin I test result
can be delivered in approximately 14 minutes. Chemistry throughput is up to 1440
tests per hour and immunoassay throughput is up to 100 tests per hour.
The system features closed-tube sampling for chemistry tests and closed-tube
aliquotting for immunoassay tests. Serum indices and clot detection features
improve the integrity of patient results. The instrument can store 24
immunoassays and 41 general chemistries onboard.
Beckman Coulter has also introduced the UniCel DxI 800 immunoassay system.
The random-access system processes up to 400 tests per hour and uses magnetic
particle separation and chemiluminescent detection technology. It incorporates
“load-on-the-fly” capability, and uses the same assay protocols as other
analyzers in the immunoassay family. Testing capabilities include cardiac,
cancer, anemia, infectious-disease, reproductive, and other endocrine tests. The
reagent packs have a standardized design, are bar coded, and ready to use.
The system has an onboard capacity of 50 reagent packs and a load capacity of
120 samples. Samples can be processed continuously at a rate of 320 samples per
hour. Point-in-space pipetting technology has been aligned with NCCLS guidelines
to allow for integration with laboratory automation systems.
Nova Biomedical (Waltham, MA) released its Stat Profile Critical Care
Xpress diagnostic analyzer, which provides a test menu comprised of 19 measured
and 29 calculated tests. The analyzer measures blood gases and electrolytes,
performs chemistry and hematology tests, and provides onboard data management.
The company reports that, while the system incorporates more onboard tests than
any competitive analyzer, it is at least 20% smaller and uses snap-in reagent
packs that contain all required liquid and gas calibrators and onboard controls.
The instrument can also utilize Nova’s remote testing management software to
provide process automation, remote control, and remote view and data capture.
Ortho-Clinical Diagnostics received 510(k) clearance for its Vitros 5, 1 FS
chemistry system. The system integrates up to 80 routine and special chemistry
assays through the use of the company’s Intelligent Parallel Processing
technology. This is the first in a series of Vitros Fusion systems designed to
integrate chemistry, special chemistry, immunoassay, and infectious-disease
assays.
The new system features several proprietary technologies including the
Intellicheck, which provides advanced clot and bubble detection; MicroSensor,
which delivers automated sample interference monitoring; and MicroTip, which
eliminates water, plumbing, drains, fixed probes, and mixing assemblies
characteristic of other comparable technologies to reduce waste and simplify
operation.
In an effort to meet the distinct needs of individual laboratories, Roche
Diagnostics released four configurations of its integrated Modular Analytics
systems, all of which combine clinical chemistry and immunoassay testing into
one platform. The systems draw from a menu of 140 tests and process all samples
in one pass with a single user interface, point of entry, and patient report.
Configurations are available to suit low- to high-volume laboratories, with the
capability of performing up to 32,000 tests per day.
Several hematology systems were released this year. Abbott Laboratories (Abbott
Park, IL) released its Cell-Dyn 1800 automated hematology analyzer. The
instrument is designed to meet the needs of small to medium-sized clinical
laboratories that run complete blood counts (CBCs). The system produces a CBC
with 18 parameters, including histograms and a three-part differential, in 60
seconds. The FDA-approved system is capable of storing 10,000 specimens,
requires the use of only three reagents, and its small footprint of 17 by 26 in.
allows it to fit under standard cabinets.
Beckman Coulter has introduced the LH1500 series of hematology automation
systems. Each system can manage the entire hematology automation process.
The instruments perform preanalytical sorting, sample tracking and processing,
automated cassette loading and unloading, and test retrieval for repeat and
reflex testing. Twelve standard configurations are available. Options include
two to four LH 700–series hematology analyzers, and integrated slide-making
and -staining capabilities. All configurations incorporate inlet and outlet
units with 200-tube capacity each, and a stockyard with 1000-tube capacity. The
instrument can be switched from automation mode to independent mode and STAT
samples can be added to the line at any time.
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| Becton Dickinson: The BD Logic glucose monitor requires only 0.3 µl of sample and generates readings within 5 seconds. |
Beckman Coulter also released a benchtop hematology analyzer that
incorporates an automated sample loader. The Coulter Ac•T 5diff autoloader
hematology analyzer accommodates up to 10 cassettes that hold ten 13 x 75-mm
sample tubes each. The analyzer uses five-part differential analysis technology
and employs absorbance cytochemistry and volume technology to measure
lymphocytes, monocytes, neutrophils, eosinophils, and basophils. A STAT
interrupt feature allows operators to bypass the instrument’s autoloader and
load an emergency sample for prioritized testing. The system software enables
operators to upload control assay values and download interlaboratory quality
assurance program data automatically to enhance the management of quality
assurance programs.
Becton Dickinson Biosciences’ automated benchtop cytometer, the Imagn system,
received FDA clearance for analysis of leucoreduced products, such as platelet
and red-cell concentrates. Blood bank application-specific software and reagents
accompany the system.
Leucoreduction, the removal of white blood cells (WBCs) to minimize transfusion
reactions, requires the evaluation of the amount of WBCs remaining in a blood
product. The Imagn system performs this task, thereby providing quality control
for various leukoreduction processes.
The American Red Cross (ARC; Washington, DC) has partnered with Ortho-Clinical Diagnostics to fully automate the ARC’s donated-blood screening. ARC will use the company’s Ortho Summit system and ID-Micro typing system gel test to perform infectious disease and antibody screening tests.
Dade Behring launched its V-Twin system, an addition to the Syva product line, for monitoring drugs of abuse. The instrument is designed to run the company’s Syva Emit drugs of abuse and serum toxicology assays, as well as the Perfect specimen validity tests. The system can run 260 Emit tests per hour, accommodate 26 methods onboard simultaneously, and perform mirror backup in which each platform can be utilized separately. A bidirectional host interface provides two-way communication with hospital laboratory information systems.
Sysmex launched its fully automated urine cell analyzer, the UF-50 in the United States. The system provides an automated urinalysis solution to mid-sized labs, thereby freeing technologists from repetitive visual identification of formed elements. Analysis is performed via fluorescent flow cytometry. The system features rack-based autosampling and offers single-tube testing for STAT processing.
For systems that require front-end sample processing, Tecan (Zurich, Switzerland) released several new features on its Genesis FE500 workcell. The workcell is a fully automated platform that performs sample processing and other applications for preanalytical automation. A new modular system provides a variety of options for individual processing steps including specimen sorting, centrifugation, decapping, and secondary tube labeling and aliquoting. An improved tube-inspection unit scans the length of the tube to detect fluid volume, and can read the volume through up to three layers of labels. Improved archiving options enable the full separation of sample from primary to secondary tubes.
BD Biosciences (San Jose) has also released an automated sample-preparation system, the BD FACS sample prep assistant. The system provides sample processing for the company’s FACSCalibur flow cytometer, and processes 40 sample tubes in one run. Automated functions include mixing and aliquoting blood from primary tubes, dispensing of antibody, addition of lysing solution, and timer functions.
In an effort to fully automate viral-load assays, Promega (Madison, WI) and Abbott are working to provide a system that will purify and extract viral RNA from patient samples using Abbott’s magnetic particle technology. This sample-preparation technology will allow for the processing of up to 96 samples on a walk-away basis.
Agilent Technologies (Palo Alto, CA) received clearance for its MIDI Sherlock Mycobacteria Identification System, for use in identifying Mycobacterium tuberculosis (TB). The Sherlock system uses the Agilent 1100-series high-performance liquid chromatograph to analyze mycolic acids in the bacterial sample and search its library of reference mycobacteria using pattern recognition software.
Point-of-Care and Home-Use Tests
The point-of-care testing market continues to grow. Although some laboratorians and industry observers still express hesitation and a lack of faith in the accuracy and connectivity solutions for these tests, it seems that this technology has found its niche in several industry sectors and is here to stay.
In April, the Centers for Disease Control and Prevention (CDC) announced a new initiative aimed at making tests for HIV more routine for pregnant women and encouraging more-widespread use of rapid HIV testing. The CDC has allocated $35 million to support the testing initiative and will fund new demonstration projects in high-HIV-prevalence settings, including correctional facilities.
According to the CDC, more than one-third of people tested in the United States for HIV do not return to receive their test results. With the availability of a rapid test, results can be presented during the initial visit, and more infected patients will be given the opportunity to properly manage their disease.
One device that may aid in the CDC initiative, and also provide patients with test results sooner, is the FDA-approved OraQuick rapid HIV-1 antibody test (reported on in the January/February issue of IVD Technology) by OraSure Technologies (Bethlehem, PA). The test is the first rapid point-of-care test approved by FDA for diagnosing HIV-1. In clinical trials, the OraQuick test had a sensitivity of 99.6% and a specificity of 100%. It can detect antibodies to HIV-1 in finger-stick or venipuncture whole blood within 20 minutes.
The test received a CLIA waiver in January, permitting its use by more than 180,000 sites in the United States, including outreach clinics, community-based organizations and physicians’ offices. In addition, OraSure has completed the necessary clinical trials and has filed for FDA approval for use of OraQuick to detect antibodies to HIV-2.
Efoora (Buffalo Grove, IL) is awaiting FDA clearance for its rapid, point-of-care HIV test. The test uses
immunochromatography to examine serum, plasma, whole blood, or fingerstick whole blood samples. The test performs at a sensitivity of 99.8% and a specificity of 99%. On-site test results are available within 20 minutes.
American BioMedica (Kinderhook, NY) and Hema Diagnostic Systems (Miami Beach, FL) launched their on-site HIV test, which detects antibodies to HIV-1 and HIV-2 viruses, but does not differentiate between the two. The assay delivers results in 15 minutes. The Rapid 1-2-3 Hema HIV test is available in international markets, but for research only in the United States.
Another point-of-care test that received clearance from FDA this year is the NIOX asthma-monitoring test by
Aerocrine (Chicago). The test measures the concentration of nitric oxide, a marker of airway inflammation, in exhaled human breath. NIOX is the first tailor-made nitric oxide–monitoring system for routine clinical use in asthma patients.
Quidel (San Diego) released a rapid CLIA-waived influenza test to help physicians distinguish between patients with flu and those suffering from other respiratory illnesses that cause patients to present flu-like symptoms. The QuickVue influenza test provides results within 10 minutes and can use samples from either a nasal swab or nasal wash. The test is 96–99% accurate.
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| Cepheid: The Smart Cycler II incorporates 16 reaction modules, each of which performs four-color, real-time fluorometric detection. |
Several point-of-care tests for use in cancer screening were released this year. One such test is an FDA-approved bladder cancer screening rapid test for the early detection of bladder cancer by
Matritech (Newton, MA). The NMP22 BladderChek test can be used in physicians’ offices to detect a bladder cancer nuclear matrix protein in patients’ urine. Results are delivered within 30 minutes. The company states that the BladderChek test is an improvement over cytology, an alternative test for bladder cancer, as the BladderChek detects three times more early-stage bladder tumors than cytology.
A test used to screen for cervical cancer has been developed by Molecular Diagnostics
(Chicago). The screening system allows for testing either in the laboratory or at the point of care. The test involves use of the FDA-approved InPath e2 Collector sampling device to obtain a cervical sample and the molecular-based InPath Cocktail-CVX and Point-of-Service instrument to analyze the sample.
Manufacturers placed many new systems that bring rapid diagnostics to the point of care on the market. One such system is Bayer Diagnostics’ Rapidpoint 405 critical-care analyzer, which provides blood gas analysis in a point-of-care testing format. The first system to offer an integrated CO-oximetry module at the point of care, the instrument provides physicians with real-time access to the oxygenation status of their critically ill patients. The CO-oximetry module offers five hemoglobin tests, tHb, 02Hb, CO hb, MetHb, and HHb. Results are reported within 60 seconds. The test menu currently includes pH, blood gas, electrolyte, glucose, hematocrit, and CO-oximetry testing, all of which can be monitored remotely by a central laboratory.
LifeScan (Milpitas, CA) brings rapid diagnostics home with its home-use monitoring device for patients on oral anticoagulation therapy in order to reduce their risk of stroke or bleeding episodes. The Harmony International Normalized Ratio (INR) monitoring system provides patients who take warfarin with clinical accuracy when conducting weekly monitoring of their blood clotting time. Results are obtained via analysis of finger-stick blood and are delivered in 90 seconds.
NetImpact (Las Vegas) introduced its lab-in-a-box disease detection device, the MDS 200. The device can detect diseases in blood, saliva, sweat, or urine samples. It runs on electricity, battery, or solar power, and transmits test results to medical facilities via portable satellite or dial-up connections. The system is as small as a suitcase and can be made into a portable instrument. Results are delivered in 30 minutes. It uses the Biodetection Enabling Analyte Delivery System (BEADS), a technology developed by scientists at the
Pacific Northwest National Laboratory (Richland, WA) as its detection technology. The device will be used in Mali, Africa, to screen for HIV and ebola early next year.
Dade Behring improved one of its point-of-care systems with its connectivity solution for the Stratus CS analyzer. When used for diagnostics in acute-care settings, patient test results can be automatically sent into the patient’s file for both medical record and billing applications.
As the result of increased governmental vigilance on an international scale, several companies received approval for devices that would aid in the protection from biothreat agents. “The increase in fear of bioterrorism increased funding for purchase of detection and diagnostic equipment for first responders and the military. There is a greater understanding of the need for equipment with greater sensitivity and reliability in this area, which is raising the standards for the equipment that is being offered,” notes Joanne Stephenson, Vice President of Business Development for Response Biomedical.
One example of such equipment is the RAMP pox test by Response Biomedical. The rapid, on-site environmental test was designed to detect orthopox viruses, including smallpox, monkeypox, and cowpox. The test has a detection level of 100,000 viral particles (3.6 ng) per swab. The company has offered to provide the pox test to “qualified governmental bodies” for evaluation.
20/20 Gene Systems (Rockville, MD) has launched a field test to aid first responders in the screening of suspicious powders for bioterrorism agents. The BioCheck powder-screening kit can detect the presence of protein, the absence of which can rule out the existence of most pathogens or toxins in a suspicious powder.
Diabetes Management. As has been the case for several years, devices for diabetes management continue to be the mainstay of the point-of-care diagnostics market. The blood sugar and insulin management devices that were approved this year brought
more sophisticated, less-painful, and more-user-friendly technology to the patients that rely on them.
The SureStep Flexx blood glucose monitor by LifeScan contributes to the advancement of diabetes management technology by simplifying point-of-care glucose monitoring with flexible sample application, allowing for from 5 to 30 µl of sample to be applied to the test strip. Off-meter sampling eliminates the need to bring the meter to the patient, and reduces the risk of blood-borne pathogen transmission between patients. The system brings photometric technology, which is generally used in clinical laboratories, to the point of care. The glucose meter connects to the DataLink data management system for automated data management and quality control.
Bayer Diagnostics introduced its first blood glucose meter to debut in the United States under the company’s Ascensia diabetes-care line. The Ascensia Breeze meter incorporates single-function buttons and automatic calibration for convenient and simple self-monitoring. The meter reads a 10-sample test disc, thereby storing 10 test strips at once, and saves information for up to 100 tests.
Another major player in the IVD market, Becton Dickson, brought its BD Logic glucose monitor to market. The monitor requires only 0.3 µl of sample, allowing for the use of 33-gauge lancets, the thinnest lancets available on the market. The system stores 250 test results and records 250 insulin doses.
Home Diagnostics (Fort Lauderdale, FL) received FDA approval for its TrueTrack Smart system, a blood glucose–monitoring system that features biosensor technology. The system requires a 1-µl blood sample, and delivers results in 10 seconds. The system provides 365-test memory, and 14- and 30-day averaging.
TheraSense (Alameda, CA) developed an updated version of its FreeStyle glucose-monitoring system. The FreeStyle Flash system includes the world’s smallest glucose meter, requiring a sample size of 0.3 µl. In addition to the small sample size, the system has a faster test time of 7 seconds, a backlit panel display and lighted test-strip port for testing at night, and programmable alarms to remind patients of their testing times. The system is awaiting FDA clearance.
Metrika (Sunnyvale, CA) received FDA clearance to make its A1cNow diabetes monitor available over the counter, without a prescription. The test can be used at home to obtain glycated hemoglobin (A1C) levels, which are indicative of diabetes control and the risk of serious long-term complications. Quantitative AlC results are available in 8 minutes from a drop of blood. In contrast to daily blood glucose monitoring that is subject to fluctuations throughout the day, AlC profiles a patient’s long-term glucose control by presenting the body’s average glucose metabolism over 2 to 3 months.
Efoora (Buffalo Grove, IL) has developed a biosensor test-strip technology platform. The precision insertion of molded sensors (PRIMOS) platform will initially be used to develop a blood glucose monitor. The new platform will offer the advantages of small (1 µl) sample size and substantially lower cost.
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| Celera Diagnostics/ Applied Biosystems: The ViroSeq HIV-1 Genotyping System is designed to detect mutations in the HIV-1 virus that are associated with drug resistance. |
A smaller sample size offers patients minimal pain, but noninvasive glucose monitoring techniques remove pain altogether.
Sontra Medical (Franklin, MA) has completed an initial clinical study for its noninvasive Symphony diabetes management system. The system provides a continuous measure of the flow of glucose through the skin via the company’s SonoPrep skin permeation device. In July, Bayer Diagnostics obtained a nonexclusive license to develop and commercialize a monitor based on Sontra’s technology.
Sysmex (Kobe, Japan) and Toshiba (Tokyo) are together developing a minimally invasive blood glucose monitor that does not require blood sampling. The technology will combine Sysmex’s microinvasive, painless, and stable fluid-extraction technology with Toshiba’s biosensor-chip-based optical sensing technology to measure glucose levels through the examination of interstitial fluid. The companies expect to place the new monitor on the market in 2005.
In addition to minimizing the pain required for blood sampling, companies have worked to increase the convenience of blood sampling and insulin dosing by providing a glucose meter and insulin pump in one device. The first device to integrate a blood glucose meter and an insulin pump with a dose calculator into one device received marketing clearance in the United States (reported on in the September issue of
IVD Technology).
The wireless device facilitates radio wave–based data interchange between the Paradigm 512 insulin pump by
Medtronic MiniMed Inc. (Northridge, CA) and the Paradigm Link blood glucose monitor by
Becton, Dickinson and Co. (BD; Franklin Lakes, NJ). The glucose monitor automatically transmits a blood sugar reading to the insulin pump, which then recommends the proper insulin dosage based upon information entered by the patient.
Deltec (Minneapolis) has also developed an integrated glucose monitor and insulin pump. The company’s CozMore insulin technology system relies on infrared signals for wireless communication between the glucose meter and insulin pump. The instrument stores both glucose measurement and insulin delivery data in an internal log. The company expects to place the CozMore on the market soon after January, 2004. According to industry observers, these new devices could be the first step toward developing a fully automated glucose-monitoring and insulin delivery system.
Molecular Diagnostics
The race to place a microarray on the clinical diagnostics market continued this year, with one front-runner breaking ahead of the pack.
Roche Molecular Diagnostics (Pleasanton, CA) made waves with the introduction of its CYP450 array in June (as reported on in the April issue of
IVD Technology). The microarray, branded AmpliChip, will be used to examine the individual ability of each patient to metabolize drugs. The AmpliChip is based on GeneChip technology by
Affymetrix (Santa Clara, CA) . The test detects mutations in genes 2D6 and 2C19 on cytochrome P450. These genes affect the liver’s ability to metabolize over 25% of the drugs available on the market. The chip will offer practitioners a tool to aid in the prescription of more-effective doses of medication and in the prevention of adverse reactions to drugs.
Initially, Roche released the test as an analyte specific reagent (ASR), rather than as a medical device. However, FDA sent the company a public letter in which it raised concerns over the ASR classification, as FDA suggested that it considers the chip a medical device. Roche and FDA are currently discussing the proper classification for the AmpliChip. Until an agreement is reached, the product will continue to be marketed as an ASR. Roche intends to eventually submit an application for FDA’s approval of the device as an IVD.
Several molecular diagnostics have been developed to aid in the prescription of individualized treatments for cancer.
Agilent Technologies (Palo Alto, CA) and Agendia (Amsterdam, The Netherlands) are working to develop the first microarray-based diagnostic test to predict the aggressiveness of breast cancer tumors based on the activity of key genes. The companies hope to develop tests that may help physicians personalize breast cancer treatments and identify prognostic patterns that could facilitate the discovery of novel drug targets or expedite the development of drugs. As microarray technologies are not currently approved for diagnostic use in the United States, Agendia will perform the microarray analysis of all samples in the Netherlands. Results of preliminary studies indicate that gene expression information may assist physicians in determining which patients may benefit from chemotherapy, and which could forego it.
In an effort to develop multibiomarker panels that may improve current techniques for the diagnosis and treatment of colon cancer,
Ciphergen Biosystems (Freemont, CA) and bioMerieux have formed a partnership. The team will use Ciphergen’s ProteinChip technology as a platform for the panels.
A blood test that may enhance a practitioner’s ability to test for colon cancer risk is in development at
Johns Hopkins University (Baltimore). The test detects a form of gene silencing called loss of imprinting (LOI) in a growth-promoting gene, insulin-like growth factor, in blood samples and colon tissue. Initial studies have shown that individuals with a family history of colon cancer were more than five times more likely to have LOI markers than those with no family history of the disease. Those with a personal family history of colon cancer were almost 22 times more likely to have LOI markers in their blood. The test will take several more years to develop and examine, as participants will have to be monitored for incidences of colon cancer.
CombiMatrix (Mukilteo, WA) is collaborating with RationalDiagnostics (Seattle) to develop a microarray-based test for the diagnosis of lymphoma. In an effort to improve upon the quality of the prognostic information currently available from existing tests for lymphoma, the nucleic acid–based test will use customizable microarrays to both detect various subtypes of lymphomas and predict the clinical outcome of the disease.
In order to provide a method for systematic testing for mixed-lineage leukemia (MLL) gene rearrangements and identification prognostic indicators,
Ipsogen (Marseilles, France) introduced its MLL FusionChip. The chip identifies which of 32 known MLL partner genes is implicated in the rearrangement with MLL. The fusion product that is identified by this test can then be used as a molecular marker, allowing for the assessment and improvement of treatment efficacy.
In addition to cancer diagnostics, molecular diagnostics–based tests have been developed to test for other diseases.
Ambion Diagnostics (Austin, TX) has developed a bead-array-based test for cystic fibrosis (CF) that it hopes to place on the market early in 2004. The DNA test panel evaluates 31 CF mutations. The test is divided into two parts, one that screens for the 25 mutations that are most likely to occur, and a separate reflex panel that can confirm the severity of any detected mutations. Following PCR amplification and hybridization of extracted DNA, the initial screening is completed in 15 seconds. As a result, laboratories will be able to run thousands of tests each week.
Celera Diagnostics (Rockville, MD) received FDA clearance for the marketing of its ViroSeq HIV-1 Genotyping System. The system is designed to detect mutations in the HIV-1 viral genome that confer drug resistance. Celera will manufacture the system, and Abbott Diagnostics will market and distribute it.
A DNA-based testing system designed to detect the presence of biological pathogens is being developed by
Integrated Nano-Technologies (Henrietta, NY). The BioDetect system will generate results in less than 30 minutes. The early prototype is small enough to be carried into the field, as it is the size of two reams of paper and weighs 12 lbs. In addition to field testing, the system can be installed in air circulation systems.
Cepheid (Sunnyvale, CA) released its next-generation real-time DNA analysis system, the Smart Cycler II. The new version of the Smart Cycler system has updated software that enables additional analysis and operational features, including the ability to move to the next PCR stage after crossing a user-defined threshold.
Conclusion
The initial impact of the attacks of September 11, 2001, and the war in Iraq that followed sent the economy into a steep downturn. However, the economy has since
bottomed out and begun to recover. Recent history has proven that these foundations of renewed stability may be shattered in an instant. However, IVD companies are in place to capitalize on renewed investments in their technology as the economy improves and funding becomes available.
IVD manufacturers seem to have carved out a permanent niche for themselves, having taken an active role in national defense and paved the way for combating emerging diseases. With a relatively new IVD office and governmental initiatives backing their efforts, IVD manufacturers seem poised to continue on their path of bringing ever more efficient and effective diagnostics to the marketplace.
IVD Technology will be there to report on their progress, each step of the way.
Jennifer Zakroff is associate editor of
IVD Technology.
Copyright ©2003 IVD Technology
