Originally Published in IVD Technology October 2004
This Year in IVDs
With the release
of molecular IVD instruments for commercial sale, IVD manufacturers and the
bodies that regulate them broke new ground in 2004.
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| The GeneChip System 3000Dx by Affymetrix (Santa Clarita, CA) is the first microarray system to be placed on the market for clinical diagnostics. |
In 2004, IVD manufacturers found that the recovering market was both hungry
for new products and ready to buy. From faster, more integrated, and more capable
laboratory instruments to tests displaying greater sensitivity and specificity
while requiring ever-smaller sample sizes, IVD manufacturers brought better
products to market.
After years of anticipation, molecular IVD systems have been placed on the market
for commercial sale. However, regulatory frameworks for molecular diagnostics
are still young and evolving. In addition to new technologies, regulatory issues
had a strong effect on the IVD market this year.
Now that the IVD Directive has been active for a year, industry has begun to
wonder whether the United States and the European Union will harmonize their
regulatory systems for IVDs so that a product approved for use in the European
Union would automatically receive approval for use in the United States and
vice versa.
In the United States this year, the spotlight shone on the regulation of molecular
tests released as analyte specific reagents (ASRs). FDA continues to take a
hands-on approach to work with industry to determine, on a case-by-case basis,
when a test can be exempt from FDA review and accurately classified as an ASR.
The agency has assured industry that these negotiations are building to a clear
policy on ASRs. However, some industry members are getting restless. “Lack
of clear policy is inhibiting investment in new technologies,” says Glen
Freiberg, vice president for regulatory, quality, and government affairs at
Gen-Probe (San Diego).
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| The BR Monitor test by Beckman Coulter (Fullerton, CA) quantitates levels of a sensitive marker of breast cancer in human serum. |
In spite of regulatory hurdles, and amidst a strong push in the molecular sector,
IVD manufacturers continued to release faster, more accurate, and generally
more capable instruments. Advances in automation, ease of operation, and test
sensitivity and specificity have given healthcare providers ever-more-effective
diagnostic tools.
Diagnostic Tests
This year, new tests relied on a variety of technologies to generate more-accurate
and -useful results more quickly. New tests are available for everything from
physical illness to biowarfare agents.
Cancer. The market potential for individualized cancer diagnostics has grown
so strong that Johnson & Johnson has established an independent company
called Veridex (Warren, NJ) that will be devoted exclusively to oncological
IVDs. The company is initially developing two complementary assay platforms.
One of these platforms, called Cellsearch, identifies, enumerates, and characterizes
circulating tumor cells directly from whole blood. The other platform, Genesearch,
uses molecular technology to diagnose, stage, and more accurately characterize
tumors. FDA has approved the Cellsearch Epithelial Cell kit under a de novo
classification.
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| For use in acute-care settings, the Triage Shortness of Breath Panel by Biosite Inc. (San Diego) aids in risk stratification of patients with coronary symptoms. |
Beckman Coulter (Fullerton, CA) has placed a new test for breast cancer
on the U.S. market. The BR Monitor test provides quantitative determination
of cancer antigen 15-3 levels in human serum. According to company representatives,
this marker is more sensitive than carcinoembryonic antigen in detecting recurrent
breast cancer. The BR Monitor test can be used to manage cancer treatment. The
test is available on the company’s Access, Access 2, and Unicell DxI 800
Access immunoassay systems, as well as on the Synchron LXi 725 clinical system.
Amidst a lively debate in the literature over how effective they are and how
their results should be used, many prostate specific antigen (PSA) tests were
developed this year. Abbott Laboratories (Abbott Park, IL) received FDA
approval for two PSA tests. The tests include Total PSA (TPSA) and Free PSA
tests, which are designed for use on the company’s AxSYM and IMx instruments.
In addition, bioMerieux (Marcy l’Etoile, France) received FDA approval
for its Vidas TPSA assay. The test is a fully automated enzyme-linked fluorescent
immunoassay and has been designed for use on the company’s Vitek immunodiagnostic
assay system.
Cardiovascular. Many companies have beefed up the menus of their immunodiagnostic
systems with the addition of new cardiovascular tests. Ortho-Clinical Diagnostics
(Raritan, NJ) expanded its immunoassay cardiology menu with the addition of
its myoglobin assay.
The test requires a sample size of 10 µl and, when run on the company’s
Vitros ECi system, generates results in 16 minutes. In addition, the assay range
is 0–2000 ng/ml and analytical sensitivity is less than 2.0 ng/ml with
precision across the entire myoglobin range.
According to Michael S. Parmacel, MD, chief of cardiovascular medicine at the
University of Pennsylvania (Philadelphia), “Based on the American
College of Cardiology’s new criteria for diagnosing myocardial infarction,
troponin has become the gold standard in diagnostic testing.” As such,
many major IVD companies have released new and improved tests for Troponin-I
(TnI).
The Acute Care Troponin I assay (cTnI) by Dade Behring (Deerfield, IL)
is the first troponin test cleared by FDA as high sensitivity. With a sensitivity
of less than 0.03 ng/ml and a precision of 8.2 CV at the 99th percentile of
normal (0.07 ng/ml), the Acute Care cTnI meets the European Society of Cardiology
(Sophia Antipolis, France) and American College of Cardiology (Bethesda,
MD) recommendation of less than 10% coefficient of variation at the 99th percentile
of normal.
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| Performed directly on blood samples, the Anthrax Quick ELISA by Immunetics Inc. (Boston) delivers results in 45 minutes. |
The test generates results quickly and thus can prove advantageous when used
in acute-care settings. Use of the assay may result in a reduction of turnaround
time from 76 minutes for tests conducted in a central lab to less than 20 minutes
for tests performed in an acute-care setting. It has been cleared for use in
the United States as an aid in the diagnosis of acute myocardial infarction
and in the risk stratification of patients with acute coronary syndrome. The
test is run on the company’s Stratus CS Acute Care diagnostic system.
Response Biomedical (Burnaby, BC, Canada) placed a new test for the cardiac
marker on the U.S. market as well. The company’s RAMP Cardiac Marker Test
for detecting TnI is designed for use as a point-of-care test (POCT) and provides
a quantitative result in 15 minutes.
Abbott Laboratories has received FDA approval for its Stat TnI assay.
The assay has been designed with the goal of improving standardization and sensitivity.
The test’s calibrators are traceable to the National Institute of Standards
and Technology (NIST; Gaithersburg, MD) value-assigned candidate reference
material near the acute myocardial infarction (AMI) cutoff. The assay detects
concentrations of TnI closer to zero with confidence, allowing the cardiac marker
to be detected earlier. The test was designed for use on the company’s
Architect i2000SR immunoassay and Architect ci8200 immunochemistry systems.
The company has also received approval for its Troponin-I ADV assay, which has
been designed for use on the company’s AxSYM automated immunoassay instrument.
Roche Diagnostics has received FDA clearance for its Troponin T Stat
test. This test has been approved for use as an aid in the differential diagnosis
of acute coronary syndrome, for risk stratification in patients with acute coronary
syndrome, and for cardiac risk in patients with chronic renal failure.
Abbott Laboratories has added a creatine kinase MB (CK-MB) test to the menu
of its Architect ci8200 immunochemistry system. The manufacturer has also added
the Stat CK-MB test to the menu of both the ci8200 and its Architect i2000SR
systems. The FDA-cleared tests can help doctors determine whether a patient’s
heart muscle has suffered damage. The instruments deliver results of the CK-MB
tests within 18 minutes.
Abbott and Axis-Shield (Dundee, UK) have received clearance to sell their
B-type natriuretic peptide (BNP) test in the United States. The test is designed
for use on Abbott’s AxSYM system, and can be used to detect early signs
of cardiac dysfunction as well as overt heart failure.
Dade Behring has received FDA clearance to sell its N-terminal pro brain natriuretic
peptide (NT-proBNP) test in the United States. The test runs on the company’s
Dimension instruments to aid in the diagnosis of patients who present with symptoms
of congestive heart failure.
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| The Immulite 2500 SMS immunoassay system by Diagnostic Products Corp. (Los Angeles) provides improved stat testing capability. |
Dade Behring has received approval to market its N high- sensitivity CRP assay
as an independent marker for cardiovascular disease risk prevention. The test
is designed to run on the company’s BN instruments and is the first hsCRP
assay to receive FDA clearance with a cardiac-specific claim.
In addition to individual tests for cardiovascular function, this year a panel
of tests designed to examine a range of cardiovascular factors received FDA
approval. The Triage Shortness of Breath panel by Biosite Inc. (San Diego)
measures the levels of five biomarkers including BNP, D-dimer, myoglobin, CK-MB,
and cardiac troponin I. Results are generated in 15 minutes. The test is performed
on whole blood in a one-step operation using a small disposable IVD and the
Triage Meterplus portable meter.
The test is designed for use with patients who present with shortness of breath
in emergency-care settings and for the diagnosis or assessment of congestive
heart failure or disseminated intravascular coagulation, and for the risk stratification
of patients with acute coronary symptoms. The company is also developing a stroke
panel.
Neurodegenerative. Although most of the progress this year on tests for neurodegenerative
disorders has been in the research arena, Nymox Pharmaceutical Corp.
(Maywood, NJ) filed a PMA application with FDA for the company’s Alzheimer’s
test. The Alzheimalert test measures in urine the level of a brain protein called
neural thread protein to help practitioners diagnose Alzheimer’s.
Celera Diagnostics (Alameda, CA) and Merck & Co. (Whitehouse
Station, NJ) have entered into a collaboration to find novel targets for diagnostic
markers related to Alzheimer’s disease. Under the terms of the agreement,
Celera will retain the rights to diagnostic applications from the studies. Also,
CombiMatrix (Mukilteo, WA) and Case Western Reserve University (Cleveland)
are collaborating on an Alzheimer’s diagnostic using the company’s
Customarray platform.
In addition, the IVD industry and research communities are making an effort
to develop better tests for amyotrophic lateral sclerosis (ALS). Massachusetts
General Hospital (Boston), the University of Pittsburgh School of Medicine,
and Metabolon (Research Triangle Park, NC) are working on an ALS Association–funded
study to develop a more rapid and accurate diagnostic test for ALS using biomarkers
found in blood and cerebrospinal fluid.
Infectious disease. Many tests designed to better diagnose infectious diseases
were released this year. Abbott Laboratories brought a fully automated hepatitis
A assay to the U.S. market. The HAVAB-M 2.0 uses microparticle enzyme immunoassay
methodology to detect the IgM antibody to hepatitis A and is designed for use
on the company’s AxSYM system.
Bayer received FDA approval for a new hepatitis B test. The Anti-HBs assay is
run on the Advia Centaur immunoassay system. The test detects the presence of
antibodies to the hepatitis B surface antigen in blood, thereby helping physicians
determine whether a patient has achieved a protective immunity to the virus.
The assay is the company’s first installment in a series of tests that
it will offer as a comprehensive and fully automated infectious-disease testing
panel that will include a tests for HBV, HAV, HCV, and HIV.
Hepatitis B tests from Ortho-Clinical Diagnostics also received FDA approval
this year. The Anti-HBc and Anti-HBc IgM assays are designed for the company’s
fully automated random-access Vitros Eci immunodiagnostic system.
Trinity Biotech (Bray, Co. Wicklow, Ireland) has received clearance to
market its Captia herpes simplex virus (HSV) IgG type-specific enzyme-linked
immunosorbent assays (ELISA) in the United States. The products detect IgG antibodies
to HSV 1 and 2 in human serum and are among the first HSV type-specific ELISAs
to receive FDA approval. The tests use recombinant glycoproteins gG-1 and gG-2,
which are specific to types 1 and 2 of the virus respectively, and differentiate
between antibodies to types 1 and 2. The glycoproteins minimize cross-reactivity.
The tests perform with a sensitivity of 100% and a specificity of 99%.
Nanogen (San Diego) and Prodesse (Waukesha, WI) are working together
to develop automated and highly sensitive microarray-based products to detect
a number of infectious- disease agents including influenza, pneumonia, adenovirus,
herpes, West Nile Virus, and severe acute respiratory syndrome (SARS). The tests
will speed up the delivery of results from a turnaround time of a week or longer
for current culture-based techniques to a turnaround time of a few hours. The
new line of products will be based upon an integration of Prodesse’s multiplex
amplification technology with Nanogen’s Nanochip platform and will be marketed
to healthcare providers and clinical reference laboratories.
Meridian Bioscience Inc. (Cincinnati) began marketing a rapid influenza
A and B test for use in physician offices and small labs. The test differentiates
between the A and B strains of influenza.
Many tests for viruses that could be used for terrorism or biowarfare were placed
on the market this year. FDA cleared the first commercially available antibody
test for Bacillus anthracis. The Anthrax Quick ELISA test by Immunetics Inc.
(Boston) is performed directly on blood samples and is faster and easier
to interpret than previous antibody testing methods. It works by detecting antibodies
to a key component of the anthrax bacillus that forms part of the toxin responsible
for its lethal effects. The test can be performed in less than an hour, compared
with 4 hours required for other methods.
FDA also cleared for use in the United States a test kit for anthrax that is
designed for use in clinical laboratories. The Redline Alert test by Tetracore
Inc. (Gaithersburg, MD) uses a laboratory culture of bacterial cells to
distinguish B. anthracis cells from other organisms. The test delivers results
within 15 minutes. When a positive result is received, confirmatory testing
is required to definitively identify B. anthracis.
Veterinary. Due to the transfer of diseases from animals to humans, many new
tests were approved for the veterinary market this year. As bovine spongiform
encephalopathy (BSE) made its first recorded appearance in the United States
this year, the U.S. Department of Agriculture (USDA) stepped up its monitoring
of beef cattle and approved several rapid tests for BSE.
Roche (Basel, Switzerland) gained permission to market the Prionics-Check
Western kit by Greiner Diagnostics (Langenthal, Switzerland), which it
licensed from Prionics (Schlieren, Switzerland). The test relies on a
Western blot technique that results in a fingerprint of the infectious particle.
The test delivered no false-positive results in 18 million tested samples. Prionics
has also developed a Check LIA test that is based on an ELISA platform. This
test is in use in Europe.
USDA also approved the rapid Enfer BSE test marketed in the United States by
Abbott and developed by Enfer Scientific (Newbridge, Co. Kildare, Ireland).
The test provides results within hours, and tests every bovine brain sample
in duplicate. If either test is reactive, the specimen is resampled and retested
in duplicate.
Idexx Laboratories (Westbrook, ME) received USDA approval for its HerdChek
BSE test, which is based on Seprion technology licensed from Microsens
(London). For faster turnaround time than other rapid tests, HerdChek simplifies
testing procedures by eliminating complex protein digestion steps in the sample
preparation process. This saves technician time and effort, and reduces the
potential for error.
USDA also granted approval to the Tesee (formerly Platelia) BSE test
by Bio-Rad Laboratories (Hercules, CA). The test was developed in collaboration
with the French atomic energy administration, the Commissariat à l’Energie
Atomique (EA Paris). The test relies on ELISA technology.
Lastly, Beckman Coulter received USDA approval for the BSE test that it licensed
from InPro (San Francisco) for sale in the United States. This Conformation-Dependent
Immunoassay (CDI-5) sets itself apart from the first generation of BSE tests
in that it relies on a detection technique that does not destroy any of the
disease-causing forms of the prion protein.
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| The Variant II Turbo hemoglobin testing system by Bio-Rad Laboratories (Hercules, CA) features whole blood primary-tube sampling. |
All of the rapid tests approved for BSE testing in the United States are conducted
postmortem on bovine brain samples. However, many companies are working toward
a test that can be performed on a live animal. GeneThera (Wheat Ridge,
CO) has developed one such test, although it is not yet commercially available.
The test uses the company’s proprietary genetic expression assay technology
to detect and quantify BSE proteins in blood samples.
West Nile Virus (WNV) made its way entirely across the United States this year,
and hit the West Coast heavily. Meanwhile, manufacturers released more-sophisticated
tests for the virus. Focus Technologies (Cypress, CA) received FDA clearance
for its third-generation IgM and IgG ELISA test kits. The tests have a sensitivity
and specificity ranging from 91 to 99%. In addition, Gen-Probe (San Diego)
began WNV testing under an investigational (IND) protocol with its Procleix
WNV assay on the company’s Tigris system. The test allows donated-blood
screening centers to test individual blood samples on a high-throughput, fully
automated nucleic acid testing (NAT) system.
Another disease prevalent in animals that has gained attention this year is
avian influenza. USDA has developed a reverse transcriptase–polymerase
chain reaction (RT-PCR)-based test for avian flu. The test initially screens
for any type-A influenza and then performs a subtyping step with which it confirms
the sample and what specific subtype it is. Eventually, USDA is planning to
work with an IVD manufacturer to put the test into a single-kit format for commercial
production.
Laboratory Instruments
With an eye to easing troubleshooting, QC, and general management of IVD systems,
manufacturers have released advanced software-driven instrument management.
Many manufacturers of larger IVD systems equip their instruments with software,
such as DRM software by Axeda Systems Inc. and remote testing management software
by Nova Biomedical, that allows for remote monitoring and software upgrades.
Laboratorians can now oversee multiple types of testing at one time as an alternative
to relying on one machine that can “do it all.” Beckman Coulter has
introduced a centralized system designed to simplify and automate lab processes
such as workflow and decision-making steps. Command Central connects up to 12
Beckman instruments, including chemistry, immunoassay, hematology, and automation
platforms. The system operator can access instruments via a network connection
in real time.
In addition to instrument management issues, end-users are demanding connectivity
and advanced data management solutions for everything from rapid point-of-care
tests (POCTs) to systems for the core lab. According to David Pearman, field
product manager, homeostasis and thrombosis diagnostics for Helena Laboratories
(Knox, IN), “Even the smallest institution (even a doctor’s office)
wants data management in order to be HIPAA compliant.”
Clinical chemistry. Nova Biomedical (Waltham, MA) has introduced the
Stat Profile Critical Care Xpress, which can measure blood gases, electrolytes,
chemistry, and hematology with onboard CO oximetry. The test menu is custom
configured, but can include as many as 19 measured and 29 calculated tests such
as pH, PCO2, PO2, SO2, hematocrit and hemoglobin, sodium, potassium, chloride,
ionized calcium, ionized magnesium, glucose, BUN, creatine, and lactate.
Snap-in reagent packs contain all required liquid and gas calibrators and onboard
controls. The system requires 50 µl of whole blood for a gas panel and
200 µl of sample for all measured tests. An automated, onboard quality
control cartridge eliminates the manual steps involved in the QC regimen and
onboard data management software allows for custom configuration of touch screen
layouts as well as data capture and output.
A fully automated random-access immunochemistry system features enhanced performance
for protein analysis. The Immage 800 by Beckman Coulter offers 40 assays, including
hsCRP and other protein, serology, and drug tests. Users can configure the test
menu to meet their unique requirements. The system has the ability to append
samples while it is running, and allows users to flag antigen access, plot UDR
data curves, and perform single-point update calibrations.
Clinical Data (Smithfield, RI) received FDA clearance to market its
Vitalab Selectra-XL in the United States. This random-access, “walk-away”
clinical chemistry analyzer offers a wide range of testing including clinical
chemistry, special proteins, drugs of abuse, therapeutic drug monitoring and
electrolytes. With a throughput of 400 tests per hour, it is designed for the
small to medium-sized laboratory or as a backup or special chemistries analyzer
for a larger laboratory.
Immunoassay. Diagnostic Products Corp. (Los Angeles) has launched its
Immulite 2500 SMS immunoassay system. The system provides improved stat testing
capability with logic-driven incubation and a sample management system. Available
applications include cardiac, routine, esoteric, infectious-disease, and allergy
testing. The sample management feature allows the system to link to any open
laboratory automation solution and perform no-pause loading and unloading of
up to 200 samples.
Ortho-Clinical Diagnostics introduced the Vitros EciQ immunodiagnostic system.
The system software provides new verification procedures. Reagent aspiration
verification, sample plus reagent verification, and well-wash dispense verification
help to ensure release of a proper reagent volume, confirm that the proper assay
and reagent volumes are contained in the well, and confirm that the proper wash
process has been completed. In addition, the system features e-Connectivity
system management that allows company support teams to have real-time access
to the system.
Bio-Rad received approval for a clinical diagnostics system that offers multiplexing
technology on a fully automated, fully integrated random-access platform. The
BioPlex 2200 fully automates bead-based multiplexing, can deliver up to 2200
results per hour, and provides clinical informatics to aid in diagnosis. Tests
initially available on the system will be used to diagnose autoimmune diseases
and disorders. Assays in development for the system include those in the areas
of serology, infectious disease, cardiac, and toxicology.
Olympus (Melville, NY) released its AU-30001 immunoassay system. The
instrument can process as many as 240 tests per hour with no-pause loading and
stat interrupt. The system uses chemiluminescent detection to deliver good linearity
for fertility, thyroid, tumor, anemia, and cardiac panels.
In an effort to make molecular testing available for smaller and point-of-care
labs, Iquum Inc. (Allston, MA) has developed a system based on its lab-in-a-tube
(Liat) technology. The system is designed to facilitate molecular testing for
infectious and genetic diseases, as well as field testing for biological agents.
With Liat technology, results are available in 30 minutes to an hour.
Biofons Diagnostics (Turku, Finland) has developed a novel immunochemical
method that uses membrane-surface plasmon resonance for sensitive and specific
results. The company’s Specimat system has been created to meet the need
for rapid diagnostics in smaller-volume laboratories. CRP testing is the first
application available on the system.
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| The Vanguard OMT rapid lateral-flow test by Calypte Biomedical Corp. (Pleasanton, CA) can detect HIV1 and 2 in oral fluid. |
Hematology. In an effort to reduce manual test procedures, patient sample size,
and required repeats, Bayer (Tarrytown, NY) has provided automated hematology
testing on its Advia 2120 system. The newly launched system has automated such
labor-intensive tests as cerebrospinal fluid analysis, reticulocyte tests, and
complete blood counts. Quality control is enhanced by internal verification
of every sample by using two methodologies to compare test results.
Designed for mid- to high-volume laboratories, the Coulter LH 500 by Beckman
Coulter offers complete blood cell counts with five-part differential analysis
and features advanced three-dimensional volume, conductivity, scatter technology.
The instrument’s expanded linearity limits extend from zero to 200,000
cells/ml for WBCs, while platelet linearity extends from zero to 2 million cells/ml.
The system provides continuous sample loading, and stat samples can be run with
minimal interruption.
Sysmex (Mundelein, IL) received FDA clearance for its pocH-100i hematology
analyzer. The system performs an automated complete blood cell and a three-point
differential with a true neutrophil count. Sampling is done in closed-tube manner.
Although this low-volume instrument is designed for the clinical laboratory
and physician office market, technology and results are comparable with other
Sysmex systems.
Stanbio Laboratory (Boerne, TX) received a CLIA waiver for its Hemapoint
H2 system, which serves as a dedicated hemoglobin and hematocrit meter for use
in physician offices, clinics, and blood centers. The instrument consists of
a microcuvette along with a photometer to measure hemoglobin in whole blood.
The system requires 10 µl of whole blood. System specifications include
a linear range of 0 to 23.5 g/dl and within-run and total precision CVs are
less than 2%.
Abaxis (Union City, CA) has introduced a new hematology analyzer for
the veterinary market. The Vetscan HMII hematology system provides an 18-point
complete blood count analysis including a three-part white blood cell differential
in a compact instrument.
FDA cleared the high-throughput Galileo blood bank automation system by ImmucourGamma
(Norcross, GA). The system offers continuous access while processing 224 different
samples at once. The test menu includes blood typing, antibody screening, antibody
identification, donor confirmation, cross-match, DAT, and weak D testing. The
instrument relies on the company’s proprietary Capture solid-phase technology
and full process controls.
Other systems. The speed and precision of high-performance liquid chromatography
(HPLC) power a new hemoglobin analyzer from Primus Corp. (Kansas City,
MO). The Ultra2 A1c and hemoglobin variants analyzer measures hemoglobin levels
and identifies and quantifies hemoglobin variants for glycemic control. The
A1c assay uses HPLC and boronate affinity columns to assess glycemic status
in 2 minutes. The system features automated sample handling, bar code reading,
and on-line sample preparation from the primary tube.
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| The Cozmonitor glucose monitor by Smiths Medical (London) works together with an insulin pump to form an integrated glucose management system. |
Another new hemoglobin analyzer that relies on HPLC is the Variant II Turbo
hemoglobin testing system by Bio-Rad Laboratories. The system doubles the throughput
capacity of the company’s top-performing HbA1c method. The system relies
on the company’s HbA1c reagent kit and features whole blood primary-tube
sampling.
Beckman Coulter released its ACL 8000 coagulation analyzer to help speed hemostatis
testing. Approximately 40 clotting, immunoturbidimetric, and chromogenic assays
are available on the system, including tests for D-dimer, Von Williebrand antigen,
and free protein S. Result accuracy is enhanced by the system’s automated
reflux and rerun testing capabilities, along with the instrument’s clot
signature curve technology. Computer-based centrifugal analysis allows for 18
samples to be tested at one time in each 20-cuvette rotor. The instrument has
an onboard capacity of 40 samples and 18 reagents. The company has also released
its ACL 10,000 analyzer, which includes an optional capper/decapper and features
an onboard capacity of 40 samples, 22 reagents, and 260 cuvettes.
For near-patient testing, the Clinitek Status by Bayer Diagnostics provides
a fully automated urinalysis instrument. The system features a 200-test-result
memory, paper printouts of results, and a touch screen display. The company
also released the Clinitest hCG pregnancy test that is designed for use exclusively
with the Clinitek analyzer.
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| Approved for use in both Europe and the United States, the Factor V Leiden and Factor II (Prothrombin) G20210A kits by Roche Diagnostics (Indianapolis) aid in the evaluation of patients suspected of having thrombophilia. |
Roche Diagnostics has also released a urinalysis system for physician office
applications. The Urisys 1100 analyzer is a small, semiquantitative analyzer
that features 100-result memory function, immediate result printouts, interfacing
capability to PC or network, and quality assurance functions.
Veridex has planned a fall 2004 release for its CellSearch system. The system
is the first automated instrument to identify and count circulating tumor cells
in peripheral blood. Results will be used to predict progression-free survival
and overall survival in patients with metastatic breast cancer.
Point-of-Care Tests
New diagnostics on the POCT market demonstrate advances in ease of use and effectiveness.
With POCTs now available in virtually every medical sector of the IVD market,
manufacturers are now striving for improvements in standardization of results.
This factor depends a good deal on built-in protection for standard sampling
and simple test processes so that user error is minimized.
Manufacturers are also working to improve sensitivity and specificity of these
devices so that results obtained from point-of-care IVDs approach the accuracy
of laboratory tests. Lastly, smaller continues to be better. Advances in miniaturization
technologies hold promise for enhancing portability and cost-effectiveness of
POCTs.
Lastly, while most POCTs offer a yes or no quantitative result, the market calls
for tests that offer more versatility. POCT systems that offer such versatility
are generally dedicated systems that are not economically justifiable for most
facilities. Once industry can make such systems affordable for more consumers,
the market for POCT will grow substantially.
HIV. Many new POCTs for HIV were placed on the market this year. With a record
5 million people having been infected with AIDS last year alone, HIV continues
to be a major concern around the world. With boosted funding to fight HIV and
AIDS, the market for new and improved HIV tests continues to thrive.
Experts from the United Nations called for required routine HIV testing in clinics
around the globe, citing the statistic that 90% of those infected with AIDS
are unaware that they are carrying it. The current strategy of leaving it to
patients to request a test is not working to curb the spread of the disease
and more-widespread testing may lead to earlier diagnosis and reduced transmission.
Although the HIV test market is booming, not much attention has been paid to
the ramifications of POCT for the virus. “There is little feedback or follow-up
studies on the implications of carrying out these tests in the doctor’s
office,” says Tony Forde, associate director of The Circa Group Europe
Ltd. (Galway, Ireland).
Beckman Coulter has filed a 510(k) application with FDA for the company’s
portable and automated test for monitoring drug therapy for HIV/AIDS patients.
The Pointcare system uses gold-coated microparticles to perform CD4 monitoring
and is suitable for use in remote locations.
The OraQuick rapid point-of-care HIV test by OraSure Technologies (Bethlehem,
PA), which last year received FDA approval for testing fingerstick and whole
blood samples for HIV1, this year received FDA approval for testing oral fluid
and plasma samples for the virus as well. FDA extended the test’s clearance
for testing all of these specimen types for both HIV1 and HIV2 strains of the
virus, and also gave the test a CLIA waiver. The OraQuick test generates results
within 20 minutes.
FDA also granted approval for the marketing and sale of the Uni-Gold Recombigen
HIV test by Trinity Biotech (Dublin, Ireland). The test detects antibodies
to HIV in human serum, plasma, or whole blood. The protocol involves only one
step and produces results within 10 minutes. In clinical trials, the product
demonstrated a test sensitivity of 100% and a specificity of over 99.7%.
In addition, Efoora (Buffalo Grove, IL) has received approval to market
its Efoora rapid HIV test, which works on whole blood, fingerstick whole blood,
serum, and plasma, and can provide a result in 20 minutes.
Calypte Biomedical Corp. (Pleasanton, CA) has completed initial field
trials of its lateral-flow rapid diagnostic HIV1 and 2 tests. The company is
developing several rapid tests, one for use with oral fluid, another with blood,
and a third with urine. In the trials, the blood, oral fluid, and urine tests
performed with accuracies of 100%, 99.8%, and 99.6%, respectively. The tests
performed so well that Abbott Laboratories signed a sublease agreement to gain
rights to patents relating to the design, manufacture, and sale of the tests.
Chembio Diagnostic Systems (Medford, NY) has begun clinical trials in
the United States of its Sure Check HIV and HIV Stat-Pak tests. In clinical
trials in Mexico, the tests performed with a sensitivity and specificity of
100%. The tests are designed to detect antibodies to HIV in fingerstick blood,
whole blood, serum, or plasma. Both deliver results within 15 minutes.
Glucose monitoring. The diabetes care market continues to comprise a large part
of the POCT market. Glucose monitors released this year offer advances in device
capabilities as well as functionality, and the ability to be integrated with
insulin pumps. The market received monitors that can perform continuous monitoring
and monitors that work as one system with an insulin pump.
Smiths Medical (London) has released its Cozmonitor blood glucose module.
The device uses Freestyle Flash technology from Abbott. The module works in
tandem with the Deltec Cozmo insulin pump to form an integrated insulin pump
and glucose-monitoring system.
Medtronic (Minneapolis) has released a stand-alone continuous glucose-monitoring
system. The FDA-approved Guardian system must be calibrated at least twice per
day and uses a glucose sensor to continuously record blood sugar readings for
up to three days. An alarm sounds when readings reach high- or low-level limits
preset by the user.
Early this year, Roche introduced its Accu-Check Go blood glucose monitor. The
monitor incorporates an out-of-the-meter blood application where test strips
that feature a capillary fill are inserted into the meter prior to blood expression
and then a blood sample of 1.5 µl is drawn into the meter via the capillary
strip. The device features reminder alarms and a test-strip ejector.
A blood glucose–monitoring system that integrates a meter and an electronic
logbook is available from LifeScan (Milpitas, CA). The Onetouch Ultrasmart
system has been designed to replace the traditional paper logbook used for recording
test results. The system requires a 1-µl sample and generates glucose
test readings in 5 seconds. System software allows input of information relating
to food, exercise, medication, and overall health. It also helps identify blood
glucose patterns and note the need for treatment changes.
Other applications. IVD manufacturers have added POCTs to many other IVD market
sectors. From drugs-of-abuse (DOA) tests to critical-care tests, these devices
can speed decision making to help save lives or take immediate action in an
emergency.
For the critical-care POCT market, Roche Diagnostics released four new models
of its Omni S 1-4 POC analyzer, which allows users to choose an optimized parameter
portfolio for their information needs. Each model is tailored to the needs of
a different critical-care setting, such as intensive care units; emergency rooms;
operating rooms; and remote labs, recovery rooms, neonatal units, and renal
dialysis. Parameters such as blood gases, electrolytes, total hemoglobin, hemoglobin
derivatives, hematocrit, and bilirubin are available on the high-end analyzer.
To aid in national defense, BioVeris Corp. (Gaithersburg, MD) introduced
its M-series M1M analyzer. This automated and portable analyzer uses electrochemiluminescence
to detect chemical and biowarfare agents in the field or laboratory. The analyzer
can detect botulism neurotoxins, anthrax, ricin, and staphylococcal enterotoxins
A and B. The instrument can also be used with tests that the company is developing
for the U.S. Department of Defense.
OraSure Technologies submitted a 510(k) application for its Uplink analyzer
and oral fluid assays for DOA testing. The POC system is based on the company’s
up-converting phosphor technology and can deliver results of tests for cocaine,
opiates, amphetamine, PCP, and marijuana from one oral fluid sample.
For weekly International Normalized Ratio (INR) testing at home, LifeScan has
introduced its Harmony INR monitoring system. This blood-clotting-time test
system uses fingerstick blood to generate results within 90 seconds.
DiaSys Corp. (Waterbury, CT) introduced 10 POC rapid tests. The four
cardiac marker POCTs include troponin I, CK-MB, myoglobin, and CRP. Three tests
for cancer markers include Id1, HMGA2, and alpha fetoprotein. Lastly, tests
for malaria, dengue IgG and IgM, and neonatal TSH are available. Each will be
sold in a POC rapid-test configuration.
Molecular Diagnostics
Molecular-based IVDs are gradually being released onto the market. Industry
has billed this technology as the face of the future of IVDs, but before effective
tests and devices can be released, IVD manufacturers must overcome numerous
technological hurdles.
Protein arrays are one platform that holds promise for molecular diagnostics.
Thus far, bead-based arrays are in use for some measurements, while solid-phase
arrays are gaining ground and have potential for use in others. Although protein
arrays are making their way from the research lab to the IVD market, some find
that the available technology has yet to reach acceptable standards.
“Protein arrays must prove to have the reproducibility required by [the
IVD] industry in order to gain acceptance,” notes John Tonkinson, PhD,
director of sales and scientific services for Prometheus Laboratories (Keene,
NH). “That hurdle will be difficult, but not impossible, to go over.”
According to Tonkinson, the availability of high-throughput, high-resolution
laser scanners for microplate footprints will increase the rate at which protein
arrays will find their way to the IVD market.
Randox Laboratories Ltd. (Crumlin, UK) manufactures biochip arrays and
is making headway in broaching the diagnostics market. The company’s Evidence
system can carry out a panel of tests on a single chip, but allows technicians
the option of downloading (and paying) for a single test. If, at a later stage,
further markers are required to provide additional information on that patient,
the system can call on data stored in its memory bank.
The biochip reaction platform comprises multiple specific ligands attached at
predefined sites on the chip surface. When the patient sample is added to the
biochip, analytes in the sample bind to specific ligands. The degree of binding
is determined via a chemiluminescent light source and quantified using a CCD
camera and imaging system. The instrument can run in excess of 2700 tests per
hour.
Gen-Probe received FDA approval for sexually transmitted disease testing on
its Tigris DTS system. The Tigris instrument is the first fully automated, high-throughput
instrument for the molecular diagnostics marketplace. “I don’t think
there is anything comparable on the market,” notes Katie Smith, PhD, senior
director, diagnostics clinical research & regulatory affairs for Prometheus
Laboratories (San Diego). “It may revolutionize nucleic acid assays by
controlling possible contamination, reducing labor costs to perform the assays,
and increasing test throughput,” says Smith.
FDA has approved the system for running the company’s Aptima Combo 2 assay,
a nucleic acid test that simultaneously detects Chlamydia trachomatis and Neisseria
gonorrhoeae.
The Tigris system can process approximately 500 samples in an 8-hour shift and
up to 1000 samples in 13 hours. The company is now working to expand the menu
of clinical tests for the system.
Affymetrix (Santa Clara, CA) achieved another first in the marketing
of molecular diagnostics. The company’s GeneChip System 3000Dx received
the CE mark. The instrument is the first microarray system on the market for
clinical diagnostics. It comprises a scanner complete with an autoloader, a
fluidics station, and proprietary software. The system allows laboratories to
analyze such microarray diagnostics as the AmpliChip CYP450 test, by Roche Diagnostics,
for drug metabolism profiles.
Correlogic Systems Inc. (Bethesda, MD) released its OvaCheck test without
FDA review because company representatives believed that its operations as a
high-complexity laboratory under the Clinical Laboratory Improvement Ammendments
of 1988 (CLIA) were sufficient. Nonetheless, FDA’s Office of In Vitro Diagnostic
Device Regulation and Safety (OIVD; Washington, DC) determined that, if installed
at laboratories outside of Correlogic’s CLIA-affiliated facility, the protein-pattern
recognition software necessary to perform the OvaCheck test will be subject
to FDA regulation.
Ventana Medical Systems (Tucson) released its human papillomavirus (HPV)
test as an ASR. Initially, FDA asked the company to pull the test from the market
because the agency disagreed with the company’s assertion that the test
was exempt from review. However, after meeting with the company, FDA gave the
company permission to market the test.
After its initial launch and ensuing OIVD oversight, Roche’s CYP450 AmpliChip
is still under FDA review. However, several other companies are developing CYP450
tests. Third Wave Technologies has released its CYP450 2D6 analysis panel for
use in clinical trials of pharmaceuticals. AutoGenomics and Gentris Corp. are
working to integrate Gentris’s CYP450 diagnostics into AutoGenomics’
automated Infiniti platform.
To aid in cardiovascular diagnostics, Roche Diagnostics received clearance to
market its Factor V Leiden (FVL) and Factor II (Prothrombin) G20210A kits in
both the United States and the European Union. The tests rely on RT-PCR to aid
in the detection and genotyping of inherited mutations in the genes that encode
proteins associated with inherited thrombophilia. The tests were developed for
use on the company’s Lightcycler instrument.
Several new molecular diagnostics for cancer have been placed on the market.
FDA approved the Rapid Capture system by Digene Corp. (Gaithersburg,
MD) that allows for high-throughput testing with the company’s hc2 High-Risk
HPV DNA test. With this system, 352 patient specimens can be analyzed for the
presence of the cervical cancer–associated virus by one technologist in
6.5 hours.
Many tests released this year for HPV, a virus that causes cervical cancer,
rely on molecular diagnostics for detecting the virus. The Amplicor HPV test
kit by Roche is a PCR-based test that can identify all 13 high-risk HPV genotypes.
Roche representatives intend the test to be used to resolve inconclusive results
obtained from Pap tests. The manufacturer is also developing a PCR-based linear-array
HPV product for use in confirming positive cervical cancer–screening results
and providing information about the HPV subtype to aid with treatment.
In an effort to reduce the number of colposcopies that result from HPV-positive
diagnoses, TriPath Imaging (Burlington, NC) is developing a second-generation,
cytology-based cervical cancer test. The test will target patients with atypical
low-grade lesions as well as those who test positive for HPV but negative on
Pap tests.
OncoMethylome Sciences (Durham, NC) has received a U.S. patent for its
gene methylation technology for the prediction of clinical response to certain
types of chemotherapeutic treatment of cancer patients. The company is developing
an assay based on this technology and has an ongoing clinical trial program
to demonstrate the utility of the assay to predict chemotherapeutic response.
Although molecular technologies are just taking their first steps into the clinical
diagnostics marketplace, they clearly hold promise for the future of IVDs. Molecular
diagnostics and miniaturization technologies will literally shape the face of
new devices. NanoInk (Chicago) is developing one such technology.
The company is developing technology to be used in the ultraminiaturization
of DNA arrays. According to the company’s CEO, Dip Pen Nanolithography
has the potential to revolutionize diagnostics by facilitating the development
of smaller, faster, more-sensitive assays that can serve the POC diagnostics
and biodefense markets.
Conclusion
With new molecular products on the market, an increased demand for instruments
with greater automation and connectivity, and ever-increasing opportunities
for bringing POCTs for a variety of samples to market, it has been a prosperous
year for IVD companies. Requests for partnership from pharmaceutical companies
have planted the seeds for the future of personalized medicine.
In addition to smaller, less-expensive, faster, and more-accurate traditional
IVDs, new tests are in development that are tied intimately to pharmaceuticals.
More and more of these personalized-medicine IVDs will likely be introduced
into the marketplace in upcoming years.
Future advances in IVDs will bring diagnostic testing even closer to the patient,
and provide more-accurate, faster, and simpler testing to the marketplace. As
IVD manufacturers deliver on the promise for ever-better diagnostics, IVD Technology
will be here to take note of their progress.
Jennifer Zakroff is associate editor of IVD Technology.
Copyright ©2004 IVD Technology
