Manufacturers turn biomarkers into broad testing menus
By Gary Tufel
Immunoassay analyzers are utilized in a wide range of clinical laboratory service areas, with the aim of improving service and quality while decreasing costs. Immunoassays are biochemical tests that measure the presence or concentration of a substance, often in solutions that contain a complex mixture of substances. Analytes in biological liquids such as serum or urine are frequently assayed using immunoassay methods, usually through the use of an antibody or, sometimes, an antigen. Keeping pace with emerging biomarkers, and consolidating a broad test menu, are both important for developing new immunoassay instruments and kits—or updating existing ones.
Most manufacturers ask about several important factors when deciding whether to launch a new instrument or test onto the market, says Jeff Ellis, vice president of sales and marketing at Now Diagnostics, Springdale, Ark. “Can it fill a void that currently exists? Might it offer more sensitive or specific results than what is currently available? Can this new offering potentially be more cost-effective to the customer—or even ultimately to the healthcare system?” he asks. “Sometimes the cost factor of a new instrument or test is a determining consideration.”
The design and functionality of new instruments are predominantly customer-driven, says Navjot Kaur, PhD, scientific leader for diagnostics at Hamilton Robotics, Reno, Nev. “Factors like the available laboratory space for placing an instrument are considered in determining the dimensions of the new instrument. Throughput needs of the customer are evaluated to decide the layout for the new instrument. And a range of workflows are considered in designing and including the components for providing a fully automated immunoassay instrument,” she says. “A graphical user interface is preferred for the software, and its development is based on keeping it user-friendly. Another important factor that is considered in launching new instruments is the latest technology, so that the instrument and software have a modern look and functionality.”
As an in vitro diagnostics company, Ortho Clinical Diagnostics, Raritan, NJ, is highly attuned to its lab customers’ needs, says Karen Davis-Fleischer, the company’s senior director of global product management. “We recognize that the challenges in the lab span a broad spectrum of needs, and that the labs look to us to provide solutions, not just instruments.
“Of course, the menu of tests is at the heart of labs’ needs, and strengthening the menu is always going to be a top priority for Ortho’s development team. But today labs are increasingly driven to be more efficient with resources,” says Davis-Fleischer. “Labs highly value workflow solutions that can quickly deliver reliable, trustworthy results at the best possible value to the hospital.”
So it’s not just instruments, says Davis-Fleischer. A new development opportunity is any solution that drives reliability of results and operational efficiency in the lab. In the past, this looked like the consolidation of assay technologies onto integrated instrument platforms. Today, it looks like open workflow solutions that automate off-instrument operations, reduce total cost of ownership, and enhance the interoperability of the lab’s equipment. “Meeting these demands for automation, scalability, and openness is a key focus for us,” she says.
IMMUNOASSAY PERFORMANCE REQUIREMENTS
Labs expect that their immunoassay instruments will meet certain performance standards. As current baselines, labs consider bare minimum performance capabilities for an immunoassay instrument to be acceptable. Performance areas of critical importance to labs include the number of samples and tests per hour; the number of different tests included on the instrument’s menu; and essential automation, connectivity, and communications capabilities. For instrument manufacturers, identifying and meeting the performance capabilities essential for their products means listening closely to what customers say they need. (For more information, visit “Ultrasensitivity in Immunoassay Technology.”)
“Labs don’t buy instruments; they buy results that drive clinical utility to their customers, the clinical decisionmakers. They buy solutions that deliver the right results in the right location,” says Davis-Fleischer. “The essential capabilities of that solution vary by the focus and mission of each lab.”
This challenge is especially acute in hospital laboratories, she says. “A lab may serve a cardiac specialty clinic that has urgent testing needs that demand high sensitivity and fast turnaround. At the other end of the spectrum is the core lab, with a need for a broad menu and high-throughput systems. The fundamental need in any lab is to meet the medical needs of their particular clinician customers. This means they must have the ability to run the right menu of assays with high confidence in the result, with a turnaround time that enables them to meet promised service levels,” she says.
“It’s been said that ‘if you know one hospital network, you know one hospital network,’ says Davis-Fleischer. “From Ortho’s perspective, the heterogeneity of hospital networks means that we must offer flexible, scalable solutions that can be right-sized for every testing location in the network,” she says.
“We usually hear from labs inquiring about the number of samples and number of different tests that can be accomplished in one run,” says Kaur. “Another criterion important to labs is the generation of an output file from the immunoassay instrument. The purpose of such a file is to meet the need for connectivity, in order to integrate the lab’s data flow with its laboratory information management system (LIMS). Clinical labs are usually looking for systems that are fully automated, so that they can introduce samples into the instrument for analysis, and receive the results at the end of the run.”
Hamilton Robotics offers a compact platform, the ELISA Nimbus, as a complete walkaway solution with an easy-to-use software interface. Its small footprint is balanced for maximum sample and reagent capacity for analysis of up to eight ELISA plates and 12 different tests in one run, Kaur says. Key components of the ELISA Nimbus include:
- Liquid handling platform with four independent pipetting channels.
- Sample carousel for either 192 tubes or three 96-well SBS plates.
- Four Hamilton incubator shakers.
- Eight-channel plate washer.
- Absorbance plate reader.
- Touchscreen display.
- Auto-locking front door.
Users benefit from the ELISA Nimbus in several ways:
- Versatile platform supporting ELISA kits from any vendor.
- End-to-end sample tracking, enabling chain-of-custody documentation.
- Easy-to-use software guides operators through assay setup.
- Complete process control with clot detection for samples.
- Quality service and customer support.
The essential capabilities of an immunoassay system can differ according to the nature of the customer’s lab (eg, a physician office lab, self-standing clinical lab, hospital lab, reference lab) or other factors (eg, cost, disease-specific specialization). Depending on the nature of the customer’s lab, says Kaur, the number of samples received for testing per day or per week may vary.
“Hamilton Robotics has different platforms besides the ELISA Nimbus to support the high-throughput needs of labs,” says Kaur. “Hamilton offers platforms ranging from smaller, lower throughput units, with the Microlab Nimbus; higher throughput units, with the Microlab Star line; and our newest vertically integrated platform, the Microlab Vantage liquid handling system, to accommodate a larger number of clinical samples, whether coming in test tubes or on microplates. The ELISA kits may use different detection technologies besides the absorbance read mode, and the well-established custom engineering department of Hamilton Robotics can easily and robustly integrate third-party plate readers with the liquid handling platforms.”
IMMUNOASSAY INSTRUMENT FEATURES
To meet competitive market demands, manufacturers typically design new immunoassay instruments to incorporate many additional capabilities and features. Such expanded feature sets often include preanalytical automation, interoperability with clinical chemistry and other analyzers, automated reflex testing protocols, automated specimen storage, automated quality control (QC), and flexible reporting methods. (For more information, visit “A Molecular Diagnostics Company Incorporates Immunoassays.”)
“For process control, automated QC performed as an integral part of an ELISA run is important for confirming the quality of the run and for assessing the test results from samples containing unknown pathogens,” says Kaur. The ELISA Nimbus analyzer’s software allows placement of controls in an ELISA plate according to the customer’s choice, by allowing customers to create the layout of the ELISA plate.
While most customers process samples as they are received, some customers may store samples for later processing or secondary screening. Hamilton Storage, an affiliate of Hamilton Robotics, designs and manufactures temperature-controlled automated sample management systems. “These systems are easily integrated with our liquid-handling platforms to expand the capabilities of an immunoassay instrument assembly,” says Kaur.
According to Davis-Fleischer, the instrument is just one part of a comprehensive system solution that meets the core need of delivering reliable results to clinicians, quickly and cost-effectively. An open, scalable, flexible, user-friendly automation solution is the key to enabling this, and that’s why it’s key to Ortho’s strategy, she says.
“Open automation wraps around all of the lab’s technology, whether it’s from one in vitro diagnostics company or several, whether it’s multiple immunoassay technologies, or pre- and postanalytical operations such as aliquoting or downstream sample storage,” says Davis-Fleischer. “Automation is the glue that makes the complete solution, right-sized for the specific needs of that testing location. Ortho focuses on simplifying and automating lab processes so that medical professionals can focus on improving patient care and enhancing medical value.”
On top of adopting features with an extensive track record of improving instrument capabilities and laboratory performance, product developers are also innovating in areas such as interoperability and communications. Factors driving the advances in these areas relate directly to operational challenges that labs face on a daily basis.
“This is an interesting space right now,” says Davis-Fleischer. “The most innovative work is actually being done off of the instrument. Workflow solutions are highly valued—anything that improves efficiency, enhances the safety and reliability of results, and keeps the instruments running is extremely valuable to resource-constrained labs. Internet-powered inventory management and technical support features such as proactive and predictive service alerts like those pioneered by Ortho help minimize downtime and promote overall laboratory productivity and workflow efficiency,” she says.
“The increase in data being generated is driving a need for data management and its linking to automated sample processing,” says Kaur. “In order to maximize the automation capabilities of the clinical laboratory, Hamilton provides a variety of software solutions that enable our automated liquid-handling platforms to generate detailed process reports, or to interface with a LIMS through a network or database. Hamilton’s software can generate and read data from many different file formats and databases.”
COMPATIBILITY AND COMPARABILITY
Instrument and assay developers have also been challenged to deal with issues involving the compatibility and comparability of test results across differing immunoassay platforms or from different laboratories.
Comparability of test results is becoming more critical as hospitals consolidate into networks, says Davis-Fleischer. While the goal of comparability was historically driven by the need for portable patient records, it is now driven by the need to have standardized clinical protocols across an entire healthcare network, she says.
“The solution to this challenge has two dimensions,” says Davis-Fleischer. “The first is to ensure that the assay conforms to a recognized reference standard. This is an ongoing initiative for the in vitro diagnostics industry, driven by our scientific and academic partners. The second is to provide common assay technologies across an entire family of analyzers. This ensures common, standardized results across a healthcare network, but it can be a significant challenge for brands with fragmented immunoassay technology portfolios.”
ELISA Nimbus methods are portable and can be run on different ELISA Nimbus systems, says Kaur. “The Hamilton software allows the creation of the ELISA plate map to include QCs and standards. By comparing QCs and standards in plates prepared and read across different platforms, the test results can be evaluated and trusted.”
FROM BIOMARKER TO ASSAY
Manufacturers are actively engaged in discovering and validating new biomarkers, creating assays for those biomarkers, and adding the assays to the menus of their instruments. But academic and clinical laboratory researchers also have roles to play in making such tests possible.
“Biomarker discovery is an iterative process that begins from either a business or scientific perspective, or a combination of both,” says Kevin Clark, CEO of Now Diagnostics. “Businesses identify market opportunities and quantify the need for new or better biomarkers. Scientists provide relevant intelligence by constantly reviewing current scientific literature, networking within the scientific community, and maintaining working relationships with researchers and opinion leaders at universities and teaching hospitals. Partners and collaborators can also initiate and advance this discovery process.”
Turning a newly discovered biomarker into an immunoassay requires the production of reagents capable of linking to the antibody or antigen biomarkers of interest. Such reagents can be acquired from reagent houses, or developed in-house or under contract to a third party.
“Academic laboratories play an important role in the discovery of new biomarkers. Due to the high risk associated with searching for new biomarkers, most manufacturers are not interested in investing in such research,” says Clark. “Clinical laboratories can make a significant contribution to validating a new assay. Assays are usually validated by conducting a clinical trial or by testing selected clinical samples.”
MEASURES OF TEST PERFORMANCE
Depending on their own purposes, labs may consider certain measures of test performance—such as sensitivity, specificity, accuracy, or speed—to be more important than others. Depending on where a test is performed and its purpose (eg, screening, diagnosis, monitoring), different measures of an individual test’s performance may be more or less important.
Most often, clinical sensitivity and specificity are the most critical features of an assay, says Clark. These features deliver the confidence upon which attending physicians can rule-in or rule-out specific diseases or pathological processes.
“Test performance is variable because performance is affected by which disease or pathological process is targeted, the testing location, and the conditions under which the test is performed,” says Clark. “However, it is important to keep in mind that test performance can result from a conscious calculation of tradeoffs. In the point-of-care testing segment, for example, sensitivity and speed are critical for addressing life-threatening situations. But for screening applications, specificity can be more important for tests used to detect a life-threatening disease.”
“As hospitals consolidate into networks, the challenge is to provide the right test in the right location,” notes Davis-Fleischer. As healthcare networks drive efficiency into their operations, labs are reorganizing into a hub-and-spoke model that puts specialty testing where it’s needed most, and concentrates high-volume testing at the core lab. The measures of test performance that matter most will vary, depending on the focus and mission of the lab, she says.
“Although we all agree that the perfect assay exhibits exquisite sensitivity and perfect specificity, assay performance is always a tradeoff,” says Davis-Fleischer. “Labs understand this and value assay performance individually along the dimensions that matter according to their clinical application—sensitivity and turnaround time for cardiac tests, sensitivity for infectious disease tests, and sensitivity and specificity for screening assays. At Ortho, we know that we need to understand the clinical domain deeply, and design each assay to optimize the right dimensions of performance.
“Regardless of their specialty, all labs need every assay to be reliable and trustworthy, and they need every assay to meet the lab’s service-level commitment to their clinicians,” adds Davis-Fleischer. “Labs value systems that integrate menu-wide features, such as in-line sample and process integrity checks, which either mitigate or report any errors that may occur.”
THE TEST MENU
When considering whether a particular immunoassay instrument is suitable for its intended purposes, labs need to look at a variety of factors—including the menu of tests that the instrument is capable of performing. Factors that help labs to assess the suitability of an instrument may include the sheer number of tests on the instrument’s menu, whether the instrument offers complete coverage of a disease-specific set of tests, or whether it is compatible with tests from other instruments.
Davis-Fleischer says that every lab in a healthcare network needs to deliver a comprehensive menu appropriate to its clinical purpose. “In a hospital network, each lab’s menu requirements will differ according to its mission and clinical focus,” she says. “Since it’s unlikely that any in vitro diagnostics company offers every test that might be required or preferred, labs must start by deciding whether to keep a test in-house or send it out. Usually, economics and the preference for retaining control over cost, quality, and turnaround time favor keeping a test in-house.
“Having the ability to customize an instrument’s menu to match each lab’s specific mission is the most important aspect of any menu offering. Open, scalable, flexible solutions are the key to enabling this, particularly when the solution requires multiple manufacturers to interoperate,” says Davis-Fleischer. “For example, open-channel tests validated by an assay partner can preclude the need to install additional instrumentation for low-volume esoteric tests,” she says. “Similarly, open and flexible automation can seamlessly integrate solutions from multiple in vitro diagnostics companies where necessary to fill a menu gap.”
According to the experts, it’s also important that an immunoassay instrument be able to accommodate menu expansions, including tests using new reagents (as opposed to reagents already in use).
“Laboratory needs and requirements may change, including the kits that are being used and have been automated on an immunoassay instrument,” says Kaur. “Hamilton Robotics instruments are specifically designed to be flexible and work with most kits—rather than just specific kits—allowing the workflow to change. Different kits can be automated without having to purchase new instruments. Any reagent solution can be used with the ELISA Nimbus analyzer, and the methods can be easily created or modified to automate the new test kits.”
Davis-Fleischer says that labs need a partner that can grow with them as volume and clinical practice evolve, and the ability to add new immunoassays to an instrument is expected. Although most significant diagnostics companies offer this capability, some, like Ortho, go one step further and offer the ability to run other manufacturers’ reagents with their instruments. “‘Open-channel’ or ‘manufacturer partnership’ assays considerably enhance the flexibility of the instrument to grow with the lab,” says Davis-Fleischer.
“More important than simply extending the menu is the ability to extend the menu simultaneously across the entire fleet of instruments,” she adds. “Common immunoassay technology across a product family enables a new assay to be implemented in every lab in the network on instruments that use familiar, common consumables and common user interfaces. This is essential to optimizing the labs’ productivity and delivering standardized, reliable, trustworthy results to their clinician customers across the entire healthcare continuum. As a newly independent company, Ortho’s nimbleness and ability to invest in innovation allows us to put these types of customer needs at the center of what we do.”
The development of new immunoassays is proceeding more rapidly for some disease areas than for others. Once created, such new tests can progress from manual to instrumented and automated formats, but the pace of such advances can be subject to obstacles and delays.
“Currently, a tremendous increase is being seen in testing for drugs of abuse and pain management,” Kaur says. “Immunoassays continue to be prevalent for confirming sexually transmitted and other infectious diseases. Meanwhile, research and monitoring for cancer is also increasing exponentially, though the trend in this area is to replace immunoassays with genetic testing.”
Labs are generally following one of two paths for making the shift from manual to automated immunoassay formats. “By one route, kit vendors collaborate with instrument companies to validate their kits. By the other, laboratory customers buy the kits and work with instrument manufacturers to automate their lab workflow in order to meet their high-throughput needs,” says Kaur. “Hamilton Robotics actively engages in both of these approaches by aiding kit vendors and customers directly with their automation needs.”
Gary Tufel is a contributing writer for CLP. For further information, contact CLP chief editor Steve Halasey via [email protected].