Originally Published IVD Technology October 2005
Assay System Components
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| The RAMP troponin I assay by Response Biomedical Corp. (Burnaby, BC, Canada) |
Similar to the days of Henry Ford, when designs would sometimes emerge from napkin sketches, modern IVD product development (PD) often starts with simple concepts. However, unlike Ford and his automotive contemporaries, modern IVD PD personnel can prototype a refined model rather than merely a good idea that will require years of evolution. The ability to outsource assay system components allows for immense ingenuity rather than reliance on hindsight after the conceptualization and feasibility phases. In other words, PD teams can source high-quality components instead of spending valuable time using handmade prototypes or crudely modified off-the-shelf materials.
Many start-up companies lie in the wake of groups that have outsourced assay system components in this “art meets science” business. These successful companies have embraced PD as a core competency, not an open-ended research process devoid of accountability. The companies mentioned in this section can provide a menagerie of solutions in this area, and many can also provide custom one-off components.
The Market
Every IVD healthcare sector has been dramatically enhanced by the availability of outsourcing. One notable area where this approach has flourished is in point-of-care testing (POCT). Abbott Diagnostics (Abbott Park, IL), Bayer Diagnostics (Tarrytown, NY), Biosite Inc. (San Diego), Roche Diagnostics (Basel, Switzerland), and Response Biomedical Corp. (Burnaby, BC, Canada) are all turning out POC assay systems that compete handsomely with their big-brother laboratory counterparts. Expert opinions of the influence of POCT have vacillated; the predictions 10 years ago it would command 35–50% of the IVD market have not been fully realized.
Not only is this shortfall driven by cost issues, but also by reduced personnel and poor or nonexistent telemetry. Front-end IVD platforms have been redesigned in an effort to reduce both sample volume and volume of required reagent (particularly since many of the new platforms use chemicals and biologics that are very costly and unstable). In addition, manufacturers have begun to adopt advanced robotics, supreme microfluidics, and ultra-high-performance chemistries and biologics. Turnaround time (TAT) has been addressed, driven by the recognition of the acuity of testing results. Beckman Coulter Inc. (Fullerton, CA), Dade Behring Inc. (Deerfield, IL), and Roche, for example, have developed “stat” or “lean” functions and protocols for IVDs such as cardiac markers. Most emergency department groups now demand that labs provide a solution to reduce vein-to-brain TAT for acute tests (i.e., cardiac markers) to below 60 minutes, with accredited chest pain centers aiming for 30 minutes or less. It is clear that critical improvements in IVD technology are a direct result of patient needs driving the market.
Pathology has become much more of a reality than a paradox in the last decade due to the high quality of IVD assay systems. Due to the advancement of IVD technology, a specialty that historically has been misunderstood has evolved into a mainstream discipline. For example, the diagnosis of metabolic syndrome, acute coronary syndrome (ACS), and certain other disorders has improved significantly as a result of test platforms with sensitivities 100 times greater than their predecessors, and TATs in minutes.
The core of assay performance is reproducibility, which is achieved by controlling each step of the testing process. Depending on the platform, assay system components are a driving force for each part of the process. In the early years of IVD testing, the majority of development resources were spent creating the machine itself; today, tweaking of the reaction vessel has become a focus for creating high-performance tests. For example, cuvettes are molded or machined from various materials offering tight optical and thermal tolerances. Cartridge assays have improved via molding techniques that create products of a high caliber that could once only be achieved by machining—a substantially slower and highly wasteful procedure. In addition, sample quantities have shrunk from milliliters to microliters (and in some cases, nanoliters), with some test platforms using saliva, sweat, or urine to detect levels of analyte as low as picogram quantities.
Advances in sample handling have also been important to assay improvement. Reference labs such as Laboratory Corporation of America (Burlington, NC), the laboratories at the Mayo Clinic (Rochester, MN), and Quest Diagnostics (Lyndhurst, NJ) have taken throughput to the next level. Each can handle thousands of samples a day, thereby servicing numerous facilities and doctors offices. Manufacturers have assisted as well, by supplying high-quality assay components, such as pipette tips from Helena Plastics Inc. (San Rafael, CA), that can accurately aspirate and deliver nanoliter volumes of samples and reagents, driving down costs dramatically.
Now that the human genome has been successfully sequenced, researchers are poised to explore the next generation of diagnostics, using gene-based technologies to sequence the proteins in a small sample of blood. The resulting expression pattern can then be run through a database that compares it to a myriad of potential pathological conditions. This technology is being used heavily in oncology research, but the future promises the investigation of an infinite number of disease states, including heart disease, metabolic syndrome, and others. Many in the field foresee the ultimate success as being defined by a fusion of traditional diagnostics and proteomics. PD personnel can look to assay system component suppliers as the catalyst in this next step of the IVD development process.
POCT is the key factor in engaging patients with personalized healthcare. The healthcare industry recognizes that customer satisfaction is a 360° process—the competition has an alternative right down the street, and administrators realize that this is the difference between operating at a profit or a loss. Even more compelling is the reality that clinics and satellite facilities offer patients shorter travel distances and substantially shorter stays in waiting rooms.
Diagnostic companies are now aligned to begin patient triage as early as possible, especially considering the acuity of certain test results, including IVDs for ACS. Some clinicians have begun to view the ambulance as beginning triage and paramedics as an extension of the lab. Shahriar Dadkhah, MD, medical director of the Chest Pain Center at Saint Francis Hospital of Evanston, in Illinois, has been recognized as a pioneer in this effort. Dadkhah has followed in the footsteps of Frank Pantridge, MD, a cardiologist who, in 1967, set up the first mobile coronary care unit. Dadkhah has determined that paramedics with appropriate training could identify acute myocardial infarction (AMI) in the prehospital setting using the 12-lead electrocardiogram and POCTs (Troponin I and myoglobin, or creatine kinase-MB [CK-MB] and myoglobin). This could easily be achieved using technology from Abbott, Biosite, or Response Biomedical. In fact, the Response Biomedical RAMP technology platform is currently being used for environmental anthrax testing onboard fire trucks and ambulances in the United States and other countries, and on military Humvees in Iraq, thus confirming the robustness of these diagnostics.
The take-home message is that ancillary testing is, in fact, an integral part of IVD testing; however, it is paramount to realize that the people running the tests are increasingly not medical technologists and that the test site could be extreme. Portability is achieved through PD relationships with instrument-housing manufacturers and molding companies. Firemen, nurses, and lay personnel do not necessarily have access to the same techniques as lab personnel. Glucose and prothrombin-time testing have already laid the groundwork for the potential future at-home market. Therefore, beyond portability, any preanalytical steps must be rudimentary both in required effort and technique; as a result, the rest of the providers of kit components make a substantial contribution as well.
Diagnostic Trends
ACS remains a major impetus for the continuing improvement of IVDs. ACS is a holistic term used to cover any group of clinical symptoms compatible with acute myocardial ischemia. Assay manufacturers are racing to find an arsenal of markers in order to triage the chest pain patient. Presently, the most commonly used cardiac marker tests are the cardiac-specific Troponins (TnI and TnT). Institutions, though, are gradually embracing a more intuitive approach, which includes markers for ischemia (ischemia-modified albumin, lactate, choline, ultra-high-sensitivity TnI, and B-type natriuretic peptide [BNP]), as well as pump-failure markers (BNP and N-terminal prohormone BNP). CK-MB is still used by many institutions as a diagnostic for AMI, although it has lost substantial ground to TnI. Myoglobin is not specific due to its release by skeletal muscle; however, it still offers 100% negative predictive value. Myeloperoxidase and high-sensitivity C-reactive protein are generating increased interest as markers for inflammation, with the latter being investigated as a tool for metabolic syndrome.
According to American Diabetes Association estimates, 6.3% of the U.S. population suffers from diabetes, with nearly one-third of these cases undiagnosed. As a result, manufacturers such as Roche, LifeScan Inc. (Milpitas, CA), and Cygnus Inc. (San Francisco) continue to reinvent the wheel in an effort to make blood glucose testing more portable, less invasive, and faster than ever.
Westernized countries now face another emerging and sinister disease state of near epidemic proportions—metabolic syndrome. Recently, the Centers for Disease Control and Prevention’s National Health and Nutrition Examination Survey reported that up to one in four American adults and a staggering 40% of adults age 40 or older have metabolic syndrome. Metabolic syndrome diagnostics encompasses testing for triglycerides, cholesterol, glucose, and urinary albumin. The secondary afflictions that include cardiovascular disorders and coagulopathy involve IVD technologies significantly. Cancer, neurological disorders, and many other important disease states are of great and simultaneous interest.
The Role of Component Manufacturers
In light of the advancements in modern diagnostics, the compelling question is how do assay components contribute to this success? Rarely could a PD team look to a single manufacturer in the past for sourcing IVD assay system components. Many researchers would spend years developing functional prototypes, while some modern manufacturers can accomplish the same progress in weeks. Furthermore, many groups offer assistance with every step, or all steps, of development. BioDot Inc. (Irvine), for example, routinely assists with feasibility testing through scale-up. The decision to outsource certain products is based on the objective to manufacture a high-performance product. Early in the race to feasibility, components of a new product may be outsourced with the intention in each category of meeting or exceeding whatever the competitor has to offer. This, of course, is achieved by building an assay that not only is of the highest quality but is competitively priced. In actuality, assay system components share many of the same issues as biochemicals and papers/membranes, such as lot-to-lot variation and within-lot variation. Tighter specifications and rigorous quality management guarantee a high-quality, economical product from most vendors.
Regardless of the assay platform, quality and overall performance translate into customer satisfaction throughout the supply chain. The ultimate customer, the patient, rightfully drives healthcare, seeking a reduction in morbidity and mortality and an improvement of overall quality of life. Medicare and insurance agencies influence healthcare costs by having direct control over reimbursement. IVD manufacturers are at the core of the solution for better, more-efficient healthcare by striving to develop more-sensitive, faster, less-invasive, and more-cost-effective products. The demand for IVDs, driven by an aging population, seems to be a vicious cycle. On one hand, healthcare is now facing the increased complications associated with increased human longevity. As the population ages, the patient load for nearly every pathological disorder increases. This is further exacerbated by the present population growth rate, decrease in proper exercise, and the increase in obesity and lack of proper diet.
The “weakest link” rationale holds true in the IVD kit arena. Sample-handling components, slides, and tubes are integral parts of a high-quality test system, even though such items might seem less critical. Every kit component has an influence on the final perceived value by the customer. The future of IVD technology has many potential avenues; however, the overall direction is guaranteed.
The current development momentum is driven by an overall reduction in cost and TAT, and increasing specificity and sensitivity. Tests used by satellite locations to ensure accurate “rule-out” assays will continue to thrive. For example, some companies manufacture microchips that track patient samples and records using radio frequencies. Lab-on-a-chip systems have been performing well in feasibility studies, and such systems, coupled with microinformatics and therapeutics implanted in the patient, will soon allow IVD assay manufacturers to reduce the entropy caused by the associated frenzy of achieving the aforementioned goals. Until then, we still need plenty of napkins.
David Pearman, Response Biomedical Corp. (Burnaby, BC, Canada)
Copyright ©2005 IVD Technology
