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Each assay system component contributes to every aspect of the essence of an IVD kit. (Photo courtesy Response Biomedical)
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While the 1990s may have been the true brink of the point-of-care (POC) era, the new millennium may be the era of mergers and acquisitions. Regardless, modern IVD technologies have changed over the last two decades at a rapid pace akin to the other technology sectors and the pharmaceutical industry. The big lab continues to get bigger, and near-patient testing/POC continues to thrive on opportunity driven by acuity and the race for healthcare providers to provide superior customer service via rapid turnaround times and less invasive sample access. The stoic patient is a thing of the past.
The ability to outsource assay system components allows for immense ingenuity rather than reliance on hindsight after the conceptualization and feasibility phases of development. In other words, development teams can source high-quality and sometimes intricate components instead of spending valuable time using handmade prototypes or crudely modified off-the-shelf materials. Outsourcing assay system components has been a cornerstone for the aforementioned development in all IVD sectors.
Many start-up companies lie in the wake of successful groups that have outsourced assay system components in this art-meets-science business. These successful companies have embraced phase development 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 IVD development, and many can also provide custom one-off components and kits.
The Market
Every IVD healthcare sector has been dramatically enhanced by the availability of outsourcing. Specialty is at the extreme with assays being developed that are faster with a level of performance that is an order of magnitude higher. 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 (Burnaby, BC, Canada) are all turning out POC assay systems that compete handsomely with their big brother laboratory counterparts. Recent newcomers such as Epocal (Ottawa, ON, Canada) and Amic (Uppsala, Sweden) promise technology incorporating multi-analyte smartcards for the former and a revolutionized cartridge for the latter promising enhanced lateral flow technology. Experts have vacillated between opinions of the influence of POCT; the predictions 15 years ago that it would command 35–50% of the IVD market have not been completely realized although the next 10 years almost read like a road map.
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), Siemens, Bayer and Roche, for example, have developed stat or lean functions and protocols for IVDs such as cardiac markers while increasing sensitivity by a factor of 10 in some cases. The latest offerings from the aforementioned have consolidated the chemistry area by combining chemistry with immunoassays in straight-line high-throughput platforms. Most emergency department (ED) 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, and institutions are well aware of the affect on the bottom line. One of the greatest modern turnaround stories can be Googled uncovering the amazing effort at Cleveland Clinic (Cleveland, OH) where Dr. Frank Peacock, FACEP, vice chair, emergency medicine and his crew brought an archaic system to its knees. Peacock’s team reinvented the ED by shortening wait times from hours to minutes, which not only has made the ED experience better for patients, but the handsome impact to the bottom line has been welcomed by the C-suite. Harnessing the true capabilities of IVDT has been a cornerstone of Peacock’s success.
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 IVDT, a specialty that historically has been misunderstood has evolved into a mainstream discipline. For example, the diagnosis of metabolic syndrome, acute coronary syndrome (ACS), as well as other disorders has improved significantly as a result of test platforms with sensitivities 100 times greater than their predecessors and TAT 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, whether custom or off the shelf, are a driving force for each part of the process. In the early years of IVD testing, the majority of development resources was spent creating the machine itself; today, tweaking of the reaction vessel/matrix 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 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 in this effort 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 by 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 with a myriad of potential pathological conditions. This technology is being used 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 360º process—the competition is 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 shorter stays in waiting rooms.
IVD 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. 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).
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 PT testing has 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.
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 phase development 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, CA), 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 is not only of the highest quality but also 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. As 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 an integral part 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. In a most recent trend, companies are allocating resources to develop the home testing market. There is a possibility that technology could leapfrog such undertakings via companies manufacturing microchips that track patient samples/records using radio frequency. 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.
