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An MD&DI April 1999 Column

COVER STORY: IN VITRO DIAGNOSTICS

Next-Generation Diagnostics: Big, Small, and Fast

Steve Halasey

In the sector of the medical device industry devoted to the design and manufacturing of in vitro diagnostics (IVDs), a quiet revolution is taking place. In the near future, say industry observers, the application of advanced technologies will lead not only to wholly new products for the diagnosis of human disease, but also to changes in how, where, and by whom such diagnostic products are used.

Advancement of the field is being forwarded by a variety of factors, not all of which can be untangled from one another. "This is a 'chicken or egg' situation," says Al Snitkof, chief technology officer at Hemadyne Research Inc. (White Plains, NY). "It is difficult to say whether marketplace trends have turned into technological trends or whether technology is driving the marketplace for IVDs.

Photo courtesy of Dade Behring Inc. (Deerfield, IL).

"Certainly, the expectations of IVD users translate into requirements for IVD designers," he adds. "But at the same time, advances in technology are giving IVD designers spectacular new abilities to anticipate the future requirements of end-users and to provide new and enhanced levels of functionality at the time they are demanded by the marketplace."

As an example, Snitkof points to the technological advances brought about in the semiconductor industry, where the rapidly decreasing cost of producing complex application-specific integrated circuits has been matched by significant increases in the density of transistors per square millimeter of chip. "Adopting such technologies enables IVD developers to achieve levels of functionality unimaginable even a year ago," he says. "The result is an improved ability to create new IVD products that meet customer requirements more quickly than ever."

BUSINESS PRESSURES

Whatever confluence of forces may be driving advancement in the IVD industry, one factor can't be ignored. "The most significant marketplace factor influencing the development of new IVDs is cost," says Tom Tsakeris, president of Devices and Diagnostics Consulting Group (Rockville, MD). "Buyers are demanding tests that are easy to use and give rapid results, and they are unwilling to compromise accuracy or reliability. All of these characteristics have to be delivered at the lowest possible cost."

During the past decade, the IVD sector has come under increasing pressure to contain costs. Health maintenance organizations have gradually reduced the amounts that they are willing to pay for laboratory tests and have pressured clinical laboratories to reduce their charges. In turn, manufacturers have also felt the pinch.

For many IVD companies, the challenge of reducing costs has led to products designed to minimize the labor involved in performing diagnostic tests. "Saving on labor costs can be achieved by designing tests to be performed by individuals with less training who are also paid less, replacing the work of a doctor or nurse with that of a ward clerk or medical technician," says Joanne Stephenson, director of business development for Response Biomedical Corp. (Vancouver, BC, Canada). "But to meet this objective, the technologies must be especially simple to use—essentially foolproof—so that valid results can be obtained consistently from an operator with little or no training."

Regulatory requirements also determine the amount of labor associated with diagnostic testing. "To meet the requirements of the Clinical Laboratory Improvement Amendments of 1988 [CLIA], most labs still need to validate test performance and quality control," says Tsakeris. "So the less work that a test requires to fulfill this function, the more marketable it will be. This is one of the reasons that the market for point-of-care [POC] devices is becoming so large, despite an ongoing debate over whether such products result in cost savings."

For Stephenson, the cost savings brought about by POC devices are not at all debatable. "Anything that saves time saves money," she says. "Products need to be cost-effective in the big picture. Those that can give immediate results as close to the patient as possible will hasten treatment and therapeutic decision making and will ultimately reduce costs by preventing additional visits to doctors' offices, longer hospital stays, additional lab tests, and so on."

All of these efforts to control costs have inevitably had an effect on the types of diagnostic products being designed to fill the pipeline. "Cost-containment pressures have begun to divide the market into two dominating sectors—automation and near-patient care," says Stephenson.

AUTOMATION

According to Katie Smith, director of clinical affairs at Gen-Probe Inc. (San Diego), the single trend that is having the greatest effect on the design of new diagnostics can be described in three words: "Automation, automation, automation." But automation means different things to different manufacturers.

Figure 1. The Architect TLA system by Abbott Diagnostics (Abbott Park, IL) can be configured to incorporate multiple immunoassays or to combine immunoassay and clinical chemistry analyzers. Shown here, the i2000 immunoassay analyzer (launched in January) combined with the c8000 clinical chemistry analyzer (scheduled for launch later this year).

At its grandest, automation means total laboratory automation (TLA), an approach that makes use of large-scale, integrated systems to automatically carry out all of the routine testing (and even some fairly esoteric testing) performed in a clinical laboratory. Planned modules of the Architect system by Abbott Diagnostics (Abbott Park, IL), for instance, can perform both clinical chemistry and immunochemistry tests (Figure 1). The CLAS by Roche Laboratory Systems (Indianapolis) can incorporate modules for clinical chemistry, hematology, coagulation, and urinalysis testing.

Depending on the type and size of its instrumentation, such a system can cost upward of $3 million—a daunting amount even for the largest clinical laboratories. Such a large price tag may be one reason that clinical laboratories have been slow to adopt the TLA approach. A 1998 survey of senior-level lab managers conducted by the Clinical Laboratory Management Association (CLMA; Wayne, PA) revealed that only 12% of laboratories expect to implement TLA in the next five years—the lowest percentage for any of the automation strategies included in the survey (Table I).

What makes TLA systems competitive is the fact that they can eliminate much of the labor involved in lab testing. According to this line of thinking, says Stephenson, "the greater the automation of a lab, the more it can save on labor costs."

But adoption of the TLA model also has significant implications for the structure of clinical laboratories. Because only those laboratories that perform the greatest number of tests can afford to support large, complex, and expensive TLA systems, the TLA approach inevitably leads to greater centralization of laboratory testing—another trend revealed by the CLMA survey. The survey results suggest that restructuring among clinical laboratories could soon result in the demise of self-standing and independent clinical laboratories. More than a third of the respondents (37.4%) said that their laboratory had joined a network or alliance in the previous 12 months, and nearly a third (29.3%) indicated that they would be doing so in the next 12 months.

Whatever its advantages, the TLA approach isn't for every laboratory—and certainly not for every manufacturer. The vast majority of instruments on the market take a less-integrated approach to automation. Some instruments include specialized components devoted to sample transport, storage, and retrieval. Others automate fluid-handling steps such as pipetting, aliquoting, and centrifugation. A few integrate some or all of these features into a self-standing automated module that resembles one portion of a TLA system.

What many of these automated analyzers have in common is their relative simplicity of operation, which can make them suitable for use in a variety of settings. "The products with the greatest appeal are those that reduce labor, those that are simple to use (and therefore simple to sell), and those that are truly platforms or can be integrated easily with existing technologies," says Stephenson.

Automated features play a large role in enhancing the marketability of all such instruments, whatever their size and complexity. But not every manufacturer takes the same approach to automating the various functions that their instruments perform. Following is a summary of some of the operations most commonly automated, and how some manufacturers are making their instruments perform those operations.

Figure 2. The bidirectional track of the Modular TLA system by Roche (Indianapolis) speeds throughput by routing samples to the first available analyzer.

Sample Transport. From the time that a patient sample is drawn to the time that it is placed in refrigerated storage, some method of transport must be provided. TLA systems don't attempt to eliminate the need for laboratory couriers, but they do offer an efficient means of moving sample tubes from test to test once they have been delivered to the lab. Generally speaking, TLA systems employ conveyers to transport sample tubes, which are usually placed in a small rack or cassette. Some systems configure the transport conveyor like a racetrack, around which sample tubes progress in order to reach each of the system's analyzers. The Modular TLA platform by Roche uses a bidirectional track to route samples to the first available analyzer, and an open processing lane within each of the system's modules enables the operator to assign stat priority to a particular sample (Figure 2).

Figure 3. The Aeroset clinical chemistry analyzer by Abbott Diagnostics (Abbott Park, IL) uses 2-D bar coding, which can carry up to six times as much information as traditional bar coding.

To keep track of the movement of the sample tubes, TLA systems employ bar code readers that scan each tube and match it with the testing instructions stored in the system's computer. Coded instructions can be used to tell the system where to send each sample tube and what tests to run when it gets there. The bar code reader used in Abbott's Architect system supports Code 39, UPC/EA coding, and ASTM Code 128. Because of the limited space available on sample test tubes, diagnostic firms have been among the first device manufacturers to adopt two-dimensional bar coding, which can carry six times as much information as traditional bar codes. The newer 2-D coding is used on Abbott's Aeroset clinical chemistry analyzer (Figure 3) and will also be incorporated in the company's Architect c8000 clinical chemistry analyzer, scheduled for launch later this year.

Although automated sample transport is a feature that generally appears only in TLA systems, stand-alone analyzers may also use racks for holding sample tubes, as well as bar coded instructions for running tests. On such instruments, transport is usually limited to the movement necessary to place the sample tube into the machine for analysis, and to withdraw it into a holding area when the test has been completed.

In all such automated transport systems, manufacturers are making extensive use of the power of computers, robotics, and bar coding technologies. Add to that sophisticated motors and motion controls and one begins to have an idea of the complexity associated with sample transport in today's IVD instruments.

Unattended Operation. The goal of reducing labor costs has significant implications for diagnostic analyzers and their features. Manufacturers of automated systems are quick to point out the "walkaway time" of their products, a key indicator of the sophistication of a product's software systems, as well as its capacity to store reagents, buffers, and waste materials. The Architect i2000 system by Abbott, for instance, boasts a five-hour walkaway time, with enough buffer to run 1000 tests and dry waste storage for 1000 reaction vessels. The Dimension RxL by Dade Behring (Deerfield, IL) features onboard tracking of reagents and other consumables and automatically prompts the operator when more supplies are needed.

A related characteristic of automated diagnostic analyzers is simplicity of use, a key factor in maximizing the marketability of such systems. Under the CLIA regulation, tests that have been granted waived status can be performed by virtually anyone, while those assigned a moderate- or high-complexity rating can be performed only by specially qualified personnel. Manufacturers are therefore working hard to make their instruments as simple to use as possible, starting with the computer-driven user interfaces that enable laboratorians to tell the systems what to do. Automated quality control and calibration are also common features of such systems, permitting them to be operated in settings other than clinical laboratories and outside the direct control of highly trained laboratorians.

Sample Preparation and Testing. When traditional testing methods or semiautomatic systems are used, some assays require significant sample preparation before the actual clinical tests can be performed. Necessary preanalytical steps can include bar code labeling, centrifugation, decapping, aliquoting, titration, dilution, and recapping and can be the most labor-intensive and time-consuming phase of testing. Diagnostic manufacturers are finding ways to eliminate such delays by integrating the needed functions into their analyzers or by redesigning the tests to eliminate steps. The Modular TLA system by Roche, for instance, can be configured with a unit that performs centrifugation, aliquoting, bar code labeling, and sorting. The Stratus CS cardiac marker analyzer by Dade Behring takes another approach, using closed-tube sampling to eliminate decapping and recapping and using premeasured reagent cartridges to eliminate the need for user mixing.

The menu of tests that can be performed by an automated system is an important element of its marketability. The Architect i2000 system by Abbott, for instance, was launched in January with an initial menu of 26 tests, with another 36 promised by 2001 and a further 26 targeted for future appearance. The BM/Hitachi 747 by Roche has a resident test capacity of 35 tests, which can be selected from a total menu of 65 applications approved for the analyzer. And the Dimension RxL by Dade Behring can accommodate 48 tests, selected from a menu of more than 60.

Figure 4. The Dimension by RxL by Dade Behring (Deerfield, IL) can house up to 88 reagent cartridges in two carousels.

Systems with such broad test capabilities require an equivalently large number of onboard reagents. With the addition of an inventory management system module, Dade Behring's Dimension RxL can be configured to house as many as 88 reagents on board (Figure 4), while Abbott's Aeroset includes 56 onboard reagents. Because the reagents approved for one company's analyzer are typically not suited for use in another company's equipment, the testing and reagent menus offered by manufacturers are often the keys to selling the system as a whole. Although laboratory users might prefer instrument platforms that can make use of reagents from a variety of sources, manufacturers of large automated systems have so far resisted such interchangeability. Instead, their sales approach has focused on convincing lab purchasers of the advantages of choosing a single company's platforms and reagents for all analytical purposes.

Throughput. Of all the measures of automated equipment, high throughput is probably the single characteristic most promoted by manufacturers. And with high-volume laboratories as the target market, such a trend seems unlikely to cease anytime soon. "Manufacturers are making more use of robotics to increase lab test throughput," says Katie Smith.

Among the immunoassay analyzers now on the market, Abbott's Architect i2000 boasts throughput of 200 tests per hour, a rate that can be increased to 800 tests per hour by linking additional systems to the original unit. Dade Behring's Dimension RxL can perform 167 immunoassays per hour or a total of 788 chemistry and immunochemistry tests per hour. Meanwhile, for clinical chemistry testing, as many as six Modular analyzers by Roche can be linked together to provide throughput of 10,000 tests per hour.

Despite manufacturer emphasis, however, throughput isn't always the best measure of an analyzer's output. The TLA systems now on the market acknowledge this in their subsystems devoted to stat and reflex testing, which offer users the ability to push a particular test ahead of others in the queue or predetermine a sequence of follow-up tests based on the result of an initial assay.

Since high throughput comes with a high price tag, manufacturers of TLA systems are offering their systems as modules that can be scaled to fit the needs of laboratory purchasers. Both the Architect i2000 by Abbott and the Modular system by Roche can be scaled up incrementally as a laboratory's volume increases, enabling these manufacturers to lock in their customers for future growth.

Electronic Interfaces. Many of the automated systems now on the market are taking advantage of information-age technologies to offer features unthinkable a few years ago. Abbott's Architect system, for instance, includes a module for computer- based training, an on-line manual, and modem-based system diagnostics. Dade Behring's Dimension RxL also offers modem-based diagnostics, and optional features include a quality assurance program that compares QC data against an existing database and bidirectional electronic links to the user's laboratory information system.

NEAR-PATIENT TESTING

For all the excitement generated by large automated diagnostic systems, most manufacturers are finding their market elsewhere. "There is a trend away from the high-volume, centralized laboratory instrumentation traditionally offered by such large healthcare corporations as Abbott and Roche," says David Carville, vice president for new product development at Array Medical (South Bend, IN).

"Many smaller companies such as Biosite, Biostar, Luminex, Quidel, and Response Biomedical are actively pursuing near-patient and point-of-care testing in all areas of the IVD market," he adds. "The precision of such tests is gradually approaching levels previously attainable only by larger analyzers in a centralized laboratory, with the coefficient of variance for many tests now at lab levels of less than 5%. Such precision is paving the way for virtually all IVD testing to be performed on a stat basis—that is, at the patient's bedside instead of in a central laboratory. In the future, only specialized tests will be performed in a central laboratory setting."

"The portion of the IVD industry not engaged in high-volume automation is becoming increasingly devoted to moving testing as close as possible to the point of care," agrees Stephenson. "And since healthcare payers have an interest in keeping patient care as far from acute-care settings as possible—and preferably in the home, where it is least expensive—there is a growing need for instruments that can be used in such settings. Manufacturers are responding by producing smaller, simpler, and increasingly accurate instruments intended especially for near-patient use. The design of such instruments is also being tailored to the retail home-use market, with greater attention to details such as styling and colors."

A variety of home-use devices are already making it possible for patients to play a greater role in managing their own health. Using approved home-use instruments, patients can monitor their own cholesterol, blood glucose, or anticoagulant levels, thereby making it easier for their physicians to design appropriate therapies. And last December FDA approved the first home-use tumor marker, the BTA stat test by Bion Diagnostic Sciences Inc. (Redmond, WA), which can be used to test for recurrence of bladder cancer.

"Development of these kinds of products is expanding the prescription home-use market," notes Tsakeris. "While there may still be some significant regulatory hurdles to overcome in this area, FDA has taken some important steps in the right direction—such as its approval of home-use testing for patients on anticoagulation therapy."

Many near-patient and point-of-care tests share a common base in the technologies of immunochromatography, which employs reagents dispensed onto a solid substrate (commonly a porous membrane) to capture proteins or other markers of a disease or condition. As in the familiar home-use pregnancy tests, a positive result is indicated by a visible line or other pattern.

Although such single-use, cassette-based products are useful for tests where a qualitative (yes/no) result is sufficient, clinicians have long complained that such qualitative testing often lacks clinical relevance. "Clinicians are demanding quantitative POC technologies that are rapid, easy to use, and have the same spectrum and accuracy as large, automated analyzers," says Stephenson. "This has proven a difficult challenge in some areas, while in others manufacturers have made outstanding progress. In the area of cardiac markers, for instance, tests that provide only qualitative results will very soon be a thing of the past."

Figure 5. Near-patient cardiac marker tests range from qualitative lateral-flow assays to fully automated quantitative analyzers. Clockwise from top: the Cardiac Status assay detects troponin I (Spectral Diagnostics; Toronto, ON, Canada); the Triage Cardiac System quantitates CK-MB, myoglobin, and troponin I (Biosite Diagnostics; San Diego); the Stratus CS system incorporates preanalytical steps into its processing (Dade Behring; Deerfield, IL).

Management of patients with cardiovascular disorders is one area for which manufacturers have been especially active in developing near-patient devices. "Because of the benefits for patient outcomes, the opportunity to move testing closer to the patient is a compelling one," says Ray Swanson, general manager for the platelet function analyzer product line at Dade Behring. Options now available to physicians include qualitative lateral-flow assays to detect common markers of acute myocardial infarction (e.g., creatine kinase, creatine kinase-MB, troponin T, troponin I), qualitative panel tests that detect two or more such markers, and near-patient analyzers that can quantitate one or more of the markers (Figure 5).

The variety of approaches taken by manufacturers is indicative of their varied responses to the needs of end-users. Manufacturers with qualitative cardiac marker tests say that their short time-to-result offers emergency-room physicians a primary tool to rule in or rule out acute myocardial infarction in patients with chest pain. To develop its Stratus CS analyzer, Dade Behring took a broader view. "We looked at how chest pain is actually triaged and the overall process of patient management in the hospital," says Kevin Clair, director of cardiac marketing at Dade Behring. "We compared the usefulness of stat test results with those from clinical laboratories, and we also looked at the major sources of test-result variability."

One of the company's findings was that preanalytical processing was the greatest cause of variations in test results. "The Stratus CS addresses this issue by controlling sample processing to provide consistent plasma samples free of particulates, as well as by using premeasured reagent cartridges that eliminate the need for user mixing."

Figure 6. The PFA platelet function analyzer by Dade Behring (Deerfield, IL) enables physicians to assess thrombolytic risk in cardiac patients.

Dade Behring is taking an additional approach to cardiac-patient management with its PFA 100 platelet function analyzer (Figure 6). "A major goal of this device is to enable physicians to better direct blood component use during surgery by assessing the status of a patient's blood platelet function," says Swanson. "Reducing health risk and lowering surgical costs by eliminating unnecessary transfusions is especially important for bypass patients and others undergoing major surgery, because these patients tend to be older and sicker and are often taking medications that affect their coagulation system."

However responsive such products may be to the needs of end-users, however, satisfying market demand may not ensure their profitability. "The evolution of IVDs has gradually reduced the number of steps and amount of sample required to perform a particular test, and this has had a significant effect on many markets," cautions Glen Freiberg, senior director for regulatory affairs at Gen-Probe. "In the point-of-care glucose test industry, for instance, tests progressed from a wipe-the-strip design to a wipe-free design; meanwhile sample size requirements were reduced, and the time required to obtain a test result also dropped. Even so, there are very few carriers that provide coverage for test-related supplies."

To succeed in today's marketplace, near-patient and point-of-care technologies may need to compete toe-to-toe with large automated systems. "Near-patient instrumentation must evolve to meet user demands," says Array's Carville. "The units will need to be handheld or portable and must be easy to use. They will need to incorporate onboard QC, calibration, and system diagnostics; and they may need to accept input from patient smart-cards or some other user-friendly data management system. They should also incorporate a printer and be capable of interfacing with the facility's hospital information and laboratory information systems."

For many such functions, microelectronics are providing the means for advancement. "Increasingly small embedded processors are enabling IVD developers to create instruments that not only provide the desired measurement, but also have the capability to analyze the result, transmit it to a physician or hospital, and interface with other devices or systems," says Snitkof.

Advanced microelectronics are also providing the basis for a very new trend that is beginning to emerge in the IVD sector. "Companies are beginning to have an interest in developing information-based product lines," observes Lyndal Hesterberg, vice president for research and development at Biostar Inc. (Boulder, CO). "The idea is to create diagnostic products that deliver more than just test data, by enriching them with resources that can help health professionals interpret the data. So far, however, few IVD technologies have demonstrated a capability to make this transition."

"In the near future, diagnostics will be expected to deliver more information than data," agrees Susan Evans, senior vice president for research and development at Dade Behring. "Next-generation systems will need to make use of the products of evidence-based medicine, which can provide healthcare professionals with an objective basis for deciding what diagnostic tests to perform and how to interpret them. The use of evidence-based medicine is already very common in the United Kingdom, and there is also growing momentum for it in the United States."

Evans says that the transition to information-based diagnostics is partly a result of changes in the way that healthcare professionals are being trained. "Younger healthcare professionals today are much more open to the use of support tools for learning, training, and interpretation."

The challenge for diagnostic companies will be to make such systems truly useful to clinicians. "Information-based resources aren't just megadatabases," says Evans. "To be useful, they will need to link together information from a wide variety of sources, including clinical databases as well as a company's own instrument diagnostics and intranet systems."

THE MOLECULAR SOLUTION

Although molecular technologies have long been touted as the future of diagnostics, their use has generally been confined to research laboratories, and they have yet to fulfill their promise in the commercial marketplace. Now, many experts believe that phase is coming to an end. "Molecular diagnostics are making steady inroads into routine clinical laboratory practice," says Tsakeris. "Many labs are taking advantage of the terms of FDA's new rule on analyte-specific reagents by using vendor-supplied raw materials to develop their own molecular diagnostic assays (e.g., genetic tests). And for now the agency seems willing to allow this specialty to grow without excessive regulatory oversight."

Industry expectations for the success of molecular diagnostics are very high. In an informal survey conducted among members of the editorial advisory and reader boards of IVD Technology magazine, more than 60% of respondents said that by the year 2010, molecular diagnostics will displace at least 15% of the tests currently on the market. At the same time, respondents also expressed optimism for market growth as a result of the adoption of molecular technologies. More than half of the respondents said that adoption of the new technologies will likely result in at least a 15% increase in the IVD market within the next decade.

One of the reasons that optimism for the field is so great is the wide range of potential applications for such molecular tools. "One emerging area is nucleic acid sequencing as a means of identifying particular types or strains of microbial pathogens," says Tsakeris. "Companies are expressing increasing interest in viral load assays for pathogens such as cytomegalovirus and the hepatitis viruses."

"DNA- and RNA-based methods for blood donor screening are being evaluated in both Europe and the United States," notes Smith. "The ability to rapidly sequence genes and detect single-point mutations in DNA or RNA will open the door to rapid detection of mutant genes and the discovery and measurement of drug-resistant genes."

And in the not-too-distant future, molecular diagnostics promise to revolutionize the practice of medicine by offering precise diagnoses of genetic diseases and conditions. "Where current tests for genetic diseases are labor-intensive—such as the tests for AML–CML translocation—the adoption of molecular technologies will simplify the process," says Frieberg. "Objective genetic testing will replace visual reading of metaphase spreads. And all of this will bring about greater public confidence in genetic forensics."

The use of genetic screening could eventually enable physicians to determine a patient's predisposition to disease, so that appropriate intervention can be carried out even before onset. "Molecular technologies offer the potential for moving from diagnostics to prognostics," says Evans, "but it will be up to the medical community to choose to use those technologies correctly."

In the meantime, she notes, nonmolecular systems have already begun to take the first steps toward determining a patient's predisposition to disease. Dade Behring's PFA 100 platelet function analyzer, for instance, enables clinicians to evaluate a patient's platelet function as a marker of their hemostatic status. The goal, she says, is to identify risk factors for cardiovascular disease and then to correlate that information with therapies that can be used to mitigate the risk. To become a successful clinical tool, genetic screening will have to demonstrate that it can accomplish the same tasks.

What seems most to be missing from the molecular diagnostics equation are standardized test formats and instrument platforms suited to the testing volumes commonly seen in clinical laboratories. Without some commonality among the available test formats and related supplies, clinical laboratories are unlikely to invest heavily in either the instrumentation or staff necessary to perform molecular testing.

Among manufacturers, there is a great deal of interest in applying so-called DNA-chip technologies to a variety of clinical tests and analytes (see first sidebar, above). "Adoption of a chip-based system to measure biologics would revolutionize test formats," notes Smith. "DNA chips would enable laboratorians to obtain very rapid results using very small sample volumes and to perform testing of multiple analytes in a single assay. All of these factors would result in reduced test costs.

"But molecular technologies are today where immunoassays were 20 years ago: labor-intensive and desperately in need of automation," Smith adds.

Figure 7. The TIGRIS system by Gen-Probe Inc. (San Diego) is being billed as the first instrument to completely automate nucleic acid amplification testing.

Not quite coincidentally, Gen-Probe is one of a number of companies working to produce just such an automated system for the analysis of molecular diagnostics. Still in the R&D stage, the company's TIGRIS analyzer is expected to be the first fully automated system for molecular diagnostics (Figure 7). All preanalytical steps will be performed within the analyzer, which will use Gen-Probe's patented transcription-mediated amplification technique to screen blood samples for the HIV-1 and hepatitis C viruses. Although industry has anticipated release of Gen-Probe's analyzer for several years, company officials remain hesitant to predict a launch date.

Eventually, integrated TLA systems may also include molecular diagnostics. But first, says Evans, the companies developing molecular technologies will have to go through a learning curve to discover how to optimize such systems. "The learning curve may be shorter because of industry's experience with integration in other systems, but there is still some distance to travel."

THE VANISHING SAMPLE

While molecular technologies are revolutionizing the practice of diagnostic medicine, other technological trends seem destined to redefine the very notion of what constitutes an in vitro diagnostic. "The application of inexpensive and functionally rich semiconductors will have a major impact on various segments of the IVD marketplace," says Snitkof. "In the very near future, diagnostics will derive their results through a combination of hardware and software, without requiring any tissue or fluid samples from the patient and without using any chemical reagents."

"Sample-free testing, such as the use of optical technologies to measure blood glucose and other analytes, is certainly in the future of IVDs," agrees Freiberg. But achieving the promise of such technologies may be a while in coming.

Blazing the path toward sample-free testing are a number of companies whose R&D efforts are devoted to the development of noninvasive technologies, especially for the lucrative blood-glucose monitoring market (see second sidebar, above). "During the past 15 years, IVD researchers have focused on minimizing sample volume requirements, making it possible to collect patient samples from sites that produce less sample but are also less painful to harvest," says Mark Vreeke, program manager for glucose monitors at SpectRx Inc. (Norcross, GA). "Along the way, manufacturers have also developed alternative methods for sample collection, including iontophoresis and microporation. Successful application of such noninvasive technologies is likely to be the next major industry advance that will directly affect patient care."

In Snitkof's view, the challenges that stand in the way of noninvasive and sample-free testing are less likely to be technological than regulatory. "Extremely complex problems relating to blood analysis—particularly in the noninvasive glucose arena—are now solvable," he says. "However, the imminent technological advances in IVD products will mean that more products are destined to become 'black boxes.' And even if such devices provide results that exceed their predecessors in accuracy, both the device validation and approval processes will be subject to an increased level of FDA scrutiny and vigilance."

CONCLUSION

Whatever new technologies the future brings to IVDs, manufacturers will have to face the familiar challenges of commercialization. "The major concern is how well IVD manufacturers can deliver on their promises," says Carol Nast, founder and managing partner of the Enterprise Catalyst Group (Palo Alto, CA). "The IVD industry has a long and distinguished history of discovering novel ways to address disease diagnosis, but it has also struggled with how to provide new products and technologies that meet expectations during the early phases of their life cycle."

According to Nast, shortfalls in IVD product performance have too often led to disappointing return on investment, with inevitable consequences for future investment in the sector. "Executive management needs to focus on the processes associated with commercialization," she says. "Targeted market research, effective and efficient design control, robust technology- and product-transfer methods, highly engineered and validated manufacturing and testing methods, thoughtful selection of distribution channels, and responsive customer support are some of the major areas where greater attention is needed."