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The immuassay handbook parte51

  1. 1. 517© 2013 David G. Wild. Published by Elsevier Ltd. All rights reserved. Immunoassays have had a major impact on diagnostic test- ing and scientific research. For many years, they were unsurpassed in specificity and sensitivity, leading to the introduction of a wide range of highly sensitive assays for diagnosis and patient monitoring. Developments to enhance the core technology with nonradioactive labels and particularly automation made the technology accessi- ble to a wide range of laboratories and within a few years, immunoassays were on the pharmacy shelf in the form of pregnancy tests. From the initial introduction, with the first commercial assay for insulin in the late 1960s, the technol- ogy has followed a typical technology development path and is now in a mature market. There is a steady stream of technology-enabled innovations in diagnostics but most enhance flexibility or scope and are not game changers. The most transformational ideas are coming from life sci- ence research, and some may make their way into diagnos- tics in the future. Although many new analytes are the subject of research each year, very few become mainstream diagnostic tests. Some are specialized tests within niche markets. This chapter explains the current market position of immunoassays, assesses the impact of the market drivers, and explores the potential for new areas of application for immunoassay technologies to fulfill unmet needs in the market. Threats to the immunodiagnostics market from alternative technologies are also evaluated. Immunoassay Market Status The overall in vitro diagnostics (IVD) business has been showing the characteristic signs of a mature market, with limited total revenue growth accompanied by consolida- tion in the industry. As expected, price reductions due to competition when a technology matures have been seen, enhanced by the pressures on health care budgets in all countries. In Japan, for example, the combined affect has been to reduce the size of the IVD market even though test numbers have risen. A one-off effect has also been seen due to the global economic crisis that started in 2008, with reductions in test numbers during 2009 and 2010, as fewer patients visited physicians because of the financial impact on the individuals concerned. The macroeconomic situa- tion will affect the short-term growth of the IVD market, but it will gradually recover over the next 5 years, due to an aging population in the developed countries and the growth of emerging markets. The quantitative picture of the laboratory diagnostics market (Fig. 1) shows that the previously projected growth to US$ 38 billion in 2008 was achieved, with 2010 sales revenue of $44.2 billion, continuing to grow in 2011 and 2012 ($50.5 billion). Growth in 2012, excluding point-of- care (POC) testing, for IVD was limited (6%) due to the global economic issues. Immunoassay had the greatest market share of the IVD market (37%) with sales of $18.6 billion in 2012. This analysis excludes the dedicated POC testing sector which had a further $ 2 billion of Immuno- assays. Further analysis confirms the importance of the markets in USA and Europe (Fig. 2). The steady growth in 2009 and 2010 was offset in the last two years by competi- tive and government-led price reductions, reflected more by a higher growth rate in the number of tests than in dol- lar return. Immunoassay grew rapidly during the 1980s and quickly became a major part of the total global IVD market, con- tinuing to increase its share of the IVD market since. Despite signs of late maturity, immunoassay continued to grow faster than other technologies within IVD as shown by a steady increase in share up to 2010 but falling in 2011. See Table 1. The impact of fast-growing areas, such as molecular diagnostics and POC testing, has diminished the immuno- assay share of the IVD market during 2012 although these new markets are relatively small compared with immuno- assay, apart from POC testing for glucose. Market Trends David Huckle ( C H A P T E R 7.2 FIGURE 1 Global Distribution of IVD Market by Technology, 2012 (The color version of this figure may be viewed at
  2. 2. 518 The Immunoassay Handbook Commercial consolidation and globalization of the mar- ket have continued over the last few years. A small band of large global corporations own most of the market, although there are several smaller international companies, which tend to be focused on specific areas of diagnostics. The business consolidation associated with laboratory IVD products is typical of the mature phase of any technology, as most companies have essentially comparable products, and this has now become true of the immunodiagnostics sector. The absence of true product differentiation gives an advantage to global companies supplying high-through- put central laboratories, because of economies of scale. With reduced market growth overall, companies can only achieve significant growth through acquisitions or merg- ers. The various acquisitions in the diagnostics sector have changed the commercial scene, particularly with the entrance of Siemens into the IVD market through the acquisition of Diagnostics Product Corporation and Dade Behring. Other major acquisitions were of the Olympus diagnostics business by Beckman Coulter (itself acquired by Danaher), ThermoFisher of Phadia, and the continued acquisitions and mergers by Alere (previously Inverness Medical) of POC testing immunoassay companies. The attempt at market entry by GE Healthcare with the failed acquisition in 2010 of the Abbott Diagnostics busi- ness has not deterred the company from its aim of securing laboratory diagnostic products to align with its diagnostic imaging business, with a new focus on molecular diagnos- tics. Wider entry into European and American markets is also being seen by companies from China, South Korea, and Japan. There is a significant group of small manufacturers that supply the home base markets, with some exports supplied through local distributors. These distributors typically operate in single countries, build up a range of products from worldwide sources, and are the market entry point into Europe for many small companies based in North America, Australia, and Japan. The biggest contribution to growth of the immunoassay market and the IVD sector overall has been the increased use of such products in the major developing markets of China, India, and the leading growth economies in South East Asia and Latin/South America. There are other factors at work in the immunodiagnos- tic market. These include rising manufacturing costs due to material cost and labor rate inflation, and the invest- ment required for product development, partly because products have become highly complex and partly due to tighter regulatory requirements. There is also more cen- tralized purchase control within the health care provider organizations, with the involvement of finance and man- agement personnel as well as scientific and clinical staff, which can increase company marketing costs and reduce profit margins. These are characteristics of a mature mar- ket. The response of some companies, or of those with new potential to exploit, has been to avoid direct confron- tation with the leading companies by shifting the customer base from the hospital laboratory to POC testing. Although significant change may seem unlikely, market dynamics suggest that the IVD industry has been going through a period of transformational change, with further major, technology-led shifts to follow, particularly from molecular diagnostics (MDx), and its impact on bio- markers for disease and infections, as will be assessed later. Established Trends MARKET DRIVERS Cost Containment and Reimbursement The economic issues of the last decade, caused by rising personal and sovereign debt in developed economies, have brought the allocation of funds for health care throughout the world into the spotlight. There was insufficient tax income to maintain the rising demand in any of the major markets, even before the global economic crisis added to these problems. FIGURE 2 Regional Global Distribution of Immunodiag- nostics Market, 2012 (The color version of this figure may be viewed at (From Adams Business Associates). TABLE 1 Immunoassay Share of Laboratory IVD Market Year Immunoassay Market Share 1985 28% 1990 33% 1995 35% 2000 38% 2005 40% 2010 44% 2011 37% 2012 37%
  3. 3. 519CHAPTER 7.2 Market Trends Providers of health care resources have major economic problems to resolve. Their response has been to try to reduce overall health care costs, directly through budget constraints or indirectly through changes to reimburse- ment. The resulting trend is to focus on more clinically useful diagnostic tests rather than to allow the uncon- trolled provision of a wide range of general tests. In the UK, rationing has effectively been applied in the National Health Service for some time. Budgets for all reagents are controlled, sometimes preventing useful new tests from being introduced widely. In the US, the concept of man- aged care has led to indirect rationing of health care resources through rigorous cost control and cost–benefit analysis. In many countries, reimbursement, approved test lists, or disease-related groups (DRGs) have been key control measures. In some cases, new products have been prevented from reaching the market effectively, even if approved by the regulatory authority, because government organizations have kept them off the reimbursement list. Another negative impact on the market has been the arbi- trary reduction of reimbursement levels, as in Japan, with a corresponding impact on revenue figures. The value of laboratory diagnostic tests in reducing long hospital stays and avoiding unnecessary drug prescriptions has not been widely recognized except by clinical chemists. However, the potential economic benefits of POC testing, through a reduction in the overall time taken between patient presentation and initiation of the correct treatment, have been widely debated. A new driver for the use of IVDs has been the application of IVD tests in personalized medicine and in biomarker assays that define populations suitable for specific therapies. These will be discussed further in the technology drivers section below as immunoassays have a potentially important role to play in these emerging sectors of health care. All new health care concepts are now challenged by the requirement for rigorous Health Technology Assess- ment (HTA), with consideration of all costs in the patient pathway leading to treatment, not merely the specific product cost. Regulatory Health care managers and regulatory agencies have become heavily involved in the scrutiny of product quality and the safety of diagnostic procedures. The FDA increased its requirements in the Quality System Regulation (QSR), which is enforced through site inspections, and now covers product design and development, with many companies obtaining certification to the ISO 9000 standard, the Inter- national Standard for quality systems. The IVD Directive in Europe introduced another comprehensive set of requirements that companies operating in Europe need to comply with. Each of these controls has been reinforced by more specific standards, with an increased emphasis on risk assessment, and attempts to reduce local regulations by adoption of ISO/TC212 and ISO 14197 approaches. In parallel, there are standards for laboratory accreditation that affect the IVD sector: ISO 15189 and in the USA, the CAP scheme based on ISO 15189. New restrictions are now being applied to the internal production of reagents by hospitals, laboratory-developed tests (LDTs). Pressures from both professionals and the public led to the tightening of standards and regulations. Professional health care providers are concerned about liti- gation, and members of the public are interested in the reli- ability of health care processes. These pressures have resulted in the FDA trying to control at least some LDTs for the US market. Materials supplied in Europe are already controlled under European legislation. Forcing these tests into regulatory controls could well open up the market to full commercial involvement—note that these tests are not included in current market figures. Controls that apply to testing laboratories, such as the Clinical Laboratory Improvement Amendments (CLIA) ‘88 regulations in the USA, have prevented many tests being taken up outside of hospital laboratories. This tem- porarily stalled the growing POC test market. However, with clear guidelines provided by CLIA for waived test classification, manufacturers have designed fully integrated products that meet these requirements. The overall effect is that responsibility for controlling the product during use has been partially transferred from the user to the manu- facturer. The absence of a demand for design controls has driven the FDA to move to regulate these products rather than leave them under the existing rules, which were the responsibility of the Centers for Medicare and Medicaid Services. The reduced regulatory requirements in the USA for products that are essentially similar to products already on the market, the 510(k) procedure, have worked well gener- ally. The FDA has recognized deficiencies in the 510(k) sys- tem, following a number of safety incidents, and this is under review together with new regulations that define products marketed in a way to avoid some of the regulatory controls, such as those labeled For Research Use Only and Assay-Specific Reagents (where test components are sold sepa- rately). Companies now have to follow formal development systems that comply with regulations such as the QSR and Quality Management Systems in most other countries. Regulations were a commercial hurdle, but there were guidelines and companies knew the procedures to follow. But during the last 5 years, due to new technologies and innovative attempts to circumvent the regulations, partic- ularly in the US market, there have been new initiatives to align the regulations with modern day technologies, including aspects of internet purchasing that can be across borders. It should be remembered that IVD regulations only came into force during the late 1970s and have been added to piecemeal since then to meet developments and advances in knowledge and capability. The position has probably now been reached where in an ideal world, the regulations should be fully harmonized globally and rewritten to be able to deal with modern IVD products, applications, and users. A specific example of the new reg- ulatory challenge is that of multiplex assays with several parameters being measured in a single test and multivari- ate analysis applied, often with proprietary algorithms. New Market Segments Including POC The increased level of automation of immunoassays and other types of laboratory tests has lessened the need for separate specialized laboratories, e.g., for microbiology,
  4. 4. 520 The Immunoassay Handbook immunology, and clinical chemistry. Studies have shown that in a typical, medium-sized hospital, around 80% of the laboratory tests are automated. In many hospitals, traditional specialist laboratories have been consolidated into core laboratories that provide a wide range of ser- vices. Many small hospitals no longer see it as cost- effective to maintain their own laboratories but prefer to use a core facility or a reference laboratory for the bulk of their testing and use POC for emergency or patient entry tests. Reference laboratories provide the widest range of services, often offering rare tests and bench tests that require special reagents and highly trained staff. Clinical biochemists are available to interpret complex and unusual data from individual patients. This model of reference laboratory operation seems to be secure for the future. Super-laboratories have the advantages of extensive automation, with its low labor costs, and price bargaining power with reagent and equipment suppliers. On the downside, they require high levels of capital investment and are sometimes located in high-cost areas such as city centers. In a reference laboratory, many of the specialized tests offered may lack automation, limiting the benefit of the fast sample handling systems. Sample collection and transport logistics extend the time before a result is received in distant patient locations, but computerization can reduce associated administrative costs. The fastest growing market sector has been POC test- ing, defined by tests that do not require laboratory facili- ties. A shift to rapid test results, which permit immediate action to be taken as part of the consultation process, has been taking place over the last decade. Despite the interest in POC testing, this sector is dom- inated by self-testing glucose carried out by the patient for routine monitoring of their diabetic state. A newer market is spreading for self-monitoring of warfarin treat- ment to prevent blood clotting problems. Testing is car- ried out in a similar way as for self-glucose testing with data presented to the doctor if there are changes. Neither of these POC testing technologies are immunoassays, and the major uses of immunoassays in POC testing are for the well-established pregnancy and fertility status over- the-counter (OTC) products. Professional applications include tests for infectious diseases (even for HIV), but immunoassays for cardiac markers are the fastest growing in the POC testing sector. The latest POC tests can pro- vide a level of accuracy and precision comparable with laboratory tests; certainly when performed by trained technicians. Sophistication is also increasing, for exam- ple, immunoassays in POC format for glycoslyated hemo- globin (HbA1c) are now in use as a complementary method to glucose testing in diabetes. There have been many issues raised by the demand from doctors and patients for POC testing. For example, health care managers are faced with reallocations of budgets between cost centers, and the immunoassay analyzer manu- facturers and their customers recognize that much of their existing business could be moved out of laboratories. An important stepping-stone in this process is seen to be clinic testing using equipment with a computer link to the central laboratory. This allows the laboratory to control local instrument performance, result quality, and test interpretation. Establishment of these working practices has reduced some of the conflict between the central labo- ratory and the use of POC testing products. The major, rapidly developing emerging markets are important new market segments, particularly for infec- tious disease tests, and while they are providing the major growth for the established product areas, they need prod- ucts that address their unique needs. For this reason, there is increased emphasis by pharmaceutical companies on the development of treatments for different cancers not common in northern hemisphere countries, such as those for gastric, liver and nasopharyngeal cancers, and treat- ments for endemic infectious diseases. These conditions require effective diagnostics at an acceptable cost, which points to the wider use of specialized IVD products, with immunoassays central to this. If established manufactur- ers do not respond to the need for economic tests, new companies will spring up in China, India, and other devel- oping countries, led by native scientists who have gained experience during academic and work placements in the US and Europe. MDx analytical tests have provided important new insights into complex diseases and helped to point the way toward effective new drug and stem cell therapies. The applications for MDx tests have been largely in cancer and infectious disease applications, but they have opened up new segments for IVD testing in the pharmaceutical industry for both drug development and matching of drugs to those patients most likely to respond to the drug, i.e., personal- ized medicine. In many cases, the application of the drug is indicated by an appropriate patient response, and the drug is approved for use in combination with the diagnostic test. ADVANCES IN TECHNOLOGY Nanotechnology is starting to move from the periphery toward the mainstream and is challenging conventional approaches to health care. The very small scale of the tech- nology is closer to the molecular level, and it is projected that internal diagnostic devices could be developed as con- tinuous monitors of health. This is not a new notion, but it is moving from concept into feasibility. Even so, the effec- tive commercialization of nanotechnology products is estimated to be 15–20 years from now. This time delay is typical for innovative technologies, as demonstrated by MDx tests. It took 20 years for the innovation of poly- merase chain reaction (PCR) technology to move into widespread clinical use, and the widespread application of nanotechnology in diagnostics has some way to go still. Alternative Assay Formats Classical (heterogeneous) immunoassays require a separa- tion of bound and free material. However, a variety of ingenious methods have been developed to allow measure- ment of free or bound material without the use of a separa- tion step. This simplifies the design of automated equipment and shortens the overall time required to carry out an assay. In the market, the most significant change was when homogeneous (non-separation) assays were introduced onto conventional clinical chemistry analyzers. Homogeneous assays have been most successful for small
  5. 5. 521CHAPTER 7.2 Market Trends molecules with concentrations above the nanograms per milliliters range and for comparatively high-concentration proteins. The strong driver for homogeneous assays has been reduced by the availability of automation for the sep- aration step in heterogeneous assays (see HOMOGENEOUS IMMUNOASSAYS). Immunometric (sandwich) assays (see COMPETITIVE AND IMMUNOMETRIC IMMUNOASSAYS) transformed assay perfor- mance in the areas of sensitivity, specificity, and range. This assay format was initially only used for large mole- cules, but anti-complex immunoassays have been devel- opedthatoffertheimprovedperformanceofimmunometric assay formats for small molecule assays (see NONCOMPETI- TIVE IMMUNOASSAYS FOR SMALL MOLECULES). A refinement to the assay format has been the develop- ment of new blockers against animal antibodies in patients that interfere with some ELISA and lateral flow immuno- assays. The problem has been known for 30 years since the early days of immunoassays, but still research is being car- ried out by commercial companies to gain some product advantages (see INTERFERENCES IN IMMUNOASSAYS). Signal Generation and Label-Free Technology Nonradioactive immunoassays had a major impact on the market, allowing tests to be performed outside of the spe- cialized Nuclear Medicine laboratory. As labels were developed with much greater specific activity than radio- isotopes, the assay sensitivity was increased, especially by use of immunometric assays (see SIGNAL GENERATION AND DETECTION SYSTEMS). The repeated turnover of substrate using enzyme labels created an amplification effect and for a while enzyme-based signal generation predominated in the market. As analyzers have become more automated, enzymes are now in the minority (in terms of volume of tests carried out). The analyzers in most common use have nonenzyme chemiluminescent signal generation. This removes one of the biological entities from the reagents, reducing complexity. Moreover, a short duration, high- strength burst of light is an advantage for high-throughput automated analyzers. Driven by work in Drug Discovery with cell-based assays, the use of label-free detection is advancing with the benefit that there is less distortion of the analyte being measured or the antibody that might be used as the detec- tion moiety. The approach is building a whole new area of research with active imaging of cells, using immunoassay methods in cell-based assays that analyze the impact of new drugs or other factors that affect metabolism. Cell- based immunoassays are also being used to detect autoan- tibodies. DNA coding for the target antigen is inserted into a plasmid for transfer into vector cells, which express the antigen on their outer surface. The method is based on the indirect immunofluorescence test. Automation Automation of immunoassay tests opened up the market enormously, particularly at a time when technical skills were declining. There were significant challenges, such as han- dling volumes on a small scale so that priming losses were minimized when handling microliter volumes for the tests. Carryover had to be eliminated by effective washing of the sampling and reagent dispensing probes in the metering systems. The more recent development and implementa- tion of microfluidics have taken this a step further leading to more advanced automated systems. Fully automated sys- tems can operate as batch processors, random-access ana- lyzers, or one-off emergency test processors. Further integration with information technology systems to plan the work schedule, deliver the tests, calculate the results, and pass these through to the clinician and the laboratory data- base as a permanent record for the patient has increased the utility and versatility of these large systems. In Vivo Monitoring Immunoassay and other in vitro tests may appear very dif- ferent to in vivo tests, and some of the electromedical equipment used in patient monitoring, but all serve a com- mon purpose: the provision of information about a patient for diagnosis or monitoring. Convergences between diag- nostic test technologies are illustrated in Fig. 3. In the few situations where noninvasive, continuous monitoring types of tests have become available in applica- tions that were once the province of immunoassays, the demise of the immunoassay test has been swift. Examples are fetal heart rate monitoring and ultrasound, which dis- placed immunoassay tests for human placental lactogen (hPL) and estriol for monitoring fetal well-being. IVD tests have the limitation that they measure an ana- lytical quantity that is a secondary indicator. They cannot compete with direct functional measurements (of equiva- lent clinical efficacy), and there is an underlying trend toward functional tests throughout the diagnostics sector. Figure 4 illustrates how different diagnostic areas develop based on patient needs, and the availability of suitable technology to meet them. FIGURE 3 Overall diagnostics market and analytical test measure- ments. This figure shows the central role of in vitro diagnostics in the overall diagnostics market, due to the importance of achieving specificity (versus non-specific monitoring) with minimal cost and invasiveness (versus in vivo diagnostics)
  6. 6. 522 The Immunoassay Handbook Molecular Diagnostics (MDx) Molecular diagnostics (MDx) is the term given to DNA- based tests, which have developed into a significant business sector. They have many potential applications in market sectors that were served by immunoassays, particularly infectious disease and cancer tests. DNA probe and amplification tests (quantitative PCR) repre- sent major breakthroughs, comparable in their signifi- cance to immunoassays. In infectious disease diagnosis, MDx tests determine the presence of DNA from the infective agent rather than the antibody response of the patient. Often, MDx tests are complementary to immu- noassays, for example, by determining the viral load of patients as they are treated to ensure the infective agent is being controlled. In some applications, there are suggestions that MDx tests should replace immuno- assays. An example is blood bank donor screening, where immunoassays are currently the predominating methodology. As well as in the complementary areas, MDx tests have opened up new clinical areas in the genetic basis for dis- ease and health conditions, including susceptibility and prognosis. There is an important spin-off for immuno- assay testing that follows from this application of MDx in disease research. The use of MDx to identify genetic features that are related to disease incidence, susceptibil- ity, or prognosis often leads to the discovery of new pro- tein biomarkers, resulting from gene activation or suppression. These biomarker proteins will almost cer- tainly be analyzed using immunoassay technology because of the greater ease of use, lower costs, and more functional relevance than the genetic information. Pro- tein biomarkers are the physiologically active outputs of the genes. Point-of-Care (POC) Manufacturers have gradually simplified laboratory immu- noassay tests through automation. The complexity and capital cost of random-access analyzers have required them to be located in a laboratory environment. However, dis- posable devices have been designed that require small ana- lyzers that are simple to use and maintain, and in some cases, an analyzer is not required. These tests do not require the support of a centralized laboratory. Their availability has coincided with an increased demand for immediate test results. POC tests are most likely to be per- formed by a nurse or paramedic with the objective of pro- viding rapid diagnosis and prompt application of the appropriate treatment. There are some practical advantages of POC tests, such as a reduced likelihood of mix-ups with samples or results, or sometimes, less travel for the patient. However, the pri- mary difference from laboratory testing is the reduced overall time between test request and result availability with the resulting changes to the patient pathway. POC tests must be just as clinically reliable as a labora- tory test to be an acceptable substitute and give clear and unambiguous results that are simple to assess, with a clear course of action associated with their results. As mentioned above, the main products are not as yet immunoassays, but as the range of tests is expanded, it is in the provision of immunoassays and molecular diagnostics where there is greatest expansion. From a marketing perspective, a sig- nificant challenge is the number of dedicated pieces of equipment required for the different tests that are being produced. In the POC testing segment, it is clear that only a small number of platforms will be acceptable, and the final test measurement device must be common for a wide range of tests. Some new POC product concepts utilize iPhone and Android Apps to aid interpretation and data analysis, to introduce some commonality to the instrumentation, but the Apps need to be regularly updated as these popular plat- forms are enhanced, and the changes require validation. The application areas for POC pathology parameters have become clearer during 2012 with increased use of Medical Device diagnostics as POC testing products. The pathology POC test market will continue to be important in value but with limited parameters and explains in part the significant slowdown in growth of this sector of the IVD market during 2012. Home Testing Pregnancy tests, based on human chorionic gonadotropin (hCG) immunoassay, are commonly used in the home. They may be purchased from pharmacies and, in many countries, in supermarkets. The technology required to deliver a foolproof test to an untrained user is similar to that used in POC testing by medical professionals, based on lateral flow immunochromatography, with a visual end point and a control indication (see LATERAL FLOW IMMUNO- ASSAY SYSTEMS; LATERAL FLOW AND CONSUMER DIAGNOS- TICS).Recently,visualcues,whichwereoftenmisinterpreted, have been replaced by digital displays, e.g., indicating the text message Pregnant with an estimate of the number of FIGURE 4 Overall diagnostics market and patient needs. This figure shows that tests that can be carried out directly on the patient in the clinic most closely meet patient needs, subject to appropriate technology becoming available.
  7. 7. 523CHAPTER 7.2 Market Trends weeks since conception. Home tests are also available for ovulation monitoring and cardiac assessment. The tech- nology exists to provide home tests for a wider variety of analytes, subject to market demand. It is important to make the distinction between these tests and the glucose or anti- coagulant tests performed at home that are supplied under prescription with the appropriate medical backup. Multiplex Testing A mix of technologies, both in assay design and in manu- facturing processes, has enabled assay designs, in micro- plate, array or bead format, that allow a range of relevant analytes to be detected at one time. These multivariate assays, often with associated software analysis for the results, have introduced a new approach to disease profil- ing. As might be expected, there have been parallel regula- tory developments. While the individual analyte results might be comparable to similar routine tests, the algorithm used to profile the results, and interpret the total informa- tion, is an additional element that must be validated. NEW ANALYTES Over the years, there has been a steady flow of new ana- lytes, such as Helicobacter pylori for gastritis, homocysteine for cardiovascular disease, and bone metabolism markers for osteoporosis. More recently, human epididymis pro- tein 4 (HE4) for ovarian cancer and anti-Müllerian hor- mone for infertility investigations and In vitro fertilization (IVF) have become established. Other advances have been in combination tests such as for detection of both HIV antigen and antibodies in a single test and a mix of anti- bodies for use with flow cytometry for lymphoid cancer. Greater attention has been given to infectious diseases of the southern hemisphere, such as Dengue fever and Cha- gas disease as these markets are opening up to modern test methods. With increased development of the Asian and South American markets, there has been more focus on infec- tions and diseases that are found to a greater extent in these countries than the mature Northern Hemisphere markets. These are addressed in the individual clinical chapters. The Future of the Immunodiagnostics Business APPLICATION OF MARKETING THEORY TO IMMUNODIAGNOSTICS The life cycles of technologies follow a pattern in the mar- ket that is known as an S-curve (Fig. 5). S-curve analysis describes the whole life of any technology from its inven- tion, to its first commercialization, and through to its demise, when an alternative technology provides improved performance or efficiency. In the early stages, much is spent on development before any income is received from sales. This is known as the functional phase of develop- ment and matches the embryonic phase of the market. As the first products come onto the market, there is a slow uptake by a few pioneer customers (early adopters), and the cost of development is still high. This is the beginning of the feature phase of development and represents the early growth phase of the market. There follows the most profitable period where sales increase rapidly as products improve in quality and features. Eventually, the technol- ogy starts to lose momentum, leading to the late growth stage of the market. Now the cost of development of new features becomes higher as the technology is stretched to its limits. Much of the effort expended in development is aimed at reducing costs, and this stage is therefore known as the process phase of development. Eventually, the product saturates its market in the mature phase, where it is most vulnerable to replacement by newer technologies. Using this principle, the development status of key diag- nostic technologies is compared for clinical chemistry, immunoassay, and molecular diagnostics in Fig. 6. For fur- ther information, the relative position of POC testing is also given although, as shown above, this is more a segment shift than a totally new technology. In practice, a scientific innovation, such as immunoas- say, often gains some initial use, but only becomes more successful in the market when linked to complementary technologies. Clinical chemistry and immunoassay both developed rapidly once automation technology allowed these methods to be applied more easily and with less skilled technicians. Automation was critically preceded for immunoassay by the development of nonradioactive, mostly enzyme, labels, and the use of monoclonal antibodies. Laboratory clinical chemistry products have reached the mature phase, while laboratory immunoassays are in the late growth phase, approaching the mature phase. From this analysis it can be seen that further advances in labora- tory applications of immunoassay technology will proba- bly be expensive to develop and limited in their scope. The majority of the most fundamental improvements in immu- noassay design (homogeneous formats, immunometric assays, monoclonal antibodies, non-isotopic labels, and FIGURE 5 S-curve model of technology development. (From Adams Business Associates).
  8. 8. 524 The Immunoassay Handbook automation) date from the last decades of the twentieth century. The new systems of the early twenty-first century have added more features to this core of integrated tech- nologies, but at considerable expense because of the com- plexity of the engineering required. As the S-curve model predicts, new improvements are becoming very costly (at least $500 million for a com- pletely new laboratory immunoassay system) with increased regulatory hurdles and progressively smaller benefits to the user. With only a limited number of com- panies able to afford these high development costs, many have withdrawn from the market, while others have focused on seeking the next technology. The focus was on biosensors for a period and, while this continues, there has been limited effective commercialization. Efforts are now aimed at MDx and the segment shift to POC testing prod- ucts. The challenge with immunoassay technology in the near-patient situation is the different product require- ments compared with laboratory use. Factors that make immunoassays an attractive option for the laboratory can actually be disadvantages for non-skilled personnel need- ing a result in a hurry. Dynamics of the market support the assessment from the technology capability aspects. Consolidation of the many companies in the immunodiagnostics business has been evident over the last few years and serves to confirm that the development of the market has reached a mature or late growth phase. Consolidation is not just limited to the industry. Laboratories specializing in different disciplines are also being consolidated into core laboratories. Market growth of the total immunoassay business has slowed to 3–6% per annum compared with up to 20% per annum during the major growth phase. The driving force for this moderate growth is much more from the emerging mar- kets in Asia and Latin America rather than the introduction of new, widely used analytes. There is now a core base of tests used by the majority of laboratories, with the other tests used in specialized situations. The increased internationalization of the market means that all the leading suppliers now have directly managed subsidiaries or regional headquarters in the major global markets. A highly active supply network of distributors remains, but they recognize that they are acting as tempo- rary market developers for the larger companies. The trend is for major companies to move to direct sales in order to control the market in each country and to increase the profits at a time of pressure on costs. The increased use of local subsidiaries and internet purchasing are further signs of maturity in the immunoassay market. FUTURE MARKET REQUIREMENTS Cost Reduction Pressures on health care budgets will continue to exert a major effect on the market. Companies with high market shares can benefit from economies of scale, as they can recoup the development costs of new products more quickly. Technology developments that reduce manufac- turing costs will also enable prices for immunoassay reagents to fall in real terms. There is an increased awareness that medical and clini- cal chemistry staffs are being assessed for their effective- ness in the total health care cycle. Interest in “outcomes” analysis is extending to all areas, and reduced bed occu- pancy is part of this critical assessment for those treating hospitalized patients. The driving force is the effective use of limited budgets. There is gradual acceptance that rigid cost center budgets (silo budgeting) are not particularly useful. A moderate FIGURE 6 S-curve model for Diagnostic Product Groups, 2011 (The color version of this figure may be viewed at (From Adams Business Associates).
  9. 9. 525CHAPTER 7.2 Market Trends increase in diagnostics expense can greatly reduce the expense in other areas. The importance of diagnostic testing is being recognized more widely as a means to minimize further costs by ensuring the correct drug or treatment is given and deter- mining the desired patient pathway. Many diagnostic tests are carried out to confirm diagno- sis and do not provide much new clinical information. Also there are many hidden costs in a testing process that takes several days to accomplish (e.g., consultation, outpa- tient appointment, test, transmission of result to doctor, and follow-up appointment). For diagnostic tests to facili- tate shorter hospital stays and more timely drug treat- ments, they must provide immediate results when and where they are needed. As an example, the issues of increased test price with POC tests compared with auto- mated laboratory tests are not the key item, but the total cost related to savings on administrative and laboratory costs, clinical benefits of immediate treatment, and savings made by the patients in their time and inconvenience. Only by applying full HTA can all these aspects be directly compared across the whole patient pathway. Even though greater investment in immunodiagnostic tests has the potential to reduce overall health care costs, budgetary constraints, and lack of understanding of the HTA approach mean that it is unlikely that the value of the immunodiagnostics market will grow at much more than 3–6% per year, even with the faster (10–15% pa) growth from new regional markets. Instantaneous Results There is an underlying demand for testing to be moved closer to the patient. This has always been the ideal situation, but the complexity of most diagnostic tests and the difficulty of interpreting the results correctly have kept them in the province of influential and high-profile central laboratories and specialist consultants in hospitals. But tests are becom- ing much simpler to use, and the addition of computerized result interpretation for some tests requires only minor tech- nology enhancements, so near-patient testing is becoming a more practical proposition. There are also many resources available via the internet to aid in result interpretation. For immunoassays to compete with new technologies, faster tests will be needed, with result generation in less than 5min and eventually in less than 1min. Homoge- neous assays are very fast but not yet universally applicable. Capillary-based and micro- or nanotechnology-based het- erogeneous assays, which have very fast reaction kinetics, could potentially provide results in less than a minute. The use of immunoassays for continuous monitoring will require a major shift in assay technology. Flow immu- noassays allow a continuous series of tests to be carried out in rapid succession, but they are not instant and require expensive equipment and a continuous supply of reagents. Atomic force microscopy has been used to mea- sure attraction between antibodies and their targets reversibly, and this suggests that a continuous monitoring immunoassay device could be designed. This will require immunoassay technology way beyond that employed in current laboratory tests, and it will be a challenge to achieve the right balance between specificity, affinity, and reversibility of binding. Sample Type Provision of immediate results will mean a shift away from processed blood (serum or plasma) as the sample medium of choice. Urine, whole blood, and capillary blood are the most likely candidates, although saliva has also been used. Determination of clinically meaningful results using whole or capillary blood is not devoid of technical difficulties. However, there are materials available that act as cell fil- ters, and such tests have been successfully developed for some analytes. The use of whole blood samples eliminates the equip- ment and time required for the isolation of serum or plasma. Other alternatives, such as urine and saliva, offer less invasive ways of sampling. More recently, experimental diagnostic devices for non- invasive testing have started to appear, especially targeted at glucose testing. Clearly, diabetic patients would prefer not to have a daily finger-prick if it could be avoided. Use of devices that sample plasma through the peripheral ves- sels of the skin are a step forward, as are those that have attempted to use wave technology such as near-infrared spectroscopy and image analysis of the eye. It is likely that the specificity and sensitivity of these tests will be enhanced using powerful data processing algorithms to reduce noise. These noninvasive technologies remain in the functional development stage of technology development (see Fig. 5). Their use in niche markets could well open the path to a wider acceptance once the key functional issues have been addressed. The ultimate goal of noninvasive testing for a wide range of analytes will be a step change for diagnostics with not only a major shift of technology but also the seg- ments where testing is carried out. User Convenience Laboratory analyzers have become highly automated. Typically technicians only have to load reagent packs and samples. However, most analyzers require a temperature- controlled, clean environment with skilled staff available for maintenance activities and to deal with the occasional problem. The main requirements for future laboratory analyzers will be wider menus of analytes and improved reliability, simplicity of operation, sensitivity, specificity, range, and speed of result. Cheaper reagents will be sought by customers, and the market will become even more cost competitive. The impact of modern user tools such as the internet, smart phones, and encoded wireless communication sys- tems will all add to the convenience factors for both physi- cians and patients. Such tools will be used to transfer diagnostic information remotely between patient and doc- tor, and between professionals. Rapid diagnostics, many using immunoassay principles, will be used by professional staff as early information to specialists—this could be for trauma patients in an ambulance or new hospital entrants at the reception point. POC testing has different requirements. In the absence of skilled laboratory technicians, tests must be absolutely reliable. This can only be achieved if the device is totally self-contained and robust to application of the sample. Internal quality control to monitor every test is essential (whereas in an analyzer, it is sufficient to run quality
  10. 10. 526 The Immunoassay Handbook control samples no more than once a day). POC tests tend to be used by nurses who have a more patient-oriented approach than laboratory staff. Charting of data from each patient is of greater interest to nurses, whereas QC charts are not a priority. Downloading of data to the hospital computer is important for POC equipment, but the Labo- ratory Information System interface may not be a conven- tional interface as used for laboratory analyzers. More likely, an infrared or other wireless link will be needed, with patient tracking software in the hand-held test unit and base station exploiting technology that is already available. Provision of Clinical rather than Analytical Information Historically, immunoassay systems have been designed pri- marily for the laboratory. They provide precise measure- ments of analyte concentration to the clinical chemist and specialist physician. Only a few existing immunoassays, such as home pregnancy tests for hCG, provide clinical information as the end point (instead of analyte concentra- tion). As testing moves nearer the patient, immunoassay products must be modified to provide the clinician with definitive clinical information. In some cases, the test will have to measure the concentrations of more than just one analyte and analyze the data to reach a clinically meaning- ful conclusion. Several products are now available that use two or more analytes and an algorithm to provide immedi- ate clinical information or combine the result with histori- cal data from the individual to make clinical decisions. The complexity of these products has led to special regulatory controls in the USA for multiplex tests. In order to inter- pret all of the analytical data, the devices need significant computing power but that is well within the capability of current microprocessor technology. Preselected multiple analyte panel tests are of little ben- efit to the laboratory as random-access analyzers already offer user-defined panel selection as an option, while retaining flexibility for different patient situations. How- ever, carefully optimized multi-analyte tests have clear advantages in POC applications, where diagnosis is the end point rather than the provision of an analytical result. An integrated test for more than one analyte is likely to provide more reliable clinical results for a comparatively small extra cost, as much of the manufacturing cost of a POC test is due to the device and the packaging rather than the immunoassay reagents. Improved Clinical Specificity and Sensitivity Achieving greater clinical specificity and sensitivity requires two objectives to be met G Selection of an analyte or functional marker that reflects the clinical condition. G An assay method with sufficient specificity and sensitiv- ity to measure the relevant concentrations of that analyte. Immunoassays now dominate the in vitro market because they excel in the second category at moderate cost and with high convenience. They are unsurpassed in their ability to measure precisely a wide range of analytes in serum or plasma, without any need for a pretest separation. How- ever, there are areas where other, more complex method- ologies can provide superior clinical sensitivity and specificity. One example is drugs of abuse testing. Gas chromatography is more accurate and specific than immu- noassay because of the physical separation of the analytes. MDx tests may also be more specific because of precise base pair matching with the PCR technology providing massive amplification, so these tests are also more sensi- tive. MDx tests may replace immunoassays for some infec- tious diseases, being capable of detecting extremely low concentrations of viral antigens, whereas immunoassays are mainly applied to determine the presence of antibod- ies, which are only detectable weeks after infection. Spe- cific examples where this progress has been achieved are viral load tests for HIV, HCV, and HPV. Use of immuno- assay tests continues with the assessment of seroconver- sion and progress of the infection. Where there is much scope for improvement in immu- noassay tests is in the first category: the selection of a useful analyte. Many current markers cannot be completely relied upon to indicate the presence or absence of a particular clinical condition. The field of cancer screening provides many such examples. For immunoassays to continue to be the test of choice in a wide variety of clinical applications, better markers would be a distinct advantage. Otherwise, functional or more specific assay tests, based on alternative technologies, may replace them. Genetic markers have weaknesses as disease indicators because the onset of dis- ease also depends on environmental and lifestyle factors, such as diet and smoking. The important impact is whether the gene is switched on or off, with the resulting protein expression determining the biological affect; these protein biomarkers will continue to be measured largely by immu- noassay methods. CHANGES IN THE CUSTOMER BASE Purchasing Budget Holder The health care administrator has an overall responsibility to control expenditure. Diagnostics companies must pro- vide convincing data that new tests will actually reduce overall health care costs. In the absence of product differ- entiation, reagents will be selected primarily on the basis of cost, although more astute administrators are seeking the lowest overall cost per delivered result rather than sim- ply buying the cheapest reagents. The Laboratory Manager Laboratory managers are increasing efficiency by consoli- dating automated tests in core laboratories. They need reliable instrumentation and reagent supplies. Automated immunoassay analyzers require wide menus of analytes and must be suitable for high and low throughputs of indi- vidual analytes, without excessive waste. Instrumentation must be easy to interface to computer systems handling samples and results. There is scope for standardization of QC, sample IDs, barcodes, sample tubes, and result data between different makes of analyzers and laboratory
  11. 11. 527CHAPTER 7.2 Market Trends interface systems. Automated laboratories require inter- faces between the analyzers and sample track systems. The mix of economic pressures and the lower cost per test achieved by these core laboratories has led to many smaller hospitals closing their own laboratories and send- ing samples out to the core facilities. A key impact is that the sample collection and data transfer of the result become the key operating factors for effective positioning in this type of market. The Clinician There is a dichotomy within diagnostics as POC tests are primarily supplied to clinicians, although some are sup- plied direct to patients through pharmacies. In contrast, the immunodiagnostics industry is primarily structured for supply to large laboratories. The growth of the POC mar- ket will have an enormous impact on the industry. The requirements for the products, support literature, promo- tion, and distribution are quite different from those of cen- tral laboratories. The Patient’s Role as End-Customer A major new trend is for patients to want a greater say in the use of diagnostics for their clinical assessment, due to their increased awareness of the benefits of early diagnos- tic procedures and a more open discussion of medical con- ditions. New breakthroughs in testing are publicized in newspapers and magazines, on television, and via the inter- net. Patients are now demanding to be considered as con- sumers. For example, the consumer does not want to travel to a city center hospital from the suburbs and may change to a different health care provider with a local laboratory or walk-in center. Consumers also prefer noninvasive tests. They are not concerned with the underlying technology behind a test. The latest trend in health care is the provision of one- stop medical centers, e.g., in shopping malls, which pro- vide a range of services on demand. Payment is for services received. This is a radical departure from the “insurance” systems that take money primarily from the well and dis- tribute services to the sick, such as HMOs and the UK National Health Service. These locations could be a growth area for POC tests with the main focus being on cardiac assessment and diagnosis of diabetes. Patient concerns are many. The increasing proportion of elderly patients, and strong demands from younger patients who expect good service, will place extra demands on systems that are already under pressure. The healthy working population has shown an unwillingness to be gen- erous in supporting the whole social structure from their earnings and taxes. POTENTIAL IMPACT OF NEW TECHNOLOGIES Molecular Diagnostics DNA analysis can, in certain situations, provide clinical information that is difficult or impossible to obtain by other means. In these areas, new markets will be created, and immunodiagnostic testing will be unaffected. How- ever, in some areas, DNA analysis provides more direct information than existing immunoassays. Diseases that are strongly influenced by genetic variation among the general population are in future likely to be tested for by DNA- based tests: cancer is the prime example. However, where the incidence of disease is only partially related to genetic variation, or where only some patients are affected, immu- noassays may continue to have an important role in moni- toring the presence or status of disease. Infectious diseases that are currently detected by the presence of antibodies may well be superseded or comple- mented by DNA or RNA detection tests, which have the potential to detect infection earlier. Immunoassays will still be useful to distinguish between different immuno- logical states, e.g., after vaccination. Cannibalization of immunoassays by molecular tests is typical of a new tech- nology targeted at an unmet need being used as a more effective tool in otherwise adequately addressed areas. The key here is that in the last 5 years, the technology behind molecular diagnostics has developed very significantly and is moving into routine use. The position of molecular diagnostics in the technology S-curve diagram demon- strates that development. MDx tests are expensive, because of their complexity, and this will restrict their use if an immunoassay can be used to achieve the same clinical objective. The specialized nature of molecular diagnostics might provide central lab- oratories with a replacement technology if simpler tests move to POC use. The application of DNA-array technol- ogy permits determination of hundreds of DNA defects at a low cost per test. The use of arrays also provides rapid screening for this large number of genetic defects with all results obtained at the same time. Biosensors Immuno-biosensors have promised to become firmly established as diagnostic tests for several decades, since the concept of a small analyzer with disposable test strips fits well with the needs of the growing POC market. Biosen- sors depend on a biomolecular detection system, and for many analytes, this is likely to be antibody based because biosensors react instantly to binding between antibody and analyte. Existing immuno-biosensor systems are mostly used in specialized laboratories, because of the complex instrumentation and operator skills required as well as the sample preprocessing steps, which add considerably to the total assay time. However, this technology has long-term potential to deliver cheap and fast POC tests if production costs and engineering issues can be overcome. The combi- nation of microfluidics, lower cost chip technology, and nanotechnology might provide the required answers. Flow Cytometry An alternative technology for provision of multi-analyte data is the FlowMetrix™ flow cytometry system from Luminex (see MICROSPHERE-BASED MULTIPLEX IMMUNOAS- SAYS: DEVELOPMENT AND APPLICATIONS USING LUMINEX® XMAP® TECHNOLOGY). This can analyze up to 500 differ- ent analytes from a single sample using a flow cytometer
  12. 12. 528 The Immunoassay Handbook and digital signal processing of a range of fluorescent color dyes. Polystyrene microspheres are dyed with various amounts of orange- and red-emitting fluorophores to pro- duce 100 different sets. Each set has a unique orange–red emission profile and is coated with a different antibody. The signal analysis is set up so that interfering substances are effectively eliminated and whole blood can be used. A third dye is available to expand the number of spectrally distinct members to 500. This approach provides cost savings through multi-ana- lyte measurement. Instrument costs have limited wider application of the technology, but the introduction of bench top systems has reduced the cost of flow cytometers. Flow cytometry remains a laboratory-based technology and falls short of providing noninvasive diagnostic tests, near-patient testing, or giving rapid test results to the cli- nician, despite being reasonably fast in operation (results are available within 30min). This platform is suitable for multiplex immunoassay applications. Capillary Electrophoresis Capillary electrophoresis can be used to assess tissue well- being. A minute sample of tissue is taken and inserted into a glass capillary tube containing a buffer. Electrophoresis, which takes about 40 min, is used to obtain the pattern of the metabolites in the tissue. This profile is compared with a ref- erence or against a historical profile from the same patient. Changes can indicate early stages of disease, from profiles containing up to 30 different substances. This technique has been proposed for early detection of diabetes and for moni- toring effectiveness of treatment. Recently, this technique has been combined with specially developed immunoassays to provide quantification of electrophoretically separated proteins that are closely related to one another. Noninvasive Tests Immunoassays have some potential disadvantages com- pared to noninvasive tests that can provide equivalent clin- ical information. Noninvasive tests not only avoid the need for blood samples, but some also have the capability to provide functional information continuously and in real time. The advent of highly sensitive ultrasonic scanners linked to powerful three-dimensional imaging software is revolutionizing the detection of diseased tissues. In some cases, this will reduce or even eliminate the need for labo- ratory tests. However, determining the specific cause of disease may still require immunoassay tests, and early detection may not be possible with imaging equipment. Several companies are working on or placing in the mar- ket glucose monitoring devices that are worn against the skin and draw material through the skin or use sensors embedded just below the surface layer of dead skin cells in the epidermis. Although such tests may be more conve- nient, they are not truly noninvasive. Use of breath as the sample medium is a slowly growing area and might well be a competitive technology for some conditions. These tests analyze small molecules directly or labeled with long life, low-dose level isotopes, such as 13C, and examples are urea for H. pylori infection and dextro- methorphan for personalized use of tamoxifen. As an alternative approach, wave technology and inno- vative signal detection systems could measure unique substances noninvasively through the skin. An example is the combination of laser diodes for direction of near- infrared light via a fiber optic device held against the skin. The reflected light is analyzed for the substance of interest. A model system has been used for glucose detection. Whether this type of technology could mea- sure a range of lower concentration analytes remains to be seen. The skin is highly variable, and there are many obstacles to overcome before noninvasive tests for immunoassay analytes, which occur at very low concentrations, become feasible. Detection of analytes in the blood vessels within the eye is one alternative being investigated, for diabetes, for example. These technologies remain in the functional development stage. IN VIVO IMAGING A halfway house between in vitro tests and noninvasive tests does exist. This involves the patient taking some kind of imaging material that can be detected by an external signal detection instrument, such as a gamma camera for the detection of radioisotope-labeled material. Antibodies are now widely used as highly specific binders in such tests, linked to signal generating molecules that can be detected externally. Experimental work has established that engineered antibody conjugates can be “activated” to generate a signal in response to a binding event within the body. These are effectively in vivo immunoassays. How- ever, such tests are expensive and impractical to apply to large numbers of patients. NEW ANALYTES Many of the clinical fields in which immunoassays have been dominant, such as thyroid and obstetrics/gynecology, are now mature. This has meant that simple tests are used in carefully optimized test panels to minimize expenditure. Newer areas for growth have not been as lucrative as once expected, although there has been much emphasis on infectious and autoimmune diseases, osteoporosis, and markers for cardiac disease and cancer. The field of molecular biology has generated a large library of genetic information including related proteins with hitherto unknown functions. Many of these have the potential to be clinically useful and could become effective biomarkers. In particular, genetically driven biomarkers will be useful in personalized medicine. Diagnostic tools that assess possible drug toxicity are already available using immunoassays for biomarkers identified through genetic studies. Genetic analysis can indicate a propensity to a clinical condition linked to gen- eration of a specific protein, which can be used to guide the clinical action for the individual patient. The new market developing for personalized medicine (already at $230 million in the USA and projected to reach $390 mil- lion by 2015) should give a boost to immunoassay test menus. However, some new test parameters are also likely to be addressed by alternative methodologies, such as gene amplification.
  13. 13. 529CHAPTER 7.2 Market Trends New analytes will not be accepted in the managed care environment unless there is proven clinical utility. This puts the onus on manufacturers to undertake comprehensive clinical trials and publish them in the literature. With lim- ited market potential for individual new analytes, invest- ment in development, validation, and demonstration of cost-effectiveness is not economically viable for larger com- panies, and it is frequently left to small companies who, if successful, issue licenses or are acquired by the larger organizations. Examples of analytes introduced recently are given in Table 2. THE ROLE OF THE CLINICAL LABORATORY The level of automation of current immunoassay analyz- ers has minimized the need to use a traditional laboratory. One of the functions of the laboratory has always been to provide an environment where complex chemical and biochemical tests can be developed and carried out, but most analyzers are effectively self-contained laboratories requiring nothing more than a power outlet. However, there are persuasive economic arguments for nonurgent testing in a hospital to be centralized. A core laboratory can be made highly efficient by investing in computeriza- tion, and making radical improvements in sample and result processing, and ancillary activities such as stock control and QC. The survival of individual core laborato- ries will therefore depend on economic considerations rather than technical capability. The laboratory professional has lost some status in the area of assay technology expertise, now that the analyzers largely take care of the science and technology. In the future, another challenge will have to be faced: clinical professionals (clinical chemists and clinicians) will find that test methodology often provides clinical (rather than analytical) results requiring little further interpretation. This will impact upon another province of clinical chem- ists: result interpretation. Although change is inevitable, the laboratories, and the professionals who manage and operate them, will have an important and influential role to play in clinical chemistry in the future. As more testing is carried out close to the patient, many clinical chemists are seeking a role in orga- nizing quality assurance and proficiency testing schemes in all the test locations, and this is welcomed by most health care administrators. Laboratorians can play a key role in evaluating new POC tests, training personnel in their use, and overseeing test and data management strat- egy in the decentralized health centers. It has been shown that the enormous growth in home glucose testing has not led to a corresponding decrease in laboratory glucose test- ing. This is an important indication that POC testing will not lead to laboratories running out of work. Instead, they will have to provide highly reliable confirmatory tests, a much wider menu of tests than can be managed in POC testing locations, and guidance on the interpretation of test data that do not fit the simple rules of computerized expert systems. Laboratory immunoassay services will have to pro- vide a wide range of tests, and menu may therefore be the key determining factor for the ultimate winner(s) among the laboratory immunoassay manufacturers, now that automation is reaching its limits. An open immuno- assay system, which allows laboratories to experiment with new markers as well as run made up reagent packs for a wide range of established analytes, would fit well in this laboratory of the future. While immunoassay test- ing may expand out of the laboratory, other, new test methodology may be limited to laboratories because of its complexity. Conclusion With immunoassay technology approaching the limits of its potential, as illustrated by the S-curve, there are likely to be new technologies to challenge immunoassays for the leading role in diagnostics. The commercialization process may be slow, but the new technology has probably been invented. As an example, MDx is having an impact already. Other technologies are certainly at the stage of functional development or embryonic market development. Proba- bly, it will be a fusion of technologies that are already well known but have not yet been applied to mainstream diag- nostics. Whatever the technology, it will most likely be applied first in niche markets. The change in technology means that new companies will enter the industry, and some of the major companies will either exit or be acquired by other companies more determined to establish and maintain their market position. Immunoassay technology could be further exploited to provide very fast POC tests, but samples still have to be taken from the patient. Antibody-based tests can also be used in flow cytometry, biosensors, and in vivo tests. Molec- ular and other diagnostic test formats will gain market TABLE 2 Examples of New Analyte Immunodiagnostic Products Product Type of Product Clinical Application Ca-9 CAIX protein Biomarker Metastasis post-cancer operation Her-2 Biomarker Suitability for Herceptin therapy in breast and gastric cancers Human epididymis protein 4 Monitoring Ovarian cancer Measles, mumps, rubella, varicella zoster, MMRV Multiplex assay Susceptibility assessment Platelet PGD Bacterial detection Transfusion screening Dengue infection Immunoassay Rapid test for early assessment Mix of p16, Ki-67 Diagnostic Screening and monitoring of cervical cancer Anti-Müllerian hormone Immunoassay Reproductive medicine Conjugate of antibody cocktail (Solastra) Flow cytometry Monitoring in hematolymphoid neoplasia
  14. 14. 530 The Immunoassay Handbook acceptance where they offer improved clinical utility. How- ever, the ultimate displacement of immunoassays from their leading position is likely to be due to noninvasive testing technology that provides functional or visual information in real time. This would probably only occur in limited clinical applications at first but could widen in scope as technology develops. Even so, immunoassays will continue to have a key role in providing complementary information. The apparent similarity between products from differ- ent manufacturers, reduced market growth, increased pressures to reduce the costs of diagnostic procedures, and the lack of differentiation of products all lead to the same conclusion. The market is mature, and this will result in major technical and commercial changes eventually. The drivers for change are already present, and the lab- oratory market is showing early signs of a response. Fur- ther evolution and development of POC tests, and falling prices, will lead to a confrontation between the existing laboratory-based market and the new near-patient seg- ments. This is going to be just as disruptive for manufac- turers as for laboratories. However, manufacturers can survive the change by offering wide menus on laboratory analyzers and more common tests in cheap, easy-to-use POC testing formats. Laboratories are now taking a lead in managing changes in the health care services, introduc- ing professional quality and data management systems. The changes will open up new markets, and diagnostic testing will increase overall, in terms of the number of tests performed and market value. Only noninvasive monitoring equipment can seriously upset the diagnostic test market, as it may not require any consumables or laboratory involvement. However, there are many obstacles to be overcome, and the impact is likely to be restricted to specific areas in the next few years. For those companies that wish to enter the market with new technology, noninvasive technology is probably the best target area. In assessing the likely areas where these niche markets will develop, it may not be advisable to look at the largest market opportunities for tests. Break- through developments are more likely to be successful in areas where there is an existing unmet need and where new technology can solve a significant clinical problem. Subsequent exploitation of the technology will create new market dynamics. The projected position of the IVD industry is shown in Fig. 7 with immunoassay products within each of the sectors indicated except for molecular diagnostics. Summary of Likely Trends in Immunodiagnostics and Related Products Here is a list of trends that we predict based on current information. G Market Quantification G Continued growth of the immunodiagnostics test market but at 3–6% per annum globally. G Growth in countries such as China, India, and Brazil will range from 10 to 15% per annum. G USA will remain the single largest market but with a reduced global share. G USA, Europe, and Japan total IVD market share will decline from 80 to 75% by 2015. G Significant growth of POC testing markets. G Major growth of molecular diagnostics will canni- balize some immunodiagnostics tests. G Reduced rate of growth in laboratory test markets. G Growth (but limited) in home testing markets. G Reduction in cost per test within each market segment. G Fewer companies supplying laboratory immunodi- agnostics market due to consolidation. G New entrants with new technology or more appro- priate distribution chains for POC market. G Market Segment Changes G New entrants that specialize in providing products to physicians in one clinical sector. G Laboratory consolidation into core laboratories. G Increased POC testing segment users outside of the laboratory. G Reduction in use of tests with unproved clinical utility. G Increased proportion of fully automated laboratory tests and fully integrated POC testing products. G Networks (intranets) between users and manufacturers. G Test services available over the internet. G Product Features G Faster tests in each market segment. G More robust tests with simpler user protocols. G Increased use of whole blood and urine samples, and less invasive sample sources. FIGURE 7 Global Distribution of Future IVD Markets by Type, 2015 (The color version of this figure may be viewed at (From Adams Business Associates).
  15. 15. 531CHAPTER 7.2 Market Trends G Increased assay sensitivity and specificity. G Improved clinical sensitivity and specificity. G Wider use of immunometric format assays for small molecules. G Wider application of homogeneous assays. G Recombinant proteins and monoclonal antibodies will be used routinely. G Further use of antibody engineering techniques (phage display, recombinant antibody conjugates, etc.). G Use of multiple analyte testing in one test unit. G Use of assay and non-assay data to compute risk. G Standardization (e.g., sample ID, barcodes, QC, results, patient information). G Smaller test disposables (reduced waste). G Use of smart phone apps linked to test result man- agement, communication, and interpretation. G Regulations G Increased control of all IVDs with new regulations for modern developments. G Increased global harmonization of IVD regulations with local specifics. G Simpler assay calibration protocols. G Improved assay standardization between manufacturers. G More detailed reference interval information for patient subpopulations. G Computer algorithms for diagnosis brought under regulatory control. G Use of probability in decision algorithms to deter- mine risk, from multiple data sources. G Greater use of patient-oriented trend analysis in diagnosis and monitoring. G Tests and services available over the internet brought under regulatory control. G Clinical Focus G Focus areas will continue to be diabetes, cardiac, and cancer with increased emphasis on infectious diseases that impact the emerging regions. G Newer shifts will be for obesity and asthma/allergy, which are both now claiming increased deaths and health care costs. G Greater influence of patients over choice of test. G Immunoassays in some clinical areas will be replaced by noninvasive techniques. G New analytes with improved clinical utility.