The In Vitro Diagnostics Market

The IVD Market, per Kalorama Information’s recent report is $83 billion.  A good portion of that is COVID-19 testing, and it’s not known how long that will be present in the market.  The consensus is at least into 2021.   This article gets into the market and why it is growing, and some important IVD industry trends such as point of care, sequencing, new venues.

In vitro diagnostic testing costs little to the healthcare system and contributes much to clinical practice. For some time this has been stated as educated conjecture; a recent study of U.S and German physicians offers proof. The study found that 66% of clinical decisions made were based on a diagnostic test, while the costs of those tests were just 2.3% of healthcare expenditure (Rohr U., Binder C, PLoS One. 2016). When the cost-effectiveness of in vitro diagnostic testing is then considered along with beneficial effects on treatment outcomes, therapy choices, and hospital management, there should be little surprise about the amount of interest in IVDs and the amount of activity in the market for them.

“When the cost-effectiveness of in vitro diagnostic testing is then considered along with beneficial effects o… there should be little surprise about the amount of interest in IVDs”  – Kalorama 

In vitro diagnostic testing costs little to the healthcare system and contributes much to clinical practice.  For some time this has been stated as educated conjecture; a recent study of U.S and German physicians offers proof.  The study found that 66% of clinical decisions made were based on a diagnostic test, while the costs of those tests were just 2.3% of healthcare expenditure (Rohr U., Binder C, PLoS One. 2016).   When the cost-effectiveness of in vitro diagnostic testing is then considered along with beneficial effects on treatment outcomes, therapy choices, and hospital management, there should be little surprise about the amount of interest in IVDs and the amount of activity in the market for them.  The diagnostics industry spends a fair amount on research and development compared to other industries. (Roche spent $1.4 billion on diagnostics R&D in 2018, bioMérieux spent $326 million and Sysmex $158 million.)

These investments and technology-driven M&A activity pay off. The industry now uses technologies that would not have been thought of when the first edition appeared two decades ago. Their influence is felt in personalized medicine, inherited diseases, pathogen detection, antibiotic resistance testing, blood banking and much more to come. Yet innovation has come with challenges, and the industry is also subject to regulation, price scrutiny and value-proving as much as any part of the healthcare system and perhaps more.  IVD testing is a 69 billion-dollar market worldwide, as seen in this figure:

IVD Market Over Time, 2008-2025 ($BN)

The industry continues to push issues and develop solutions for diseases that fall into the paradigm of early testing benefiting outcomes. It can even claim that some known healthcare problems in some way are the result of a lack of testing. Anti-microbial resistance continues to be an area where IVD shines; there is a growing realization that blind prescribing of antibiotics could be reduced with faster and more targeted testing.

Despite great attention and much action, the opioid crisis continues to plague the United States and countries of the world. 2018 total overdose numbers remained over 70,000, per CDC statistics, indicating that the problem is still severe. The American Association of Clinical Chemistry released a position statement at their 2019 convention, calling for increased collaboration between clinical laboratories and other stakeholders. Early detection of cancer and the popularity of consumer genetic tests are also likely contributors to increased recognition of IVD testing.  While this is happening, various worldwide payor schemes are pressuring prices. The response is consolidation of lab operations and facilities. Same with IVD vendors. Consolidation remains the rule in the industry among both customers and vendors. Top-tier IVD companies accounted for some $55 billion of IVD product sales last year. Part of this development is related to organic company growth but also to strategic acquisitions that add revenue streams and product innovations.

As the COVID-19 pandemic continues to grow, attention has been focused on how to effectively scale up the diagnostic testing that is needed to correctly handle patients and track the disease’s spread. Countries have been trying to apply the lessons learned in the regions that were hit first. China appears to have dramatically slowed the disease, and one of the key aspects of that effort has been large-scale diagnostic testing. In the United States, there had been regulatory hiccups as well as problems with the initial CDC test kits sent out, which resulted in delays and significant concern about the ability to scale up in the necessary timeframe. In addition, there have been shortages of associated products needed to run the tests, such as controls and RNA extraction kits. Gradually the companies and labs have been addressing these needs.

Indeed, the top tier plus next-tier companies listed in the market tables in Chapter 2 of this report – less than 40 companies – account for a majority of the world market for IVDs. The remainder is held by 100s of companies, some of which specialize in specific test segments and others that serve their local markets.

That should foretell no lack of dynamism in the industry. Beyond the market numbers, the pace of mergers and acquisitions is brisk. There are also IVD startups and ventures. According to an August 2019 estimate from EY Parthenon there were $3 billion dollars invested in IVD-related businesses and more than 170 investment rounds between May 2018 and April 2019. There were also over 9 IPOs worldwide, raising $500M for diagnostic-related ventures. These new ventures create technology that may fail or may create the next Foundation Medicines, Aleres or Pacific Biosciences that will be consumed by a larger player in the future. Or like Illumina, they may yet grow to become technology leaders and dominant in their own right.

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This technology innovation produced by these companies and ventures will run up against another trend: value-based testing. What clear benefit does a given new technology add to the status quo of practice? How does a discovered biomarker relate to the doctor and the patient? The EU IVDR directives insert clinical validity into requirements directly into permission to market a product in Europe, with staggering processes and paperwork requirements, and an upshfiting of classification where contagious conditions or expensive treatments are involved. In the United States and other nations, expect these trends to enter in the payment process if not the regulatory one. Because in vitro diagnostics are so integral to patient care, particularly for oncology, developers must be aware of how quality and efficacy data pertaining to their device will be used.

COVID-19 Tests Blooming, Other Testing Down

While molecular tests for SARS-Cov-2 and all related test supplies are in the most extreme demand, the effect of hospital elective surgery closures and social distancing is taking a hit on traditional testing. Quest Diagnostics released an 8K reporting: “The Company’s operating results in January and February were consistent with the guidance for full year 2020 provided on January 30, 2020. However, in March, the Company experienced, and anticipates it will continue to experience, a material decline in testing volumes due to the COVID-19 pandemic. During the last two weeks of March, volumes declined in excess of 40% inclusive of COVID-19 testing. Federal, state and local governmental policies and initiatives designed to reduce the transmission of COVID-19 have resulted in, among other things, this has lead to a significant reduction in physician office visits, and also

During the last two weeks of March, volumes declined in excess of 40% inclusive of COVID-19 testing. – Quest Diagnostics April 2020 8K.

“The cancelation of elective medical procedures, customers closing or severely curtailing their operations (voluntarily or in response to government orders), and the adoption of work-from-home or shelter-in-place policies, all of which have had, and we believe will continue to have, an impact on the Company’s operating results, cash flows and financial condition.” This is consistent with reports Kalorama has received from other IVD vendors. General chemistries, traditional immunoassays such as TSH and allergy tests, diabetes and hematology testing could be among those that will see reduced markets, at least while social distancing measures are in place.

The market continues to grow, but what the dollars represent is changing. Twenty years ago, clinical chemistry and immunoassays were most of testing. Still today, the traditional core lab test segments – chemistry/immunoassay, hematology and coagulation – make up 34% of the dollar value of the IVD market in 2019, while they are over sixty percent of tests run. As molecular, infectious disease, and cancer tests increase in importance, the market share of these core tests will decrease to 29% in 2024.

Trends to Watch in the In Vitro Diagnostics Market

The following long-term trends will tend to inform what the future IVD market size in various segments will reach.

China and Top Emerging Nations IVD Markets

China is the world’s largest and one of the fastest-growing IVD markets. Thus it is a target by all major IVD vendors for replacing some revenue lost to slower growth in developed healthcare markets. The global industry has increased activities here in the past decade, and companies not only sell IVDs but manufacture and distribute here as well. In 2019, the Chinese market for IVD reagents was estimated at approximately $3.8 billion and is expected to show annual growth of 8% over the next five years.

Expanding beyond the top seven emerging markets is essential for growth in the global IVD industry. Eastern Europe, LATAM (outside of Brazil) and Eastern Europe represent next-tier emerging regions.

With a longer-term focus, Africa must be part of 5- and 10-year business plans for companies not already in the region. There are already global companies in the region.  More than half of global population growth between now and 2050 is expected to occur in Africa, according to the U.N.   The American Association for Clinical Chemistry announced an expansion of their Global Lab Quality Initiative (GLQI) to Africa next year. The program circulates testing best practices, providing method verification workshops and other training and education. For 8 years, the GLQI has worked with partner associations in Latin America and the Pacific region. A quality control workshop is slated for Ethiopia in 2020, and a newborn screening workshop is planned in Morocco in the coming year.

Next-Generation Sequencing and IVD Markets

Next-generation sequencing accompanied by data analysis algorithms can allow clinicians and researchers to uncover the hidden aspects of antibiotic resistance, cancer pathways and rare and chronic diseases. This could mean precision medicine is beginning to put one-size-fits-all medicine in the archives of therapeutics. Their usage will be a large factor in the future growth of diagnostics.
On average, more than 14 Genetic Testing Units (GTUs) per day are entering the commercial market, a pace faster than in previous high-growth years. Most disease processes involve a number of genes and cell pathways. New multi-gene diagnostics tests by whole genome and next-generation sequencing that examine thousands of specific gene sequences might one day hold the key to assessing disease risk, diagnosing diseases and guiding precision medicine treatment decisions. However, artificial intelligence algorithms are needed to interpret the mass of test data produced by these tests.

The testing of cell free and tumor DNA (liquid biopsy) is becoming an important tool for early and metastatic cancer detection. The technology is also playing a part in pathogen epidemiology.  Established and new molecular techniques are being developed to realize the dream of unequivocal near patient and point-of-care testing for infectious diseases and acute care analytes. This is important for resource-poor situations worldwide.

And then there is the emerging science of linkages between the human microbiome and the manifestation of a whole host of diseases. This phenomenon is creating a new approach to disease detection and therapeutics.  Molecular tests, especially for inherited diseases and some FISH analyses, are extremely complex. The tests provide raw data, the interpretation of which sometimes baffles even the most experienced molecular biologists. New sequencing technologies are expanding the number of causative genes known for genetic disorders. Gene identification is a first step for future development of a targeted therapeutic especially for cancer and rare diseases. Exosomes carry nucleic acids and proteins from their host cells and are widely considered to be essential for biomarker discovery for personalized healthcare diagnostics. Tumor cells, for instance, release exosomes which contain tumor specific RNAs that can be isolated easier from biofluids such as blood and urine than from biopsies.  It is expected that exosome-based tests in routine genomic diagnostics will provide an alternative to tissue biopsies and create new opportunities in molecular testing, especially for cancer liquid biopsy analysis.

Direct-to-Consumer IVD Markets

There has been an explosion of genetic test services that aim to predict a person’s risk of developing various chronic diseases such as diabetes, cardiovascular conditions, arthritis, Alzheimer’s, breast cancer, celiac disease and psychological syndromes.
For a long time these test services flew under the radar, but with increased consumer demand, the US FDA leaped into action. The most advanced company is 23andMe (Mountainview, CA). Although the FDA approval for these 23andMe services may have surprised some, the company has fastidiously conducted studies to prove the utility of its human genome direct-to-consumer test services. The company’s over-the-counter use tests are intended for use on genomic DNA isolated from human specimens collected by the user. March 2019, 23andMe began offering a new genetic Health Predisposition report that offers customers insight into their likelihood of developing type 2 diabetes. March 2018, 23andMe received FDA clearance for the BRCA1/BRCA2 (Selected Variants) Genetic Health Risk report. This was the first-ever FDA authorization for a direct-to-consumer genetic test for cancer risk. Yet, despite the well-known benefits of genomics to improve patient outcomes, access to genomic information in healthcare remains limited. It is generally accepted that a critical step in the commercialization of a test modality is the availability of quality control standards.

Information Technology and AI

Laboratory IT and Clinical scoring systems and algorithms have been used in medical practice for some time; recently there has been an increase in the application of machine learning (artificial intelligence) to improve these tools. While traditional algorithms require all calculations to be pre-programmed, machine-learning algorithms deduce the optimal set of calculations by searching for patterns in large collections of patient data. Chapter 4 details products and partnerships in AI.

There have been extraordinary advances in artificial intelligence, the end-game for information technology. Similar to the product commercialization process that is evident in the liquid biopsy market, IVD companies’ efforts have been supported by the US FDA’s efforts to give products expedited review. This helps patients have more timely access to devices and technology that provide more effective treatment or diagnosis for life-threatening diseases.

More products have been cleared for clinical use, more new research use only applications have come to market and many more are in development – companies are collaborating to improve the power of data analysis for patient care. Over the past several years, healthcare has witnessed a transformation with a shift from paper-based records systems to electronic records and incorporation of digital health monitoring devices and advanced patient screening systems. These advances have resulted in a data explosion, which can best be manipulated and analyzed using artificial intelligence (AI) technology.

Evidence to support AI’s use in diagnostics is building: an August 2019 in JAMA Network Open found that a novel artificial intelligence algorithm outperformed pathologists in differentiating ductal carcinoma in situ (DCIS) from atypical hyperplasia, a job that is “considered the most diagnostically difficult task in clinical practice,” researchers wrote in the paper published online. The researchers compared the performance of machine learning with the interpretation of digitized images by 87 practicing pathologists. A machine-learning algorithm that analyzed two features (tissue distribution and structure) had lower sensitivity than the pathologists when it came to distinguishing between invasive and noninvasive cancer.

New Venues – Urgent & Retail Care, “Microhospitals”

IVD marketers cannot ignore the trend of healthcare following the patient. Urgent care centers are not new but have taken on new importance as convenient healthcare options. Kalorama Information’s recent report, The Market for Urgent Care Centers, projects that there will be 1,000 new urgent care centers in the next five years. Some of these will compete for patients with existing locations and all may not survive, but they will add an estimated $3 billion extra into that market, and create millions of dollars in new sales to these new centers of equipment, including point-of-care IVDs. Retail clinics within CVS and Walgreens chains in the U.S. are venues for respiratory disease testing and some POCs. These new venues will drive some test business to reference labs as well. Watch urgent care opening up near retail pharmacies in the same location rather than an inside clinic.

There is a new opportunity opening for clinical laboratories: micro-hospitals. Micro-hospitals feature 8 to 10 inpatient beds (but can have as many as 50 beds), and range from 15,000 to 50,000 square feet, whereas full-service hospitals are 100,000 square feet or more. At a cost of $7 million to $30 million, micro-hospitals are significantly less expensive than large hospitals to bring to market. For patients, micro-hospitals offer the 24-hour care that cannot be found at healthcare clinics located inside drugstores or urgent care clinics.

Cancer and Infectious Disease Drive IVD Sales: Tissue-based testing for cancer and molecular tests for both cancer and infectious diseases are the growth engine among larger segments; growing at 50% higher than the overall market. Concern over sepsis and respiratory conditions should ensure that infectious disease will remain in the fast-growth categories. Specialty immunoassays, continuous glucose tests, mass spectrometry and inherited diseases are other large and high-growth segments.

Clear Majority of Market Outside US: 58% of the market is now outside of US. Developed markets (N. America/Europe/Japan) still make up the bulk of IVD sales but growth is dependent on developing nation IVD markets. Among these markets are China, India, Korea, Turkey, and Brazil but IVD vendors are finding new emergent nations, like the Philippines at 9% revenue growth or Malaysia, with 8% growth. There are others. Both Colombia and Romania are charting better-than-world growth rates with 6% CAGR. There is also an IVD market recovery in Europe and growth in Japan. Chapter 3 has estimates of the global IVD market.

Mass Spectrometry (MS) Has Arrived: MS is a significant category in the market, especially in developed markets, for the identification of bacteria, fungi and mycobacteria. The MALDI-TOF market has exploded in recent years in microbiology labs, thanks largely to the IVD regulatory approval of the VITEK MS and MALDI Biotyper Histopathology is a new area of interest – Bruker Corp is developing technology to make MALDI imaging viable in histopathology. Throughput and operational complexity are limits, despite this fast growth in usage.

Migration, Customer Protection in the Core Laboratory: Major chemistry vendors are developing improved models selling their existing customers on staying with them – to preserve and expand revenue, as well as create barrier entry against other vendors in a shrinking lab environment. Footprint improvements, IT enhancements, EMR, automation and expanded menus are part of this change. While this is not part of traditional IVD commercialization, web-based and TV marketing has helped in a few categories and usage of such mechanisms would boost this category.

Companies Buy to Grow: No one company owns all the technology to compete in an increasingly complex world. Chapter 2 lists over 60 recent mergers and acquisitions related to IVD. Significant recent deals. Last year Abbott brought POC leader Alere into its operations, completing an acquisition finalized in 2017. Beckman Coulter Life Sciences acquired Cytobank in June 2019, a privately held, single cell data analysis, software as a service (SaaS) company. Beckman Coulter Life Sciences recently acquired Labcyte, best known for its Echo acoustic droplet ejection technology. In June 2019, Meridian Bioscience completed its purchase of GenePOC with an eye towards a syndromic testing strategy. Thermo Fisher Scientific acquired Slovakia-based mass spectrometry software developer HighChem, Ltd. in June 2019.

Hospitals Driving Point of Care: It is a mistake to think that point of care is only used by physicians or self-testing. Hospitals are by far the biggest users of rapid IVD tests, and decentralizing certain tests for improved outcomes can boost the right system if the cost case can be made. The direct-to-consumer trend, recently successful in genomic type tests, is one to watch. OTC HIV, cholesterol and colon cancer tests are available alongside well-established pregnancy and glucose tests. Individuals can purchase lab tests in retail outlets or via the Internet.

Decentralization in Hematology is a trend to watch. In the US alone, there are approximately 35-40 million CBC tests run in physician offices. The market potential for decentralized hematology testing, worldwide, has led to the development of several tabletop and hand-held hematology analyzers designed specifically for small labs and decentralized test sites such as physician offices and clinics. Dedicated POC devices for hemoglobin/hematocrit have been available for many years. Hemoglobin test systems are used by office labs, hospitals, blood banks, dialysis centers and public health agencies.

Big Data and Histology: Histology, covered in Chapter 13 of this report, represents the bulk of testing for cancer. Histological or tissue analysis involves a two-step procedure: preanalytical sample preparation and advanced staining. As workloads increase and properly-trained staff becomes scarce or too expensive, automated solutions for histology bring a much-needed efficiency to the lab workflow, and digital pathology is ushering in the next step: the ”big data” era of medical care that is referred to as computational pathology.

New Drugs and Coagulation Testing’s Future? In coagulation, patients with atrial fibrillation and artificial valves are beginning to switch from warfarin to next-generation drugs. This will affect routine screening clotting time assays – prothrombin time tests (PT) and activated thromboplastin time tests (aPTT) – that provide a gross assessment of coagulation capability. But this also provides another test opportunity in coagulation testing. Several companies have already commercialized tests for the monitoring of the new anticoagulant drugs.

Sepsis is a growing problem and early detection is crucial for patients. Approximately 1.7 million individuals in the US develop sepsis each year and there is currently no gold standard for diagnosis in the clinical setting. Procalcitonin (PCT) and lactate are two established biomarkers for sepsis, but there are limitations. Several European studies have reported reduction in antibiotic usage with PCT-guided decision making, but a large multi-center US discussion did not show results. A novel marker, Human Neutrophil Lipocalin (HNL), a glycoprotein released from activated neutrophils during bacterial infections, has attracted some attention. Several POC sepsis analyzers have been introduced to the market, including Siemens Healthineers’ RAPIDPoint 500, Roche’s Cobas b 221, and IL’s GEM Premier 5000. Portable devices have also been introduced, including Nova Biomedical’s StatStrip Lactate and Abbott’s iSTAT. s

More Immunoassays Run on Workstations: Traditional specialization barriers, such as microbiology, hematology, blood banking, immunology and even anatomical pathology, are fading. In the past few years, a number of analytes that would normally be found only on dedicated immunoanalyzers have migrated to consolidated workstations including vitamin D, HbA1c, NGAL, D-dimer, anti-CCP, hsTroponin, hsCRP, cystatin, procalcitonin, HE4 cancer marker and markers for Graves’ disease.

Companion Test Progress: FoundationOne CDx’s approval as the first FDA approved companion diagnostic test for solid tumors is a positive signal to companies developing companion diagnostics for oncology indications. Companion testing has expanded since the commercial success of Herceptin (trastuzumab) and Gleevec (imatinib), both of which required testing with companion diagnostics before they could be prescribed. In April 2019, Myriad Genetics expanded its agreement with AstraZeneca and Merck to utilize its BRACAnalysis companion diagnostic to identify men with metastatic castration-resistant prostate cancer (mCRPC) and germline BRCA mutations who may respond to olaparip (Lynparza). Qiagen has been pioneering the use of liquid biopsy-based companion diagnostics as a less-invasive option to complement surgical biopsies for genomic profiling of cancer.

Blood Banking Under Siege Globally: According to WHO statistics, 78 countries collect over 90% of their blood supply from voluntary unpaid blood donors, and 56 of those countries do so for all of their blood supply. Around 117.4 million units of donated blood are collected globally each year. That progress comes with a threat. With increased globalization of tropical diseases, blood systems in the developed world are under siege. First it was hepatitis B and C, then HIV, Chagas, BSE and West Nile and more recently emerging threats Zika Virus, Plasmodium species (malaria), Dengue virus, chikungunya and yellow fever. These will factor into some component of the growth in this market.

The Competitive Situation

Roche

Roche Diagnostics continues to dominate the industry. Until 2018, Roche’s revenues were twice that of its nearest competitors. However, Abbott Diagnostics’ acquisition of Alere added some $2 billion to the company’s revenue base to reach $9.4 billion in 2018 and so placed Abbott firmly in the number two spot. Roche Diagnostics dominates the IVD market by its shear presence in just about every test segment. The company reports year-to-year sales growth of 7%-8% in CER (constant exchange rate), which beats the diagnostics market growth of approximately 4%. This has been accomplished via innovations in its legacy product lines in combination with those that were inherited with the merger with Boehringer Mannheim in 1997.

Roche’s growth is linked to its molecular (PCR) IP, chemistries, immunoassays, HPV testing and its diabetes franchise (even though it is not as strong as it once was). The company has reinforced its molecular and sequencing offerings, and branched out into prenatal analysis, genomics, hematology, microbiology and cfDNA for cancer testing.

Roche continues to expand geographically with special emphasis on the top seven emerging countries: Brazil, Russia, India, China, South Korea, Mexico, and Turkey. Roche’s prescient purchase of PCR molecular technology from Cetus in 1991 launched the company into a dominant position in molecular diagnostics that it holds to today. Similarly, Roche holds a major role in cancer tissue diagnostics with the acquisition of Ventana Medical Systems. More recently Roche entered the hematology test segment with a pioneering digital system.

Roche’s molecular test business for the future is largely based on the development of companion tests in collaboration with pharmaceutical companies, the FDA cleared HPV assay as a primary screening test for cervical cancer; the launch of the firm’s ultra-high-throughput PCR-based testing systems; and the launch of POC molecular tests.

The digital PCR space now appears poised to become more competitive in the future with the recent announcement that Roche is developing a six-channel digital PCR system that will compete with leaders Bio-Rad Laboratories and Thermo Fisher Scientific.

Roche continues to expand its test offerings in frontier areas. In May 2017, Roche launched its RUO suite of Avenio brand circulating cell-free DNA assays outside the U.S. In June 2017, the test panels were introduced in the U.S. The kits include all reagents, bioinformatics and software to make ctDNA testing accessible to all next generation sequencing laboratories.

Data generated by medical laboratories and diagnostic providers takes an increasing role in treatment and precision medicine. Further it allows greater analysis of data and integration of data into the care process. Roche has made a concerted effort to integrate patient data into its pathology product line.

Roche’s growth is linked to its molecular (PCR) IP, chemistries, immunoassays, HPV testing and its diabetes franchise (even though it is not as strong as it once was). The company has reinforced its molecular and sequencing offerings and has branched out into prenatal analysis, genomics, hematology, microbiology and cfDNA for cancer testing. Roche is turning towards big data. At the most recent AACC Convention, Roche showcased its NAVIFY Decision Support cloud-based precision healthcare suite and apps. Its initial product, the NAVIFY Tumor Board, developed under a partnership with GE Healthcare, was first introduced to the clinical market in 2017. The Tumor Board is an evolution of electronic medical record systems, enabling multidisciplinary and comprehensive review of the entirety of a patient’s cancer treatment timeline, including imaging and sequencing records, using an intuitive browser-based interface. Video conferencing functionality facilitates collaboration and coordination of the care team within the clinical institution, while access, with customizable limitations, can be granted to others for outside consultations.

Abbott Diagnostics (2018 revenue, $9,428 million) moved solidly into the number two spot in 2018. In the past few years Abbott Diagnostics and Siemens Healthineers had battled for second place in the IVD market. However the acquisition of Alere’s $2 billion point-of- care testing business catapulted the company firmly into second place among IVD companies. Alere is the leader in point of care, especially for infectious diseases. Alere also markets gene-based oncology tests for targeted therapeutics.

Now, Abbott is the world leader of rapid point-of-care tests, with a focus on cardiometabolic disease, infectious disease and toxicology. Abbott’s portable strip tests, along with its benchtop systems and analyzers, can provide immediate, actionable test information.

Abbott Diagnostics

Abbott Diagnostics (2018 revenue, $9,428 million) moved solidly into the number two spot in 2018. In the past few years Abbott Diagnostics and Siemens Healthineers had battled for second place in the IVD market. However, the acquisition of Alere’s $2 billion point-of-care testing business catapulted the company firmly into second place among IVD companies. Alere was the leader in point-of-care, especially for infectious diseases. Alere also marketed gene-based oncology tests for targeted therapeutics.

Now, Abbott is the world leader of rapid point-of-care tests, with a focus on cardiometabolic disease, infectious disease, and toxicology. Abbott’s portable strip tests, along with its benchtop systems and analyzers, can provide immediate, actionable test information.

Abbott is preparing for the future with the development of advanced diabetes care products, next generation systems, informatics to help labs manage and retrieve test data, and new infectious disease diagnostics. Abbott also reinforced its core lab product line with the addition of coagulation and advanced hematology systems.

In 2018, Abbott strengthened its position in core lab diagnostics with the continued roll-out of Alinity, a full range of automated instrument platforms, tests and services.

Sales growth in 2018 was led by FreeStyle Libre, Abbott’s continuous glucose monitoring system, with worldwide sales of $379 million in 2018, demonstrated an increase of 70.2% on a reported basis and 80.1% on an organic basis versus 2017. In July 2018, Abbott reported that the FreeStyle Libre system is the number one continuous glucose monitoring system worldwide. With the launch of FreeStyle Libre, Abbott revolutionized diabetes care by eliminating the need for routine fingersticks.

Abbott is a leader in immunoassays and is translating this expertise to molecular assays. Abbott is making a huge effort to improve its molecular test menu. Abbott Molecular (www.abbottmolecular.com) analyzes DNA, RNA, and proteins at the molecular level. In general, Abbott Molecular focuses on tests for the evaluation and management of cancer, prenatal disorders, infectious diseases and other genetic diseases.

Physicians already use results from Abbott’s PathVysion HER-2 probes to help determine which patients may be the best candidates for personalized therapy. In February 2018, Abbott announced that it will provide its PathVysion HER-2 DNA FISH probe kits for use in Angle plc’s (UK) breast cancer liquid biopsy study.

Danaher Corporation

Danaher Corporation (2018 revenue, $6,285 million) is a diversified company whose business segments include Professional Instrumentation, Medical Technologies, Industrial Technologies and Tools & Components. The Medical Technologies segment encompasses three key businesses: Dental Equipment and Consumables, Life Sciences, and Diagnostics. The diagnostic companies of Danaher Corporation include Beckman Coulter, Cepheid, Leica Biosystems, Radiometer, and SCIEX Diagnostics.
Danaher established a diagnostics business in 2004 with the acquisition of Radiometer and has expanded the business via numerous subsequent acquisitions. In 2018, the diagnostics business consists of clinical laboratory, molecular, critical care and anatomical pathology products. The result of the acquisition of key IVD players (most specifically Beckman Coulter and Cepheid) catapulted Danaher into the number three spot surpassing Siemens Healthineers.

Danaher reported that diagnostic revenues grew 7%, paced by Beckman Coulter, which improved in most major product lines. Demand in the clinical lab business increased on a year-over-year basis led by continuing strong demand in high-growth markets, particularly China. Increased demand in the immunoassay products drove the majority of growth for 2018, with immunoassay sales surpassing that of Beckman Coulter’s clinical chemistry portfolio for the first time.

Siemens Healthineers

Siemens Healthineers  diagnostics business was created with the merger of products from Diagnostics Products Corp. (DPC), the Bayer Diagnostics Division (without Bayer Diabetes Care) and Dade Behring Diagnostics. Traditionally, this original Siemens conglomerate competed with Abbott Diagnostics for the second-place position in the IVD market. More recently Siemens’ IVD business growth has stalled, and Abbott Diagnostics has moved firmly into the second-place position.

Siemens Healthineers is a major player in medical imaging, laboratory diagnostics, and medical information technology. The diagnostics division includes products for clinical chemistry, drug testing, hematology, coagulation, immunoassay, infectious diseases, microbiology, molecular diagnostics, plasma proteins, point-of-care testing, blood gases/electrolytes, and urinalysis. In addition, Siemens operates a clinical laboratory and offers laboratory informatics and automation.

The Siemens Health business was reorganization in 2014. With growth essentially stalled, Siemens had initiated the Vision 2020 plan to stimulate product development. As part of its Vision 2020 strategy Siemens AG announced in 2014 that its healthcare business would be separately managed as a company within the company with a new organizational setup. Thus, in May 2016, Siemens Healthcare unveiled the new brand for Siemens’ healthcare business. The new Healthineers business segment was organized into six business areas: Diagnostic Imaging, Laboratory Diagnostics, Advanced Therapies, Ultrasound, Point of Care Diagnostics and Services with a reported revenue of some 15 billion euro ($20 billion).

Since the creation of the Healthineers business entity revenues for the in vitro diagnostics business segment have remained relatively flat. In fact, Siemens Healthineers reported a decrease in revenue in Euros from 4,164 million in 2017 to 3,962 million in 2018. The company reported: “This decrease was driven by negative currency translation effects. On a geographical basis, comparable revenue growth in EMEA and Asia and Australia were partly offset by a decrease in the Americas.”
In August 2017, Siemens announced the company planned an initial public offering of its healthcare unit in the first half of 2018. The announcement came as Siemens published third-quarter 2017 results that missed expectations.

In January 2018, Siemens reported that it is proceeding with its initial public offering (IPO) for Healthineers and the company made its stock market debut on March 16, 2018. Thereafter, Bloomberg reported that the Siemens Healthineers AG IPO raised 4.2 billion euros ($5.2 billion) in the country’s second-biggest initial public offering in almost two decades.

In May 5, 2018, Siemens Healthineers posted its first post-IPO earnings. The company reported: “in the Diagnostics Segment the solid revenue growth in Europe/Middle East/Africa and the slight growth in the Asia-Pacific region were offset by consumer restraint in Americas. Revenue was EUR 970 million in the second quarter, equivalent to a low growth on a comparable basis.”
In February 2019, Siemens reported: “The initial public offering of Siemens Healthineers on March 16, 2018, was extremely successful. The company is in an excellent position to benefit from the opportunities of a highly attractive market: The crucial factors here are, first of all, greater entrepreneurial freedom; and second, more flexibility to set up a company that can focus exclusively on the special features of the healthcare market.”

With diagnostics division growth essentially stalled, in January 2018 Siemens Healthineers introduced its strategy to bolster its market leadership by 2025 and beyond, aimed at accelerating profitable growth and delivering return by showing the company’s commitment to its in vitro diagnostics business with an expansion to support molecular diagnostics. In December 2017, Siemens Healthineers acquired Fast Track Diagnostics (Luxembourg). Fast Track markets CE-marked PCR-based kits and multi-syndromic panels that can be added to Siemens’ Versant kPCR Molecular System menu.
As part of the strategy, “the integration of the blood gas portfolio of Epocal and the acquisition of molecular diagnostics company Fast Track Diagnostics are important steps for Siemens Healthineers to strengthen its laboratory diagnostics business.”

Thermo Fisher Scientific

Thermo Fisher Scientific was born out of a merger between Thermo Electron and Fisher Scientific in 2006. The company is best known for its focus on the life sciences. Thermo Fisher is a major manufacturer and distributor of clinical diagnostics reagents, instruments and supplies. The Thermo Fisher conglomerate serves healthcare, drug discovery, academia, government and industrial laboratories. Thermo Fisher offers a range of scientific instruments from basic equipment to advanced mass spectrometers. It also sells chemicals, agents, and antibodies for biotech research.

Thermo Fisher Scientific is organized in four segments: Analytical Instruments, Specialty Diagnostics, Life Sciences Solutions and Laboratory Products and Services. These complementary businesses provide science tools that are expected to work toward taking research test modalities to clinical practice. While the company as a whole reported organic growth of 9%, diagnostics business revenues have remained stable around the $3 billion mark for the past few years. The company intends to migrate its offerings in human genome and sequencing products and systems in research settings to products for clinical labs.

The following is a list of the company’s reported clinical diagnostics holdings: Phadia: allergy and autoimmunity diagnostics; B.R.A.H.M.S.: novel biomarkers (procalcitonin); TREK Diagnostics: microbiology solutions; Sure-Vue and PathoDx Rapid Serology Tests; One-Lambda: HLA for transplant testing; and brand names Oxoid, Remel and Sensititre Systems: traditional microbiology tests.

The company’s life sciences brands include: Thermo Scientific, Applied Biosystems, Invitrogen, Fisher Scientific and Unity Lab Services.

Thermo Fisher has been successful in its expansion to China and India and expects to repeat the formula it used there in other countries such as Korea, Taiwan, Brazil, and Russia. Thus, Thermo Fisher anticipates that its product sales in emerging markets will increase from 19% – 25% of total revenues in 2019. The focus will be specialty diagnostics: microbiology, histology and immunoassays.

In 2017, Thermo Fisher established a relationship with KingMed Diagnostics, China’s leading 3rd-party diagnostic services provider. The partners plan to promote the adoption of advanced molecular and immunodiagnostic tools in the country. The company also opened a Precision Medicine Customer Experience Center in Guangzhou, China in 2017 to capture some of the estimated $9 billion market opportunity (according to Thermo Fisher) in the country.
A major part of the company’s molecular business is based on Thermo Fisher’s diagnostic platforms for genetic analysis that include the Ion Torrent line, Applied Biosystems 3500 Dx Series genetic analyzers and the Applied Biosystems QuantStudio Dx real-time PCR instrument.

In 2018, Thermo Fisher announced a company strategy to migrate life science tools to applied and clinical markets. Examples of this already executed are the automated Cascadion SM Clinical Analyzer; the QuantStudio Dx Real-time PCR approved for in vitro diagnostic use; and the Ion PGM Dx System, an in vitro diagnostic next-generation sequencing platform.

Thermo Fisher also anticipates accelerating digital capabilities for scientific acceleration with cloud-connectivity for all new instruments; algorithm-based, predictive instrument maintenance enabled by remote monitoring and diagnostics; and informatics tools for data curation and actionable insight generation.

Thermo Fisher reported the company is “uniquely” positioned to take advantage of precision medicine opportunities by virtue of its population stratification studies, translational research, molecular diagnostics and integrated therapeutics.
In September 2018, Thermo Fisher licensed intellectual property for CRISPR technologies from the Broad Institute and ERS Genomics (Ireland). Thermo Fisher obtains global non-exclusive rights to products, tools, and research services involving the technologies. Thermo Fisher holds exclusive rights to IP for the Tal Effector Nuclease (TALEN) technology, which complements CRISPR.
Thermo Fisher reported: “The combination of CRISPR and TALEN technologies provides a complete genome editing toolbox that moves researchers closer to the promise of delivering on the potential of synthetic biology.”

In March 2018, Thermo Fisher and Biocept (San Diego, CA) signed a non-binding memorandum of understanding to validate Thermo Fisher’s Oncomine next-generation sequencing liquid biopsy panels in Biocept’s CLIA-certified laboratory. Thermo Fisher also announced a plan to designate Biocept as a Center of Excellence for oncology liquid biopsy initiatives and to pursue commercial opportunities with the company. In addition, the companies may develop new products that integrate Biocept’s Target Selector technology with Thermo Fisher’s Ion Torrent NGS platforms and Oncomine liquid biopsy panels.
In February 2018, Thermo Fisher launched the Applied Biosystems Axiom Microbiome Array for simultaneous detection of archaea, bacteria, fungi, protozoa and viruses in human and non-human samples. Developed in collaboration with the Lawrence Livermore National Laboratory (LLNL), the array is designed to increase the understanding of microorganisms, while accelerating the translation of these insights into human health and agricultural applications.

Sysmex Corporation

Sysmex Corporation  is an integrated manufacturer of laboratory software and diagnostic systems involved in the development, production, marketing, and servicing of clinical laboratory testing devices and reagents. Since its establishment in 1968, Sysmex had concentrated in hematology and urinalysis. More recently Sysmex has expanded into hemostasis, immunochemistry, and clinical chemistry; and has expanded its global operations in hematology, coagulation, immunochemistry, and urinalysis.

At this time Sysmex is beginning to expand its presence in molecular analysis and liquid biopsy testing primarily for cancer, based on the establishment of Sysmex Inostics for next generation sequencing, and flow cytometry from the acquisition of Partec and its partnership with Riken Genesis for clinical PCR.
Sysmex is the undisputed leader in the hematology market, worldwide. The company made its mark by introducing the first 5-part differential and then marketing a number of innovations. Sysmex has gained market share in the U.S. by establishing its own sales force and negotiating contracts with reference labs and hospital systems.

As Sysmex celebrates its 50th anniversary the company has begun to increase its focus on international markets in particular for emerging molecular and oncology test modalities. In April 2018, Sysmex announced a new corporate message: “Lighting the way with diagnostics.” The goal is “to reshape the world of testing and diagnostics, and open the future in healthcare, we will continue to take on challenges in line with our new corporate message.” Sysmex reported that the company will strengthen and expand its core business portfolios in hematology, urinalysis, coagulation and immunochemistry fields.

As part of this strategy, in May 2018, Sysmex announced plans to establish the Bio-Diagnostic Reagent Center to “boost the Company’s competitiveness and provide a stable supply of diagnostic reagents using proteins and substances derived from living organisms (bio-diagnostic reagents).” Operations were expected to begin in April 2019, in Seishin Industrial Park (Nishi-ku, Kobe).
In July 2017 Sysmex announced the expansion of Sysmex Reagents of America’s reagent factory in the United States and the reinforcement of its reagent production system, in response to expected increases in demand in the Americas.

bioMérieux

In 2019 bioMérieux celebrated its 55th anniversary. bioMérieux (2018 revenue, $2,625 million) is present in more than 150 countries through 39 subsidiaries and a large network of distributors. For clinical diagnostics, bioMérieux provides diagnostic solutions (reagents, instruments, software), which are used for diagnosing infectious diseases, blood bank screening, blood culture, cancer screening and monitoring and cardiovascular emergencies.

bioMérieux is best known for its microbiology business that includes immunoassays, traditional microbiology and chromogenic media; however the company is moving to capitalize on its acquisition of Organon Technika’s molecular technology, BOOM and NASBA technologies. Most of those patents expired in 2010.
bioMérieux is using its dominant position in microbiology to build a molecular test business with a focus on oncology and infectious diseases. In September 2013, bioMérieux acquired molecular test innovator Biofire Diagnostics, Salt Lake City, ID (formerly Idaho Technologies). BioFire is the inventor, manufacturer, and marketer of its multiplex Polymerase Chain Reaction FilmArray system and a menu of market approved tests for infectious diseases.

Since then the FilmArray business has made a major contribution to bioMérieux’ revenue stream with reported sales of $147 million in 2015 and $570 million in 2018 for a 40% CAGR over the 4 years.
In July 2017, bioMérieux and Sysmex announced that they will dissolve a nearly 10-year-old joint venture, transferring all of Sysmex’s holdings in the company to bioMérieux. In 2008, the companies formed the JV, called Sysmex bioMérieux, to promote and commercialize bioMérieux’s IVD reagents and medical instruments in Japan through Sysmex’s sales and marketing infrastructure. Sysmex held a 34% stake in the JV, with bioMérieux owning the remaining 66%. Sysmex continued to distribute bioMérieux products in Japan until October 31, 2017 and provide customer service for these products until March 31, 2018. bioMérieux said that it intends to build its own commercial structure in Japan to take over activities previously handled by Sysmex.
bioMérieux has intensified the competition in the market for mass spectrometry testing in microbiology. bioMérieux was awarded the CE Mark for the VITEK MS, an automated microbial identification system that uses mass spectrometry technology (MALDI-TOF). The system was developed in collaboration with Shimadzu (Kyoto, Japan) in an agreement in May 2010. bioMérieux reported that at least 55 systems have been installed. This partnership competes directly with the BD/Bruker and Beckman Coulter/Bruker microbiology mass spec products.

bioMérieux continues to engage in partnerships and acquisitions to expand its product portfolio and market presence with its bioMérieux in China enterprise. In July 2018, bioMérieux reported: the Mérieux family has developed close ties with China spanning three generations. Today, China holds an important role in the strategy of bioMérieux: 3rd largest bioMérieux subsidiary in terms of revenue; 400 people working in R&D, manufacturing and sales; and 6 offices: Shanghai, Beijing, Chengdu, Guangzhou, Hong Kong and Taipei.
In November 2018, bioMérieux acquired 54% of Chinese immunoassay company, Suzhou Hybiome Biomedical Engineering Suzhou. bioMérieux had already acquired a minority stake in July 2018. Founded in 2009, Hybiome specialized in automated immunoassay tests. The company develops, manufactures and markets a complete range of diagnostic solutions (reagents, instruments and software) cleared by the China Food and Drug Administration (CFDA).

Werfen

Werfen,  established in 1966, has a direct presence in about 30 countries and more than 100 territories through distributors. It has a team of over 5,000 people, and its R&D and manufacturing activities are carried out in the United States and Europe.
Werfen made its first concerted effort to move into clinical diagnostics with the acquisition of Instrumentation Laboratory in 1991. This was followed by Chromogenix (Sweden) in1996; Homoliance (U.S., coagulation) in 1999; Inova Diagnostics (U.S., autoimmune); the Binding Site (UK, autoimmune); and Tem and Accriva in 2017.
Werfen’s main subsidiary companies include: Instrumentation Laboratory (IL), Inova Diagnostics (Boston, MA), Biokit (Spain) and Systelab specializing in laboratory and hospital software solutions. Werfen is also involved in medical devices through its company Leventon and the distribution of other companies’ products.
Werfen maintains its position in the IVD industry by concentrating on reinforcing its main areas of expertise in coagulation and autoimmune testing and has added to its acute care diagnostics with Instrumentation Laboratory’s recent acquisition of Tem and Accriva Diagnostics.
Werfen specializes in the areas of clinical chemistry, clinical software, hemostasis and acute care diagnostics through its company, Instrumentation Laboratory. In the area of autoimmunity it specializes through its company, Inova Diagnostics. Werfen also provides OEM manufacturing for third parties (reagents and biomaterials) and infectious disease serology through its company, Biokit.
Werfen reported a 7% increase in IVD revenues in 2018 compared to 2017. Werfen reported that 2018 was a year of major milestones, including securing key U.S. patents to advance innovations in Hemostasis, Blood Gas and CO-Oximetry testing, in addition to the installation of more than 1,000 of Radiometer’s GEM Premier 5000 blood gas systems in medical facilities worldwide.
For 2018, Werfen reported above market growth of 6.5% with growth in North America of 6.5%, Asia-Pacific and Latin America regions of 6.2%, driven mainly by hemostasis, acute care diagnostics and autoimmunity.
Werfen reported that it has strengthened its presence in all regions, especially in China. North America represents 26% of total sales and Western Europe represents 42% of total sales. Werfen anticipates that the areas with the greatest potential for growth are Latin America and EEMEAI (Eastern Europe, Middle East, Africa and India), each of which generated approximately 8% of total sales.
Werfen company news: Instrumentation Laboratory (IL, 2018 revenue, $1,047 million) founded in 1959, is a worldwide developer, manufacturer and distributor of in vitro diagnostic instruments, related reagents and controls for use primarily in hospitals and independent clinical laboratories. The company will celebrate its 60th anniversary in the IVD industry. The company’s product lines include Critical Care systems, Hemostasis systems and Information Management systems.

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Ortho Clinical Diagnostics

In 2017, Ortho Clinical Diagnostics has received a number of industry awards. In September 2018, Ortho Clinical Diagnostics was named The Trailblazer 2018 Company of the Year in the Medical Device/Diagnostics Category by PM360, a publication for marketing decision-makers in the pharmaceutical, biotech and medical device industries. This recognition, selected by the PM360 Editorial Advisory Board, recognizes companies that have made a significant impact in the health care industry through achievements in innovation, social responsibility and talent development.

In July 2018, the company announced that, for the third year in a row, the Ortho Care service and support program was the highest-ranked original equipment manufacturer for overall service performance in the diagnostics industry. The rankings were published in three IMV 2018 ServiceTrak reports, which are based on opinions of laboratory professionals working in U.S. hospitals representing more than 3,000 systems. Respondents were randomly distributed across the U.S., both geographically and by hospital size.

In April 2018, Ortho was selected for a gold-level Edison Award in the Best New Product Awards category for its VITROS NEPHROCHECK Test. VITROS NEPHROCHECK (according to Ortho) is the first fully automated risk assessment tool for predicting acute kidney injury (AKI), a serious and potentially fatal condition affecting hospital patients worldwide.

Ortho focuses on several lab segments. In transfusion medicine, Ortho in collaboration with Novartis Diagnostics markets blood virus ELISA screening tests for hepatitis B and C, HIV to blood banks. Ortho is also a leader in instrumentation and reagent systems for clinical chemistry, immunoassays and blood typing.
Ortho describes its innovation for IVD testing: “Ortho has reimagined clinical lab flexibility through its patented dry slide technology. Its reliable, accurate, precise testing ended a long industry reliance on liquid chemistry and simplified lab operations. Ortho is the only global provider of this technology, which helps eliminate variables associated with water quality, which can impact the integrity of test results.”

In spite of being among the top five diagnostics companies, Ortho has been performing below expectations – it was neither #1 nor #2 in the major segments where it operated. Also, Ortho has little or no involvement in the high growth test segments: infectious diseases, oncology, tissue and molecular diagnostics. Further, while the other top tier companies have been showing growth (albeit modest), Ortho’s revenues have slipped.
Private equity firm Carlyle Group LP acquired Ortho Clinical Diagnostics from Johnson & Johnson in 2014 for $4 billion. In November 2017, Carlyle announced it is exploring a sale or initial public offering of Ortho that could be valued at more than $7 billion, including debt. Carlyle had decided to pursue an IPO since the company had received interest from potential suitors and it is likely that an IPO would result in a higher valuation. To date, an IPO has not been initiated.

Becton Dickinson & Co

Becton Dickinson & Co is a leading global medical technology company that develops, manufactures and sells medical devices, instrument systems and reagents. Founded in 1897 and headquartered in Franklin Lakes, New Jersey, BD employs nearly 30,000 associates in more than 50 countries throughout the world. The company serves healthcare institutions, life science researchers, clinical laboratories, the pharmaceutical industry and the general public.

Although the company’s diagnostics revenues are far behind the IVD leaders, BD’s legacy IVD involvement is in infectious disease testing and flow cytometry, where the company is an industry leader.
BD has operated in China since 1994 and in India since 1996. At the 37th annual JP Morgan Healthcare Conference, San Francisco, CA in December 2018, BD reported that the company had signed its sixth memorandum of understanding with the Chinese government related to reducing hospital-acquired infections.
In October 2015, BD reorganized its business into a two-segment structure comprising Life Sciences and Medical. The Life Sciences segment houses the pre-analytical systems, diagnostic systems, and biosciences business units, while the Medical segment is now composed of the medical/surgical systems, pharmaceutical systems, and diabetes care units.
BD Diagnostics’ menu includes products for the collection and transport of diagnostics specimens, as well as instruments and reagent systems to detect a broad range of infectious diseases, healthcare-associated infections (HAIs) and cancers. Specific products include microorganism identification and drug susceptibility systems, liquid-based cytology systems for cervical cancer screening and HPV testing, rapid immunoassays, microbiology plated media, microbiology laboratory automation, automated blood culturing systems and molecular testing systems for infectious diseases and women’s health.

Qiagen N.V.

Qiagen N.V. (2018 revenue, $1,502 million) is a holding company with subsidiaries in Germany, the United States, China, Japan, the United Kingdom, Switzerland, France, Italy, Australia, Norway, Austria, Canada, Sweden, and the Netherlands. Qiagen is a leading global provider of molecular sample and assay technologies.
Qiagen entered the fledgling molecular testing market in 1984, when it pioneered DNA and RNA extraction technology for molecular test sample preparation. For the past few years, Qiagen has transformed itself into a molecular diagnostics company with acquisitions of DxS, Eppendorf’s DNA reagent business, eGENE, Genaco, Biotage, Corbett Life Science and Digene (the company that established HPV as a precursor to cervical cancer).
Qiagen’s acquisitions have expanded its position in molecular diagnostics from $398 million in 2005 to $1,502 million in 2018 and the product portfolio includes tests in just about every facet of molecular testing.
Qiagen’s revenue stream does not reflect the position that the company occupies as an IVD innovator in automated DNA sample processing, molecular HPV testing, companion test development, liquid biopsy, next generation sequencing automation and last but not least digital PCR. These are but a few of the areas where Qiagen is building its molecular test enterprise.

Qiagen is developing a pipeline of assays for preventive screening and diagnostic profiling of diseases, detection of biomarkers to guide Precision Medicine in cancer and other diseases, and other molecular targets that will be added to the QIAsymphony, QIAstat-Dx, NeuMoDx and GeneReader NGS automation systems in the coming years.

Bio-Rad Laboratories

Founded in 1952, veteran IVD company Bio-Rad Laboratories, Inc. (2018 revenue, $1,420 million) markets a broad range of products for the life science research and clinical diagnostic markets. In 2017, Bio-Rad celebrated its 65th year of operations. The company offers more than 3,000 different products that cover more than 300 clinical diagnostic tests to clinical diagnostic customers including hospital laboratories, reference laboratories, transfusion laboratories and physician office laboratories.

Bio-Rad’s growth comes from its strength in multi-niche markets including infectious disease immunoassays, diabetes hemoglobin A1c testing, autoimmune immunoassays, neonatal screening, allergy testing, blood typing, microbiology media and pathogen identification tests, and quality control products.

In 2011, Bio-Rad began to migrate its expertise in molecular life sciences testing to clinical diagnostics with the acquisition of QuantaLife, Inc. (Pleasanton, CA). QuantaLife has commercialized the Droplet Digital (ddPCR) system. In August 2012, Bio-Rad Laboratories launched a Digital Biology Center to focus on the development of new products based on QuantaLife’s droplet partitioning technology. The first product based on this technology is the Bio-Rad QX100 Droplet Digital PCR.

In January 2017, Bio-Rad acquired RainDance Technologies (Billerica, MA), a leading digital droplet PCR developer. The company is now part of Bio-Rad’s Life Science business segment. RainDance Technologies offers a proprietary droplet technology that enables research in areas such as non-invasive liquid biopsy. The product menu includes: RainDrop Digital PCR, ThunderStorm, and ThunderBolts Next-Generation Sequencing Enrichment for the detection of genetic variations in cancer and inherited and infectious diseases.
In September 2016, Bio-Rad announced the first prospective clinical trial of a blood-based DNA test conducted by researchers at the Dana-Farber Cancer Institute (DFCI) in Boston using Bio-Rad’s droplet digital PCR (ddPCR) platform for the detection of cell-free DNA (cfDNA) as a diagnostic tool that may predict melanoma recurrence.

In February 2019, Bio-Rad Laboratories received FDA clearance to market the QXDx AutoDG ddPCR System, which uses Bio-Rad’s Droplet Digital PCR technology, and the QXDx BCR-ABL %IS Kit. This is the company’s first liquid biopsy assay and Droplet Digital PCR system for diagnostic use.
In December 2017, Bio-Rad was awarded the CE Mark for a droplet-digital PCR assay to detect BCR-ABL gene fusions. The test can be used to monitor response to treatment in patients with chronic myeloid leukemia and is Bio-Rad’s first clinical ddPCR assay to receive a CE mark.
In December 2018, Bio-Rad Laboratories entered into a collaboration with Genetic Analysis AS (Oslo, Norway) and Bioaster, a French microbiology research institute, to study gut microbiome alterations in metabolic disorders.

Bio-Rad brings over 40 years of expertise in diabetes testing as an early marketer of HPLC-based benchtop instrumentation. One of the company’s newest products is the D-100 System, which aids in the diagnosis and monitoring of diabetes. The D-100 features Smart HPLC, designed to meet the quality and productivity demands of high-volume labs. Bio-Rad’s onboard Advisor software automatically reviews results.

Hologic

Hologic, Inc. (2018 revenue, $1,159 million) is active in several markets: diagnostic products, medical imaging systems, and surgical products. The company operates four core business units focused on diagnostics, breast health, gynecological surgical and skeletal health.

Hologic’s diagnostics revenues are approximately 37% of the company’s total sales with some 78% generated in the U.S. Hologic’s diagnostics business is based primarily on molecular tests acquired with the acquisition of Gen-Probe Inc. in August 2012. Until that time, Hologic was best known for the ThinPrep Pap test and ThinPrep Imaging system for cervical cancer screening with a liquid cervical fluid sample and single layer slide preparation. In 2018, Hologic reported it is planning to reinvigorate its legacy ThinPrep cytology sample preparation and Pap test products via a Pap – HPV co-testing campaign.

In 2017, Hologic has made a strategic decision to focus on high value molecular tests. Hologic reported that molecular diagnostics has emerged as a “sustainable growth driver for the company,” specifically fueled by growth across Aptima women’s health products on the fully automated Panther and Tigris platforms.
As part of the company’s strategic move, in January 2017, Grifols acquired Hologic’s interest in their existing joint-business whereby Grifols now owns all customer service activities. The agreement encompasses the acquisition of the Hologic unit engaged in research, development and manufacture of assays and instruments based on NAT (Nucleic Acid Testing) technology for transfusion and transplantation screening. The assets acquired include a plant in San Diego, CA, as well as development rights, licenses to patents and access to product manufacturers. Hologic’s viral load assays are not part of the sale of the blood screening business to

Grifols

The strategy has had a measure of success. In 2018, Hologic reported that it is a market leader with some 1,500 Panther Dx units installed globally. The company looks to a solid future based on its partnership with large test services organizations including Quest Diagnostics and LabCorp and a growing molecular test portfolio for women’s health, and viral and respiratory infections.

Speaking at the 37th annual JP Morgan Healthcare Conference (December 2018, San Francisco, CA) Hologic CEO Stephen MacMillan said that diagnostics bring in about 36% of revenues. This is driven by new tests, increased utilization, and international sales growth, molecular revenue growth increased 12% in 2017 and 7% in 2018.

He noted that Hologic’s diagnostics businesses have grown over recent years, transforming it from a niche player in sexually transmitted disease testing to a “broad-based molecular diagnostics leader with strong customer partnerships.” Molecular diagnostics sales increased approximately 7% in 2018 compared to 2017. Growth was driven primarily by continued strength across Aptima women’s health products on the Panther platform.

Immunoassays

Immunoassays have been used in clinical laboratory medicine since the 1960s, and are indispensable tools in clinical diagnostics. A wide range of types of immunoassays are now used to measure proteins (including antibodies), hormones, drugs, and other analytes. Fully automated immunoassay systems are now found in clinical laboratories. Even though the field of immunoassays is now mature, companies have continued to develop new immunoassays and immunoassay instrument platforms to further improve the sensitivity of the assays, to make multiplexing possible, to miniaturize the platforms for point-of-care, and to identify and develop assays for novel biomarkers, thus further expanding the potential of immunoassays for the future.

Table: Selected Companies Marketing Central Lab-Based Immunoassays Worldwide

Company Product
Abbott ARCHITECT family of analyzers; Alinity i
AccuBio Tech Lateral flow; ELISA
Acon Labs Foresight EIA Test Kits
Aesku.Diagnostics AESKULISA ELISA test kits, IFA reagents, SQII and HELMED analyzers
Alere Enzyme immunoassay analyzers:  Agility, DSX ELISA Automation System, and DS2 ELISA Automation System
APLCO Diagnostics ELISA, RIA, chemiluminescent immunoassays
Ani Biotech Oy Orgenium Laboratories ELISA tests
ARK Diagnostics Homogeneous enzyme immunoassays
Arlington Scientific Serology agglutination tests; IVT AllergyTM 2 Screen and the IVT Allergy Reader System
Associates of Cape Cod (1.3)-ß-D-glucan analysis (test service); Fungitell Kit
Astra Biotech ELISA
Athera Biotechnologies CVDefine test
Atlas Link Lateral flow, ELISA
Audit Dx Lateral flow, ELISA
Autobio Diagnostics Lateral flow; ELISA; CLIA
Awareness Technology ELISA; CLIA
Avioq ELISA
AXA Diagnostics ELISA, IFA, immunoblot, immunodot, and Immunoquick technologies
Beckman Coulter/ Danaher DxC 600i, DxC 660i, DxC680i, DxC 860i, and DxC880i Immunoassay analyzers:  DxC 600i, DxC 660i, DxC680i, DxC 860i, and DxC880i
Beijing Chemclin Biotech Chemiluminescence assays
Beijing Wantai Biological Pharmacy ELISA, Dot-ELISA Rapid Tests and Colloidal Gold Rapid Tests
BG Medicine ELISA
Bhat Bio-Tech India Lateral flow, ELISA
Binding Site Assays on SPAplus® Special Protein Analyzer, and also on analyzers marketed by Siemens, Roche, and Beckman Coulter
Biocare Diagnostics Lateral flow, ELISA
BioCheck ELISA
BIOCLIN ELISA, Lateral flow
Biokit BIO-FLASH, BIO-ELISA
Biomerica Lateral flow, ELISA
bioMérieux VIDAS immunoassay analyzers
BioPorto Diagnostics ELISA
Bio-Rad Labs BioPlex 2200 Multiplexing Platform; EVOLIS system
Bioscience (Tianjin) Dx Technology CLIA
Biotech Atlantic Lateral flow, ELISA, CLIA
Biotron Dx Lateral flow, ELISA
Boditech Med Lateral flow, ELISA
Boson Biotech Lateral flow, CLIA
Calypte Biomedical ELISA
Cellmid ELISA
Cisbio Bioassays ELISA, RIA
Corgenix Medical Lateral flow; ELISA; immunoturbidimetry (IT)
Critical Diagnostics Lateral flow; ELISA
CTK Biotech Lateral flow; ELISA
Denka Seiken Latex-enhanced turbidimetric immunoassays for use on clinical chemistry analyzers
diaDexus ELISA
Diagenics Lateral flow, ELISA
DIALAB Lateral flow, ELISA
Diametra ELISA
DiaSorin LIAISON and LIAISON XL automated platforms for immunoassays
DIAsource Immunoassays Lateral flow, ELISA
Diaxonhit Lateral flow, ELISA
DIESSE Diagnostica ELISA
Dr Fooke Lateral flow, ELISA
DRG Lateral flow, ELISA
D-Tek ELISA
Erba Diagnostics Mago (Fully automated ELISA and IFA processor), Erba Lisa Scan (Automated ELISA 7 Microbiology Reader)
EUROIMMUN Blot techniques:  Western blot, EUROASSAY, EUROLINE, EUROLINE-WB ELISA assays; BIOCHIPs; EUROASSAY
Eurospital Lateral flow, ELISA, IFA
Fujirebio RIA; EIA; Lumipulse instrument systems for automated CLEIA (Chemiluminescence Enzyme Immunoassay)
GenBio Lateral flow; ImmunoWELL and in an immunofluorescence format called ImmunoFA
Grifols Triturus automated (ELISA analyzer)
Hema Diagnostic Lateral flow; ELISA
Hipro Biotechnology CLIA
HYCOR Biomedical HYTEC 288 immunoassay analyzer and Ultra-Sensitive EIA System quantitative determination of specific IgE
Immunetics ELISA
Immunodiagnostic Systems IDS-iSYS Fully Automated Immunoassay System
Immuno-Mycologics Lateral flow; ELISA
InBios Lateral flow; ELISA
Inova Dx BIO-FLASH (fully automated, random access chemiluminescent analyzer) plus microtiter plate processor
InTec ELISA
j.Mitra ELISA
Labor Diagnostika Lateral flow, ELISA, RIA
MagnaBioSciences Magnetic Immuno-Chromatographic Test (MICT
Medipan ELISA, RIA
Mercodia ELISA
Monobind ELISA, CLIA
Novatec Immunodiagnostika ELISA
Oasis Dx ELISA
Omega Dx VISITECT two-site sandwich immunoassays for POC testing; ELISA
Operon Lateral flow, ELISA
Orgentec Diagnostika ELISA; Alegria fully automated instrument
Ortho Clinical Dx VITROS line of automated chemistry analyzers and immunoassay analyzers, plus one integrated system
Point Scientific ELISA
PreCheck Bio Lateral flow, ELISA
Prestige Dx Lateral flow, latex serology tests, ELISA
Pro-Lab Dx ProlisaTM line of immunoassay tests (EIA)
Radiometer Medical/Danaher AQT90 FLEX immunoassay analyzer
Randox Labs Biochip Array Technology (BAT) and three BAT analyzers:  Evidence MultiStat, Evidence Investigator, and Evidence Evolution
Rapid Pathogen Screening Direct Sampling Micro-Filtration (DSMF) and Direct Multi-Planar Chromafiltography (DMC) technology
R-Biopharm Lateral flow; immunofluorescence assay (IFA)
Reagena Group Lateral flow with hand-held refractometer ReaScan and ReaMobile software; ELISA
Roche Dx cobas line of analyzers (clinical chemistry analyzers, immunoassay analyzers, and cobas 8000 modular analyzer series; Elecsys series
Savyon Dx Lateral flow, ELISA
ScheBo-Biotech  ELISA
Shanghai Kehua Bio-engineering Lateral flow, ELISA
Siemens Healthineers Dimension EXL integrated chemistry systems, Immulite 2000 XPi Immunoassay System; Immulite 1000 Immunoassay System
Snibe Automated Chemiluminescence Immunoassay (CLIA) System – Maglumi 1000, Maglumi 2000, Maglumi 2000 PLUS analyzers -Semi-automated Chemiluminescence Immunoassay (CLIA) System -Maglumi semi-auto chemiluminescence analyzers -Magnetic enzyme immunoassay analyzer
Syntron Bioresearch Lateral flow, ELISA
TECHLAB  ELISA
Teco Dx Lateral flow, ELISA
Theradig ELISA, FIDIS multiplex platform, Immunofluorescence
Thermo Fisher Scientific ImmunoCAP Lab Tests, Phadia line of laboratory instrument systems, ImmunoCAP ISAC
Tianjin Bio-Enoche Engineering ELISA
Tosoh Corp AIA Automated Immunoassay systems
Transasia Bio-Medicals ELISA, IFA
Trinity Biotech Lateral flow; ELISA (lab instruments include TrinLab D2, TrinLab DX, TrinBlot System, plus plates and readers)
Tulip Group One-step membrane, ELISA
Vital Dx PATHFAST CLEIA Analyzer (Chemiluminescence Immunoassay Analyzer)
Wako Dx µTASWako® i30 microfluidic-based clinical immunoanalyzer
WAMA Dx Lateral flow, ELISA
Wiener Labs ELISA
ZEUS Scientific Immunofluorescence assays (IFA), ELISA and multiplex (AtheNA Multi-Lyte) immunoassays

Lab Automation

Clinical lab medicine plays an integral role in healthcare and disease management.  It is estimated that some 70% of diagnoses and treatment plans are based on clinical lab test results.  Diagnostic laboratory medicine has changed dramatically since the 1970s.  Until the 1970s lab medicine was comprised of some 500 to 4000 tests performed manually with the aid of test tubes and a spectrophotometer or microscope.  Proteomic research then led to the discovery of important disease markers such as proteins, enzymes and hormones.  Enzyme immunoassay techniques provided a tool by which to assay these and other markers.

In the 1980s, the development of enzyme immunoassays and automation led to an almost a doubling in the number of tests that could be performed in hospital labs.  Then the launch of polymerase chain reaction (PCR), the completion of the Human Genome Project and molecular test modalities added yet another dimension to clinical lab testing.  By the 1990s and 2000s developments in molecular biology, proteomics, disease management research and the unraveling of the human genome further expanded the menu of tests available.  Thus tests used to analyze biopsied tissue; to measure nucleic acids in blood, sputum, urine, cervical fluid and other samples; and to diagnose infectious diseases created a rapid expansion in clinical lab medicine.  These tests provide physicians information that could be readily applied to therapy selection and patient outcome particularly in cancer diagnosis and disease management, in diabetes and in infectious diseases.

A brochure summarizing lab test activities at Baylor University Medical Center (Wako, TX) during 1951–1952 reported that 245,296 laboratory tests were completed, for a daily average of 672 tests.  Since that time, the article states “the number of tests processed has tended to increase at a rate of about 10% per year” and therefore by our calculation the Baylor labs would have processed at least 100 million tests in 2019 (or some 285,000 tests per day).  The figure shown below illustrates the expansion of tests available for inclusion in a laboratory’s test menu.

It is obvious that the manual test methods used in most labs until the mid 1960s and 1970s could not cope with the increased expansion of the test menu.  Automated instrumentation was a solution that allowed test results to be generated in a fraction of the time that they used to take.  For the purposes of this report; laboratory automation is defined as the use of technology to streamline or substitute manual manipulation of test processes including: simple capping and decapping of sample tubes and bottles, creating test lists, high throughput screening of test samples, the storage of patient samples and the communication of test results to a laboratory information system.

The use of automation in labs progressed step by step.  Barcoding and scanners replaced hand-written test lists and have speeded up the specimen tracking process.  This was accompanied by automated clinical chemistry, immunoassay and hematology/coagulation instrumentation.  Next came what are termed independent “islands of automation” used to conduct pre-analytical sample manipulation, automated testing and sample storage modules.  The final and most sophisticated phase resulted in “total lab automation” whereby these independent modules are linked by a track that is powered by advanced robotic solutions with multiple connectivity options.  These track-based automation solutions are scalable and flexible to meet the demands of any size laboratory.

Total automation solutions can be open or closed.  Closed automation track solutions are provided by instrument manufacturers and typically connect only to instruments from that vendor or assigned partners.  All of the major diagnostic companies including Abbott Diagnostics, Beckman Coulter/Danaher Diagnostics, Ortho Clinical Diagnostics, Roche Diagnostics and Siemens Healthineers offer total lab automation solutions.  Open automation solutions are designed and acquired by labs independently and can interface with any instrument, regardless of the vendor.  They are built by independent companies and interface to the instruments and the lab information system to automate the pre- and post-analytical work flow.

Tecan Group, Copan, Kiestra, Hitachi High Technologies, and others are among the major automation companies that partner with IVD companies to provide customized automation solutions.

One of the most popular automation solutions for any size lab has been the pre-analytical sample preparation station.  This is because the pre-analytical phase is associated with more than half of all laboratory costs and has been shown to be the source of laboratory errors due to specimen mislabeling, misidentification, missorting, and improper routing, and decanting.  While Beckman Coulter/Danaher has been a pioneer in this area, other major IVD vendors now offer a variety of automated pre-analytical solutions including Bio-Rad Laboratories, Abbott Diagnostics, Siemens Healthineers, Roche Diagnostics and others.

The ultimate goal of these various automated systems is to minimize labor intensive manual work previously performed by medical technicians (sorting tubes, decapping, centrifuging, loading analyzers, prepping and sorting materials for storage, etc.) while optimizing workflow, improving productivity, and increasing patient safety.

Simply put, a fully automated laboratory is one in which samples are loaded into racks, transported to and loaded onto/off analyzers and stored for further processing – all without the human touch.  All analyzers are linked together physically by sample conveyor systems and electronically by a laboratory information system.

Automation of lab equipment is not necessarily new, but the technology is advancing and spreading across more fields than ever anticipated.  At this time, just about every lab discipline has incorporated some form of automation.  The fields of clinical chemistry and hematology were the first to be fully automated.  Microbiology has begun the journey with the arrival of fully automated microbiology platforms that automate the entire work flow with one system.  Molecular diagnostics and anatomic pathology followed.  Evidence of this is automated instruments such as immunostainer platforms in hematology, microbiology and anatomic pathology or DNA extraction and amplification in molecular diagnostics.  The convergence of the disciplines of laboratory medicine (anatomic pathology, clinical pathology, molecular diagnostics) is driving the movement of specimens across disciplines.  Therefore laboratory automation has come to the fore to expand and to connect all parts of the laboratory as well.

The major reasons for automation in the laboratory are fast test procedures, error reduction and staff augmentation. This is driven by increased testing demands and laboratory staffing needs.  With the current situation of labs having to do more with less, total lab automation has become a necessity for large hospital and reference laboratories.  Various degrees of automated systems are also a must have for any clinical laboratory.

Automation has long been regarded as an important means for clinical laboratories to achieve greater efficiency, accuracy, standardization, and test quality.  Lab consolidation increases the number of samples processed in one facility and with increasing competition and demands for higher levels of performance, the need for automation has become more and more essential, even among smaller labs that have often resisted high priced automation solutions.  Meanwhile, the development of new generations of automated stand-alone and benchtop equipment has made lab automation a more and more viable option for labs of all sizes.  The remainder of this report summarizes the progress of automation in various clinical laboratory departments.

 Test Efficiencies with Automation

The first automated instrument was introduced in 1957. The Technicon Corp. (U.S.) Autoanalyzer I, utilized continuous flow analysis to perform basic chemistry tests then referred to as a Chem 7.  AutoAnalyzers automated repetitive sample analysis steps, which would otherwise be done manually.  This way, an AutoAnalyzer could analyze hundreds of samples every day by only one operator.  Ultimately, after a series of purchases the Autoanalyzer technology became the property of Siemens Healthineers.

Technicon was not alone for long.  From the 1960s to the present other companies including Abbott Diagnostics, Bayer Diagnostics (now Siemens Healthineers), Beckman Instruments (now Beckman Coulter), Roche Diagnostics, and Boehringer Mannheim (now part of Roche Diagnostics) and Nova Biochem brought automated systems to market.

In the 1980s Japan demonstrated the potential of full automation with the introduction of a fully automated urinalysis lab where urine samples for standard dipstick analysis were tested without any human intervention.  Japanese chemist Dr. Masahide Sasaki developed the first fully automated laboratory, and he popularized this innovation internationally.  Sasaki and his associates invented total lab automation, which was to become the greatest revolution in clinical laboratory technology since Technicon’s Autoanalyzer.

Sasaki is credited with being the father of modern clinical laboratory automation.  His work with conveyor belts, circuit boards, and programmable robots created the first automated laboratory.  This opened the door for the expansion of automation outside the confines of the instrument to reach pre- and post-analytical work flows.  The automation trend continues today with each new generation of instruments that increase the number of patient samples that can be tested at any one time and also the number of assays available on a single instrument.

Laboratory information systems/laboratory information management systems (LIS/LIMS) began to take shape in the 1970s.  LIS/LIMS platforms brought electronic data management to the laboratory to manage the work flow and electronic interfaces to the instruments.  Driven by an initial need to accurately capture billing codes, these systems helped automate laboratory operation by removing paper-based patient/test lists and capturing data electronically, directly from laboratory instruments.  Coupled with automated instruments, the throughput of the clinical laboratory dramatically increased around the marriage of information systems and automated instruments.

Automation in The Core Lab

Senior lab professionals can remember the time when chemistry, hematology, coagulation, microbiology immunoassays and molecular testing were housed in separate rooms.  For at least the past 20-25 years this has been replaced by the core lab concept. Large institutions may still house molecular testing in a separate room because of the need for ultra sterile test conditions and special instrumentation to perform a wide variety of tests.  The core lab trend has been driven by the need to economize on lab personnel, the commercialization of connect-ready instrumentation and information technologies that can accommodate the amalgamation of disparate test modalities.  These needs also apply to smaller labs where there too the lab walls have come down.  They that have begun to invest in core lab workstation instrumentation and/or some form of lab automation.

For the purposes of this report core lab instrumentation is defined as the chemistry/immunoassay workstation and individual clinical chemistry, hematology and immunochemistry analyzers linked by a track or by some sort of laboratory automation and information technology tools.

At this time, almost all chemistry analyzers offer a mix of clinical chemistries with a selection of immunoassays that test for analytes in clinical chemistry, infectious diseases, hematological markers, cancers and chronic diseases.  Therefore a more widely used term for chemistry/immunoassay analyzers is clinical workstations.

The trend for the consolidation of routine lab tests from multiple disciplines – chemistry, immunoassay, urinalysis, microbiology, coagulation, HPV cytology – into the core lab continues apace.  In the past few years the number of analytes that would normally be found only on dedicated immunoanalyzers and that have migrated to consolidated workstations has increased dramatically.  This table lists some of the immunoassays that have migrated to clinical chemistry/immunoassay workstations.

 Selected Workstation Immunoassays

anti-CCP, autoimmune marker
BNP
cystatin
D-Dimer (coagulation)
HCV
HE4 cancer marker
Hepatitis assays
HgA1c (diabetes)
HIV
hsCRP
Lipid profiles
NGAL cardiac marker
Procalcitonin for sepsis
vitamin D

In fact, traditional specialization barriers, such as microbiology, hematology, blood banking, immunology and even anatomical pathology are fading.  This trend makes the core lab a true hub for lab medicine.  The next logical step is to incorporate a variety of molecular tests in the core lab.  At that time, the lineup of red, lavender, green, gray, yellow and blue stoppered tubes would eventually be treated in an automated core lab.

The expansion of the core lab is a response to a number of environmental conditions.  Economic pressures and labor shortages have been further exasperated by the economic meltdown of 2008.  There is also a continuous addition of new tests to the lab menu.  At this time there are at least 80 immunoassays available on clinical workstations.  Therefore, it is not too unrealistic to anticipate that most routine tests that would require manual processing will one day be automated.

The push for economies has led even smaller hospitals to amalgamate routine tests from different disciplines into a core lab.  In response to this demand, new tabletop instruments designed for small labs are multianalyte workstations that run chemistries and a large menu of immunoassays.  New instruments (large and small) for clinical chemistry, immunoassays, hematology, coagulation, urinalysis, and microbiology (urines) are now developed with the capability to link to a lab information system and to a central lab track.

Of particular interest is the migration of advanced technologies to the core lab.  With clinical market clearance for mass spectrometry instruments such as the Bruker Maldi Typer and bioMérieux’s VITEK MS, it is not too farfetched to see microbiology and other tests on mass spectrometry come to the core lab.  This eventuality is supported by preanalytical sample preparation system that can decap and process screw cap tubes used to transport urinalysis, cytology and microbiology samples as well as traditional blood tubes.

Already mass spectrometry specialist AB Sciex has introduced a test for HbA1c and the company also offers a mass spec kit for vitamin D.  Newomics Inc. (U.S.) was awarded the CE Mark for its IVD-MS Kit for 25-OH-vitamin D2/D3 on a Sciex mass spec system.  Liposcience (U.S.) is developing a silicon-microfluidic-chip, LC-MS, for HgA1c.   Others tests are bound to follow.

The importance of HgA1c in monitoring diabetic glucose management has been advanced with the market clearance of this test for diabetes diagnosis as well as disease monitoring.  The result has been a spate of HgA1c tests on automated analyzers.  More importantly, major quality control companies have launched HgA1c control products in an effort to standardize test results.

High sensitivity troponin (hsTroponin) testing has become a method of choice in the triage of acute cardiac disease in emergency room patients.  The past few years a number of these tests have been added to the traditional cardiac marker panel: BNP, myoglobin and troponin.

Lipid profile and cholesterol testing has gained importance, driven by growing awareness about the risks of heart attack and increasing realization among individuals to control their cholesterol levels.  Overall growth in the testing volumes is driven by factors such as aging population and growing number of people at risk of cardiovascular disease including those with hypertension, diabetes mellitus, and abdominal obesity.  Thus automated lipid profile tests are becoming more and more evident in the core lab.

Vitamin D deficiency has been linked to various diseases including cancers, cardiovascular disease, diabetes, osteoporosis, multiple sclerosis, Alzheimer’s disease and all-cause mortality. This new understanding of importance of Vitamin D levels has driven an increase in the number of physician requests for total 25-Hydroxy Vitamin D tests in the United States and worldwide.

In spite of research indicating the overestimate of the impact that a lack of vitamin D may have on overall wellness and decreased disease risk, vitamin D testing has quickly migrated from dedicated immunoanalyzers and ELISA testing to integrated chemistry analyzers.

For esoteric immunoassays, microplate-based ELISA assays are commonly used to process tests that are not available on automated platforms.  With the ongoing consolidation among laboratories, however, the demand for esoteric immunoassays is reaching volumes that require automation.  Therefore ELISA system manufacturers have automated the test process from stand-alone washers and readers to fully automated workstations and solutions so that they can respond to a clinical laboratory’s assay and throughput requirements.

The table below presents a selection of automation innovations (across lab disciplines) that continue to expand the reach of the core lab in the centralized execution of patient testing.  Company reports indicate the trend is to more and more consolidation of clinical chemistry, immunoassays, infectious diseases, blood and plasma screening, hematology, cytology, and molecular diagnostics — all on a single modular automated solution.  The first target for this advanced automation strategy is large hospital and reference labs.  However with modular adjustments even smaller institutions could modify their core labs to be more multidisciplinary.

Selected Lab Automation Innovations

Abbott Diagnostics has chosen to the open lab automation concept with its GLP, ACCELERATOR and Alinity lines of lab-automation system.  The strategy involves the development of next-generation blood screening, hematology, and immunochemistry instrument systems, as well as assays in various areas including: infectious disease, cardiac care, metabolics, and oncology for the core lab.  Therefore, Abbott’s high end ACCELERATOR a3600 and GLP automation solutions allow labs to connect multiple vendors on a single automation platform.

On the drawing board is the Alinity automation solution a next-generation family of instruments, across key laboratory disciplines, that is designed to simplify diagnostics. The Alinity portfolio includes clinical chemistry, immunoassay, blood and plasma screening, point of care, hematology and molecular diagnostics, along with Abbott’s Alinity PRO software that works to fully maximize the potential of the network of linked instruments.

Beckman Instruments (now Beckman Coulter Diagnostics) was one of the first diagnostics companies to market lab automation and its most popular module at that time was the AutoMate family of systems that managed pre-analytical test procedures.  July 2018, Beckman Coulter showcased its lab automation portfolio, including the Power Express laboratory automation system, with a full complement of clinical information technology solutions.  Beckman Coulter’s Power Express laboratory automation system connects all core disciplines on one line, providing a single point of entry for the company’s pre-analytical, clinical chemistry, immunoassay and hematology analyzers, with the flexibility to connect with select third-party analyzers.

Beckman Coulter’s latest addition to its automation portfolio, the CE Marked DxA 5000 total laboratory automation solution.  The first in a suite of DxA systems in development, the DxA 5000 is a key component of its vision to bring workflow automation to laboratories of all sizes.  The DxA 5000 utilizes Intelligent Routing dynamic system software to bring automated patient-centric workflow.  It continuously calculates the most expeditious route for every patient sample—both STAT and routine.

In the area of information technology, Beckman Coulter provides a comprehensive suite of software and middleware.  According to Beckman Coulter, the company’s DxONE Workflow Manager is the “first and only cloud-based middleware offered by a major in-vitro diagnostics organization, designed to help low-volume laboratories deliver timely results for patient care by enhancing consistency, accuracy and efficiency.” Beckman Coulter reports that leveraging cloud-based technology enables laboratories to utilize their existing IT hardware while requiring very little support from hospital IT personnel.  The IT solution allows laboratories to standardize and automate workflows across Beckman Coulter’s chemistry, immunoassay and hematology platforms.  The DxONE Workflow Manager builds upon Beckman Coulter’s middleware solutions, which include REMISOL Advance for higher volume laboratories.

Ortho Clinical Diagnostics offers the VITROS Automation Solutions an open platform that is both expandable and flexible.  The company’s Open Connectivity strategy enables labs to connect to third-party analyzers that complement VITROS clinical chemistry and immunoassay instrumentation in disciplines such as coagulation and hematology, as well as to select immunoassay platforms that broaden the test menu. Flexible Data Management using Instrument Manager allows small and mid-sized labs to configure solutions that address their specific needs in pre-analytical, analytical and post-analytical test processes.

On the drawing board is the enGen Laboratory Automation system, used in combination with the VITROS Systems and informatics solutions.  enGen Automation helps streamline sample handling by eliminating operator interventions, reduce time spent searching for samples with automated Sample Tracking, optimize workflow with results-based routing, and eliminate barcode reading errors.

Beckman Coulter /Danaher and Ortho Clinical Diagnostics have a partnership whereby Beckman Coulter will place Ortho’s VITROS 3600 System running HIV and hepatitis assays in labs that currently run Beckman’s Power Processor Sample Handling Systems, automation solution, and in certain very high-volume laboratories.  The companies also collaborated to obtain FDA market to connect the VITROS 3600 System to the Power Processor to run infectious disease tests.

Roche Diagnostics is the largest diagnostics company with products for every lab discipline and as such markets automation solutions across the board including blood donor screening, molecular tests and the core lab.  Roche Diagnostics and Hitachi High Technologies have maintained an alliance with an extended 10-year agreement for the joint development and manufacture of the next generation of instruments and workflow automation solutions under the Cobas brand name.

The cobas 8100 automated workflow solution is the result of 35 years of partnership between Roche and Hitachi High Technologies.  Combined with Roche’s sample archiving solutions, cobas 8100 provides connectivity, simplifying and speeding up routines for analysis, archiving and on-demand retrieval of blood samples.

Roche’s MODULAR PRE-ANALYTICS (MPA) system is a turnkey automation solution that also includes the cobas 6500 analyzer series fully automated solution for urinalysis testing.

Roche offers the cobas p 480 instrument for automated preanalytic processing of primary vial molecular diagnostic samples.  The instrument provides automated uncapping and recapping of primary sample vials used for liquid-based cytology (LBC) and molecular assays run on the cobas 4800 System.  For assays such as the cobas HPV and cobas CT/NG 4800 Test, the instrument allows primary vials to be loaded directly onto the cobas 4800 System without a need to aliquot into a secondary vial.  Roche commented: “For the first time, laboratories now have an option to directly load LBC primary vials for preanalytical and analytical processing through a combination of cobas systems that support molecular testing.”

The cobas 4800 System offers walk-away automation of nucleic acid purification, PCR set-up and real-time PCR amplification and detection. The system menu in the U.S. currently includes the cobas CT/NG Test (Chlamydia trachomatis/Neisseria gonorrhoeae), cobas HPV Test, cobas MRSA/SA Test, cobas Cdiff Test, cobas BRAF V600 Mutation Test, cobas EGFR Mutation Test and cobas KRAS Mutation Test.

In the area of central laboratory automation Siemens Healthineers reports it is the only single-source provider able to connect all four key laboratory disciplines—chemistry, immunoassay, hematology, and coagulation — to the automation track.  Siemens’ Aptio Automation solution connects with the company’s Advia Centaur XP system, Immulite systems, and Dimension integrated systems.  Siemens’ CentraLink Data Management System provides lab process management capabilities for Aptio Automation, thus managing patient and quality control data from multiple instruments, and providing centralized control over lab processes.

Siemens Healthineers recently introduced Atellica, a new automation system.  Siemens claims the system features patented bidirectional magnetic sample-transport technology that is 10 times faster than conventional conveyors.  The system can be fit into hundreds of configurations to make the product appealing to mid-size labs with limited space.   Siemens demonstrated the system connected to a clinical chemistry analyzer and an immunoanalyzer; however, the system is designed so that it can be customized and use with many different types of analyzers.

Becton Dickinson Diagnostics’ BD Totalys MultiProcessor is an automated instrument for cytology and molecular testing that integrates the pre-processing for the BD SurePath Liquid-based Pap Test with a molecular aliquot, maintaining sample integrity while improving efficiency in the lab.
Qiagen has introduced the QIAensemble Decapper for liquid cytology vials.  While this new instrument is intended for cytology labs that process Pap smears from liquid cervical fluid samples, it opens the door for a host of sexually transmitted disease tests and assays for gynecological cancers to be run on immunoanalyzers and eventually on the new breed of molecular instruments, all of which have made their way into the core lab.
Hologic is taking this one step farther with the development of a system to present liquid based cytology samples for molecular HPV and sexually transmitted tests on the company’s TIGRIS and PANTHER instruments.

Hematology Automation

Hematology is the study of peripheral blood and bone marrow cells in order to diagnose various diseases of the blood including leukemias, anemia and autoimmune diseases.  The basis of hematology testing is the complete blood count (CBC) that provides information on blood components: hemoglobin, hematocrit, red blood cells, white blood cells, reticulocytes, platelets.  Samples that have abnormal levels of any of these components have a microscopic examination of the cell contents performed, called a blood cell differential.  A drop of blood is placed on a microscope slide and stained.  The slide is then examined under a microscope and the red and white blood cells are analyzed.

Today and over the past 60 years, the CBC has made an enormous impact on patient care.  A CBC is run on every hospitalized patient and it is a vital part of a yearly annual checkup.  The information clinicians derive from the CBC is used in the evaluation of just about every medical condition.

In the late 60’s and early 70’s instrumentation began to replace manually preparing a blood cell stain and counting each cell under a microscope, a process that typically took at least 20-30 min.  This instrumentation is known as the Coulter Counter that is based on the Coulter Principle that was developed by Wallace H. Coulter in 1947 and was commercialized by Coulter Electronics (now Beckman Coulter Diagnostics. and part of Danaher).  The Coulter instruments were revolutionary and just about every lab used a Coulter Counter that provided cell counts and a 3-part differential (lymphocytes, eosinophiles and basophiles.  This blood cell morphologic information was achieved by maintaining the blood cells in a liquid flow and by using the Coulter impedance-based cell-sizing gateway combined with laser-based cytometry.

Since their invention in the 1950s, automated hematology analyzers have become increasingly sophisticated, allowing more precise and accurate CBC and WBC differential test results.  Hematology instrumentation is now offered by more than 15 companies including the major vendors: Beckman Coulter/Danaher, Sysmex Corp/Partec, Abbott/Cell-Dyn, Siemens Healthineers, and Horiba Medical/ABX.  Coulter dominated hematology automation for at least 30 years.

Until the 1980s, hematology instruments automated only the previously manual cell counting and analysis activities.  Operators opened the blood tubes in order to present the sample to the instrument for testing.  Sysmex revolutionized CBC automation with the introduction of needle through the stopper technology, an extended 5-part cell differential for cell morphology and instrumentation that combined cell analysis with integrated slide-making staining technologies.  These advances permitted hematology to be included in track-based lab automation since they eliminated operator intervention.   The major vendors followed Sysmex’s lead.  They offer high end instrumentation with the same features and have also expanded the menu of blood cell-based tests available on the instruments.

Hematology analyzer product differentiation is accomplished by adding new parameters to a basic instrument – such as platelet counting, reticulocyte counting and CD4/CD8 analysis.  The second approach is expansion into body fluids other than blood.  The third avenue for differentiation is in automation strategies that include integration onto a core lab automation track, the addition of an automated slide maker and stainer, cell imaging technology and bioinformatic software.  Abbott Diagnostics, Beckman Coulter/Danaher, Siemens Healthineers and Horiba Medical offer specialized platelet, red blood cell and white blood cell analysis and automatic slide makers/stainers.

Horiba Medical has further differentiated itself from the other vendors with the introduction of the Yumizen H500 hematology analyzer, a compact hematology analyzer that offers 27 CBC parameters including a 6-part differential, an artificial intelligence system with automatic startup and shutdown, and volume cytochemistry based flow-cytometry.

The slide making/staining feature functioned when the instrument signaled n abnormality in any of the CBC analytes.  This reduced the number of patient samples that were then further analyzed by a manual cell differential count by a technologist.  The process is labor intensive and requires considerable expertise. Thus the next frontier in hematology automation is the introduction of digital analysis of a stained blood smear slide.

Hematology lab managers and hematologists look to technology that can reduce costs and shorten turnaround time while maintaining or increasing quality.  They now have digital technology options designed for the hematology lab.  Facilitating digital hematology is automated consistent slide staining that optimizes quality and enables standardization to help ensure accurate identification of white blood cells, red blood cell morphology and platelet assessment.  Digital imaging is a technology by which a camera, combined with appropriate optics and illumination, creates a numerical representation of a physical object, in this case blood cells.  Once in a digital format, the image can be analyzed, displayed, printed, or manipulated in ways that might not otherwise be possible.

The lead company in this area is CellaVision (Lund, Sweden).  The company’s major products are the CellaVision DM series of cell imaging and analysis systems were introduced in 2000.  The major hematology vendors market CellaVision’s digital cell analysis systems along with their high end instruments.

Fully digital hematology received a boost in July 2013 when Roche Diagnostics acquired Constitution Medical, Inc. (CMI, Westborough, MA).  Constitution Medical has developed the Bloodhound Integrated Hematology Analyzer, a totally digital concept.  The instrument addresses the entire core lab hematology station workflow – slide making; slide staining; complete blood count; differentials; and streamlined, software-assisted manual review of slided, stained and imaged cells.  The Bloodhound System combines a digital image-based cell locator, cell classifier and cell counter with its own slide maker and stainer.  It produces a CBC and 5-part differential and automatically analyzes reticulocytes.  Following processing, a comprehensive set of results are provided to medical technologists through the Bloodhound Viewing Station, an integrated, interactive display that features cell galleries that sort white blood cells, red blood cells and platelets. The system also isolates unclassified cells of interest and presents them for classification.

June 2015, Roche introduced the cobas m 511 integrated hematology analyzer.  Featuring Bloodhound technology, the cobas m 511 combines a digital morphology analyzer, cell counter and classifier into one streamlined instrument preparing, staining and analyzing microscopy blood slides.  The analyzer counts, identifies, isolates and categorizes white blood cells, red blood cells and platelets and presents the digital images of all these cell types on the viewing station including a standard CBC and 5 part differential.

Microbiology Lab Automation

The goal of microbiology and virology testing (further referred to as microbiology) is to detect pathogens in humans and determine a course of antimicrobial and viral treatment that is the most appropriate for the patient.  Microbiology tests are super time sensitive tests—an infection detected and treated early can sometime make a difference between life and death or severe morbidity.

One of the most important aspects of microbiology testing is the regular need for detecting bacterial and viral infections.  Infectious disease testing is always evolving because new pathogen strains develop each year, such as in seasonal influenza, Lyme disease, West Nile, malaria and most recently the novel coronavirus (COVID-19) pandemic.  Additionally, hospital acquired infections, such as Methicillin-resistant Staphylococcus aureus (MRSA), necessitate increased testing.

For most of the 1900s clinical microbiology relied on standard culture techniques, and little automation.  In the last 20-25 years there has been a shift to automated systems in microbiology.  The net result is that microbiology, faced with the added weight of current and emerging pathogens, has had to join the crowd and look for cost effective solutions.  Part of the new toolbox is the automation of routine tests such as sample processing and plating and urine culture that makes up some 80% of the microbiology workload.  With the commercialization of automated urine testing, cytology vial decappers and automated plate streakers, it is not farfetched to one day see microbiology join the track in the core lab.  In fact this type of automation now available the leading microbiology vendors including bioMérieux, Becton Dickinson, Beckman Coulter Thermo Fisher Scientific and Siemens Healthineers are making this possible, should a lab decide to do so.

The backbone of microbiology testing is organism identification and antimicrobial sensitivity testing, known as ID/AST (identification/antibiotic sensitivity test).  Identification systems are utilized to obtain the identification (genus and species) of an organism. These systems contain fluorogenic and chromogenic substrates.  When the organism comes into contact with the substrates, the organism either reacts with the substrate (positive reaction) or there is no reaction (negative reaction).  When the positive and negative reactions are combined, the identification of the organism is determined.

Susceptibility systems are utilized to determine which antimicrobials will be most effective in treating an organism.  The organism is tested against various concentrations of drugs, determining the organism’s resistance (ineffective) or susceptibility (effective) to the antimicrobial.   The complete manual ID/AST test process usually took 1 day for negative specimens and 2-4 days for those that showed bacterial colony growth.

Approximately 60% of microbiology specimens originate from what are expected to be sterile sites – urines, blood cultures and cerebrospinal fluid (CSF) and other biological fluids.  It has been estimated that 80% of urines, 99% of CSFs and 95% of blood cultures test negative, thus consuming a considerable amount of resources – materials and labor.  The answer is expected to be quick universal screens for these specimens that would add up to enormous savings.

Bacteria detected using ID/AST reagents and systems include those originating from blood, wounds, post-surgical dressings and sutures, urogenital, urine, joint and respiratory samples.  The most time sensitive ID/AST work-ups are done on hospitalized patient samples that include screens and workups for hospital acquired infections, urines, wound swabs, aspirates and blood cultures.  Outpatient samples, which make up some 85% of the workload, include respiratory samples for throat and lung infections, urogenital samples for STDs, and urines for urinary tract infections.

Since the mid 1990s ID/AST vendors have responded to the need for quicker test systems, and in fact for many sample types these systems can have a definitive test result in 6 hours versus 1-2 days with non-automated systems.  A differentiating factor among these system is the reagent mix contained in the panels and bioinformatics that provides more specific analysis if bacterial identification to the genus/species level.

Microbiology leader, bioMérieux got the automation ball rolling with the 1990s launch of the Vitek instrumentation combined with the extensive API database of bacterial reagent reactions.  The first version was developed to process urine samples directly without culture.  August 2010, bioMérieux introduced the FDA cleared and CE marked VITEK 2, a compact, bench top completely automated system providing same-day identification and antibiotic susceptibility results.

Following this bioMérieux and microbiology product vendors including: Siemens Healthineers, Trek Diagnostic Systems (now part of Thermo Fisher Scientific) and Becton Dickinson invested in automation to speed up the test process, especially the pre-analytical sample preparation steps.   This has been significantly more difficult than other core lab test segments.  They all use blood tubes of some sort that have been highly standardized.  In microbiology there is a more diversified sample mix that includes swabs, blood, feces, sputum, pus, and urine, all of which arrive at the lab in different types of containers.  Therefore a system that would automate sample processing for ID/AST required a bit more innovation.

The leader in this regard that has absolutely revolutionized ID/AST automation is Copan Diagnostics.  The company had a vested interest in the development of devices and technologies essential for quantitative diagnostics and automated microbiology laboratory workflow. Copan is the leading vendor of sample collection and transport products.  Copan began building the pieces needed for what the company anticipated was the future for microbiology – Liquid Based Microbiology (LBM).  According to Copan LBM opens the door to specimen standardization and streamlined processing, similar to that available in chemistry and hematology.  This being a prerequisite to microbiology joining the core lab and improved test turnaround time.

Copan’s LBM technology can be integrated with compatible robotic planting and streaking instrumentation such as Copan’s Walk-Away Specimen Processor (WASP), or other automated specimen processing platforms, including those for molecular biology applications and bacterial analysis of liquid cytology samples collected for the Pap smear.  Thus bringing more diverse automated multitasking to the core lab.

The critical step was to automate all the pre-analytical steps: open the vial; remove liquid containing microorganism; transfer the liquid to solid and or liquid growth media that is dictated by the type of sample and analysis required; incubate the media; process positive samples for ID/AST analysis.

Copan’s automation strategy began in 2008 when Copan launched the WASP: Walk-Away Specimen Processing system for automatic planting and streaking of all microbiology samples.  Combined with ESwab flocked swabs WASP offered fully automated liquid based microbiology.  WASP automatically de-caps, plants, streaks, and recaps specimens in seconds.  The system interfaces with the institution’s LIS system or acts as a standalone instrument. WASP was designed as an open modular platform that is able to interface with major microbiology ID/AST systems.

After the WASP processes specimens, plates are moved automatically from the WASP using a conveyor system to the WASPLab Incubator.  The WASPLab Incubator scans the plates’ barcodes and automatically inverts each plate.  Unlike traditional incubators that simply store plates in piles or stacks within racks, the WASPLab Incubator has a unique incubator design comprising of a 2 meter tall rotating spindle with removable easy to clean circular stainless steel shelves. Each circular shelf has 14 positions, each individual location intended for one plate.  The incubator has a storage capacity of 770 plates and handles one plate every 10 seconds.

In 2010, Copan introduced a WASP module that includes the ability to automatically inoculate enrichment broths, and the Gram SlidePrep, which automatically prepares Gram slides prior to staining.  Gram SlidePrep prepares a Gram slide after the sample has been inoculated onto culture plates.  It makes a smear, with a customizable amount of sample volume, spreading the specimen within a defined area of the slide. Patient information is then immediately printed onto the slide using an inkjet printer. Slides will then pass along a conveyor belt, where they are gently air dried until they are ready for unloading and fixing with Methanol or processing by the operator.

April 2011, Copan launched WASPLab, a barcode driven and conveyor-connected specimen processing system, which utilizes robotic plate management to automate specimen workflow in Microbiology.  WASPLab can manage various aspects of specimen processing and workup including planting and streaking, Gram slide preparation, enrichment broth inoculation, robotic incubation and storage, plate image analysis, AST/ID inoculum preparation, Kirby-Bauer disk application, and even MALDI-TOF Target Plate Seeding.

In the last step Copan is developing WASPLab image acquisition and analysis that offers the ability to view, workup, and report cultures remotely from anywhere with internet access.

The major microbiology companies have recognized the potential of full microbiology automation and liquid microbiology.  Some have partnered with Copan and others have gone their own route.  In all cases, the net result is faster, more standardized ID/AST testing.

At this time, the major vendors of automated ID/AST instruments and test panels are bioMérieux’s Vitek systems, Siemens Healthineers MicroScan systems, Trek Diagnostic Systems’ Sensititre systems (now part of Thermo Fisher Scientific) and Becton Dickinson Diagnostics’ Phoenix.  These systems have reduced the test time for some specimens to as little as 5-6 hours versus days using non-automated procedures.

Healthcare Diagnostics and Copan have entered into a partnership whereby U.S. laboratories can add Copan’s Walk-Away Specimen Processor (WASP) to the Siemens MicroScan system.

Becton Dickinson completed its microbiology lab product menu with the acquisition of Dynacon’s (Toronto, ON) Lab Systems business, which offers microbiology specimen-processing technologies.  The purchase gave BD Diagnostics two new products, the InocuLab system for processing microbial specimens and the Innova Preanalytical Automated Microbiology Specimen Processor, which is a higher-throughput, automated version of the InocuLab.  BD reported that the Innova System accommodates the “full range of microbiology specimen containers, streak patterns, protocols, and workflows.”  BD Diagnostics later introduced the BD Innova Preanalytical Automated Microbiology Specimen Processor.

The BD Kiestra Total Lab Automation (TLA) system offers standardized and scalable automated solutions for inoculation, incubation, plate imaging, culture reading and result reporting.  The BD Kiestra Work Cell Automation (WCA) system automates specimen processing, plate incubation and digital imaging in a compact footprint for labs of any size.  The Kiestra ReadA Compact intelligent incubation and imaging system.  The system combines automatic dynamic digital imaging and individual plate storage.  It uses a high resolution industrial camera and three different LED light sources, ensuring an optimal image is created for all sample and media types.

bioMérieux introduced FMLA (Full Microbiology Lab Automation) in 2008 with an aim to streamline the workflow of the microbiology laboratory, from sample reception and distribution, organism identification and antimicrobial resistance analysis, to result management and interpretation.  bioMérieux also developed Myla, a middleware solution to improve connectivity, laboratory workflow and information management.  Part of bioMérieux’s FMLA solution, Myla is a browser-based application that consolidates and manages microbiology data generated from a variety of sources and converts these data into actionable information for treatment decisions.

bioMérieux also markets the Previ Isola automated plate streaker that is part of bioMérieux’s Full Microbiology Lab Automation strategy.

Siemens Healthineers expanded its post-analytical workflow functionally with expansion of the MicroScan LabPro Information Management System.  LabPro 4.0 and LabPro Connect give laboratories access to Siemens Healthineers most updated microbiology information management tools.  The system provides management of microbiology test results from order to lab information system transmission using intuitive, customizable features to enable faster workflow and delivery of important test results.  Siemens Healthineers also offers the LabPro Information Manager, a single database and interface connection for multi-user access, this system expands microbiology data analysis and reporting capabilities.

Trek Diagnostic Systems (now part of Thermo Fisher) received FDA clearance for a next generation ID/AST system.  The Vizion System adds digital-imaging capability to the company’s ARIS 2X automated Sensititre System with SWIN (Sensititre for Windows) software.  The system offers on-screen display of large, easy-to-read digital images with quantitative minimum inhibitory concentration and color-coded qualitative results.  Trek also developed the Sensititre AIM Automated Inoculation Delivery System for use with all Sensititre dried plates.  The system doses microtitre plates for antibiotic-susceptibility testing (AST).

Emerging is nucleic acid testing and pathogen analysis with immunoassays, mass spectrometry and whole genome sequencing.  These technologies have decreased test turnaround times from as long as a week to days and in other cases from days to hours.  In addition they provide specific genus/species information for pathogens necessary in epidemiological studies and for therapy decisions.  Immunoassays and molecular tests are gaining importance in microbiology specially for sepsis, urogenital testing for sexually transmissible diseases and human papilloma virus for (cervical cancer) because these organisms are notoriously difficult to culture and for respiratory disease testing on throat swabs and sputa because these are time sensitive tests and can be used in physicians’ decisions for antibiotic use.

On the horizon is mass spectrometry for microbiological analyses that is on its way to make a significant contribution to routine pathogen testing in terms of test speed and accuracy.  Although microbiologic culture is a standard method for detecting pathogens, this technique may take days to weeks.  Specific PCR and serological assays are used to confirm the presence of a pathogen.  Real-time PCR assays offer a rapid, sensitive, and specific method for the detection and differentiation of pathogens.  But these test modalities can only go so far; they do not drill down into the genetics of a pathogen to discover elements of virulence and antibiotic resistance.

Mass spectrometry (mass spec) applications are quite common in immunoassays for therapeutic drug monitoring of organ transplant immune suppression drugs, toxicology screening and confirmation, steroid and thyroid proteins, and vitamin D analyses.

Mass spectrometry is quickly emerging as one of the most significant developments in bacterial detection.  Mass spec uses a molecular approach based on specific proteomic fingerprints from bacterial and fungal strains and published studies have highlighted the greater accuracy offered, as well as the typically much faster time-to-result.  Invasive fungal infections are associated with high morbidity and mortality while prompt diagnosis can result in more optimized therapy reducing both mortality and costs of treatment. Current methods for identification of fungi include biochemical, phenotypic, microscopic and molecular methods.  In addition to microbial identification, mass spec is increasingly being used for functional resistance mechanism detection, mass spectrometry allows for an exact determination of the molecular weight of a broad range of antibiotics.

Microbial identification with mass spec is done using a proteomic fingerprint.  This unique species-specific pattern is automatically compared with proteomic fingerprints of reference spectra. Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF) has made mass spec applicable to bacterial testing.  In MALDI-TOF, microbes are identified by matching the protein profiles of sample organisms generated via the procedure to profiles contained in a proprietary database. Like molecular methods, MALDI-TOF is used on positive blood culture bottles or other cultured bacteria. However, since it does not require an amplification step, it is even more rapid, returning results for each sample in minutes.  Other advantages of MALDI-TOF MS are that it is not necessary to predetermine whether an organism is gram-positive or gram-negative and it has the potential for future susceptibility testing.

Launched in Europe in 2010, leading the mass spec evolution in microbiology is Bruker Biosciences’ (Billerica, MA) MALDI Biotyper that is CE Marked and FDA cleared.  To add power to the system the MALDI Biotyper reference library holds information on more than 2100 species in the MALDI Bioptyper library has broader coverage of microbial species.  Bruker also markets the MALDI Sepsityper kit, a set of consumables that enables a rapid and easy identification workflow after a blood culture bottle has tested positive.

Bruker’s system is barely on the market and there are already moves to automate the process.  Bruker has struck a partnership with KIESTRA Lab Automation (Netherlands and now part of Becton Dickinson).  The companies have signed a research and development agreement to integrate Bruker’s mass spec-based MALDI Biotyper and Kiestra’s MalditofA, an automatic colony picker that allows the automatic transfer of a colony to the target plate and also creates the suspension fluid at. e.g. 0.5 McFarland.  Bruker and KIESTRA Lab Automation have worked with a number of customers applying both technologies in their laboratories.

All the major microbiology companies have joined the mass spec revolution. Microbiology market leader, bioMérieux markets the CE Marked and FDA cleared VITEK MS, ID/AST application on the Shimadzu mass spec system.  Becton Dickinson and Bruker market the BD Bruker MALDI Biotyper System a blood culture system that integrates the MALDI Biotyper with BD’s Phoenix ID/AST system.  The major reference labs and large hospital-based microbiology labs have also launched services using Bruker’s Maldi Biotyper.

The microbiology field is undergoing radical change, with new automation technologies improving the accuracy and response time of test results.  These enhancements enable more appropriate use of antibiotics, overall better individualized patient management, and more efficient epidemiological and public health surveillance.

Automated Molecular Testing

The roots of clinical analyses using molecular methodologies were established in the 1960s but the birth of modern molecular testing is the development of PCR by Dr. Chary B. Mullis while working as a chemist for Cetus Corp. in Emeryville, CA.  In 1991, Cetus sold the PCR intellectual property to F. Hoffmann-La Roche Ltd. for $300 million.  Interestingly, at that time it was generally thought that Roche overpaid.  However, PCR proved to be the major building block of modern molecular testing and is the catalyst for the beginning of modern molecular testing.

At some point thereafter the Roche LightCycler and Amplicore families of PCR-based molecular instrumentation were ubiquitous in molecular test labs.  At this time Roche continues its dominance of the molecular test discipline with a battery of cobas brand fully automated PCR systems that concentrate primarily on infectious disease testing and blood transfusion donor screening.  This table presents a selection of automated molecular test instrumentation.

 Selected Automated Molecular Test Instrument Platforms

Company Location Technology Details
Abbott Diagnostics U.S. PCR Alinity m molecular
Abbott Diagnostics U.S. PCR Plex-ID platform
Abbott Diagnostics U.S. PCR Abbott m2000 RealTime System
Becton Dickinson U.S. SDA BD ProbeTec ET System and Viper
Biocartis Switzerland PCR Fast-Track oncology assays on Idylla
bioMérieux/BioFire U.S. PCR FilmArray Torch platform, random access multiplex PCR
Cepheid U.S. PCR SmartCycler and GeneXpert
DiaSorin Italy PCR LIAISON MDX disc platform
Fast-Track Diagnostics/Siemens Healthineers Luxembourg PCR multiplex PCR kits for infectious diseases, open system
GeneSTAT Molecular Diagnostics U.S. PCR RT-PCR GeneSTAT platform, RNA, DNA
GenMark Diagnostics U.S. PCR ePlex sample-to-answer system, PCR
Genomica Spain platform CLART (Clinical Array Technology) platform
Great Basin Scientific U.S. chip Portrait Analyzer, biochip-based multiplexed molecular tests
Great Basin Scientific U.S. PCR GB550 molecular diagnostic analyzer
Hologic U.S. TMA Aptima reagents on Tigris and Panther instruments
Luminex/Nanosphere U.S. PCR Verigene SP System, automated inf dis testing
Meridian Bioscience U.S. PCR Revogene infectious diseases
Meridian Bioscience U.S. LAMP Alethia (illumigene)
PerkinElmer U.S. platform Applied Biocode’s multiplexed, BioCode MDx 3000 system
Qiagen Netherlands PCR QIAsymphony RGQ MDx system for clinical labs
Quidel U.S. HDA Solana molecular system
Roche Diagnostics U.S. PCR cobas 6800 system
Roche Diagnostics U.S. PCR cobas Liat PCR system, CLIA waived
Siemens Healthineers U.S. PCR VERSANT kPCR Molecular System
Siemens Healthineers U.S. PCR Atellica MDX 160 Molecular System
Thermo Fisher Scientific U.S. PCR Ion Torrent line

Source: Kalorama Information, company reports

The ultimate goal is total hands free molecular automated testing that has been termed sample to result molecular testing.  Qiagen N.V. entered the then fledgling molecular testing market in 1984 and slowly developed to become the leading company in pre-analytical sample preparation in molecular diagnostics.  The company’s QIAsymphony instrumentation set the stage for automated DNA and RNA extraction from blood and other body fluids that later were integrated into just about every modern automated molecular test platform.

Molecular technology is making a valuable contribution to clinical diagnostics on many fronts.  Commercially available kits are used for a variety of conditions including: infectious diseases, primarily hospital acquired infections, tuberculosis, hepatitis, gonorrhea, HIV, and chlamydia; coagulation gene mutations; HLA tissue typing; hereditary and chronic diseases; and a slew of cancers.  In most cases the information provided by these tests will affect the choice of therapy and the aggressiveness of the therapeutic strategy to be taken.

In light of the extraordinary times we are now living as a result of the novel coronavirus (COVID-19) pandemic and other infectious disease epidemics, the remainder of this report will focus on molecular testing for microbiology and virology.  Molecular diagnostic tests directly target infectious agents, such as bacteria and viruses, by utilizing DNA and RNA probes that recognize the genetic signature of the bacterial and viral agents.

The menu of molecular diagnostics has expanded since the 1990’s introduction of PCR tests for tuberculosis, HIV and Chlamydia Trachomatis/Neisseria Gonorrhoeae (CT/NG) by Roche Diagnostics, Gen-Probe (now part of Hologic) and Becton Dickinson.

The first PCR-based instruments performed tests as unique entities.  Now molecular platforms from companies such as Abbott Diagnostics, Luminex, bioMérieux/BioFire’s Film Array, Roche Diagnostics and others can run panels of up to 30 targets, and in less than 1 hour in some cases.  They also are leading the way to random access rather than batch testing, which, while commonplace with immunoassays has been slower coming to microbiology.  This is because traditional microbiology has a history of treating each sample in a unique process.

In 2020, molecular diagnostics tests are widely being adopted for testing infectious diseases (HIV, HCV, HPV, HAI and others), respiratory disease pathogens, and emerging infectious diseases including: chagas, chikungunya, dengue, Ebola, leishmaniasis, leptospirosis, malaria, onchocerciasis, yellow fever, and Zika.

Many of these tests have been released as EUA (Emergency Use Authorization) that make available diagnostic and therapeutic medical devices to diagnose and respond to public health emergencies.  A list of tests that have this designation can be found at https://www.fda.gov/medical-devices/emergency-situations-medical-devices/emergency-use-authorizations.  This page lists current and terminated FDA declared Emergency Use Authorizations including those for the novel coronavirus.

The anticipated demand for molecular infectious disease tests has encouraged the commercialization of molecular instrumentation for microbiology and virology testing.  Thus microbiology companies continue to expand their product menu and upgrade their systems, primarily in the automation of microbiology test procedures for all areas of the test segment.  The result is the development of a variety of new platforms that bypass the traditional ID/AST first step with direct testing from blood, urine, nasal swabs, sputum, etc.  Note that mass spectrometry analysis is performed on a bacterial culture colony.

In an era of rapid automated test results microbiology still has a lot to do.  The imperative for the 21st century is to determine as quickly as possible if a person has an infection, decide to treat or not to treat and then select a method of treatment.  All too often patients have been given antibiotics when not required.  This has contributed to the present problem of bacterial antibiotic resistance.  It can be argued that efficient rapid tests in hospitals, clinics, physician offices and other care sites would have solved many issues related to infectious disease diagnostics.

Yet challenges remain in seeing the new methods developed completely, past regulatory hurdles, and integrated successfully in clinical practice.  Further, The main advantages culture has over newer methods are its comparatively low cost and proven antimicrobial susceptibility testing.

Several trends are evident as the field of molecular infectious diseases evolves:

  • integrated sample to answer test systems respond to the need for easy to use molecular tests for all size labs
  • random access sample processing on instrumentation
  • direct tests from sample without time consuming sample pretreatment for DNA extraction
  • tests for high demand pathogens are coming to market including: C. difficile, TB, respiratory infections, and STDs
  • companies are beginning to develop sequencing systems for a wide variety of targets
  • CLIA moderate molecular test instruments provide smaller labs the opportunity to run molecular tests in-lab without having to send them out

This is but the beginning, the wholesale and routine use of molecular tests is yet to be realized.  Most smaller laboratories are only beginning to establish molecular test departments.  There are almost 100 companies preparing to help them out in this regard. The recent coronavirus pandemic has spurred more and more devices that can provide rapid test results.  At least 40 user-friendly, tabletop and lab-based automated molecular tests have recently been commercialized for this coronavirus under the EUA directive.

IVD Mergers and Acquisitions on the Increase

As companies in in vitro diagnostics seek to reach additional markets, new partners and technologies are needed.  There were more than 60 recent mergers and acquisitions in IVD in the past year, and there have been hundreds in the last five years.  These are covered in detail in our report, IVD Mergers and Acquisitions 

Roche
Roche remains the world’s largest biotech company, with truly differentiated medicines in oncology, immunology, infectious diseases, ophthalmology and diseases of the central nervous system. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner in diabetes management. One of the ways Roche drives business growth is through mergers & acquisitions (M&A), so the company seems perpetually active in this area. Roche’s recent acquisitions include the following:
• In June 2018, it was announced that Roche would be buying complete control in Foundation Medicine for $2.4 billion; Roche had already owned a majority stake in the company, valued at $5.3 billion. Roche appears to be interested primarily in the company’s genomic data, as this is the second data-related acquisition Roche has made in 2018, having picked up Flatiron Health. The merger will seek to accelerate broad availability of comprehensive genomic (CGP) profiling in oncology, with the companies leveraging expertise in genomics and molecular information to enhance the development of personalized medicines and care for patients with cancer. Foundation will continue to operate independently, as part of the deal.
• Roche in April 2018, for $1.9 billion, completed the acquisition of Flatiron Health – a maker of oncology-focused electronic health records – to help accelerate industry-wide development and delivery of breakthrough medicines for patients with cancer. The addition of Flatiron, a healthcare technology and services company whose offerings are designed to support cancer care providers and life science companies, expands Roche’s presence in personalized medicine and oncology. Roche, reinforcing its capabilities in information technology, is partnering with Flatiron Health for the development of oncology-focused electronic health records. Flatiron Health will continue its operations as a separate legal entity.

• Roche completed in February 2018 the acquisition of biotech Ignyta for $1.7 billion, giving Roche rights to a drug, entrectinib, currently in testing for cancers that contain specific types of genetic mutations — NTRK or ROS1 fusions. Ignyta develops potentially life-saving, precisely targeted therapeutics (Rx) guided by diagnostic (Dx) tests to patients with cancer.
• Roche acquired Viewics, Inc. in November 2017, allowing Roche to expand its leading position in the integrated core laboratory with business analytics capabilities. The Viewics solution allows for efficient integration of Big Data from a variety of IT systems in the laboratory and beyond, pioneering a new way in extracting, cleansing, transforming, and augmenting data. This cloud-based solution is secure, infrastructure-agnostic, interactive, and accessible from multiple devices (e.g., smart phones, tablets, desktop computers).

Abbott’s Molecular Diagnostics Business Post-Acquisition of Alere

The acquisition of Alere was finally completed in October 2017 after the deal went through many ups and downs since the initial announcement was made in February 2016. After the $5.3 billion acquisition, Alere became a subsidiary of Abbott. In 2017 Alere generated revenues of approximately $2.3 billion of which the divested cardiovascular and toxicology product sales were approximately $1,200 million. Therefore Abbott inherited potential Alere revenues of approximately $1,100 million and reported Alere revenue of $540 million in Q4 2017.

 Selected Acquisitions of Diagnostic Companies – More Mergers and Acquisitions available in our report IVD Mergers and Acquisitions:

July -19 Exact Sciences Genome Health Gain access to oncology sales force
July-19 Invitae Singular Bio cfDNA prenatal testing
Jun-19 Eurofins Transplant Genomics Inc. Eurofins expands its transplantation testing footprint
Jun-19 Invitae Singular Bio For $55M; acquires Singular Bio’s single-molecule, cell-free DNA analysis technology, enables lower cost NIPS testing
Jun-19 Meridian Bioscience GenePOC GenePOC purchase completed with an eye towards a syndromic testing strategy
Jun-19 Thermo Fisher HighChem HighChem is a provider of mass spectrometry software
Jun-19 Beckman Coulter Life Sciences Cytobank Cytobank, a single cell data analysis, SaaS company
May-19 Bio-Rad Undisclosed company Disclosed during an earnings call that it had acquired an undisclosed company that will expand its genomic reagents product portfolio
May-19 Caris Life Sciences Pharmatech The goal: to redefine how pharma and biotech companies identify and rapidly enroll patients in precision oncology trials
May-19 Ginkgo Bioworks Warp Drive Bio’s bioinformatics platform To advance efforts against drug-resistant bacterial infections
May-19 Thermo Fisher Brammer Bio For $1.7 billion, completed acquisition of Brammer Bio, involved in viral vector manufacturing for gene and cell therapies
May-19 QIAGEN U.K.-based organizations Launched APIS Assay Technologies Ltd., a company that aims to improve the success rate of biomarker commercialization
Apr-19 PerkinElmer Cisbio Bioassays Cisbio develops and manufactures kits and reagents for life sciences and diagnostics
Apr-19 Charles River Labs Citoxlab Completes acquisition of preclinical services firm Citoxlab for $510 million
Apr-19 CareDx OTTR Complete Transplant Management For $16M; CareDx to integrate the EMRs of patients at transplant centers with longitudinal patient surveillance data
Apr-19 Canopy Biosciences Zellkraftwerk To use Zellkraftwerk’s microfluidic cell-capture technology to further develop drug-development research and biomarker discovery
Apr-19 Caprion Biosciences Serametrix Corporation Immune monitoring and biomarker services to biopharma
Apr-19 Prescient Medicine AutoGenomics To further development and commercialization of the Infiniti Neural Response Panel to identify patients who may be at risk for opioid use disorder
Apr-19 Caprion Biosciences Serametrix Caprion expands its biomarker and immune monitoring franchise
Apr-19 Yourgene Health Elucigene Diagnostics Mol Dx group Yourgene Health’s first commercialized CE-IVD products are non-invasive prenatal screening solutions for Down’s Syndrome and other genetic disorders
Apr-19 Co-Diagnostics Inc. Synbiotics Pvt Ltd Launch CoSara Diagnostics Pvt Ltd JV
Mar-19 Guardant Bellwether Bio To further advance Guardant’s early detection cancer Dx product pipeline
Mar-19 Precision for Medicine SimplicityBio Adds AI to Precision’s QuartzBio multiomic data integration and informatics platform
Mar-19 Grifols Shanghai RAAS Grifols acquired $1.9B Stake in Shanghai RAAS; to become Grifols’ exclusive distributor of plasma-derived products and transfusion diagnostic solutions in China
Mar-19 Bruker Arxspan Cloud software firm to better provide software tools for customers
Mar-19 Summa Equity Olink Proteomics Olink Proteomics has developed a unique technology for human biomarker discovery
Mar-19 Guardant Health Bellwether Bio To advance Guardant’s LUNAR early cancer detection and monitoring assays
Mar-19 Discovery Life Sciences HudsonAlpha’s Genomic Services Lab The new HudsonAlpha Discovery division will provide a range of services to the pharma, biotech, and diagnostics industries
Feb-19 Danaher Corp. GE Biopharma For $21.4 billion; GE Biopharma, part of GE Life Sciences, supports research, development and manufacturing of biopharmaceutical drugs
Feb-19 bioMérieux Invisible Sentinel Invisible Sentinel, a US-based company specialized in food and beverage molecular testing
Feb-19 ICON plc MolecularMD Expands ICON’s capabilities in MDx and also adds expanded testing platforms, including NGS and immunohistochemistry
Jan-19 QIAGEN N-of-One, Inc. N-of-One is a pioneer in molecular oncology decision support services
Jan-19 Eli Lilly Loxo Oncology $8 billion purchase broadens Lilly’s oncology portfolio into precision medicines
Jan-19 Luminex MilliporeSigma’s flow cytometry unit Luminex completed $75M purchase to expands its offering of flow-based detection systems
Jan-19 Beckman Coulter Life Sciences Labcyte Labcyte acquired to expand laboratory automation business
Jan-19 PHC Holdings Anatomical Pathology business from Thermo Fisher Scientific Part of Thermo Fisher’s Specialty Diagnostics Segment
Jan-19 ArcherDx Baby Genes ArcherDx expands further into assay development
Jan-19 OraSure Technologies CoreBiome CoreBiome (St. Paul, MN) is an early-stage microbiome services provider
Jan-19 OraSure Technologies Novosanis Novosanis (Antwerp, Belgium), urine sample collection devices targeted primarily at liquid biopsy, STI screening, urological cancer
Dec-18 10x Genomics Spatial Transcriptomics Spatial Transcriptomics is a pioneer in the emerging field of spatial genomics
Nov-18 Illumina Pacific Biosciences Acquired for $1.2 billion; expected to close mid-2019, to broaden Illumina’s access to long-read sequencing
Nov-18 bioMérieux Suzhou Hybiome Biomedical Engineering Suzhou Hybiome, an automated immunoassay manufacturer based in China
Nov-18 Agilent ACEA Biosciences For $250 million; ACEA has developed two platforms that are complementary to Agilent’s current portfolio
Nov-18 LGC SeraCare LGC strengthens its position in clinical quality control tools
Nov-18 Illumina Ventures Stilla Technologies Led a €16 million ($18 million) series A round for Stilla, a Paris-based developer of digital PCR solutions for genetic analysis
Nov-18 Quest Diagnostics Oxford Immunotec U.S. Lab Services Business Includes Oxford’s T-SPOT.TB tuberculosis and Accutix tick-borne disease testing services
Oct-18 Bruker Corporation 80% majority interest in Hain Lifescience Completed the acquisition of MDx infectious disease specialist Hain
Oct-18 NeoGenomics Genoptix For $140M; Genoptix is a clinical oncology laboratory, specializing in hematology and solid tumor testing
Oct-18 Luminex Merck’s flow cytometry business For $75 million; gives Luminex access to an adjacent flow-based technology
Oct-18 Precision for Medicine ApoCell Adds ApoCell’s ApoStream liquid biopsy technology
Oct-18 Grifols 25% share in Mecwins Capital EUR 2 million in Mecwins’ capital increase through Progenika Biopharma; allows Grifols to take positions in the diagnostic nanotechnology field