The IVD industry is infused with innovation, and the pace of discovery and development during the past 15 years has indeed been staggering. During this time period, genetic sequencing has been perfected and applied to the human genome, opening up numerous diagnostic and therapeutic opportunities. Significant advances in microfluidics and nanotechnology have enabled research lab discoveries to develop into clinical patient applications, both in the hospital and the physician’s office. Special IVD needs surfacing in emerging markets are driving new technology initiatives.1 And regulatory bodies around the world have pushed ahead to streamline and update their approval processes.2 This article will examine a small selection of examples in the context of market forces driving the IVD industry and its supporting instrumentation during this time period.

A Focus on Diseases
A brief look at the trends in a number of health areas will help to highlight the environment in which IVD instruments have been developed during the past 15 years. The following are examples from the sectors in which major investments in research, diagnosis, and prevention are being made, and in which new or resurgent diseases are driving trends and the direction of IVD development.

Tuberculosis. Tuberculosis infects one third of the world’s population, and 10% of all infections become active at some point.3 The recent escalation in drug-resistant tuberculosis strains has made managing this disease epidemic more complex and reliant on accurate IVD testing. The trend is to move away from culturing to a molecular diagnostic approach that delivers faster and more sensitive results. This theme is reproduced in many other areas in which the rapid development of molecular diagnostic techniques are yielding significant benefits.

Acute Lower Respiratory Infections. Acute lower respiratory infections, including various types of pneumonia and bronchitis, kill more people in the United States each year than any other infection.4 Those patients most at risk from acute lower respiratory infections are the elderly and young people, particularly in the developing world. The challenge therefore is to bring rapid diagnostics to large populations in remote locations and harsh environments with little or no healthcare infrastructure.

Malaria. Each year, more than 300 million new cases of malaria develop worldwide. Resurgent drug resistance is making malaria more complex and expensive to treat. Sensitivity is a diagnostic challenge in malaria because of its cyclical nature. Molecular diagnostic methods are becoming available and are helping to target strain-
specific therapies.5

HIV. Because the development of detectable levels of possible markers can take two weeks to six months from the point of infection, test sensitivity continues to be a major issue driving development of HIV diagnostics.6 Because of the public health threat that HIV poses and the controversial nature of the disease, the management of HIV test data and results is a critical element in the IVD solution.

Avian Flu. The H5N1 virus has evolved into a highly pathogenic strain during the last ten years and is now a significant global pandemic threat.7 Successful early identification of outbreaks continues to be essential to containing this potential threat. This factor is driving the development of molecular diagnostics for this area since there is much more interest in this strain of flu, which has also caused significant growth in the flu virus RNA analysis area.

Cardiac. Cardiovascular disease is the leading cause of death in industrialized countries. Coronary artery disease predisposes patients to thrombus formation, potentially leading to myocardial infarction and stroke. Recent clinical data support the role of a specific enzyme activity (sPLA2) in determining the risk of these adverse cardiovascular events. Cardiac troponin assays that detect heart muscle injury have greatly improved sensitivity. Two assays, T (cTnT) and I (cTnI), are the newest additions to the list of cardiac markers.8

Autoimmune Diseases. With autoimmune diseases, the immune system mistakenly attacks its own organs, leading to many common debilitating disorders, including the following: type-1 diabetes, graves disease, inflammatory bowel disease, lupus, and multiple sclerosis. More than eighty illnesses are caused by autoimmunity.

Cancer. In its various forms, cancer accounted for 7.4 million deaths (around 13% of all deaths) in 2004. There is now evidence from research that many types of cancers (i.e., lung, breast, ovarian, and colon cancers) may be detected via a blood test that looks for reduced immune responses in patients. While such a test for lung cancer is currently being released commercially across the United States, the challenge will be to identify other specific antigens that are related to other types of cancer.

HPV. Associated with HPV, cervical cancer is globally the third most common cancer and is the leading cause of death from cancer among women in developing countries. Approximately 500,000 new cases are diagnosed each year. HPV diagnostics is booming.

As more is learned about the diseases themselves, the biomarkers that enable their detection, and the therapies that depend on accurate identification of the disease states, opportunities are being created in the IVD industry. At the same time, the tasks in terms of humanitarian needs are both immense and complex. If significant gains in public healthcare are to be realized, there is an urgent and on-going need for ever-increasing cost effectiveness, and test specificity and sensitivity from the assays and instrumentation that enable their detection.

Regulatory Affairs
FDA. During the past 15 years, FDA has made significant efforts to improve its responsiveness to IVD product submissions and approvals. For example, the FDA Modernization Act of 1997 exempted many low-risk Class 1 devices and a significant number of Class 2 devices from the 510(k) application process.

In addition, FDA is now encouraging electronic submissions of all 510(k) applications and is providing freeware to facilitate the compilation of applications, which is aimed at speeding up their subsequent processing. In the near future, electronic submissions may become mandatory, changing the application process significantly.2

In response to increasing hazards and threats in the area of homeland security, the U.S. Congress passed the Project BioShield Act of 2004, which allows FDA to grant Emergency Use Authorization (EUA) in order to strengthen public health protection.18 In a recent example of the use of this authority, FDA issued in April 2009 EUAs for IVDs and antiviral agents aimed at managing the H1N1 2009 swine flu epidemic, which first emerged in Mexico and spread around the world in 3 weeks.

Evaluating the success of these efforts at streamlining the regulatory process via exemptions, abbreviated and special 510(k), and e-submissions is an ongoing discussion. However, such initiatives signal FDA’s intent to maintain a responsive regulatory environment that is actively involved in speeding up the introduction of new IVD technologies to the market.

European IVD Directive. The European Union’s In Vitro Diagnostic Directive 98/79/EC was released on December 7, 1998, and a seven-year transition period allowed for suppliers to come to full compliance. This regulation ushered in a substantial change in the European IVD market by breaking down the need to gain approvals in multiple sovereign states and releasing IVD manufacturers from the need to satisfy esoteric regulatory demands to access small markets.9

While regulations continue to grow stronger and the attempts to unify the means of securing patient safety and efficacy continue, regulatory bodies are breaking down barriers to markets and streamlining paths to approval. As a result, the IVD industry has seen, and should continue to see, a more rapid introduction of new technologies and innovations.

Economic Factors
Even though the global financial crisis has significantly affected the IVD industry, the latest estimate of the size of the global IVD market in terms of revenues is still around $40 billion in 2009, sufficient to support numerous companies of substantial size.10 The passage of President Obama’s healthcare reform bill in the United States will increase the demand for IVD services in the United States and put even more pressure on managing high-volume testing at lower costs.11

Throughout the developed world, the pool of skilled laboratory technicians is declining. In a self-fulfilling cycle, test environments have become more automated, and well-developed instruments are being operated by technicians with lower skill levels.

In the developed world with established infrastructure, the focus for IVD instrumentation is driving down the cost per test in central labs. Such focus is supported by multiplexed testing and decentralized instrumentation, which allows the justification of more expensive capital investments (see Figure 1).12 But in emerging markets with little or no infrastructure, the need for overall cost reduction makes large capital investments unattractive and not feasible. Coupled with the need to test in difficult environments with unregulated power supplies, poor water quality, extremes in temperature and humidity, and rough transport conditions, the emerging markets require IVD equipment with specialized capabilities.

Figure 1. Bio-Rad’s fully automated, random-access multiplex system for disease-oriented multi-marker assays includes internal quality control and eFlex software.

The IVD markets in Brazil, Russia, India, and China (BRIC) are expected to grow from $2.9 billion in 2009 to $7.5 billion in 2014, a growth rate of 20%.13 In comparison, the growth rate of the global IVD market is much flatter at 6% during the same period. China will continue to account for more than 50% of the IVD market among the BRIC nations.
The ability to gain market share in the emerging markets is fraught with many logistical and competitive barriers. However, organizations such as the Foundation for Innovative New Diagnostics (FIND) and the World Health Organization (WHO) are facilitating an orderly introduction of appropriate IVD technologies to these markets.

IVD Industry Responses
Whether the IVD industry is driven by the decreasing availability of skilled laboratorians in the developed world or the lack of laboratory infrastructure in emerging markets, there is a strong drive in the industry toward simplified detection technologies, a higher level of foolproof operation, and a focus on cheap microfluidics.

During the past 15 years, the IVD industry has responded to the increasing global need for improved diagnostics. During this time, the industry has moved from clinical chemistry and hematology (which are still useful in assessing organ performance and blood disorders) to immunoassays (for detecting viral and autoimmune diseases and even cancer) to molecular diagnostics in order to provide the high specificity required for accurate pathogen identification and treatment countermeasures.

The following eight significant trends have emerged during the past few years:

Decentralization continues even though point-of-care (POC) and physician office laboratory (POL) tests are still significantly more expensive than central lab tests on a per-test basis. Shortening the time from sample to result can improve treatment options and lower the overall cost of healthcare by reducing repeat consultations and the use of capital-intensive infrastructure to transport and track samples, and return the results to physicians and therapy managers.

Microbiology is on the crest of the molecular diagnostics wave, with many tests moving from research-only status to clinical application. With the need to identify drug resistance becoming more important (e.g., hospital-acquired infections), molecular assays hold the key to rapid and accurate diagnosis, cost-effective patient management, and informed management of evolving epidemic diseases. The current challenge is to reduce test turnaround time and make the tests more durable and rugged for application in the field in developing nations.

In emerging markets, there is demand for reduced overall test costs, rapid results, and simplified operations in which the ideal IVD process from whole blood sample to result requires no operator intervention.

Microfluidics has made significant progress, allowing complex lab-on-a-chip functions to be reproduced at low enough costs to make a disposable lab card test economically viable, which in turn should drive further decentralization. An example of this forthcoming technology is shown in Figure 2.

Figure 2. The PanNAT system for point-of-care nucleic acid assay-based detection of infectious disease by Micronics Inc.). This sample-to-result PCR platform incorporates all reagents in assay-specific cartridges actuated by a low-cost, battery- or mains-operable, Wi-Fi-enabled reader.

New fluidic drivers (e.g., those employing electrostatics or electro-wetting) obviate the need for pumps and valves, and appear to offer many advantages for lab card-based POL and POC applications.

Detection Technologies. While optical detection technologies have become customary (ranging from absorbance to various means of fluorometry to chemiluminescence), they inevitably become more expensive as sensitivity increases. Alternative detection technologies such as impedance measurement and electromagnetic detection of binding events using magnetic beads are emerging, which appear to offer much promise at reduced costs.

Mass spectrometry is poised to make its clinical lab entry in microbiology applications, where it is aimed at reducing turnaround times on tests that currently require cultured cells or immunoassays. In May 2009, Bruker Daltonics obtained a CE mark for its MALDI Biotyper Workflow for microbial identification of a broad range of microorganisms. The Biotyper is at the beginning of its product lifecycle as a clinically applicable IVD.

Progress in Data Management. The development of middleware and improvements in a lab instrumentation’s ability to integrate with laboratory information systems (LIS) during the last ten years has resulted in major advances in productivity and improvements in turnaround time, both in reduced time-to-result and the variability of that time.14 When the need arises to track important samples, (e.g., STAT orders), middleware will alert the lab that an urgent specimen is coming and send a message when the results are ready. LIS and middleware applications can autovalidate 85-95% of tests made in hospital central labs.15

Basic delta checking exists in every LIS and is a valuable tool to compare a patient’s current test results with historical records. Middleware enhances this utility by implementing rule-based decisions, such as the following: evaluating the age of previous test results to determine clinical significance; developing different delta criteria so that, for example, end-stage renal patients are not evaluated the same way as outpatients; and providing the last several results immediately to the medical technologist for rapid assessment.

Productivity and Safety Through Automation. As labs replace older instruments with new-generation instrumentation, they are using middleware to implement real-time repeat, rerun, and add-on testing procedures. In many new-generation instruments, an LIS can send additional testing instructions for a sample while it is being processed. Lab technologists would previously have to locate the sample and place it back on the instrument for additional testing, which consumes valuable time.

The awkwardness, repetitiveness, stress, and tedium inherent in traditional pipetting are all harbingers of repetitive strain injuries, a major source of pain and lost productivity among numerous pipette users. Similarly, automation is now being applied in the microbiology laboratory to automate agar plate streaking (see Figure 3). Automation has effectively eliminated many of these occurrences.

Figure 3. bioMerieux’s PREVI Isola is a system for automating routine agar plate inoculation. It maximizes colony isolation, eliminates risks, and standardizes plate inoculation and results in a fully automated approach.

Not only the samples but also many of the reagents needed in IVDs present technicians with significant biohazards. The trend toward automated processing in closed systems protects lab workers from having to directly handle or manipulate biohazardous procedures.

Conclusion
The IVD industry faces challenges from growing public health issues in the developed world (e.g., diabetes and flu epidemics) and from epidemics in developing nations (e.g., tuberculosis, HIV, the re-emergence of drug-resistant malaria). Technologies are available to address such challenges, coming from advances in information technology, microfluidics, molecular diagnostics, nanotechnology, and most recently proteomics-based mass spectrometry. The opportunities lie in matching progress in the development of biomarkers of disease with technologies and identifiable improvements in therapeutic outcomes.

With regulatory bodies increasingly aware of the need for swift and flexible responses and for developing procedures and information technology infrastructure to speed up product approvals, the landscape ahead for IVD manufacturers continues to present significant challenges and correspondingly large opportunities. As ever, the way forward is there for those IVD companies that are best able to match IVD solutions to market needs.

References
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2. MA Hanna, “The Evolution of the 510(k) Submission: Part 2,” IVD Technology 15, no. 6 (2009): 18-23.

3. “Tuberculosis Factsheet,” the World Health Organization Website (Geneva, Switzerland, March 2010 [cited 29 June 2010]); available from Internet: www.who.int/mediacentre/factsheets/fs104/en/
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5. M Petra, et al., “Detection and Identification of Human Plasmodium Species with Real-Time Quantitative Nucleic Acid Sequence-Based Amplification,” Malaria Journal 2006, 5:80; available from Internet: www.malariajournal.com/content/5/1/80

6. “HIV Test Factsheet,” Lab Tests Online Website (Washington, DC, 18 June 2010 [cited 29 June 2010]); available from Internet: www.labtestsonline.org/understanding/analytes/hiv_antibody/test.html

7. A Gambotto, et al., “Human Infection with Highly Pathogenic H5N1 Influenza Virus,” The Lancet 371, no. 9622 (2008): 1464-1475.

8. M Heron, “Deaths: Leading Causes for 2006,” National Vital Statistics Reports 58, no. 14 (2010); available from Internet: www.cdc.gov/nchs/data/nvsr/nvsr58/nvsr58_14.pdf

9. P Kaars-Wiele, “Examining the Effects of the IVD Directive,” IVD Technology 11, no. 6 (2005): 30-35.

10. K Weinert and H Poola, “Global IVD Market and Industry Outlook,” presentation at AACC International Market Briefing, Chicago, IL, 2009.

11. L Litvan, J Rowley, and K Jensen, “House Passes Landmark Legislation Overhauling U.S. Health Care,” Business Week, March 21, 2010; available from Internet: www.businessweek.com/news/2010-03-21/house-passes-landmark-legislation-o...

12. T Raichle, “In-Vitro Diagnostik: Heute und in der Zukunft,” Programleiter dezentrale diagnostik, Roche Instrumentation, Hombrechtikon, 19 January 2009.

13. “In Vitro Diagnostics (IVD) Market in BRIC (2010-2014),” available from Internet:  topmedicaldevice.wordpress.com/2010/04/09/in-vitro-diagnostics-ivd-market-in-bric-2010-2014/

14. R Berman, “Maximizing the Benefits of Lab Automation Systems with Advanced Middleware,” IVD Technology 12, no. 6 (2006): 57-65.

15. H Bagwell, “Middleware: Providing Value Beyond Autoverification,” IVD Technology 14, no. 6 (2008): 35-41.

Warren Hancock is a director at Invetech, with a focus on business development in biomedical instrumentation. He can be reached at wjh@invetech.com.au.