Clinical diagnostics is changing dramatically. A revolution in bioinformatics has allowed scientists to mine the human genome to derive new and hopefully better biomarkers for some of the most pressing health problems, such as cancer, cardiac disease, diabetes, and autoimmune disorders. This development has contributed to growth in nucleic acid tests.

The next 5-10 years will see an intensification of the healthcare industry’s emphasis on informatics, wireless communications, data networking, and cost-effective healthcare delivery that has been in progress since the 1990s. This article will discuss the past fifteen years in IVD development and the advancements that will empower IVD tests and devices to maintain their central role in disease management.

IVD Upswing
The IVD industry is on an upswing. For the past 15 years, the number of assays introduced has been growing at a remarkable rate. Until the 1970s, the majority of lab tests were performed manually with the aid of test tubes and a spectrophotometer or microscope. In the 1980s, the development of enzyme immunoassays and automation led to a significant increase in the number of tests that could be performed in hospital labs.

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. Such tests are used to analyze biopsied tissue, measure nucleic acids in blood, sputum, urine, cervical fluid, and other samples, and diagnose infectious diseases, thereby creating a rapid expansion of the IVD industry. Such tests provide physicians with information that can be readily applied to therapy selection and patient outcome, particularly in cancer diagnosis and disease management, diabetes, and infectious diseases.

The new battery of tests have also erroded the market position of the core IVD segments in a matter of 15 years (see Table I). In 1995, the core IVD test segments (i.e., chemistry, hematology, coagulaton, and immunoassays) accounted for 70% of IVD market sales. But in 2010, their share will have decreased to 41%.

This decline has not escaped the attention of the major IVD companies, and during the past few years, they have ventured into relatively new areas. In 2001, Abbott Laboratories added Vysis’ FISH-based genetic tests for cancer, prenatal disorders, and other diseases to its product line. Roche Diagnostics’ acquisition of Ventana Medical brought the company into histopathology, and Becton Dickinson’s purchase of TriPath Imaging had the same result. bioMérieux acquired AviaraDx’s cancer diagnostics. Danaher Corp. has established a foothold in microscopy and digital imaging with the acquisition of Leica, Vision Systems, and Genetix.

Molecular Diagnostics
Molecular methodologies such as nucleic acid amplification (in particular PCR) and in situ hybridization (ISH) are the major drivers of the test expansion. Their contribution is extraordinary in terms of the number of tests and test services commercialized and in explosive products sales. A handfull of IVD companies earned global combined molecular product revenues of $2.6 billion in 2008 and $3 billion in 2009. This increase is a compound annual growth rate (CAGR) of 17%, compared to 6% for the IVD industry as a whole. Table II shows the molecular test sales of selected companies.

But this growth is only the beginning, since the wholesale and routine use of molecular tests is yet to be realized. Most smaller laboratories are only starting to establish molecular pathology departments. Almost 100 IVD companies offer reagents, test kits, and instrumentation for the many aspects of molecular testing. Numerous user-friendly molecular diagnostic technologies are being prepared to make a mark in the IVD market.

Molecular diagnostic technologies are making a valuable contribution to clinical diagnostics on many fronts. Commercially available test kits are used for various conditions including the following: infectious diseases (primarily hospital acquired infections, tuberculosis, hepatitis, gonorrhea, HIV, and chlamydia), coagulation gene mutations, HLA tissue typing, hereditary hemochromotosis, and a number of cancers. Furthermore, genetic techniques are used in laboratory service organizations in the diagnosis and monitoring of cancer, inherited diseases, diabetes, and many other diseases. In most cases, the information provided by such tests will affect the choice of therapy and the aggressiveness of the therapeutic strategy taken.

Emergence of LDTs
Molecular and histopathology analyses are also at the root of another major development in IVDs: tests developed in-house by commercial reference laboratories. The reference lab or contract research organization business has always been robust so this development is not a new business model. However, during the past few years, the trend for homebrew or laboratory-developed tests (LDT) has re-emerged. In the 1980s, Corning, Roche Diagnostics, and Beckman Coulter owned reference labs, which were the predecessors of present day LabCorp and Quest Diagnostics. LDTs are becoming a major route for highly sophisticated and specialized tests. The most successful LDTs involve anatomical pathology (histology/cytology) and molecular assays, primarily ISH and PCR analysis of biopsied tissue.

The LDT business model is primarily a phenomenon in the United States, and there is a long history for commercializing highly specific assays as LDTs. Many groundbreaking tests in the areas of viral load testing, special anatomical pathology analyses, and molecular assays were first launched by reference labs in the United States. This sensitized the medical community to the value of LDTs. The first generation of these tests targeted small markets where the financial investment for FDA market approval, especially the PMA route that would have been required for these unique tests, would have been difficult to recouperate with a commercial test kit. In fact, FDA opened the door to a proliferation of LDTs. Many LDTs are performed with FDA-cleared analyte specific reagents (ASRs) and ASR-like products.

The first LDTs made their appearance in the mid 1990s. Myriad Genetics, Athena Laboratories, and Nymox Pharmaceuticals were among the first companies to offer their patented and proprietary assays as LDTs. Of these, two LDTs caused a stir and continue to do so today. Myriad’s BRCA test for inherited risk for breast cancer and Athena’s ApoE test for Alzheimer’s disease risk are not widely available in laboratories. Many healthcare professionals and organizations considered this unethical because the proprietary position taken by Myriad and Athena prevented widespread access to what were considered important tests. Furthermore, both companies pursued labs that infringed on their patent positions and threatened them with litigation. Myriad’s patent position is still a target of vigorous litigation.

Nonetheless, many payer groups have begun to pay as much as $3500 for a test that is available from a single source. Genomic Health’s Oncotype DX test for breast cancer recurrence risk is conducted only in the company’s CLIA-registered laboratory. LDTs are now one of the fastest growing segments in the IVD market, far outpacing any other in the IVD industry. Table III illustrates the revenue growth of a selection of LDTs. Seven companies earned global revenues of $867 million in 2008 and $1.1 billion in 2009. This growth is a CAGR of 32%, compared to 17% for the major molecular diagnostics companies and 6% for the IVD industry as a whole.

The LDT phenomenon has also been adopted by several life sciences companies looking to enter the IVD market. Affymetrix’s CLIA-certified Affymetrix Clinical Services Laboratory offers microarray-based molecular diagnostic testing services. Illumina is combining its molecular probe technology with easy-to-use bead arrays to be commercialized as IVD tests. These tests will be offered by Illumina’s CLIA- certified laboratory, which was certified in 2009. Some companies such as Agendia, Aureon Laboratories, Monogram Biosciences, Pathwork Diagnostics, Vermillion, and XDx have sought FDA market clearance and/or EU CE mark for their proprietary tests.

Wireless Emedicine
Wireless communication technologies are now almost a necessity in healthcare facilities, and wireless networks are cheaper to install than laying cable throughout a hospital or a hospital network. This development could generate exciting growth opportunities for point-of-care testing devices that have wireless communication capabilities.
The greatest developments of wireless applications have so far been in the area of home management of diabetes. An integrated, wireless-enabled, blood glucose testing system automatically sends test results to caregivers and adds the results to patients’ electronic medical records. Every major vendor of glucose self-testing devices and almost all new entrants to the market offer a meter equipped with wireless data transmissions by Bluetooth or some other tool. Some IVD companies have also developed diabetes management applications that are used by diabetics and healthcare professionals.

AgaMatrix Inc., the maker of the WaveSense line of blood glucose monitoring products, announced that the latest version of its WaveSense Diabetes Manager App provides users with streaming video content provided by dLife.
Johnson & Johnson offers the LifeScan iPhone app, which diabetics can use to upload and manage their personal health information, including glucose levels. The LifeScan application can calculate sugar intake during meals, which helps users adjust their diet for achieving the best glucose levels. The application can even estimate, based on the diet entered into the device, how much insulin is needed after each meal. The application also provides a graph showing glucose level trends and lists each previous reading by users.

Bayer has developed the Didget glucometer, which connects to Nintendo game systems to encourage children with diabetes to monitor their blood sugar levels. The Didget is a glucose meter modeled on Bayer’s Contour meter. A diabetic is rewarded points for consistent glucose readings, and the meter transfers those points to a Nintendo system to unlock games or access new levels. The Didget also provides access to an online community of other diabetic Didget users, building on the addictive nature of video games to promote a community of supportive peers.

Roche Diabetes Care has partnered with MYLEstone Health, the developer of the Glucose Buddy. The Glucose Buddy iPhone application and Website include Accu-Chek Testing in Pairs, an easy-to-use tool that shows the before-and-after effects of meals, activities, and other specific events on blood glucose levels. The tool is designed for use when patients want to focus on one thing in their daily eating habits or routine.

For medical professionals, anatomical pathology wireless communications help to provide needed specialty consultations to rural and underserved areas. Pathologists can now provide a diagnosis without accessing a computer, microscope, or the original specimen. Moreover, they can do so from the comfort of their own homes or any other location that has cell phone reception.

For example, the Institute for Medical Informatics (Oslo, Norway) introduced Interpath for the iPhone, an application for reviewing and navigating high-quality images of pathology slides on a multimedia cell phone. Interpath uses a microscope slide scanner and Web server.

Health Discovery Corp. is developing a melanoma/skin cancer mobile phone application, which will enable people to take a picture of a mole, lesion, or birthmark on their bodies using their mobile phones, send the image to Health Discovery, and immediately receive on their phones a risk assessment for melanoma and other skin cancers.

Bringing Together IVDs and In Vivo Diagnostics
As disparate as they may seem at this time, the future of in vivo and in vitro diagnostics is linked to similar technologies: information technology, molecular and protein markers, and imaging technology. The benefit of combining of these two diagnostic methods is becoming most evident in cancer detection, prognosis, and therapy monitoring. In fact, in vivo testing has been the mainstay of solid tumor diagnosis and monitoring for decades.

The joining of in vitro and in vivo technologies is expected to make a significant contribution to the advancement of personalized medicine, in which diseases are detected at earlier stages and specific treatments are tailored to patients. The first stages of a synergy between in vivo and in vitro diagnostics have already begun. For example, the two areas have been amalgamated at the U.S. Veterans Administration Atlanta Healthcare Network since 1997.
More radiologists and pathologists are working side-by-side to review each other’s primary images and issue a single, integrated diagnostic report for cancer patients. In vivo molecular imaging has the potential to revolutionize how disease is diagnosed, treated, and monitored. The possibility of this happening has been fueled by the recent interest in clinical IVDs by the major imaging companies, such as Siemens, General Electric, and Philips.

The lead company in this regard is Siemens Healthcare, which acquired Bayer Diagnostics, Diagnostic Products Corporation, and Dade Behring. Siemens’ rationale for the future success of combining in vivo and in vitro diagnostics lies in the fact that antibodies and probes created for IVD testing can also be linked to imaging agents to make specific tumors visible throughout the body. More recently, Siemens Healthcare and National Jewish Health formed a strategic alliance to improve and develop novel imaging and diagnostic technologies using genomics, proteomics, and integrated research and clinical care.

At the heart of joining together in vivo and in vitro diagnostic is the development of imaging agents that can highlight the cellular targets being imaged. The technology has been gaining ground in diagnosis and risk assesment, especially for neurological diseases such as Alzheimer’s and Parkinson’s. The new frontier is using in vivo imaging to follow drug efficacy. For example, researchers at Harvard Medical School and Massachusetts General Hospital (Boston) have discovered a biomarker used with an MRI to scan the brains of patients with recurrent malignant brain tumors after they took the experimental drug cediranib. The researchers reported that they were able to identify, even after a single dose, those patients who best responded to the treatment.

Direct-to-Consumer IVDs
A number of direct-to-consumer (DTC) genomic services offer genetic tests that they claim can detect a risk for diseases such as cancer, diabetes, and cardiovascular disease before any symptoms are apparent. The goal is to give individuals information they can then use to make lifestyle changes and avoid getting sick.

DTC genetic test services caused quite a furor when they first came on the market. Supporters declared a new age of consumer power. But opponents feared that the test results would lead consumers to embark on unapproved and perhaps dangerous medical therapies. Such tests have been developed for nearly 1,300 diseases and conditions, including baldness, allergies, food sensitivity, diet management, and the standard paternity and disease risk tests.

Although some companies may be of questionable reputation, there are also genetic test services backed by well-known firms including deCode Genetics, 23andMe, DNA Direct, Knome, Navigenics, and LabCorp. But to date, these services have had little success. For example, 23andMe began offering its services directly to consumers in the United States in December 2007, and the average price was $999. However, in September 2008, the company announced a reduction in price for its Personal Genome Service to $399.

Consumer reticence to such genetic test services is supported by the results of Burrill & Company’s Personalized Medicine and Wellness Survey. The survey found that consumers are wary of these products, the benefits they offer, and the personal risks users may encounter. The survey found that doctors are still the most important source of information for consumers on genetic testing. While people are concerned about genetic-based diseases, they are reluctant to use genetic tests that could provide early warning about devastating illnesses. About 35% of those surveyed said that they would not undergo genetic testing because of privacy concerns (14%), because they would not want to know the results (5%), or both (16%).

Marketers of DTC test services could have taken a page from the experiences of OTC diagnostic tests. Self testing is the final frontier in lab medicine, but the OTC market has stalled. The most widely used patient self-tests are for glucose, pregnancy, and ovulation. The global market for OTC tests (excluding glucose monitoring) is estimated to be approximately $500 million, and pregnancy tests account for 79% of that market.

IVD manufacturers anticipated overwhelming consumer acceptance of home tests for drugs-of-abuse, fecal occult blood, STDs, cholesterol, HIV, coagulation/PT and H. pylori. But these tests have had minimal appeal. The need for a blood sample has limited the use of most self tests. The primary dilemma for self testing is what does it all mean. More often than not, consumers are attracted to the notion of doing tests in the privacy of their homes, but once the test is done, they are not sure how to interpret the results.

Conclusion
These are exciting times for IVDs. In expectation that current trends will continue for the next 5-10 years, a number of automated, user-friendly molecular systems will bring mainstream molecular tests into the core lab. This eventuality is driven partly by technological advancements in microfluidics and isothermal amplification techniques, and partly by economics. Labs around the world are cutting their budgets, and there are not enough trained technicians to run molecular tests in their present configuration.

The new age of in vivo diagnosis and patient monitoring is bound to take more space in personalized medicine. This trend makes sense since in vivo imaging is relatively noninvasive and provides a view of the whole body or tissue and organ of interest, versus a small sample that is supposed to represent what is happening in a disease process. This is not to discount the value of IVDs, but a partnership between in vivo and in vitro diagnostics will become the norm in the years to come.

Overall, diagnostics is hot. The new pharmaceutical model tailors therapies to a patient’s particular disease physiology often determined by the results of an IVD test. So more tests (molecular and immunoassays) will come to market; some will have a high cost, and some will not. But price will not be the deciding factor. Test adoption in this scenario is based on performance data, contribution to patient outcome, and cost/benefit analysis.

Shara Rosen owns and operates StratCom (Montreal), which provides market information and consultation services to IVD and medical biotechnology companies. She can be reached at stratcom@total.net.