Medical Device Link.

COMMENTARY

Tiffany Olson is president and chief executive officer of Roche Diagnostics Corp. (Indianapolis). She can be reached at tiffany.olson@roche.com.

An article published two years ago (IVD Technology, September 2004) discussed several trends in the healthcare industry as a whole, and their influence on the evolution and growth of molecular diagnostics. Those trends are still relevant today.

In the infectious diseases area, the SARS scare has been supplanted by the threat of an avian flu pandemic. Consumer-directed healthcare through direct-to-consumer marketing has exploded, especially in the pharmaceutical industry. While consumer marketing for diagnostic testing has increased somewhat, specifically in women's health, the margins in diagnostics do not allow the same level of investment in advertising.

The population continues to age, with the first wave of baby boomers turning 60 this year. That milestone is affecting another trend: labor shortages. According to a study by the Lewin Group (Falls Church, VA), there will be a 60–69% decline in specialized clinical laboratory personnel through 2012.¹ Many workers with decades of experience will be retiring, and the number of trained staff needed to replace them is not available.

That has fueled another prominent trend from 2004: the increased need for automation. During the past two years, many IVD companies have introduced smarter, more-intuitive platforms that depend less on highly skilled medical technicians and more on technology. There is also a growing awareness of the need for knowledge-based software that can transform laboratory data into actionable information that directly affects patient management. However, even with the new automated systems, the need for faster, more-accurate, and more-intelligent instruments is going to escalate. While some progress has been made in addressing the issue of reimbursement, much more work still needs to be done in this area.

Although the underutilization of diagnostic testing was already a concern in 2004, it has now become a significant and more confounding trend. As healthcare costs continue to skyrocket, hospitals consistently demonstrate that diagnostic testing saves money. Nonetheless, IVD tests are still overwhelmingly underused. As cited in the Lewin report, studies have found a 30–50% reduction in direct hospital and outpatient charges by accurately monitoring and detecting changes in a patient's health status. According to a study conducted by the Rand Corp. (Los Angeles), diagnostic tests recommended as standards of care are underused 51% of the time. In addition, the National Committee for Quality Assurance reported that low compliance with diagnostics-based quality measures for diabetes, cardiovascular disease, colorectal cancer, and breast cancer was linked to 34,000 avoidable deaths and $899 million in avoidable healthcare costs.¹

It is clear the trends that were being monitored in 2004 remain, and not only are still relevant, but are even stronger and more influential today. It should also be no surprise that molecular diagnostics, which responded to the trends more positively than any other area in the IVD industry, is now the fastest-growing field in diagnostics.

Breakthroughs in Molecular Diagnostics

Since the mapping of the human genome was completed more than five years ago, innovative technologies and tests have emerged, based on a better understanding of the role that genes play in disease and therapy. Based on nucleic acid testing technologies, molecular diagnostics has been uniquely positioned to take advantage of that knowledge. From generating negligible revenues seven years ago, molecular diagnostics has become a $1.8 billion industry today. Its predicted growth rate during the next five years is estimated at 15–20%, reaching $4 billion by 2010.

Such growth is largely due to the exponential increase in genetic and infectious-disease testing. In 2000, FDA reported that a total of 301 genetic tests were offered in the United States, and 158 labs conducted such clinical tests. By May 2006, 598 laboratories were using genetic testing for 1230 diseases, a substantial increase. According to annual reports from the largest reference laboratories, genetic testing is their strongest growth area. One of the most striking examples of this increase in genetic testing is cystic fibrosis. A few years ago, the American College of Obstetrics and Gynecology recommended that couples in the childbearing years should be genotyped for the mutations associated with this disease. Subsequently, there has been a large increase in the demand for this molecular test.

Recent highlights in the field of molecular diagnostics include the first microarray for clinical diagnostics use, innovative uses for nucleic acid testing technologies, and new frontiers in the field of genetic testing such as pharmacogenomics and proteomics. All of these developments are beginning to contribute to advancements in personalized medicine, in which therapies are tailored to a patient's individual genetic makeup. Such advances also enable doctors to monitor the effects of treatment on the molecular properties of a disease.²

Personalized Medicine

The definition of personalized medicine has changed considerably. Initially, personalized medicine was limited to using genotyping to predict an individual patient's response to a particular drug. Now, the definition is expanding to include any test that guides, modifies, or customizes treatment of a specific disease in a patient. Under this broader definition, the new generation of molecular diagnostic testing that expands an understanding of individual disease susceptibility or predisposition can also be considered personalized medicine. For example, a genetic test for BRCA-1 and -2 mutations can indicate an increased risk for developing breast or ovarian cancer. With this knowledge, physicians and patients can take preventive actions to mitigate that risk.

Molecular testing is also giving insights into how to treat diseases better. For example, FDA recently cleared the 510(k) application for Roche Diagnostics' AmpliChip CYP450 test, the first pharmacogenomic diagnostics product. This test identifies mutations in two genes and identifies whether a patient is a fast, normal, or slow metabolizer of drugs metabolized by the CYP2d6 and CYP2c19 gene products, which make up about one-fourth of all currently prescribed drugs. This information can aid physicians in determining safe and effective dosages, and can help them to avoid the traditional trial and error approach, which can be costly, time-consuming, and risky.

The HER-2/neu test identifies those breast cancer patients (approximately 25% of all such patients) who express extra copies of the HER-2 gene. For this group of patients, the targeted cancer therapy drug Herceptin can be a highly effective treatment, and should also be considered an example of personalized medicine.

Other cancers such as leukemia are currently being explored in large-scale, international studies to investigate gene expression patterns and how they correlate with disease classification and treatment responses. Microarray-based testing is also being used to study the clinical implications of p53 gene mutations in a variety of cancers such as bladder cancer and breast cancer. Because p53 gene mutations are found in most tumor types, such tests may one day help doctors choose the anticancer therapies that are best suited to their patients' needs. Finally, there is considerable evidence that microarray-based analyses of gene expression patterns can play an important role in subclassifying breast cancers and certain non-Hodgkin's lymphomas into aggressive and less-aggressive subtypes that require different types of treatment. The hope is that a better classification of human cancers can be developed, which is based on molecular signatures that will accurately guide subsequent treatment.

Proteomics

Proteomics is a relatively new branch of medical science, and another valuable tool that may produce new clinical diagnostic tests. By studying specific proteins, physicians can get a more detailed picture of a patient's bodily functions and malfunctions at the molecular level. While the genotype of an individual remains fixed, the phenotype and protein expression patterns are highly variable, and are influenced by environmental and genetic factors. For example, certain drugs and chemicals can induce changes in the protein levels of liver cells, even though the genotype remains unchanged. In addition, genotype does not always correspond to phenotype because of a variety of genetic factors such as allelic heterogeneity, locus heterogeneity, variable expressivity, and the influence of sex chromosomes on the effects of testosterone and estrogen. Assuming that disease is an altered flow of information with proteins as the carriers of that information, then analyzing the type and quantity of proteins present should indicate the disease process itself in a manner that is independent of the genotype.

Proteomics allows scientists to study the full complement of proteins expressed by a cell during a particular growth phase and under specific environmental conditions. These conditions can include the effects of certain drugs. The interplay between genes, environment, and proteins is where drugs exert their impact and where researchers are looking to create targeted therapies. Many IVD companies are now looking into proteomics programs to identify novel biomarkers in such indication areas as colorectal cancer, breast cancer, Alzheimer's disease, and rheumatoid arthritis. Some promising initial results using proteomics have been reported in the early detection of colorectal and ovarian cancer.

Overcoming Hurdles

Significant technical obstacles must be overcome before proteomics and pharmacogenomics can make the transition from the laboratory bench to the clinical laboratory and patient bedside. Furthermore, regardless of whether it's molecular diagnostics or the IVD industry as a whole, there are many other hurdles that must also be overcome. Otherwise, the industry risks stalling its own growth.

For example, the disturbing trend of underutilizing diagnostics testing was mentioned earlier. The IVD industry can mitigate this trend and overcome this hurdle if it educates the public and private sectors on the value of diagnostics and, when necessary, demonstrates the clinical utility of its products and services. The industry can do this by providing solid evidence that diagnostics improve medical decision making while also fostering huge healthcare savings.

To leverage the power of diagnostics fully, the IVD industry also needs to take a serious look at reimbursement reforms. The Medicare Clinical Laboratory Fee Schedule (CLFS), which contains the payment rates for all lab tests, has not been updated for inflation in 13 of the past 15 years. As a result, each dollar paid under the CLFS is equivalent to only 75 cents in 1984 dollars.¹

While there have been some improvements to the system, because reimbursement has not kept pace with inflation, this hurdle has the potential to jeopardize future development of innovative tests. Both IVD manufacturers and laboratories will need financial incentives for them to continue investing their resources in research, development, and production.

Conclusion

The growth and expansion of molecular technologies and automation will continue to improve patient outcomes while helping to rein in skyrocketing healthcare costs. With the breakthroughs in molecular diagnostics and advances in laboratory equipment, this piece of the diagnostics pie is going to play an increasingly large role in early diagnosis, monitoring, and targeted pharmaceutical intervention.

The value of diagnostics needs to be further understood outside of the IVD industry and better understood by payers. It is particularly critical for the industry to demonstrate the clinical utility and impact of IVDs on health economics so that payers will be motivated to reimburse at the value the test provides to doctors and patients versus the cost assigned by an outdated system. The future of diagnostics depends on it.

It is fascinating to imagine what innovations and developments might be discussed two years from now. Whatever they are, they will no doubt be as exciting as what is being seen today.