Medical Device Link.

Editor's Page

Building a diagnostics market: One molecule at a time

Eileen G. Gorman

Eileen G. Gorman, PhD, is CEO of DNA Bridges Inc. (Wilmington, DE), a management consulting firm focused on growth options for therapeutics and IVDs. She can be reached via the firm's Web site at http://www.dnabridges.com and at Eileen@DNABridges.com.

New technologies that are being developed as tools for genomics research and drug discovery have the potential to alter significantly the field of clinical diagnostic testing by making possible advances in the realm of molecular diagnostics. Despite this potential, however, many of the companies focused on developing such molecular tools and techniques have chosen to pursue other markets and business models. As a result, many of the latest molecular technologies are finding application primarily in nonclinical arenas where there are fewer regulatory requirements and where access to investment capital is easier.

A number of factors have contributed to the gradual draining of interest in advancing the field of molecular diagnostics. Lack of early participation by major IVD companies, for instance, created a field that was wide open for small, entrepreneurial biotechnology research companies—but without significant funding. In turn, when those companies whose original business plan was to identify genetic disease markers discovered that they could realize higher revenues by licensing their technologies for other applications, many chose to follow the money. Together, these factors have helped to create an ever-changing landscape of corporate participants in the field of molecular diagnostics.

Data from an experiment showing the expression levels of thousands of genes on a single GeneChip probe array by Affymetrix (Santa Clara, CA). The data are shown at two different magnification levels.

Growth Opportunities?

Although more than 200 major companies are involved in the $20 billion global market for clinical diagnostics, only seven have sales of over $1 billion, creating an environment that is still ripe for consolidation and partnering. Of the top seven companies, only Beckman Coulter (Fullerton, CA) and Dade Behring (Deerfield, IL) are not part of a larger corporate structure that includes a pharmaceutical division.

For IVD companies, the greatest growth potential lies in the fields of molecular diagnostics, microbiology, and virology (see Table I).^1–3 Infectious-disease testing, where fully automated systems have been developed, utilizes some of the same technologies used in molecular diagnostics. Other opportunities are presented through the discovery of new genetic markers, which are often developed initially as tools for life sciences researchers but find their first clinical use in the form of molecular diagnostics.

Table I. Projections for growth in selected categories of IVDs through 2003. Total size of 2003 market is projected to reach $24 billion.

The ability of companies to take advantage of such growth opportunities in clinical diagnostics has been limited by a decade of healthcare cost-containment efforts. In recent years, payers have cast a skeptical eye on the costs of diagnostic testing, and the resulting focus on cost per test result has had a significant influence over which IVD technologies have gained clinical and marketplace acceptance. The resulting price pressure on IVD companies has limited their ability to conduct research and development in areas of new technology.

In addition, this price pressure has reduced the profit margins and growth rates of traditional diagnostic companies, limiting most segments of the industry to single-digit growth. There are few segments of the IVD industry, as it is currently structured, with opportunities for double-digit growth. By contrast, products related to the fields of biotechnology and drug discovery have experienced aggressive investment and growth.

Biotech Breakthroughs. As might be expected, the Human Genome Project has had an enormous impact on the development of molecular technologies for clinical diagnostic applications. However, the vast majority of analytical methodologies and technologies that were utilized for the genome project were developed outside the influence of clinical laboratories.

One result of this fact is that few companies have devoted their efforts toward developing technologies for use in clinical testing for patient management. Instead, exploration of new technology applications has emphasized further life sciences research or drug-discovery applications. The development of microarrays and high-throughput screening technologies offer examples of this trend.

For companies accustomed to the research settings of the genome project, avoidance of the clinical diagnostic marketplace has the benefit of translating into earlier revenues than might otherwise be possible. The high costs of validating a disease marker for FDA approval and the lengthy lag time between the introduction of a new marker and its widespread adoption by the clinical community are often key factors in discouraging companies from entering the IVD marketplace.

By applying and validating their technologies in custom research settings, where they are free from regulatory requirements and associated product-introduction delays and expenses, companies can turn their technological advances into profit-making products much more quickly. At present, for example, the majority of microarray-based testing is taking place not in clinical laboratories, but in research settings.

The development of instruments for the biotechnology research market has traditionally been seen as a market entirely unto itself. However, it seems inevitable that such new technologies will eventually be introduced into clinical laboratories, perhaps in versions that have evolved to embody complete automation, including sample handling and random access. For this reason, current projections of revenues for biotechnology instrumentation may shed light on future growth areas for the clinical laboratory (see Table II).⁴ Many such DNA-chip or microarray-based instruments are already in use—in research settings—for DNA sequencing, genotyping, phenotyping, and testing for genetic predisposition to certain diseases. The North American market for such instruments accounts for approximately 45% of global sales in this marketplace.

Table II. North American revenues for biotechnology instrumentation, compared with global revenue.

The Pharmaceutical Temptation. The profit margins of companies in the pharmaceutical industry are generally far greater than those of companies with an exclusive focus on the development of diagnostic testing applications. While diagnostics companies are able to attain only single-digit growth, profit margins for pharmaceutical companies can reach over 30% on a pretax basis. This disparity in profit margins—and the corresponding allocation of financial resources to pharmaceutical research instead of diagnostic research—has contributed to the inability of companies to form strong interrelated diagnostic and pharmaceutical business units. This is true even for business units under the same corporate umbrella.

One exception to this is the development of antiretroviral drugs for HIV and the use of viral-load testing. Successful viral-load testing businesses have been developed independent of relationships with pharmaceutical companies. For example, Gen-Probe (San Diego) is developing a significant and growing business as a manufacturer of test kits and instrumentation for viral-load testing.

LabChips by Agilent Technologies (Palo Alto, CA) are typical of advanced technologies that many companies are using to target the drug-discovery market rather than the market for clinical diagnostics.

The Impact on Diagnostic Advances. Using investment resources dedicated to life sciences research and drug-discovery advances, new companies are continuing to develop new molecular technologies. However, few of these technologies are being targeted at the diagnostic industry. As a result, capitalizing on the introduction of new technologies into the field of clinical diagnostics will likely require IVD companies to acquire technology from others, or to pursue a strategy based on in-licensing, strategic alliances, or corporate acquisitions.

The success of such new technologies in the life sciences and drug-discovery arenas could make them expensive for the diagnostic industry. There is a precedent for this in two notable historical cases. Polymerase chain reaction (PCR) technology was not originally developed for diagnostics. When Roche Diagnostics (Indianapolis) gained access to this technology, however, it quickly developed a strong licensing strategy. High pricing enabled Roche to gain value for its technology and to develop a business based on its Amplicor platform. A similar example is provided by the licensing of reagents required to perform HIV-2 testing. The Pasteur Institute (Paris) was the first to develop this critical technology, and was able to demand high royalties for its use.

If the nonclinical developers of molecular technologies demand such high pricing for access to their new technologies, the effects on the development of clinical applications could prove far ranging. In an environment of limited access to technology, the field would be wide open to new competitors entering and dominating specialty fields, forcing both new and established companies to develop innovative business models that will enable them to compete.

On the other hand, when combined with the experience of IVD firms—especially in the field of infectious-disease testing—the growth already experienced in biotechnology instrumentation could point the way to the future growth areas for molecular diagnostics. For example, the identification of new molecular markers, combined with the application of complete automation to laboratory segments that are lacking it today, may offer the growth spark needed to advance the field.

The Convergence of Technical Disciplines

Automated molecular tests, such as the PathVision assay by Vysis (Downers Grove, IL), suggest that greater automation is likely for molecular testing labs.

Technologies such as miniaturization, microfluidic systems, image enhancement, robotics, and automation are all playing a role in the development of instruments suitable for molecular testing applications. Some such platforms are already being aggressively marketed to life sciences researchers with specialties in the fields of agriculture and pharmaceuticals, and could be adapted for clinical testing applications in the near future.

Advances in other fields may also be exploited by the developers of such molecular testing platforms. For example, compound libraries are generally made using either a solution- or solid-phase format. Although solution-phase systems have advantages such as easier handling, the stability of such compounds can be an issue. Synthesis on a solid phase could overcome this shortcoming. As a result, useful new methods for monitoring a reaction on a solid support—something that immunochemists have addressed over the past two decades—could find widespread use in the new diagnostic formats.

Similarly, strategies that have been developed to improve the operation of immunoassays (e.g., signal enhancement, smaller reaction volumes, homogeneous reactions, and automation) are now also being applied to the detection of genetic materials and proteins. For example, Applied Biosystems (Foster City, CA), now part of Applera Corp. (Norwalk, CT), has developed a strategy for the use of seven colors in a homogeneous detection of six different PCR products.⁵

A GeneChip array by Affymetrix (Santa Clara, CA) with over 400,000 unique features.

A number of such companies have adopted business plans that make them a hybrid of sorts. No longer focused enough to be considered traditional diagnostic or pharmaceutical companies, they have instead become "tool" companies, offering tools and know-how to others who are involved in research and development for molecular applications. To date, all of the products offered by such tool companies have been intended only for research purposes, but it is probably only a matter of time before some of their products begin to be adopted in systems specifically designed for clinical use.

Just as academic collaboration was an important factor in the early development of immunoassay technology, collaboration with the prestigious National Institutes of Health is playing a major role in the business strategies of companies that are developing molecular technologies. Investigators expect that at least some of the tests developed for molecular and genetic research applications as a result of such collaborations will eventually become routine clinical tests.

Automation in New Areas

Some segments of the IVD marketplace are experiencing growth through the application of total laboratory automation, creating niche opportunities for manufacturers. Inevitably, such automated technologies will also find their way into molecular diagnostics, thereby freeing laboratorians from the tedium of manual sample preparation and reducing the risk of sample contamination that can invalidate test results. However, such widespread automation of molecular diagnostics remains some distance in the future.

The HercepTest by Dako (Carpinteria, CA), one of several companies that have commercialized test kits for detection of HER-2.

Where innovative uses of automation technology are applied to the new settings of molecular diagnostics, they can create new markets. One example of such a combination is the blending of fluorescence in situ hybridization (FISH) and automated image analysis, which is making it possible for clinicians to conduct genetic analyses as a component of routine prenatal screening. To make this diagnostic application a reality, Vysis (Downers Grove, IL) combined its proprietary FISH DNA-probe technology with the QuipsUIPS genetic workstation, a modular automated processing system that incorporates SmartCapture software acquired under exclusive license from Digital Scientific Ltd. (Cambridge, UK).

Even with a promising new market under development, however, molecular technology companies must continue to explore every option for company growth. Vysis chose to grow by licensing distribution of its products to a major IVD player, Abbott Laboratories (Abbott Park, IL). In April, Vysis signed an agreement under which Abbott obtained exclusive North American and European distribution rights for two of Vysis's DNA-based cancer tests: the PathVysion assay, which is used to detect and quantify the HER-2 gene in breast cancer patients; and the Uro Vysion assay, which detects genetic changes in bladder cancer cells found in urine. In addition, the agreement gives Abbott an option for exclusive distribution rights for both assays in South America and the Asia/ Pacific region (except Japan).

PathVysion, which received FDA marketing clearance in 1998, and UroVysion, which is pending FDA clearance, are both based on Vysis's FISH technology, which can be used to detect an increased number of genes or chromosomes in human cells.⁶ Work to detect fetal cells in maternal blood—which would enable easy, in utero detection of such genetic diseases as cystic fibrosis—is an active area of research.⁷

With a little help from Abbott, Vysis's two automated molecular tests are poised both to create and exploit a market in genetic screening. They suggest that greater automation is likely to come for molecular laboratory segments that lack it today.

Tailored Patient Management

Many researchers in the field of molecular diagnostics envision a future in which patient management includes the use of therapies tailored according to the genetic profile of the individual. While such tailored patient management remains a future wish and vision, however, development of the diagnostic and therapeutic tools that would make it a reality is not advancing as quickly as originally projected.

The Diagnostic Edge. For IVD researchers, the complexity of the task is enormous. Candidate technologies for this application include emerging microarray and microfluidic devices that are highly complex from both the engineering and chemical perspectives, and each aspect contributes to the overall complexity of a given analytical technology.⁸ Attaining information processing at the level necessary to interpret large amounts of genetic-screening data, for instance, requires instrumentation of greater sophistication than previous generations of diagnostic instruments—and usually in a format that operates invisibly to the user.

Alternatively, the analysis may employ highly sophisticated reagents that can be processed and interpreted without the use of an instrument. This possibility remains an active area of research. Achievement of large-scale functional analysis using peptide or protein arrays has been reported.⁹

It may eventually be possible to test for an array of gene expression, and perhaps to relate the results of such testing to disease prognosis. Such a diagnostic technology would create a direct link between genomics and patient management that would undoubtedly stimulate significant research in the field. In the meantime, however, most applications of the pertinent technologies are occurring only in R&D settings.

The Pharmaceutical Product Stream. Although pharmaceutical companies are increasingly interested in exploring tailored patient management as a part of their drug-discovery processes, the pharmaceutical product stream that will result from this capability remains a long way in the future. The delay is attributable, at least in part, to the long development cycles typically required for therapeutics.

Eventually, it is expected that the technologies now under development will result in both genomic-based diagnostics and tailored patient management. When this occurs, patient population stratification will speed the development of new drugs customized for specific cohorts rather than for general populations. In turn, it will become more common to use diagnostic tools to confirm that a given patient is a good candidate to receive a particular therapy, and to optimize the patient's dosage and therapy schedule.

While researchers in the field have long shared this broad vision of the future of medicine, recognition that it may take a long time to accomplish is just beginning to set in. To date, only one excellent example stands out. Such an integrated patient management approach is in use for treatment of metastatic breast cancer patients with Herceptin (Trastuzumab), a humanized monoclonal developed by Genentech (South San Francisco, CA) to treat patients diagnosed with overexpression of the oncogene HER-2/neu.¹⁰ Herceptin generated $275 million in sales revenue for Genentech in 2000. Here, appropriate diagnostics to guide therapy are critical for successful treatment.

Multiple histochemical technologies have been developed to determine the overexpression of HER-2/neu. One approach detects gene amplification, quantitatively measuring multiple copies of the gene. Another qualitatively measures protein overexpression, measuring the extra copies of the protein that the gene expresses. In addition, an immunoassay has been developed for use on the Immuno-1 analyzer by Bayer Diagnostics (Tarrytown, NY).¹¹

Genentech recognized that a diagnostic would be needed for clinical trials and later for patient management, and therefore entered into a number of partnerships to commercialize automated systems for detection of HER-2. Ventana Medical Systems (Tucson, AZ) markets the Inform test for HER-2. Vysis has obtained FDA approval of its PathVysion HER-2 DNA probe kit for detecting HER-2 gene amplification. And the HercepTest by DAKO (Carpinteria, CA) detects protein overexpression.

A recent report details the use of Herceptin as a first-line, single-agent treatment for metastatic breast cancer.¹² Meanwhile, researchers are exploring the use of HER-2/neu as a marker for other cancers.^13,14 And clinical trials are under way to evaluate the use of Herceptin for other breast cancer indications.

Any expansion in the diagnostic utility of the HER-2 gene or of the therapeutic applications of Herceptin would also extend the use of this integrated patient-management approach. So far, however, the model is not being widely practiced with any other combination of diagnostics and therapeutics.

New applications of the model may be on the way. In an emerging example, clinical researchers have reported on the use of gene-expression profiling to identify distinct types of diffuse large B-cell lymphomas—a technique that could prove useful in guiding therapy.¹⁵ Such an approach could help tailor the best available therapeutic intervention for specific patients and assist in monitoring them for early signs of relapse.

High-Content Screening. Among the key tools being used to forward discovery of the diagnostic markers and therapeutic agents that will make tailored patient management a reality are microarrays and biochips capable of screening genetic components rapidly and in vast quantities. Such tools for high-throughput screening have generated significant interest—and investment—over the past few years.

Today, however, high-throughput screening is evolving into high-content screening, a field devoted to developing technologies that can provide even more useful information for the same amount of effort. High-content screening is focused on determining the effect of genetic variations on target cellular constituents over time. Early entries in the field include Biolog (Hayward, CA), a company that has produced phenotype microarrays (PMs) arranged to analyze cell phenotypes. The company's current PM was developed for use with microbial cells. The system enables investigators to evaluate many cell functions and could potentially be applied to testing specific cell types for genetic differences resulting from exposure to drugs or other chemicals. Data on toxicity and efficacy can all be measured and correlated.

Commercializing a high-density biochip technology is the goal of a five-year partnership among Clinical Micro Sensors (Pasadena, CA), a business unit of Motorola's life sciences division; Packard Instruments, a wholly owned subsidiary of Packard Bioscience; and the U. S. government's Argonne National Laboratory (Oak Ridge, TN). The partnership has resulted in an automated system with initial applications in life sciences discovery. Motorola is looking for partners to develop clinical applications for the new technology and is marketing the system to reference laboratories.

The use of fewer tests to gather ever-greater amounts of information seems likely to be a major theme in the future of clinical laboratory testing. However, investigators are just now beginning to recognize the challenges they will face in unraveling the massive amounts of data that can be generated by such high-content screening systems. In addition to causing changes in the laboratory, the availability of such information will also bring about changes in clinical practice.

Ethical Considerations. As more researchers develop proprietary genetic technologies and seek to gain exclusive value from them, their approach has come under fierce attack from academic centers and laboratories. Some argue that the granting of gene patents to individual companies or laboratories places unethical constraints on the practice of clinical laboratory medicine.¹⁶ Debate continues between those supporting proprietary development, which could result in limiting the number of sites at which specific types of testing can be conducted, and those in favor of unrestricted testing that can be carried out in many clinical laboratories.

Meanwhile, in January 2001, the United States Patent and Trademark Office issued final rules regarding gene patenting. These new guidelines for examination of biotechnology patents are not substantially different from recent practice. Within those rules, industry and academic institutions will need to find ways to develop licensing agreements that fit both business and patient-management needs.

Evolving Business Models

Fortunately for companies that have been involved in the early development of the field of molecular diagnostics, use of the pertinent technologies usually does not require exclusivity. Companies have therefore begun to develop new business models that allow them to continue with their research into clinical testing applications while taking on new projects in drug research and development. Some such hybrid companies offer testing services to provide information that could be useful for clinical management, while also seeking to take advantage of the richer financial resources available in the field of drug discovery.

In some cases, companies that were originally focused on discovering molecular diagnostic markers for the clinical laboratory market have changed their product-development priorities, forming new divisions to focus on the more lucrative drug-discovery market. High-profile examples of this trend include diaDexus (Santa Clara, CA) and Myriad Genetics (Salt Lake City), both early entrants in the field of diagnostic-marker discovery. Both companies still make testing for new markers available, either directly or through strategic partnerships. However, the processing of genes for discovery of drug targets is becoming a more important part of their business. Ventana Medical Systems has also recently developed a division focused on marketing to pharmaceutical researchers.

Genetic testing continues to evolve as the fastest-growing segment of the IVD market. Myriad Genetics, the Genetics and IVF Institute (Fairfax, VA), and Genzyme Diagnostics (Cambridge, MA) have established successful genetic testing service laboratories. For example, Myriad Genetics has launched the Cardia Risk profiling service for evaluating genetic predisposition to cardiovascular disease, which represents a new approach to individualized cardiovascular risk assessment and management. The goal is to use Cardia Risk to individualize therapy by analyzing genetic factors that influence each patient's physiology and responsiveness to various interventions. CardiaRisk tests for the T235 variant of the angiotensinogen (AGT) gene, which has been associated with an increased risk of coronary heart disease and certain forms of hypertension. With growth occurring in molecular genetic testing, laboratories are expanding to offer services.

Myriad also provides BRACAnalysis testing through various partnerships with laboratories. In June, the company announced a partnership with Bioscientia (Ingelheim, Germany), an esoteric testing provider in Europe. With partnerships such as this, Myriad has worked to establish itself as a source of information for predictive medicine. However, the value of such predictive testing will be limited until therapeutic interventions become available to physicians and patients.

The Consumer Angle. Consumers may exercise a decisive influence over the acceptance of new technologies. Much has been written about the impact of the aging baby-boom generation. The change in U.S. demographics is frequently discussed in the popular press. This generation represents an aging, sophisticated market with a focus on personal wellness and health. Its interest in and demand for advanced diagnostic information and medical care are driving forces in the healthcare marketplace.

Coverage in the popular press can result in consumer demand for products, services, and information. For example, Cytyc (Boxborough, MA) developed a strong launch agenda for its new product, the ThinPrep Pap test. The company invested heavily in demonstrating to FDA that its product represented an advance over traditional Pap smear testing, and also submitted cost analyses to the Health Care Financing Administration (now the Centers for Medicare and Medicaid Services; Bethesda, MD) to show that the product could reduce overall healthcare costs. The company then conducted a direct-to-consumer marketing campaign, using advertising in women's magazines, which resulted in many women asking for this improvement in their annual Pap testing. As a result of this combined regulatory, reimbursement, and advertising strategy, initial sales of the ThinPrep Pap test soared.¹⁷ Using this strategy, Cytyc has built a company that earned $142 million in revenues in 2000.¹⁸

The Cytyc example suggests that direct-to-consumer marketing can result in more patients asking for specific diagnostic and treatment regimens as part of their healthcare. Inevitably, such demand will result in greater debate over the appropriate application of diagnostics and therapeutics. In turn, such debate could have a profound effect on the marketability of certain technologies.

Conclusion

For IVD manufacturers and investors alike, the traditional segments of the IVD marketplace offer low growth rates. As a result, companies are seeking to take advantage of growth opportunities by combining technical disciplines, developing innovative automation for new parts of the laboratory, pursuing research into the technologies necessary to achieve tailored patient management, and seeking out new business models.

Concurrent with changes in the tools used for testing, changes are occurring in the molecules detected—the heart of molecular diagnostics. Clearly, in the future, new proteins and metabolites will be correlated with disease states and become new markers in the IVD testing market. However, the use of nucleic acids as analytes—in applications that extend beyond viral-load testing and chromosome analysis for prenatal screening—is also a distinct possibility.

Over the next 5 to 10 years, the definition of molecular diagnostics will continue to evolve, and diagnostic testing will change dramatically. Technology, healthcare policy, cost, and consumer trends will each contribute significantly to the exciting changes on the horizon.

References

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Photo Courtesy Affymetrix

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