COMMENTARY
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James R. Prudent is chief scientific officer at EraGen Biosciences Inc. (Madison, WI). He can be reached at jprudent@eragen.com. |
Another major event in the molecular diagnostics industry was that polymerase chain reaction (PCR) patents began to expire (see sidebar). While the impact of these initial expirations on the IVD market has been modest so far, it is anticipated to grow considerably as patents on PCR upgrades expire and other IVD companies develop their own relevant upgrades. Owned by Roche, PCR has been the main technology driver for the molecular diagnostics industry. The expiration of these core patents allows companies to sell and use products that incorporate PCR (not the numerous other PCR upgrades) without having to pay royalties to Roche. While this will positively affect the IVD companies that have enabled their own PCR technologies by not requiring the Roche upgrades, it will have little to no impact on the companies that still depend on Roche’s other PCR-related patents.
As the molecular diagnostics industry moves into 2006, rapid expansion is expected in most segments, including infectious diseases, genomics, oncology, and blood screening. The expansion will be driven by the following factors: products with improved specificity and sensitivity; technology that simplifies, automates, and speeds up testing; an increase in high-quality molecular markers; and a market ready for the molecular world.
Molecular Markers
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Sidebar:
Expiration of Core PCR Patents |
As molecular diagnostic testing gains greater acceptance, the key questions for the IVD industry in the years to come will focus on the molecular marker business, developing and selling test kits that analyze for the presence of specific gene sequences or sequence mixes in biological fluids (e.g., blood), stool, or biopsies. The results of such kits correlate to disease states such as cancer or Alzheimer’s. Of course, the molecular marker business is nothing new. For example, screening for cervical cancer and prostate cancer uses marker-specific tests (see Table I). Cervical cancer testing with Pap smears is a good example of a success story that may someday be replaced by human papillomavirus (HPV) molecular marker testing. Other marker tests that are regularly performed remain controversial, such as prostate specific antigen (PSA) testing, with plenty of debate concerning the positive predictive value of PSA testing.1 Industry experts will be closely watching this debate to determine how the newer molecular tests will perform.
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Table I. (click to enlarge) Markers currently being used for cancer screening. |
The new molecular marker business is more sophisticated than its predecessor. Since the human genome was sequenced, the number of molecular and immunologic targets has exploded, followed by new technologies that allow ultrasensitive quantitative multiplexed detection. However, when asked about the business prospects of this next generation of molecular markers, experts vary in their opinions. Strong backers think the new marker business will lead the molecular revolution, while skeptics believe the business will cost too much and produce too little.
A PubMed search for diagnostic markers results in almost 150,000 citations, and a molecular markers search another 72,000 articles. Such results show the intense interest in finding, owning, and using markers. While many of the new markers will become drug and diagnostic targets, only a few are likely to become commercially relevant. That is the challenge that still confronts the IVD industry. What is potentially the most important part of the molecular diagnostics business could be in danger of becoming a resource dumping ground, leaving investors leery once again.
Validation and Market Acceptance
The difficult road that lies ahead in the molecular marker business is exemplified by any of the prospective predictive cancer tests and the studies needed to validate them. For such tests, a series of clinical trials is required. Initially, marker sets are identified through preclinical exploratory testing. Much of the preclinical testing involves quantitative methods that can be complex. Once the marker subsets are identified, multiplexed tests are developed on clinically relevant testing platforms. At this point, the marker sets may be patented by either a university or company that wants to continue developing them.
The tests are then validated in another set of clinical studies that focus on achieving reproducible results within and between testing sites, and distinguishing disease states from normal control states. Since markers are used in many cases for predictive values, another set of studies that test repositories of clinical specimens prior to disease onset is compared with test results using samples from healthy controls. Such studies are critical as they allow developers to follow marker levels prior to the clinical phase and to understand better how such levels relate to disease. The results are needed to determine if early intervention after prognosis lowers disease burden.
Beyond validation studies, molecular marker tests need market acceptance: payers prepared to pay for them, and doctors enthusiastic to order them. Such acceptance will depend on a number of factors, including efficacy, cost, FDA approval, CPT coding, marketing, organizational recommendations, and test complexity.
Some of these factors have come to light recently with a test called the Oncotype DX by Genomic Health Inc. (Redwood City, CA). The Oncotype DX analyzes gene-expression profiles and is being clinically tested and sold with CPT coding to predict the likelihood of breast cancer recurrence and to help clinicians better target therapies to patients. The test is gaining acceptance after two years of extensive evaluation. Yet, in a announcement this year, Genomic Health said that FDA invited the company to discuss the appropriate regulatory status of the assay. In early 2005, FDA was considering whether the test may be subject to FDA premarket review.
The main difference between the current molecular marker tests and the newer marker tests will be complexity. The newer tests will be more complex, consisting of multiplexed and possibly quantitative panels. The best marker panels will provide black-and-white results—that is, a series of answers to yes-or-no questions that can be definitively linked to a disease. Infectious disease testing is an example of such panels, which is one of the reasons for the success in the infectious disease diagnostics market.
A set of promising molecular markers for cancer that closely matches this criteria is the specific genetic mutations indicating leukemia. The targets suitable for PCR studies are leukemia-specific fusion transcripts, such as the BCR-ABL, E2A-PBX1, and TEL-AML1 gene fusions, and clone-specific immunoglobulin and T-cell receptor gene rearrangements. Other promising markers can be used to select therapies and predict therapy outcomes. Kinase inhibitors, such as Gleevec, are good examples of targeted therapeutics in which molecular marker tests can be used to detect slight changes that confer therapeutic resistance. Specifically, one BCR-ABL kinase mutation (T315I) accounts for most cases of Gleevec resistance.
However, molecular marker tests that provide yes-or-no answers will not always be the norm. The subtle changes in the results from molecular marker testing will be difficult to interpret without using sophisticated software that takes into account vast amounts of clinical data. Easy-to-read test reports will need to incorporate statistics from the clinical trials, continuously update the new data, and average the information as it relates to control targets. Software can make or break any good testing system, and the easier and more universal the software is, the better. The good news is that in many cases, software engineers have been sensitive to such concerns, allowing in-depth analysis through user-friendly interfaces.
Conclusion
Will the complexity of the new molecular marker tests lead to clinical confusion or market expansion? A combination of good science, ingenious testing platforms, and expanding software capabilities will provide testing systems for a number of disease states. However, what is difficult to predict is whether the market will embrace such molecular marker tests. At this time, there do not appear to be effective IVDs for cancer that are highly specific, sensitive, and cost-effective. Clinical leaders will require solid evidence that the test results are clinically relevant and show efficacy. As new therapies, new diagnostic platforms, and a better understanding of the molecular world emerge, market expansion could occur. The successful IVD companies will have the best technologies and the seasoned management teams that quickly focus on the most-promising market opportunities.
1. FA Vicini et al., “Limitations in the Use of Serum Prostate Specific Antigen Levels to Monitor Patients After Treatment for Prostate Cancer,” The Journal of Urology 173, no. 5 (2005): 1456–1462.
