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FDA Clears ParagonDx's Genetic Warfarin Assay; Firm Highlights Same-Day Turnaround

ParagonDx's Rapid Genotyping Assay this week became the third genetic test for warfarin sensitivity the FDA has cleared in less than a year, making it ever necessary for developers of such tests to differentiate them from the competition.
For the time being, ParagonDx is touting its test’s same-day turnaround, which may be an important adoption-driver in the warfarin market.
“ParagonDx's genotyping assay is the first cleared product to deliver results in less than one hour and incorporate human genomic quality controls,” the company said in a statement this week announcing that the assay received a 510(k) clearance from the FDA. “This rapid turnaround time means that treatment can be customized quickly and decrease the chance that a patient will have excessive bleeding or suffer other adverse events such as heart attack or stroke.”
After the Critical Path Institute released a brochure in March to educate physicians about gene-based warfarin dosing, President Ray Woosley told Pharmacogenomics Reporter that there are a lot of factors to consider when dosing a patient on warfarin, among them time-to-treatment.
According to Woosley, the warfarin dose may differ for a patient who lives 20 miles from the clinic versus one who lives only a mile from the clinic. “Every case is so different,” he said. “It’s truly personalized medicine.” [see PGx Reporter 03-19-2008].
Given the nature of adverse events related to warfarin treatment, the time-to-treatment — the time it takes from taking a patient's sample, running it through the test, and returning the results to the physicians' office — may or may not be a factor when doctors decide which genetic test to adopt into their practices.
While test developers attempt to distinguish their products in an increasingly crowded market, an expert from the American College of Medical Genetics said that gene-based warfarin testing as a whole is not ready to become the standard of care when dosing the anticoagulant.
“At the present time the clinical evidence does not warrant routine use of warfarin tests” by physicians, ACMG board member Marc Williams told Pharmacogenomics Reporter this week.
He pointed out that the speed with which a patient needs to go on warfarin will vary depending on the nature of his or her ailment. Williams, who co-authored ACMG's 2007 Comprehensive Review of Genetic Testing and Warfarin Dosing, noted in that paper that the clinical meaningfulness of how soon genetic information is necessary in the administration of warfarin needs further study.
Racing Over Run Times
“There should be a distinction between the assay turnaround time, referred to as the time to result, and the time it takes to get the results to the physician,” ParagonDx CEO Michael Murphy explained to Pharmacogenomics Reporter this week. “Typically for these types of assays, that time frame does not include the sample preparation time. Although in our case, we actually have been able to do the whole DNA purification and assay run in less than one hour.”
ParagonDx claims that its Rapid Genotyping Assay has a run time of less than 30 minutes and claims its product is the fastest among FDA-approved warfarin sensitivity assays. This speed is what enables the company to deliver test results to the doctor in the same day.
However, ParagonDx is entering a competitive market already occupied by AutoGenomics and Nanosphere's FDA-approved tests, as well as by homebrew assays marketed by Laboratory Corporation of America, Harvard Medical, and Clinical Data, among others.
According to Murphy, among ParagonDx's numerous competitors, Idaho Technology's non-FDA-cleared warfarin assay has a run time of less than one hour. Nanosphere's Verigene System has a run time of 1.5 hours, while AutoGenomics' product completes the process in 10.6 hours. Third Wave's 96-well platform and Luminex's Tag-It assay, which are not FDA cleared, report run times of around three hours.
Although ParagonDx might have the fastest machine on the market, what is more important is how quickly the results get to the doctor. In this regard, several companies have been touting services whose speed rivals ParagonDx’s.

“The definitive studies have not really answered the question as to whether you need to know [genotype] information right at the time of the first dose.”

AutoGenomics also offers same-day results. Meanwhile, Kimball Genetics and Harvard Medical School’s testing services, which use Third Wave’s Invader assay, promise to return test results as early as one business day. Other companies have turnaround times ranging from three to seven days [see PGx Reporter 10-10-2007].
According to Murphy, how fast the results get to the doctor can shift based on the testing laboratory and how the testing is carried out. “If the testing is performed in batches it will be determined when they run the batch,” he said. “If each sample is performed as it comes in and is done close to the patient then it should not take longer than one to two hours to act on the results.”
Other factors affect the speed at which results reach the doctor, include the reporting channels the test results have to go through before they are sent out, he added.
“Obviously, the quicker the assay can be performed the larger the effect on time to get results out to the doctor and patient,” Murphy said.
However, ACMG's Williams told Pharmacogenomics Reporter this week that the focus on turnaround times may be a bit premature.
“The assumption was that that biggest impact of this information would be with the first dose of warfarin, but some of the more recent studies are suggesting that may not be the case,” he said. “The definitive studies have not really answered the question as to whether you need to know [genotype] information right at the time of the first dose.”
According to Williams, the immediacy with which a patient needs to go on warfarin will vary according to a patients' ailment. For instance, if the patient is undergoing surgery for a joint replacement, the doctors can afford to wait for genetic information before giving the patient a dose of warfarin. On the other hand, “for the person that presents to the emergency room with atrial fibrillation, where you really want to start warfarin right away, having genomic information right at the first dose” isn't a priority, he said.
ParagonDx is currently planning its marketing strategy for the Rapid Genotyping Assay, and Murphy said that the company will initially target centers where close patient testing will matter, such as cardiac care centers and coagulation clinics.
Other Features
While ParagonDx is currently highlighting the turnaround time of its test, the company will need to differentiate the test on multiple levels in order to ensure that its product stands out. 
The Rapid Genotyping Assay,based on Cepheid's real-time PCR SmartCycler diagnostic platform, detects the presence of variations in the CYP2C9 and VKORC1 genes.
Murphy characterized the assay as “user friendly” since reagents are provided as lyophilized beads, not as a wet mix, and it runs on a “well accepted” technology base in the field. Additional features of the assay include human genomic DNA quality controls in the kit, as well as a negative control that provides labs with added assurance regarding the test’s accuracy and reliability.
Most importantly, Murphy said, is that the assay has lower “no call” rates — instances when a result is not reported and testing needs to be repeated — compared to competing products. ParagonDx's assay, according to Murphy, has a no call rate of less than 1 percent, while other products range between 5 percent and 10 percent.
“This difference could result in a significant financial difference to the lab and prevent waiting time for the doctor and patient when others require retesting,” Murphy said.
The technology platform stands to be another point of differentiation in the warfarin-testing market. Cepheid's SmartCycler system integrates DNA/RNA amplification and detection, and allows testing on 16 different modules.
“The technology is real-time PCR. Real-time PCR allows for simultaneous DNA amplification and detection, which decreases the number of steps in the reaction process,” Murphy said. “The Cepheid SmartCycler is designed to allow for rapid thermal cycling, which directly translates to a reduction in assay time.”
Meanwhile, Nanosphere claims that its nanoparticle technology-based Verigene system is at least 100 times more sensitive than systems based on enzyme-linked immunosorbent assays, and can detect nucleic acids with greater specificity “without the … risk of contamination inherent in the use of amplification techniques such as PCR.”
However, the company recently had to institute a Class II recall of eight lots of its warfarin nucleic acid test cartridge system after “a warfarin [CYP]2C9*2 mutant capture signal was found to be high enough to result in an aberrant result (i.e. wild-type called heterozygous).” Although Nanosphere maintains that the cartridge recall is a small blip, product “defects” in a competitive market and amid a difficult reimbursement environment could potentially hurt perceptions and deter adoption its test. [see PGx Reporter 04-23-2008].
Warfarin genetic-test makers have also tried to differentiate their products based on the various CYP2C9 and VKORC1 polymorphisms their products look at.
While most warfarin-sensitivity assays look for the 2C9 *2 and *3, and the 3673 (-1639G>A) VKORC polymorphisms, AutoGenomics boasts that its microarray-based INFINITI assay detects 15 2C9 and VKORC1 variants, more variations than any other company in the market. Some of the polymorphisms detected by the INFINITI assay occur only in certain ethnicities, which would allow the company to personalize warfarin dosing in those specific populations.
However, the ACMG's review of gene-based warfarin testing found that these additional polymorphisms may not be as clinically significant in terms of dosing the anticoagulant.
“Some of the platforms that are measuring additional variants, some that are race- and ethnicity-specific, some of which occur in very low frequencies,” Williams noted. “In our evidence review we do present some information on these other variants, but we essentially conclude that there ... is less robust clinical information ... associated with the impact of those variants on dose.”
Finally, cost remains the final determinant to genetic testing adoption. So far, genetic tests for warfarin cost between $200 and $500. Paragon didn't specify what its test would cost patients, but said that the cost of the test will be determined by the labs that offer it.

“Sales force and how the product will be advertised is currently under review but should be announced in the next couple of weeks,” Murphy said.

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