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U of Florida PGx Program Adopts Life Tech OpenArray Assays to Screen Catheterization Patients

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The University of Florida Academic Health Center has adopted Life Technologies' QuantStudio 12K Flex real-time PCR system using OpenArray consumable plates to implement a new personalized medicine strategy to screen all incoming catheterization patients for their likelihood of responding to the anti-platelet drug clopidogrel (Plavix) and other treatments.

The new program diverges somewhat from the more commonly explored Plavix pharmacogenomics strategy of administering to patients a single CYP2C19 genotyping test to identify responders, and is largely enabled by some of the unique aspects of Life Tech's platform, UF researchers and Life Tech officials said this week.

As reported this week by PCR Insider sister publication PGx Reporter, researchers within the Personalized Medicine Program at UF collaborated with Stanford University and Life Tech to develop a custom multiplexed PCR assay that interrogates the seven CYP2C19 SNPs linked to Plavix response, as well as 249 SNPs associated with a number of heart-related conditions and treatments.

UF has garnered CLIA certification to analyze the CYP2C19 alleles associated with Plavix response as part of a laboratory-developed test, and is currently working on getting CLIA certification to run the additional SNPs.

Genotyping results for Plavix response will be stored in UF's health IT system and become a part of patients' electronic medical records. If a patient has a genotype that indicates reduced response to Plavix, a physician prescribing the drug would receive a "best practices advisory alert" to help guide treatment.

In the meantime, researchers at the program will collect results for the other 249 gene variations to continue investigating which ones might be clinically actionable and become the basis for additional PGx tests for other treatments such as warfarin and statins.

Such a strategy may not have been feasible — due mostly to throughput and cost constraints — without running OpenArray consumables on the QuantStudio, a research-use-only platform that Life Tech launched in October (PCR Insider, 10/13/2011).

The platform allows users to perform both low-throughput and high-throughput quantitative and digital PCR on the same sample using the same software interface with a variety of the company's formatted assay cards — for example, 96- and 384-well TaqMan assays, 384-well TaqMan array cards, and OpenArray digital PCR cards — in interchangeable blocks.

The UF program will be using the OpenArray architecture, which, when its throughput is maximized by running four OpenArray plates in a single run on the QuantStudio, provides the equivalent of 32 traditional 384-well plates, or 12,000 data points.

"[UF] has this PGx clinical research initiative … and we looked at our platform technology … the QuantStudio … then looked at [the] assays that we had in our portfolio, which is on the order of several million," Jami Elliott, associate director of strategic solutions in the Genetic Analysis group at Life Tech, told PCR Insider.

"There is a subset of assay content that we've had for several years called the DME [drug-metabolizing enzyme] assay portfolio, about 2,700 assays [for] drug-metabolizing and genes [that are] well-characterized in the literature," he added. "And when we looked out at the market, really the folks who were involved in PGx research were usually thinking in terms of chips, largely [from] our competitors Affy, Illumina, or AutoGenomics."

Elliott said that Life Tech concluded that the flexibility and potential throughput of the QuantStudio would give researchers a "significant throughput and cost advantage at pretty much every format … knowing that this research community is really focused on 200 or fewer assays that are really looked at routinely across populations for clinical research."

Julie Johnson, director of the Personalized Medicine Program at UF, echoed those comments in an interview with PGx Reporter, noting that her group settled on developing a custom OpenArray panel after identifying several limitations in alternative technologies.

"For example, the Illumina [VeraCode ADME panel] holds 32 samples. That's great for research purposes," Johnson said. However, "if you want to do daily genotyping and you don't have a cath lab that's running 32 patients a day, which most don't, then you're going to end up either having to batch those and therefore not turn it around in a timely fashion or you're going to waste a lot of spots, which makes it even more expensive."

"If you look at the QuantStudio OpenArray, where you have a flexible format … you can go down to a format of 16, and although you'll have some empty positions … you'd be able to do assays for as few as, say, 144 samples … up to 1,000 samples in a single day with one user," Life Tech's Elliott said. "That format flexibility gives you a tremendous cost-per-sample advantage. In each of our competitors' cases you'd be looking at each well [costing] over $50 per sample. We'd be looking at below $10 a sample at list price."

Vanee Pho, product manager for OpenArray instrumentation, added that the QuantStudio's ability to perform real-time genotyping also makes it attractive for these types of high-throughput, multiplexed genotyping applications.

"The added value that QuantStudio has been able to provide is… you're cycling on the instrument itself," she said. "You're able to see the amplification plots. And that does give some reassurance of the data and the clustering. And it's not just UF, even our other customers, such as in [the agricultural biology market], really like that ability to see those amplification plots. And when you're dealing with a platform that's running several hundred targets at once … it's good to have added knowledge that something was actually amplified in the well."

Most companies developing CYP2C19 genotyping tests have been focusing on designing a single- or few-biomarker assay and platform that can be run quickly in the acute care setting. Examples include Quest Diagnostics subsidiary Focus Diagnostics, which is developing such an assay for the 3M Integrated Cycler in collaboration with scientists from Scripps Translational Science Institute and Scripps Health (PCR Insider, 3/17/2011); and Canadian molecular diagnostics firm Spartan Bioscience, which offers a CYP2C19 molecular test on its Spartan platform that has already received a CE Mark for in vitro diagnostic use (PCR Insider, 12/23/2010).

In general, while waiting for solutions such as these to hit the market, most laboratories in the US have been approaching pharmacogenomic testing using a laboratory-developed approach, according to Life Tech's Elliott.

"As a technology provider, [Life Tech] can't engage in the clinical validation of this content for diagnostic purposes," Elliott said. "But if you're going to take a market view, PGx is a field dominated by RUO platforms."

The reason for this, he added, is that "there are really only about 100 markers that are clinically actionable," Elliott added. "There are labs that, for diagnostic purposes, want to validate all of those. But you can't take a test like that through [regulatory] approval … because it doesn't have a singular diagnostic application. You'd have to take that through for every diagnostic indication that you'd want, and that would be a tremendously expensive proposition."

Life Tech's Pho said that the company has no immediate plans to seek regulatory approval for the OpenArray architecture or the QuantStudio platform. However, Elliott noted that the company has strived in recent years to develop platforms that are "validatable" for clinical use to support Life Tech's fledgling molecular medicine strategy.

"We've seen a migration of pharma dollars from basic research into clinical trials," Elliott said. "If you follow the dollars, and say we want to be in that space and partner with pharma – which is a prerequisite – that means we have to have platforms that are validatable, and solutions that are validatable."

Currently, he added, most of the money in the rapidly growing PGx market is derived from clinical trial distribution. "There is certainly a growing PGx diagnostic segment, but we're focused really on the clinical trial enablement piece," he said. "From a vendor standpoint, the validation requirements for clinical trials that we … enable would organically be picked up by diagnostic labs without any guidance, and this has been a natural continuum for all platform manufacturers."

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