The University of Florida Academic Health Center this week launched a new personalized medicine effort in which all patients visiting its catheterization lab will receive a multi-gene test that will be used to discern whether they are likely to respond to the anti-platelet drug clopidogrel (Plavix) and other treatments.
Researchers involved in the personalized medicine program at UF have developed a custom chip based on Life Technologies' QuantStudio real-time PCR platform with OpenArray technology, which they believe will allow them to genotype patient samples faster and cheaper than most commercially available Plavix PGx tests. Furthermore, the custom chip, which was developed in collaboration with Stanford University, interrogates not only the seven CYP2C19 SNPs linked to Plavix response, but an additional 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 lab-developed test. The university is 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" in the patient's EMR.
The advisory is set up in a way that "the clinician can't just ignore it," Julie Johnson, director of the Personalized Medicine Program at UF, told PGx Reporter. Based on the recommendations generated by the system, the doctor must click on a particular treatment strategy. Although physicians can choose to administer low-dose clopidogrel to patients who have loss-of-function CYP2C19 alleles, "they have to tell us why," she noted. "So, we're allowing doctors to do what they want, but we're also not making it easy to ignore the alert."
With patient consent, test results for the other 249 gene variations will be stored in a secure database for research use. UF's pharmacy and therapeutics committee will evaluate the literature and decide which SNPs, beyond the seven CYP2C19 alleles, are ready to be used to guide medical decisions. Warfarin and statins are some of the other drugs that UF's genetic testing program might personalize in the future with the help of PGx data.
Only when the committee formally moves certain SNPs from a research to a clinical setting will genotype data for those SNPs become part of patients' electronic medical records. If patients don't consent to being tested for the SNPs considered to be for research-use only, then that information will not be saved in UF's research database.
UF is trying to distinguish its personalized medicine program by adopting tools and strategies that may not be the standard of care today, but will be in a few years. "We elected to go the route [of developing a multi-gene custom chip] instead of a single CYP2C19 test, because we feel that the 'one-test-at-a-time' [model] is not the future," Johnson said.
The UF team decided to develop a custom chip after identifying several limitations in terms of cost, hands-on time, and turnaround time of other genotyping options. "For example, the Illumina [VeraCode ADME panel] holds 32 samples. That's great for research purposes," Johnson observed. 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."
UF's custom chip analyzes 12 samples per chip, which is approximately the number of samples that the academic center anticipates running per day. The test yields results in about five hours and the chip costs $30 to run a single sample. "That's about one-sixth to one-tenth the cost of commercial PGx chips," Johnson estimated. Furthermore, once labor is factored into the price, since "hands-on time is minimal," the total cost of UF's test will be less than or similar to currently marketed tests, she added.
Lengthy turnaround times for genetic testing results have hindered doctors from adopting PGx tests to inform treatment strategies for certain acute conditions. For the most part, UF is promising that test results will be available for patients within 24 hours. "Patients seen very late in the day in the cath lab may not have their genotyping results available the next day," Johnson said.
Although current commercially available CYP2C19 genotyping tests have turnaround times of up to a week, several diagnostics developers are working on developing faster tests. For example, Quest subsidiary Focus is collaborating with scientists from Scripps Translational Science Institute and Scripps Health to develop a CYP2C19 genotyping test that could return results in less than an hour (PCR Insider 3/17/2011). Separately, Spartan and Nanosphere are developing point-of-care CYP2C19 tests (PGx Reporter 8/11/2010).
A Screening Strategy
Another point of differentiation for the UF program is that it is implementing genetic testing as a way to screen for multiple mutations associated with disease or treatment response in all patients treated in the cath lab, regardless of whether this information has immediate clinical utility.
"We're generating genotype data on all patients presenting to the cath lab. It doesn't necessarily matter whether or not they end up on clopidogrel," Johnson explained. "It's a clinical lab, so [the genetic testing has] been established as part of the standard set of lab tests ordered ahead of the [catheterization procedure]."
Although insurers have not spoken favorably of broadly implementing genetic tests as part of a screening strategy, healthcare providers in certain disease settings are starting to administer genetic tests early on in patients' treatment paradigm, so their PGx data are available should such information become necessary if their disease progresses. For example, a recent survey revealed that oncologists are starting to test patients for BRAF mutations when they are diagnosed with melanoma, instead of waiting to run the PGx test when the disease has metastasized (PGx Reporter 5/16/2012).
"The justification for doing it on everybody that comes into the cath lab is that we know that only a portion of those [patients] will have an intervention and end up on clopidogrel. But we also know that those who show up to the cath lab and don't have an intervention now, at some point probably will and may well require clopidogrel," Johnson explained. "At that point, their CYP2C19 genotype information would be available as needed in the [electronic] medical record for them."
Insurance coverage for Plavix PGx testing performed at UF is not an immediate concern for the center but it is something the university will work to obtain in the future. For the time being, PGx testing will be covered through National Institutes of Health funding.
The National Center for Advancing Translational Sciences is providing $500,000 through its Clinical and Translational Science Awards program to fund the UF personalized medicine program and its collaboration with Stanford University, which will launch a similar PGx testing program next month. UF's program has an additional $350,000 for its program through the NIH Pharmacogenomics Research Network.
"We have very, very active participation from our pathology department … and they are committed to working toward a billable test … We're hoping to make that transition over the first year," Johnson said. "Having a laboratory professional involved at that level will hopefully provide some opportunities to interface more with insurance providers and understand what the barriers are if they won't reimburse for the test and eventually try to overcome that."
In contrast to UF's Plavix PGx testing program, Scripps Health is administering PGx testing to personalize treatment with the drug only for patients who have undergone a stent procedure. The clinical evidence validating the association between CYP2C19 loss-off-function alleles and reduced response to Plavix is strongest in this patient subset.
Eric Topol, chief academic officer of Scripps Health, told PGx Reporter that clinicians within the southern California-based non-profit health system are currently evaluating different rapid genotyping assays with turnaround times of around 20 minutes. "We have done exome sequencing to identify other genomic interactions and plan [to use] a multi-gene panel at some point in the future, but not yet," Topol said.
Moving Beyond Plavix PGx
Before it lost patent protection this year, clopidogrel was known under the brand name Plavix and marketed by Bristol-Myers Squibb. The Food and Drug Administration first updated the label for Plavix in 2009 to inform doctors that CYP2C19 poor metabolizers experienced diminished response to the drug and that PGx tests could be used to identify genotypes linked to variable treatment response. Then, in 2010, the FDA added a "black box" warning to Plavix's label to highlight that poor metabolizers, or patients with the CYP2C19*2/*2 genotype, "exhibit higher cardiovascular event rates following acute coronary syndrome or percutaneous coronary intervention than patients with normal CYP2C19 function." (PGx Reporter 3/17/2010)
Despite FDA's vote of confidence in the association between certain CYP2C19 loss-of-function alleles and reduced response to Plavix, there is disagreement among healthcare providers about whether PGx testing in this setting is ready for broad implementation.
Scripps Health was an early adopter of PGx testing for Plavix. When in 2009, Scripps Health and Quest Diagnostics inked a deal to offer CYP2C19 testing to patients undergoing stent procedures, many doctors felt the program was premature given the evolving nature of the science (PGx Reporter 10/28/2009). The controversy has only gotten more contentious as several published meta-analyses have yielded conflicting results as to the validity of the association between genotype and drug response (PGx Reporter 3/28/2012).
The FDA has maintained that the available evidence supports its genetic testing recommendation for Plavix. In this regard, it is perhaps fitting that a forward-looking genetic testing program for Plavix is being launched at UF. Lawrence Lesko, former director of the Office of Clinical Pharmacology at FDA's Center for Drug Evaluation and Research, who played a leadership role in adding PGx information to Plavix's label, currently heads UF's Center for Pharmacometrics and Systems Pharmacology and plays a leadership role in the university's personalized medicine activities.
According to Johnson, UF launched its personalized medicine program with Plavix PGx testing because the black box warning on the drug's label provided regulatory backing for implementing such testing. Additionally, "the things you potentially can impact with testing, such as major cardiovascular events, are clinically important," she added. "We also felt that [since] the CYP2C19-clopidogrel effect is strongest in patients who are post percutaneous coronary interventions, that would allow us to focus on a very small patient population and a small number of physicians."
Although UF's genetic testing program is currently focused on cardiac patients who could potentially be treated with Plavix, the university has much bigger personalized medicine plans. "As we begin to roll out other pharmacogenomic indications [for cardiology patients] … we will also move past the cath lab … to the heart failure or electrophysiology clinic," Johnson said, adding that the university intends to eventually implement genetic testing programs for gastroenterology patients.
"CYP2C19 testing for Plavix is just our starting point, so we can really work out the kinks, figure out how to educate the clinicians, figure out the barriers in a relatively confined setting," she said. "But really, our goal is that we would run this chip on everybody presenting to the health system."