Having garnered 510(k) regulatory clearance in August for its rapid-analysis CYP2C19 genetic test, Spartan Bioscience will continue to work with the US Food and Drug Administration to try to gain the agency's okay for marketing the test in the point-of-care setting.
The product label for the Spartan Rx CYP2C19 assay states that physicians can use it to help them determine therapeutic strategies for patients when considering treatment with drugs metabolized by CYP2C19 enzymes. The anti-platelet drug Plavix (clopidogrel), the high blood pressure treatment Inderal (propranolol), the depression drug Celexa (citalopram), and the acid reflux drug Prilosec (omeprazole) are a few pharmaceuticals that fall into this category.
Since the test yields results in under an hour, the fastest sample-to-result CYP2C19 test currently out on the market, Spartan is promoting the test as an "on-demand" tool that healthcare providers can use in "time critical" scenarios to quickly determine whether patients have certain CYP2C19 gene mutations that will hinder their response to treatments.
Spartan initially sought a point-of-care claim for the CYP2C19 test, but changed course during the regulatory process once it realized that the evidence requirements were steep and the path more uncertain. At a minimum, FDA has told Spartan that in order to get such a labeling indication for its test, the firm will have to do studies involving healthcare personnel, such as nurses, who deal with patients at the point of care but aren't skilled in laboratory sciences.
For the recent 510(k) clearance, Spartan performed studies for the CYP2C19 test involving a mix of lab professionals and nurses. Eyeing a point-of-care designation for the CYP2C19 test for the future, the firm is planning substudies involving the specific types of personnel the FDA wants to see, Spartan CEO Paul Lem told PGx Reporter.
"In the beginning, we were planning to go for point-of-care, and what we realized pretty early on is that there has never been any CLIA-waived [genetic] test that's been approved by the FDA, even though others have tried," Lem said.
Unclear path for test developers
A laboratory in the US that performs testing on human biological samples in order to provide information that is used to diagnose, treat, or prevent diseases must meet quality standards under the Centers for Medicare & Medicaid Services' Clinical Laboratory Improvement Amendments program. The FDA is responsible for categorizing commercially marketed in vitro diagnostics performed at labs under one of three CLIA regulatory categories: "waived," "moderate complexity," or "high complexity."
CLIA categorizations are assessed based on a number of criteria, such as how much knowledge is required to perform the test; how much training is required during the preanalytic, analytic, and post-analytic phases of the test; and how stable and reliable the test reagents and materials are.
For IVD CLIA categorizations, if the FDA has approved a test procedure for home use, if the test involves simple lab procedures that have a very low likelihood of erroneous results, or poses no reasonable risk to the patient if performed incorrectly, then the requirement that the test be performed in a CLIA-certified lab may be waived. According to FDA's website, blood glucose testing using urine dip sticks, fecal occult blood testing, or urine pregnancy tests are examples of CLIA-waived IVDs.
Meanwhile, the FDA has its own, separate regulatory requirements for test developers seeking premarket approval or 510(k) clearance for medical devices. In order to market a test with the agency's blessing, the sponsor needs to submit data proving its analytical validity – can the assay accurately and reliably measure the analyte of interest – and its clinical validity – can the assay accurately detect the patient outcome of interest .
Although the FDA granted the Spartan Rx CYP2C19 System 510(k) clearance, Spartan didn't satisfy the agency's requirements to garner clearance for the test with a point-of-care indication. Within the FDA's three-level device risk classification system, the agency deemed Spartan's cheek swab-based CYP2C19 genetic test that runs on a PCR system to be a Class II device. This means that the FDA finds the assay to carry an intermediate level of risk that requires greater regulatory controls than Class I devices to ensure its safety and effectiveness.
Separately, it seems Spartan also didn't meet requirements to achieve CLIA-waived status.
FDA spokesperson Susan Laine emphasized that the process for getting CLIA waivers and FDA regulatory approval for molecular tests are distinct paths and should not be conflated. Moreover, the data requirements to achieve the reliability and performance characteristics required for CLIA waived status may differ based on the intended use of a particular test and the setting in which it will be utilized.
"For example, a urine drug screening test may not need to be as accurate to meet the standard since positive results are confirmed by another test, while an HIV test may need to have extensive studies done to demonstrate that there is an insignificant risk of an erroneous result because of the risk to the public of false negative results," Laine noted. "The technology behind genetic testing has not yet been demonstrated by any manufacturer to be simple enough to be [CLIA] waived, but we would expect that to change at some point."
Meanwhile, Laine noted test developers seeking a point-of-care indication for a diagnostic will likely need to seek FDA's review. As such, molecular diagnostics developers eyeing the lucrative point-of-care market are pursing FDA regulatory approval or clearance, but are also seeking CLIA waived status, since that would allow them to sell their tests more broadly and a wide range of trained and untrained healthcare personnel would be able to perform the test.
Although the FDA has not yet green lighted a point-of-care genetic test that also has a CLIA waiver, molecular diagnostics firms have attempted to gain these designations for platforms they believe would be clinically useful in a variety of healthcare settings and improve patient outcomes. Specifically in the case of the anticoagulant clopidogrel, a test that is easy enough for nurses to operate and quickly identifies poor responders to the drug, would help healthcare providers determine on the spot the best treatment strategies for those with acute heart conditions and avoid adverse reactions.
The FDA in 2010 issued a black box warning for Plavix, informing patients and healthcare providers that those with diminished CYP2C19 function are at greater risk of cardiovascular adverse events after an acute coronary syndrome or percutaneous coronary intervention than are normal metabolizers of the drug. However, within community healthcare settings, where physicians see acute cardiac patients needing immediate care, uptake of CYP2C19 genotyping has been hindered due to the lag between when genetic testing is performed and when test results are returned to the doctor to inform treatment decisions.
Three years ago, when the FDA issued the black box warning for clopidogrel, the turnaround time for CYP2C19 tests was a week or longer. In the past few years, the agency has cleared faster CYP2C19 genotyping tests developed by Nanosphere and by AutoGenomcics. Nanosphere's test yields results in under 2.5 hours, while AutoGenomics takes longer. Neither of these tests have a point-of-care indication.
The approximate hour-long workflow for the Spartan test involves swabbing a patient's cheek, placing it in the sample tube, scanning the test's barcode, depositing the sample tube in the test system, and pushing the start button on a laptop linked to the machine. Although Spartan set out to fill an unmet medical need aiming to develop the first point-of-care CYP2C19 test, in taking the assay through the FDA "what we realized is that the bar is very high," Lem said. "So, we decided to stop going down that path and go for straight up [clearance] first, before we tried to bite off the CLIA-waived, point-of-care designation."
Cepheid is another company that has for some time been hoping to launch a flu test on its Xpert platform with a CLIA-waiver, which would enable the test to be performed in doctor's offices, small nurse practitioner clinics, and in emergency rooms (PCR Insider 7/25/2013; 2/2/2012). The company had talked about launching CLIA-waived tests for other indications on the Xpert system, but most have so far been designated "moderate complexity" by the FDA, which means that the tests will still be subject to proficiency testing and CLIA requirements, and will need to be performed by trained healthcare personnel.
For tests that Cepheid has sought FDA's regulatory blessing, such as the recently cleared Xpert MTB/RIF test for detection of tuberculosis and drug resistance, the agency granted 510(k) clearance but not with a point-of-care indication. Additionally, the FDA categorized the Xpert MTB/RIF test as "moderate complexity" under CLIA. Cepheid officials were unavailable to respond to emailed questions for this article.
Although FDA device regulations and CLIA IVD categorization are separate processes, there is confusion among test developers as to how to achieve these designations for their tests. Having gone through the regulatory process with the FDA for its CYP2C19 test, Lem couldn't outline what evidence the company will need to submit to get the agency to okay a point-of-care indication for the tests, as well as grant a CLIA waiver.
"We're not sure that there are very clear rules or very clear criteria" around these processes, Lem said. "What is the difference between a point-of-care and CLIA-waived test? It's unclear," Lem said. "It was unclear to us when we were going through this process."
Spartan is planning to hold additional meetings with the FDA to get a more detailed understanding of what types of data it will need to submit before it can market its CYP2C19 assay as a point-of-care test that non-lab professionals can operate. "The FDA, I don't think, is allowed to say, 'You do this study, show us this result, and we'll give you approval,'" said Lem. "It's a more roundabout process where you have a discussion with the FDA and they give you some kind of indication about the studies you need to do, you submit the data, and the FDA has more questions."
According to the label for Spartan's CYP2C19 test, the company submitted data from multiple studies to establish the analytical validity of the test and compare it with others out on the market. Spartan conducted a study at three sites to establish the reproducibility of the test, which gauges CYP2C19 mutations *2, *3, and *17. Out of 960 tests, 10 yielded inconclusive results and had to be repeated. After retesting those samples with inconclusive results, Spartan's diagnostic yielded a correct call rate of 99 percent, with one incorrect call.
Spartan also conducted analysis to see if test calls would be impacted by substances in patients' mouths before their cheeks were swabbed, such as mouthwash, cigarette smoke, and chewing gum. This study showed that when patients chewed gum, it produced the most number of inconclusive results, with one result remaining inconclusive upon re-testing. The test label recommends that patients rinse their mouths out with water before submitting a buccal sample for analysis.
In granting 510(k) clearance to Spartan's CYP2C19 test, the FDA found it to be substantially equivalent to AutoGenomics' Infiniti CYP2C19 Assay. According to the label for the Spartan RX CYP2C19 assay, the two tests gauge the same gene markers and have the same indication. The main differences between the two tests is that the Spartan RX CYP2C19 test analyzes buccal swab samples and operates on a PCR-based platform and the Infiniti CYP2C19 Assay analyzes purified DNA from a blood sample and uses a microarray-based platform.
Spartan referenced published literature to establish the clinical validity of the CYP2C19 test.
Researchers estimate that approximately 15 percent of all prescribed drugs are metabolized by the CYP2C19 enzyme. However, currently the bulk of the clinical evidence backing the use of CYP2C19 testing is to determine whether cardiac patients undergoing stent procedures will respond to the antiplatelet clopidogrel. However, even in this setting, some mainstream cardiologists have balked at adopting CYP2C19 genoytping due to the lack of large, prospective studies definitively proving that genetic testing improves patients' outcomes (PGx Reporter 3/28/2012).
The Center for Individualized Medicine at the Mayo Clinic is sponsoring a prospective outcomes trial involving nearly 6,000 patients to gauge the clinical utility of CYP2C19 genotyping using Spartan's test. The TAILOR-PCI trial will investigate whether genotyping cardiac stent patients at the time of angioplasty can help doctors personalize treatment decisions with either AstraZeneca's Brilinta (ticagrelor) or clopidogrel, and improve patients' outcomes.
Noting that past clinical utility studies for CYP2C19 testing have involved smaller cohorts, Lem said that the Mayo Clinic "wants to run the definitive landmark trial," which would establish whether CYP2C19 testing is clinically useful or not. "The key opinion leaders have said that they want to see a randomized, prospective trial of personalized anti-platelet therapy versus one drug for everyone," he noted. "This trial is meant to put those questions to rest."
Spartan also has plans to develop a second-generation CYP2C19 test that shrinks the test system down to the size of a coffee cup that can link to a smart phone or a tablet. However, Lem noted that the current size of the CYP2C19 test, likened to a desktop printer, would not hinder its use at the point of care, that is if the company is able to achieve this designation through further interactions with the FDA.