This story has been updated from a previous version to clarify comments regarding the Aptima HPV test specificity.
By Ben Butkus
Having received 510(k) clearance from the US Food and Drug Administration this week for its Aptima HPV assay, Gen-Probe is betting that the test's high degree of specificity will help differentiate the product from competing tests in a rapidly crowding market.
In addition, data demonstrating the lower false-positive rates associated with Gen-Probe's test should be considered by the US Preventive Services Task Force as it gathers feedback over the next few weeks on its recently released draft recommendation on cervical cancer screening and HPV testing, according to one expert.
Gen-Probe's Aptima HPV assay, which runs on the company's fully automated Tigris molecular diagnostics platform, uses transcription-mediated amplification to detect mRNA from two viral oncogenes, E6 and E7, in 14 of the highest-risk HPV types associated with cervical cancer and precancerous lesions.
The company submitted a premarket approval application for the test to the FDA last December after completing the Clinical Evaluation of Aptima HPV RNA, or CLEAR, trial, which involved approximately 11,000 women undergoing routine Pap testing at 18 US clinics. (PCR Insider, 12/2/10).
This week, FDA approved Aptima HPV to test women age 21 and older whose Pap tests showed atypical squamous cells of undetermined significance, meaning they were neither normal nor clearly indicative of pre-cancerous changes; and to screen women age 30 and older as an adjunct to Pap testing.
With the approval, Gen-Probe jumps into a molecular HPV testing market occupied primarily by three assays: Qiagen's Digene HC2 HPV DNA test, which is based on the hybrid capture 2 signal-amplification technology; Hologic's Cervista, which uses Invader signal amplification chemistry to detect DNA from 14 high-risk HPV types; and Roche's Cobas 4800 HPV test, which uses PCR amplification of target DNA and nucleic acid hybridization to also detect 14 high-risk HPV types.
Gen-Probe's CLEAR study compared the Aptima HPV assay with Qiagen's Digene HC2 test, which is currently believed to be the most widely administered test on the market, and found that Aptima HPV had comparable sensitivity for the detection of cervical disease, but a higher degree of specificity.
Research published last December by researchers at the Institute of the Cervix at the Federation Mutualiste Parisienne in Paris yielded similar results. That study, published in the International Journal of Cancer, found that both the Gen-Probe and Qiagen tests had superior sensitivity to cytology, but that the Gen-Probe test had specificity superior to that of the Qiagen test but comparable to that of cytology.
Even though Gen-Probe has stated that Aptima HPV has advantages due to the fact that it detects mRNA, thus indicating an active infection; and that it runs on what it believes is a superior molecular diagnostics platform in the Tigris; it appears that this specificity difference may be a true differentiator as Gen-Probe attempts to wrestle away market share from its competitors over the next year.
"Given the data we have thus far, I think you do see a significantly improved specificity of the test," Jennifer Smith, a research associate professor of epidemiology at the University of North Carolina and a co-author on last year's JCI study, told PCR Insider this week.
"The sensitivities are quite comparable between the Aptima and other DNA assays on the market," added Smith, who is also director of public health partnership Cervical Cancer-Free America. "That increased specificity will lead to fewer false positive tests, and eventually that will lead to fewer referrals to [colposcopy] and fewer unnecessary positive results and worry from patients."
Smith added that the question now "is whether the comparative difference is going to be a real clinical advantage, and that's where we need to have some cost-effective modeling exercises."
In a conference call this week discussing the company's third-quarter financial results, CEO Carl Hull noted that Gen-Probe "believes that the strength of the product’s performance and the specificity improvements that we are seeing resonate extremely well with three target audiences.
"One is the national [key opinion leaders] who drive guidelines [and] policy decisions, and heavily influence the decisions of others," Hull added. "Secondly, regional [key opinion leaders] and senior physicians in different geographies in the US; and then finally … our lab customers … because they’re dealing with customer complaints from physicians when they have a high number of false positive HPV results, and they're looking for solutions to that problem."
In a statement this week, Tom Wright, professor of pathology and cell biology at the Columbia University Medical Center, noted that Aptima HPV "has consistently shown similar sensitivity and better specificity than the most frequently used DNA-based test. This means the … assay is highly accurate in detecting cervical disease, but is less likely to raise false alarms that can result in unnecessary medical procedures."
The potential administration of such procedures is also something being heavily considered by the US Preventive Services Task Force, or USPSTF, an independent panel of primary care providers and non-federal experts in prevention and evidence-based medicine whose recommendations influence whether diagnostic tests will be covered under government healthcare programs such as Medicare and Medicaid.
Last month, USPSTF issued draft recommendations on cervical cancer screening. The full draft recommendation can be found here, but one of the group's preliminary findings was that "current evidence is insufficient to assess the balance of benefits and harms of HPV testing, alone or in combination with cytology, for screening for cervical cancer in women ages 30 years and older." The group also recommended against screening for cervical cancer using HPV testing, alone or with cytology, in women younger than 30.
Although they are only preliminary (and are open for comment until Nov. 16), Smith said that the recommendations as they currently stand could result in women who are uninsured and seeking care at the state or national level to be denied coverage for HPV-based cervical cancer screening.
And, Smith said, HPV screening data such as obtained in the recently completed Aptima HPV studies needs to be taken into consideration by the task force.
"[Aptima HPV] provides improvement in the false positive rate," Smith said. "[But] it depends on what level of false positive rate would be … acceptable by the USPSTF."
"An improvement is a great thing, but would it influence the USPTF? I don't know," she said. "In light of the new performance data [and] in light of the lower [false] positivity rates that are seen … these data should be considered during the USPSTF's review as they move forward toward their final recommendation."
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