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New Guidelines Encouraging NAATs for Chlamydia, Gonorrhea Screens May Increase MDx Competition

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NEW YORK (GenomeWeb) ― In the first update since 2007, the US Preventative Services Task Force recently provided new guidelines to clinicians for chlamydia and gonorrhea screening. These follow an update on recommendations for laboratory detection of the pathogens issued earlier this year by the US Centers for Disease Control and Prevention.

While the new USPSTF guidelines are essentially the same with respect to patient populations, both new updates strongly emphasize the benefits of commercially available nucleic acid amplification tests.

Clinical lab experts and test makers concur that a strong endorsement of NAATs — coupled with encouragement to screen millions of sexually active but asymptomatic women under age 24 as well as any patient with increased risk factors — will likely lead to increased NAAT uptake in the future.

How this may in turn shape the commercial landscape could depend on the needs or preferences of clinical labs, as well as commercial exploitation of sample niches or unique technological advances.

The new guidelines were based on a meta-analysis published in September in Annals of Internal Medicine, and, along with an evidence summary, highlight the high specificity and sensitivity of NAATs for chlamydia and gonorrhea.

The 10 fair-quality studies that met the USPSTF's requirements assessed molecular diagnostics from four different companies — Roche, Becton-Dickinson, Gen-Probe (now a part of Hologic), and Cepheid. Other companies with US Food and Drug Administration-cleared in vitro diagnostics for chlamydia and gonorrhea, such as Abbott and Qiagen's Digene, were omitted, likely because studies of their products didn't meet the cut-offs for inclusion.

The meta-analysis presented diagnostic accuracy data on multiple products from the companies.

Importantly, the authors and the companies emphasized this was not a head-to-head comparison of the products. That said, the USPSTF considered each of the tests to be highly accurate. Although sensitivity varied somewhat, specificity was above 97 percent for all tests, regardless of specimen type.

"The main question from the USPSTF was, 'Are the tests accurate?'," Heidi Nelson, a professor of clinical epidemiology and medicine at Oregon Health and Science University and co-author of the meta-analysis, explained in an email. She noted that the task force did not seek to determine which test was the most accurate.

The USPSTF analysis concluded that evidence shows NAATs to be effective overall and an improvement over culture-based methods for basic screening, and thus recommends that chlamydia and gonorrhea infections should be diagnosed by using NAATs. However, it does not make a recommendation about what specific NAATs to use.

The question, then, is how clinical labs choose which test to use.

PCR Insider spoke with experts in this field, as well as commercial entities, to get a sense of the forces shaping decision making, which in turn may shape the molecular diagnostics market.

John Papp, a microbiologist in the CDC's division of STD prevention, recently helped author the agency's update of its recommendations for chlamydia and gonorrhea laboratory testing.

In a summary of the recommendations, the CDC declared that sensitivity, specificity, and ease of specimen transport of NAATs is better than any other tests, and, with exception of some types of pediatric cases, "laboratories should use NAATs to detect chlamydia and gonorrhea."

According to Papp, CDC made the first recommendation to use NAATs for these infections in 2002. At that point, the first assays had become commercially available, and the agency updated its previous recommendations because it "recognized there was a technological shift in laboratory diagnostics," Papp said. At that time, there were three tests that had been in place for about five years, and "the data was very favorable that the performance was much better than culture-based tests," he said.

The key for screening, however, is that NAATs are amenable to non-invasive or less-invasive specimen collection, Papp noted.

The updated CDC recommendations, like those from the USPSTF, now include different specimen types. From 2002 to 2014, the real shift for the CDC was that the recommendations now encourage self- or clinician-collected vaginal swabs as the preferred screening specimen over urine for women, Papp explained.

From the laboratories' perspective, Papp said lab directors will likely look at these recommendations, note that NAATs are strongly recommended, and that there are many that are FDA-cleared.

Clinical labs will then need to consider many variables to choose which test to use.

They will likely look at performance of the different tests, the space the platform requires, whether or not the test runs on a multipurpose platform, whether it is an open or closed amplification system, and test complexity, Papp said. Labs will also look at cost and throughput, asking "how many specimens am I getting a month, how many can I run on this [platform] per day, what are the technical requirements, and is it a walk-away test?" he said.

Romney Humphries, chief of the clinical microbiology lab at the University of California, Los Angeles, described similar considerations as factors influencing lab directors' purchases.

"Ten years ago, there were hardly any FDA-cleared molecular diagnostics on the market for infectious diseases," Humphries noted. "In the last five years, or even in the last two, it's just exploded."

She noted that labs have the ability to run lab-developed tests provided there are no FDA-cleared alternatives available. "If there is an FDA-cleared test, technically you should be running the FDA-cleared test," she said.

Labs think about capital equipment. "A lot of these assays have pretty big, expensive instruments that you need in order to run them, and many of them are for fairly high throughput," she said.

Having a different platform for each different assay is problematic, so labs also try to consolidate as much as possible.

Which specimen types are cleared is also important. "We do a lot of liquid cytology specimens usually collected for pap smear, and there are a couple of different manufacturers of that liquid cytology preservative; not all of the assays have FDA-clearance for all of those," Humphries said.

The available menu is also really important to lab directors. "To give an example, in our lab right now we run Abbott m2000 for chlamydia and gonorrhea. That's the only assay that we run on that platform, which maybe is OK because we process enough specimens so that instrument is running full time, all the time. But if it goes down, we're stuck because we don't have a back-up instrument," Humphries said.

She also pointed out that labs need to train technicians to run different test methods, so it makes staffing more difficult when a director has to make sure everyone is "cross trained on all the different tasks." Some assays also require more cleaning procedures, which increases hands-on time.

"The ideal would be to have one platform that does all of your high-throughput molecular infectious diseases screening — [human papillomavirus], chlamydia, gonorrhea, Trichomonas vaginalis, and so forth," Humphries said.

In terms of sensitivity and specificity, Humphries noted that although the NAATs are purportedly quite similar, for gonorrhea there have been some assays that have cross-reacted with other Neisseria species. This is particularly a problem when testing non-FDA-cleared specimens like throat and anal swabs. "There may be normal flora there that cross-react with your assay, so that is something we spend a lot of time thinking about," she said. Similarly, targets for chlamydia testing are cryptic phages, and some strains in Europe have lost the phage, which could lead to a false negative result.

Importantly, retaining the ability to do culture-based testing is still required, Humphries noted. It is particularly valuable for symptomatic infections, and in efforts to stave off the development of a gonorrhea "superbug," which some researchers see as a looming threat.

But if all the NAATs perform really well, "it really comes down to workflow," Humphries said.

Existing data on NAATs was not sufficient to show any benefit for routine screening of all men. But both the meta-analysis and the test makers interviewed for this story pointed out that non-invasive molecular tests using urine samples are a huge leap forward over urethral swabs for men.

From the commercial perspective, sample niche is key. Becton-Dickinson makes the ProbeTec ET system and CT/CG Q amplified DNA assay, both of which are mentioned in the diagnostic accuracy assessment by the USPSTF.

"What we are seeing is different in the new guidelines is a statement about the use of self-collected vaginal swabs as the preferred sample in women, and urine as the preferred sample for men," explained Nikos Pavlidis, director of the worldwide market segment for BD Diagnostics. "Also, this is the first time that we have seen some guidelines on the use of molecular tests for non-genital specimens for high-risk groups, specifically pharyngeal and rectal swabs," Pavlidis noted.

The recommendation to test self-collected vaginal swabs was particularly interesting to Pavlidis, who pointed out that BD has an FDA claim for this type of specimen. That, and the recommendation for non-genital testing, might drive labs to expand testing in general, he suggested. BD's FDA claim for liquid-based cytology specimens, both SurePath and ThinPrep, could also provide an edge, Pavlidis suggested.

BD's recently-launched Viper LT platform also addresses needs for automation in small and medium labs, while the Viper XTR is for automated testing for high-volume and reference-type labs. "We have quite an extended portfolio of automated solutions that enable these labs to adapt or automate their testing," Pavlidis explained. The assays also have a reduced number of unreportable results, enabling labs to report results faster and allowing clinicians to deliver treatment more quickly.

While some of the FDA-cleared IVDs have 501(k) claims for clinician-collected vaginal swabs, others have claims for patient- or self-collected vaginal swabs, a method that may be generally gaining acceptance among women's health practitioners. In the decision summaries, however, it is noted that self-collection kits are for cases where a pelvic exam is not otherwise indicated, not for home use.

Roche's Cobas 4800 and Amplicor CT/NG tests can also be used with various types of specimens.

John Osiecki, director of scientific affairs for Roche Molecular Systems, emphasized in an interview that convenience of getting samples for molecular tests is very important from a patient perspective. For example, "the new studies show that urine testing is equally as sensitive as a urethral swab," so these recommendations may overcome reluctance to testing among patients.

Roche's Cobas 4800 CT/NG has been characterized in a clinical trial evaluating over 50,000 samples, Osiecki said, and the "dual target approach" of the tests means they can detect strains that may have mutated. "We also did extensive studies on many different sample types and that is a definite advantage for the laboratories ... because then they have a broader menu of samples that they can perform their testing with," Osiecki noted, pointing out that the company has gotten FDA claims for a variety of samples.

Roche is also introducing several new assays on the Cobas 4800 system. It has clearance for liquid-based cytology testing of HPV on that platform, as well as other genomics and oncology applications for the same system. "A broad menu is beneficial, not only being able to provide lots of sample types for CT/NG testing but also other analyses that can be evaluated on the same system," he said. This consolidation is a benefit for the laboratory, particularly for medium- to high-volume labs, he said. The Cobas 4800 also enables loading of primary sample tubes, has engineering and enzymatic controls to prevent contamination, is automated, and has a rapid turnaround, Osiecki noted.

In terms of molecular menu, BD recently launched HSV-1 and -2 tests as well as a Trichomonas vaginalis assay on the Viper XTR, which allows labs to test for these other infections on the same run. The company will launch a CT/GC and Trichomonas assay in Europe on the BD Max platform in the coming year, and forecasts a 2016 US launch date. The firm is also working on a vaginitis/vaginosis assay on BD Max, also for 2016, as reported in its recent quarterly earnings call.

The USPSTF and CDC will not say if any one test is "better" than the others. Papp did, however, note one advantage to Cepheid's product. It is a closed system, so it doesn't require the personnel needed for a highly complex test.

Isothermal 'game changer?'

Currently, clinicians send samples to labs, which report back results. Then clinicians must track down the patient in order to initiate any necessary treatment. "That takes about three days," Papp said, "Depending on the day of the week, and depending on the risk, that is a great chance for continued transmission, especially if that patient is in some sort of network where he or she could be reinfected."

Both Papp and Humphries said an FDA-validated, CLIA-waived, rapid, point-of-care chlamydia and gonorrhea test would be a "game changer" for public health.

"If there is a chance of decreasing the time from detection to treatment, that would be a real change," Papp said. "If you can disrupt the transmission cycle quicker, that would be amazing; if you go into a doctor's office [and] get a result, and proper medication, before you leave ... that would be a remarkable shift."

Papp noted the Cepheid test takes 90 minutes and is near-patient, and pointed out that although 90 minutes is a long clinic visit, that platform is also cleared for a broader menu.

Another test fitting this description is currently being developed to run on Alere's isothermal platform, the Alere i. Norman Moore, director of scientific affairs for infectious disease at Alere, could not comment on a development timeline, but expects the test to be faster than 30 minutes. The Alere i was recently FDA-cleared to run a rapid isothermal influenza A/B test.

Whether a rapid chlamydia and gonorrhea test will ultimately be CLIA-waived is the key, according to Humphries. To date, no test has achieved that, although "Cepheid is really actively working towards that goal for their chlamydia and gonorrhea test," she said.

With a CLIA-waived, POC test like Alere's, a future USPSTF update could look dramatically different.

The ultimate question is whether new guidelines — which are just suggestions, after all — even make a difference in clinical practice.

That is why the CDC is now partnering with the Association of Public Health Laboratories to survey labs. The agency hopes to track how the guidelines have impacted clinician behavior.

"Before the 2014 recommendations, the APHL put out a survey, and they are [now repeating] that survey," Papp said. One factor being tracked is whether or not there has been a strong shift in the use of vaginal swabs, as well as testing of rectal and pharyngeal specimens, for screening.

The APHL is expected to release the results of this survey next week.

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