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As FDA's 2009 H1N1 EUAs Expire, PCR Test Makers Refine Plans for Next Flu Season


By Bernadette Toner

On June 23, a number of PCR-based assays for detecting 2009 H1N1 influenza lost their emergency use authorization by the US Food and Drug Administration as the agency declared the H1N1 public health emergency for the 2009/2010 season to be officially over.

The EUA program, initiated in April 2009 as the H1N1 pandemic emerged, enabled the FDA to rapidly approve certain in vitro diagnostic devices, personal respiratory-protection devices, and antiviral products for detecting and treating 2009 H1N1 influenza.

The EUA period was originally set to expire on April 26, but the FDA extended it in March after determining the virus remained a public health threat.

The FDA awarded its first EUA approval for a PCR-based test to the Centers for Disease Control and Prevention last April, and since then around a dozen developers have gained EUA approvals for their assays, including Cepheid, DxNA, Epoch BioSciences, Quest subsidiary Focus Diagnostics, IntelligentMDx, IQuum, Longhorn Vaccines and Diagnostics, Gen-Probe's Prodesse subsidiary, Qiagen, Roche Diagnostics, the US Army Medical Material Development Activity branch, and ViraCor Laboratories.

To date, however, only two of those tests have received 510(k) clearance for use after the EUA expiration: the CDC's swine Influenza Virus Real-Time RT-PCR Detection Panel and Focus Diagnostics' Simplexa Influenza A H1N1 (2009) device.

In letters sent to test developers ahead of last week's EUA period termination, the FDA said that it "encourages" manufacturers of authorized 2009 H1N1 assays to submit any additional information that may be necessary to obtain FDA clearance or approval for their tests.

"FDA is fully prepared and welcomes the opportunity to work with the manufacturer of each of the authorized in vitro diagnostic devices for detection of 2009 H1N1 virus to help facilitate the rapid efficient review of such tests," it said.

Many test developers have signaled that they intend to pursue 510(k) clearance for their assays. Cepheid, which gained EUA approval in January for the use of its Xpert Flu A Panel test in CLIA-approved moderate-complexity labs, is developing an expanded influenza panel that will test for influenza A subtypes H1, H3, and 2009 H1N1, and influenza B, and has said that it plans to submit a 510(k) application for that product some time this year.

‪Likewise, Gen-Probe is developing a subtyping assay designed to differentiate H1N1 from regular seasonal flu A and from the A-H3 subtype, which can be more severe.

"We are now in the final stages of submitting a 510(k) for this assay, which will be called ProFAST+, to the FDA," Michael Watts, a Gen-Probe spokesman, told PCR Insider.‬

Watts noted that the Prodesse Pro-Flu+ assay, which received 510(k) approval last August, detects H1N1 as a type of influenza A, but does not differentiate H1N1 from regular seasonal flu A.‬
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He added that the market has slowed for flu testing since the height of the emergency last fall, but said that the company believes it has gained market share "so we are optimistic that we're in a strong position to meet our customers' needs when flu returns.‬"

To be sure, not every test manufacturer is seeking 510(k) approval. Roche Diagnostics, for one, does not plan to pursue further clearance for its RealTime Ready Influenza A/H1N1 Detection Set, according to a spokesperson. The assay gained EUA approval in December 2009 for use in CLIA high-complexity labs.

The Next Generation?

Some smaller test developers gained EUA approval for their assays relatively late in the 2009/2010 flu season, but that hasn't stopped them from moving forward on 510(k)-approved tests for the upcoming season.

For example, IQuum wasn't granted an EAU for its "lab-in-a-tube" H1N1 assay until May, but company officials told PCR Insider at the time that the approval served as a stepping stone for 510(k) approval (PCR 5/13/10).

And IntelligentMDx, whose IMDx 2009 influenza H1N1 real-time RT-PCR test gained EUA status in March, is currently developing a test that will be able to subtype for 2009 H1N1 and identify strains that are resistant to Roche's antiviral Tamiflu (oseltamivir).

"We're working to prepare for the next influenza season, both in the US and abroad," CEO Alice Jacobs told PCR Insider. "Our plan is to pursue 510(k) clearance for a comprehensive test for influenza … that is designed to detect all clinically relevant strains with a high degree of sensitivity and specificity in a rapid time period."

Jacobs declined to provide details on the assay, but noted that it is intended to "contain all of the relevant information necessary for a clinician to make treatment decisions."

The IMDx H1N1 test was authorized for use on Life Technologies' Applied Biosystems 7500, 7500 FAST real-time PCR systems, and 7500 Fast Dx real-time PCR instrument. The company said that it was the first 2009 H1N1 test to be approved for use on multiple instrument platforms by CLIA high-complexity laboratories.

Jacobs acknowledged that the EUA came relatively late, so the company didn't experience much of a sales boost from it, though she noted that those labs that did work with it reported positive feedback — particularly regarding the its ability to distinguish oseltamivir-resistant strains.

Jaber Aslanzadeh, director of the Division of Clinical Microbiology at Hartford Hospital and Clinical Lab, supported this claim.

Aslanzadeh told PCR Insider that his group evaluated several H1N1 assays, including the IMDx test, the Prodesse test, and an internally developed home-brewed test. While the IMDx test "came kind of late," Aslanzadeh said that it "did have something that none of the other tests did — it could detect resistance to Tamiflu."

This characteristic is a crucial feature during outbreaks, he said, because it helps clinicians decide immediately whether to treat the patient with oseltamivir or another antiviral drug.

As far as the next flu season, Aslanzadeh said he is hoping that IMDx can gain 510(k) approval for its test. "If they do, they will be a strong contender and we'll re-evaluate it," he said. He noted, however, that his lab would only consider using the test if it gains FDA approval.

Jacobs declined to provide a timeline for when the company expects to finish developing its assay and file for 510(k) approval, other than to say that IMDx is working "diligently" to get ready for the next flu season.