FDA raises the bar for flu tests, aiming for better testing and better outcomes 

By K.C. McGrath

FDA’s recent regulatory reclassification of antigen-based rapid influenza diagnostic tests (RIDTs) from Class I to Class II was prompted by concerns about the tests’ performance during severe flu seasons, most notably during the H1N1 influenza pandemic of 2009. The goal of the reclassification is to improve point-of-care influenza testing, in order to reduce misdiagnoses and accelerate linkage to appropriate treatment.1

The significant burden of influenza makes this goal important not only for patients, but also for the public health, broadly defined. Flu is associated with a worldwide annual attack rate of 5% to 10% among adults, and 20% to 30% among children.2 In the United States, the Centers for Disease Control and Prevention (CDC) estimates that there are between 9 million and 60 million cases every year, leading to 140,000 to 710,000 inpatient hospital stays and between 12,000 and 56,000 deaths.3

Rapid and accurate diagnosis followed by connection to appropriate treatment can help to reduce the substantial morbidity and mortality associated with influenza, and potentially, its direct costs. It can also help to reduce inappropriate antibiotic prescriptions, improve influenza infection control procedures, and reduce rates of repeat doctor visits.1 Reducing inappropriate use of antibiotics, in particular, has very wide implications, as antibiotic misuse is a key driver of antimicrobial resistance, a significant and growing public health threat.

The Rationale for Reclassification

FDA’s device classification system reflects the regulatory controls needed to ensure that devices are safe and effective for human use. There are three device classifications based on risk: Class I, Class II, and Class III.4 All three classes of devices must satisfy basic requirements specified by FDA (‘general controls’), such as proper packaging and labeling.5

Current office-based RIDTs were originally approved as Class I devices, the category reserved for devices that pose the lowest risk to patients. Class I devices may include patient scales, elastic bandages, and tongue depressors. According to FDA, Class I devices “are not intended for use in supporting or sustaining life or to be of substantial importance in preventing impairment to human health, and they may not present a potential unreasonable risk of illness or injury.”5

Class II devices, which are associated with moderate to high risk, must meet additional standards (‘special controls’) to ensure their safety and effectiveness. Such special controls are generally specific to the device, and can include performance standards, postmarketing surveillance, patient registries, special labeling, and other requirements.4

Reclassified as Class II devices, RIDTs must now meet the requirements of special controls designed to improve their performance to better address public health needs in an ever-evolving influenza landscape. These new requirements include minimum performance standards, annual analytical reactivity testing, emergency reactivity testing upon notification from FDA, and label updates to report test results (see Class II Special Controls for RIDTs).6 Misdiagnosis of influenza is expected to decrease as more reliable RIDTs that meet these new performance standards enter the market. Additionally, annual and emergency testing ensures that RIDTs are being continually monitored in the postmarket setting.1

FDA notified the public of its decision to reclassify RIDTs to Class II devices in early 2017, but the extensive process began years earlier (see Key Milestones in RIDT Reclassification). After convening a panel of experts in 2013, FDA proposed RIDT reclassification and solicited public comments in 2014. Commenters—who represented device manufacturers, healthcare professionals, and consumers—supported the revision based in large measure on the potentially serious consequences of influenza misdiagnosis. Among the consequences mentioned by commenters: a possibly critical situation arising from the use of antibiotics instead of antivirals in false-negative cases, poor infection control, and increased hospitalizations and return visits to the doctor. According to FDA, “Overall, there was a general consensus among the commenters that the proposed special controls address and mitigate the risks to health.”1

Prior to the reclassification, manufacturers of Class I tests were not obligated to conduct any postmarket studies or to report on any postmarket performance analyses. Such an absence of ongoing assessment and feedback created challenges for clinicians, since they could not know exactly how one test compared with another, or how the tests performed across flu seasons.

Figure 1. Influenza virus marked by ongoing mutation.8 The constant changes in flu viruses primarily involve the surface proteins neuraminidase (NA) and hemagglutinin (HA). These mutations affect the efficacy of vaccines, antiviral medications, and diagnostic tests.  Image courtesy of the Centers for Disease Control and Prevention.

Figure 1. Influenza virus marked by ongoing mutation.8 The constant changes in flu viruses primarily involve the surface proteins neuraminidase (NA) and hemagglutinin (HA). These mutations affect the efficacy of vaccines, antiviral medications, and diagnostic tests.
Image courtesy of the Centers for Disease Control and Prevention.

A lack of ongoing feedback would be problematic for any diagnostic test, but none more so than tests for influenza, because this virus is marked by virtually continual mutation as it circulates from season to season, and even within seasons (Figure 1). Virus mutations affect every aspect of the medical and public health approach to influenza, including surveillance, prophylaxis, vaccination, testing and diagnosis, treatment, and infection control measures.

The Importance of Better Point-of-Care Flu Testing

FDA reclassification of RIDTs addressed issues and concerns raised by stakeholders as well as those that were important to regulators. In its published final order on the new classification, FDA detailed its concerns and decisions on topics such as the timing associated with meeting the new Class II requirements, appropriate RIDT comparators, and access to annual and emergency analytical reactivity test panels.1

Deadline for Meeting New Requirements. Despite some calls for delays in timing for implementation of the new controls, FDA stood firm on a 1-year grace period for manufacturers to meet the new standards, ending in January 2018. As FDA stated in the final order, “We . . . do not believe, given the risk that poor performance of antigen-based RIDTs pose to public health, a delay in implementation of more than 1 year is appropriate.”1

Figure 2. In April 2017, the Alere Reader and BinaxNow Influenza A & B Card 2 became the first reformulated rapid influenza diagnostic test (RIDT) to receive FDA premarket notification (510(k)) clearance under the agency’s Class II reclassification requirements for RIDTs.

Figure 2. In April 2017, the Alere Reader and BinaxNow Influenza A & B Card 2 became the first reformulated rapid influenza diagnostic test (RIDT) to receive FDA premarket notification (510(k)) clearance under the agency’s Class II reclassification requirements for RIDTs.

During the grace period, manufacturers whose currently marketed devices do not meet the new minimum performance standards can significantly modify or replace their devices, following premarket notification (510(k)) submission requirements (see Figure 2).1

RIDT Comparators. Currently, there are two FDA-accepted comparators for RIDTs: an FDA-cleared nucleic acid-based test, or a correctly performed viral culture method. FDA received public comments voicing concerns regarding the use of two distinct methods for evaluating clinical performance. Additionally, stakeholder feedback also raised concerns about the reliability issues associated with nonstandardized culture practices.1

FDA acknowledged the challenges associated with the viral culture method, but determined that when performed properly, the viral culture method has been shown to deliver accurate results and is thus a valid comparator. Therefore, in establishing the special controls for RIDTs, FDA has specified that “a viral culture comparator method used to demonstrate that a device meets the minimum performance criteria . . . must be correctly performed.”1

While the only FDA-accepted comparators for RIDTs at this time are FDA-cleared nucleic acid-based tests or a correctly performed viral culture method, the agency has left the door open for additional comparator methods in the future. To qualify as an FDA-accepted comparator for RIDTs, the new method must demonstrate comparable flu detection accuracy versus an FDA-cleared nucleic acid-based test.1

Access to Annual Standardized Test Panels. Another concern addressed in the final regulation was the observation that equal access to annual analytical reactivity test strains might not extend to all device manufacturers. One commenter noted that without fair, timely, and non-cost restrictive access to these test strains, some companies that innovate new flu diagnostics might no longer be able to do so. But according to FDA, device manufacturers should be able to obtain annual standardized seasonal flu virus test panels at the same time from CDC or, if CDC is unable to provide the annual strains, from an alternative source identified by FDA.1

As a point of interest, the test panels will be primarily determined by the World Health Organization (WHO) selection of strains for the annual vaccine, and are expected to include circulating viruses from recent flu seasons.1

Label Changes. Concerns also emerged around the need for timely availability of the annual and emergency analytical test panels to meet the deadline for analytical reactivity testing and label updates as specified in the special controls. FDA indicated that for the annual testing requirement, manufacturers will be provided access to the designated samples in sufficient time to complete testing and label updates by July 31 of each calendar year. For emergency testing, manufacturers will be given 60 days following notice of sample availability to complete testing and label requirements. If updating the printed label might place the manufacturer at risk of missing the deadline, FDA has established provisions for publishing the test results electronically on the manufacturer’s public website.1

Clinical Performance by Sample Type. Some RIDTs may demonstrate accuracy in detecting the flu virus when using certain sample types, but not when using other sample types. The special controls specify that the device must meet performance standards in all sample types listed in the intended use of the device.1 When postmarket test results show that one or more strains have not been detected by the device, the label update must include a statement of limitation that specifies the undetected strain(s).1

Improvements Benefit Patients, Providers, and Public Health

Higher performing point-of-care influenza tests will have many benefits for patients, healthcare providers, and public health.

“Increasing the number of devices that can reliably detect the influenza virus [at the point of care is] expected to lower the number of misdiagnosed influenza infections,” according to FDA. This should increase healthcare provider confidence in relying on these test results for clinical decisionmaking, which, in turn, could increase the use of point-of-care testing overall.

When more patients are diagnosed accurately and rapidly, a greater proportion of those with influenza will receive appropriate antivirals, those with bacterial infections will receive indicated antibiotics, and those who require supportive care only will avoid unnecessary medications and their associated risks (see A Note about Influenza . . .).

Rapid and accurate patient diagnosis also facilitates appropriate infection control procedures among close contacts. This is especially important for people who come in contact with very young, immunocompromised, or elderly individuals who are risk of hospitalization, death, or long-term disability from influenza.

Figure 3. The Alere i influenza A & B test is the first CLIA-waived molecular test for the rapid diagnosis of influenza A and B.

Figure 3. The Alere i influenza A & B test is the first CLIA-waived molecular test for the rapid diagnosis of influenza A and B.

The reclassification has already had a positive impact on the market. Recently, point-of-care molecular testing devices that have been granted waived-complexity status under the terms of the Clinical Laboratory Improvement Amendments of 1988 (CLIA) have become available to hospitals as well as physician office laboratories (see Figure 3). These tests offer new options that already meet the minimum performance criteria required by the FDA reclassification, and in some cases provide results even more rapidly than lateral-flow RIDT tests.

Conclusion

Optimal treatment of any disease begins with accurate diagnosis. Once fully implemented, reclassification of RIDTs as Class II devices will have a substantial and positive impact on influenza diagnosis. The more-rigorous Class II standards will improve patient and public health outcomes and give clinicians more confidence in the value of the tests from season to season as circulating influenza viruses mutate.

The RIDT reclassification creates a more-rigorous performance standard for RIDTs. Another key benefit of the reclassification is the annual performance data reporting provision, which is critically important given the variability of circulating flu viruses each year. By generating more performance data more frequently, the RIDT classification will help clinicians be better prepared each flu season.

Clinicians and patients will benefit from the RIDT reclassification, which will ensure not only a minimum level of performance among lateral-flow tests, but also that these tests have met that level for varying influenza virus strains. This will also yield public health benefits in the form of better linkage to appropriate care (eg, antiviral, antibiotic, or supportive care) and fewer unintended consequences (eg, negative impact on antibiotic resistance). It will also help ensure that manufacturers are continually assessing the sensitivity and specificity of their assays.

K.C. McGrath is senior marketing manager for point-of-care molecular devices at Alere, Waltham, Mass. For further information, contact CLP chief editor Steve Halasey via [email protected].

References

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  1. Microbiology devices; reclassification of influenza virus antigen detection test systems intended for use directly with clinical specimens. 79 Federal Register 99 (May 22, 2014):29387–29392. Available at: www.gpo.gov/fdsys/pkg/FR-2014-05-22/pdf/2014-11635.pdf. Accessed August 8, 2017.
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