What it means to you and your customers
Almost three years after publishing a proposed order, the U.S. Food and Drug Administration in February issued a final order reclassifying antigen-based RIDTs (rapid influenza virus antigen detection test systems) from Class I into Class II devices. The reclassification to Class II – a higher-risk designation – is intended to improve the quality of testing for influenza. The change was driven by concerns about the performance of antigen-based RIDTs during the influenza pandemic of 2009.
The new minimum performance requirements for these tests are intended to lower the number of misdiagnosed influenza infections by increasing the number of devices that can reliably detect the influenza virus. In addition, the special controls requiring annual and emergency analytical reactivity testing provide a process for continued monitoring of the performance of antigen-based RIDTs. As part of that process, the Centers for Disease Control and Prevention and FDA will collaborate on an annual basis to ensure that there is an influenza virus analytical reactivity test panel available to all manufacturers of antigen-based RIDTs for evaluation of the analytical reactivity of their assays with circulating viruses.
Repertoire asked three manufacturers of flu tests – Alere, Cepheid and Sekisui Diagnostics — to answer questions about the reclassification and its impact on customers and distributor reps.
Q&A: Alere
Repertoire: Can you explain, in laypersons’ terms, the reclassification of influenza diagnostics by the FDA? What do distributor reps need to know in order to be conversant with physician office staff?
Alere: Flu reclassification affects lateral flow flu tests, both visual and reader read tests. The reclassification was put forth by the FDA to improve the performance, especially the sensitivity, of these antigen tests.
The reclassification is a way of setting a minimum performance standard that all current and upcoming tests will have to meet. Tests that are reclassified will have to meet the minimum performance criteria set forth by the FDA and be tested yearly against the proposed circulating strains. Due to this reclassification, healthcare providers will have access to tests that not only meet this new, higher standard of performance, but also detect strains of flu for the current season.
The reclassification also brings into focus the availability of newer molecular testing devices, such as Alere™ i, that provide high sensitivity, are CLIA-waived, and are available in hospitals as well as in physician office laboratories. These newer molecular tests are already Class II devices and are not affected by flu reclassification.
Repertoire: What will be the impact of this on the physician practice?
Alere: There should not be any changes for physician practices for the entire 2017 flu season. If they are using a test that does not get “reclassified,” they may continue to purchase any and all products until January 12, 2018, and after that date continue to use the test through the shelf life of the kit. If they have a test that already meets the criteria, they may continue to purchase and use the test they currently use. In both scenarios, offices may look to molecular testing devices, such as Alere i, to address the limitations of traditional antigen testing. Nevertheless, the important takeaway is, if enough tests for the season are purchased by January 12, 2018, no changes are needed for the upcoming respiratory season.
Repertoire: What can distributor sales reps do to help their physician office customers comply with the new system?
Alere: The best thing to do for all customers is education. Be confident that reclassification focuses only on antigen (visual/reader) read tests and is focused on improving diagnosis, treatment, and patient outcomes. Physician office customers have many choices, and it is important to educate them about all the options that are available and to help them identify the methodology and test that best fits their need. Customers should also consider adopting molecular testing methodologies, such as the one utilized by Alere i, as these tests already meet the new FDA performance criteria and are CLIA-waived for flu and several other infectious diseases. Molecular testing allows for sample amplification, resulting in increased performance compared to antigen testing.
Repertoire: What impact will this have on the sale of your products? What do Repertoire readers need to advise their customers?
Alere: For all manufacturer products that do not meet reclassification, distributors will be able to continue to provide tests to customers until January 12, 2018. After that point, tests that do not meet the reclassification criteria can no longer be sold to customers. However, customers can continue to use the tests that they have in inventory through the shelf life of the kit. Alere currently provides a lateral flow test as well as a molecular test for flu that meets the FDA reclassification criteria. This a great opportunity to educate customers about Alere i. Alere i Influenza A & B is CLIA-waived and delivers molecular flu results in less than 15 minutes on our unique Alere i platform, making it significantly faster than other molecular methods and more accurate than conventional rapid tests. Rapid diagnostic tests with increased sensitivity are essential for the reliable detection of influenza A and B and enable immediate, effective treatment decisions.
Q&A: Cepheid
Repertoire: Can you explain, in laypersons’ terms, the reclassification of influenza diagnostics by the FDA? What do distributor reps need to know in order to be conversant with physician office staff?
Cepheid: In June 2013, the FDA, with input from many entities, including manufacturers of diagnostic tests, healthcare organizations, the CDC and healthcare providers, decided that rapid immunoassay tests (RIDTs) that detect influenza needed to be reclassified to class II devices.1 The FDA classifies devices based on the risks associated with the devices, and class II denotes that there are higher regulatory controls implemented to provide reasonable assurance of the device’s safety and effectiveness.2 Flu RIDTs that were reviewed as part of the reclassification decision performed with sensitivities that ranged from 50 percent to 80 percent This performance was considered sub-par in comparison to other technologies on the market today, such as nucleic acid amplification-based tests (NAATs) — also known as PCR-based technology. The FDA issued its final order for this reclassification on January 17, 2017.
The new standards that RIDTs must meet are:
- Sensitivity and specificity for Flu A and B must be at least 80 percent3and 95 percent3, respectively, when compared to a NAAT (molecular) method.
- Sensitivity for Flu A must be greater than 90 percent, sensitivity for Flu B must be greater than 80 percent, and specificity for both Flu A and B must be at least 95 percent when compared to viral culture.3
Distributor representatives should understand the performance of the tests that they are selling to physicians, and should always try to position assays with the highest performance first. When a test performs with low sensitivity, accurate interpretation of results can be challenging. For example, negative results might actually be positive, and for tests with low specificity, positive results might actually be negative. Influenza testing by a NAAT method is emerging as the preferred testing approach, due to the high sensitivity and specificity of the methods. The turnaround time with these methods is also attractive; many yield multi-analyte results in less than one hour. These three characteristics of NAATs will help the physician take action toward patients care with confidence and in a timely manner,
Repertoire: What will be the impact of this on the physician practice?
Cepheid: We believe the FDA reclassification of RIDTs will have a positive impact on the standard of care that physicians can provide. With better performance, physicians should take comfort that this reclassification order will lead to the removal of ineffective tests from the marketplace. More importantly, they can be confident that the better performance of NAATs will return more accurate results for their patients.
With the emergence of new, rapid PCR-based all-in-one test formats, such as Cepheid’s Xpert® Xpress Flu and Xpert® Xpress Flu/RSV tests4, the time to a positive result can be as soon as 20 minutes5. And the workflow to obtain a test result is greatly reduced: only three simple steps follow collection of the patient specimen. Rapid detection of influenza may reduce the inappropriate use of antibiotics. If the patient does present with a positive influenza result, the physician can prescribe Tamiflu, provided the patient has been seen within the appropriate treatment window for this therapeutic.6
Repertoire: What can distributor sales reps do to help their physician office customers comply with the new system?
Cepheid: Distributor representatives need to understand which tests in their portfolio do not meet the performance criteria defined in FDA’s final order on the reclassification. They should discuss their findings with their manufacturer partners, and understand what alternatives could be proposed to the physician practices that they serve today. The distributor representative is viewed as a trusted and unbiased partner to the physician practice, and should offer that same perspective when helping the physician choose a new influenza diagnostic assay.
Repertoire: What impact will this have on the sale of your products? What do Repertoire readers need to advise their customers?
Cepheid: Cepheid has been a leader in infectious disease testing by molecular methods. Our influenza and RSV assays have consistently met the FDA standards for performance7. With the launch of our Xpert Xpress Flu and Xpert Xpress Flu/RSV tests, we believe that the combination of our menu, the GeneXpert® systems, and the workflow flexibility that we offer, is a winning combination that can quickly provide critical diagnostic information to support physician decision-making.
1 Federal Register https://www.regulations.gov/docket?D=FDA-2014-N-0440
2 https://www.fda.gov/AboutFDA/Transparency/Basics/ucm194438.htm
3 When considering these results, vendors may also factor in a lower 95% Confidence Interval (CI), this translates into a minimum sensitivity of greater than 70% and minimum specificity of greater than 90%.
4 For in vitro Diagnostic Use
5 Delivering positive results in as soon as 20 minutes, negative and combined results are reported in 30 minutes
6 https://patient.info/medicine/oseltamivir-capsules-and-suspension-tamiflu
7 Medical/Scientific Affairs Bulletin “Xpert® Flu/RSV XC Test Improves Sensitivity over Xpert® Flu and Expands Coverage for Circulating Strains; Xpert® Xpress Flu/RSV Delivers Results in 30 Minutes”
Q&A: Sekisui Diagnostics
Responses provided by Susan Ward, senior global product manager, point of care, Sekisui Diagnostics.
Repertoire: Can you explain, in laypersons’ terms, the reclassification of influenza diagnostics by the FDA?
Susan Ward: On January 12, 2017, the FDA notified the public of its decision to reclassify antigen-based rapid influenza virus antigen detection test systems (RIDTs) from Class I devices into a more stringent Class II devices, with special controls to provide assurance of the safety and effectiveness of these devices.
Manufacturers reclassifying their Class I devices to Class II devices will need to meet the following standards:
- Minimum clinical performance criteria. (See table.)
- Manufacturers are required to perform annual testing of contemporary influenza strains that will be identified by FDA in consultation with CDC and tested according to a standardized protocol.
- Keep labeling up to date with results of current influenza emergency testing issued by the FDA and other health agencies as well as the results of the annual testing.
Minimum clinical performance criteria
When Compared to Viral Culture:
| Analyte | Sensitivity | Specificity |
| Flu A | 90% (LB* of 95% CI* >80%) | 95% (LB of 95% CI >90%) |
| Flu B | 80% (LB of 95% CI >70%) | 95% (LB of 95% CI >90%) |
When compared to molecular
| Analyte | Positive Percent Agreement | Negative Percent Agreement |
| Flu A | 80% (LB of 95% CI >70%) | 95% (LB of 95% CI >90%) |
| Flu B | 80% (LB of 95% CI >70%) | 95% (LB of 95% CI >90%) |
*LB = lower bound; CI = confidence interval
Repertoire: What do distributor reps need to know in order to be conversant with physician office staff?
Ward: At this time, customers can continue to purchase their existing test methods. Distributions reps need to know what the minimum clinical performance is and what test methods meet the criteria. It is important for reps to understand that there are choices in testing to meet the customer needs. There are manual, reader, and molecular testing methods available. It is important for the rep to know all the advantages and disadvantages of each test method and work with the physician to help guide them to the best test method for their particular needs.
Repertoire: What will be the impact of this on the physician practice?
Ward: The physician’s office will need to evaluate their current test system and decide if the test method that they are currently utilizing meets the reclassification requirements.
If the current test method does not meet the reclassification requirements, according to the FDA Final Rule, the ‘reclassification’ will not be enforced until January 12, 2018. Therefore, physicians’ offices can continue to utilize their current test method until further notification from the manufacturer.
If the current system meets the regulation, then a physician can continue to utilize that assay. If they are unsure if their current method meets the requirements, they are encouraged to contact the manufacturer.
Repertoire: What can distributor sales reps do to help their physician office customers comply with the new system?
Ward: Be proactive in the accounts to help determine if the test method that their customers are utilizing meet the requirements. Work with the customers to see what testing characteristics are important to them. Depending on those characteristics, provide them all the options that are best suited for their practice.
Repertoire: What impact will this have on the sale of your products? What do Repertoire readers need to advise their customers?
Ward: Sekisui Diagnostics will take the appropriate actions to ensure that our influenza products comply with the requirements imposed by the FDA to meet the Class II standards for rapid influenza diagnostic testing.
The OSOM Ultra Flu A&B Test was approved in November 2016 for CLIA Waiver status for Nasal and Nasopharyngeal Swabs and is confirmed by the FDA that the test meets the performance criteria stated in the Final Rule.