Surplus retrospective (frozen) respiratory specimens from clinical trial sites
Retrospective clinical specimens were used to establish the clinical sensitivity and specificity of the BD Directigen EZ Flu A+B test compared to cell culture.
Retrospective clinical specimens; Clinical performance; Influenza A and B
Clinical Evidence
Study Design
Population
Comparator
Key Endpoints
Multi-center clinical study (2003-2005); Multi-center study using prospective and retrospective (frozen) respiratory specimens; Follow-up/Duration: 2003-2005 respiratory seasons; Study Period: 2003-2005
Symptomatic patients (pediatric and adult) suspected of having influenza; Sample Size: 735 prospective specimens (plus retrospective specimens); Number of Sites: 18 sites total (5 in 2003-2004, 13 in 2004-2005)
Cell culture
Clinical sensitivity and specificity for Influenza A and B
Indications for Use
The BD Directigen™ EZ Flu A+B test is a rapid chromatographic immunoassay for the direct and qualitative detection of influenza A and B viral antigens from nasopharyngeal washes/aspirates and throat swabs of symptomatic patients. The BD Directigen™ EZ Flu A+B test is a differentiated test, and therefore influenza A viral antigens can be distinguished from influenza B viral antigens from a single processed sample using a single device. The test is to be used as an aid in the diagnosis of influenza A and B viral infections. All negative test results should be confirmed by cell culture.
Device Story
Rapid chromatographic immunoassay for qualitative detection of influenza A and B viral antigens; utilizes respiratory specimens (nasopharyngeal washes/aspirates, throat swabs). Mucolytic reagent breaks down mucus to expose antigens; processed sample flows via capillary action across test strips. Influenza A/B antigens bind to specific monoclonal antibodies conjugated to colloidal gold; antigen-conjugate complex captured by antibody lines on membrane. Positive result indicated by reddish-purple lines at test and control positions; negative result indicated by absence of test line. Used in clinical settings; performed by laboratory personnel. Provides rapid visual diagnostic aid; negative results require confirmation by cell culture. Detects highly conserved nucleoprotein, minimizing impact of antigenic drift.
Clinical Evidence
Multi-center study (n=735 prospective specimens) across 2003-2005 seasons. Compared against cell culture. Influenza A sensitivity: 86% (nasopharyngeal), 77% (throat swabs); specificity: 99% (nasopharyngeal), 86% (throat swabs). Influenza B sensitivity: 80% (nasopharyngeal), 69% (throat swabs); specificity: 100% (nasopharyngeal), 99% (throat swabs). Reproducibility 99.6%.
Technological Characteristics
Chromatographic immunoassay; lateral flow test strip format. Employs anti-influenza antibodies conjugated to visualizing particles. Qualitative visual readout. Standalone device; no electronic components or software.
Indications for Use
Indicated for symptomatic patients requiring rapid qualitative detection and differentiation of influenza A and B viral antigens from nasopharyngeal washes/aspirates and throat swabs.
Regulatory Classification
Identification
An influenza virus antigen detection test system is a device intended for the qualitative detection of influenza viral antigens directly from clinical specimens in patients with signs and symptoms of respiratory infection. The test aids in the diagnosis of influenza infection and provides epidemiological information on influenza. Due to the propensity of the virus to mutate, new strains emerge over time which may potentially affect the performance of these devices. Because influenza is highly contagious and may lead to an acute respiratory tract infection causing severe illness and even death, the accuracy of these devices has serious public health implications.
Special Controls
*Classification.* Class II (special controls). The special controls for this device are:(1) The device's sensitivity and specificity performance characteristics or positive percent agreement and negative percent agreement, for each specimen type claimed in the intended use of the device, must meet one of the following two minimum clinical performance criteria:
(i) For devices evaluated as compared to an FDA-cleared nucleic acid based-test or other currently appropriate and FDA accepted comparator method other than correctly performed viral culture method:
(A) The positive percent agreement estimate for the device when testing for influenza A and influenza B must be at the point estimate of at least 80 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 70 percent.
(B) The negative percent agreement estimate for the device when testing for influenza A and influenza B must be at the point estimate of at least 95 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 90 percent.
(ii) For devices evaluated as compared to correctly performed viral culture method as the comparator method:
(A) The sensitivity estimate for the device when testing for influenza A must be at the point estimate of at least 90 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 80 percent. The sensitivity estimate for the device when testing for influenza B must be at the point estimate of at least 80 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 70 percent.
(B) The specificity estimate for the device when testing for influenza A and influenza B must be at the point estimate of at least 95 percent with a lower bound of the 95 percent confidence interval that is greater than or equal to 90 percent.
(2) When performing testing to demonstrate the device meets the requirements in paragraph (b)(1) of this section, a currently appropriate and FDA accepted comparator method must be used to establish assay performance in clinical studies.
(3) Annual analytical reactivity testing of the device must be performed with contemporary influenza strains. This annual analytical reactivity testing must meet the following criteria:
(i) The appropriate strains to be tested will be identified by FDA in consultation with the Centers for Disease Control and Prevention (CDC) and sourced from CDC or an FDA-designated source. If the annual strains are not available from CDC, FDA will identify an alternative source for obtaining the requisite strains.
(ii) The testing must be conducted according to a standardized protocol considered and determined by FDA to be acceptable and appropriate.
(iii) By July 31 of each calendar year, the results of the last 3 years of annual analytical reactivity testing must be included as part of the device's labeling. If a device has not been on the market long enough for 3 years of annual analytical reactivity testing to have been conducted since the device received marketing authorization from FDA, then the results of every annual analytical reactivity testing since the device received marketing authorization from FDA must be included. The results must be presented as part of the device's labeling in a tabular format, which includes the detailed information for each virus tested as described in the certificate of authentication, either by:
(A) Placing the results directly in the device's § 809.10(b) of this chapter compliant labeling that physically accompanies the device in a separate section of the labeling where the analytical reactivity testing data can be found; or
(B) In the device's label or in other labeling that physically accompanies the device, prominently providing a hyperlink to the manufacturer's public Web site where the analytical reactivity testing data can be found. The manufacturer's home page, as well as the primary part of the manufacturer's Web site that discusses the device, must provide a prominently placed hyperlink to the Web page containing this information and must allow unrestricted viewing access.
(4) If one of the actions listed at section 564(b)(1)(A)-(D) of the Federal Food, Drug, and Cosmetic Act occurs with respect to an influenza viral strain, or if the Secretary of Health and Human Services (HHS) determines, under section 319(a) of the Public Health Service Act, that a disease or disorder presents a public health emergency, or that a public health emergency otherwise exists, with respect to an influenza viral strain:
(i) Within 30 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation, the manufacturer must have testing performed on the device with those viral samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate. The procedure and location of testing may depend on the nature of the emerging virus.
(ii) Within 60 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation and continuing until 3 years from that date, the results of the influenza emergency analytical reactivity testing, including the detailed information for the virus tested as described in the certificate of authentication, must be included as part of the device's labeling in a tabular format, either by:
(A) Placing the results directly in the device's § 809.10(b) of this chapter compliant labeling that physically accompanies the device in a separate section of the labeling where analytical reactivity testing data can be found, but separate from the annual analytical reactivity testing results; or
(B) In a section of the device's label or in other labeling that physically accompanies the device, prominently providing a hyperlink to the manufacturer's public Web site where the analytical reactivity testing data can be found. The manufacturer's home page, as well as the primary part of the manufacturer's Web site that discusses the device, must provide a prominently placed hyperlink to the Web page containing this information and must allow unrestricted viewing access.
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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY
A. 510(k) Number:
K042472
B. Purpose of Submission:
Clearance of new device
C. Analyte:
Influenza A and B viral antigens
D. Type of Test:
Rapid chromatographic immunoassay that differentiates influenza A viral antigens from influenza B viral antigens
E. Applicant:
Becton, Dickinson and Company
F. Proprietary and Established Names:
BD Directigen™ EZ Flu A+B Kit
G. Regulatory Information:
1. Regulation section:
21 CFR§866.3330
2. Classification:
I
3. Product Code:
GNX – Antigens, CF including CF controls), Influenza Virus A, B, C.
4. Panel:
83 Microbiology
H. Intended Use:
1. Intended use(s):
The BD Directigen™ EZ Flu A+B test is a rapid chromatographic immunoassay for the direct and qualitative detection of influenza A and B viral antigens from nasopharyngeal washes/aspirates and throat swabs of symptomatic patients. The BD Directigen EZ Flu A+B test is a differentiated test, and therefore influenza A viral antigens can be distinguished from influenza B viral antigens from a single processed sample using a single device. The test is to be used as an aid in the diagnosis of influenza A and B viral infections. All negative test results should be confirmed by cell culture.
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2. Indication(s) for use:
The BD Directigen™ EZ Flu A+B test is a rapid chromatographic immunoassay for the direct and qualitative detection of influenza A and B viral antigens from nasopharyngeal washes/aspirates and throat swabs of symptomatic patients. The BD Directigen EZ Flu A+B test is a differentiated test, and therefore influenza A viral antigens can be distinguished from influenza B viral antigens from a single processed sample using a single device. The test is to be used as an aid in the diagnosis of influenza A and B viral infections.
3. Special condition for use statement(s):
For Prescription Use Only
4. Special instrument Requirements:
Not applicable
I. Device Description:
The BD Directigen™ EZ Flu A+B test is a chromatographic assay to qualitatively detect influenza A and B viral antigens in samples processed from respiratory specimens. When specimens are processed and added to the test device, influenza A and/or B viral antigens bind to anti-influenza antibodies conjugated to visualizing particles in the corresponding A and B test strips. The antigen-conjugate complex migrates across the test strip to the reaction area and is captured by the line of antibody on the membrane. A positive result for influenza A is visualized as a reddish purple line at the Test "T" position and the Control "C" position in the BD Directigen™ EZ Flu A read window and a visible reddish purple line at the Control "C" position in the BD Directigen™ EZ Flu B read window. A positive result for influenza B is visualized as a reddish purple line at the Test "T" position and the Control "C" position in the BD Directigen™ EZ Flu B read window and a visible reddish purple line at the Control "C" position in the BD Directigen™ EZ Flu A read window.
J. Substantial Equivalence Information:
1. Predicate device name(s):
Viral cell culture, direct fluorescent antibody (DFA) tests,
BD Directigen™ EZ Flu A+B test (K001364),
and the Remel Xpect FLU A/B test (K031565).
2. Predicate K number(s):
K001364, K031565,
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3. Comparison with predicate(s):
| Similarities | | | | | |
| --- | --- | --- | --- | --- | --- |
| Item | Device | Predicate | Predicate | Predicate | Predicate |
| | BD Directigen™ EZ Flu A+B | Viral Cell Culture | Direct Fluorescent Antibody (DFA) | BD Directigen™ Flu A+B | Remel Xpect™ FLU A/B |
| Intended use | an in vitro diagnostic product for direct and qualitative detection of influenza A and B viral antigens from nasopharyngeal washes/aspirates and throat/lower nasal swabs | Viral cell culture uses kidney cell lines or other cell lines for the recovery of live influenza A or B viruses from direct specimens of symptomatic patients. | The DFA test is a fluorescent antibody assay for the detection of influenza A and/or B antigens from cell culture or intact epithelial cells from respiratory specimens. | The BD Directigen™ Flu A+B Test is a rapid in vitro enzyme immunoassay (EIA) membrane test for the direct and qualitative detection of influenza A and B viral antigens from respiratory specimens listed below. It is not intended for detection of influenza C. | REMEL's Xpect™ FLU A/B is a rapid in vitro immunochromatographic test for the direct, qualitative detection of influenza A and influenza B viral antigen (nucleoprotein) from respiratory specimens listed below. It is an aid in the rapid diagnosis of influenza A and influenza B viral infections. Negative tests should be confirmed by cell culture. |
| Specimen types | nasopharyngeal washes/aspirates, throat/lower nasal swabs | Respiratory tract specimens | Respiratory tract specimens | nasopharyngeal washes/aspirates, nasopharyngeal swabs, lower nasal swabs, throat swabs and bronchoalveolar lavages | nasal washes, nasal swabs and throat swabs |
| Assay Technology | Immuno-chromatographic | Tissue culture | Microscopic slide immunofluorescence | EIA (enzyme immunoassay) – Flow through capture | Immuno-chromatographic |
| Detection of Flu A + B viruses | Differentiated influenza A and influenza B | Differentiated influenza A and influenza B | Differentiated influenza A and influenza B | Differentiated influenza A and influenza B | Differentiated influenza A and influenza B |
| Differences | | | | | |
| --- | --- | --- | --- | --- | --- |
| Item | Device | Predicate | Predicate | Predicate | Predicate |
| | BD Directigen™ EZ Flu A+B | Viral Cell Culture | Direct Fluorescent Antibody (DFA) | BD Directigen™ Flu A+B | Remel Xpect™ FLU A/B |
| Assay Technology | Immuno-chromatographic | Tissue culture | Microscopic slide immunofluorescence | EIA (enzyme immunoassay) – Flow through capture | Immuno-chromatographic |
| Total assay time | Less than 30 min | Up to 14 days | ~ 1-2 hours | Less than 30 min | Less than 30 min |
| Level of | Moderately complex | Complex | Complex | Moderately complex | Moderately complex |
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| skill | CEID_{50}/ml | Not available | Not available | CEID_{50}/ml | CEID_{50}/ml |
| --- | --- | --- | --- | --- | --- |
| Limit of detection | | | | | |
| A/PR/8/34 (H1N1) | 1.75 x 10^{4} | | | 8.2 x 10^{3} | 8.9 x 10^{3} |
| A/FM/1/47 (H1N1) | 1.98 x 10^{3} | | | 5.9 x 10^{2} | 7.9 x 10^{1} |
| A/NWS/33 (H1N1) | 1.00 x 10^{4} | | | 1.6 x 10^{2} | NA |
| A1/Denver/1/57 (H1N1) | 5.56 x 10^{3} | | | 6.5 x 10^{1} | NA |
| A/New Jersey/8/76 (H1N1) | 4.45 x 10^{3} | | | 2.1 x 10^{2} | 8.9 x 10^{1} |
| A/Port Chalmers/1/73 (H3N2) | 1.00 x 10^{3} | | | 2.9 x 10^{2} | 4.0 x 10^{1} |
| A/Hong Kong/8/68 (H3N2) | 2.78 x 10^{2} | | | NA | 2.8 x 10^{1} |
| A2/Aichi2/68 (H3N2) | 3.50 x 10^{3} | | | NA | NA |
| A/Victoria/3/75 (H3N2) | 2.78 x 10^{4} | | | 3.3 x 10^{4} | 8.9 x 10^{2} |
| B/Lee/40 | 6.95 x 10^{5} | | | 1.2 x 10^{6} | 7.9 x 10^{3} |
| B/Allen/45 | 2.00 x 10^{3} | | | 1.8 x 10^{2} | 4 |
| B/GL/1739/54 | 5.56 x 10^{3} | | | 2.5 x 10^{3} | 8.9 x 10^{1} |
| B/Taiwan/2/62 | 3.50 x 10^{2} | | | 6.6 x 10^{2} | 3 |
| B/Hong Kong/5/72 | 2.23 x 10^{4} | | | 2.3 x 10^{3} | 1.58 x 10^{2} |
| Item | Device | Predicate | Predicate | Predicate | Predicate |
| | BD Directigen™
EZ
Flu A+B | Viral Cell Culture | Direct Fluorescent Antibody (DFA) | BD Directigen™
Flu A+B | Remel Xpect™
FLU A/B |
| Clinical sensitivity/
Clinical specificity | Influenza A:
Nasal washes/
aspirates (n=466):
85.8% (79.9-91.7%)
99.4% (97.8-99.9%)
Throat swabs(n=269)
76.8% (63.6-87.0%)
86.4% (81.6-91.0%)
Influenza B:
Nasal washes/
aspirates (n=466)
80.3% (69.1-88.8%)
99.7% (98.6-100%)
Throat swabs(n=269)
69.1% (55.2-80.9%)
98.6% (96.0-99.7%) | Not available | Not available | Influenza A:
Nasal aspirates (n = 350):
95.7% (85.2-99.5%)
91.4% (87.6-94.3%)
Throat swabs(n=389)
76.7% (65.4-85.8%)
90.8% (87.1-93.8)
Influenza B:
Nasal aspirates (n = 350)
87.5% (71.0-96.5%)
98.1% (95.9-99.3%)
Throat swabs(n=389)
0% (0.0-97.5%)
100% (99.1-100%) | Influenza A:
Nasal washes/
aspirates (n=239):
92.5% (79.6-98.4%)
100% (98.2-100%)
Throat swabs (n=30)
100% (69.2-100%)
100% (83.2-100%)
Influenza B:
Nasal washes/
aspirates (n=268)
100% (90.3-100%)
100% (98.2-100%)
Throat swabs (n=30)
100% (39.8-100%)
100%(86.8-100%) |
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## K. Standard/Guidance Document referenced (if applicable):
Not applicable
## L. Test Principle:
The device is a chromatographic assay for qualitative influenza A and B viral antigen detection in respiratory specimens. Mucolytic agents (reagent E) breaks down mucous in a patient specimen to expose viral antigens and enhance detection in the assay device. Processed specimens are expressed through a filter tip into each of two sample wells in the device. The applied specimen flows across the device membrane through capillary action for detection of influenza antigens. The influenza A antigen in the specimen binds to anti-influenza A monoclonal antibody conjugated to colloidal gold and the gold complex is captured on the test line ("T") of the reaction strip in the Flu A read window by a second anti-influenza A monoclonal antibody. The influenza B antigen in the specimen binds to anti-influenza B monoclonal antibody conjugated to colloidal gold and is captured on the test line ("T") of the reaction strip in the Flu B read window by a second anti-influenza B monoclonal antibody. Any unbound antibody-colloidal gold complex continues to flow up the reaction strip and is captured by the control line ("C") of the respective reaction strip. The viral antigens detected by device are highly conserved nucleoprotein of the influenza viruses, not hemagglutinin (HA) or neuraminidase (NA) proteins. Therefore, minor point mutations (i.e., antigenic drift) to either one or both of the surface proteins (i.e., HA or NA) should not affect the BD Directigen EZ Flu A+B test.
A positive result for influenza A is visually interpreted as a reddish purple line at the test position ("T") and the control position ("C") within the Flu A read window. A positive result for influenza B is visually interpreted as a reddish purple line at the test position ("T") and the control position ("C") within the Flu B read window. A negative result for influenza A and influenza B antigens is visually interpreted as the absence of a reddish purple line at the "T" positions with the presence of a reddish purple line at the "C" positions in both read windows.
## M. Performance Characteristics (if/when applicable):
1. Analytical performance:
a. Precision/Reproducibility:
The reproducibility of BD Directigen™ EZ Flu A+B assay was determined with a panel of twenty simulated samples (influenza positive and negative). Four clinical trial sites conducted the test. The panel for Influenza A and B had known negative (n=10), low positive (n=4, 2xLoD, and medium positive (n=6, 8xLoD) members. The samples were coded and randomly sorted to prevent their identification during testing. Each site tested the panel on three separate, successive days using two different kit lots of BD Directigen™ EZ Flu A+B. Three of the 4 sites demonstrated 100% reproducibility, one site misidentified one sample on one of the days
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resulting in a total reproducibility of 98.3% for that site. The overall reproducibility for all sites was determined as 99.6%.
b. Linearity/assay reportable range:
Not applicable
c. Traceability (controls, calibrators, or method):
Not applicable
d. Detection limit:
The limit of detection (LoD) for each viral strain was defined as the lowest concentration level of the strain that produced a positive reaction with all three replicates of the test using a two-fold dilution serious. Each set of two-fold dilutions (one set per viral strain) was required to contain at least one dilution that resulted in negative results with all three replicates. Additionally each set of serial dilutions was required to contain at least two consecutive dilutions that both resulted in positive results for all three replicates.
The limit of detection (LoD) for the BD Directigen EZ Flu A+B test was established for a total of 15 influenza strains; nine influenza A and six influenza B. The ATCC reported concentration of viral particles of each strain was used to calculate the lowest concentration detectable by the BD Directigen EZ Flu A+B test from the highest dilution that resulted in positive results.
| Type | Influenza Viral Strain | LoD (CEID_{50}/mL*) |
| --- | --- | --- |
| A | A/PR/8/34 (H1N1) | 1.75 X 10^{4} |
| A | A/FM/1/47 (H1N1) | 1.98 X 10^{3} |
| A | A/NWS/33 (H1N1) | 1.00 X 10^{4} |
| A | A1/Denver/1/57 (H1N1) | 5.56 X 10^{3} |
| A | A/New Jersey/8/76 (H1N1) | 4.45 X 10^{3} |
| A | A/Port Chalmers/1/73 (H3N2) | 1.00 X 10^{3} |
| A | A/Hong Kong/8/68 (H3N2) | 2.78 X 10^{2} |
| A | A2/Aichi2/68 (H3N2) | 3.50 X 10^{3} |
| A | A/Victoria/3/75 (H3N2) | 2.78 X 10^{4} |
| B | B/Lee/40 | 6.95 X 10^{5} |
| B | B/Allen/45 | 2.00 X 10^{3} |
| B | B/GL/1739/54 | 5.56 X 10^{3} |
| B | B/Taiwan/2/62 | 3.50 X 10^{2} |
| B | B/Hong Kong/5/72 | 2.23 X 10^{4} |
| B | B/Hong Kong/5/72 | 2.23 X 10^{4} |
* CEID50/mL = Chick Embryo Infectious Dose at which 50% of the embryos perish
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e. Analytical specificity:
Evaluation of media for preservation and transport of respiratory specimens:
Simulated positive samples were prepared by diluting influenza A (Flu A/PR/8/34) or influenza B (Flu B/Lee/40) in each medium to a concentration equivalent to two times the LOD. Two aliquots of each spiked medium (one at room temperature for 1-2 hours and one stored overnight at −20 ± 5 °C) were tested in triplicate devices as processed samples to examine for interference and any effects of storage on performance in the BD Directigen EZ Flu A+B test. Of the 24 media tested in this evaluation, 21 demonstrated the expected results and met the acceptance criteria for both storage conditions.
The following media are compatible with the BD Directigen EZ Flu A+B test: Phosphate Buffered Saline (PBS), PBS plus 0.5% gelatin, PBS plus 0.5% BSA, Veal Infusion Broth (VIB), VIB plus 0.5% BSA, Hanks Basal Salt Solution, M4 Media, M5 Media, Bartel ViraTran Media, Sucrose Phosphate (2-SP), Trypticase Soy Broth, Trypticase Soy Broth plus 0.5% gelatin, Trypticase Soy Broth plus 0.5% BSA, Earle's Minimal Essential Medium (EMEM), EMEM plus 0.5% BSA, EMEM plus 1.0% BSA, Modified Stuarts liquid Culture Swab, Amies (liquid) Culture Swab, M4 RT Media, Starplex Multitrans, Cellmatics.
EMEM plus 0.5% lactalbumin and EMEM plus 1.0% lactalbumin media are not compatible with the device and this will be reflected in the package insert. Regarding normal saline, the data show that this media is not appropriate for the overnight frozen storage of samples.
Therefore, frozen storage of specimens collected in normal saline is not recommended for this test.
Cross reactivity Study:
Dulbecco's phosphate buffered saline (D-PBS) inoculated with the following microbial agents (to a final sample concentration of approximately 1.5 X 10⁸ CFU/mL (CFU – Colony Forming Unit) do not react with the BD Directigen EZ Flu A+B test: Acinetobacter baumannii(calcoaceticus), Actinobacillus suis, Bacteroides fragilis, Bordetella pertussis, Candida albicans, Candida glabrata, Cardiobacterium hominis, Chlamydia trachomatis LGVII, Corynebacterium diphtheriae, Corynebacterium diphtheriae, Eikenella corrodens, Enterococcus faecalis, Enterococcus gallinarum, Escherichia coli, Fusobacterium nucleatum, Gardnerella vaginalis, Haemophilus aphrophilus, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus paraphrophilus, Kingella kingae, Klebsiella pneumoniae, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus plantarum, Legionella pneumophila, Listeria monocytogenes,
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Moraxella catarrhalis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium tuberculosis, Mycoplasma orale, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria mucosa, Neisseria sicca, Neisseria subflava, Peptostreptococcus anaerobius, Porphyromonas asaccharolyticus, Prevotella oralis, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella choleraesuis sub Minnesota, Serratia marcescens, Staphylococcus aureus, Staphylococcus aureus-Cowan 1, Streptococcus bovis II Group D, Staphylococcus epidermidis, Streptococcus mutans, Streptococcus oralis, Streptococcus pneumoniae, Streptococcus pyogenes Group A, Streptococcus sanguis, Streptococcus sp. Group B, Streptococcus sp. Group C, Streptococcus sp. Group F, Streptococcus sp. Group G, Veillonella parvula. Relevant concentrations of the following viruses do not react with the assay: Adenovirus, type 3 (GB), Adenovirus, type 5 (Adenoid 75), Adenovirus, type 7 (Gomen), Adenovirus, type 10 (J.J.), Adenovirus, type 18 (D. C.), Coronavirus (229E), Coxsackievirus Type A9 (Griggs), Coxsackievirus Type A9 (P.B. Bozek), Coxsackievirus Type B5 (Faulkner), Coxsackievirus Type B6 (Schmitt), Coxsackievirus Type A21 (Kuykendall), Cytomegalovirus (AD-169), Echovirus Type 2 (Cornelis), Echovirus Type 3 (Morrisey), Echovirus Type 6 (D'Amori), HSV Type 1 (HF), HSV Type 2 (MS), Influenza A/PR/8/34 (H1N1), Influenza A/Victoria/3/75 (H3N2), Influenza B/Hong Kong/5/72, Influenza B/Lee/40, Influenza B/Allen/45, Influenza B/GL/1739/54, Influenza B/Maryland/1/59, Influenza B/Taiwan/2/62, Measles virus (Edmonston), Mumps virus (Enders), Parainfluenza Type 1 (Sendia/52), Parainfluenza Type 2 (Greer), Parainfluenza Type 3 (C243), Rhinovirus Type 1A (2060), Rhinovirus Type 2 (HGP), Rhinovirus Type 13 (353), Rhinovirus Type 15 (1734), Rhinovirus Type 16 (11757), Rhinovirus, Type 37 (151-1), RSV Type A (Long), RSV Type B (Wash/18537/62), VZV (Ellen)
## Interference study:
An interference study was conducted and the following substances were determined to have no effect on test results when present in spiked samples in the concentrations indicated: Whole Blood (2%), Mouthwash (25%, Scope, Listerine, Tom's of Maine), Cough drops (25% Lozenge, Halls, Cold-Eeze, Sucrets), Nasal Spray (10%, Afrin, 4-Way, Giant brand, 4-Acetamidophenol (10 mg/mL), Acetylsalicylic acid (20 mg/mL), Chlorpheniramine maleate (5 mg/mL), Dextromethoraphan (10 mg/mL), Diphenhydramine HCl (5 mg/mL), Pseudoephedrine HCl (20 mg/mL), Guaiacol Glyceryl Ether (20 mg/mL), Ibuprofen (10 mg/mL), Oxymetazoline(0.05 mg/mL), Phenylephrine(1 mg/mL), Loratidine (100 ng/mL),
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Fexofenadine (500 ng/mL), Zanamavir (1 mg/mL), Amantadine (500 ng/mL), Rimantadine (500 ng/mL), Albuterol (0.083 mg/mL), Oseltamivir (500 ng/mL), Ribavirin (500 ng/mL), Synagis (0.1 mg/mL).
f. Assay cut-off
Not applicable.
2. Comparison studies:
a. Method comparison with gold standard: see clinical studies
b. Matrix comparison:
Not applicable
3. Clinical studies: General remarks: Performance characteristics for the BD Directigen EZ Flu A+B test were established in a multi-center study conducted at five trial sites during the 2003-2004 respiratory season and 13 trial sites during the 2004-2005 respiratory season. The clinical centers were located in geographically diverse areas within the United States, Japan and Hong Kong. The study consisted of four segments:
a) Proficiency Evaluation,
b) Clinical Specimen Performance,
c) Reproducibility Testing, and
d) Clinical Specimen Stability.
Proficiency and reproducibility were conducted using panels of simulated samples provided by BD. Clinical performance was conducted on surplus prospective and retrospective (frozen) respiratory specimens. Clinical specimen stability testing was conducted using surplus prospective respiratory specimens
a. Proficiency evaluation
Five clinical centers performed testing for the BD Directigen EZ Flu A+B assay. Each clinical site was required to demonstrate at least 90% proficiency with a panel of twenty simulated influenza samples prior to enrolling clinical specimens. The panel included the following samples: influenza A and B positive (both A & B: n = 4 low positive, 2X LoD; n = 4 medium positive, 8X LoD). Eighteen (18) technologists participated in the clinical study. All eighteen of the technologists passed the proficiency panel testing (i.e., demonstrated at least 90% proficiency) for the BD Directigen EZ Flu A+B in their first attempt.
b. Clinical sensitivity:
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A total of 735 prospective specimens were evaluated using the BD Directigen EZ Flu A+B test and cell culture. These specimens consisted of nasopharyngeal washes, nasopharyngeal aspirates, and throat swabs from patients suspecting of having influenza.
The performance characteristics for BD Directigen EZ Flu A+B test as compared to cell culture for each specimen type are presented in Tables 1 through 4.
Table 1: Summary of the Performance of the BD Directigen EZ Flu A+B Test Compared to Culture for all Specimen Types -- Influenza A Combined 2003-2004 and 2004-2005 Respiratory Seasons
| | | Cell Culture | |
| --- | --- | --- | --- |
| Specimen Type | BD Directigen EZ Flu A+B Test | P | N |
| Nasopharyngeal washes/aspirates | P | 115 | 02 |
| | N | 19 | 330 |
| Sensitivity: 86% (95% CI: 79% - 91%)
Specificity: 99% (95% CI: 98% - 100%) | | | |
| Throat/lower nasal swabs | P | 43 | 29 |
| | N | 13 | 184 |
| Sensitivity: 77% (95% CI: 64% - 87%)
Specificity: 86% (95% CI: 81% - 91%) | | | |
Table 2: Summary of the Performance of the BD Directigen EZ Flu A+B Test Flu A+B Test Compared to Culture for all Specimen Types -- Influenza B Combined 2003-2004 and 2004-2005 Respiratory Seasons
| | | Cell Culture | |
| --- | --- | --- | --- |
| Specimen Type | BD Directigen EZ Flu A+B Test | P | N |
| Nasopharyngeal wash/aspirates | P | 57 | 1 |
| | N | 14 | 394 |
| Sensitivity: 80% (95% CI: 69% - 89%)
Specificity: 100% (95% CI: 99% - 100%) | | | |
| Throat/lower nasal swabs | P | 38 | 3 |
| | N | 17 | 211 |
| Sensitivity: 69% (95% CI: 55% - 81%)
Specificity: 99% (95% CI: 96.4% - 100%) | | | |
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Table 3: Summary of the Performance of the BD Directigen EZ Flu A+B Test Compared to Culture for all Specimen Types by Population – Influenza A
Combined 2003-2004 and 2004-2005 Respiratory Seasons
| | | Cell Culture | | | |
| --- | --- | --- | --- | --- | --- |
| Specimen Type | BD Directigen EZ Flu A+B Test | Pediatric | | Adult | |
| Nasopharyngeal washes/aspirates | | P | N | P | N |
| | P | 94 | 2 | 21 | 0 |
| | N | 11 | 294 | 8 | 36 |
| Sensitivity: Pediatric: 90% (95% CI: 82% - 95%); Adult: 72% (95% CI: 53% - 87%) Specificity: Pediatric: 99% (95% CI: 98% - 100%); Adult: 100% (95% CI: 90% - 100%) | | | | | |
| Specimen Type | BD Directigen EZ Flu A+B Test | Pediatric | | Adult | |
| Throat swabs | | P | N | P | N |
| | P | 38 | 23 | 5 | 6 |
| | N | 10 | 151 | 3 | 33 |
| Sensitivity: Pediatric: 79% (95% CI: 65% - 90%); Adult: 63% (95% CI: 24% - 91%) Specificity: Pediatric: 87% (95% CI: 81% - 91%); Adult: 85% (95% CI: 69% - 94%) | | | | | |
Table 4: Summary of the Performance of the BD Directigen EZ Flu A+B Test Compared to Culture for all Specimen Types by Population – Influenza B
Combined 2003-2004 and 2004-2005 Respiratory Seasons
| | | Cell Culture | | | |
| --- | --- | --- | --- | --- | --- |
| Specimen Type | BD Directigen EZ Flu A+B Test | Pediatric | | Adult | |
| Nasopharyngeal washes/aspirates | | P | N | P | N |
| | P | 49 | 1 | 8 | 0 |
| | N | 13 | 338 | 1 | 56 |
| Sensitivity: Pediatric: 79% (95% CI: 67% - 88%); Adult: 89% (95% CI: 52% - 100%) Specificity: Pediatric: 100% (95% CI: 98% - 100%); Adult: 100% (95% CI: 94% - 100%) | | | | | |
| Specimen Type | BD Directigen EZ Flu A+B Test | Pediatric | | Adult | |
| Throat swabs | | P | N | P | N |
| | P | 19 | 1 | 19 | 2 |
| | N | 12 | 190 | 5 | 21 |
| Sensitivity: Pediatric: 61% (95% CI: 42% - 78%); Adult: 79% (95% CI: 58% - 93%) Specificity: Pediatric: 99% (95% CI: 97% - 100%); Adult: 91% (95% CI: 72% - 99%) | | | | | |
b. Clinical specificity: Refer to (a.) above
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c. Other clinical supportive data (when a and b is not applicable)
Clinical Specimens Stability Study:
This study tested the stability of the influenza viruses in clinical specimens under various storage conditions before testing with the BD Directigen™ EZ Flu A+B test.
The data generated in this study provides evidence that clinical specimens maintain positivity or negativity in the BD Directigen EZ Flu A+B test for up to 72 hours at 2-8°C or up to one week at -20°C.
4. Clinical cut-off:
Not applicable
5. Expected values/Reference range: (Interpretive Criteria)
Not applicable.
N. The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.
O. Conclusion:
The submitted information in this Premarket notification is complete and supports a substantial equivalence decision.
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Learn the FDA Browser
Two short videos show you everything — or skip straight to the written tutorial if you'd rather read. You can reopen this any time from the Tutorial button in the top bar.
Part 1 — Search, results, and everyday workflows 16 min
Part 2 — Embeddings: the galaxy map 3 min
1. Search: exact and fuzzy
Type a phrase like "coronary artery calcification" into the search box. You get two kinds of results. Exact results match the literal phrase — prefix searches work ("coronary artery calcificati") but suffix searches do not. Fuzzy results match on the meaning and intent of your phrase rather than the exact words, and are sorted by relevance score. Hover over the Exact or Fuzzy badge on any row to see exactly why it matched.
Use the checkboxes above the results to narrow: SaMD keeps only software-only devices, AI / ML keeps only devices with AI.
Exact vs. fuzzy search: what's the difference?
Exact matches on the literal phrase (prefix search works, suffix does not). Fuzzy matches on the meaning and intent of the phrase rather than the exact words. Hover over the badge on any row to see why it matched.
You search "coronary artery calcification" and want only software devices with AI. What two filters do you apply?
Narrow by SaMD (software-only devices), then narrow by AI/ML (devices with AI).
2. The results table
Scroll right in the results table. The intended use is extracted for you — no need to open the PDF. The device story gives a high-level snapshot of what the device does and how it's used. The AI Performance sub-table shows each output name, acceptance criteria, observed values, and development/test dataset descriptions — the same format Innolitics uses for regulatory strategy outputs, and the fastest high-level fingerprint of an AI device. It is AI-generated but has been very reliable in practice.
Where do you find a device's intended use without opening the PDF?
Scroll right in the search results table. The intended use column is extracted for you; no need to dig into the 510(k) summary PDF.
What does the AI Performance sub-table show, and why is it useful?
Output name, acceptance criteria, observed values, development dataset description, and test dataset description. It's the same format we use for regulatory strategy output and Fast 510(k) input, and the fastest high-level fingerprint of an AI device. AI-generated but reliable in practice.
3. Judging fuzzy relevance
Fuzzy results trail off in relevance as you scroll. Use three signals to decide how far down to go: the fuzzy badge explanations, the intended use column, and whether your target output (e.g., Cobb angle) still appears in the AI Performance sub-table. Once it stops appearing, you're past the relevant zone. A top hit with a low score (~0.4) and a stretched explanation is a hint the closest predicates are far away — the project may be headed for De Novo. Note the fuzzy search is a pattern match: it doesn't handle negation ("not") well, and hardware devices can appear — filter by SaMD/AI ML to cut them.
How do you judge how far down fuzzy search results to go?
Use the relevancy signals: the fuzzy badge explanations, the intended use column, and whether the target output (e.g., Cobb angle) still appears in the AI Performance sub-table. Once it stops appearing, results are trailing off in relevancy.
4. Device detail page: chat and citations
Click a device name to open its detail page: device facts on the left, a chat window on the right. Ask something like "Describe the training data". The answer carries little citation bubbles — click one to jump to the highlighted passage in the source PDF, so you can verify every AI answer against the document. There's also a Download PDF button for sharing.
How do you verify an AI chat answer on the device detail page?
Click the citation bubbles to jump to the relevant highlight in the source document.
Reading rule for every project: how many summaries do you read in full?
At least the three most relevant 510(k) or De Novo summaries, in full. After that, use targeted chat questions to confirm your memory quickly. The tool supports this professional habit — it doesn't replace it.
5. Side-by-side comparison
Select multiple rows in the results table (aim for under ~10), then open the PDF Viewer tab. Ask one question — it goes to all selected devices in parallel, each with citations. This is the fastest way to compare and contrast devices: training data, PCCP scope, how they handled adding new scanners, and so on.
What does the side-by-side PDF viewer mode do?
Select multiple devices, open the PDF viewer tab, and ask one question (e.g., "Describe the training data"). It queries all selected devices simultaneously with citations, so you can compare and contrast quickly.
6. Collections
With rows selected, go to the Collections tab and create a labeled collection (e.g., "Cobb Angle Project"). Reload that selection any time — before a client call, pull up the collection and ask questions across all of its devices at once.
How do you save a set of selected devices for later use?
Select the rows, go to the Collections tab, and create a labeled collection (e.g., "Cobb Angle Project"). You can reload the selection anytime and carry it into the PDF viewer and other tabs that support selections.
7. Product codes and the regulations tree
Click a product code in the results to jump to it in the regulations tree — identification text, sibling product codes, and devices you can open in a PDF viewer on the right. Click a regulation number to see its identification, special controls, and related product codes. You can also search by product code or regulation number at the top of the tree. Always read the special controls if any exist for your device — it broadens your search and sharpens pre-kickoff research.
What can you do from the regulations tree view?
Browse product codes and regulation numbers, read the identification text and special controls, browse sibling product codes, open device PDFs on the right, and search by product code or regulation number at the top of the tree.
8. Chart view
Click Show Chart and segment by regulation number (or product code) to see which regulations dominate your result set. Clicking a regulation takes you into the regulations tree. Great for spotting that most matches are, say, hardware laparoscopic devices — a cue to go back and filter.
How do you see which regulations dominate a search result set?
Click "Show Chart" and segment by Regulation Number. Clicking a regulation takes you to the regulations tree.
9. The predicate graph
Open the Predicates tab for a family-tree view of predicate relationships. Click a node to trace its parents and children; selections from search carry over pre-selected. Commonly predicated devices are worth reading — a lot of people predicated them for a reason. The visual lineage is also handy on client calls, e.g. to show how a predicate family evolved and justify why your predicate still holds.
In the predicate graph, why are commonly predicated devices worth reading?
A lot of people predicated them for a reason. Clicking a node traces parents and children, and selections from search carry over pre-selected.
10. Embeddings: the galaxy map
The Embeddings tab plots every matching document in a 2-D "galaxy map" where semantically similar devices cluster together. Hover or click clusters to explore, and let AI label the clusters for you. Embeddings beat product codes for grouping: two devices can carry different product codes (LLZ vs. QIH) yet do the same thing — the embedding captures the meaning of the intended use and device story. This is also exactly how retrieval-augmented generation (RAG) works under the hood, and it makes a great visual on client calls.
Try it yourself
Head to the search page and work through a few of these AI/ML fuzzy searches to build intuition: perivascular fat on CT · aortic valve calcification opportunistic screening on noncontrast CT · breast cancer prediction on digital pathology slides · autism detection · gestational age prediction · a hearing aid that can also detect a pulse · foundation model based analysis of ECG · large language models · penetration test. Watch how the relevance scores, intended use, and AI Performance tables tell you when results stop being meaningful.
