510(k) substantial equivalence determination decision ... · guidance document, deciding when to...

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Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993-0002

www.fda.gov

510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

ASSAY AND INSTRUMENT

I Background Information:

A 510(k) Number: K191957

B Applicant: GeneOhm Sciences Canada, Inc. (BD Diagnostics)

C Proprietary and Established Names: BD MAX Vaginal Panel, BD MAX System

D Regulatory Information:

1. Regulation section:

21 CFR 866.3975. Device that detects nucleic acid sequences from microorganisms associated with vaginitis and bacterial vaginosis.

2. Classification:

Class II (Special Controls)

3. Product code(s):

PQA OUY OOI NSU

4. Panel:

83 - Microbiology

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II Submission/Device Overview:

A Purpose for Submission: This submission describes post-market changes to the BD MAX Vaginal Panel, performed on the BD MAX System, an in vitro diagnostic test market-authorized under DEN160001 for the direct detection of DNA from vaginal swabs for patients who are symptomatic for vaginitis/vaginosis. Routine post market surveillance activities informed BD of an unanticipated high rate of non-reportable result rate for the BD MAX Vaginal Panel. Through investigations, BD identified four design modifications intended to improve the tolerance of the BD MAX Vaginal Panel without significantly impacting the validated clinical and analytical performance. Utilizing the FDA Guidance Document, Deciding When to Submit a 510(k) for a Change to an Existing Device (October 2017), three of the modifications described herein are insignificant and do not require submission of a new 510(k). Reliance on the established BD Quality System reasonably assures the safety and effectiveness of the modified device for these three modifications. One of the four design modifications was determined to be significant with the potential to affect the safety or effectiveness of the device and is the focus of this submission. The cumulative changes require minor modifications to the labeling.

B Measurand: The assay detects and identifies nucleic acids of the following organisms:

• Bacterial vaginosis (BV) markers (Results for individual organisms are not reported. Qualitative BV results are based on detection and quantitation of targeted organisms)

o Lactobacillus spp (L. crispatus and L. jensenii) o Gardnerella vaginalis o Atopobium vaginae o Bacterial Vaginosis Associated Bacteria-2 (BVAB-2) o Megasphaera-1

• Candida spp. (Reported as Cgroup: includes C. albicans, C. tropicalis, C. parapsilosis,

C. dubliniensis) • Candida glabrata • Candida krusei • Trichomonas vaginalis

C Type of Test:

The BD MAX Vaginal Panel, performed on the BD MAX System, is a nucleic acid-based test for the detection of the above listed bacteria, yeast and parasites in vaginal specimens obtained from symptomatic patients.

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III Intended Use/Indications for Use:

A Intended Use(s): See Indications for Use below.

B Indication(s) for Use: The BD MAX Vaginal Panel performed on the BD MAX System is an automated qualitative in vitro diagnostic test for the direct detection of DNA targets from bacteria associated with bacterial vaginosis (qualitative results reported based on detection and quantitation of targeted organism markers), Candida species associated with vulvovaginal candidiasis, and Trichomonas vaginalis from vaginal swabs in patients who are symptomatic for vaginitis/vaginosis. The test utilizes real-time polymerase chain reaction (PCR) for the amplification of specific DNA targets and utilizes fluorogenic target-specific hybridization probes to detect and differentiate DNA from:

• Bacterial vaginosis markers (Individual markers not reported) o Lactobacillus spp. (L. crispatus and L. jensenii) o Gardnerella vaginalis o Atopobium vaginae o Bacterial Vaginosis Associated Bacteria-2 (BVAB-2) o Megasphaera-1

• Candida spp. (C. albicans, C. tropicalis, C. parapsilosis, C. dubliniensis) • Candida glabrata • Candida krusei • Trichomonas vaginalis

The BD MAX Vaginal Panel is intended to aid in the diagnosis of vaginal infections in women with a clinical presentation consistent with bacterial vaginosis, vulvovaginal candidiasis and trichomoniasis.

C Special Conditions for Use Statement(s): Rx - For Prescription Use Only

D Special Instrument Requirements: BD MAX System

IV Device/System Characteristics:

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A Device Description: The BD MAX System and the BD MAX Vaginal Panel are comprised of an instrument with associated hardware and accessories, disposable microfluidic cartridges, master mixes, unitized reagent strips, and extraction reagents. The instrument automates sample preparation including target lysis, DNA extraction and concentration, reagent rehydration, target nucleic acid amplification and detection using real-time PCR. The assay includes a Sample Processing Control (SPC) that is present in the Extraction Tube. The SPC monitors DNA extraction steps, thermal cycling steps, reagent integrity and the presence of inhibitory substances. The BD MAX System software automatically interprets test results. For the BD MAX Vaginal Panel, a test result may be called as POS, NEG or UNR (Unresolved) based on the amplification status of the targets and of the Sample Processing Control. IND (Indeterminate) or INC (Incomplete) results are due to BD MAX System failure.

B Principle of Operation: The BD MAX Vaginal Panel is designed for use with the BD MAX UVE Specimen Collection kit. Samples are transported to the testing laboratory in BD MAX UVE Sample Buffer Tubes (SBT). The Sample Buffer Tubes, are vortexed to release cells from the swab into the buffer. The Sample Buffer Tubes, Unitized Reagent Strips and PCR Cartridges are loaded on the BD MAX System. No further operator intervention is necessary, and the following automated procedures occur. A combination of lytic and extraction reagents are used to perform cell lysis and DNA extraction. Nucleic acids released from the target organisms are captured on magnetic affinity beads. The beads, together with the bound nucleic acids, are washed and the nucleic acids are eluted by a combination of heat and pH. Eluted DNA is neutralized and transferred to the Master Mix Tubes to rehydrate the PCR reagents. After reconstitution, the BD MAX System dispenses a fixed volume of PCR-ready solution containing extracted nucleic acids into the PCR Cartridge. Microvalves in the cartridge are sealed by the system prior to initiating PCR in order to contain the amplification mixture and thus prevent evaporation and contamination. The amplified DNA targets are detected using hydrolysis probes, labeled at one end with a fluorescent reporter dye (fluorophore), and at the other end, with a quencher moiety. Probes labeled with different fluorophores are used to detect the target analytes in different optical channels of the BD MAX System. When the probes are in their native state, the fluorescence of the fluorophore is quenched due to its proximity to the quencher. However, in the presence of target DNA, the probes hybridize to their complementary sequences and are hydrolyzed by the 5’-3’ exonuclease activity of the DNA polymerase as it synthesizes the nascent strand along the DNA template. As a result, the fluorophores are separated from the quencher molecules and fluorescence is emitted. The amount of fluorescence detected in the optical channels used for the BD MAX Vaginal Panel is directly proportional to the quantity of the corresponding probe that is hydrolyzed. The BD MAX System monitors these signals at each cycle of the PCR and interprets the data at the end of the reaction to provide qualitative test results for each vaginitis analyte as well as qualitative results for bacterial vaginosis based on detection and quantitation of targeted bacterial vaginosis markers.

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C Instrument Description Information:

Modes of Operation Yes No Does the applicant’s device contain the ability to transmit data to a computer, webserver, or mobile device?

Does the applicant’s device transmit data to a computer, webserver, or mobile device using wireless transmission?

Software

FDA has reviewed applicant’s Hazard Analysis and software development processes for this line of product types.

1. Instrument Name:

BD MAX System

2. Specimen Identification: Specimens are identified via barcode.

3. Specimen Sampling and Handling: Sample Buffer Tubes containing vaginal swab specimens are vortexed for one minute on the Multi-tube Vortexer, after which the user uncaps each specimen, removes the excess fluid from the swab, discards the swab and then recaps the tube with a blue septum cap. Specimens are then loaded into the BD MAX System Rack on the BD MAX System after which all additional specimen handling steps are automated.

4. Calibration: The system is calibrated by the manufacturer on-site as part of the installation procedure as well as during biannual preventive maintenance.

5. Quality Control: Internal Control Each Extraction Tube contains a Sample Processing Control (SPC) comprised of plasmids containing a synthetic target DNA sequence. The SPC monitors the efficiency of DNA capture, washing and elution during the sample processing steps, as well as the efficiency of DNA amplification and detection during PCR analysis. If the SPC result fails to meet the acceptance criteria, the result of the specimen will be reported as Unresolved for the Master Mix reaction. Each Master Mix contains its own Sample Processing Control; thus, Unresolved results are determined independently for each Master Mix. An Unresolved result is indicative of specimen-associated inhibition or reagent failure. The operator is directed to repeat any specimen reported as Unresolved.

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External Controls External quality control materials are not provided with the BD MAX Vaginal Panel and the BD MAX System software does not require inclusion of external controls for the purpose of sample test results interpretation. However, the instructions for use indicate that one external positive control and one external negative control should be run at least daily until adequate process validation is achieved on the BD MAX System in each laboratory setting. After such validation has been completed, laboratories are directed to perform external quality control testing according to guidelines or requirements of local, state and federal accrediting organizations. The following are recommended in the package insert for external control testing with the BD MAX Vaginal Panel. External Negative Controls

• Suspension of commercially available Lactobacillus iners strain • Previously characterized negative clinical specimen

External Positive Controls

• Suspension of available organisms listed in the Table below. • Previously characterized positive clinical specimen

Table 1: Recommended Organisms for External Controls Positive controls Negative controls

Vaginitis

Trichomonas vaginalis ATCC 30001 Lactobacillus iners ATCC 55195 Candida albicans ATCC 10231

Candida glabrata ATCC 2001

Candida krusei ATCC 6258 Vaginosis BV Positive External Controla

a Mixture of Gardnerella vaginalis and Atopobium vaginae

V Substantial Equivalence Information:

A Predicate Device Name(s): BD MAX Vaginal Panel, BD MAX Instrument

B Predicate 510(k) Number(s): DEN160001

C Comparison with Predicate(s):

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Device & Predicate Device(s): K191957 DEN160001

Device Trade Name Same BD MAX Vaginal Panel General Device Characteristic Similarities

Intended Use/Indications For Use

Same

The BD MAX Vaginal Panel performed on the BD MAX System is an automated qualitative in vitro diagnostic test for the direct detection of DNA targets from bacteria associated with bacterial vaginosis (qualitative results reported based on detection and quantitation of targeted organism markers), Candida species associated with vulvovaginal candidiasis, and Trichomonas vaginalis from vaginal swabs in patients who are symptomatic for vaginitis/vaginosis. The test utilizes real-time polymerase chain reaction (PCR) for the amplification of specific DNA targets and utilizes fluorogenic target-specific hybridization probes to detect and differentiate DNA from: • Bacterial vaginosis markers (Individual markers not

reported) - Lactobacillus spp. (L. crispatus and L. jensenii) - Gardnerella vaginalis - Atopobium vaginae - Bacterial Vaginosis Associated Bacteria-2 (BVAB-

2) - Megasphaera-1

• Candida spp. (C. albicans, C. tropicalis, C. parapsilosis, C. dubliniensis)

• Candida glabrata • Candida krusei • Trichomonas vaginalis The BD MAX Vaginal Panel is intended to aid in the diagnosis of vaginal infections in women with a clinical presentation consistent with bacterial vaginosis, vulvovaginal candidiasis and trichomoniasis.

Specimen Type Same Clinician and patient-collected female vaginal swab Technology Same PCR

Organisms Detected Same

• Bacterial vaginosis markers (Lactobacillus spp., Gardnerella vaginalis, Atopobium vaginae, BVAB-2, Megasphaera-1

• Candida spp. • Candida glabrata • Candida krusei • Trichomonas vaginalis

Sample Prep/Interpretation of Results

Same Automated by BD MAX System

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Device & Predicate Device(s): K191957 DEN160001

Assay Controls Same Sample Processing Control Collection/Transport Device

Same MAX UVE Specimen Collection Kit

Interpretation of Results

Same Qualitative

General Device Characteristic Differences Software ADF version 3.0 ADF version 2.0

VI Standards/Guidance Documents Referenced: Not Applicable

VII Performance Characteristics (if/when applicable):

A Analytical Performance: 1. Reproducibility Study:

Please refer to previously FDA-cleared De Novo Premarket Notifications, DEN160001 for Precision/Reproducibility performance. No additional testing was conducted.

2. Linearity/Assay Reportable Range: Not Applicable

3. Traceability, Stability, Expected Values (controls, calibrators, or methods): Please refer to previously FDA-cleared De Novo Premarket Notifications, DEN160001 for Traceability, Stability and Expected Values performance. No additional testing was conducted.

4. Specimen Stability: Please refer to previously FDA-cleared De Novo Premarket Notifications, DEN160001 for Specimen Stability performance. No additional testing was conducted.

5. Detection Limit: Please refer to previously FDA-cleared De Novo Premarket Notifications, DEN160001 for Detection Limit performance. No additional testing was conducted.

6. Analytical Inclusivity: Please refer to previously FDA-cleared De Novo Premarket Notifications, DEN160001 for Inclusivity performance. No additional testing was conducted.

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7. Mixed Infection/Competitive Interference Study:

Please refer to previously FDA-cleared De Novo Premarket Notifications, DEN160001 for Mixed Infection/Competitive Interference Study performance. No additional testing was conducted.

8. Analytical Specificity/Cross-reactivity: Please refer to previously FDA-cleared De Novo Premarket Notifications, DEN160001 for Analytical Specificity/Cross-reactivity Study performance. No additional testing was conducted.

9. Evaluation of Potentially Interfering Substances: A study was performed to assess the potential inhibitory effects of lubricants that may be present in vaginal swab specimens on the BD MAX Vaginal Panel results. This testing supplements the potentially interfering substances data previously FDA-cleared De Novo Premarket Notifications, DEN160001. Exogenous (e.g., prescription and Over-the-Counter drugs, creams and/or gels) substances were evaluated in samples spiked with the highest concentration expected to be present in vaginal specimens. Each potentially interfering substance was evaluated in both negative and low positive samples. Samples for targeted vaginitis analytes were spiked with low concentrations (<2x LoD) of Candida albicans, Candida glabrata, Candida krusei or Trichomonas vaginalis. Positive BV samples were spiked with organism compositions designed to generate results near the assay BD MAX Vaginal Panel cutoffs for BV (i.e., C95). An overall summary of the analysis is provided in the Table 2 and 3 below. Three of the four substances tested at the initial concentration failed to meet the qualitative acceptance criteria. MUKO Lubricating Jelly met the qualitative acceptance criteria but not the PCR metric equivalence criteria. The concentration of each substance was incrementally reduced in the Sample Buffer Tube until interference (either qualitative or PCR metric) was no longer observed. Substances were tested at 50μL, 10μL, 5μL and 1 μL. Acceptable levels of substance in the Sample Buffer Tube were determined only for MUKO Lubricating Jelly. No acceptable level was obtained for the remaining three substances. A limitation is included in the package insert listing all substances that demonstrated interference with the BD MAX Vaginal Panel.

Table 2: Overall Summary of Initial Testing Results

Substance Level Tested (in SBT)

Substance Interferinga

Vaginitis Metrics

Vaginosis Metrics

Risk of Interferenceb

MUKO Lubricating Jelly

50 µL

No Fail Fail Yes Surgilube

Yes N/A Lubricating Jelly Aquasonic Clear

a Substance interfering according to qualitative acceptance criteria. b Risk of interference identified based on PCR metric equivalence analysis.

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Table 3: Overall Summary of Secondary Testing Results

Substance Level Tested (in SBT) a

Vaginitis Metrics

Vaginosis Metrics

Risk of Interferenceb

MUKO Lubricating Jelly 3.3 µL Pass Pass Low

Surgilube No Passing Level Obtained Lubricating Jelly

Aquasonic Clear a Substance interfering according to qualitative acceptance criteria. b Risk of interference identified based on PCR metric equivalence analysis.

10. Matrix Equivalence Study:

Please refer to previously FDA-cleared De Novo Premarket Notifications, DEN160001 for Matrix Equivalence Study performance. No additional testing was conducted.

11. Assay Cut-off: Please refer to previously FDA-cleared De Novo Premarket Notifications, DEN160001 for Assay Cut-off performance. No additional testing was conducted.

12. Carry-Over:

Please refer to previously FDA-cleared De Novo Premarket Notifications, DEN160001 for Carry-Over performance. No additional testing was conducted.

B Comparison Studies: 1. Re-analysis of Clinical Performance Data:

The original clinical study database in DEN160001 was reprocessed and analyzed according to the new ADF version 3.0 and the resulting data demonstrated that the assay robustness was improved with an acceptable minimal impact on the BD MAX Vaginal Panel assay performance. BD MAX Vaginal Panel Sensitivity and Specificity The reanalyzed clinical performance is presented in Table 4. There was a decrease in the clinical performance for BV sensitivity (0.4% for clinician-collected and 0.9% for patient-collected vaginal swabs) and clinician-collected group sensitivity (0.2% patient-collected vaginal swabs). All other performance measurements remained unchanged or increased slightly.

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Table 4: Overall Clinical Performance Comparison – Original vs. Modified

Target Specimen Type Sens./Spec. Original estimate

with 95% CI New estimate with 95% CI

Change in Estimate (New - Original)

BV

Clinician- collected

Sensitivity 90.5% 88.3-92.2

90.1% 88.0-91.9 -0.4%

Specificity 85.8% 83.0-88.3

86.2% 83.4-88.6 0.4%

Self-collected Sensitivity 90.7%

88.6-92.5 90.5%

88.4-92.3 -0.2%


84.6% 81.8-87.1 0.1%

C. glabrata



75.9% 57.9-87.8 0.0%


99.7% 99.4-99.9 0.0%


70.3-94.7 86.7%

70.3-94.7 0.0%


99.6% 99.2-99.8 0.0%

C. krusei

Clinician- collected Specificity 99.8%

99.4-99.9 99.8%

99.4-99.9 0.0%

Self-collected Specificity 100% 99.8-100

100% 99.8-100 0.0%

Candida group



90.9% 88.1-93.1 0.0%


94.2% 92.7-95.5 0.1%


89.5-94.2 92.0%

89.3-94.0 -0.2%


92.1% 90.3-93.5 0.2%

T. vaginalis



93.1% 87.4-96.3 0.0%


99.3% 98.7-99.6 0.0%


87.6-96.4 93.2%

87.6-96.4 0.0%


99.3% 98.7-99.6 0.0%

Impact of Reanalysis on BV Table 5 through Table 8 summarize the impact of the new ADF (version 3.0) on BV results relative to the final results for the original ADF that was presented in DEN160001. Results are presented by specimen type and reference method result. Numbers in bold indicate where the results changed status between the original ADF and the new ADF. For the clinician-collected reference method positive samples, one vaginal swab that originally reported positive and two samples that originally reported Unresolved were reported as negatives with the new ADF (Table 5). For the clinician-collected reference

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method negative samples, a total of eighteen clinician-collected samples previously reported as Unresolved or Not Available were reported as true negatives with the new ADF (Table 6). In the patient-collected reference method positive condition, two samples previously reported as Unresolved or Not Available were negative with the new ADF (Table 7). Lastly, in the patient-collected reference method negative condition, a total of five samples originally reported as either Unresolved or Indeterminate were reported as true negatives with the new ADF (Table 8).

Table 5: Comparison of BV Results for Clinician-collected Vaginal Swabs - Original vs. New ADF (Reference Method Positive)

BV New AD Version 3.0 Total Original

ADF Estimate POS NEG INV

a Partial UNR

Full UNR IND INC Not Available b

POS Count 796 1 0 0 0 0 0 0 797

NEG Count 0 84 0 0 0 0 0 0 84 INV a Count 0 0 6 0 0 0 0 0 6

Partial UNR Count 0 2 0 0 0 0 0 0 2

Full UNR Count 0 0 0 0 0 0 0 0 0

IND Count 0 0 0 0 0 3 0 0 3

INC Count 0 0 0 0 0 0 1 0 1 Not Avail.b Count 0 0 0 0 0 0 0 2 2

Total Count 796 87 6 0 0 3 1 2 895 a INV=POS or NEG or UNR with External Control Fail b Not Available means no result from a valid repeat

Table 6: Comparison of BV Results for Clinician-collected Vaginal Swabs - Original vs. New ADF (Reference Method Negative)

BV New ADF Total Original


a Partial UNR

Full UNR IND INC Not Available b

POS Count 96 0 0 0 0 0 0 0 96



Full UNR Count 0 0 0 0 3 0 0 0 3

IND Count 0 0 0 0 0 8 0 0 8 INC Count 0 0 0 0 0 0 1 0 1

Not Availb Count 0 4 0 0 0 0 0 1 5


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Table 7: Comparison of BV Results for Patient-collected Vaginal Swabs - Original vs. New ADF (Reference Method Positive)



a Partial UNR

Full UNR

IND INC Not Available b

POS Count 803 0 0 0 0 0 0 0 803



Full UNR Count 0 0 0 0 1 0 0 0 1

IND Count 0 0 0 0 0 1 0 0 1



Table 8: Comparison of BV Results for Patient-collected Vaginal Swabs - Original vs. New ADF (Reference Method Negative)



a Partial UNR

Full UNR


POS Count 108 0 0 0 0 0 0 0 108



Full UNR Count 0 0 0 0 0 0 0 0 0

IND Count 0 1 0 0 0 7 0 0 8



Table 9 summarizes the overall BV performance according to the original ADF. The reanalyzed overall BV performance is presented in Table 10. The BV sensitivity with the new ADF changed to 90.1% and 90.5%, compared to 90.5% and 90.7% for the clinical-collected and the self-collected swabs respectively. The specificity increased to 86.2% and 84.6% compared to 85.8% and 84.5% for the clinical-collected and the self-collected swabs respectively.

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Table 9: BV Overall Performance by Specimen Type – Original ADF Reference Method

Total Specimen Type BD MAX P N

Clinician-collected

P 797 96 893

N 84 582 666

Total 881 678 1559

Sensitivity: 90.5% (88.3%, 92.2%) Specificity: 85.8% (83.0%, 88.3%)

Self-collected

P 803 108 911

N 82 589 671

Total 885 697 1582

Sensitivity: 90.7% (88.6%, 92.5%) Specificity: 84.5% (81.6%, 87%)

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Table 10: BV Overall Performance by Specimen Type – New ADF Reference Method


Clinician-collected

P 796 96 892

N 87 600 687

Total 883 696 1579


Self-collected

P 803 108 911

N 84 594 678

Total 887 702 1589


Impact of Reanalysis on C. glabrata Table 11 through Table 14 summarize the impact of the new ADF (version 3.0) on C. glabrata results relative to the final results for the original ADF that was presented in DEN160001. Results are presented by specimen type and reference method result. Numbers in bold indicate where the results changed status between the original ADF and the new ADF. There was no impact to the results for the clinician-collected reference method positive population when reanalyzed using the new ADF (Table 11). In the clinician-collected reference method negative condition, one sample previously reported as positive and three samples originally reported as either Unresolved or Indeterminate were reported as true negatives (Table 12). There was no impact to the results for the clinician-collected reference method positive population when reanalyzed using the new ADF (Table 13). Lastly, a total of four patient-collected samples originally reported as either Unresolved or Indeterminate were reported as true negatives according to the reference method negative result once reanalyzed (Table 14).

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Table 11: Comparison of C. glabrata Results for Clinician-collected Vaginal Swabs - Original vs. New ADF (Reference Method Positive)

C. glabrata New ADF Total Original

ADF Estimate POS NEG INV a Partial

UNR Full UNR


POS Count 22 0 0 0 0 0 0 0 22

NEG Count 0 7 0 0 0 0 0 0 7

INVa Count 0 0 0 0 0 0 0 0 0


Full UNR Count 0 0 0 0 0 0 0 0 0

IND Count 0 0 0 0 0 0 0 0 0



Table 12: Comparison of C. glabrata Results for Clinician-collected Vaginal Swabs - Original vs. New ADF (Reference Method Negative)



UNR Full UNR


POS Count 4 1 0 0 0 0 0 0 5



Full UNR Count 0 0 0 0 3 0 0 0 3

IND Count 0 1 0 0 0 12 0 0 13



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Table 13: Comparison of C. glabrata Results for Patient-collected Vaginal Swabs - Original vs. New ADF (Reference Method Positive)



UNR Full UNR


POS Count 26 0 0 0 0 0 0 0 26



Full UNR Count 0 0 0 0 0 0 0 0 0

IND Count 0 0 0 0 0 0 0 0 0

INC Count 0 0 0 0 0 0 0 0 0 Not Avail,b Count 0 0 0 0 0 0 0 0 0


Table 14: Comparison of C. glabrata Results for Patient-collected Vaginal Swabs - Original vs. New ADF (Reference Method Negative)



UNR Full UNR


POS Count 6 0 0 0 0 0 0 0 6



Full UNR Count 0 0 0 0 1 0 0 0 1

IND Count 0 1 0 0 0 8 0 0 9



Table 15 summarizes the overall C. glabrata performance according to the original ADF with the reanalyzed overall C. glabrata performance presented in Table 16. The sensitivity and specificity of C. glabrata with the new ADF did not change.

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Table 15: C. glabrata Overall Performance by Specimen Type – Original ADF

Reference Method Total

Specimen Type BD MAX P N

Clinician-collected

P 22 5 27

N 7 1584 1591

Total 29 1589 1618


Self-collected

P 26 6 32

N 4 1592 1596

Total 30 1598 1628


Table 16: C. glabrata Overall Performance by Specimen Type – New ADF

Reference Method


Clinician-collected

P 22 4 26

N 7 1588 1595

Total 29 1592 1621


Self-collected

P 26 6 32

N 4 1596 1600

Total 30 1602 1632


Impact of Reanalysis on C. krusei Table 17 and Table 18 summarize the impact of the new ADF (version 3.0) on C. krusei results relative to the final results for the original ADF that was presented in DEN160001. Results are presented by specimen type and reference method result. Numbers in bold indicate where the results changed status between the original ADF and the new ADF. In the clinician-collected reference method negative population, three samples that originally reported as either Unresolved or Indeterminate were resolved to true negatives (Table 17).

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There was no impact to the results for the clinician-collected reference method positive population when reanalyzed using the new ADF (Table 18).

Table 17: Comparison of C. krusei Results for Clinician-collected Vaginal Swabs – Original vs. New ADF (Reference Method Negative)

C. krusei New ADF Total Original


UNR Full UNR


POS Count 4 0 0 0 0 0 0 0 4

NEG Count 0 1614 0 0 0 0 0 0 1614

INV a Count 0 0 7 0 0 0 0 0 7


Full UNR Count 0 0 0 0 3 0 0 0 3

IND Count 0 1 0 0 0 12 0 0 13



Table 18: Comparison of C. krusei Results for Patient-collected Vaginal Swabs - Original vs. New ADF (Reference Method Negative)

C. krusei New ADF Total Original


UNR Full UNR


POS Count 0 0 0 0 0 0 0 0 0



Full UNR Count 0 0 0 0 1 0 0 0 1

IND Count 0 1 0 0 0 8 0 0 9



Table 19 summarizes the overall C. krusei performance according to the original ADF with the reanalyzed overall C. krusei performance presented in Table 20. The sensitivity and specificity of C. krusei with the new ADF did not change.

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Table 19: C. krusei Overall Performance by Specimen Type – Original ADF Reference Method


Clinician-collected

P 0 4 4

N 0 1614 1614

Total 0 1618 1618

No Data for Sensitivity Calculation Specificity: 99.8% (99.4%, 99.9%)

Self-collected

P 0 0 0

N 0 1628 1628

Total 0 1628 1628

No Data for Sensitivity Calculation Specificity: 100% (99.8%, 100%)

Table 20: C. krusei Overall Performance by Specimen Type – New ADF



Clinician-collected

P 0 4 4

N 0 1617 1617

Total 0 1621 1621

No Data for Sensitivity Calculation Specificity: 99.8% (99.4%, 99.9%)

Self-collected

P 0 0 0

N 0 1632 1632

Total 0 1632 1632

No Data for Sensitivity Calculation Specificity: 100% (99.8%, 100%)

Impact of Reanalysis on Candida group Table 21 through Table 24 summarize the impact of the new ADF (version 3.0) on the Candida Group results relative to the final results for the original ADF that were presented in DEN160001. Results are presented by specimen type and reference method result. Numbers in bold indicate where the results changed status between the original ADF and the new ADF. There was no impact to the results for the clinician-collected reference method positive population when reanalyzed using the new ADF (Table 21). In the clinician-collected reference method negative condition, one sample previously reported as positive and three

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samples originally reported as either Unresolved or Indeterminate were reported as true negatives (Table 22). In the patient-collected reference method positive condition, one sample previously reported as Indeterminate was changed to negative (Table 23). Lastly, one patient-collected sample originally reported as positive and three samples previously reported as Unresolved were reported as true negatives according to the reference method negative result (Table 24).

Table 21: Comparison of Candida Group Results for Clinician-collected Vaginal Swabs - Original vs. New ADF (Reference Method Positive)

Candida group New ADF Total Original


UNR Full UNR


POS Count 462 0 0 0 0 0 0 0 462



Full UNR Count 0 0 0 0 1 0 0 0 1

IND Count 0 0 0 0 0 8 0 0 8



Table 22: Comparison of Candida Group Results for Clinician-collected Vaginal Swabs - Original vs. New ADF (Reference Method Negative)



UNR Full UNR


POS Count 64 1 0 0 0 0 0 0 65



Full UNR Count 0 0 0 0 2 0 0 0 2

IND Count 0 1 0 0 0 4 0 0 5



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Table 23: Comparison of Candida Group Results for Patient-collected Vaginal Swabs - Original vs. New ADF (Reference Method Positive)



UNR Full UNR


POS Count 470 0 0 0 0 0 0 0 470



Full UNR Count 0 0 0 0 1 0 0 0 1

IND Count 0 1 0 0 0 5 0 0 6



Table 24: Comparison of Candida Group Results for Patient-collected Vaginal Swabs - Original vs. New ADF (Reference Method Negative)



a Partial UNR

Full UNR


POS Count 89 1 0 0 0 0 0 0 90



Full UNR Count 0 0 0 0 0 0 0 0 0

IND Count 0 0 0 0 0 3 0 0 3

INC Count 0 0 0 0 0 0 2 0 2 Not

Available b Count 0 0 0 0 0 0 0 0 0


Table 25 summarizes the overall Candida group performance according to the original ADF with the reanalyzed overall Candida group performance presented in Table 26. The sensitivity of the Candida group overall performance with the new ADF remained the same for the clinician-collected swabs. Sensitivity slightly decreased from 92.2% to 92.0% for the self-collected swabs. The specificity increased to 94.2% and 92.1% compared to 94.1% and 91.9% for the clinical-collected and the self-collected swabs respectively.

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Table 25: Candida Overall Performance by Specimen Type – Original ADF Reference Method


Clinician-collected

P 462 65 527

N 46 1045 1091

Total 508 1110 1618


Self-collected

P 470 90 560

N 40 1028 1068

Total 510 1118 1628


Table 26: Candida Overall Performance by Specimen Type – New ADF Reference Method


Clinician-collected

P 462 64 526

N 46 1049 1095

Total 508 1113 1621


Self-collected

P 470 89 559

N 41 1032 1073

Total 511 1121 1632


Impact of Reanalysis on T. vaginalis

Table 27 through Table 30 summarize the impact of the new ADF (version 3.0) on T. vaginalis results relative to the final results for the original ADF that was presented in DEN160001. Results are presented by specimen type and reference method result. Numbers in bold indicate where the results changed status between the original ADF and the new ADF. There was no impact to the results for the clinician-collected reference method positive population when reanalyzed using the new ADF (Table 27). A total of three clinician collected samples previously reported as Unresolved or Indeterminate were reported as true negatives according to the reference method result (Table 28).

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There was no impact to the results for the clinician-collected reference method positive population when reanalyzed using the new ADF (Table 29). Lastly, a total of five patient-collected samples originally reported as either Unresolved or Indeterminate were resolved to true negatives according to the reference method negative result (Table 30).

Table 27: Comparison of T. vaginalis Results for Clinician-collected Vaginal Swabs - Original vs. New ADF (Reference Method Positive)

T. vaginalis New ADF

Total Original ADF

Estimate POS NEG INV a Partial UNR

Full UNR


POS Count 121 0 0 0 0 0 0 0 121



Full UNR Count 0 0 0 0 0 0 0 0 0

IND Count 0 0 0 0 0 2 0 0 2



Table 28: Comparison of T. vaginalis Results for Clinician-collected Vaginal Swabs - Original vs. New ADF (Reference Method Negative)

T. vaginalis New ADF Total Original


UNR Full UNR


POS Count 11 0 0 0 0 0 0 0 11



Full UNR Count 0 1 0 0 1 0 0 0 2

IND Count 0 1 0 0 0 10 0 0 11



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Table 29: Comparison of T. vaginalis Results for Patient-collected Vaginal Swabs - Original vs. New ADF (Reference Method Positive)



UNR Full UNR


POS Count 124 0 0 0 0 0 0 0 124



Full UNR Count 0 0 0 0 0 0 0 0 0

IND Count 0 0 0 0 0 0 0 0 0



Table 30: Comparison of T. vaginalis Results for Patient-collected Vaginal Swabs - Original vs. New ADF (Reference Method Negative)



UNR Full UNR


POS Count 11 0 0 0 0 0 0 0 11



Full UNR Count 0 1 0 0 0 0 0 0 1

IND Count 0 1 0 0 0 7 0 0 8



Table 31 summarizes the overall T. vaginalis performance according to the original ADF with the reanalyzed overall T. vaginalis performance presented in Table 32. The performance of T. vaginalis was not affected by the new ADF.

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Table 31: T. vaginalis Overall Performance by Specimen Type – Original ADF Reference Method


Clinician-collected

P 121 11 132

N 9 1459 1468

Total 130 1470 1600


Self-collected

P 124 11 135

N 9 1466 1475

Total 133 1477 1610


Table 32: T. vaginalis Overall Performance by Specimen Type – New ADF



Clinician-collected

P 121 11 132

N 9 1463 1472

Total 130 1474 1604


Self-collected

P 124 11 135

N 9 1471 1480

Total 133 1482 1615


BD MAX Vaginal Panel Non-Reportable Rate The new ADF reduced the initial Unresolved rate for combined targets by 2.7% and 2.2%, respectively for clinician and self-collected specimens. The final Unresolved rate for combined targets was reduced by 1.1% and 0.5%, respectively for clinician and self-collected specimens. A comparison of non-reportable rates are presented in Table 33 for clinician-collected vaginal swabs and in Table 34 for self-collected vaginal swabs.

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Table 33: Non-reportable Rate for Clinician-Collected Vaginal Swabs Master Mix Result

Stage Result Type Original Estimate with 95% CI

New Estimate with 95% CI Difference

BV MM and

Candida/TV MM combined

Initial Incomplete 1.4% 0.9-2.1

1.4% 0.9-2.1 0.0%

Indeterminate 3.7% 2.9-4.7

3.7% 2.9-4.7 0.0%

Unresolved 3.0% 2.3-3.9

0.3% 0.2-0.8 -2.7%

Non- reportable

8.1% 6.9-9.5

5.4% 4.5-6.6 -2.7%

Final Valid Repeat Incomplete 0.2%

0.1-0.5 0.2%

0.1-0.5 0.0%


0.7% 0.4-1.2 -0.1%


0.2% 0.1-0.5 -1.1%

Non- reportable

2.2% 1.6-3.0

1.0% 0.7-1.6 -1.2%

BV MM


1.4% 0.9-2.1 0.0%


3.7% 2.9-4.7 0.0%


0.2% 0.1-0.5 -2.4%

Non- reportable

7.7% 6.5-9.0

5.2% 4.3-6.4 -2.5%

Final Valid Repeat

Incomplete 0.2% 0.1-0.5

0.2% 0.1-0.5 0.0%


0.7% 0.4-1.2 -0.1%


0.2% 0.1-0.5 -1.0%

Non- reportable

2.0% 1.5-2.8

1.0% 0.7-1.6 -1.0%

Candida/TV MM


1.4% 0.9-2.1 0.0%


3.7% 2.9-4.7 0.0%


0.3% 0.2-0.8 -0.3%

Non- reportable

5.7% 4.7-6.9

5.4% 4.5-6.6 -0.3%

Final Valid Repeat Incomplete 0.2%

0.1-0.5 0.2%

0.1-0.5 0.0%


0.7% 0.4-1.2 -0.1%


0.2% 0.1-0.5 -0.1%

Non-

reportable

1.3% 0.8-1.9

1.0% 0.7-1.6 -0.3%

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Table 34: Non-reportable Rate for Self-Collected Vaginal Swabs

Master Mix Result Stage Result Type Original Estimate

with 95% CI New Estimate with 95% CI Difference

BV MM and Candida/TV MM

combined

Initial


1.4% 0.9-2.0 0.0%


2.7% 2.0-3.6 0.0%


0.7% 0.4-1.2 -2.2%

Non- reportable

7.0% 5.9-8.3

4.8% 3.9-5.9 -2.2%

Final Valid Repeat


0.2% 0.1-0.6 0.0%


0.5% 0.3-1.0 -0.1%


0.1% 0.0-0.3 -0.5%

Non- reportable

1.4% 1.0-2.1

0.8% 0.5-1.3 -0.6%

BV MM

Initial


1.4% 0.9-2.0 0.0%


2.7% 2.0-3.6 0.0%


0.3% 0.1-0.7 -2.1%

Non- reportable

6.5% 5.4-7.7

4.4% 3.5-5.4 -2.1%

Final Valid Repeat


0.2% 0.1-0.6 0.0%


0.5% 0.3-1.0 -0.1%


0.1% 0.0-0.3 -0.4%

Non- reportable

1.3% 0.8-1.9

0.8% 0.5-1.3 -0.5%

Candida/TV MM

Initial


1.4% 0.9-2.0 0.0%


2.7% 2.0-3.6 0.0%


0.7% 0.4-1.2 -0.2%

Non-reportable

5.0% 4.0-6.1

4.8% 3.9-5.9 -0.2%

Final Valid Repeat


0.2% 0.1-0.6 0.0%


0.5% 0.3-1.0 -0.1%


0.1% 0.0-0.3 -0.2%

Non-reportable

1.1% 0.7-1.7

0.8% 0.5-1.3 -0.3%

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2. Matrix Comparison:

Please refer to previously FDA-cleared De Novo Premarket Notifications, DEN160001 for Matrix Comparison performance. No additional testing was conducted.

C Clinical Studies: 1. Clinical Sensitivity:

Please refer to previously FDA-cleared De Novo Premarket Notifications, DEN160001 for Clinical Sensitivity performance. No additional testing was conducted.

2. Clinical Specificity:

Please refer to previously FDA-cleared De Novo Premarket Notifications, DEN160001 for Clinical Specificity performance. No additional testing was conducted.

3. Other Clinical Supportive Data (When 1. and 2. Are Not Applicable): Not Applicable

D Clinical Cut-Off: Please refer to previously FDA-cleared De Novo Premarket Notifications, DEN160001 for Assay Cut-off performance. No additional testing was conducted.

E Expected Values/Reference Range: Please refer to previously FDA-cleared De Novo Premarket Notifications, DEN160001 for Expected Values/Reference Range. No additional testing was conducted.

F Other Supportive Instrument Performance Characteristics Data: Not Applicable

VIII Proposed Labeling: The labeling supports the finding of substantial equivalence for this device.

IX Conclusion: The submitted information in this premarket notification is complete and supports a substantial equivalence decision.