Who is the manufacturer of BD MAX Vaginal Panel, BD MAX Instrument?

Geneohm Sciences Canada, Inc. (Bd Diagnostics) filed the De Novo classification request for BD MAX Vaginal Panel, BD MAX Instrument (DEN160001).

What is the FDA product code for BD MAX Vaginal Panel, BD MAX Instrument?

PQA. It is classified under 21 CFR 866.3975 as a Class 2 device in the Microbiology panel.

What is the regulatory pathway for BD MAX Vaginal Panel, BD MAX Instrument?

De Novo classification (submission type: Direct).

Who can help prepare an FDA De Novo submission like BD MAX Vaginal Panel, BD MAX Instrument?

Innolitics — a medical-device software consultancy — provides regulatory and engineering support for FDA De Novo submissions. See https://innolitics.com/services/regulatory/ or contact https://innolitics.com/contact.

BD MAX Vaginal Panel, BD MAX Instrument

DEN160001 · Geneohm Sciences Canada, Inc. (Bd Diagnostics) · PQA · Oct 28, 2016 · Microbiology

Device Facts

Record ID	DEN160001
Device Name	BD MAX Vaginal Panel, BD MAX Instrument
Applicant	Geneohm Sciences Canada, Inc. (Bd Diagnostics)
Product Code	PQA · Microbiology
Decision Date	Oct 28, 2016
Decision	DENG
Submission Type	Direct
Regulation	21 CFR 866.3975
Device Class	Class 2

Intended 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) 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.

Device Story

BD MAX Vaginal Panel is an automated in vitro diagnostic test; processes vaginal swab samples to detect DNA targets of specific microorganisms associated with vaginitis/vaginosis. System utilizes real-time PCR for DNA amplification; employs fluorogenic target-specific hybridization probes for detection/differentiation of bacterial vaginosis markers, Lactobacillus spp., Gardnerella vaginalis, Atopobium vaginae, BVAB-2, Megasphaera-1, Candida spp., and Trichomonas vaginalis. Device operates on the BD MAX System; intended for use in clinical laboratory settings. Output provides qualitative results for targeted organisms; aids clinicians in diagnosing vaginal infections when combined with clinical signs, symptoms, and other laboratory findings. Benefits include rapid, automated identification of pathogens to guide appropriate patient management.

Clinical Evidence

The document does not provide specific clinical study results or performance metrics (e.g., sensitivity, specificity, AUC). It mandates that future premarket notifications for this device type must include detailed documentation from a prospective clinical study comparing device performance to well-accepted comparator methods in an appropriate study population.

Technological Characteristics

Nucleic acid-based test using real-time PCR. Employs hydrolysis probes with fluorophore/quencher pairs. Automated on BD MAX System using disposable microfluidic cartridges, master mixes, and magnetic affinity beads for DNA extraction. Detects DNA targets via six optical channels. Software-based result interpretation. Requires BD MAX UVE Specimen Collection kit. No external controls provided; internal Sample Processing Control (SPC) monitors extraction and amplification.

Indications for Use

Indicated for symptomatic women presenting with signs/symptoms of vaginitis/vaginosis to aid in the diagnosis of bacterial vaginosis, vulvovaginal candidiasis, and trichomoniasis.

Regulatory Classification

Identification

A device that detects nucleic acid sequences from microorganisms associated with vaginitis and bacterial vaginosis is a qualitative in vitro diagnostic device intended for the detection of microbial nucleic acid sequences in vaginal specimens collected from patients with signs and symptoms of vaginitis or bacterial vaginosis. This device is intended to aid in the diagnosis of vaginitis or bacterial vaginosis when used in conjunction with clinical signs and symptoms and other laboratory findings.

Special Controls

*Classification.* Class II (special controls). The special controls for this device are:(1) Design verification and validation must include: (i) Documentation with a detailed device description of device components; ancillary reagents required but not provided; and explanation of the methodology including primer/probe sequence, design, and rationale for sequence selection. (ii) Documentation with information that demonstrates the performance characteristics of the device, including: (A) Limit of Detection; (B) Precision (reproductivity); (C) Analytical specificity; (D) Analytical reactivity (inclusivity); (E) Specimen stability; and (F) Effects of interfering substances. (iii) Detailed documentation from a prospective clinical study. As appropriate to the intended use, the prospective clinical study must be performed on an appropriate study population, including women of various ages and ethnicities. The prospective clinical study must compare the device performance to results obtained from well-accepted comparator methods. (iv) Detailed documentation for device software, including software applications and hardware-based devices that incorporate software. (2) The labeling required under § 809.10(b) of this chapter must include: (i) A detailed explanation of the interpretation of results and acceptance criteria; (ii) For devices with an intended use that includes detection of nucleic acid sequences from bacteria associated with bacterial vaginosis, clinical performance stratified by patient demographics such as race, ethnicity, age, and pregnancy status. (iii) For devices with an intended use that includes detection of nucleic acid sequences from bacteria associated with bacterial vaginosis, a summary of device results in an asymptomatic population with demographic characteristics appropriate to the intended use population. (iv) For devices with an intended use that includes detection of either Candida species or bacteria associated with bacterial vaginosis, a limitation that *Candida* species and bacterial compositions associated with bacterial vaginosis can be present as part of normal vaginal flora and results should be considered in conjunction with available clinical information.

Related Devices

K191957 — BD MAX Vaginal Panel · Geneohm Sciences Canada, Inc. (Bd Diagnostics) · Oct 21, 2019
K201017 — BD MAX Vaginal Panel, BD MAX System, BD Molecular Swab Collection Kit · Geneohm Sciences Canada, Inc. (Bd Life Sciences) · Oct 18, 2021
K223653 — BD Vaginal Panel · Becton, Dickinson and Company · Mar 6, 2023
K243725 — BD Vaginal Panel · Becton, Dickinson and Company · Dec 19, 2024

Submission Summary (Full Text)

{0}------------------------------------------------ ## EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR BD MAX Vaginal Panel ## DECISION SUMMARY ## A. DEN Number: DEN160001 ## B. Purpose for Submission: De Novo request for evaluation of automatic class III designation for the BD MAX Vaginal Panel ## C. Measurands: 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) - Lactobacillus spp (L. crispatus and L. jensenii) O - Gardnerella vaginalis O - O Atopobium vaginae - Bacterial Vaginosis Associated Bacteria-2 (BVAB-2) O - Megasphaera-1 o - Candida spp. (Reported as Cgroup: includes C. albicans, C. tropicalis, C. parapsilosis, ● C. dubliniensis) - Candida glabrata ● - Candida krusei - Trichomonas vaginalis ● ## D. 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. ## E. Applicant: GeneOhm Sciences Canada, Inc. (BD Diagnostics) ### F. Proprietary and Established Names: BD MAX™ Vaginal Panel {1}------------------------------------------------ BD MAX™ (Instrument) ## G. 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): POA OUY OOI NSU - 4. Panel: 83 - Microbiology ## H. Indications for Use: - 1. Indications 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) - Gardnerella vaginalis о - o Atopobium vaginae - Bacterial Vaginosis Associated Bacteria-2 (BVAB-2) o - o Megasphaera-1 - Candida spp. (C. albicans, C. tropicalis, C. parapsilosis, C. dubliniensis) ● - Candida glabrata - Candida krusei ● - Trichomonas vaginalis {2}------------------------------------------------ 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. - 3. Special conditions for use statement(s): For Prescription Use Only ## 4. Special instrument requirements: The BD MAX Vaginal Panel is performed on the BD MAX System. ## I. 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. ### J. Standard/Guidance Document Referenced: - CLSI EP 17-A2, Evaluation of Detection Capability for Clinical Laboratory . Measurement Procedures, 2012 - CLSI EP5-A2, Evaluation of Precision Performance of Quantitative Measurement ● Methods, Approved Guideline, 2004 - CLSI EP12-A2, User Protocol for Evaluation of Qualitative Test Performance, 2008 ● ## K. Test Principle: 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 {3}------------------------------------------------ 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. 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. # L. Performance Characteristics: - 1. Analytical Performance: - a. Precision/Reproducibility Studies # Reproducibility/Precision Study Panel Member Composition For the precision and reproducibility studies, panel members were prepared with targeted organisms (or plasmid DNA for Megasphaera-1 and BVAB-2) spiked into simulated vaginal matrix. Table 1 describes organisms that were used to prepare panel members. | MasterMix | Assay Target | Organism | |-----------|--------------|-------------------------| | Vaginosis | BV Markers | Lactobacillus crispatus | | | | Lactobacillus jensenii | | | | Gardnerella vaginalis | | | | Atopobium vaginae | | | | Megasphaera type 1 | | | | BVAB-2 | | Vaginitis | Cgroup | Candida albicans | | | Ckru | Candida krusei | | | Cgla | Candida glabrata | | | TV | Trichomonas vaginalis | Table 1: Organisms for Reproducibility/Precision Study Panel Members {4}------------------------------------------------ For Cgroup (Candida albicans). C. glabrata and C. krusei panel members, samples were spiked at high negative, low positive and moderate positive concentrations based on the assay Limit of Detection (LoD). For BV panel members, sample compositions were designed to represent the flora of BV positive and negative specimens with specific target organism combinations based on results from clinical specimen testing. Because a variety of targeted BV organism combinations can be present in vaginal specimens, multiple panel members for each level were prepared with different targeted organism compositions at varying loads. Each BV negative panel member was spiked with two target organisms. Each BV low positive and moderate positive panel member was prepared with three or more target organisms. Sample compositions were determined based on assay cutoffs for positive and negative BV results. The design for study panel members is described in Table 2. | Concentration Designation | Bacterial Vaginosis1 (% of positive results expected at the designated concentration) | Candida spp. and Trichomonas vaginalis (x LoD) | |------------------------------|---------------------------------------------------------------------------------------------|------------------------------------------------------| | Moderate Positive | ~100 | $\ge$ 2 to $\le$ 5 | | Low Positive | ~95 | < 2 | | High BV Negative | ~20-80 | | | BV Negative | < 5 | | | True Negative | 0 (No Target) | No Target | Table 2: Precision/Reproducibility Study Panel Member Design Multiple panel members with different organism compositions used for BV positive and BV negative samples. {5}------------------------------------------------ ### Precision Study Within-laboratory precision was evaluated for the BD MAX Vaginal Panel at one site. Testing of two different panels was performed over 12 days. Two operators performed two runs each per day, for a total of 48 runs per panel. For evaluation of BV, testing included four different BV high negative panel members, six different BV low positive panel members and one BV negative panel member, each spiked with varying compositions of targeted BV organisms. Results from the study are shown in Table 3. | | Percent Agreement with Expected Result [95 % Confidence Interval] | | | | | |-----------------------|----------------------------------------------------------------------|-------------------------------------|-----------------------------------|-------------------------------------|-------------------------------------| | Concentration | Bacterial Vaginosis | Trichomonas vaginalis | Candida albicans | Candida glabrata | Candida krusei | | True Negativea,b | 100.0 (288/288) [98.7, 100.0] | 100.0 (240/240) [98.4, 100.0] | 99.6 (239/240) [97.7, 99.9] | 100.0 (240/240) [98.4, 100.0] | 100.0 (240/240) [98.4, 100.0] | | Low Positivec | 100.0 (287/287) [98.7, 100.0] | 100.0 (48/48) [92.6, 100.0] | 100.0 (48/48) [92.6, 100.0] | 100.0 (48/48) [92.6, 100.0] | 100.0 (48/48) [92.6, 100.0] | | Moderate Positived | 100.0 (192/192) [98.0, 100.0] | 100.0 (48/48) [92.6, 100.0] | 100.0 (48/48) [92.6, 100.0] | | | | High BV Negatived | 37.5 (72/192) [31.0, 44.5] | | | | | | BV Negativea | 100.0 (48/48) [92.6, 100.0] | | | | | | Table 3: Oualitative Precision Study Results Summary- Vaginitis/Vaginosis | | | |---------------------------------------------------------------------------|--|--| | | | | aTThe expected assay results were deemed to be negative. 'Samples containing specific targets used for analyses of one Master Mix (vaginitis or vaginosis) were used as a TN for the other Master Mix. " Performance includes combined results from replicates of six panel members containing different organism compositions. "Performance includes combined results from replicates of four panel members containing different organism compositions. ### Reproducibility Study A multi-site reproducibility study was performed using the same sample categories as defined above for the precision study with the exception that the high negative category was not evaluated for BV. For BV panel members, the study included two different sample compositions each for low positive and moderate positive samples. Testing was performed using multiple instruments at three different testing sites over eight days. At each site, two operators performed two runs per day on alternating days, for a total of 48 runs tested. The overall Site-to-Site Reproducibility percent agreement for panel member results ranged from 98.5 % to 100% for true negatives, 99.0% to 100% for low positive samples, and 99.5% to 100% for moderate positive samples. Table 4 includes overall qualitative reproducibility results and Table 5 includes qualitative results stratified by site. In addition, Second Derivative Peak Abscissa (SDPA), an internal criterion used to determine a final assay result, was selected as a means of assessing quantitative assay reproducibility. Mean SDPA values with variance components (SD and % CV) are shown in Table 6. {6}------------------------------------------------ | | Percent Agreement with Expected Result | | | | | |-----------------------|----------------------------------------|--------------------------|---------------------|---------------------|-------------------| | Concentration | [95 % Confidence Interval)] | | | | | | | Bacterial vaginosis | Trichomonas vaginalis | Candida albicans | Candida glabrata | Candida krusei | | | True Negativea | 100.0 | 100.0 | 98.5 | 100.0 | | (576/576) | | (480/480) | (473/480) | (480/480) | (478/480) | | [99.3, 100.0] | | [99.2, 100.0] | [97.0, 99.3] | [99.2, 100.0] | [98.5, 99.9] | | Low Positiveb | 99.0 | 100.0 | 100.0 | 100.0 | 100.0 | | | (190/192) | (96/96) | (96/96) | (96/96) | (96/96) | | | [96.3, 99.7] | [96.2, 100.0] | [96.2,100.0] | [96.2, 100.0] | [96.2, 100.0] | | Moderate Positiveb | 99.5 | 100.0 | 100.0 | | | | | (191/192) | (96/96) | (96/96) | | | | | [97.1, 99.9] | [96.2, 100.0] | [96.2, 100.0] | | | | BV Negativea | 100.0 | | | | | | | (96/96) | | | | | | | [96.2, 100.0] | | | | | # Table 4: Qualitative Reproducibility Study Results Summary ªThe expected assay results were deemed to be negative. "Performance includes combined results from replicates of two panel members containing different organism compositions. ## Table 5: Qualitative Site to Site Results | Target | Concentration/ Sample | Site 1 | Site 2 | Site 3 | All | |--------------------------|--------------------------|-----------------|-----------------|-----------------|-----------------| | Bacterial Vaginosis | True Negative | 100 192/192 | 100 192/192 | 100 192/192 | 100 576/576 | | | BV Negative | 100 32/32 | 100 32/32 | 100 32/32 | 100 96/96 | | | Low BV Positivea | 100 64/64 | 96.9 62/64 | 100 64/64 | 99.0 190/192 | | | Moderate Positivea | 100 64/64 | 98.4 63/64 | 100 64/64 | 99.5 191/192 | | Trichomonas vaginalis | True Negative | 100 160/160 | 100 160/160 | 100 160/160 | 100 480/480 | | | Low Positive | 100 32/32 | 100 32/32 | 100 32/32 | 100 96/96 | | | Moderate Positive | 100 32/32 | 100 32/32 | 100 32/32 | 100 96/96 | | Candida albicans | True Negative | 98.8 158/160 | 98.8 158/160 | 98.1 157/160 | 98.5 473/480 | | | Low Positive | 100 32/32 | 100 32/32 | 100 32/32 | 100 96/96 | | | Moderate Positive | 100 32/32 | 100 32/32 | 100 32/32 | 100 96/96 | | Candida glabrata | True Negative | 100 160/160 | 100 160/160 | 100 160/160 | 100 480/480 | | | Low Positive | 100 32/32 | 100 32/32 | 100 32/32 | 100 96/96 | | Candida krusei | True Negative | 99.4 159/160 | 99.4 159/160 | 100 160/160 | 99.6 478/480 | | | Low Positive | 100 32/32 | 100 32/32 | 100 32/32 | 100 96/96 | ª Performance includes combined results from replicates of two panel members containing different organism compositions {7}------------------------------------------------ | Concentration | | SDPA | | | Within Run | | Between Run | | Between Day | | Between Operator | | Between Site | | Total | | |--------------------------|----------------------|------|------|------|---------------|------|----------------|------|----------------|------|---------------------|------|-----------------|------|-------|--| | | | N | Mean | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | | | Candida albicans | Low Positive | 96 | 29.9 | 0.71 | 2.4 | 0.00 | 0.0 | 0.00 | 0.0 | 0.04 | 0.1 | 0.08 | 0.3 | 0.71 | 2.4 | | | | Moderate Positive | 96 | 28.5 | 0.48 | 1.7 | 0.00 | 0.0 | 0.10 | 0.3 | 0.00 | 0.0 | 0.19 | 0.7 | 0.52 | 1.8 | | | Candida glabrata | Low Positive | 96 | 29.6 | 0.32 | 1.1 | 0.00 | 0.0 | 0.00 | 0.0 | 0.04 | 0.1 | 0.08 | 0.3 | 0.33 | 1.1 | | | Candida krusei | Low Positive | 96 | 30.6 | 0.25 | 0.8 | 0.16 | 0.5 | 0.00 | 0.0 | 0.11 | 0.4 | 0.06 | 0.2 | 0.32 | 1.1 | | | Trichomonas vaginalis | Low Positive | 96 | 32.9 | 0.33 | 1.0 | 0.11 | 0.3 | 0.00 | 0.0 | 0.05 | 0.2 | 0.00 | 0.0 | 0.36 | 1.1 | | | | Moderate Positive | 96 | 31.7 | 0.31 | 1.0 | 0.10 | 0.3 | 0.00 | 0.0 | 0.01 | 0.0 | 0.00 | 0.0 | 0.33 | 1.0 | | Table 6: Quantitative Site to Site Results Additional evaluation of lot-to-lot reproducibility of the BD MAX Vaginal Panel was performed at one site with three assay lots over eight days. At the testing site, two operators performed two runs on alternate days, for a total of 48 runs. Lot-to lot reproducibility results are reported below in Tables 7, 8 and 9. Table 7: Qualitative Reproducibility Study Results Summary - Lot to Lot | Category | Percent Agreement with Expected Result [95 % Confidence Interval] | | | | | |----------------------|----------------------------------------------------------------------|-------------------------------------|-----------------------------------|-------------------------------------|------------------------------------| | | Bacterial vaginosis | Trichomonas vaginalis | Candida albicans | Candida glabrata | Candida krusei | | True Negativea | 100.0 (576/576) [99.3, 100.0] | 100.0 (480/480) [99.2, 100.0] | 99.2 (476/480) [97.9, 99.7] | 100.0 (480/480) [99.2, 100.0] | 99.8 (479/480) [98.8, 100.0] | | Low Positive | 100.0b (192/192) [98.0, 100.0] | 100.0 (96/96) [96.2, 100.0] | 100.0 (96/96) [96.2, 100.0] | 100.0 (96/96) [96.2, 100.0] | 100.0 (96/96) [96.2, 100.0] | | Moderate Positive | 100.0b (192/192) [98.0, 100.0] | 100.0 (96/96) [96.2, 100.0] | 100.0 (96/96) [96.2, 100.0] | | | | BV Negative | 100.0 (96/96) [96.2, 100.0] | | | | | 4 The expected assay results were deemed to be negative. b Performance includes combined results from replicates of two panel members containing different organism compositions {8}------------------------------------------------ | Target | Concentration/ Sample | Lot 1 | Lot 2 | Lot 3 | All | |--------------------------|--------------------------|-----------------|-----------------|-----------------|-----------------| | Bacterial Vaginosis | True Negative | 100 192/192 | 100 192/192 | 100 192/192 | 100 576/576 | | | BV Negative | 100 32/32 | 100 32/32 | 100 32/32 | 100 96/96 | | Bacterial Vaginosis | Low BV Positivea | 100 64/64 | 100 64/64 | 100 64/64 | 100 192/192 | | | Moderate Positivea | 100 64/64 | 100 64/64 | 100 64/64 | 100 192/192 | | Trichomonas vaginalis | True Negative | 100 160/160 | 100 160/160 | 100 160/160 | 100 480/480 | | | Low Positive | 100 32/32 | 100 32/32 | 100 32/32 | 100 96/96 | | | Moderate Positive | 100 32/32 | 100 32/32 | 100 32/32 | 100 96/96 | | Candida albicans | True Negative | 98.8 158/160 | 99.4 159/160 | 99.4 159/160 | 99.2 476/480 | | | Low Positive | 100 32/32 | 100 32/32 | 100 32/32 | 100 96/96 | | | Moderate Positive | 100 32/32 | 100 32/32 | 100 32/32 | 100 96/96 | | Candida glabrata | True Negative | 100 160/160 | 100 160/160 | 100 160/160 | 100 480/480 | | | Low Positive | 100 32/32 | 100 32/32 | 100 32/32 | 100 96/96 | | Candida krusei | True Negative | 99.4 159/160 | 100 160/160 | 100 160/160 | 99.8 479/480 | | | Low Positive | 100 32/32 | 100 32/32 | 100 32/32 | 100 96/96 | Table 8: Qualitative Lot-to-Lot Results 4 Performance includes combined results from replicates of two panel members containing different organism compositions Table 9: Quantitative Lot-to-Lot Results | Target | Concentration | SDPA | | Within Run | | Between Run | | Between Day | | Between Operator | | Between Lot | | Total | | |--------------------------|----------------------|------|------|------------|-----|----------------|-----|----------------|-----|---------------------|-----|-------------|-----|-------|-----| | | | N | Mean | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | | Candida albicans | Low Positive | 96 | 30.2 | 0.53 | 1.7 | 0.00 | 0.0 | 0.00 | 0.0 | 0.00 | 0.0 | 1.11 | 3.7 | 1.23 | 4.1 | | Candida albicans | Moderate Positive | 96 | 28.9 | 0.43 | 1.5 | 0.00 | 0.0 | 0.00 | 0.0 | 0.00 | 0.0 | 1.04 | 3.6 | 1.13 | 3.9 | | Candida glabrata | Low Positive | 96 | 29.6 | 0.32 | 1.1 | 0.00 | 0.0 | 0.06 | 0.2 | 0.00 | 0.0 | 0.21 | 0.7 | 0.39 | 1.3 | | Candida krusei | Low Positive | 96 | 30.5 | 0.18 | 0.6 | 0.15 | 0.5 | 0.05 | 0.2 | 0.00 | 0.0 | 0.24 | 0.8 | 0.33 | 1.1 | | Trichomonas vaginalis | LowPositive | 96 | 32.7 | 0.37 | 1.1 | 0.00 | 0.0 | 0.00 | 0.0 | 0.06 | 0.2 | 0.32 | 1.0 | 0.50 | 1.5 | | Trichomonas vaginalis | Moderate Positive | 96 | 31.6 | 0.28 | 0.9 | 0.05 | 0.2 | 0.00 | 0.0 | 0.00 | 0.0 | 0.18 | 0.6 | 0.34 | 1.1 | {9}------------------------------------------------ ## b. Linearity/Assay Reportable Range: ## Not Applicable - c. Traceability, Stability, Expected Values (controls, calibrators, or methods): ## 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. ## 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 Table 10. ● - . Previously characterized positive clinical specimen | | Positive controls | Negative controls | |-----------|----------------------------------|--------------------------| | | | | | Vaginitis | Trichomonas vaginalis ATCC 30001 | Lactobacillus iners ATCC | | | Candida albicans ATCC 10231 | 55195 | | | Candida glabrata ATCC 2001 | | | | Candida krusei ATCC 6258 | | | Vaginosis | BV Positive External Controla | | ### Table 10: Recommended Organisms for External Controls a Mixture of Gardnerella vaginalis and Atopobium vaginae {10}------------------------------------------------ In the prospective clinical study, one external positive and one external negative control were evaluated each day of testing. A rotation scheme consisting of five different positive controls was used to cover all assay targets at each testing site. The external control success rate was 97.6% (445/456) with 6/456 (1.3%) controls generating unexpected results and 5/546 (1.1%) controls generating non-reportable results. Results are presented by analyte in Table 11. | Control | External Control Pass Rate | |----------------------|----------------------------| | BV Positive | 100% (53/53) | | C albicans | 100% (22/23) | | C. glabrata | 96.2% (51/53) | | C. krusei | 98.1% (52/53) | | T. vaginalis | 93.5% (43/46) | | BV Negative | 99.2% (119/120) | | Negative (No target) | 97.2% (105/108) | Table 11: External Control Results -Clinical Study ### Specimen Stability Evaluation of specimen stability was performed to demonstrate that target DNA is stable in vaginal specimens prior to testing with the BD MAX Vaginal Panel. The study combined different storage conditions in a nested design. The study was conducted using five different combinations of reagent lots (Master Mix, Extraction Tubes, Reagent strips and SBTs). For vaginitis analytes, 25 different strains of targeted vaginitis organisms (Candida spp. or T. vaginalis) were used to prepare low positive samples at <2x LoD. Each vaginitis sample was prepared in a unique natural negative vaginal matrix. For BV samples, panel members included 13 low-positive BV organism pools and two negative organism pools. A minimum of 24 sample replicates were evaluated for each panel member and storage condition. To demonstrate stability at each storage condition, a minimum of 95% agreement with the expected result was required. Study results met the study acceptance criteria and therefore substantiate the claimed stability of amplifiable DNA in vaginal specimens containing low positive concentrations of vaginitis DNA targets, low positive compositions of BV analytes, as well as negative specimens for the following claimed storage conditions: - Dry swabs: Storage of dry swab for up to two hours at 2-30°C after collection and before transfer to BD MAX UVE Sample Buffer Tube (SBT). - . Specimen in capped SBT (transport and pre-testing storage): Storage of specimen in SBT up to eight days at 2-30°C or for a maximum of 14 days at 2-8°C. - . SBT post vortex: Storage of vortexed specimen up to four hours at 2-30°C. After this time period the vortexing step must be repeated before testing. - . SBT post testing: Storage of SBT for up to five hours when stored at 2-30°C after completion of the run. {11}------------------------------------------------ The study data provided support the specimen handling recommendations described in the BD MAX Vaginal Panel package insert. ## d. Limit of Detection: A study was conducted to determine the LoD for a representative strain of each targeted organism detected by the BD MAX Vaginal Panel. Serial dilutions of targeted strains were inoculated into simulated vaginal matrix in BD MAX UVE Sample Buffer. A total of 24 replicates were evaluated for each dilution to determine the assay LoD for each target (i.e., organism concentration at which >95% of replicates are detected). To further confirm the LoD for vaginitis analytes, a total of 24 sample replicates were each tested at the LoD in both simulated and natural vaginal matrix. Because natural vaginal matrix contains BV analytes as part of the normal vaginal flora, confirmation of the LoD for BV analytes was performed only in simulated matrix. Table 12 lists the confirmed LoD for organisms strains evaluated in the study. | Assay Target | Organism | Strain ATCC# | LoD | | |-----------------------------------|-------------------------|-----------------|---------------|-----------| | | | | Concentration | Units | | Vaginitis | Candida albicans | 18804 | 17787 | CFU/mL | | | Candida glabrata | 2001 | 202 | CFU/mL | | | Candida krusei | 6258 | 1035 | CFU/mL | | | Candida dubliniensis | MYA-646 | 4002 | CFU/mL | | | Candida tropicalis | 750 | 313 | CFU/mL | | | Candida parapsilosis | 22019 | 30660 | CFU/mL | | | Trichomonas vaginalis | 30001 | 22 | Cells/mL | | Bacterial Vaginosis Markers | Atopobium vaginae | BAA-55 | 127 | CFU/mL | | | Gardnerella vaginalis | 14018 | 962 | CFU/mL | | | Lactobacillus crispatus | 33820 | 55 | CFU/mL | | | Lactobacillus jensenii | 25258 | 510 | CFU/mL | | | Megasphaera-1 | NAᵃ | 2265 | Copies/mL | | | BVAB 2 | | 464 | Copies/mL | a LoD determined with plasmid DNA. ### e. Analytical Inclusivity: An analytical inclusivity study was conducted to evaluate the BD MAX Vaginal Panel for detection of a variety of organism strains, taking into account phylogenetic diversity, geographic origin and temporal diversity. The microbial strains evaluated were from public collections or well-characterized clinical isolates. Testing included five strains each for targeted Candida species (C. albicans, C. dubliniensis, C. parapsilosis, C. tropicalis, C. glabrata, and C. krusei) and nine strains of Trichomonas vaginalis (including one metronidazole resistant strain). In addition, ten strains of Gardnerella vaginalis and five strains each of Atopobium vaginae, Lactobacillus crispatus, and Lactobacillus iensenii were evaluated. Samples were inoculated at < 3x LoD of the corresponding reference strain evaluated in the LoD study. The BD MAX Vaginal Panel correctly identified 60 of the strains tested upon initial testing. Results from four strains {12}------------------------------------------------ of Gardnerella vaginalis and one strain of Lactobacillus crispatus did not meet acceptance criteria and were further evaluated to determine the minimum concentration sufficient for detection. Upon repeat, one G. vaginalis strain was detected at < 3x LoD and three strains were detected at ~9x LoD. The L. crispatus strain was detected at ~5x LoD. - Mixed Infection/Competitive Interference Study: f. A mixed infection/competitive interference study was designed to evaluate the BD MAX Vaginal Panel for detection of targeted analytes at low positive concentrations in the presence of other targets at high concentrations. The following organisms and concentrations were evaluated: - Assay targets at high concentrations: L. crispatus (8.7 x 104 CFU/mL), G. ● vaginalis (5.0 x 106 CFU/mL), A. vaginae (8.0 x 105 CFU/mL), Megasphaera-1 (2.4 x 10' cp/mL) and T. vaginalis (3.3 x 10 to 1.0 x 10° cells/mL), C. albicans (1 x 106 CFU/mL), C. glabrata (1 x 10° CFU/mL) - High concentrations of non-targeted vaginal flora organisms: Dialister . microaerophilus, Prevotella melaninogenica, Streptococcus mitis, Bifidobacterium breve and Mobiluncus curtisii (each at 1.0 x 10°CFU/mL). - . Low positive loads of vaginitis targets were evaluated at < 2x LoD. Low positive BV samples were prepared with BV organism compositions sufficient to obtain 95% positive BV results. Study samples were each prepared in simulated vaginal matrix. The following series of organism pools simulating mixed infections were evaluated: - . High positive BV organisms with low positive loads of: - o T. vaginalis and C. albicans - 0 C. krusei and C. glabrata - High positive C. albicans with low positive loads of: ● - 0 C. krusei and C. glabrata - 0 T. vaginalis - o BV - High positive C. glabrata with low positive loads of: ● - o T. vaginalis - o BV - High positive C. krusei with low positive BV ● - High positive T. vaginalis with low positive loads of: - o BV - o C. albicans {13}------------------------------------------------ - C. krusei o - o C. glabrata - . High positive loads of non-targeted vaginal flora organisms with low positive loads of: - T. vaginalis and BV o - C. albicans and BV o - C. glabrata and BV o - 0 C. krusei and BV The study demonstrated that samples containing T. vaginalis at low concentrations as well as low positive BV samples were successfully detected by the BD MAX Vaginal Panel when tested in combination with high concentrations of other assay targets or high concentrations of other selected organisms of the vaginal flora. Competitive inhibition was observed for samples containing low positive Candida spp. when present in samples containing high concentrations of T. vaginalis or BV analytes. - For low positive samples containing Candida albicans, 92% of positive results ● were obtained in presence of BV analytes at high loads - . For low positive samples containing Candida albicans, C. krusei or C. glabrata, BD MAX Vaginal Panel generated 42%, 61% and 33% of expected results respectively in presence of Trichomonas vaginalis at a load of 3.3 x 10° cells/mL. ### g. Analytical Specificity/Cross-reactivity: The BD MAX Vaginal Panel was evaluated for potential cross-reactivity with samples containing phylogenetically related species and other organisms likely to be present in vaginal specimens. Bacteria, yeasts, parasites and viruses were tested in the BD MAX UVE Sample Buffer Tube at ≥10° bacteria, cells or genome equivalents/mL, or > 10° PFU/mL or TCID50/mL or equivalent amount of RNA/DNA per PCR reaction. In total, 118 organisms were evaluated and those organisms are listed in Table 14 below. For organisms that generated unexpected positive results, additional testing was performed to evaluate the organism load that no longer cross-reacts with the BD MAX Vaginal Panel. Table 13 describes organisms that demonstrated cross-reactivity and the concentrations at which detection was observed. A limitation is included in the package insert describing all cross-reactive organisms. {14}------------------------------------------------ | Cross Reacting Organism | BD MAX Vaginal Panel Target | Additional Testing | |--------------------------------------------|--------------------------------|------------------------------------------| | Candida guillermondii1 | Cgroup | Not detected at <6.0 x 103 CFU/mL | | Candida haemulonii1 | Cgroup | Detected at all concentrations evaluated | | Candida orthopsilosis12 | Cgroup | Detected at all concentrations evaluated | | Pichia fermentans | C krusei | Not detected at <6.0 x 103 CFU/mL | | Trichomonas tenax | Trichomonas vaginalis | Detected at all concentrations evaluated | | Atopobium rimae | Atopobium vaginae (BV) | Not detected at <4.4 x 104 CFU/mL | | Olsenella uli | Atopobium vaginae (BV) | Not detected at <6.6 x 104 CFU/mL | | Lactobacillus delbrueckii subsp. lactis | L. crispatus/jensenii (BV) | Not detected at <3.9 x 103 CFU/mL | | Lactobacillus acidophilus | L. crispatus/jensenii (BV) | Detected at all concentrations evaluated | ## Table 13: Cross Reacting Organisms | Candida guilliermondii, Candida haemulonii and Candida orthopsilosis have each been reported as occasional causes of vulvovaginal candidiasis 2 Candida metapsilosis and Candida orthopsilosis are both subgroups of C. parapsilosis, which is a target of the assay. These two targets were predicted to cross-react based on in silico analysis. # Table 14: Organisms Evaluated For Specificity/Cross-Reactivity | Organisms tested (Cross-reacting Organisms Bolded) | | | | | | |----------------------------------------------------|-------------------------------|---------------|--------------------------------------------|---------------|----------------------| | BACTERIA | | BACTERIA | | BACTERIA | | | Genus | Species | Genus | Species | Genus | Species | | | BVAB-1 | Kocuria | rhizophila | Sneathia | amnii | | | BVAB-3 | | acetotolerans | | sanguinegens | | Acinetobacter | baumannii | | acidophilus | Streptococcus | agalactiae | | | calcoaceticus | | amylophilus | | mitis | | Actinomyces | israelii | | animalis | | mutans | | | pyogenes | | coleohomonis | | salivarius | | Aerococcus | viridans | Lactobacillus | delbrueckii subsp. lactis | | thermophilus | | Alcaligenes | faecalis (subsp. faecalis) | | fornicalis | Treponema | pallidum | | Anaerococcus | tetradius | | gasseri | Veillonella | atypica | | | minutum | | iners | | parvula | | Atopobium | parvulum | | johnsonii | Vibrio | parahaemolyticus | | | rimae | | pontis | Yersinia | enterocolitica | | Bacillus | subtilis | | sharpeae | YEASTS | | | | caccae | | vaginalis | | catenulata | | Bacteroides | fragilis | Legionella | pneumophila subsp. pneumophila | | famata | | | stercoris | Listeria | monocytogenes | | guilliermondii | | Bifidobacterium | adolescentis | Megasphaera-2 | Megasphaera Type-2 | | haemulonii | | | breve | Mobiluncus | curtisii | Candida | inconspicua | | | coryneforme | | mulieris | | intermedia | | | longum | Moraxella | catarrhalis | | kefyr | | | minimum | Morganella | morganii subsp. morganii | | lusitaniae | | Brevibacterium | linens | Mycobacterium | smegmatis | | norvegica | | Burkholderia | cepacia | Mycoplasma | genitalium | | orthopsilosis | | Campylobacter | jejuni | | hominis | | rugosa | {15}------------------------------------------------ | Chlamydia | trachomatis | Neisseria | gonorrhoeae | | utilis | |-----------------|-------------------------------|--------------------|-----------------|-------------------|------------------------| | Citrobacter | freundii | Olsenella | uli | Issatchenkia | occidentalis2 | | Clostridium | perfringens | Pantoea | agglomerans | Kodamaea | ohmeri1 | | Corynebacterium | genitalium | Peptostreptococcus | anaerobius | Pichia | fermentans | | Dialister | microaerophilus | Plesiomonas | shigelloides | | norvegensis3 | | Eikenella | corrodens | Porphyromonas | asaccharolytica | Saccharomyces | cerevisiae | | Enterobacter | aerogenes | | melaninogenica | | VIRUSES | | Enterococcus | faecalis | Prevotella | oris | HBV | Human herpesvirus 2 | | | faecium | Propionibacterium | acnes | HIV | HPV | | Erysipelothrix | rhusiopathiae | Proteus | mirabilis | HSV type 1 | Varicella-zoster | | Escherichia | coli GC10 coli top 10 | Providencia | stuartii | Hepatitis C Virus | virus Ellen | | Fusobacterium | nucleatum subsp. nucleatum | Salmonella | aeruginosa | PARASITES | | | Gemella | haemolysans | Serratia | typhimurium | Pentatrichomonas | hominis | | Kingella | denitrificans | Shigella | marcescens | Trichomonas | tenax | | Klebsiella | pneumoniae | Staphylococcus | flexneri | | | 1 Also reported as Pichia ohmeri, C. guilliermondii 2 Also reported as C. sorbosa 3 Also reported as C. norvegensis The following additional unexpected detections were observed in the study. Repeat testing indicated that these organisms do not cross-react with the BD MAX Vaginal Panel targets. - A single replicate each containing Lactobacillus delbrueckii subsp. lactis or Chlamydia trachomatis initially generated a false positive result for Cgroup. Repeat testing generated 10/10 expected negative results for Cgroup for both of these organisms - A single replicate each containing Bifidobacterium breve, E. coli GC10 or . Lactobacillus acetotolerans initially generated a false positive result for the A. vaginae signal. Repeat testing generated 10/10 expected negative results for A. vaginae for these three organisms #### h. Evaluation of Potentially Interfering Substances/Organisms A study was performed to evaluate potentially interfering biological and chemical substances that may be present in vaginal specimens. Exogenous (e.g., prescription and Over-the-Counter drugs, creams and/or gels) and endogenous (e.g., blood, hormones, mucus) 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 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). KY Jelly Personal Lubricant and Whole Blood were found to interfere at levels above >12.5 µL/mL (1.25% V/V). Zovirax Acyclovir 5 % Cream and VCF Contraceptive Foam were found to interfere at levels above > 3.1 uL/mL. Preparation H Hemorrhoidal {16}------------------------------------------------ Cream was found to interfere above > 0.8 uL/mL. Interference with the following substances was observed at all tested levels: Conceptrol Vaginal Contraceptive Gel, Clotrimazole Vaginal Cream, Monistat 3 Cream, Vagisil Cream, Replens Vaginal Moisturizing Gel, Metronidazole, Leukocytes. Table 15 shows results for the potentially interfering substances evaluated in the study. Substances that demonstrated interference may result in unresolved, indeterminate or false negative results. A limitation is included in the package insert listing all substances that demonstrated interference with the BD MAX Vaginal Panel. | No Interference Observed | | Interference Observed | | |--------------------------|------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------| | | Substance | Substance | Level Below Which No Interference Observed (µL/mL) | | Exogenous | Tioconzole Ointment, 6.5% | VCF Contraceptive Foam | ≤ 3.1 | | | VCF Contraceptive Film | Zovirax, Acyclovir 5% Cream | ≤ 3.1 | | | Summer's Eve Douche | Preparation H Hemorrhoidal Cream | ≤ 0.8 | | | FDS Feminine Deodorant Spray | KY Jelly Personal Lubricant | ≤ 12.5 | | | Progesterone | Conceptrol Vaginal Contraceptive Gel | Interference observed at each level evaluated | | | Estradiol | Clotrimazole Vaginal Cream, USP 2% Monistat 3 Cream, Miconazole Nitrate, 4% Vagisil, Benzocaine 20%, Resorcinol 3% Replens Vaginal Moisturizing Gel Metronidazole 0.75% Gel | | | Endogenous | Mucus (Bovine Cervical, 5% v/v) | Whole Blood | | | | Semen (5% v/v) | Leukocytes | | Table 15: Exogenous and Endogenous Substances Tested for Interference® " In total, with the BD MAX Vaginal Panel in the presence of potentially interfering substances, 2672 samples were tested for vaginosis targets and 3252 for vaginitis targets. For vaginitis targets, rates of 8.27% INR results were recorded. For BV, rates of 9.92% IND and 1.83% UNR results were recorded. Additional testing was performed to evaluate potential interference from microorganisms included in probiotic formulations. A total of 14 probiotic Lactobacillus species listed in Table 17 were evaluated at high concentrations (> 6.7 x 10 CFU/mL of Sample Buffer) in combination with low positive vaginitis analytes, low positive BV samples as well as negative samples containing no targeted analytes. Interference was not observed for detection of Candida albicans, Candida glabrata, Candida krusei, or Trichomonas vaginalis in samples spiked with each of the probiotic organisms. False negative results for BV were observed in the presence of the following probiotic organisms: Lactobacillus amvlovorus. Lactobacillus delbrueckii subsp. bulgaricus, Lactobacillus kefirgranum and Lactobacillus helveticus. The probiotic organisms evaluated are shown in Table 16. {17}------------------------------------------------ | No Interference Observed | | Interference Observed | |-----------------------------------------------|------------------------------------------|------------------------------------------------| | Lactobacillus plantarum | Lactobacillus casei | Lactobacillus delbrueckii subsp. bulgaricus | | Lactobacillus reuteri | Lactobacillus fermentum | Lactobacillus amylovorus | | Lactobacillus rhamnosus | Lactobacillus paracasei | Lactobacillus helveticus | | Lactobacillus salivarius subsp. salivarius | Bifidobacterium animalis subsp lactis | Lactobacillus kefirgranum | | Lactobacillus brevis | Bifidobacterium longum subsp infantis | | ## Table 16: Interference Testing: Probiotic Microorganisms #### i. Matrix Equivalence Study Because the BV analytes detected by the BD MAX Vaginal Panel are present in normal vaginal flora, it was necessary to use a simulated vaginal matrix for preparation of samples for some analytical studies. Equivalence between the simulated matrix and natural vaginal matrices was assessed using data generated in the LoD confirmation study for Candida spp. and T. vaginalis. In this study, LoD values initially determined using samples prepared in simulated vaginal matrix were confirmed in the presence of both simulated and real vaginal matrices. A minimum of 24 sample replicates for each organism evaluated (six different Candida species and one T. vaginalis strain) were tested in both simulated and real vaginal matrices, at the LoD (95% concentration) previously determined in in simulated matrix. All targets evaluated generated 100% positive results in both matrices except for C. krusei which generated only 79.2% positive results for samples prepared in natural vaginal matrix. To further evaluate differences for detection of C. krusei in natural and simulated matrices, higher concentrations were tested in natural matrix, resulting in 91.6% of positive results obtained at 1.99x and 2.5x LoD. These study results together with C. krusei results from contrived clinical specimens prepared in natural vaginal matrices (i.e., 50/50 specimens with C. krusei at 1.99x LoD generated positive results) demonstrated that the assay LoD for C. krusei in natural matrix was ~1.99 x the LoD for this target in simulated matrix. In summary, the matrix equivalency study results substantiated equivalence between the simulated vaginal matrix and natural vaginal matrices for all analytes evaluated with the exception of C. krusei, which demonstrates a higher LoD in natural matrix. This difference was deemed to be acceptable because analytical study samples for C. krusei were prepared with concentrations based on the applicable LoD for the matrix used. #### j. Assay Cut-off Assay cut-offs for the BD MAX Vaginal Panel were initially determined in pre-clinical studies. Data collected in the multi-site prospective clinical study was subsequently used to validate these cut-offs. For this validation, PCR metrics from vaginitis analytes and results generated by the BV call algorithm were graphically and statistically analyzed in comparison to results from applicable reference methods. ROC curve analysis was {18}------------------------------------------------ performed to confirm the optimal cutoffs for each vaginitis analyte as well for the cutoffs used to determine results for bacterial vaginosis. - 2. Clinical Studies: Clinical performance characteristics for the BD MAX Vaginal Panel were evaluated in a prospective clinical study performed at 10 geographically diverse specimen collection sites. Of the 10 collection sites seven sites performed specimen collection only and three sites performed both specimen collection as well as testing with the BD MAX Vaginal Panel. For consented adult female subjects presenting with symptoms of vaginitis or bacterial vaginosis, one self-collected and one clinician-collected vaginal swab were collected using the BD MAX UVE Specimen Collection Kit and tested independently with the BD MAX Vaginal Panel. Three additional vaginal swabs were collected for reference method testing. The following reference methods were performed for each patient: - . BV status was determined using a combination of Nugent Score and Amsel's criteria. Specimens with normal flora as per the Nugent Score were considered negative: those positive for BV flora were considered positive while those with intermediate BV flora were segregated into positive or negative categories using Amsel's criteria. Samples positive for 2 out of the 3 following criteria were considered Amsel's positive: vaginal pH > 4.5, presence of clue cells and positive Whiff test. - . Candida spp. status was determined by selective (Candida) chromogenic medium and Sabouraud Dextrose Emmons plate cultures. PCR amplification targeting the its2 gene was performed followed by bi-directional sequencing to identify all yeast isolates recovered by culture. - . Trichomonas vaginalis status was determined by a composite of microscopic visualization of motile trichomonads in saline wet mounts of vaginal secretion and by culture. A positive result either by wet mount or by culture was sufficient to categorize the patient as positive for Trichomonas vaginalis. A total of 1763 subjects were enrolled in the prospective clinical study. Of those, 1740 subjects were compliant and 23 were found non-compliant as per protocol criteria. For clinician-collected specimens, the numbers of compliant specimens with reportable reference method and BD MAX Vaginal Panel results were 1559 for bacterial vaginosis, 1618 for Candida and 1600 for Trichomonas vaginalis. For self-collected specimens, the numbers of compliant specimens with reportable reference method and BD MAX Vaginal Panel results were 1582 for bacterial vaginosis, 1628 for Candida and 1610 for Trichomonas vaginalis. # BV Performance Table 17 includes overall and per site performance for reporting of BV as observed in the prospective clinical study. The sensitivity and specificity for BV were 90.5% and 85.8 % {19}------------------------------------------------ respectively for clinician-collected vaginal swabs, and 90.7% and 84.5 % respectively for self-collected vaginal swabs. For the population tested, this resulted in Positive Predictive Values (PPV) of 89.0 and 88.1 % for clinician-collected and self-collected specimens, respectively. Negative Predictive Values (NPV) of 87.7 % and 87.8% were obtained for clinician-collected and self-collected specimens, respectively. BV prevalence was 55.8% for patients with compliant reference method results. | Site | Clinician-collected | | Self-collected | | |---------|------------------------------------|------------------------------------|------------------------------------|------------------------------------| | | Sensitivity Percent (95% CI) | Specificity Percent (95% CI) | Sensitivity Percent (95% CI) | Specificity Percent (95% CI) | | 1 | 76.5 26/34 (60.0, 87.6) | 96.6 113/117 (91.5, 98.7) | 80.0 28/35 (64.1, 90.0) | 94.1 111/118 (88.3, 97.1) | | 2 | 92.3 48/52 (81.8, 97.0) | 78.9 30/38 (63.7, 88.9) | 88.5 46/52 (77.0, 94.6) | 76.9 30/39 (61.7, 87.4) | | 3 | 92.3 36/39 (79.7, 97.3) | 81.0 17/21 (60.0, 92.3) | 92.3 36/39 (79.7, 97.3) | 70.0 14/20 (48.1, 85.5) | | 4 | 92.3 12/13 (66.7, 98.6) | 66.7 4/6 (30.0, 90.3) | 84.6 11/13 (57.8, 95.7) | 66.7 4/6 (30.0, 90.3) | | 5 | 89.6 199/222 (84.9, 93.0) | 87.9 131/149 (81.7, 92.2) | 89.1 197/221 (84.4, 92.6) | 88.0 139/158 (82.0, 92.2) | | 6 | 87.1 81/93 (78.8, 92.5) | 87.8 72/82 (79.0, 93.2) | 88.3 83/94 (80.2, 93.3) | 85.4 70/82 (76.1, 91.4) | | 7 | 95.7 44/46 (85.5, 98.8) | 84.8 28/33 (69.1, 93.3) | 100.0 47/47 (92.4, 100.0) | 80.0 28/35 (64.1, 90.0) | | 8 | 93.4 198/212 (89.2, 96.0) | 75.0 87/116 (66.4, 82.0) | 93.5 201/215 (89.4, 96.1) | 78.5 95/121 (70.4, 84.9) | | 9 | 96.0 144/150 (91.5, 98.2) | 77.6 52/67 (66.3, 85.9) | 97.3 145/149 (93.3, 99.0) | 73.5 50/68 (62.0, 82.6) | | 10 | 45.0 9/20 (25.8, 65.8) | 98.0 48/49 (89.3, 99.6) | 45.0 9/20 (25.8, 65.8) | 96.0 48/50 (86.5, 98.9) | | Overall | 90.5 797/881 (88.3, 92.2) | 85.8 582/678 (83.0, 88.3) | 90.7 803/885 (88.6, 92.5) | 84.5 589/697 (81.6, 87.0) | Table 17: BV Performance by Collection Type and Collection Site Tables 18, 19 and 20 include BV performance for clinician-collected and self-collected vaginal specimens stratified respectively by age group, ethnicity and patient clinical condition. {20}------------------------------------------------ | Age Group | Clinician-collected | | Self-collected | | |-------------|------------------------------------|------------------------------------|------------------------------------|------------------------------------| | | Sensitivity Percent (95% CI) | Specificity Percent (95% CI) | Sensitivity Percent (95% CI) | Specificity Percent (95% CI) | | 18 - 29 | 90.3 531/588 (87.6, 92.4) | 84.2 341/405 (80.3, 87.4) | 91.2 539/591 (88.6, 93.2) | 83.0 347/418 (79.1, 86.3) | | 30 - 39 | 91.0 182/200 (86.2, 94.2) | 86.7 130/150 (80.3%, 91.2) | 89.9 179/199 (85.0, 93.4) | 85.0 130/153 (78.5, 89.8) | | 40 - 49 | 94.8 73/77 (87.4, 98.0) | 89.8 79/88 (81.7, 94.5) | 94.9 75/79 (87.7, 98.0) | 87.8 79/90 (79.4, 93.0) | | 50 and over | 68.8 11/16 (44.4, 85.8) | 91.4 32/35 (77.6, 97.0) | 62.5 10/16 (38.6, 81.5) | 91.7 33/36 (78.2, 97.1) | Table 18: BV Performance Stratified By Age Group Table 19: BV Performance Results Stratified by Ethnicity | | | Clinician-collected Specimens | | | | Self-collected Specimens | | | | |--------------------------------|------------------|------------------------------------|------------------------------------|----------------------------|----------------------------|------------------------------------|------------------------------------|----------------------------|----------------------------| | Ethnicity | Prevalencea | Sensitivity Percent (95% CI) | Specificity Percent (95% CI) | PPV Percent (95% CI) | NPV Percent (95% CI) | Sensitivity Percent (95% CI) | Specificity Percent (95% CI) | PPV Percent (95% CI) | NPV Percent (95% CI) | | Asian | 50.9% 29/57 | 79.3 23/29 (61.6, 90.2) | 100.0 26/26 (87.1, 100.0) | 100.0 (87.3, 100.0) | 82.4 (70.8, 92.4) | 79.3 23/29 (61.6, 90.2) | 88.9 24/27 (71.9, 96.1) | 88.1 (73.3, 97.0) | 80.6 (68.3, 91.1) | | Black or African American | 65.2% 559/857 | 91.9 502/546 (89.4, 93.9) | 79.1 223/282 (74.0, 83.4) | 89.2 (86.9, 91.3) | 84.0 (79.8, 87.6) | 92.5 506/547 (90.0, 94.4) | 77.0 224/291 (71.8, 81.4) | 88.3 (86.0, 90.4) | 84.6 (80.4, 88.2) | | Hispanic/Latino | 39.5% 58/147 | 83.9 47/56 (72.2, 91.3) | 84.9 73/86 (75.8, 90.9) | 78.3 (69.1, 86.5) | 89.0 (82.5, 94.2) | 83.9 47/56 (72.2, 91.3) | 87.5 77/88 (79.0, 92.9) | 81.4 (72.2, 89.2) | 89.3 (82.9, 94.4) | | White (not Hispanic/Latino) | 41.3% 164/397 | 90.7 146/161 (85.2, 94.3) | 92.0 207/225 (87.7, 94.9) | 88.9 (84.0, 92.8) | 93.3 (89.9, 96.0) | 90.2 148/164 (84.7, 93.9) | 90.4 207/229 (85.9, 93.6) | 86.9 (81.9, 91.0) | 92.9 (89.5, 95.7) | | Others/Mixed/ Unknown | 58.6% 89/152 | 88.8 79/89 (80.5, 93.8) | 89.8 53/59 (79.5, 95.3) | 92.5 (86.0, 96.9) | 85.0% (76.7, 91.8) | 88.8 79/89 (80.5, 93.8) | 91.9 57/62 (82.5, 96.5) | 94.0 (87.8, 97.8) | 85.3 (77.0, 91.8) | ª Prevalence was calculated for specimens with compliant reference method results. {21}------------------------------------------------ | Table 26. BV Performance Stratified by Clinical Condition | | | | | |-----------------------------------------------------------|-----------------------------------------------------------|-----------------------------------------------------------|------------------------------------------------------|------------------------------------------------------| | Subgroup | Clinician-collected Sensitivity Percent (95% CI) | Clinician-collected Specificity Percent (95% CI) | Self-collected Sensitivity Percent (95% CI) | Self-collected Specificity Percent (95% CI) | | Pregnant patients | 88.9 8/9 (56.5, 98.0) | 90.9 10/11 (62.3, 98.4) | 88.9 8/9 (56.5, 98.0) | 90.0 9/10 (59.6, 98.2) | | Patients with estrogen therapy | 86.4 57/66 (76.1, 92.7) | 84.3 75/89 (75.3, 90.4) | 91.0 61/67 (81.8, 95.8) | 82.0 73/89 (72.8, 88.6) | | Patients using anti-fungals | 80.4 45/56 (68.2, 88.7) | 93.8 75/80 (86.2, 97.3) | 80.0 44/55 (67.6, 88.4) | 90.9 80/88 (83.1, 95.3) | | Patients with unprotected intercourse in the last 24 h | 89.7 61/68 (80.2, 94.9) | 68.3 28/41 (53.0, 80.4) | 89.6 60/67 (80.0, 94.8) | 69.8 30/43 (54.9, 81.4) | | Patients with recurrent symptoms | 87.6 162/185 (82.0, 91.6) | 87.1 155/178 (81.4, 91.2) | 86.1 161/187 (80.4, 90.3) | 85.9 159/185 (80.2, 90.2) | | Patients using oral antibiotics | 82.3 79/96 (73.5, 88.6) | 93.8 76/81 (86.4, 97.3) | 84.4 81/96 (75.8, 90.3) | 83.3 70/84 (73.9, 89.8) | | Patients with menses | 83.3 40/48 (70.4, 91.3) | 86.5 32/37 (72.0, 94.1) | 85.7 42/49 (73.3, 92.9) | 86.8 33/38 (72.7, 94.2) | | Patients without menses | 90.8 754/830 (88.7, 92.6) | 85.7 546/637 (82.8, 88.2) | 91.0 758/833 (88.9, 92.8) | 84.3 552/655 (81.3, 86.9) | Table 20: BV Performance Stratified by Clinical Condition ## Cgroup Performance Table 21 includes overall and per site performance for detection of Cgroup (Candida albicans, Candida tropicalis, Candida parapsilosis and/or Candida dubliniensis) as observed in the prospective clinical study. The sensitivity and specificity were 90.9 and 94.1 % respectively for clinician-collected vaginal swabs, and 92.2 and 91.9 % respectively for self-collected vaginal swabs. For the population tested, this resulted in a PPV of 87.8 and 84.1 % for clinician-collected and self-collected specimens, respectively. NPV's of 95.7 and 96.2 % were obtained for clinician-collected and selfcollected vaginal swabs, respectively. The prevalence of these Candida species combined was 31.6% for patients with compliant reference method results. {22}------------------------------------------------ | | Clinician-collected | | Self-collected | | |---------|---------------------------------|-----------------------------------|---------------------------------|-----------------------------------| | | Sensitivity | Sensitivity | Specificity | Specificity | | Site | Percent (95% CI) | Percent (95% CI) | Percent (95% CI) | Percent (95% CI) | | 1 | 96.4 53/55 (87.7, 99.0) | 97.0 98/101 (91.6, 99.0) | 98.2 54/55 (90.4, 99.7) | 93.1 95/102 (86.5, 96.6) | | 2 | 82.8 24/29 (65.5, 92.4) | 93.9 62/66 (85.4, 97.6) | 93.1 27/29 (78.0, 98.1) | 93.9 62/66 (85.4, 97.6) | | 3 | 61.5 8/13 (35.5, 82.3) | 89.1 41/46 (77.0, 95.3) | 83.3 10/12 (55.2, 95.3) | 91.3 42/46 (79.7, 96.6) | | 4 | 100.0 3/3 (43.9, 100.0) | 100.0 17/17 (81.6, 100.0) | 100.0 3/3 (43.9, 100.0) | 94.1 16/17 (73.0, 99.0) | | 5 | 96.1 99/103 (90.4, 98.5) | 94.4 268/284 (91.0, 96.5) | 91.3 95/104 (84.4, 95.4) | 90.9 259/285 (87.0, 93.7) | | 6 | 91.9 57/62 (82.5, 96.5) | 96.6 114/118 (91.6, 98.7) | 85.2 52/61 (74.3, 92.0) | 91.6 109/119 (85.2, 95.4) | | 7 | 90.9 30/33 (76.4, 96.9) | 93.9 46/49 (83.5, 97.9) | 91.2 31/34 (77.0, 97.0) | 87.8 43/49 (75.8, 94.3) | | 8 | 95.4 104/109 (89.7, 98.0) | 93.9 214/228 (90.0, 96.3) | 96.4 107/111 (91.1, 98.6) | 91.0 212/233 (86.6, 94.0) | | 9 | 86.4 70/81 (77.3, 92.2) | 89.1 131/147 (83.1, 93.2) | 90.0 72/80 (81.5, 94.8) | 93.9 138/147 (88.8, 96.7) | | 10 | 70.0 14/20 (48.1, 85.5) | 100.0 54/54 (93.4, 100.0) | 90.5 19/21 (71.1, 97.3) | 96.3 52/54 (87.5, 99.0) | | Overall | 90.9 462/508 (88.1, 93.1) | 94.1 1045/1110 (92.6, 95.4) | 92.2 470/510 (89.5, 94.2) | 91.9 1028/1118 (90.2, 93.4) | Table 21: Cgroup Performance per Collection Type and Collection Site Table 22 includes Cgroup performance stratified by each applicable Candida species identified by the reference culture and sequencing of the its2 gene. {23}------------------------------------------------ | Species (its2 gene ID) | Sensitivity | | |------------------------------------------------------------|------------------------------------|------------------------------------| | | Clinician-collected | Self-collected | | | Estimate 95% CI | | | Candida albicans | 91.0% 445/489 (88.1%, 93.2%) | 92.0% 451/490 (89.3%, 94.1%) | | Candida albicans (co-infected with C. glabrata) | 92.3% 12/13 (66.7%, 98.6%) | 100% 13/13 (77.2%, 100.0%) | | Co-infection Candida albicans and Candida tropicalis | 100.0% 1/1 (20.7%, 100.0%) | 100.0% 1/1 (20.7%, 100.0%) | | Candida dubliniensis | 100.0% 3/3 (43.9%, 100.0%) | 100.0% 3/3 (43.9%, 100.0%) | | Candida tropicalis | 50.0% 1/2 (9.5%, 90.5%) | 66.7% 2/3 (20.8%, 93.9%) | | Overall…

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