(291 days)
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
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.
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.
Acceptance Criteria and Study for BD MAX Vaginal Panel
The BD MAX Vaginal Panel is an automated qualitative in vitro diagnostic test for the direct detection of DNA targets from bacteria associated with bacterial vaginosis, Candida species associated with vulvovaginal candidiasis, and Trichomonas vaginalis from vaginal swabs in symptomatic patients. The device's performance was evaluated through a prospective clinical study and various analytical studies.
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria for this device are not explicitly stated as distinct numerical thresholds in the provided document for all metrics. Instead, the document presents detailed performance characteristics from various studies, implying that the observed performance was acceptable for De Novo classification. For the purpose of this response, I will infer "acceptance criteria" where possible from general regulatory expectations for diagnostic devices and the context of the reported results (e.g., successful detection, high agreement). The "Reported Device Performance" will reflect the results from the clinical and analytical studies.
| Performance Characteristic | Acceptance Criteria (Inferred/General Expectation) | Reported Device Performance |
|---|---|---|
| I. Clinical Performance | ||
| Bacterial Vaginosis (BV) | High sensitivity and specificity for both clinician-collected and self-collected samples, with confidence intervals indicating reliable performance. (Typically >80% sensitivity and specificity for nucleic acid-based tests in this context) | Clinician-collected: Sensitivity 90.5% (95% CI: 88.3, 92.2), Specificity 85.8% (95% CI: 83.0, 88.3)Self-collected: Sensitivity 90.7% (95% CI: 88.6, 92.5), Specificity 84.5% (95% CI: 81.6, 87.0) |
| Cgroup (Candida spp.) | High sensitivity and specificity for both clinician-collected and self-collected samples. | Clinician-collected: Sensitivity 90.9% (95% CI: 88.1, 93.1), Specificity 94.1% (95% CI: 92.6, 95.4)Self-collected: Sensitivity 92.2% (95% CI: 89.5, 94.2), Specificity 91.9% (95% CI: 90.2, 93.4) |
| Candida glabrata | High specificity, and acceptable sensitivity given potentially lower prevalence. Supplemented by contrived specimens. | Clinician-collected: Sensitivity 75.9% (95% CI: 57.9, 87.8), Specificity 99.7% (95% CI: 99.3, 99.9)Self-collected: Sensitivity 86.7% (95% CI: 70.3, 94.7), Specificity 99.6% (95% CI: 99.2, 99.8)Contrived specimens: 100% positive agreement for all spiked concentrations (High, Moderate, Low Positive). |
| Candida krusei | High specificity, and acceptable sensitivity through contrived specimens, especially given typically very low prevalence in clinical studies. | Clinician-collected: Specificity 99.8% (95% CI: 99.4, 99.9)Self-collected: Specificity 100.0% (95% CI: 99.8, 100.0)No positive clinical specimens identified for sensitivity calculation.Contrived specimens: 100% positive agreement for all spiked concentrations (High, Moderate, Low Positive). |
| Trichomonas vaginalis | High sensitivity and specificity for both clinician-collected and self-collected samples. | Clinician-collected: Sensitivity 93.1% (95% CI: 87.4, 96.3), Specificity 99.3% (95% CI: 98.7, 99.6)Self-collected: Sensitivity 93.2% (95% CI: 87.6, 96.4), Specificity 99.3% (95% CI: 98.6, 99.7) |
| Non-reportable Rates | Low rates of unresolved, indeterminate, and incomplete results, with further reduced rates after retesting. (Typically <5% for initial and <2% for final) | Clinician-collected: Initial 8.1%, Final 2.2%Self-collected: Initial 7.0%, Final 1.4% (All rates are for total non-reportable results, broken down further by type in the document) |
| II. Analytical Performance | ||
| Precision/Reproducibility | High percent agreement with expected results across different concentrations (True Negative, Low Positive, Moderate Positive, High BV Negative), sites, operators, and reagent lots. (Typically >95% for qualitative agreement for diagnostic assays) | Precision Study (Within-lab): Most categories 100% agreement, with BV high negative at 37.5%. Candida true negative ranges from 99.6-100%.Reproducibility Study (Multi-site, Lot-to-lot): Overall Site-to-Site Reproducibility percent agreement for panel member results ranged from 98.5 % to 100% (true negatives), 99.0% to 100% (low positive samples), and 99.5% to 100% (moderate positive samples). Lot-to-lot results were similar. |
| Limit of Detection (LoD) | Consistent and sufficiently low LoD for all targeted organisms, demonstrating adequate detection capability for clinical relevance. (Typically defined as >95% detection rate) | Confirmed LoD values for each organism were established (e.g., C. albicans 17787 CFU/mL, T. vaginalis 22 Cells/mL), with 24 replicates tested at each dilution, showing >95% detection. |
| Analytical Inclusivity | Correct detection of a wide variety of strains for each targeted organism, including phylogenetic and geographic diversity, at clinically relevant concentrations. (Typically >95% detection of tested strains) | 60 of the initial strains correctly identified. Five strains (4 G. vaginalis, 1 L. crispatus) did not meet initial criteria but were detected at slightly higher, yet clinically relevant, concentrations upon repeat testing (G. vaginalis at <3x LoD and ~9x LoD, L. crispatus at ~5x LoD). Overall performance was deemed acceptable. |
| Mixed Infection/Competitive Interference | Accurate detection of targets at low positive concentrations even in the presence of other targets or non-targeted vaginal flora at high concentrations. Minimal interference. (Typically >90% detection) | Detection of T. vaginalis and BV at low positive concentrations was successful in the presence of high concentrations of other targets or vaginal flora. Some competitive inhibition observed for Candida spp. when T. vaginalis or BV analytes were at high concentrations (C. albicans: 92% positive with high BV, 42% with high T. vaginalis; C. krusei: 61% with high T. vaginalis; C. glabrata: 33% with high T. vaginalis). These limitations are noted in the package insert. |
| Analytical Specificity/Cross-reactivity | No significant cross-reactivity with phylogenetically related species or other organisms likely to be present in vaginal specimens. If cross-reactivity is observed, it should be at very high concentrations unlikely to be encountered clinically, or clearly disclosed as a limitation. (Typically shows <5% false positive rate) | 118 organisms evaluated. Detected cross-reactivity with Candida haemulonii, Candida orthopsilosis, Trichomonas tenax, and Lactobacillus acidophilus at all tested concentrations. Other organisms (e.g., C. guilliermondii, Pichia fermentans, Atopobium rimae, Olsenella uli, L. delbrueckii subsp. lactis) showed no detection below specific concentrations. A limitation is included in the package insert. |
| Interfering Substances/Probiotics | Device performance should not be significantly impacted by common endogenous or exogenous substances found in vaginal specimens or probiotic organisms. (Typically <5% false positive/negative rate) | Several substances (e.g., KY Jelly Personal Lubricant, Whole Blood, Zovirax, VCF Contraceptive Foam, Preparation H, Conceptrol, Clotrimazole, Monistat 3, Vagisil, Replens, Metronidazole, Leukocytes) were found to interfere. These interferences are noted as limitations. False negative BV results observed with specific probiotic Lactobacillus species (L. amylovorus, L. delbrueckii subsp. bulgaricus, L. kefirgranum, L. helveticus). These limitations are noted. |
| Specimen Stability | Maintains performance over claimed storage conditions and durations. (Typically >95% agreement with expected results) | Met acceptance criteria (>95% agreement) for dry swab up to 2 hours (2-30°C), in capped SBT up to 8 days (2-30°C) or 14 days (2-8°C), and post-vortex up to 4 hours (2-30°C), and post-testing up to 5 hours (2-30°C). |
2. Sample Sizes Used for the Test Set and Data Provenance
Test Set (Clinical Study):
- Total subjects enrolled: 1763
- Compliant subjects: 1740
- Compliant specimens with reportable results:
- Bacterial Vaginosis: 1559 (clinician-collected), 1582 (self-collected)
- Candida: 1618 (clinician-collected), 1628 (self-collected)
- Trichomonas vaginalis: 1600 (clinician-collected), 1610 (self-collected)
- Asymptomatic Women (separate evaluation): 202 women
- Contrived Specimens for C. glabrata and C. krusei: 50 strains each, developed at various concentrations, plus 50 true negative specimens for each organism.
Data Provenance:
- The data for the primary clinical study was prospective.
- Specimen collection occurred at 10 geographically diverse specimen collection sites. Seven sites performed collection only, and three performed both collection and testing with the BD MAX Vaginal Panel. (The country of origin is not explicitly stated but is implicitly the US given FDA submission context).
- Analytical studies (Precision, LoD, Inclusivity, Interference, Stability, Specificity) used simulated vaginal matrix and/or natural negative vaginal matrix, and commercially available organisms/plasmid DNA.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications
The document specifies the reference methods used to establish ground truth but does not explicitly state the number or qualifications of experts involved in the interpretation of these reference methods.
- BV status: Determined using a combination of Nugent Score and Amsel's criteria. These methods typically involve microscopic evaluation by trained laboratory personnel or clinicians, but specific expert qualifications (e.g., years of experience, specific certifications) are not detailed.
- Candida spp. status: 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 yeast isolates. Interpretation of cultures and sequencing results would be performed by trained microbiologists or laboratory specialists.
- Trichomonas vaginalis status: Determined by a composite of microscopic visualization of motile trichomonads in saline wet mounts of vaginal secretion and by culture. A positive result by either method categorized the patient as positive. Microscopic visualization implies examination by trained personnel.
4. Adjudication Method for the Test Set
The document does not explicitly describe an adjudication method for discordant results between the reference methods themselves or between the device and reference methods.
- For BV, "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." This implies a defined algorithm for combining the reference standards rather than a separate expert adjudication panel.
- For Trichomonas vaginalis, "A positive result either by wet mount or by culture was sufficient to categorize the patient as positive." This constitutes a composite reference standard.
- For analyses of discordant results (e.g., for T. vaginalis false negatives and false positives, or C. glabrata false negatives), the document mentions further evaluation with an "FDA-cleared molecular method" or assessing growth levels from chromagar, which indicates further diagnostic investigation rather than expert consensus adjudication of initial reference results.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, a multi-reader multi-case (MRMC) comparative effectiveness study was not conducted. This device is an automated, standalone molecular diagnostic test. It does not involve human readers interpreting images or data to make a diagnosis that would then be compared with and without AI assistance. Therefore, there is no effect size reported for human readers improving with vs. without AI assistance.
6. Standalone Performance Study
Yes, a standalone (i.e., algorithm only without human-in-the-loop performance) was done. The entire premise of the clinical and analytical studies is to evaluate the BD MAX Vaginal Panel's performance on its own, comparing its direct output (qualitative detection of DNA targets) to established reference methods. The system automates sample preparation, DNA extraction, amplification, detection, and interpretation of test results (POS, NEG, or UNR). The clinical performance metrics (sensitivity, specificity, PPV, NPV) presented in Tables 17-36 represent the standalone performance of the device.
7. Type of Ground Truth Used
The ground truth used for the clinical study was a composite reference standard:
- Bacterial Vaginosis: A combination of Nugent Score and Amsel's criteria.
- Candida spp.: Culture (chromogenic medium and Sabouraud Dextrose Emmons plate cultures) followed by PCR amplification targeting the its2 gene and bi-directional sequencing for species identification.
- Trichomonas vaginalis: A composite of microscopic visualization of motile trichomonads in saline wet mounts of vaginal secretion and culture.
This approach combines multiple diagnostic methods to establish the most accurate possible "true" status for each patient's sample.
8. Sample Size for the Training Set
The document does not explicitly state the sample size for a separate "training set" in the context of machine learning or AI model development. The BD MAX Vaginal Panel is described as a nucleic acid-based test utilizing real-time PCR with fluorogenic target-specific hybridization probes, and software for automated interpretation based on amplification status. While there's an "Assay Cut-off" section mentioning use of pre-clinical studies and prospective clinical study data to "validate these cut-offs" and "ROC curve analysis was performed to confirm the optimal cutoffs," this typically refers to refining analytical thresholds based on observed performance from early testing rather than training a complex AI model in the conventional sense.
The "pre-clinical studies" and "LoD confirmation study" using simulated and natural vaginal matrices, as well as the "multi-site prospective clinical study" mentioned for validation of cut-offs, represent data used to establish and confirm the device's operational parameters. However, calling these a "training set" in the context of advanced AI algorithms (like those in machine learning) might be a misinterpretation given the nature of a PCR-based diagnostic with defined analytical cut-offs. The largest dataset mentioned for performance evaluation is the prospective clinical study (1763 enrolled subjects).
9. How the Ground Truth for the Training Set Was Established
As noted above, a distinct "training set" for an AI model (in the sense of supervised learning) is not explicitly described. However, if we interpret "training set" broadly as the data used to initially establish and refine the device's operational parameters and cut-offs, the ground truth was derived from the following:
- Pre-clinical studies: Utilized targeted organisms (or plasmid DNA) spiked into simulated vaginal matrix at varying, known concentrations (e.g., for LoD determination, precision studies). The "expected result" in these analytical studies served as the ground truth.
- Prospective clinical study data: Data from the 1763 enrolled subjects (used to "validate these cut-offs" and performing ROC analysis) employed the composite reference standards described in section 7 (Nugent/Amsel for BV, Culture/Sequencing for Candida, Wet Mount/Culture for T. vaginalis). These reference methods collectively established the ground truth for clinical specimens against which the device's performance, including its cut-offs, was evaluated and confirmed.
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EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR BD MAX Vaginal Panel
DECISION SUMMARY
A. DEN Number:
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
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BD MAX™ (Instrument)
G. Regulatory Information:
-
- Regulation section:
21 CFR 866.3975. Device that detects nucleic acid sequences from microorganisms associated with vaginitis and bacterial vaginosis.
- Regulation section:
-
- Classification:
Class II (Special Controls)
- Classification:
-
- Product code(s): POA OUY OOI NSU
-
- Panel:
83 - Microbiology
H. Indications for Use:
-
- 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:
- Indications for Use:
-
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
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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.
-
- Special conditions for use statement(s):
For Prescription Use Only
- Special conditions for use statement(s):
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
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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:
-
- 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
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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.
| ConcentrationDesignation | Bacterial Vaginosis1(% of positive results expected at thedesignated concentration) | Candida spp. and Trichomonasvaginalis(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.
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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 | BacterialVaginosis | Trichomonasvaginalis | Candidaalbicans | Candidaglabrata | Candidakrusei |
| 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] |
| ModeratePositived | 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 BVNegatived | 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.
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| Percent Agreement with Expected Result | |||||
|---|---|---|---|---|---|
| Concentration | [95 % Confidence Interval)] | ||||
| Bacterialvaginosis | Trichomonasvaginalis | Candidaalbicans | Candidaglabrata | Candidakrusei | |
| TrueNegativea | 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] | |
| LowPositiveb | 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] | |
| ModeratePositiveb | 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 |
|---|---|---|---|---|---|
| BacterialVaginosis | True Negative | 100192/192 | 100192/192 | 100192/192 | 100576/576 |
| BV Negative | 10032/32 | 10032/32 | 10032/32 | 10096/96 | |
| Low BV Positivea | 10064/64 | 96.962/64 | 10064/64 | 99.0190/192 | |
| Moderate Positivea | 10064/64 | 98.463/64 | 10064/64 | 99.5191/192 | |
| Trichomonasvaginalis | True Negative | 100160/160 | 100160/160 | 100160/160 | 100480/480 |
| Low Positive | 10032/32 | 10032/32 | 10032/32 | 10096/96 | |
| Moderate Positive | 10032/32 | 10032/32 | 10032/32 | 10096/96 | |
| Candida albicans | True Negative | 98.8158/160 | 98.8158/160 | 98.1157/160 | 98.5473/480 |
| Low Positive | 10032/32 | 10032/32 | 10032/32 | 10096/96 | |
| Moderate Positive | 10032/32 | 10032/32 | 10032/32 | 10096/96 | |
| Candida glabrata | True Negative | 100160/160 | 100160/160 | 100160/160 | 100480/480 |
| Low Positive | 10032/32 | 10032/32 | 10032/32 | 10096/96 | |
| Candida krusei | True Negative | 99.4159/160 | 99.4159/160 | 100160/160 | 99.6478/480 |
| Low Positive | 10032/32 | 10032/32 | 10032/32 | 10096/96 |
ª Performance includes combined results from replicates of two panel members containing different organism compositions
{7}------------------------------------------------
| Concentration | SDPA | WithinRun | BetweenRun | BetweenDay | BetweenOperator | BetweenSite | Total | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N | Mean | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | |||
| Candidaalbicans | LowPositive | 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 | |
| ModeratePositive | 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 | ||
| Candidaglabrata | LowPositive | 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 | |
| Candidakrusei | LowPositive | 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 | |
| Trichomonasvaginalis | LowPositive | 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 | |
| ModeratePositive | 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 | Trichomonasvaginalis | Candida albicans | Candida glabrata | Candida krusei | |
| TrueNegativea | 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] |
| LowPositive | 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] |
| ModeratePositive | 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 |
|---|---|---|---|---|---|
| BacterialVaginosis | True Negative | 100192/192 | 100192/192 | 100192/192 | 100576/576 |
| BV Negative | 10032/32 | 10032/32 | 10032/32 | 10096/96 | |
| BacterialVaginosis | Low BVPositivea | 10064/64 | 10064/64 | 10064/64 | 100192/192 |
| ModeratePositivea | 10064/64 | 10064/64 | 10064/64 | 100192/192 | |
| Trichomonasvaginalis | True Negative | 100160/160 | 100160/160 | 100160/160 | 100480/480 |
| Low Positive | 10032/32 | 10032/32 | 10032/32 | 10096/96 | |
| ModeratePositive | 10032/32 | 10032/32 | 10032/32 | 10096/96 | |
| Candida albicans | True Negative | 98.8158/160 | 99.4159/160 | 99.4159/160 | 99.2476/480 |
| Low Positive | 10032/32 | 10032/32 | 10032/32 | 10096/96 | |
| ModeratePositive | 10032/32 | 10032/32 | 10032/32 | 10096/96 | |
| Candida glabrata | True Negative | 100160/160 | 100160/160 | 100160/160 | 100480/480 |
| Low Positive | 10032/32 | 10032/32 | 10032/32 | 10096/96 | |
| Candida krusei | True Negative | 99.4159/160 | 100160/160 | 100160/160 | 99.8479/480 |
| Low Positive | 10032/32 | 10032/32 | 10032/32 | 10096/96 |
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 | BetweenRun | BetweenDay | BetweenOperator | Between Lot | Total | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N | Mean | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | ||
| Candidaalbicans | 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 |
| Candidaalbicans | ModeratePositive | 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 |
| Candidaglabrata | 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 |
| Candidakrusei | 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 |
| Trichomonasvaginalis | 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 |
| Trichomonasvaginalis | ModeratePositive | 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.
| AssayTarget | Organism | StrainATCC# | 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 | |
| BacterialVaginosisMarkers | 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 VaginalPanel 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 delbrueckiisubsp. 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 | Humanherpesvirus 2 |
| faecium | Propionibacterium | acnes | HIV | HPV | |
| Erysipelothrix | rhusiopathiae | Proteus | mirabilis | HSV type 1 | Varicella-zoster |
| Escherichia | coli GC10coli 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 NoInterference 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 DeodorantSpray | KY Jelly Personal Lubricant | ≤ 12.5 | |
| Progesterone | Conceptrol Vaginal Contraceptive Gel | Interference observed ateach level evaluated | |
| Estradiol | Clotrimazole Vaginal Cream, USP 2%Monistat 3 Cream, Miconazole Nitrate, 4%Vagisil, Benzocaine 20%, Resorcinol 3%Replens Vaginal Moisturizing GelMetronidazole 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 subsplactis | Lactobacillus kefirgranum |
| Lactobacillus brevis | Bifidobacterium longum subspinfantis |
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.
-
- 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.
- Clinical Studies:
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 | ||
|---|---|---|---|---|
| SensitivityPercent(95% CI) | SpecificityPercent(95% CI) | SensitivityPercent(95% CI) | SpecificityPercent(95% CI) | |
| 1 | 76.526/34(60.0, 87.6) | 96.6113/117(91.5, 98.7) | 80.028/35(64.1, 90.0) | 94.1111/118(88.3, 97.1) |
| 2 | 92.348/52(81.8, 97.0) | 78.930/38(63.7, 88.9) | 88.546/52(77.0, 94.6) | 76.930/39(61.7, 87.4) |
| 3 | 92.336/39(79.7, 97.3) | 81.017/21(60.0, 92.3) | 92.336/39(79.7, 97.3) | 70.014/20(48.1, 85.5) |
| 4 | 92.312/13(66.7, 98.6) | 66.74/6(30.0, 90.3) | 84.611/13(57.8, 95.7) | 66.74/6(30.0, 90.3) |
| 5 | 89.6199/222(84.9, 93.0) | 87.9131/149(81.7, 92.2) | 89.1197/221(84.4, 92.6) | 88.0139/158(82.0, 92.2) |
| 6 | 87.181/93(78.8, 92.5) | 87.872/82(79.0, 93.2) | 88.383/94(80.2, 93.3) | 85.470/82(76.1, 91.4) |
| 7 | 95.744/46(85.5, 98.8) | 84.828/33(69.1, 93.3) | 100.047/47(92.4, 100.0) | 80.028/35(64.1, 90.0) |
| 8 | 93.4198/212(89.2, 96.0) | 75.087/116(66.4, 82.0) | 93.5201/215(89.4, 96.1) | 78.595/121(70.4, 84.9) |
| 9 | 96.0144/150(91.5, 98.2) | 77.652/67(66.3, 85.9) | 97.3145/149(93.3, 99.0) | 73.550/68(62.0, 82.6) |
| 10 | 45.09/20(25.8, 65.8) | 98.048/49(89.3, 99.6) | 45.09/20(25.8, 65.8) | 96.048/50(86.5, 98.9) |
| Overall | 90.5797/881(88.3, 92.2) | 85.8582/678(83.0, 88.3) | 90.7803/885(88.6, 92.5) | 84.5589/697(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.
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| Age Group | Clinician-collected | Self-collected | ||
|---|---|---|---|---|
| SensitivityPercent(95% CI) | SpecificityPercent(95% CI) | SensitivityPercent(95% CI) | SpecificityPercent(95% CI) | |
| 18 - 29 | 90.3531/588(87.6, 92.4) | 84.2341/405(80.3, 87.4) | 91.2539/591(88.6, 93.2) | 83.0347/418(79.1, 86.3) |
| 30 - 39 | 91.0182/200(86.2, 94.2) | 86.7130/150(80.3%, 91.2) | 89.9179/199(85.0, 93.4) | 85.0130/153(78.5, 89.8) |
| 40 - 49 | 94.873/77(87.4, 98.0) | 89.879/88(81.7, 94.5) | 94.975/79(87.7, 98.0) | 87.879/90(79.4, 93.0) |
| 50 and over | 68.811/16(44.4, 85.8) | 91.432/35(77.6, 97.0) | 62.510/16(38.6, 81.5) | 91.733/36(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 | SensitivityPercent(95% CI) | SpecificityPercent(95% CI) | PPVPercent(95% CI) | NPVPercent(95% CI) | SensitivityPercent(95% CI) | SpecificityPercent(95% CI) | PPVPercent(95% CI) | NPVPercent(95% CI) |
| Asian | 50.9%29/57 | 79.323/29(61.6, 90.2) | 100.026/26(87.1,100.0) | 100.0(87.3,100.0) | 82.4(70.8,92.4) | 79.323/29(61.6,90.2) | 88.924/27(71.9,96.1) | 88.1(73.3,97.0) | 80.6(68.3,91.1) |
| Black or AfricanAmerican | 65.2%559/857 | 91.9502/546(89.4, 93.9) | 79.1223/282(74.0,83.4) | 89.2(86.9, 91.3) | 84.0(79.8,87.6) | 92.5506/547(90.0,94.4) | 77.0224/291(71.8,81.4) | 88.3(86.0,90.4) | 84.6(80.4,88.2) |
| Hispanic/Latino | 39.5%58/147 | 83.947/56(72.2, 91.3) | 84.973/86(75.8,90.9) | 78.3(69.1,86.5) | 89.0(82.5,94.2) | 83.947/56(72.2,91.3) | 87.577/88(79.0,92.9) | 81.4(72.2,89.2) | 89.3(82.9,94.4) |
| White (notHispanic/Latino) | 41.3%164/397 | 90.7146/161(85.2, 94.3) | 92.0207/225(87.7,94.9) | 88.9(84.0,92.8) | 93.3(89.9,96.0) | 90.2148/164(84.7,93.9) | 90.4207/229(85.9,93.6) | 86.9(81.9,91.0) | 92.9(89.5,95.7) |
| Others/Mixed/Unknown | 58.6%89/152 | 88.879/89(80.5, 93.8) | 89.853/59(79.5,95.3) | 92.5(86.0,96.9) | 85.0%(76.7,91.8) | 88.879/89(80.5,93.8) | 91.957/62(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-collectedSensitivityPercent(95% CI) | Clinician-collectedSpecificityPercent(95% CI) | Self-collectedSensitivityPercent(95% CI) | Self-collectedSpecificityPercent(95% CI) |
| Pregnant patients | 88.98/9(56.5, 98.0) | 90.910/11(62.3, 98.4) | 88.98/9(56.5, 98.0) | 90.09/10(59.6, 98.2) |
| Patients with estrogen therapy | 86.457/66(76.1, 92.7) | 84.375/89(75.3, 90.4) | 91.061/67(81.8, 95.8) | 82.073/89(72.8, 88.6) |
| Patients using anti-fungals | 80.445/56(68.2, 88.7) | 93.875/80(86.2, 97.3) | 80.044/55(67.6, 88.4) | 90.980/88(83.1, 95.3) |
| Patients with unprotected intercourse inthe last 24 h | 89.761/68(80.2, 94.9) | 68.328/41(53.0, 80.4) | 89.660/67(80.0, 94.8) | 69.830/43(54.9, 81.4) |
| Patients with recurrent symptoms | 87.6162/185(82.0, 91.6) | 87.1155/178(81.4, 91.2) | 86.1161/187(80.4, 90.3) | 85.9159/185(80.2, 90.2) |
| Patients using oral antibiotics | 82.379/96(73.5, 88.6) | 93.876/81(86.4, 97.3) | 84.481/96(75.8, 90.3) | 83.370/84(73.9, 89.8) |
| Patients with menses | 83.340/48(70.4, 91.3) | 86.532/37(72.0, 94.1) | 85.742/49(73.3, 92.9) | 86.833/38(72.7, 94.2) |
| Patients without menses | 90.8754/830(88.7, 92.6) | 85.7546/637(82.8, 88.2) | 91.0758/833(88.9, 92.8) | 84.3552/655(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 | 96.453/55(87.7, 99.0) | 97.098/101(91.6, 99.0) | 98.254/55(90.4, 99.7) | 93.195/102(86.5, 96.6) |
| 2 | 82.824/29(65.5, 92.4) | 93.962/66(85.4, 97.6) | 93.127/29(78.0, 98.1) | 93.962/66(85.4, 97.6) |
| 3 | 61.58/13(35.5, 82.3) | 89.141/46(77.0, 95.3) | 83.310/12(55.2, 95.3) | 91.342/46(79.7, 96.6) |
| 4 | 100.03/3(43.9, 100.0) | 100.017/17(81.6, 100.0) | 100.03/3(43.9, 100.0) | 94.116/17(73.0, 99.0) |
| 5 | 96.199/103(90.4, 98.5) | 94.4268/284(91.0, 96.5) | 91.395/104(84.4, 95.4) | 90.9259/285(87.0, 93.7) |
| 6 | 91.957/62(82.5, 96.5) | 96.6114/118(91.6, 98.7) | 85.252/61(74.3, 92.0) | 91.6109/119(85.2, 95.4) |
| 7 | 90.930/33(76.4, 96.9) | 93.946/49(83.5, 97.9) | 91.231/34(77.0, 97.0) | 87.843/49(75.8, 94.3) |
| 8 | 95.4104/109(89.7, 98.0) | 93.9214/228(90.0, 96.3) | 96.4107/111(91.1, 98.6) | 91.0212/233(86.6, 94.0) |
| 9 | 86.470/81(77.3, 92.2) | 89.1131/147(83.1, 93.2) | 90.072/80(81.5, 94.8) | 93.9138/147(88.8, 96.7) |
| 10 | 70.014/20(48.1, 85.5) | 100.054/54(93.4, 100.0) | 90.519/21(71.1, 97.3) | 96.352/54(87.5, 99.0) |
| Overall | 90.9462/508(88.1, 93.1) | 94.11045/1110(92.6, 95.4) | 92.2470/510(89.5, 94.2) | 91.91028/1118(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 | |
| Estimate95% 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 Candidaalbicans and Candidatropicalis | 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 | 90.9462/508(88.1, 93.1) | 92.2470/510(89.5, 94.2) |
Table 22: Cgroup Performance Stratified by Candida Species
Tables 23, 24 and 25 include Cgroup performance for clinician-collected and selfcollected vaginal specimens stratified respectively by age group, ethnicity and patient clinical condition.
| Age Group | Clinician-collected | Self-collected | ||
|---|---|---|---|---|
| SensitivityPercent(95% CI) | SpecificityPercent(95% CI) | SensitivityPercent(95% CI) | SpecificityPercent(95% CI) | |
| 18 - 29 | 90.6326/360(87.1, 93.2) | 93.5618/661(91.4, 95.1) | 91.2331/363(87.8, 93.7) | 91.3608/666(88.9, 93.2) |
| 30 - 39 | 93.992/98(87.3, 97.2) | 94.3250/265(90.9, 96.5) | 96.892/95(91.1, 98.9) | 91.7244/266(87.8, 94.5) |
| 40 - 49 | 90.237/41(77.5, 96.1) | 94.5120/127(89.1, 97.3) | 88.438/43(75.5, 94.9) | 93.0119/128(87.2, 96.3) |
| 50 and over | 77.87/9(45.3, 93.7) | 100.057/57(93.7, 100.0) | 100.09/9(70.1, 100.0) | 98.357/58(90.9, 99.7) |
Table 23: Cgroup Performance Stratified by Age Group
{24}------------------------------------------------
| Clinician-collected Specimens | Self-collected Specimens | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Ethnicity | Prev.a | Sensitivity | Specificity | PPV | NPV | Sensitivity | Specificity | PPV | NPV |
| Percent(95% CI) | Percent(95% CI) | Percent(95% CI) | Percent(95% CI) | Percent(95% CI) | Percent(95% CI) | Percent(95% CI) | Percent(95% CI) | ||
| Asian | 20.0% | 90.9 | 97.8 | 91.3 | 97.7 | 90.9 | 93.8 | 78.4 | 97.6 |
| 12/60 | 10/11 | 45/46 | 10/11 | 45/48 | |||||
| (62.3, 98.4) | (88.7, 99.6) | (67.5, 99.7) | (90.6, 99.9) | (62.3, 98.4) | (83.2, 97.9) | (57.1, 93.9) | (90.5, 99.9) | ||
| Black or AfricanAmerican | 32.5% | 91.3 | 92.8 | 85.9 | 95.7 | 92.4 | 92.3 | 85.3 | 96.2 |
| 287/884 | 253/277 | 542/584 | 257/278 | 541/586 | |||||
| (87.4, 94.1) | (90.4, 94.6) | (82.1, 89.3) | (93.9, 97.1) | (88.7, 95.0) | (89.9, 94.2) | (81.5, 88.6) | (94.5, 97.6) | ||
| Hispanic/Latino | 36.1% | 92.2 | 96.7 | 94.0 | 95.6 | 92.3 | 92.4 | 87.2 | 95.5 |
| 53/147 | 47/51 | 88/91 | 48/52 | 85/92 | |||||
| (81.5, 96.9) | (90.8, 98.9) | (85.3, 98.6) | (90.3, 98.7) | (81.8, 97.0) | (85.1, 96.3) | (78.0, 94.0) | (90.2, 98.6) | ||
| White (notHispanic/Latino) | 30.9% | 88.8 | 95.0 | 88.7 | 95.0 | 92.0 | 90.4 | 81.0 | 96.2 |
| 126/408 | 111/125 | 264/278 | 115/125 | 253/280 | |||||
| (82.1, 93.2) | (91.7, 97.0) | (82.9, 93.2) | (92.3, 97.1) | (85.9, 95.6) | (86.3, 93.3) | (75.1, 86.3) | (93.6, 98.0) | ||
| Others/Mixed/Unknown | 28.7% | 93.2 | 95.5 | 89.3 | 97.2 | 90.9 | 92.9 | 83.6 | 96.2 |
| 45/157 | 41/44 | 106/111 | 40/44 | 104/112 | |||||
| (81.8, 97.7) | (89.9, 98.1) | (79.1, 95.9) | (92.9, 99.4) | (78.8, 96.4) | (86.5, 96.3) | (73.2, 91.7) | (91.7, 98.9) |
Table 24: Cgroup Performance Stratified by Ethnicity
4 Prevalence was calculated for specimens with compliant reference method results.
| Clinician-collected | Self-collected | |||
|---|---|---|---|---|
| Subgroup | Sensitivity(95% CI) | Specificity(95% CI) | Sensitivity(95% CI) | Specificity(95% CI) |
| Pregnant patients | 100.011/11(74.1, 100.0) | 88.98/9(56.5, 98.0) | 90.09/10(59.6, 98.2) | 88.98/9(56.5, 98.0) |
| Patients with estrogentherapy | 96.352/54(87.5, 99.0) | 91.7100/109(85.0, 95.6) | 98.151/52(89.9, 99.7) | 90.9100/110(84.1, 95.0) |
| Patients using anti-fungals | 89.844/49(78.2, 95.6) | 89.787/97(82.1, 94.3) | 92.046/50(81.2, 96.8) | 86.086/100(77.9, 91.5) |
| Patients with unprotectedintercourse in the last 24 h | 94.736/38(82.7, 98.5) | 93.167/72(84.8, 97.0) | 95.038/40(83.5, 98.6) | 93.167/72(84.8, 97.0) |
| Patients with recurrentsymptoms | 90.393/103(83.0, 94.6) | 92.7253/273(89.0, 95.2) | 93.5100/107(87.1, 96.8) | 91.2248/272(87.2, 94.0) |
| Patients using oralantibiotics | 94.956/59(86.1, 98.3) | 92.2119/129(86.3, 95.7) | 96.657/59(88.5, 99.1) | 86.8112/129(79.9, 91.6) |
| Patients with menses | 85.718/21(65.4, 95.0) | 94.063/67(85.6, 97.7) | 95.521/22(78.2, 99.2) | 95.564/67(87.6, 98.5) |
| Patients without menses | 91.3443/485(88.5, 93.5) | 94.2978/1038(92.6, 95.5) | 92.2448/486(89.4, 94.3) | 91.7959/1046(89.9, 93.2) |
Table 25: Cgroup Performance Stratified by Health Condition
{25}------------------------------------------------
Candida glabrata Performance
Table 26 includes overall and per site performance for detection of C. glabrata as observed in the prospective clinical study. The sensitivity and specificity were 75.9 and 99.7 % respectively for clinician-collected vaginal swabs and 86.7 and 99.6 % respectively for self-collected vaginal swabs. For the population tested, this resulted in PPV of 81.6 and 81.0 % for clinician-collected and self-collected specimens, respectively. NPV of 99.6 and 99.8 % were obtained for clinician-collected and selfcollected specimens, respectively. The prevalence of C. glabrata was 1.8% for patients with compliant reference method results.
| Site | Clinician-collected | Self-collected | ||
|---|---|---|---|---|
| SensitivityPercent(95% CI a) | SpecificityPercent(95% CI a) | SensitivityPercent(95% CI a) | SpecificityPercent(95% CI a) | |
| 1 | 100.03/3(43.9, 100.0) | 100.0153/153(97.6, 100.0) | 100.03/3(43.9, 100.0) | 100.0154/154(97.6, 100.0) |
| 2 | 0.00/1(0.0, 79.3) | 100.094/94(96.1, 100.0) | 0.00/1(0.0, 79.3) | 100.094/94(96.1, 100.0) |
| 3 | 100.01/1(20.7, 100.0) | 100.058/58(93.8, 100.0) | 100.01/1(20.7, 100.0) | 100.057/57(93.7, 100.0) |
| 4 | 100.01/1(20.7, 100.0) | 100.019/19(83.2, 100.0) | 100.01/1(20.7, 100.0) | 100.019/19(83.2, 100.0) |
| 5 | 100.05/5(56.6, 100.0) | 99.7381/382(98.5, 100.0) | 100.05/5(56.6, 100.0) | 99.2381/384(97.7, 99.7) |
| 6 | 40.02/5(11.8, 76.9) | 100.0175/175(97.9, 100.0) | 83.35/6(43.6, 97.0) | 100.0174/174(97.8, 100.0) |
| 7 | No data forSensitivitycalculation | 100.082/82(95.5, 100.0) | No data forSensitivitycalculation | 98.882/83(93.5, 99.8) |
| 8 | 60.03/5(23.1, 88.2) | 99.1329/332(97.4, 99.7) | 60.03/5(23.1, 88.2) | 99.4337/339(97.9, 99.8) |
| 9 | 100.06/6(61.0, 100.0) | 99.5221/222(97.5, 99.9) | 100.06/6(61.0, 100.0) | 100.0221/221(98.3, 100.0) |
| 10 | 50.01/2(9.5, 90.5) | 100.072/72(94.9, 100.0) | 100.02/2(34.2, 100.0) | 100.073/73(95.0, 100.0) |
| Overall | 75.922/29b,c(57.9, 87.8) | 99.71584/1589(99.3, 99.9) | 86.726/30d,e(70.3, 94.7) | 99.61592/1598(99.2, 99.8) |
Table 26: Candida glabrata Performance by Collection Type and Collection Site
ª CI: Confidence interval
b Out of 7 C.glabrata false negative results, 6 showed chromagar results consistent with low C.glabrata load (1+ to 2+ growth level) and 1 showed chromagar result consistent with high C.glabrata load (3+ growth level)
& The BD MAX Vaginal Panel detected BV and/or Cgroup signals in 6 out of 7 specimens with C.glabrata false negative results
{26}------------------------------------------------
d Out of 4 C.glabrata false negative results, 3 showed chromagar results consistent with low C.glabrata load (1+ to 2+ growth level) and 1 showed chromagar result consistent with high C.glabrata load (3+ growth level) ® The BD MAX Vaginal Panel detected BV and/or Cgroup signals in the 4 specimens with C.glabrata false negative results
Tables 27, 28 and 29 include Candida glabrata performance for clinician-collected and self-collected vaginal specimens stratified respectively by age group, ethnicity and pregnancy status.
| Age Group | Clinician-collected | Self-collected | ||
|---|---|---|---|---|
| SensitivityPercent(95% CI) | SpecificityPercent(95% CI) | SensitivityPercent(95% CI) | SpecificityPercent(95% CI) | |
| 18 - 29 | 73.714/19(51.2, 88.2) | 99.6998/1002(99.0, 99.8) | 78.915/19(56.7, 91.5) | 99.71007/1010(99.1, 99.9) |
| 30 - 39 | 100.01/1(20.7, 100.0) | 100.0362/362(98.9, 100.0) | 100.01/1(20.7, 100.0) | 99.4358/360(98.0, 99.8) |
| 40 - 49 | 83.35/6(43.6, 97.0) | 99.4161/162(96.6, 99.9) | 100.07/7(64.6, 100.0) | 99.4163/164(96.6, 99.9) |
| 50 and over | 66.72/3(20.8, 93.9) | 100.063/63(94.3, 100.0) | 100.03/3(43.9, 100.0) | 100.064/64(94.3, 100.0) |
Table 27: Candida glabrata Performance Stratified by Age Group
Table 28: Candida glabrata Performance Stratified by Ethnicity
| Ethnicity | Prev.ᵃ | Clinician-collected Specimens | Self-collected Specimens | ||||||
|---|---|---|---|---|---|---|---|---|---|
| SensPercent(95% CI) | SpecPercent(95% CI) | PPVPercent(95% CI) | NPVPercent(95% CI) | SensPercent(95% CI) | SpecPercent(95% CI) | PPVPercent(95% CI) | NPVPercent(95% CI) | ||
| Asian | 3.3%2/60 | 50.0(1/2)(9.5, 90.5) | 100.0(55/55)(93.5, 100.0) | 100.0(6.1, 100.0) | 98.3(96.7, 100.0) | 50.0(1/2)(9.5, 90.5) | 100.0(57/57)(93.7, 100.0) | 100.0(6.3, 100.0) | 98.3(96.7, 100.0) |
| Black or AfricanAmerican | 1.6%14/884 | 78.6(11/14)(52.4, 92.4) | 99.6(844/847)(99.0, 99.9) | 78.1(54.0, 94.1) | 99.7(99.2, 99.9) | 85.7(12/14)(60.1, 96.0) | 99.5(846/850)(98.8, 99.8) | 74.6(53.5, 91.4) | 99.8(99.3, 100.0) |
| Hispanic/Latino | 2.0%3/147 | 66.7(2/3)(20.8, 93.9) | 100.0(139/139)(97.3, 100.0) | 100.0(28.4, 100.0) | 99.3(98.1, 100.0) | 100.0(3/3)(43.9, 100.0) | 100.0(141/141)(97.3, 100.0) | 100.0(44.0, 100.0) | 100.0(98.5, 100.0) |
| White (notHispanic/Latino) | 1.7%7/408 | 66.7(4/6)(30.0, 90.3) | 99.7(396/397)(98.6, 100.0) | 82.2(41.4, 99.2) | 99.4(98.7, 99.9) | 85.7(6/7)(48.7, 97.4) | 99.7(397/398)(98.6, 100.0) | 85.6(51.0, 99.4) | 99.8(99.0, 100.0) |
| Others/Mixed/Unknown | 2.5%4/157 | 100.04/4(51.0, 100.0) | 99.3150/151(96.3, 99.9) | 79.8(39.7, 99.4) | 100.0(98.4, 100.0) | 100.04/4(51.0, 100.0) | 99.3151/152(96.4, 99.9) | 79.9(39.9, 99.4) | 100.0(98.4, 100.0) |
ª Prevalence was calculated for specimens with compliant reference method results.
{27}------------------------------------------------
| Subgroup | Clinician-collected | Self-collected | ||
|---|---|---|---|---|
| Sensitivity | Specificity | Sensitivity | Specificity | |
| Percent (95% CI) | Percent (95% CI) | Percent (95% CI) | Percent (95% CI) | |
| Pregnant patients | No data for Sensitivity calculation | 100.020/20(83.9, 100.0) | No data for Sensitivity calculation | 100.019/19(83.2, 100.0) |
Table 29: Candida glabrata Performance in Pregnant Patients
Due to the low prevalence of Candida glabrata observed in the prospective clinical study, evaluation of contrived specimens was performed to supplement the clinical data collected. Contrived specimens were prepared by spiking 50 different Candida glabrata strains individual negative vaginal matrices. True negative specimens, containing vaginal matrix only, were interspersed with positive specimens and all specimen identities were blinded to the user. Strains were spiked at various clinically relevant organism concentrations and randomly distributed among three clinical testing sites for BD MAX Vaginal Panel testing. The study results demonstrated 100% positive agreement for all contrived positive specimens evaluated. Results for contrived specimens are presented in Table 30.
| Candida glabrata | Percent Agreement | |
|---|---|---|
| Category | Load (x LoD) | Percent(95% CI) |
| High Positive | $\geq$ 10 and $<$ 20 | 100.0(5/5)(56.6, 100.0) |
| Moderate Positive | $\geq$ 2 and $<$ 10 | 100.0(20/20)(83.9, 100.0) |
| Low Positive | $\geq$ 1 and $<$ 2 | 100.0(25/25)(86.7, 100.0) |
| True Negative | No organisms | 100.0(50/50)(92.9, 100.0) |
Table 30: Candida glabrata Contrived Specimens Results
Candida krusei Performance
Performance of the BD MAX Vaginal Panel for detection of Candida krusei is presented in Table 31. No Candida krusei positive specimens were identified in the prospective study by the reference method: thus no data is available for sensitivity calculation. The specificity was 99.8 and 100.0 % for clinician-collected and self-collected vaginal swabs respectively.
{28}------------------------------------------------
| Collection Type | SensitivityPercent(95% CI) | SpecificityPercent(95% CI) |
|---|---|---|
| Clinician-collected | No data forSensitivitycalculation | 99.81614/1618(99.4, 99.9) |
| Self-collected | No data forSensitivitycalculation | 100.01628/1628(99.8, 100.0) |
Table 31: Candida krusei Performance Results
Due to the lack of positive results for C. krusei observed in the prospective clinical study, evaluation of contrived specimens was performed to supplement the clinical data collected. Contrived specimens were prepared by spiking 50 different Candida krusei strains into individual negative vaginal matrices. True negative specimens, containing vaginal matrix only, were interspersed with positive specimens and all specimen identities were blinded to the user. Strains were spiked at various clinically relevant organism concentrations and randomly distributed among three clinical testing sites for BD MAX Vaginal Panel testing. The study results demonstrated 100% positive agreement for all contrived positive specimens evaluated. Results for contrived specimens are presented in Table 32.
| Candida krusei | PercentAgreement | |
|---|---|---|
| Category | Load (x LoD) | Percent(95% CI) |
| High Positive | ≥10 and <20 | 100.05/5(56.6, 100.0) |
| ModeratePositive | ≥2 and <10 | 100.020/20(83.9, 100.0) |
| Low Positive | ≥1 and <2 | 100.025/25(86.7, 100.0) |
| True Negative | 0 | 100.050/50(92.9, 100.0) |
Table 32: Candida krusei Contrived Specimens Results per Category
Trichomonas vaginalis Performance
Table 33 includes overall and per site performance for detection of T. vaginalis as observed in the prospective clinical study. The assay sensitivity and specificity were 93.1 and 99.3 % respectively for clinician-collected vaginal swabs and 93.2 and 99.3 % respectively for self-collected vaginal swabs. For the population tested, this resulted in PPV of 91.8% and NPV of 99.4% for both collection types. The prevalence of T. vaginalis was 8.2% for patients with compliant reference method results.
{29}------------------------------------------------
| Clinician-collected | Self-collected | |||
|---|---|---|---|---|
| Sensitivity | Specificity | Sensitivity | Specificity | |
| Site | Percent | Percent | Percent | Percent |
| (95% CIª) | (95% CIª) | (95% CIª) | (95% CIª) | |
| 1 | No data for Sensitivitycalculation | 100.0168/168(97.8, 100.0) | No data for Sensitivitycalculation | 100.0169/169(97.8, 100.0) |
| 2 | 100.04/4(51.0, 100.0) | 97.992/94(92.6, 99.4) | 100.05/5(56.6, 100.0) | |
| 3 | 100.017/17(81.6, 100.0) | 97.845/46(88.7, 99.6) | 100.017/17(81.6, 100.0) | |
| 4 | 60.03/5(23.1, 88.2) | 100.015/15(79.6, 100.0) | 60.03/5(23.1, 88.2) | |
| 5 | 86.726/30(70.3, 94.7) | 99.4308/310(97.7, 99.8) | 86.726/30(70.3, 94.7) | |
| 6 | 90.910/11(62.3, 98.4) | 98.3170/173(95.0, 99.4) | 100.012/12(75.8, 100.0) | |
| 7 | 100.06/6(61.0, 100.0) | 100.067/67(94.6, 100.0) | 100.06/6(61.0, 100.0) | |
| 8 | 93.127/29(78.0, 98.1) | 99.4320/322(97.8, 99.8) | 90.027/30(74.4, 96.5) | |
| 9 | 100.027/27(87.5, 100.0) | 99.5206/207(97.3, 99.9) | 100.027/27(87.5, 100.0) | |
| 10 | 100.01/1(20.7, 100.0) | 100.068/68(94.7, 100.0) | 100.01/1(20.7, 100.0) | |
| Overall | 93.1121/130b(87.4, 96.3) | 99.31459/1470c(98.7, 99.6) | 93.2124/133b(87.6, 96.4) |
Table 33: Trichomonas vaginalis Performance by Collection Type and Collection Site
ª CI: Confidence interval
b 9 false-negative results were recorded. Of those, 7 were found negative with an FDA-cleared molecular method.
6 1 1 false-positive results were recorded. Of those, 10 were found positive with an FDA-cleared molecular method.
Tables 34, 35 and 36 include Candida glabrata performance for clinician-collected and self-collected vaginal specimens stratified respectively by age group, ethnicity and patient clinical condition.
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| Age Group | Clinician-collected | Self-collected | ||
|---|---|---|---|---|
| SensitivityPercent(95% CI) | SpecificityPercent(95% CI) | SensitivityPercent(95% CI) | SpecificityPercent(95% CI) | |
| 18 - 29 | 94.974/78(87.5, 98.0) | 99.6924/928(98.9, 99.8) | 95.076/80(87.8, 98.0) | 99.5928/933(98.8, 99.8) |
| 30 - 39 | 96.326/27(81.7, 99.3) | 98.2326/332(96.1, 99.2) | 96.326/27(81.7, 99.3) | 98.2325/331(96.1, 99.2) |
| 40 - 49 | 93.815/16(71.7, 98.9) | 99.3150/151(96.3, 99.9) | 94.116/17(73.0, 99.0) | 100.0153/153(97.6, 100.0) |
| 50 and over | 66.76/9(35.4, 87.9) | 100.059/59(93.9, 100.0) | 66.76/9(35.4, 87.9) | 100.060/60(94.0, 100.0) |
Table 34: Trichomonas vaginalis Performance Stratified by Age Group
Table 35: Trichomonas vaginalis Performance Results Stratified by Ethnicity
| Ethnicity | Prevalencea | Clinician-collected Specimens | Self-collected Specimens | ||||||
|---|---|---|---|---|---|---|---|---|---|
| SensitivityPercent(95% CI) | SpecificityPercent(95% CI) | PPVPercent(95% CI) | NPVPercent(95% CI) | SensitivityPercent(95% CI) | SpecificityPercent(95% CI) | PPVPercent(95% CI) | NPVPercent(95% CI) | ||
| Asian | 1.6%1/61 | 100.0(1/1)(20.7,100.0) | 98.2(56/57)(90.7,99.7) | 48.7(2.8,97.4) | 100.0(98.4,100.0) | 100.0(1/1)(20.7,100.0) | 100.0(59/59)(93.9,100.0) | 100.0(6.3,100.0) | 100.0(98.4,100.0) |
| Black or AfricanAmerican | 11.8%105/887 | 94.1(95/101)(87.6,97.2) | 99.2(756/762)(98.3,99.6) | 94.1(88.4,97.6) | 99.2(98.3,99.7) | 94.2(97/103)(87.9,97.3) | 99.3(759/764)(98.5,99.7) | 95.1(89.5,98.3) | 99.2(98.4,99.7) |
| Hispanic/Latino | 3.5%5/141 | 100.0(5/5)(56.6,100.0) | 99.2(130/131)(95.8,99.9) | 82.8(46.5,99.5) | 100.0(98.1,100.0) | 100.0(5/5)(56.6,100.0) | 99.2(132/133)(95.9,99.9) | 83.0(46.9,99.5) | 100.0(98.1,100.0) |
| White (notHispanic/Latino) | 3.4%14/412 | 100.0(13/13)(77.2,100.0) | 99.5(392/394)(98.2,99.9) | 87.4(65.9,98.4) | 100.0(99.1,100.0) | 100.0(14/14)(78.5,100.0) | 99.2(392/395)(97.8,99.7) | 82.2(61.5,95.7) | 100.0(99.2,100.0) |
| Others/Mixed/Unknown | 7.3%10/137 | 70.0(7/10)(39.7,89.2) | 99.2(125/126)(95.6,99.9) | 87.4(55.4,99.5) | 97.7(95.1,99.5) | 70.0(7/10)(39.7,89.2) | 98.4(124/126)(94.4,99.6) | 77.6(48.1,97.0) | 97.7(95.1,99.4) |
4 Prevalence was calculated for specimens with compliant reference method results.
{31}------------------------------------------------
| Subgroup | Clinician-collected | Self-collected | ||
|---|---|---|---|---|
| SensitivityPercent(95% CI) | SpecificityPercent(95% CI) | SensitivityPercent(95% CI) | SpecificityPercent(95% CI) | |
| Pregnant patients | 100.01/1(20.7, 100.0) | 100.018/18(82.4, 100.0) | 100.01/1(20.7, 100.0) | 100.017/17(81.6, 100.0) |
| Patients withrecurrent symptoms | 92.023/25(75.0, 97.8) | 99.7338/339(98.3, 99.9) | 92.324/26(75.9, 97.9) | 99.4338/340(97.9, 99.8) |
Table 36: Trichomonas vaginalis Performance Stratified by Health Condition
Multi-Analyte Detection Rates
The rates of multi-analyte detections by the BD MAX Vaginal Panel observed in the prospective clinical study are presented in Table 37. The data presented includes specimens with compliant results for all targets by both the BD MAX Vaginal Panel and reference methods. The most prevalent multi-analyte detection was a combination of BV and Cgroup with 13.9% and 15.3% for clinician and self-collected specimens respectively. In total, 21.5% of clinician-collected and 23.3% of self-collected specimens resulted in more than one BD MAX Vaginal Panel analyte or result reported.
| Analytes Detected | Clinician-collected | Self-collected |
|---|---|---|
| BV and Cgroup | 13.9%205/1471 | 15.3%229/1494 |
| BV and TV | 4.9%72/1471 | 4.6%68/1494 |
| BV and Cgroup and TV | 1.4%21/1471 | 1.5%23/1494 |
| BV and Cgroup and Cgla | 0.5%7/1471 | 0.6%9/1494 |
| BV and Cgla | 0.2%3/1471 | 0.5%7/1494 |
| Cgroup and TV | 0.3%4/1471 | 0.3%5/1494 |
| Cgroup and Cgla | 0.2%3/1471 | 0.4%6/1494 |
| BV and Cgroup and Ckru | 0.1%2/1471 | 0.0%0/1494 |
| BV and Cgla and TV | 0.0%0/1471 | 0.1%1/1494 |
| Total | 21.5%317/1471 | 23.3%348/1494 |
Table 37: BD MAX Vaginal Panel Multi-Analyte Detection Rates
A comparison of multi-analyte detections based on all reportable specimen results is presented in Table 38 for clinician and self-collected specimens. Bolded entries represent multi-analyte detection events with concordant reference method and BD MAX Vaginal Panel results. Non-bolded entries represent specimens with discordant results. Concordant single detections are not represented.
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| Total Number of Occurrences Clinician collected / Self- collected | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Reference Method | |||||||||||||||
| OrganismDetections | BV | BV,Cgroup | BV,C.glabrata | BV, CgroupC. glabrata | BV, TV | BV, CgroupTV | BV,C.glabrata,TV | Cgroup | Cgroup,C.glabrata | Cgroup, TV | Cgroup,C.glabrata | TV | Negative | ||
| BD MAX Vaginal Panel | BV | 16/17 | 2/1 | - | 2/2 | - | - | - | - | - | - | - | - | ||
| BV, Cgroup | 37/51 | 139/143 | 0/1 | 1/1 | - | 0/1 | - | 36/42 | 2/1 | - | - | - | 3/3 | ||
| BV,C.glabrata | 1/2 | - | 1/1 | - | - | - | - | - | - | - | 1/4 | - | - | ||
| BV, Cgroup,C.glabrata | 0/1 | 2/1 | - | 4/4 | - | - | - | 1/0 | 1/3 | - | 0/1 | - | - | ||
| BV, Cgroup,C.krusei | 1/0 | 1/0 | - | - | - | - | - | - | - | - | - | - | - | ||
| BV, TV | 7/7 | 1/0 | - | - | 48/47 | 5/5 | - | 0/1 | - | 2/1 | - | - | 16/11 | 1/0 | |
| BV, CgroupTV | - | - | - | - | 3/2 | 17/18 | - | - | - | 1/3 | - | - | 0/2 | - | |
| BV,C.glabrata,TV | - | - | - | - | - | - | 0/1 | - | - | - | - | - | - | - | |
| Cgroup | - | 33/32 | - | - | - | 1/0 | - | - | 1/0 | 1/0 | - | - | - | - | |
| Cgroup,C.glabrata | - | - | - | 1/1 | - | - | - | - | 1/2 | - | 1/0 | 0/2 | - | 0/1 | |
| Cgroup, TV | - | - | - | - | - | - | - | 2/2 | - | 1/3 | - | - | 1/0 | - | |
| TV | - | 0/1 | - | - | 10/12 | - | - | - | - | 1/0 | - | - | - | - | |
| Negative | - | 2/2 | - | - | 1/1 | - | - | - | 1/0 | - | - | - | - | - |
Table 38: Multi-Analyte Detections Observed in the Prospective Clinical Study
Non-Reportable Rates
Of all specimens initially evaluated with the BD MAX Vaginal Panel in the prospective clinical study, 3.0 and 2.9 % initially reported as Unresolved for clinician and selfcollected specimens, respectively. Following a valid repeat test, 1.3 and 0.6% remained Unresolved for clinician and self-collected specimens, respectively. Of all specimens initially evaluated with the BD MAX Vaginal Panel, 3.7 and 2.7 % initially reported as Indeterminate for clinician and self-collected specimens, respectively. Following a valid repeat test, 0.8 and 0.6 % remained Indeterminate for clinician and self-collected specimens, respectively. Of all specimens initially evaluated with the BD MAX Vaginal Panel, 1.4% initially reported as Incomplete for both collection types. Following a valid repeat test, 0.2 % remained Incomplete for both collection types. The total rates of nonreportable results were 8.1 and 7.0% for clinician and self-collected specimens, respectively. Following a valid repeat test, 2.2 and 1.4 % remained non-reportable for clinician and self-collected specimens, respectively. Results are presented in Table 39.
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| CollectionType | Unresolved Rate | Indeterminate Rate | Incomplete Rate | Total Rate | ||||
|---|---|---|---|---|---|---|---|---|
| InitialPercent(95% CI) | FinalaPercent(95% CI) | InitialPercent(95% CI) | FinalaPercent(95% CI) | InitialPercent(95% CI) | FinalaPercent(95% CI) | InitialPercent(95% CI) | FinalaPercent(95% CI) | |
| Clinician-collected | 3.052/1734(2.3, 3.9) | 1.322/1725(0.8, 1.9) | 3.764/1734(2.9, 4.7) | 0.813/1725(0.4, 1.3) | 1.424/1734(0.9, 2.1) | 0.23/1725(0.1, 0.5) | 8.1140/1734(6.9, 9.5) | 2.238/1725(1.6, 3.0) |
| Self-collected | 2.950/1736(2.2, 3.8) | 0.611/1733(0.4, 1.1) | 2.747/1736(2.0, 3.6) | 0.610/1733(0.3, 1.1) | 1.424/1736(0.9, 2.0) | 0.24/1733(0.1, 0.6) | 7.0121/1736(5.9, 8.3) | 1.425/1733(1.0, 2.1) |
Table 39: Non-reportable Rates
a The final rate is calculated with valid repeats only
Evaluation of the BD MAX Vaginal Panel in Asymptomatic Women
Although the BD MAX Vaginal Panel is not intended for testing specimens from asymptomatic women, presence of Candida species, T. vaginalis and BV markers has been reported in this population. The BD MAX Vaginal Panel was evaluated for detection of Candida species, T. vaginalis and BV markers with vaginal specimens collected from 202 asymptomatic women. BD MAX Vaginal Panel vaginitis targets were detected with rates varying from 1.5% for C. krusei to 20.8% for Cgroup. Positive BV results were generated for 34.2% of asymptomatic women. Results from the study are presented in Table 40 which also includes results for the most prevalent ethnic groups enrolled. BV, Cgroup and T. vaginalis were detected in all ethnic categories.
| Table 40: BD MAX Vaginal Panel Positive Rates in Asymptomatic Women | ||
|---|---|---|
| Target | Overall | By Ethnic Group | ||
|---|---|---|---|---|
| Black/African American | White (not Hispanic) | Othersa | ||
| BV | 34.2% | 40.4% | 28.8% | 28.6% |
| 69/202 | (38/94) | (23/80) | (8/28) | |
| Cgroup | 20.8% | 22.3% | 16.3% | 28.6% |
| 42/202 | (21/94) | (13/80) | (8/28) | |
| C. glabrata | 5.9% | 11.7% | 0.0% | 3.6% |
| 12/202 | (11/94) | (0/80) | (1/28) | |
| C. krusei | 1.5% | 1.1% | 2.5% | 0.0% |
| 3/202 | (1/94) | (2/80) | (0/28) | |
| T. vaginalis | 11.4% | 22.3% | 1.3% | 3.6% |
| 23/202 | (21/94) | (1/80) | (1/28) |
ª Including: American Indian or Alaska natives, Asian, Mixed Ethnicity and Unknown
3. Clinical Cutoff:
See Assay Cut-off Section L.1.j above.
4. Expected Values:
The incidence of each BD MAX Vaginal Panel result as observed in the prospective clinical study is presented in Table 41, stratified by clinic type and specimen type.
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| CollectionType | Clinic Type | BacterialVaginosis | Cgroupa | Candidaglabrata | Candidakrusei | Trichomonasvaginalis |
|---|---|---|---|---|---|---|
| Clinician-collected | STD / HIV | 72.7%(224/308) | 34.0%(105/309) | 2.6%(8/309) | 0.3%(1/309) | 15.9%(49/309) |
| FamilyPlanning | 60.7%(683/1125) | 33.3%(379/1138) | 1.2%(14/1138) | 0.1%(1/1138) | 7.5%(85/1138) | |
| OB/Gyn | 20.6%(52/252) | 29.6%(75/253) | 2.0%(5/253) | 0.8%(2/253) | 0.4%(1/253) | |
| Total | 56.9%(959/1685) | 32.9%(559/1700) | 1.6%(27/1700) | 0.2%(4/1700) | 7.9%(135/1700) | |
| Self-collected | STD / HIV | 74.6%(229/307) | 33.9%(104/307) | 2.3%(7/307) | 0.0%(0/307) | 16.0%(49/307) |
| FamilyPlanning | 60.1%(687/1143) | 35.1%(403/1147) | 1.7%(19/1147) | 0.0%(0/1147) | 7.7%(88/1147) | |
| OB/Gyn | 22.0%(56/255) | 34.5%(88/255) | 2.4%(6/255) | 0.0%(0/255) | 0.4%(1/255) | |
| Total | 57.0%(972/1705) | 34.8%(595/1709) | 1.9%(32/1709) | 0.0%(0/1709) | 8.1%(138/1709) |
Table 41: BD MAX Vaginal Panel Positivity Rate by Clinic Type
ª Candida albicans, Candida tropicalis, Candida parapsilosis and/or Candida dubliniensis
M. Instrument Name
BD MAX System
N. System Descriptions:
1. Modes of Operation:
The BD MAX System fully automates cell lysis, nucleic acid extraction, PCR set-up, target amplification and detection. For the BD MAX Vaginal Panel, the system can process and analyze up to 12 specimens in one cartridge with two cartridges running simultaneously on the instrument. The system includes external and internal barcode reading, ensuring traceability throughout the extraction and PCR processes. The system includes a heater module, temperature sensors, and a fluorescence detection system with six optical channels.
2. Software:
FDA has reviewed applicant's Hazard Analysis and software development processes for this line of product types:
Yes
-
- Specimen Identification:
Specimens are identified via barcode.
- Specimen Identification:
-
- 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
- Specimen Sampling and Handling:
{35}------------------------------------------------
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.
-
- Calibration:
The system is calibrated by the manufacturer on-site as part of the installation procedure as well as during biannual preventive maintenance.
- Calibration:
-
- Quality Control:
See Quality Control Section above (Section L.1.c)
- Quality Control:
O. Other Supportive Instrument Performance Characteristics Data Not Covered In The "Performance Characteristics" Section above:
Not Applicable
P. Proposed Labeling:
The labeling is sufficient and it satisfies the requirements of 21 CFR Parts 801 and 809 and the specials controls for this device type.
Q. Identified Risks to Health and Identified Mitigations:
| Identified Risks to Health | Identified Mitigations |
|---|---|
| Incorrect identification or lack of identificationof a pathogenic microorganism by the devicecan lead to improper patient management | General controls and special controls (1), (2), (3), and (4) |
| Failure to correctly interpret test results | General controls and special controls (5), (6), (7), and (8) |
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R. Benefit/Risk Analysis:
| Summary | |
|---|---|
| Summary ofthe Benefit(s) | The BD MAX Vaginal Panel detects nucleic acids from microorganisms associated with bacterial vaginosis, candidiasis and trichomoniasis from a clinician or self-collected vaginal swab to aid in the diagnosis of bacterial vaginosis, vulvovaginal candidiasis and trichomoniasis. The BD MAX Vaginal Panel provides molecular detection of analytes that are typically diagnosed clinically and/or with microscopy, which may reduce human error from microscopy or clinical diagnosis of signs and symptoms. The BD MAX Vaginal Panel may reduce operator error and provide for more uniform diagnosis of bacterial vaginosis, vulvovaginal candidiasis and trichomoniasis. |
| Summary ofthe Risk(s) | False positives and false negative results are the primary risks associated with the BD MAX Vaginal Panel. False positive results would result in an unnecessary course of oral or topical antimicrobials. False negative results could result in delayed diagnosis of bacterial vaginosis or trichomoniasis. Patients who remain symptomatic are likely to be retested, or receive empiric therapy. |
| Summary ofOtherFactors | None. |
| ConclusionsDo theprobablebenefitsoutweigh theprobablerisks? | The probable benefits of the BD MAX Vaginal Panel outweigh the potential risks in light of the established special controls and applicable general controls, including design controls. The BD MAX Vaginal Panel is the first multiplex panel using nucleic acid amplification to detect multiple microorganisms associated with bacterial vaginosis, vulvovaginal candidiasis and trichomoniasis. Potential risks include false positive and false negative results, but it is highly unlikely that a patient would suffer a serious adverse event as a result of an erroneous result from the BD MAX Vaginal Panel given the clinical performance demonstrated in the prospective clinical trial and the special controls established for this device. Risks are further mitigated by the use of the device in association with clinical assessment, supplemental laboratory testing, natural progression of clinical symptoms and clinical judgment. Ultimately, the majority of risks associated with the BD MAX Vaginal Panel may be minimized with appropriate precautions and the BD MAX Vaginal Panel may better standardize the assessment of vaginosis/vaginitis. |
Patient Perspectives:
This submission did not include specific information on patient perspectives for this device.
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S. Conclusion:
The information provided in this de novo submission is sufficient to classify this device into class II under regulation 21 CFR 866.3975. FDA believes that the stated special controls, and applicable general controls, including design controls, provide reasonable assurance of the safety and effectiveness of the device type. The device is classified under the following:
| Product Code: | PQA, OUY, OOI, NSU |
|---|---|
| Device Type: | Device that detects nucleic acid sequences from microorganismsassociated with vaginitis and bacterial vaginosis |
| Class: | II (special controls) |
| Regulation: | 21 CFR 866.3975 |
- (a) Identification. A device that detects nucleic acid sequences from microorganisms associated with vaginitis and bacterial vaginosis is a qualitative in vitro 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.
- (b) Classification. Class II (special controls). A device that detects nucleic acid sequences from microorganisms associated with vaginitis and bacterial vaginosis is subject to the following special controls:
-
- Premarket notification submissions must include a detailed device description of the following:
- Device components: (i)
- Ancillary reagents required but not provided; and (ii)
- (iii) Explanation of the methodology including primer/probe sequence, design, and rationale for sequence selection.
-
- Premarket notification submissions must include information that demonstrates the performance characteristics of the device, including:
- Limit of Detection; (i)
- Precision (reproducibility); (ii)
- Analytical specificity; (iii)
- Analytical reactivity (inclusivity); (iv)
- (v) Specimen stability; and
- Effects of interfering substances. (vi)
-
- Premarket notification submissions must include 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
-
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compare the device performance to results obtained from well-accepted comparator methods.
-
- Premarket notification submissions must include detailed documentation for device software, including, but not limited to, software applications and hardwarebased devices that incorporate software.
-
- A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling.
-
- For indications for use that include detection of nucleic acid sequences from bacteria associated with bacterial vaginosis, the 21 CFR 809.10(b)(12) compliant labeling must include clinical performance stratified by patient demographics such as race, ethnicity, age, and pregnancy status.
-
- For indications for use that include detection of nucleic acid sequences from bacteria associated with bacterial vaginosis, the 21 CFR 809.10(b)(12) compliant labeling must include a summary of device results in an asymptomatic population with demographic characteristics appropriate to the intended use population.
-
- For indications for use that include detection of either Candida species or bacteria associated with bacterial vaginosis, the 21 CFR 809.10 compliant labeling must include 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.
§ 866.3975 Device that detects nucleic acid sequences from microorganisms associated with vaginitis and bacterial vaginosis.
(a)
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.(b)
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.