Predicate Devices

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The description details a standard automated PCR system with software for interpreting results based on predefined amplification thresholds. There is no mention of AI/ML algorithms for data analysis or interpretation.

Therapeutic

No
The device is an in vitro diagnostic test intended to aid in the diagnosis of C. difficile infection by detecting specific genetic material, not to treat or cure a condition.

Diagnostic

Yes

The "Intended Use / Indications for Use" section explicitly states that the BD MAX™ Cdiff Assay is an "automated in vitro diagnostic test" and is "intended to aid in the diagnosis of CDI."

SaMD (Software as a Medical Device)

No

The device description explicitly states that the system is comprised of an instrument with associated hardware and accessories, disposable cartridges, reagents, and sample tubes, in addition to the software.

IVD (In Vitro Diagnostic)

Yes, this device is an IVD (In Vitro Diagnostic).

The "Intended Use / Indications for Use" section explicitly states: "The BD MAX™ Cdiff Assay performed on the BD MAX™ System is an automated in vitro diagnostic test for the direct, qualitative detection of the Clostridium difficile toxin B gene (tcdB) in human liquid or soft stool specimens from patients suspected of having C. difficile infection (CDI)."

This statement clearly identifies the device as an in vitro diagnostic test.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

The BD MAX™ Cdiff Assay performed on the BD MAX™ System is an automated in vitro diagnostic test for the direct, qualitative detection of the Clostridium difficile toxin B gene (tcdB) in human liquid or soft stool specimens from patients suspected of having C. difficile infection (CDI). The test. performed directly on the specimen, utilizes real-time polymerase chain reaction (PCR) for the amplification of C. difficile toxin B gene DNA and fluorogenic target-specific hybridization probes for the detection of the amplified DNA. The BD MAX ™ Cdiff Assay is intended to aid in the diagnosis of CDI.

Product codes (comma separated list FDA assigned to the subject device)

OZN, OOI

Device Description

The BD MAX™ System and the BD MAX™ Cdiff Assay are comprised of an instrument with associated hardware and accessories, disposable microfluidic cartridges, master mixes, unitized reagent strips, extraction reagents, and sample buffer tubes. The instrument automates sample preparation including target Ivsis. DNA extraction and concentration, reagent rehydration, and 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 result may be called as NEG (negative), POS (positive) or UNR (unresolved) based on the amplification status of the target and of the Sample Processing Control. IND (indeterminate) or INC (incomplete) results are due to BD MAX™ System failure.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Not Found

Indicated Patient Age Range

Not Found

Intended User / Care Setting

For prescription use

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Not Found

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Analytical Performance:

Precision: Within-laboratory precision was evaluated at one site. The panel consisted of 5 sample categories in simulated sample matrix: Moderate Positive (2-5 x LoD), Low Positive (1-2 x LoD), High Negative 1:10 (10-fold dilution of 1 x LoD), High Negative 1:100 (100-fold dilution of 1 x LoD), and True Negative. Testing was performed in duplicate, over 12 days, with 2 runs per day, by 2 technologists. Results for Negative, LP, and MP samples demonstrated 100% agreement. HN1:100 and HN1:10 showed 95.8% and 58.3% agreement, respectively.
Reproducibility: Evaluated with the same sample categories as Precision. Samples in each category were tested in triplicate, on 5 distinct days, with 2 panels tested by 2 technologists per day, at 3 clinical sites using 1 lot of reagents (Site-to-Site). One site also tested 2 additional lots (Lot-to-Lot).
- Site-to-Site Reproducibility: Overall percent agreement was 100% for MP, LP, and Neg categories. HN1:100 and HN1:10 showed 92.2% and 50.0% negative agreement, respectively.
- Lot-to-Lot Reproducibility: Overall percent agreement was 100% for MP, LP, and Neg categories. HN1:100 and HN1:10 showed 96.7% and 64.4% negative agreement, respectively.
Analytical Sensitivity (Limit of Detection or LoD): Determined by testing individual inoculating loops dipped into C. difficile bacterial suspensions at different concentrations (0-64,000 CFU/mL) for four C. difficile strains representing three toxinotypes (0, III, VIII). Each strain was tested in 24 replicates per concentration, by two operators, using three production lots. The LoD ranged from 125 to 265 CFU per loop for each strain.
Analytical Inclusivity: Sixty-four (64) toxigenic C. difficile strains (23 toxinotypes, 21 countries) were tested at ~3xLoD. The assay correctly identified 62 of 64 strains. Two strains produced low signal and were false-negative in one out of five replicates.
Analytical Specificity: Performed on samples containing phylogenetically related species (other Clostridium) and other organisms (bacteria, viruses).
- Six non-tcdB C. difficile strains (≥ 1 X 10^6 CFU/mL) - negative results.
- Thirty other Clostridium strains (≥ 1 X 10^6 CFU/mL) - negative results.
- Ninety-five out of 98 other bacterial strains (≥ 1 X 10^8 CFU/mL) - negative results. Bacteroides stercoris (ATCC 43183), Gemella morbillorum (ATCC 27824), and Peptoniphilus asaccharolyticus (ATCC 14963) gave initial positive results due to contamination.
- Seven viruses (≥ 1 X 10^6 PFU/mL) - negative results.
Interfering Substances: Evaluated 25 biological and chemical substances, and two organisms (E. coli ATCC 25922 and non-toxigenic C. difficile ATCC 700057 at high loads). Mesalamine rectal suspension enema and Gynol II® showed slight inhibition (delay of Second Derivative Peak Abscissa) but expected assay results were still obtained.
Carryover / Cross-Contamination: A study was conducted with high positive and negative panel members. No false positive results due to carryover contamination were observed.

Clinical Performance Studies:

Study Type: Multi-site prospective investigational study.
Sample Size: 2071 soft or liquid stool specimens initially, 1819 compliant and reportable results with BD MAX™ Cdiff Assay.
Reference Method: Direct culture complemented by enriched culture. Anaerobic culture to isolate C. difficile, followed by confirmation and Tissue Culture Cytotoxicity Assay for toxigenicity.
Key Results (vs. Reference Method):
- Sensitivity: 87.7% (265/302) (95% CI: 83.6%, 91.0%)
- Specificity: 96.8% (1469/1517) (95% CI: 95.8%, 97.6%)
- PPV: 83.5% (95% CI: 79.4%, 87.1%)
- NPV: 97.7% (95% CI: 97.0%, 98.4%)
- Discordant Results: 27 of 48 False Positive BD MAX™ Cdiff specimens were positive by another FDA-cleared RT-PCR. 32 of 37 False Negative BD MAX™ Cdiff specimens were negative by another FDA-cleared RT-PCR.
Key Results (vs. Direct Culture):
- Positive Percent Agreement: 96.5% (194/201) (95% CI: 93.0%, 98.3%)
- Negative Percent Agreement: Not explicitly stated as "Specificity" but 1507/1625, for a 92.7% (95% CI: 91.4%, 93.9%).
Unresolved Rate: 3.1% (58/1860) initially, 0.5% (10/1844) after repeat.
Indeterminate Rate: 1.1% (21/1916) initially, 0% after repeat.
Incomplete Rate: 1.5% (28/1916) initially, 0% after valid repeat.

Comparison Studies:

Study Type: Comparison with two other commercially available FDA-cleared molecular assays.
Sample Size: 2013 specimens at two external sites.
Results (vs. FDA-cleared Molecular Assay 1):
- PPA: 99.1% (95% CI: 94.9%-99.8%)
- NPA: 97.4% (95% CI: 95.7%-98.4%)
Results (vs. FDA-cleared Molecular Assay 2):
- PPA: 95.5% (95% CI: 92.1%-97.5%)
- NPA: 98.8% (95% CI: 97.9%-99.3%)

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

Sensitivity: 87.7% (265/302) (95% CI: 83.6%, 91.0%)
Specificity: 96.8% (1469/1517) (95% CI: 95.8%, 97.6%)
PPV: 83.5% (95% CI: 79.4%, 87.1%)
NPV: 97.7% (95% CI: 97.0%, 98.4%)
Positive Percent Agreement (vs. Direct Culture): 96.5% (194/201) (95% CI: 93.0%, 98.3%)
Negative Percent Agreement (vs. Direct Culture): 92.7% (1507/1625) (95% CI: 91.4%, 93.9%)
Positive Percent Agreement (vs. FDA-cleared Molecular Assay 1): 99.1% (Cl: 94.9%-99.8%)
Negative Percent Agreement (vs. FDA-cleared Molecular Assay 1): 97.4% (Cl: 95.7%-98.4%)
Positive Percent Agreement (vs. FDA-cleared Molecular Assay 2): 95.5% (Cl: 92.1%-97.5%)
Negative Percent Agreement (vs. FDA-cleared Molecular Assay 2): 98.8% (Cl: 97.9%-99.3%)

Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.

K081920

Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).

Not Found

Regulation Number and Section

§ 866.3130 Clostridium difficile toxin gene amplification assay.

(a)
Identification. AClostridium difficile toxin gene amplification assay is a device that consists of reagents for the amplification and detection of target sequences inClostridium difficile toxin genes in fecal specimens from patients suspected of havingClostridium difficile infection (CDI). The detection of clostridial toxin genes, in conjunction with other laboratory tests, aids in the clinical laboratory diagnosis of CDI caused byClostridium difficile. (b)
Classification. Class II (special controls). The special controls are set forth in FDA's guideline document entitled: “Class II Special Controls Guideline: Toxin Gene Amplification Assays for the Detection ofClostridium difficile; Guideline for Industry and Food and Drug Administration Staff.” See § 866.1(e) for information on obtaining this document.

Summary

0

510(k) Summary

APR 0 2 2013

ﺮ ﺍﻟ

March 28, 2013

	BD Diagnostics BD MAX™ Cdiff Assay
Submitted by:	GeneOhm Sciences Canada Inc. (BD Diagnostics)
2555 Boul. Parc-Technologique
Quebec (Quebec), Canada
G1P 4S5
Contact:	Patricia Dionne, Ph.D.
Device:
510(k) Number:	K130470
Trade Name:	BD MAX™ Cdiff Assay
Common Name:	Clostridium difficile tcdB detection assay
Type of Test:	Qualitative Nucleic Acid Amplification Test for C. difficile toxin B gene
from liquid or soft stool specimens
Classification:	II
Regulation Name:	Clostridium difficile Toxin Gene Amplification Assay
Regulation Number:	866.3130
Product Code:	OZN, OOI
Panel:	Microbiology (83)
Predicate Device:	BD GeneOhm™ Cdiff Assay
Predicate 510(k) number:	K081920

Intended Use:

The BD MAX™ Cdiff Assay performed on the BD MAX™ System is an automated in vitro diagnostic test for the direct, qualitative detection of the Clostridium difficile toxin B gene (tcdB) in human liquid or soft stool specimens from patients suspected of having C. difficile infection (CDI). The test. performed directly on the specimen, utilizes real-time polymerase chain reaction (PCR) for the amplification of C. difficile toxin B gene DNA and fluorogenic target-specific hybridization probes for the detection of the amplified DNA. The BD MAX ™ Cdiff Assay is intended to aid in the diagnosis of CDI.

Indication for Use:

The BD MAX™ Cdiff Assay performed on the BD MAX™ System is an automated in vitro diagnostic test for the direct, qualitative detection of the Clostridium difficile toxin B gene (todB) in human liquid or soft stool specimens from patients suspected of having C. difficile infection (CDI). The test,

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1

performed directly on the specimen. utilizes real-time polymerase chain reaction (PCR) for the amplification of C. difficile toxin B gene DNA and fluorogenic target-specific hybridization probes for the detection of the amplified DNA. The BD MAX™ Cdiff Assay is intended to aid in the diagnosis of CDI.

Special Conditions for Use Statement:

For prescription use

Special Instrument Requirements:

The BD MAX™ System

Device Description:

The BD MAX™ System and the BD MAX™ Cdiff Assay are comprised of an instrument with associated hardware and accessories, disposable microfluidic cartridges, master mixes, unitized reagent strips, extraction reagents, and sample buffer tubes. The instrument automates sample preparation including target Ivsis. DNA extraction and concentration, reagent rehydration, and 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 result may be called as NEG (negative), POS (positive) or UNR (unresolved) based on the amplification status of the target and of the Sample Processing Control. IND (indeterminate) or INC (incomplete) results are due to BD MAX™ System failure.

Test Principle:

The BD MAX™ Cdiff Assay performed on the BD MAX™ System is an automated in vitro diagnostic test for the direct, qualitative detection of the Clostridium difficile toxin B gene (todB) in human liguid or soft stool specimens from patients suspected of having C. difficile infection (CDI).

A liquid or soft stool specimen is collected and transported to the laboratory. For testing, a disposable 10µL inoculating loop is dipped into the stool material and the contents dispersed into a BD MAX™ Cdiff Sample Buffer Tube. The Sample Buffer Tube is closed with a septum cap and vortexed. A worklist is created and the Sample Buffer Tube, the BD MAX™ Cdiff unitized reagent strip and the BD MAX™ PCR Cartridge are loaded onto the BD MAX™ System.

Following enzymatic cell lysis, the released nucleic acids are captured on magnetic beads. The beads, with the bound nucleic acids, are washed using Wash Buffer and the nucleic acids are eluted by heat in Elution Buffer. Eluted DNA is neutralized using Neutralization Buffer and transferred to a Master Mix to rehydrate PCR reagents. After reconstitution, the BD MAX™ System dispenses a fixed volume of PCR-ready solution containing extracted nucleic acids into the BD MAX™ PCR Cartridge. Microvalves in the BD MAX™ PCR Cartridge are sealed by the system prior to initiating PCR to contain the amplification mixture, thus preventing evaporation and contamination.

The amplified DNA targets are detected using hydrolysis (TaqMan®) 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 tcdB and SPC amplicons in two different

2

optical channels of the BD MAX™ System. When the probes are in their native state, the fluorescence of the fluorophore is quenched due to its proximity to the quencher. However, in the presence of target DNA, the probes hybridize to their complementary sequences and are hydrolyzed by the 5-3' exonuclease activity of the DNA polymerase as it synthesizes the nascent strand along the DNA template. As a result, the fluorophores are separated from the quencher molecules and fluorescence is emitted. The amount of fluorescence detected in the two optical channels used for the BD MAX™ Cdiff Assay 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 program to provide a final result.

Substantial Equivalence:

Table 1 shows the similarities and differences between the BD MAX™ Cdiff Assay and the predicate device.

3

Item	Device	Predicate
SIMILARITIES
Intended Use	The BD MAX™ Cdiff Assay performed
on the BD MAX™ System is an
automated in vitro diagnostic test for
the direct, qualitative detection of the
Clostridium difficile toxin B gene ( tcdB )
in human liquid or soft stool specimens
from patients suspected of having C. difficile infection (CDI). The test,
performed directly on the specimen,
utilizes real-time polymerase chain
reaction (PCR) for the amplification of
C. difficile toxin B gene DNA and
fluorogenic target-specific
hybridization probes for the detection
of the amplified DNA. The BD MAX™
Cdiff Assay is intended to aid in the
diagnosis of CDI.	The BD GeneOhm™ Cdiff Assay is a
rapid in vitro diagnostic test for the
direct, qualitative detection of C. difficile toxin B gene ( tcdB ) in human
liquid or soft stool specimens from
patients suspected of having
Clostridium difficile -associated disease
(CDAD). The test, based on real-time
PCR, is intended for use as an aid in
diagnosis of CDAD. The test is
performed directly on the specimen,
utilizing polymerase chain reaction
(PCR) for the amplification of specific
targets and fluorogenic target-specific
hybridization probes for the detection
of the amplified DNA.
Mode of
detection for
toxin B	Presence of the toxin B ( tcdB ) gene	Presence of the toxin B ( tcdB ) gene
Specimen
Type	Liquid and soft stool specimens	Liquid and soft stool specimens
Assay Format	Amplification: PCR
Detection: Fluorogenic target-specific
hybridization	Amplification: PCR
Detection: Fluorogenic target-specific
hybridization
Interpretation
of test
results	Automated (Diagnostic software of BD
MAX™ system)	Automated (Diagnostic software of
SmartCycler® system)
DIFFERENCES
Analysis
Platform	BD MAX™ System	SmartCycler® System
PCR Sample
Preparation	Automated by the BD MAX™ System	Manual
Detection
Probes	TaqMan® Probe	Molecular Beacon Probe

Table 1: Substantial Equivalence Information

:

4

| Assay Controls | Specimen Processing Control (SPC) | Positive (DNA from Clostridium difficile
bearing the tcdB gene ATCC 43255) |
|----------------|-----------------------------------|-------------------------------------------------------------------------------|
| | | Negative (DNA from Escherichia coli
ATCC 25922) |
| | | Internal procedural control |

Analytical Performance:

Precision

Within-laboratory precision was evaluated for the BD MAX™ Cdiff Assay at one (1) site. The Precision panel consisted of 5 sample categories in simulated sample matrix as follows:

Moderate Positive (MP): 2 5 x LoD .
. Low Positive (LP): 1- 2 x LoD
. High Negative 1:10 (HN1:10): 10-fold dilution of 1 x LoD
High Negative 1:100 (HN1:100): 100-fold dilution of 1 x LoD .
True Negative (Neg)

Testing was performed in duplicate, over 12 days, with 2 runs per day, by 2 technologists. Precision study results for Neq. LP and MP samples demonstrated 100% agreement. Precision study results for HN1:100 and HN1:10 demonstrated agreement of 95.8% and 58.3%, respectively. Precision performance was acceptable for the LP, MP, and Neg sample categories. No specific acceptance criteria were defined for either of the high negative sample categories.

Reproducibility

Reproducibility was evaluated with a panel that consisted of the same sample categories described for the Precision study. Samples in each category were tested in triplicate, on 5 distinct days, wherein each day 2 panels were tested by 2 technologists, at 3 clinical sites using 1 lot of reagents (Site-to-Site). One of these clinical sites participated in an extended study where 2 additional lots of reagents were tested (Lot-to-Lot). Results are shown for each sample category.

For Site-to-Site Reproducibility, the overall percent agreement was 100% for MP. LP and Neg categories. The Site-to-Site Reproducibility results demonstrated 92.2% and 50.0% negative agreement for HN1:100 and HN1:10 categories, respectively (Table 2).

For Lot-to-Lot Reproducibility, the overall percent agreement was 100% for MP, LP and Neg The Lot-to-Lot Reproducibility results demonstrated 96.7% and 64.4% negative categories. agreement for HN1:100 and HN1:10 categories, respectively (Table 3).

Site-to Site and Lot-to-Lot Reproducibility performance was acceptable for the LP, MP, and Neg sample categories. No specific acceptance criteria were defined for either of the high negative sample categories.

Lot-to-Lot and Site-to-Site quantitative reproducibility study results for positive and negative samples were stratified as follows (see Tables 2 to 5):

. Within run
Between runs within day .
. Between days within lot

5

Between lots .

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.

: .

\

.

:

6

BD MAX™ Cdiff Assay
PreMarket Notification

| | | | Table 2. Lot-to-Lot Quantitative Reproducibility | Stud | ട്ട
Result | Lots
100000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000
across | and Runs,
Jays | | and within Run \ | Sam
e
for Positiv | રેક | I |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------|-------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Free Property of Children Comments of Children | EP | | Within Run | | Between | Run within Day | Between Day within Lot | | Between | Lof | Overal | |
| Category
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | T | Mear | SD | %CV | SD | %CV | SD | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
%CV | SD | %C1 | SD | 00 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 - 10 -
%CV |
| HN1:10 | 32 | 316. | 101.89 | 32.2% | 53.21 | 16.8% | 0.00 | 0.0% | 0.00 | 0.0% | 114.95 | 36.4% |
| LP | 90 | 748.6 | 67.05 | 22.3% | 74.75 | 10.0% | 21.14 | 2.8% | 64.47 | 8.6% | 195.18 | 26.1% |
| MP | 90 | 975.6 | 201.66 | 20.7% | .85
47 | 4.9% | 41.24 | 4.2% | 58.00 | 5.9% | 219.14 | 22.5% |
| | | | | | | | I | | | | | |
| ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | vabus | | | Nithin Run | Rotwoon | Run within Nav | Batween Dav within
College of the comments of | | Batween | | Overa | |
| | SDPA | | | Within Run | | Between Run within Day
Comments of Children Colors of Children | tween Day within ﺍ
Bet | Lot | Between | n Lot | Overal | |
| Category | N | Mean | SD | %CV | SD
And Address of Act Act Act Act Act Act Act Access And | %CV | SD | %CV | SD | %CV | SD | %CV
managements of the first the first the first the first the first the first the first the first the first the first the first the first the first the first the first the first |
| HN1:10
A | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
32 | OCCUPOR COLORIOS COLLECTION
34.4 | 0.73 | 2.1% _________________________________________________________________________________________________________________________________________________________________________ | 0.29 | 0.8% | 0.00 | 0.0% | 0.58 | 1.7% | 0.97 | 2.8% |
| LP | 90 | 32.8 | 0.74 | 2.3% | 0.21 | 0.6% | 0.00 | 0.0% | 0.16 | 0.5% | 0.78 | 2.4% |
| MP | 90 | 32.1 | 0.80 | 2.5% | 0.00 | 0.0% | 0.00 | 0.0% | 0.06 | 0.2% | 0.80 | Canadian and Canadian Canadian Canadian Canadian Canada Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Car
2.5% |
| | | | | | | | | | | | | And Analysis and Career of Children |
| Carles of Children Company of Children Company of Children Company of Children Comments of Children Comments of Children Comments of Children Comments of Children Comments of | SDPH | | | Within Run | | Between Run within Day | Between Day within Lot | | | Between Lot | Overall | |
| Category | N | Mean | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %AFBS AC% |
| HN1:10 | 32 | 3.7 | 1.37 | 37.3% | 0.47 | 12.7% | 0.00 | 0.0% | 0.00 | 0.0% | 1.45 | |
| LP | 90 | 0.4 | 2.34 | 24.8% | 0.89 | 9.5% | 0.28 | 3.0% | 0.89 | 9.4% | 2.67 | 28.3% |
| MP | 90 | 12.8 | 2.96 | 23.1% | 0.72 | 5.6% | 0.54 | 4.2% | 1.36 | 10.6% | 3.38 | 26.3% |
| | SDPA | | | Comment John A
Within Run | Between Run within Day | | etween Day within L
6 | Lot | | Between Lot | | Overall |
| Category | 1 | Mean | SD | %CV | SD | %CV | SD | %CV | SD | %CV | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
SD | %CV
Property |
| HN1:100 | 87 | 29.0

                                                                                                                                                                        | 0.40                                             | 1.4%

------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | 0.00 | 0.0% | 0.09 | 0.3% | 0.40 | .4% | 0.57 | |
| HN1:10 | ട്ക | 29.0 | 0.29 | 1.0% | 0.00 | 0.0% | 0.05 | 0.2% | 0.50 | 1.7% | 0.58 | 5 %D %DF %D75 %D75 |
| Neg | 90 | 29.0 | 0.37 | 1.3% | 0.00 | 0.0% | 0.00 | 0.0% | 0.43 | .5% | 0.57 | |
| | | | | | | | | | | | | BANDACTORS |
| | SDPH
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | | | Within Run | | Between Run within Day | letween Day within
. B | Lot | Between | Lot | | Overall |
| Category | N | Mean | SD | %CV | SD | %CV | ട് പ് | %CV | SD | %CV | SD | %CV |
| HN1:100 | 87 | 89.5 | 6.58
------------ | 9.5% | .97 | 2.8% | 0.00 | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
0.0% | 4.10 | 5.9%
1 | 8.00
| 11.5% |
| HN1:10 | ક્ષ્ઠ | ಲ್ಲೂ ರಿ | 7.72 | 11.2% | 5.04 | 7.3% | 0.00 | 0.0% | 2.83 | 4.1% | 9.64 | 14.0% |
| Neg | 90 | ﻨﺴﻴﺴﺘﻌﻠﻨﺖ ﺍﻟﻤﺴﺘﺸﻔﻴﻨﻴﺔ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺴﺘﺸﻔﻴﺔ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺴﺘﻮﻯ ﺍﻟﻤﺴﺘﺸﻔﻴﺔ ﺍﻟﻤ
89.5 | 6.56 | 9.4% | 2.09 | 3.0% | 0.00 | 0.0% | 4.52 | 6.5% | 8.23 | 11.8% |

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MAX™ Cdiff Ass
Market Notificatio

13.4% 16.3% 13.8% %CV Overall 752.18 718.58 865.50 SD ble 3. Lot-to-Lot Quantitative Reproducibility Study Results across Lots, Days and Runs, and within Run for Negative Samples
8.5% 6.8% 9.2% %CV 455.55 361.57 498.52 SD 0.0% 0.0% 0.0% %CV 0.00 0.00 0.00 SD 4.1% 2.7% 8.2% %CV 219.72 148.59 432.84 SD 12.4% 10.0% 9.5% %CV 510.44 543.30 656.51 SD 5432.3 5361.3 Mean 5296.7 06 18
N 89 Category HN1:100 HN1:10 Neg

9.4% Neg

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able 4. Site-to-Site Quantitative Reproducibility Study Results for the Target across Sites, Days and Runs and within Run using one Lot
restive Samples

Overall

Between Site

Between Day within Site

Between Run within Day

Within Run

EP

Category	N	Mean	SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
HN1:100	7	279.7	56.11	20.1%	0.00	0.0%	186.31	66.6%	0.00	0.0%	194.58	69.6%
HN1:10	45	314.7	151.79	48.2%	67.47	21.4%	0.00	0.0%	12.53	4.0%	166.58	52.9%
LP	90	948.8	149.65	15.8%	89.99	9.5%	0.00	0.0%	361.55	38.1%	401.51	42.3%
MP	90	1217.4	224.30	18.4%	150.77	12.4%	0.00	0.0%	374.72	30.8%	462.02	37.9%
	SDPA			Within Run		Between Run within Day		Between Day within Site		Between Site	Overall
Category	N	Mean	SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
HN1:100	7	33.4	2.17	6.5%	5.53	16.6%	0.00	0.0%	0.00	0.0%	5.94	17.8%
HN1:10	45	35.1	0.95	2.7%	0.20	0.6%	0.32	0.9%	0.55	1.6%	1.16	3.3%
LP	90	32.5	0.60	1.8%	0.00	0.0%	0.19	0.6%	0.45	1.4%	0.77	2.4%
MP	90	31.6	0.75	2.4%	0.19	0.6%	0.00	0.0%	0.26	0.8%	0.82	2.6%
	SDPH			Within Run		Between Run within Day		Between Day within Site		Between Site	Overall
Category	N	Mean	SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
HN1:100	7	3.9	0.23	5.9%	0.00	0.0%	2.99	76.5%	0.00	0.0%	2.99	76.7%
HN1:10	45	4.2	2.34	55.8%	0.96	23.0%	0.00	0.0%	0.00	0.0%	2.53	60.4%
LP	90	13.1	2.37	18.2%	1.36	10.4%	0.00	0.0%	5.28	40.4%	5.94	45.5%
MP	90	17.6	3.83	21.8%	2.42	13.7%	0.00	0.0%	5.50	31.3%	7.13	40.5%

alues shown are those obtained for the C. difficile target in the samples that gave a positive resu

21.8%

3.83

61.18

9

BD MAX™ Cdiff Assay	PreMarket Notification
---------------------	------------------------

Table 5. Site-to-Site Quantitative Reproducibility Study Results across Sites, Days and Runs and within Run using one Lot for Negative
Samples'

| 15.5%
14.3%
15.4%
%CV
Overal
774.12
803.26
717.73
sp
MAR E
1001
0.5%
8.3%
8.4%
%CV
e
40
Sit

Between

، .67
417.35
543.70
SD
421
100 mm 10 10

0.0%
0.0%
0.0%
%CV
Da
Between
0.00
0.00
0.00

SD
Da
3.2%
5.0%
4.0%

%CV		The Property of Children Company of the Career	------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
	etween
00
Within Rur		un within D	within Site
	SD
%CV
A Brand Book Boom Add American A MARK A
SD
Mear
	62.27
12.6%
i
631.46
.
5020.4
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------		I
	250.03

10.5%
524.23
5006.5 | | | | | | | |
| | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
204.88
A MARK ALL A BRITACH A
10.7%
554.66

5166.0
| | | | | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | | ------------------- |

| | SDPA | ------------ | Within Run
I | | Between | Run within Day | Between | ו Day within Site
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | Between | Site | Overali | |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| AAAAAAAAAAAAAAAAAA
Category
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | | Mear | SD | %CV
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | SD | The state of the status and the commend of the first to the first to the first to the first the
%CV | SD | %CV
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
SD | Land annual Access & Lawren & La
%CV | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
SD
I | %CV
. |
| HN1:100
l | 83 | 28.8
1 | 0.35 | LE E REAL I RESEARCHING MENT EXTERNAL MENTER AND
1.2% | 0.00 | 0.0% | 0.00 | I
0.0% | 0.18

A LEAS - CALLER	0.6%
0.39	1.4%
HN1:10	45
28.8	0.32
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------	1.1%
Neg	90
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------	0.27
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

A	SDPH
A	etween
0	Site
Day within	Between

Active-And American Archively American American American A | Site | Overal
| ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ |
| Categor | | Mean | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
SD | %CV | SD | A-4-4-40-48-44-44-44-44-44-44-44-44-44-44-44-44-44-44-44-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4
%CV | The first and the comments of the comments of the comments of the comments of the comments of the comments of the comments of the comments of the comments of the comments of
SD | %CV
Actually Addition Add | SD | %CV | SD | %CV
A |
| HN1:100
I | 83 | 64.8
I | -
9.84 | 15.2% | 0.00 | 0.0% | 0.00
BARRANT . | 0.0%
. |
4.65 | 7.2% | 10.89 | 16.8% |
| HN1:10 | 45 | 64.5 | 7.47
I | 11.6% | 2.15 | 3.3% | 0.00 | 0.0% | 4.43 | 6.9% | 8.94 | 3.9% |
| Neg | 90 | 67.0 | 6.51 | 9.7% | 2.40 | 3.6% | 0.00 | 0.0% | 6.55 | 9.8% | 9.54 | 14.2% |
| | | Calculated for the Specimen Processing Control of nega | I | | Canada Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Cara Ca
ative samples | | | . | CALL PROPERTY | . | | |

10/19

10

Second Derivative Peak Abscissa (SDPA), an internal criteria used to determine a final assay result, was selected as an additional means of assay reproducibility. Overall mean SDPA values with variance components (SD and %CV) are shown in Tables 6 and 7.

	SITE							SDPA Values1
Category	Site 1
Percent
Agreement		Site 2
Percent
Agreement		Site 3
Percent
Agreement		Overall Percent
Agreement		Overall
Mean	SD	%CV
Neg1	30/30	100.0%	30/30	100.0%	30/30	100.0%	100.0% (95% CI: 95.9%, 100.0%)	28.7	0.30	1.1
HN1:1001,2	28/30	93.3%	25/30	83.3%	30/30	100.0%	92.2% (95% CI: 84.8%, 96.2%)	28.8	0.39	1.4
HN1:101,2	17/30	56.7%	8/30	26.7%	20/30	66.7%	50.0% (95% CI: 39.9%, 60.1%)	28.8	0.35	1.2
LP	30/30	100.0%	30/30	100.0%	30/30	100.0%	100.0% (95% CI: 95.9%, 100.0%)	32.5	0.77	2.4
MP	30/30	100.0%	30/30	100.0%	30/30	100.0%	100.0% (95% CI: 95.9%, 100.0%)	31.6	0.82	2.6

Table 6: Site-To-Site Reproducibility Study Results using One Lot of the BD MAX™ Cdiff Assay
----------------------------------------------------------------------------------------------

For the Negative and High Negalive, SDPA values reported are for the SPC. For other reported are for the toxigent C. difficile target.

2 For the High Negative calegones, the expective. Therefore, Therefore, percent agreement was calculated for negative results.

Table 7: Lot-to-Lot Reproducibility Study Results using Three Lots of the BD MAX™ Cdiff Assay

	LOT							SDPA Values¹
Category	Lot 1
Percent
Agreement		Lot 2
Percent
Agreement		Lot 3
Percent
Agreement		Overall Percent
Agreement		Overall
Mean	SD	%CV
Neg¹	30/30	100.0%	30/30	100.0%	30/30	100.0%	100.0%	(95% CI: 95.9%, 100.0%)	29.0	0.57	2.0
HN1:1001,2	29/30	96.7%	28/30	93.3%	30/30	100.0%	96.7%	(95% CI: 90.7%, 98.9%)	29.0	0.57	2.0
HN1:101,2	17/30	56.7%	21/30	70.0%	20/30	66.7%	64.4%	(95% CI: 54.2%, 73.6%)	29.0	0.58	2.0
LP	30/30	100.0%	30/30	100.0%	30/30	100.0%	100.0%	(95% CI: 95.9%, 100.0%)	32.8	0.78	2.4
MP	30/30	100.0%	30/30	100.0%	30/30	100.0%	100.0%	(95% CI: 95.9%, 100.0%)	32.1	0.80	2.5

For the Negative and High Negative satesories SDPA values reported are for the SPC. For other reported are for the baile in Coricenic C. difficile target.

2 For the High Negative categories, the expective. Therefore. Therefore, percent arreement was calculated for negative results

Sample Storage

Collected specimens can be stored at 2-25°C for a maximum of 48 hours or at 2-8°C for a maximum of 120 hours (5 days) before testing. In case of repeat testing from the Sample Buffer Tube, the following storage conditions apply:

up to 5h after the end of the initial run when stored at 25 ± 2℃ or .
. up to 120h after the end of the initial run when stored at 2-8°C.

Controls

External Control materials are not provided by BD. Various types of External Controls are recommended to allow the user to select the most appropriate for their laboratory quality control program:

Commercially available control materials (e.g., ATCC® 43255, a C. difficile strain . bearing the tcdB gene, and ATCC® 700057, a non-toxigenic C. difficile strain, can be used as positive and negative controls, respectively);
Suspensions of bacterial strains characterized by the user as toxigenic or non-toxigenic; .

11

Previously characterized clinical specimens known to be positive or negative for . toxigenic C. difficile.
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.

Analytical Sensitivity

The analytical sensitivity (Limit of Detection or LoD) for the BD MAX™ Cdiff Assay was determined as follows: individual inoculating loops were dipped into C. difficile bacterial suspensions at different concentrations, prepared and quantified from cultures of four C. difficile strains representing three toxinotypes (0, III, VIII). Nine bacterial concentrations ranging between 0 and 64,000 CFU/mL were tested for each toxinotype. Each loop was then transferred to a SBT, already containing fecal matrix negative for toxigenic C. difficile. Each C. difficile strain was tested in replicates of 24 per concentration, by two different operators, using three different production lots of the BD MAXTM Cdiff Assay. The results were analyzed using a statistical linear logistic model. Briefly, the method models the positive response (expressed in percentage) as a function of Log (CFU/mL). The logistic model equation for the fitted curve allows the computation of the LoD by inverse prediction using the parameter estimates and their 95% confidence interval. The LoD was defined as the lowest concentration at which 95% of all replicates tested positive. The LoD ranged from 125 to 265 CFU per loop for each strain (Table 8).

C. difficile Strain	Toxinotype	LoD in CFU per loop
ATCC® 43255	0	265 (95% CI: 140, 502)
ATCC® 9689	0	156 (95% CI: 82, 298)
ATCC® BAA-1805	III	205 (95% CI: 102, 412)
ATCC® 43598	VIII	125 (95% CI: 66, 235)

Table 8: Limit of Detection of the BD MAX™ Cdiff Assay

Analytical Inclusivity

A variety of toxigenic C. difficile strains were included in this study taking into account geographic origin, toxinotype, NAP1 outbreaks and temporal diversity. Sixty-four (64) strains including 23 toxinotypes and representing 21 countries were tested, including strains from public collections and well-characterized clinical isolates (see Table 9). The assay correctly identified 62 of the 64 toxigenic C. difficile strains which were tested at ~3xLoD. Two (2) strains produced low signal results and were false-negative in one out of five replicates.

12

Strain ID	Toxinotype	Strain ID	Toxinotype	Strain ID	Toxinotype
ATCC 700792 (14797-2)		DII1		M30761	VI
ATCC 17858 (1253)		QI1		57267	VII
ATCC 51695 (BDMS 18AN)		MI23	ND1	ATCC 43598	VIII
ATCC 43600 (2149)		Ell1		51680	IX
ATCC 43599 (2022)		PI2		M46722	IX
ATCC 43596 (545)		M14614	0	M40767	IX
ATCC 43594 (W1194)		M39177	0	8864	X
ATCC 17857 (870)		ATCC 43255	0	M26479	XII
ATCC BAA-1382 (630)		ATCC 9689	0	IS25	XII2
141		M16256	I	R9367	XIII
CD11	ND1	AC008	II	R10870	XIV
301		M14473	III	R9385	XV2
CD 246		M28681	III	SUC36	XVI
NCTC 11382		M37992	III	J9965	XVII
NCTC 11204		M41124	III	K095	XVIII
NI1		M1137	III	TR13	XIX
C13		ATCC BAA-
1805	III	CH6223	XXI
F19		SE844	IIIa	M13883	XXI
L16		55767	IV	8785	XXIII
K13		M25097	IV	597B	XXIV
GII1		SE881	V
HI1		51377	VI

Table 9: Strains Tested in the Inclusivity Study of the BD MAX™ Cdiff Assay.

1 ND = Not Determined.

2 The repeat result is presented here. The initial result was negative. Positive results were obtained upon retest from SBT and in an additional test performed with 3 replicates. Overall, 4/5 test results were found positive.

Analytical Specificity

The BD MAX™ Cdiff Assay was performed on samples containing phylogenetically related species (Clostridium other than toxigenic C. difficile) and other organisms (bacteria, viruses) likely to be found in stool specimens (Table 10).

Six (6) out of six C. difficile strains not bearing the tcdB gene, tested at a . concentration ≥ 1 X 10° CFU/mL, produced negative results with the BD MAX™ Cdiff Assay;
. Thirty (30) out of 30 Clostridium strains other than C. difficile, including four strains of C. sordelli, tested at a concentration ≥ 1 X 10° CFU/mL, produced negative results with the BD MAX™ Cdiff Assay;
. Ninety-five (95) out of 98 other bacterial strains, including 93 species and subspecies, were tested at a concentration ≥ 1 X 108 CFU/mL (or ~ 1 X 108 genomic DNA cp/mL or 1 X 10° elementary bodies/mL) and produced negative results with the BD MAX " Cdiff Assay. The following strains gave a positive result:
- . Bacteroides stercoris (ATCC 43183)
- Gemella morbillorum (ATCC 27824) .

13

Peptoniphilus asaccharolyticus (ATCC 14963)

.

An investigation was conducted and determined that the false-positive results were due to contamination. Overall, out of 5 replicates, the three strains each gave an initial positive result due to contamination. ATCC 27824 gave negative results for the 4 other replicates. However, ATCC 43183 and ATCC 27824 gave another positive result due to instrument issue and the 3 last replicates were found negative.

Seven (7) out of seven viruses, tested at a concentration ≥ 1 X 10° PFU/mL, produced negative results with the BD MAX" Cdiff Assay.

Table 10: Species Tested for the Cross-Reactivity Study
Clostridium species (≥ 1x10° CFU/mL)
Clostridium beijerinckii	Clostridium histolyticum	Clostridium septicum
Clostridium bifermentans	Clostridium innocuum	Clostridium sordellii
Clostridium bolteae	Clostridium nexile	Clostridium lavalense
Clostridium butyricum	Clostridium novyi	Clostridium sphenoides
Clostridium chauvoei	Clostridium orbiscindens	Clostridium spiroforme
Clostridium difficile
(non-toxigenic strains)	Clostridium paraputrificum	Clostridium sporogenes
Clostridium difficile
(Xla (A-B-tox bin+) and XIb)	Clostridium perfringens	Clostridium symbiosum
Clostridium fallax	Clostridium ramosum	Clostridium tertium
Clostridium haemolyticum	Clostridium scindens	Clostridium tetani
Other Bacterial Species (≥ 1x108 CFU/mL)
Abiotrophia defectiva	Enterococcus faecium VanA	Plesiomonas shigelloides
Acinetobacter baumannii	Enterococcus gallinarum	Porphyromonas
asaccharolytica
Acinetobacter Iwoffii	Enterococcus hirae	Prevotella melaninogenica
Aeromonas hydrophila	Enterococcus raffinosus	Proteus mirabilis
Alcaligenes faecalis subsp.
faecalis	Escherichia coli	Proteus penneri
Anaerococcus tetradius	Escherichia fergusonii	Providencia alcalifaciens
Bacillus cereus	Escherichia hermannii	Providencia rettgeri
Bacteroides caccae	Fusobacterium varium	Providencia stuartii
Bacteroides stercoris	Gardnerella vaginalis	Pseudomonas aeruginosa
Bifidobacterium adolescentis	Gemella morbillorum	Pseudomonas putida
Bifidobacterium longum	Hafnia alvei	Ruminococcus bromii
Campylobacter coli	Helicobacter cinaedi	Salmonella enterica subsp.
enterica
Campylobacter jejuni subsp.
jejuni	Helicobacter pylori	Salmonella enterica subsp.
arizonae
Candida albicans	Klebsiella oxytoca	Serratia liquefaciens
Candida catenulata	Klebsiella oxytoca	Serratia marcescens
Cedecea davisae	Klebsiella pneumoniae subsp.
pneumoniae	Shigella boydii
Citrobacter amalonaticus	Lactobacillus acidophilus	Shigella dysenteriae
Citrobacter freundii	Lactobacillus reuteri	Shigella sonnei
Citrobacter koseri	Lactococcus lactis subsp. lactis	Staphylococcus aureus
subsp. aureus
Citrobacter sedlakii	Leminorella grimontii	Staphylococcus epidermidis
Collinsella aerofaciens	Listeria grayi	Stenotrophomonas

Table 10: Species Tested for the Cross-Reactivity Study

14

Corynebacterium genitalium	Listeria innocua	Streptococcus agalactiae
Desulfovibrio piger	Listeria monocytogenes	Streptococcus dysgalactiae
subsp. dysgalactiae
Edwardsiella tarda	Mitsuokella multacida	Streptococcus intermedius
Eggerthella lenta	Mobiluncus curtisii subsp.
holmesii	Streptococcus uberis
Enterobacter aerogenes	Moellerella wisconsensis	Trabulsiella guamensis
Enterobacter cloacae subsp.
cloacae	Morganella morganii subsp.
morganii	Veillonella parvula
Enterococcus casseliflavus	Neisseria gonorrhoeae	Vibrio parahaemolyticus
Enterococcus cecorum	Parabacteroides merdae	Yersinia bercovieri
Enterococcus dispar	Peptoniphilus asaccharolyticus	Yersinia rohdei
Enterococcus faecalis	Peptostreptococcus anaerobius
Intracellular bacteria
(1x108 elementary bodies/mL)	Vibrio cholerae species
(~1x108 cp/mL)	Human sample
(~1x109 cp/mL)
Chlamydia trachomatis	Vibrio cholerae	Homo sapiens
virus (≥ 1x106 PFU/mL)
Adenovirus Type 14	Enterovirus	Cytomegalovirus, Strain AD-
169
Rotavirus, stain WA	Echovirus 19 (Strain Burke)
Norovirus group 1	Coxsackie virus B1 (Com-5)

Interfering Substances

Twenty-five (25) biological and chemical substances occasionally used or found in perianal, rectal and/or stool specimens were evaluated for potential interference with the BD MAX™ Cdiff Assay. Two (2) organisms (E. coli ATCC 25922 and non-toxigenic C. difficile ATCC 700057) were also tested at high loads in order to assess bacterial interference. Toxigenic C. difficile negative specimens and toxigenic C. difficile positive specimens at 2-3X LoD were tested with the highest amount of each compound likely to be found in the specimens or with interfering organisms (1 X 10° CFU/mL of each strain). Potentially interfering substances include calcium carbonate (Tums®) as well as magnesium and aluminum hydroxide (Maalox® liquid). Results demonstrated no reportable interference with any other tested substance except for Mesalamine rectal suspension enema and Gynol II® that both showed slight inhibition (delay of Second Derivative Peak Abscissa) in the BD MAX™ Cdiff Assay. however, expected assay results were still obtained (Table 11).

15

| Brand Name or Description | Weight or
Volume
Tested/SBT | Result | Brand Name or Description | Weight or
Volume
Tested/SBT | Result |
|----------------------------------------------------------|-----------------------------------|--------|-----------------------------------------|-----------------------------------|--------|
| Nystatin | 10 µL | NI | Pepto Bismol™ | 10 µL | NI |
| Hyderm™ Hydrocortisone
(cream) | 0.0246 g | NI | Ex-Lax® | 0.0134 g | NI |
| Glycerin Suppositories | 0.0129 g | NI | Metronidazole | 10 µL | NI |
| Ihle's Paste | 0.0388 g | NI | Vancomycin | 10 µL | NI |
| Anusol® Plus | 0.0123 g | NI | Polysporin® | 0.0240 g | NI |
| Preparation H® with Bio-
Dyne® (cream) | 0.0222 g | NI | Naproxen | 10 µL | NI |
| Major Prep® with
Phenylephrine | 0.0111 g | NI | Tucks® Personal
Cleansing Pads | 3 mm² | NI |
| Tums® | 0.0395 g | I | Triglyceride Mix (C2-C10) | 10 µL | NI |
| Maalox® (liquid) | 10 µL | I | Palmitic Acid | 25 mg | NI |
| Mesalamine Rectal
Suspension Enema | 10 µL | * | Stearic Acid | 10 mg | NI |
| Fleet® Mineral Oil Enema | 0.0182 g | NI | Blood | 10 µL | NI |
| Gynol II® Vaginal
Contraceptive
(with Nonoxynol-9) | 0.0262 g | * | Mucus | 10 µL | NI |
| Imodium AD® | 0.0062 g | NI | E. coli + non-toxigenic
C. difficile | 10 µL | NI |

Table 11: Endogenous and Commercial Exogenous Substances tested with the BD MAX™ Caiff Assay

I: Interference with the BD MAX™ Cdiff Assay.

NI: No reportable interference with the BD Cdiff™ Assay.

Mesalamine rectal suspension enema and Gynol II® (with nonoxynol-9) showed slight inhibition (delay of Second Derivative Peak Abscissa) in the BD MAX™ Cdiff Assay, however, expected assay results were still obtained.

Carryover / Cross-Contamination

A study was conducted to investigate within-run carryover and between-run carryover while processing specimens with high bacterial load of toxigenic C. difficile in the BD MAX™ Cdiff assay. A panel made of one high positive member and one negative member was used to prepare numerous samples. A Clostridium difficile strain (Tox 0, ATCC 9689) was used for the high positive C. difficile panel member (~3x108 CFU/mL). The negative member did not contain any target analyte. Twelve (12) replicates of the high positive panel member and 12 replicates of the negative panel member were tested in each run by alternating negative and positive samples. Three (3) operators performed 3 consecutive runs for a total of 9 runs of 24 samples. There were no false positive results due to carryover contamination.

Clinical Performance Studies

Clinical performance characteristics of the BD MAX™ Cdiff Assay were determined in a multi-site prospective investigational study. Six (6) investigational centers participated in the study. To be enrolled in the study, specimens had to be from patients suspected of having C. difficile infection for which diagnostic tests were indicated and ordered. Only soft or liguid stools, and only one specimen per patient, were included.

The Comparative Reference Method consisted of direct culture complemented by enriched culture. Enriched culture analysis was completed for all specimens that were negative for

16

toxigenic C. difficile by direct culture. The anaerobic culture was used to isolate C. difficile, if present. This was followed by confirmation of the isolate identification and a Tissue Culture Cytotoxicity Assay to determine the toxigenicity of the isolate.

Of the 2071 soft or liguid stool specimens compliant with the Reference Method (Direct and Enriched Culture). 1819 gave compliant and reportable results with the BD MAX ™Cdiff Assay. In comparison to the Reference Method, the BD MAX™ Cdiff Assay identified 87.7% of the toxigenic C. difficile positive specimens and 96.8% of the toxigenic C. difficile negative specimens (Tables 12 and 13).

Table 12: Results Obtained with the BD MAX™ Cdiff Assay in Comparison to the Reference Method

All Sites	Reference Method
	+	-	Total
BD MAX TM Cdiff
Assay	265	481	313
	371	1469	1506
Total	302	1517	1819
Sensitivity: 87.7% (265/302) (95% CI: 83.6%, 91.0%)
Specificity: 96.8% (1469/1517) (95% CI: 95.8%, 97.6%)
PPV: 83.5% (95% CI: 79.4%, 87.1%)
NPV: 97.7% (95% CI: 97.0%, 98.4%)

1 Further investigation was performed on specimens with discordant results between the Reference Method and the BD MAX™ Cdiff Assay.

27 of 48 False Positive BD MAX™ Cdiff specimens were also found to be positive using another . commercially available FDA-cleared RT-PCR assay targeting the C. difficile todB gene.

32 of 37 False Negative BD MAX™ Cdiff specimens, were also found to be negative using another . commercially available FDA-cleared RT-PCR assay targeting the C. difficile tcdB gene.

	Table 13. Results Obtained by Site using the BD MAX™ Cdiff Assay in Comparison to the
		Reference Method

Site	Sensitivity	Specificity
Site 1	90.0% (18/20)
(69.9%, 97.2%)1	95.3% (202/212)
(91.5%, 97.4%)
Site 2	84.4% (38/45)
(71.2%, 92.3%)	95.3% (205/215)
(91.7%, 97.5%)
Site 3	94.7% (36/38)
(82.7%, 98.5%)	97.9% (275/281)
(95.4%, 99%)
Site 4	83.8% (31/37)
(68.9%, 92.3%)	95.8% (322/336)
(93.1%, 97.5%)
Site 5	96.1% (49/51)
(86.8%, 98.9%)	98.4% (186/189)
(95.4%, 99.5%)
Site 6	83.8% (93/111)
(75.8%, 89.5%)	98.2% (279/284)
(95.9%, 99.2%)
Overall Study	87.7% (265/302)
(83.6%, 91.0%)	96.8% (1469/1517)
(95.8%, 97.6%)

Numbers in parentheses express the 95% confidence interval boundaries

17

In comparison to direct culture, the BD MAX™ Cdiff Assay identified 96.5% of the toxigenic C. difficile positive specimens and 92.7% of the toxigenic C. difficile negative specimens (Tables 14 and 15).

All Sites		Direct Culture
		+	-	Total
BD MAX TM Cdiff
Assay	+	194	118	312
	-	7	1507	1514
Total		201	1625	1826
Positive Percent Agreement: 96.5% (194/201) (95% CI: 93.0%, 98.3%)

Table 14: Results Obtained with the BD MAX™ Cdiff Assay in Comparison to Direct Culture

Table 15. Results Obtained by Site using the BD MAX™ Cdiff Assay in Comparison to Direct Culture

.

| Site | SensitivityPositive
Percent Agreement | Negative Percent
Agreement |
|---------------|------------------------------------------|-------------------------------------|
| Site 1 | 92.9% (13/14)
(68.5%, 98.7%) 1 | 93.1% (203/218)
(89.0%, 95.8%) |
| Site 2 | 100.0% (26/26)
(87.1%, 100%) | 90.6% (213/235)
(86.2%. 93.7%) |
| Site 3 | 96.0% (24/25)
(80.5%. 99.3%) | 93.9% (276/294)
(90.5%. 96.1%) |
| Site 4 | 93.8% (15/16)
(71.7%, 98.9%) | 91.7% (330/360)
(88.4%. 94.1%) |
| Site 5 | 95.7% (45/47)
(85.8%, 98.8%) | 96.4% (188/195)
(92,8%. 98.3%) |
| Site 6 | 97.3% (71/73)
(90.5%. 99.2%) | 92.0% (297/323)
(88.5%. 94.4%) |
| Overall Study | 96.5% (194/201)
(93.0%, 98.3%) | 92.7% (1507/1625)
(91.4%, 93.9%) |

1 Numbers in parentheses express the 95% confidence interval boundaries

Out of 1860 soft or liquid stool specimens tested with the BD MAX™ Cdiff Assay, 58 (3.1%) were initially reported as unresolved. 42 of those were repeated and 32 were resolved upon repeat testing. Overall, 0.5% remained unresolved after repeat (Table 16).

Initial Unresolved Rate	Unresolved Rate After Repeat
3.1% (58/1860)* (95% CI: 2.4%, 4.0%)	0.5% (10/1844) (95% CI: 0.3%, 1.0%)

| Table 16: Unresolved Rate
|

-------------------------------

18

Total number based on compliant specimens and BD MAX™ Cdiff Assay results.

Out of 1916 soft or liquid stool specimens tested with the BD MAX™ Cdiff Assay, 21 (1.1%) were initially reported as indeterminate. Out of a total of 1844 compliant results, no result remained Indeterminate upon repeat (considering valid results and compliant repeats).

Out of 1916 soft or liquid stool specimens tested with the BD MAX™ Cdiff Assay, 28 (1.5%) were initially reported as incomplete. Out of a total of 1844 compliant results, no result remained Incomplete upon valid repeat (considering valid results and compliant repeats).

Comparison Studies

In addition to the multi-site investigational study, a comparison study was performed using the BD MAX™ Cdiff assay and two (2) commercially available FDA-cleared molecular assays for the detection of the C. difficile tcdB gene. Testing was performed on 2013 specimens at two external sites.

In comparison to one FDA-cleared molecular test (Table 10a), the PPA and NPA of the BD MAX™ Cdiff Assay were 99.1% (Cl: 94.9%-99.8%) and 97.4% (Cl: 95.7%-98.4%). respectively.

In comparison to a second FDA-cleared molecular test (Table 10b), the PPA and NPA of the BD MAX™ Cdiff Assay were 95.5% (Cl: 92.1%-97.5%) and 98.8% (Cl: 97.9%-99.3%), respectively.

All Sites		FDA-cleared Molecular Assay 1
		+	-	Total
BD MAX TM Cdiff
Assay	+	106	14	120
	-	1	526	527
	Total	107	540	647

Table 17a: Results Obtained with the BD MAX™ Cdiff Assay in Comparison to a Commercially Available FDA-cleared Molecular Assay for C. difficile.

19

	FDA-cleared Molecular Assay 2
All Sites	+	-	Total
BD MAXTM Cdiff
Assay +	233	14	247
BD MAXTM Cdiff
Assay -	11	1108	1119
Total	244	1122	1366

Table 17b: Results Obtained with the BD MAX™ Cdiff Assay in Comparison to a second Commercially Available FDA-cleared Molecular Assay for C. difficile.

Expected Values

In the BD MAX™ Cdiff Assay clinical study a total of 1834 reportable results, from specimens compliant at the specimen and PCR levels, were obtained from 6 geographically diverse sites and compared with Direct and Enriched culture. The study population was grouped into in-patient, out-patient and unknown categories. The number and percentage of positive cases, as determined by the BD MAX™ Cdiff Assay, are presented in Table 18 below.

| Group | Total Number of
Specimens | BD MAX™ Cdiff Assay
Number Positive | Number
Negative | Positive Percentage |
|-------------|------------------------------|----------------------------------------|--------------------|---------------------|
| In-patient | 1249 | 184 | 1065 | 14.7% (184/1249) |
| Out-patient | 457 | 114 | 343 | 24.9% (114/457) |
| Unknown | 128 | 17 | 111 | 13.3% (17/128) |
| Total1 | 1834 | 315 | 1519 | 17.2% (315/1834) |

Table 18: Expected Values

1Total number of specimens based on compliant PCR results

20

DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/20/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized depiction of an eagle or bird-like figure with three curved lines representing its wings or feathers. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES · USA" is arranged in a circular fashion around the emblem.

Public Health Service

Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

PATRICIA DIONNE DIRECTOR, REGULATORY AFFAIRS GENEOHM SCIENCES CANADA, INC. (BD DIAGNOSTICS) 2555 BOUL. DU PARC-TECHNOLOGIQUE QUEBEC (QUEBEC) G1P 4S5 CANADA

April 2, 2013

Re: K130470

Trade/Device Name: Bd MAX Cdiff Assay Regulation Number: 21 CFR 866.3130 Regulation Name: Clostridium difficile Toxin Gene Amplification Assay Regulatory Class: II Product Code: OZN, OOI Dated: February 22, 2013 Received: February 27, 2013

Dear Dr. Dionne:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug. and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration. Iisting of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

21

If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Office of In Vitro Diagnostics and Radiological Health at (301) 796-5450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/MedicalDevices/Resourcesfor You/Industrv/default.htm.

Sincerely yours,

Uwe Scherf -S for

Sally A. Hojvat, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

22

1.2 Indications for Use Statement

510(k) Number (if known): K_130470

Device Name: _________________________________________________________________________________________________________________________________________________________________

Intended Use:

The BD MAX™ Cdiff Assay performed on the BD MAX™ System is an automated in vitro diagnostic test for the direct, qualitative detection of the Clostridium difficile toxin B gene (tcdB) in human liquid or soft stool speciments from patients suspected of having C. difficile infection (CDI). The test, performed directly on the speciment utilizes real-time polymerase chain reaction (PCR) for the amplification of C. difficile toxin B gene DNA and fluorogenic target-specific hybridization probes for the detection of the amplified DNA. The BD MAX™ Cdiff Assay is intended to aid in the decedion of Clif

OR

Prescription

Use	XXX
-----	-----

(Per 21 CFR 801.109)Over-The-Counter Use

(Optional Format 1-2-96)

(PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of In Vitro Diagnostic Devices Evaluation and Safety (OIVD)

Raquel A. Peat-S
2013.04.02 12:52:34 -04'00'

Division Sign-Off Office of In Vitro Diagnostics and Radiological Health 510 (k) K130470

Intended Use / Indications for Use

Product codes (comma separated list FDA assigned to the subject device)

Device Description

Mentions image processing

Mentions AI, DNN, or ML

Input Imaging Modality

Anatomical Site

Indicated Patient Age Range

Intended User / Care Setting

Description of the training set, sample size, data source, and annotation protocol

Description of the test set, sample size, data source, and annotation protocol

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.

Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.

Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).

§ 866.3130 Clostridium difficile toxin gene amplification assay.

510(k) Summary

APR 0 2 2013

March 28, 2013

Intended Use:

Indication for Use:

Device Description:

Test Principle:

Substantial Equivalence:

Table 1: Substantial Equivalence Information

Analytical Performance:

Precision

Reproducibility

Between lots .

Between

، .67 417.35 543.70 SD 421 100 mm 10 10

0.0% 0.0% 0.0% %CV Da Between 0.00 0.00 0.00

Table 7: Lot-to-Lot Reproducibility Study Results using Three Lots of the BD MAX™ Cdiff Assay

Sample Storage

Controls

Analytical Sensitivity

Analytical Inclusivity

Table 9: Strains Tested in the Inclusivity Study of the BD MAX™ Cdiff Assay.

Analytical Specificity

Peptoniphilus asaccharolyticus (ATCC 14963)

Table 10: Species Tested for the Cross-Reactivity Study

Interfering Substances

Table 11: Endogenous and Commercial Exogenous Substances tested with the BD MAX™ Caiff Assay

Carryover / Cross-Contamination

Clinical Performance Studies

Comparison Studies

Expected Values

Table 18: Expected Values

DEPARTMENT OF HEALTH & HUMAN SERVICES

Uwe Scherf -S for

1.2 Indications for Use Statement

(PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON ANOTHER PAGE IF NEEDED)

، .67
417.35
543.70
SD
421
100 mm 10 10

0.0%
0.0%
0.0%
%CV
Da
Between
0.00
0.00
0.00