Cepheid Xpert C. difficile/Epi Control Panel

K190463 · Microbiologics, Inc. · PMN · Apr 19, 2019 · Microbiology

Device Facts

• Record ID: K190463
• Device Name: Cepheid Xpert C. difficile/Epi Control Panel
• Applicant: Microbiologics, Inc.
• Product Code: PMN · Microbiology
• Decision Date: Apr 19, 2019
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.3920
• Device Class: Class 2

Indications for Use

The Cepheid Xpert® C. difficile/Epi Control Panel is intended for use as external assayed positive and negative quality controls to monitor the performance of in vitro laboratory nucleic acid testing procedures for the qualitative detection of Clostridioides (Clostridium) difficile performed with the Cepheid Xpert® C. difficile/Epi assay on the GeneXpert® Dx System. The controls comprise cultured and inactivated Clostridioides (Clostridium) difficile 027-NAP1-B1 as the positive control and Clostridium sordellii as the negative control. The Cepheid Xpert® C. difficile/Epi Control Panel is not intended to replace manufacturer controls provided with the device.

Device Story

External assayed quality control material; lyophilized positive and negative control swabs. Positive control contains heat-inactivated Clostridioides difficile 027/NAP1/B1 strain; negative control contains heat-inactivated Clostridium sordellii. Used in clinical laboratories to monitor DNA extraction, amplification, and detection processes of Cepheid Xpert C. difficile/Epi assay on GeneXpert Dx System. Operators rehydrate swabs in sample reagent; process on GeneXpert instrument. Output consists of qualitative positive/negative results for toxin B (tcdB), binary toxin genes, and tcdC gene deletion. Ensures assay performance and validity of patient test results.

Clinical Evidence

No clinical data. Bench testing only. Reproducibility study conducted at three sites over five days with three lots of controls (n ≥ 90 replicates per control). All replicates produced expected qualitative results. Mean cycle threshold (Ct) and endpoint fluorescence values were consistent across sites, operators, and lots. Stability studies support 18-month shelf-life at 2-25°C and 5-hour in-use stability at 20°C.

Technological Characteristics

Lyophilized swab format; heat-inactivated microbial organisms. Positive control: Clostridioides difficile 027/NAP1/B1. Negative control: Clostridium sordellii. Compatible with GeneXpert Dx System. Standards referenced: CLSI EP25-A (stability), CLSI EP05-A3 (precision).

Indications for Use

Indicated for use as external quality control material for laboratory personnel performing nucleic acid testing for Clostridioides difficile using the Cepheid Xpert C. difficile/Epi assay on the GeneXpert Dx System.

Regulatory Classification

Identification

An assayed quality control material for clinical microbiology assays is a device indicated for use in a test system to estimate test precision or to detect systematic analytical deviations that may arise from reagent or analytical instrument variation. This type of device consists of single or multiple microbiological analytes intended for use with either qualitative or quantitative assays.

Special Controls

An assayed quality control material for clinical microbiology assays must comply with the following special controls: (1) Premarket notification submissions must include detailed device description documentation and information concerning the composition of the quality control material, including, as appropriate: (i) Analyte concentration; Expected values: (ii) Analyte source: (iii) (iv) Base matrix; (v) Added components; (vi) Safety and handling information; and, (vii) Detailed instructions for use. (2) Premarket notification submissions must include detailed documentation, including line data as well as detailed study protocols and a statistical analysis plan used to establish performance, including: (i) Description of the process for value assignment and validation. (ii) Description of the protocol(s) used to establish stability. (iii) Line data establishing precision/reproducibility. (iv) Where applicable, assessment of matrix effects and any significant differences between the quality control material and typical patient samples in terms of conditions known to cause analytical error or affect assay performance. (v) Where applicable, identify or define traceability or relationship to a domestic or international standard reference material and/or method. (vi) Where applicable, detailed documentation related to studies for surrogate controls. (3) Premarket notification submissions must include an adequate mitigation (e.g., realtime stability program) to the risk of false results due to potential modifications to the assays specified in the device's 21 CFR 809.10 compliant labeling. (4) Your 21 CFR 809.10 compliant labeling must include the following: (i) The intended use in your 21 CFR 809.10(a)(2) and 21 CFR 809.10(b)(2) compliant labeling must include the following: (A) Assayed control material analyte(s); (B) Whether the material is intended for quantitative or qualitative assays: (C) Stating if the material is a surrogate control; (D)The system(s), instrument(s), or test(s) for which the quality control material is intended. (ii) The intended use in your 21 CFR 809.10(a)(2) and 21 CFR 809.10(b)(2) compliant labeling must include the following statement: "This product is not intended to replace manufacturer controls provided with the device." (iii)A limiting statement that reads "Quality control materials should be used in accordance with local, state, federal regulations, and accreditation requirements."

*Classification.* Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include detailed device description documentation and information concerning the composition of the quality control material, including, as appropriate: (i) Analyte concentration; (ii) Expected values; (iii) Analyte source; (iv) Base matrix; (v) Added components; (vi) Safety and handling information; and (vii) Detailed instructions for use. (2) Premarket notification submissions must include detailed documentation, including line data as well as detailed study protocols and a statistical analysis plan used to establish performance, including: (i) Description of the process for value assignment and validation. (ii) Description of the protocol(s) used to establish stability. (iii) Line data establishing precision/reproducibility. (iv) Where applicable, assessment of matrix effects and any significant differences between the quality control material and typical patient samples in terms of conditions known to cause analytical error or affect assay performance. (v) Where applicable, identify or define traceability or relationship to a domestic or international standard reference material and/or method. (vi) Where applicable, detailed documentation related to studies for surrogate controls. (3) Premarket notification submissions must include an adequate mitigation (e.g., real-time stability program) to the risk of false results due to potential modifications to the assays specified in the device's 21 CFR 809.10 compliant labeling. (4) Your 21 CFR 809.10 compliant labeling must include the following: (i) The intended use of your 21 CFR 809.10(a)(2) and (b)(2) compliant labeling must include the following: (A) Assayed control material analyte(s); (B) Whether the material is intended for quantitative or qualitative assays; (C) Stating if the material is a surrogate control; and (D) The system(s), instrument(s), or test(s) for which the quality control material is intended. (ii) The intended use in your 21 CFR 809.10(a)(2) and (b)(2) compliant labeling must include the following statement: “This product is not intended to replace manufacturer controls provided with the device.” (iii) A limiting statement that reads “Quality control materials should be used in accordance with local, state, federal regulations, and accreditation requirements.”

Predicate Devices

• Cepheid Xpert® GBS LB Control Panel (K182472)

Submission Summary (Full Text)

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Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
www.fda.gov

# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

ASSAY ONLY

## I Background Information:

A 510(k) Number

K190463

B Applicant

Microbiologics, Inc.

C Proprietary and Established Names

Cepheid Xpert C. difficile/Epi Control Panel

D Regulatory Information

| Product Code(s) | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| PMN | Class II | 21 CFR 866.3920 - Assayed Quality Control Material For Clinical Microbiology Assays | IM - Immunology & MI - Microbiology |

## II Submission/Device Overview:

A Purpose for Submission:

To obtain a substantial equivalence determination for the Cepheid Xpert C. difficile/Epi Control Panel.

B Measurand:

Quality control panel comprised of inactivated microorganisms.

C Type of Test:

External assayed quality control material used to monitor the performance of the Cepheid Xpert C. difficile/Epi assay (K110203) for the detection of Clostridium (Clostridioides) difficile toxin B gene sequences and the presumptive identification of 027/NAP1/B1 strains of C. difficile in liquid or unformed stool specimens.

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III Intended Use/Indications for Use:

A Intended Use(s):
The Cepheid Xpert C. difficile/Epi Control Panel is intended for use as external assayed positive and negative quality controls to monitor the performance of in vitro laboratory nucleic acid testing procedures for the qualitative detection of Clostridioides (Clostridium) difficile performed with the Cepheid Xpert C. difficile/Epi assay on the GeneXpert Dx System. The controls comprise cultured and inactivated Clostridioides (Clostridium) difficile 027-NAP1-B1 as the positive control and Clostridium sordellii as the negative control.

The Cepheid Xpert C. difficile/Epi Control Panel is not intended to replace manufacturer controls provided with the device.

B Indication(s) for Use:
Same as Intended Use

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

For in vitro diagnostic use.

The Cepheid Xpert C. difficile/Epi Control Panel is not intended to replace manufacturer controls provided with the device

D Special Instrument Requirements:
Cepheid GeneXpert Dx System

IV Device/System Characteristics:

A Device Description:
The Cepheid Xpert C. difficile/Epi Control Panel comprises lyophilized Positive and Negative Control swabs that are individually packaged in foil pouches containing dessicant. The Positive Control swabs are formulated with a heat-inactivated 027/NAP1/B1 strain of Clostridium (Clostridioides) difficile that carries each of the targets detected by the Cepheid Xpert C. difficile/Epi Assay (i.e., the toxin B [tcdB] and binary toxin genes and a single base deletion in the tcdC gene). The Negative Control Swab contains a heat-inactivated strain of Clostridium sordellii that lacks the toxin B, binary toxin and tcdC targets.

B Principle of Operation:
The Cepheid Xpert C. difficile/Epi Control Panel is intended for use as assayed quality control material to monitor the DNA extraction, amplification and detection processes associated with

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the Cepheid Xpert C. difficile/Epi Assay (K110203) performed on the Cepheid GeneXpert System.

# V Substantial Equivalence Information:

A Predicate Device Name(s): Cepheid Xpert GBS LB Control Panel
B Predicate 510(k) Number(s): K182472

C Comparison with Predicate(s):

| Device & Predicate Device(s): | K190463 | K182472 |
| --- | --- | --- |
| Device Trade Name | Cepheid Xpert C. difficile/Epi Control Panel | Cepheid Xpert GBS LB Control Panel |
| General Device Characteristic Similarities | | |
| Intended Use/Indications For Use | The Cepheid Xpert C. difficile/Epi Control Panel is intended for use as external assayed positive and negative quality controls to monitor the performance of in vitro laboratory nucleic acid testing procedures for the qualitative detection of Clostridioides (Clostridium) difficile performed with the Cepheid Xpert C. difficile/Epi assay on the GeneXpert Dx System. The controls comprise cultured and inactivated Clostridioides (Clostridium) difficile 027-NAP1-B1 as the positive control and Clostridium sordellii as the negative control. | The Cepheid Xpert GBS LB Control Panel is intended for use as external assayed positive and negative quality control materials to monitor the performance of in vitro laboratory nucleic acid testing procedures for the qualitative detection of Group B Streptococcus (GBS) performed with the Cepheid Xpert GBS LB Assay on the GeneXpert Instrument System. The controls comprise cultured and inactivated Streptococcus agalactiae as the positive control and Lactobacillus acidophilus as the negative control. The Cepheid Xpert GBS LB Control Panel is not intended to replace the |

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| Device & Predicate Device(s): | K190463 | K182472 |
| --- | --- | --- |
| | The Cepheid Xpert C. difficile/Epi Control Panel is not intended to replace manufacturer controls provided with the device. | manufacturer controls provided with the device. |
| Control Format | Lyophilized swab | Same |
| Control Composition | Cultured and inactivated organisms | Same |
| General Device Characteristic Differences | | |
| Positive Control | Clostridioides (Clostridium) difficile 027/NAP1/B1 | Streptococcus agalactiae |
| Negative Control | Clostridium sordellii | Lactobacillus acidophilus |
| Measurand | tcdB gene
Binary toxin gene
tcdC deletion | 3' untranslated region of the cfb gene |
| Assay Compatibility | Cepheid Xpert C. difficile/Epi Assay | Cepheid Xpert GBS LB Assay |
| Instrument System | GeneXpert Dx System | GeneXpert Instrument Systems
GeneXpert Dx
GeneXpert Infinity-48
GeneXpert Infinity-80 |

VI Standards/Guidance Documents Referenced:

CLSI. Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline. CLSI Document EP25-A. Wayne, PA: Clinical and Laboratory Standards Institute; 2009.

CLSI. Evaluation of Precision of Quantitative Measurement Procedures: Approved Guideline - Third Edition. CLSI Document EP05-A3. Wayne, PA: Clinical and Laboratory Standards Institute; 2014.

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# VII Performance Characteristics (if/when applicable):

# A Analytical Performance:

# 1. Precision/Reproducibility:

The reproducibility of results obtained with the Cepheid Xpert C. difficile/Epi Control Panel was evaluated in a study performed at three sites over five days, with two operators per site. Each operator tested at least three Positive and three Negative Control Swabs on each day of the study according to the instructions for use (3 sites x 5 days x 2 operators x $\geq 3$ replicates = $\geq 90$ replicates per control in total). Three lots of Positive and Negative Controls were included in the study, the results of which are summarized in Tables 1 and 2. Repeat testing was performed for three controls (1 Positive; 2 Negative) that were associated with run failures due to instrument or reagent error. After repeat testing, all Positive and Negative Control swabs produced the expected results. The reproducibility of the Cepheid Xpert C. difficile/Epi Control Panel within and between sites/GeneXpert Dx Systems, operators and within and between lots was determined to be acceptable.

Table 1. Summary of qualitative Cepheid Xpert C. difficile/Epi Control Panel results from the Reproducibility Study

| Site | Expected Result/Number Tested (%) | |
| --- | --- | --- |
| | Positive Control | Negative |
| 1 | 30/30 (100) | 30/30 (100) |
| 2 | 31/31 (100) 1,2 | 31/31 (100) 1,2 |
| 3 | 30/30 (100) | 30/30 (100) |
| All Sites Combined | 91/91 (100) | 91/91 (100) |

One Positive and two Negative Controls at Site 2 were reported as "ERROR" due to instrument or reagent failure. The expected results were obtained upon retesting with new reagents and controls.
2 One additional replicate of the Positive and Negative Controls was tested at Site 2

Table 2. Summary of cycle threshold and endpoint fluorescence values obtained in the Reproducibility Study with the Cepheid Xpert C. difficile/Epi Control Panel

| Site | Mean (%CV) | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | tcdB | | Binary Toxin | | tcdC | | Process Control1 | |
| | Ct | EP | Ct | EP | Ct | EP | Ct | EP |
| 1 | 29.5(2.6) | 250(6.0) | 29.0(2.5) | 645(3.0) | 28.8(2.5) | 392(8.4) | 32.7(2.1) | 375(11.0) |
| 2 | 29.7(2.2) | 255(6.7) | 29.2(2.1) | 649(5.6) | 29.1(2.1) | 387(12.5) | 32.3(1.6) | 430(12.2) |
| 3 | 29.3(1.5) | 246(2.9) | 28.7(1.6) | 651(2.6) | 28.6(1.6) | 397(7.9) | 32.5(2.0) | 400(11.4) |
| All Sites | 29.5(2.2) | 250(5.6) | 28.9(2.2) | 648(4.0) | 28.8(2.2) | 392(9.8) | 32.5(2.0) | 402(12.8) |

Ct: Cycle Threshold; %CV: Percent Coefficient of Variation; EP: relative endpoint fluorescence
1 The values shown are only for testing performed with Negative Controls

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2. Linearity:
Not applicable.

3. Analytical Specificity/Interference:
Not applicable.

4. Assay Reportable Range:
Not applicable.

5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):

Reagent Stability
Reagent shelf-life was established in an Accelerated Stability Study that was performed with three lots of Cepheid Xpert C. difficile/Epi Control Panels that were placed at 43, 53 or 63°C for up to 42 days. All qualitative control results were as expected and there was no evidence of product degradation under the conditions tested. The results of this study were used to support a claimed shelf-life of 18 months at 2-25°C, which will be verified by conducting a Real-time Stability Study.

In Use Stability
The stability of Cepheid Xpert C. difficile/Epi Control Panel members after expression in Cepheid Xpert C. difficile/Epi Sample Reagent was evaluated by holding rehydrated controls at ambient temperature for different lengths of time prior to testing. The results of the study support use of the Cepheid Xpert C. difficile/Epi Control Panel within 5 hours of reconstitution in Sample Reagent when held at 20°C.

6. Detection Limit:
Not applicable.

7. Assay Cut-Off:
Not applicable.

B Comparison Studies:

1. Method Comparison with Predicate Device:
Not applicable.

2. Matrix Comparison:
Not applicable.

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C Clinical Studies:

1. Clinical Sensitivity:
Not applicable.

2. Clinical Specificity:
Not applicable.

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

D Clinical Cut-Off:
Not applicable.

E Expected Values/Reference Range:
The Cepheid Xpert C. difficile/Epi Control Panel does not have assigned values and the panel members are reported as positive or negative for each of the target analytes, as appropriate. Performance was evaluated through testing at three sites using three different GeneXpert Dx Instruments and three lots of controls (refer to Section VII A(1)).

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

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

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