The Sensititre HP MIC Susceptibility plate with Oritavancin (0.0005-8mcg/ml)

K143526 · Thermo Fisher Scientific · JWY · Mar 5, 2015 · Microbiology

Device Facts

• Record ID: K143526
• Device Name: The Sensititre HP MIC Susceptibility plate with Oritavancin (0.0005-8mcg/ml)
• Applicant: Thermo Fisher Scientific
• Product Code: JWY · Microbiology
• Decision Date: Mar 5, 2015
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.1640
• Device Class: Class 2

Indications for Use

The Sensititre Haemophilus influenzae/Streptococcus pneumoniae (HP) MIC Susceptibility plate is an in vitro diagnostic product for clinical susceptibility testing of Haemophilus influenzae, Streptococcus pneumoniae and Streptococcus species.

Device Story

Sensititre HP MIC Susceptibility plate is an in vitro diagnostic device used in clinical laboratories for antimicrobial susceptibility testing. It utilizes microbroth dilution to determine the Minimum Inhibitory Concentration (MIC) of Oritavancin against fastidious Streptococcus species. The device consists of plates containing specific concentrations of the antimicrobial agent. Laboratory technicians inoculate the plates with patient isolates; after incubation, growth is observed to determine the MIC. The resulting MIC value assists clinicians in selecting appropriate antibiotic therapy for patients with bacterial infections. The device provides standardized, quantitative susceptibility data to guide clinical decision-making and improve patient outcomes.

Clinical Evidence

Clinical study conducted at three sites using 411 clinical and 65 challenge Streptococcus spp. isolates. Performance evaluated against CLSI broth microdilution reference method. Combined Essential Agreement (EA) was 94.7% (automated) and 94.3% (manual). Category Agreement (CA) was 95.4% (automated) and 95.6% (manual). A downward MIC trend was observed; labeling includes limitations for isolates yielding 0.25 µg/mL MIC due to potential for very major errors (false susceptible).

Technological Characteristics

Multi-well plastic microtiter plate; contains doubling dilutions of antimicrobial agents and fluorogenic substrate. Sensing principle: fluorescence detection of bacterial surface enzyme activity. Energy source: electrical (for automated readers). Connectivity: standalone or networked (ARIS/OptiRead). Software: automated interpretation of fluorescence intensity. Sterilization: not specified.

Indications for Use

Indicated for clinical susceptibility testing of fastidious isolates, specifically Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus anginosus group (S. anginosus, S. intermedius, and S. constellatus).

Regulatory Classification

Identification

An antimicrobial susceptibility test powder is a device that consists of an antimicrobial drug powder packaged in vials in specified amounts and intended for use in clinical laboratories for determining in vitro susceptibility of bacterial pathogens to these therapeutic agents. Test results are used to determine the antimicrobial agent of choice in the treatment of bacterial diseases.

Submission Summary (Full Text)

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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE

A. 510(k) Number:
K143526

B. Purpose for Submission:
Addition of Oritavancin to the Sensititre HP MIC susceptibility plate for testing *Streptococcus* species

C. Measurand:
Oritavancin in the dilution range of 0.0005-8 µg/mL

D. Type of Test:
Quantitative Antimicrobial Susceptibility Test (AST), growth based fluorescence.

E. Applicant:
ThermoFisher Scientific

F. Proprietary and Established Names:
Sensititre Haemophilus influenza/Streptococcus pneumoniae MIC Susceptibility Plate

G. Regulatory Information:
1. Regulation section:
21 CFR 866.1640 Antimicrobial Susceptibility Test Powder
2. Classification:
Class II
3. Product code(s):
JWY - Manual Antimicrobial Susceptibility Test Systems
LRG - Instrument for Auto Reader & Interpretation of overnight susceptible systems

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LTT – Panels, Test, Susceptibility, Antimicrobial

4. Panel:
83 - Microbiology

H. Intended Use:

1. Intended use(s):
The Sensititre Haemophilus influenza/Streptococcus pneumoniae plates are in vitro diagnostic products for clinical susceptibility testing of Haemophilus influenzae, Streptococcus pneumoniae and Streptococcus species.

2. Indication(s) for use:
The Sensititre HP MIC Susceptibility plate is an in vitro diagnostic product for clinical susceptibility testing of fastidious isolates.

This 510 (k) is for the newly approved Oritavancin in the dilution range of 0.0005-8μg/mL to the Sensititre HP MIC Susceptibility plate for testing Streptococcus spp.

The approved primary “Indications for Use” and clinical significance for Streptococcus spp. is for the following species:

Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus)

3. Special conditions for use statement(s):
Prescription use only

The ability of the Sensititre system to detect resistance or non-susceptibility to antimicrobics as shown below is unknown because an insufficient number of resistant or non-susceptible strains were available at the time of comparative testing. If such a strain is observed, it should be submitted to a reference laboratory

4. Special instrument requirements:
The Sensititre Autoinoculator/AIM
The Sensititre Optiread System
The Sensititre Vizion

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# I. Device Description:

Each plate is dosed with antimicrobial agents at appropriate dilutions. Results can be read manually by visual reading of growth or automatically on an ARIS®/Autoreader®/ OptiRead® using fluorescence. The Sensititre Autoreader/OptiRead® system utilizes fluorescence technology. The technology involves the detection of bacterial growth by monitoring the activity of specific surface enzymes produced by the test organism. Growth is determined by generating a fluorescent product from a non-fluorescent (fluorogenic) substrate. The non-fluorescent substrate is prepared by conjugating a fluorescent compound to the specific enzyme substrates with a bond, which prevents fluorescence. The fluorophore is then said to be quenched. The plates are prepared with the substrate already added to the plate. Enzymatic action of the bacterial surface enzymes on the specific substrates cleaves this bond releasing the fluorophore, which is now capable of fluorescence. The amount of fluorescence detected is directly related to the activity of the bacterial surface enzymes and, therefore, to the bacterial growth.

# J. Substantial Equivalence Information:

1. Predicate device name(s):

MICroSTREP plus Panel

2. Predicate 510(k) number(s):

K021184

3. Comparison with predicate:

Table 1. Comparison with the Predicate Device

| Similarities | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Intended Use | The Sensititre Haemophilus influenzae/Streptococcus pneumoniae (HP) MIC Susceptibility plate is an in vitro diagnostic product for clinical susceptibility testing of Haemophilus influenzae: Streptococcus pneumoniae and Streptococcus species. | MICroSTREP plus panel is designed for use for in vitro for clinical susceptibility testing of Streptococcus including Streptococcus pneumoniae. |
| Test Panel | Each 96 well plate is precision dosed with selected antimicrobial agents and substrate for the fluorescent reads, then dried. The bacterial | Antimicrobial agents are precision dosed into 96 wells and combined with culture media in the panel then dried. The bacterial standardized suspension is |
| | stereotactic material. | stereotactic material is used in the test panel. |
| Tested | Each 96 well plate is precision dosed with selected antimicrobial agents and substrate for the fluorescent reads, then dried. The bacterial standardized suspension is | stereotactic material is used in the test panel. |

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| Similarities | | |
| --- | --- | --- |
| Item | Device | Predicate |
| | suspension in the appropriate broth is used to rehydrate the plate | used to rehydrate the panel. |
| Test Organisms | Streptococcus spp. | Same |
| Incubation | 20-24 hours | Same |
| Specimen | Isolated colonies from pure culture | Same |
| Incubation Temperature | 34-36°C | Same |
| Differences | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Product Name | Sensititre Haemophilus/Streptococcus pneumoniae (HP) MIC Susceptibility Plates | MICrosTREP plus panel k021184 |
| Instrumentation | Each plate is dosed with antimicrobial agents at appropriate dilutions and inoculated with standardized organism suspension. Results can be read automatically on ARIS®/Autoreader®/OptiRead® using fluorescence or manually on the Vizion or a manual viewer, by visual reading of growth. | The MICroSTREP plus panel is inoculated with a standardized organism suspension, incubated in a non-CO2 incubator, and visually read. |
| Antibiotic/Assay | Oritavancin | Clindamycin |
| Reading method | Fluorescence | Organism growth |

# K. Standard/Guidance Document Referenced (if applicable):

1. Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucmO71462.pdf
2. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, Approved Standard-9th Edition, Document M07-A9
3. Performance Standards for Antimicrobial Susceptibility Testing - $24^{\text{th}}$ Informational Supplement, M100-S24 (QC parameters only)

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L. Test Principle:

The Sensititre 20-24 hour Haemophilus influenzae/Streptococcus pneumoniae MIC
Susceptibility plates are multi-well plastic microtiter plates that contain doubling dilution of antibacterial agents. Each plate includes antimicrobial agents at appropriate dilutions. Results can be read manually by visual reading of growth or automatically on an AutoReader via fluorescence.

The Sensititre AutoReader /OptiRead System utilize fluorescence technology to read the micro-broth dilution plates after 20 to 24 hours incubation. The technology involves the detection of bacterial growth by monitoring the activity of specific surface enzymes produced by the test organism. Growth is determined by generating a fluorescent product from a non-fluorescent (fluorogenic) substrate. The non-fluorescent substrate is prepared by conjugating a fluorescent compound to the specific enzyme substrates with a bond which prevents fluorescence. The enzymatic action of the bacterial surface enzymes on the bound non-fluorescent substrate cleaves the bond releasing the fluorescence. The amount of fluorescence detected is directly related to the activity of bacterial growth. The MIC is determined by observing the lowest dilution of antimicrobial agent that inhibits growth of the organism. The non-fluorescent (fluorogenic) substrate can be added to the inoculum broth which is dispensed into the test plate at the same time as the test organism, or, the plates can be prepared with the substrate already added to each micro-well.

Streptococcus pneumoniae and Streptococcus spp. plates can either be read manually or automatically on the AutoReader /ARIS/OptiRead. Haemophilus influenzae can only be read on the Vizion or manual viewer.

M. Performance Characteristics (if/when applicable):

1. Analytical performance:

a. Precision/Reproducibility:

A reproducibility study was conducted at three study sites using 24 Streptococcus spp consisting of 1 S. anginosus, 1 S. dysgalactiae, 10 S. pyogenes, and 12 S. agalactiae. The Sensititre plates were inoculated by the Sensititre Autoinoculator/AIM. The organisms were tested one time at each of three sites for each reading method (Vizion for manual, OptiRead for automated read). The mode MIC value was determined and the reproducibility was calculated based on MICs falling within ± 1 dilution of the mode MIC value. The reproducibility was 97.2% for the manual (Vizion) and 95.8% for the automated (Optiread) reading methods. The testing resulted in overall reproducibility results of greater than 95% for both Manual and Automated read methods. The results were acceptable.

b. Linearity/assay reportable range:

Not applicable

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c. Traceability, Stability, Expected values (controls, calibrators, or methods):

The organism recommended by both the FDA (CDER) and the CLSI, S. pneumoniae ATCC 49619 was tested against Oritavancin. Quality control was performed at all sites using the Sensititre Autoinoculator/AIM for inoculation, read by the manual (i.e. Vizion) and the automated (i.e. OptiRead) read methods. Table 2 below represents the frequency of the results and all results were in acceptable range.

Table 2. Summary of Quality Control Results for Oritavancin for Fastidious Organisms

| ORGANISMS | Oritavancin (μg/mL) | Reference Manual Read | Sensititre- Read Method | |
| --- | --- | --- | --- | --- |
| | | | Optiread | Manual (Vizion) |
| S. pneumoniae ATCC 49619 | 0.0005 | 0 | 0 | 0 |
| 0.004-0.015 μg/mL | 0.001 | 25% (15/60) | 63.3% (38/60) | 65%(39/60) |
| | 0.002 | 65% (39/60) | 30%(18/60) | 30%(18/60) |
| | 0.004 | 10%(6/60) | 6.6%(4/60) | 5%(3/60) |
| | 0.008 | 0 | 0 | 0 |

Quality Control results for the Sensititre Susceptibility System using either reading methods demonstrated that the system could produce the expected quality control results. The quality control (QC) results with S. pneumoniae ATCC 49619 were within the expected range $>95\%$ of the time but a downward MIC trend of Sensititre Susceptibility System was observed compared to the reference method. For the manual read (the primary method used in the clinical study) almost $65\%$ of the QC reference MIC results are at $0.002\mu \mathrm{g / mL}$ , while $65\%$ of the Sensititre Susceptibility System manual read QC results are at $0.001\mu \mathrm{g / mL}$ . For the Automated reading method $63.3\%$ of the QC MIC results are at $0.001\mu \mathrm{g / mL}$ . This MIC trend was addressed by adding a footnote in the labeling.

The quality control results are acceptable.

d. Detection limit:

Not applicable

e. Analytical specificity:

Not applicable

f. Assay cut-off:

Not applicable

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2. Comparison studies:

a. Method comparison with predicate device:

Performance was established through a clinical study which was conducted at three sites. Studies have been conducted with the Sensititre dried susceptibility plates containing Oritavancin to test susceptibility Gram positive isolates (Sensititre *Streptococcus* spp. HP MIC plate). The CLSI microdilution reference methods with 0.002% Polysorbate 80 containing the same antimicrobial in the same dilutions were used for a comparison and evaluation of performance. Sensititre panels were prepared using an alternative method that was developed to provide comparable results to the reference method containing polysorbate-80.

The following footnote was added to the Performance Information insert of the device labeling:

“According to the FDA approved pharmaceutical antimicrobial agent package insert, polysorbate-80 should be used for testing freshly prepared or frozen microtiter trays with Oritavancin. Oritavancin on the Sensititre panel has been developed with an alternative method to provide equivalent performance to the reference method that contained polysorbate-80.”

All isolates were tested using the same 13 two-fold dilutions of Oritavancin in both the Sensititre and reference panels. Dilutions tested were appropriate for the interpretive breakpoints established for the drug.

The performance of Oritavancin with *Streptococcus* spp was performed using the Aim autoinoculator. The inoculum was prepared using the Sensititre Nephelometer which was calibrated at the start of each test. Plates were inoculated and incubated at 35° C. The reading was done automatically on the Optiread and manually using the Vizion at 20-24 hours.

The device labeling indicates that the *Haemophilus influenzae*/*Streptococcus pneumoniae* MIC panels can be manually inoculated. However, this procedural option was not utilized for testing either the clinical isolates or the challenge isolates.

Therefore, the sponsor was asked to include a limitation in the device package insert stating the following:

“The performance of Oritavancin with *Streptococcus* spp. was performed using the AIM autoinoculator. The use of an alternative inoculation system when testing Oritavancin has not been evaluated.”

For the manual read, clinical testing was performed on 411 *Streptococcus* spp (165 *Streptococcus pyogenes*, 165 *Streptococcus agalactiae* and 44 *Streptococcus anginosus* and 37 *Streptococcus dysgalactiae*).

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For the Auto Read, clinical testing was performed on 410 Streptococcus spp. (164 Streptococcus pyogenes, 165 Streptococcus agalactiae, 44 Streptococcus anginosus and 37 Streptococcus dysgalactiae). All were freshly collected clinical isolates; no stock isolates were tested during the clinical studies.

In addition, testing was performed on 65 Streptococcus spp. stock challenge isolates (25 Streptococcus pyogenes, 25 Streptococcus agalactiae, 10 Streptococcus anginosus and 5 Streptococcus dysgalactiae) for both automated and manual Read. The performance evaluations are shown in table 3-7 below.

Footnotes for Tables 3-6:
a There are no intermediate or resistant interpretive criteria for Oritavancin. The current absence of resistant isolates precludes defining any results other than "Susceptible."
b The number of potential major errors.
c These isolates would be considered potential very major errors (i.e. false susceptible)

Table 3. Overall Performance of Clinical and Challenge Isolates, Automated Read Method

| | Tot | No. EA | EA % | Eval Tot | No. Eval EA | Eval EA % | No. CA | CA % | No. NS | No. S | mina | majab | vmjc |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Clinical | 410 | 385 | 93.9 | 401 | 376 | 93.8 | 395 | 96.3 | 29 | 381 | N/A | 5 | 10 |
| Challenge | 65 | 65 | 100 | 65 | 65 | 100 | 58 | 89.2 | 5 | 60 | N/A | 4 | 3 |
| Combined | 475 | 450 | 94.7 | 466 | 441 | 94.6 | 453 | 95.4 | 34 | 441 | N/A | 9 | 13 |

Table 4. Trek Oritavancin Performance of Clinical and Challenge Isolates by Species, Automated Read (Optiread)

| | TOT | EA N | EA % | Eval Tot | Eval EA N | Eval EA % | CA N | CA % | No. NS | mina | majab | vmjc |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Streptococcus pyogenes | | | | | | | | | | | | |
| Clinical | 164 | 156 | 95.1 | 164 | 156 | 95.1 | 153 | 93.3 | 12 | N/A | 5 | 6 |
| Challenge | 25 | 25 | 100 | 25 | 25 | 100 | 22 | 88 | 2 | N/A | 1 | 2 |
| Combined | 189 | 181 | 95.8 | 189 | 181 | 95.8 | 175 | 92.6 | 14 | N/A | 6 | 8 |
| Streptococcus agalactiae | | | | | | | | | | | | |
| Clinical | 165 | 152 | 92.1 | 165 | 152 | 92.1 | 165 | 100 | 3 | N/A | 0 | 0 |
| Challenge | 25 | 25 | 100 | 25 | 25 | 100 | 23 | 92 | 1 | N/A | 1 | 1 |
| Combined | 190 | 177 | 93.2 | 190 | 177 | 93.2 | 188 | 98.9 | 4 | N/A | 1 | 1 |
| Streptococcus dysgalactiae | | | | | | | | | | | | |
| Clinical | 37 | 36 | 97.3 | 34 | 33 | 97.05 | 33 | 89.2 | 12 | N/A | 0 | 4 |
| Challenge | 5 | 5 | 100 | 5 | 5 | 100 | 4 | 80 | 2 | N/A | 1 | 0 |
| Combined | 42 | 41 | 97.6 | 39 | 38 | 97.4 | 37 | 88.1 | 14 | N/A | 1 | 4 |
| Streptococcus anginosus grp (S. anginosus, S. intermedius, and S. constellatus) | | | | | | | | | | | | |
| Clinical | 44 | 41 | 93.2 | 36 | 39 | 92.3 | 44 | 100 | 2 | N/A | 0 | 0 |
| Challenge | 10 | 10 | 100 | 10 | 10 | 100 | 9 | 90 | 0 | N/A | 1 | 0 |
| Combined | 54 | 51 | 94.4 | 46 | 49 | 93.9 | 53 | 98.1 | 2 | N/A | 1 | 0 |

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Table 5. Overall Performance of Clinical and Challenge Isolates, Manual Read Method

| | Tot | EA N | EA % | Eval EA Tot | Eval EA N | Eval EA % | CA N | CA % | No. NS | No. S | mina | majab | vmjc |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Clinical | 411 | 385 | 93.7 | 403 | 377 | 93.5 | 397 | 96.6 | 29 | 382 | N/A | 4 | 10 |
| Challenge | 65 | 64 | 98.5 | 65 | 64 | 98.5 | 58 | 89.2 | 5 | 60 | N/A | 4 | 3 |
| Combined | 476 | 449 | 94.3 | 468 | 441 | 94.2 | 455 | 95.6 | 34 | 442 | N/A | 8 | 13 |

Table 6. Trek Oritavancin Performance of Clinical and Challenge Isolates by Species, Manual Read (Vizion)

| | TOT | EA N | EA % | Eval Tot | Eval EA N | Eval EA % | CA N | CA % | No. NS | mina | majab | vmjc |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Streptococcus pyogenes | | | | | | | | | | | | |
| Clinical | 165 | 154 | 93.3 | 165 | 154 | 93.3 | 155 | 93.9 | 12 | N/A | 4 | 6 |
| Challenge | 25 | 24 | 96 | 25 | 24 | 96 | 22 | 88 | 2 | N/A | 1 | 2 |
| Combined | 190 | 178 | 93.7 | 190 | 178 | 93.7 | 177 | 93.2 | 14 | N/A | 5 | 8 |
| Streptococcus dysgalactiae | | | | | | | | | | | | |
| Clinical | 37 | 36 | 97.3 | 32 | 33 | 97.0 | 33 | 89.2 | 12 | N/A | 0 | 4 |
| Challenge | 5 | 5 | 100 | 5 | 5 | 100 | 4 | 80 | 2 | N/A | 1 | 0 |
| Combined | 42 | 41 | 97.6 | 37 | 38 | 97.4 | 37 | 88.1 | 14 | N/A | 1 | 4 |
| Streptococcus agalactiae | | | | | | | | | | | | |
| Clinical | 165 | 154 | 93.3 | 165 | 154 | 93.3 | 165 | 100 | 3 | N/A | 0 | 0 |
| Challenge | 25 | 25 | 100 | 25 | 25 | 100 | 23 | 92 | 1 | N/A | 1 | 1 |
| Combined | 190 | 179 | 94.2 | 190 | 179 | 94.2 | 188 | 98.9 | 4 | N/A | 1 | 1 |
| Streptococcus anginosus group (S. anginosus, S. intermedius, and S. constellatus) | | | | | | | | | | | | |
| Clinical | 44 | 41 | 93.2 | 37 | 40 | 92.5 | 44 | 100 | 2 | N/A | 0 | 0 |
| Challenge | 10 | 10 | 100 | 10 | 10 | 100 | 9 | 90 | 0 | N/A | 1 | 0 |
| Combined | 54 | 51 | 94.4 | 47 | 50 | 94 | 53 | 98.1 | 2 | N/A | 1 | 0 |

EA-Essential Agreement CA-Category Agreement NS-not susceptible

Essential agreement (EA) is when the Sensititre panels agree with the reference test panel results exactly or within one doubling dilution of the reference method. Category agreement (CA) is when the Sensititre panel result interpretation agrees exactly with the reference panel result interpretation. Evaluable EA is when the MIC result is on scale for both the Sensititre and the reference and have on-scale EA.

The EA% is acceptable when compared to the reference method as described in the FDA AST Special Controls Guidance.

EA and CA for all organisms were greater than $90\%$ as shown in Table 7 below. In accordance with the FDA AST Special Controls Guidance, the CA of S. dysgalactiae of $88.1\%$ was considered acceptable because of very good EA of the evaluable test results of $97.4\%$ .

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Table 7. Performance of Sensititre Panels Read on the Optiread and on the Vizion

| ORGANISMS | Number of isolates tested | % EA | % CA |
| --- | --- | --- | --- |
| Automated Read Method-Optiread | | | |
| S. agalactiae | 190 | 93.2 | 98.9 |
| S. pyogenes | 189 | 95.8 | 92.6 |
| S. dysgalactiae | 42 | 97.6 | 88.1 |
| S. anginosus | 54 | 94.4 | 98.1 |
| Manual Read Method-Vizion | | | |
| S. agalactiae | 190 | 94.2 | 98.9 |
| S. pyogenes | 190 | 93.7 | 93.2 |
| S. dysgalactiae | 42 | 97.6 | 88.1 |
| S. anginosus | 54 | 94.4 | 98.1 |

For manual reading method, the combined data from clinical and challenge study demonstrated that there were 21 categorical errors; 13 of which were S. pyogenes, two of which were S. agalactiae, five of which were S. dysgalactiae, and one was S. anginosus.

For the automated reading method, the combined data from clinical and challenge study demonstrated that there were 22 categorical errors; two of which were S. agalactiae, 14 were S. pyogenes, five were S. dysgalactiae, and one was S. anginosus.

Currently, there are no intermediate or resistance interpretative criteria for Oritavancin. The data was analyzed for major (maj) and very major (vmj) errors only, considering any false susceptible as vmj error and any false non-susceptible as maj error. An analysis was conducted to calculate the vmj error (i.e. false susceptible) as described in Table 8 below.

Table 8. Analysis of False Susceptible Results

| Organism | Total # of NS by reference method | # vmj (false susceptible) | % of false susceptible | # within EA |
| --- | --- | --- | --- | --- |
| Manual Read | | | | |
| S. agalactiae | 4 | 1 | 25 | 1 |
| S. pyogenes | 14 | 8 | 57.2 | 6 |
| S. dysgalactiae | 14 | 4 | 28.6 | 4 |
| S. anginosus | 2 | 0 | 0 | NA |
| Total | 34 | 13 | 38.2 | 11 |
| AutoRead | | | | |
| S. agalactiae | 4 | 1 | 25 | 1 |
| S. pyogenes | 14 | 8 | 57.2 | 7 |
| S. dysgalactiae | 14 | 4 | 28.6 | 4 |
| S. anginosus | 2 | 0 | 0 | NA |
| Total | 34 | 13 | 38.2 | 11 |

We observed that there is a high rate of false susceptible in S. agalactiae, S. pyogenes and S. dysgalactiae by both manual and automated reading methods. Using the data provided by the sponsor in the diagonal table format recommended in the AST Guidance, the majority of the vmj error (i.e. false susceptible) were observed when the Sensititre MIC is at $0.25\mu \mathrm{g / mL}$ and the reference method is at one double doubling dilution (MIC $0.5\mu \mathrm{g / mL}$ ). Due to the lack of an intermediate interpretation for this drug, there is a high potential for occurrence of very major error for S. agalactiae, S. pyogenes and S. dysgalactiae that could otherwise be considered minor

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errors if an intermediate category existed. Any Streptococcus isolates that yield MIC results 0.25 $\mu \mathrm{g} / \mathrm{mL}$ for Oritavancin should be submitted to a reference laboratory for additional testing.

The potential for occurrence of vmj error(s) for Oritavancin when testing Streptococcus spp was addressed by adding the following limitation in labeling:

"Due to the lack of an intermediate and resistant interpretations for Oritavancin, there is a potential very major error rate. There were 13 isolates out of 34 non susceptible isolates that reported one doubling dilution lower than the reference. Use an alternative testing method prior to reporting results for Streptococcus spp. with Oritavancin when the Sensititre MIC is $0.25\mu \mathrm{g} / \mathrm{mL}$ (breakpoint) if critical to patient care".

# MIC Trend Analysis:

Using the data provided by the sponsor in the diagonal table format recommended in the AST Guidance, an analysis was conducted to check for trending in MIC values.

A lower reading trend was observed in the overall performance of Streptococcus spp in both manual and automated reading methods compared to the CLSI broth micro-dilution method, which raises concerns for potential very major errors as summarized in Table 9 below.

Table 9. Trending of Results by Automated Read Method in Combined Clinical and Challenge Study

| Organism | Difference in MIC as Compared to the CLSI Reference Method | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | -3 | -2 | -1 | 0 | +1 | +2 |
| S. agalactiae | 0.52% (1/190) | 6.31% (12/190) | 64.21% (122/190) | 23.15% (44/190) | 5.78% (11/190) | 0 |
| S. pyogenes | 1% (2/189) | 2.1% (4/189) | 52.4% (99/189) | 25.4% (48/189) | 17.9% (34/189) | 1% (2/189) |
| S. anginosus | 3.7% (2/54) | 1.9% (1/54) | 57.4% (31/54) | 27.7% (15/54) | 9.3% (5/54) | NA |
| S. dysgalactiae | 0 | 2.4% (1/42) | 50% (21/42) | 33.3% (14/42) | 14.3% (6/42) | 0 |
| Total | 5 (1.2%) | 18 (4.2%) | 273 (63%) | 121 (27.9%) | 56 (12.9%) | 2 (0.5%) |

Table 10. Trending of Results by Manual Method in Combined Clinical and Challenge Study

| Organism | Difference in MIC as Compared to the CLSI Reference Method | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | -3 | -2 | -1 | 0 | +1 | +2 |
| S. agalactiae | 1 | 5.3 (10/190) | 63.15 (120/190) | 22.63 (43/190) | 8.42 (16/190) | 0 |
| S. pyogenes | 4 | 3.68 (7/190) | 54.21 (103/190) | 24.73 (47/190) | 14.73 (28/190) | 0.52 (1/190) |
| S. dysgalactiae | 0 | 2.4 (1/42) | 57.14 (24/42) | 30.95 (13/42) | 9.52 (4/42) | 0 |
| S. anginosus | 3.7 (2/54) | 1.85 (1/54) | 57.4 (31/54) | 31.48 (17/54) | 5.55 (3/54) | 0 |

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12

| Total | 7
(1.5%) | 19
(4.0%) | 278
(58.4%) | 120
(25.2%) | 51
(10.7%) | 1
(0.2%) |
| --- | --- | --- | --- | --- | --- | --- |

This trending and the potential for occurrence of very major errors(s) for Oritavancin when testing *Streptococcus spp* was also addressed in labeling. This was addressed by adding the following footnote in the interpretation table in labeling:

“Sensititre Oritavancin MIC values for fastidious gram positive organisms tended to be one doubling dilution lower in *Streptococcus spp* Manual and AutoRead compared to reference broth micro-dilution”.

“*Streptococcus spp* with an interpretation of non-susceptible for Oritavancin is uncommon in most institutions or may result from technical errors. Verify AST if this phenotype has not been previously encountered from this patient or institution”.

## Growth Rate:

In the Automated Read the no growth rate was 0.5% (2/410) *S. pyogenes* and *S. dysgalactiae*.

In the Manal Read the no growth rate was 0.2% (1/411) *S. dysgalactiae*.

The growth rate for the manual and automated reading methods was greater than 90%; this meets the acceptance criteria of ≤10% non-growth of organisms tested.

### b. Matrix comparison:

Not Applicable

### 3. Clinical studies:

#### a. Clinical Sensitivity:

Not Applicable

#### b. Clinical specificity:

Not Applicable

#### c. Other clinical supportive data (when a. and b. are not applicable):

Not applicable

### 4. Clinical cut-off:

Not applicable

{12}

# 5. Expected values/Reference range:

The FDA interpretative criteria were used to evaluate all performance data:

Table 11. FDA Interpretive Criteria for Oritavancin

| Organism | Interpretive Criteria (Oritavancin MIC in μg/mL) | | |
| --- | --- | --- | --- |
| | S | I | R |
| Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus anginosus Streptococcus dysgalactiae | ≤0.25 | - | - |

# N. Proposed Labeling:

The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.

# O. Conclusion:

The submitted information in this premarket notification is complete and supports a substantial equivalence decision