K Number
K181156
Manufacturer
Date Cleared
2018-07-27

(87 days)

Product Code
Regulation Number
866.3740
Reference & Predicate Devices
Predicate For
N/A
AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdpartyExpeditedreview
Intended Use

The Panther Fusion GBS assay is an automated qualitative in vitro diagnostic test utilizing real-time PCR for detection of Group B Streptococcus DNA from either Lim or Carrot enrichment broth cultures of vaginal/rectal swabs from antepartum women following 18-24 hours incubation.

This test is performed on the Hologic Panther Fusion system and is intended to aid in determining the GBS colonization status of antepartum women. This assay does not diagnose or monitor treatment for GBS infections. The Panther Fusion GBS assay does not provide susceptibility results. Culture isolates are needed for performing susceptibility testing as recommended for penicillin-allergic women.

Device Description

The Panther Fusion GBS assay involves the following steps: Sample lysis, nucleic acid capture and elution, and multiplex RT-PCR where analytes (when present) are simultaneously amplified, detected and differentiated. Nucleic acid capture and elution takes place in a single tube on the Panther Fusion system. The eluate is transferred to the Panther Fusion system reaction tube containing the assay reagents. RT-PCR is then performed for the eluted nucleic acid on the Panther Fusion system.

Sample Collection and Enrichment: After collecting and transporting a swab sample to the laboratory, the swab is placed in Lim Broth or Carrot Broth for 18 to 24 hours of enrichment. Prior to testing on the Panther Fusion system, enriched specimens are then transferred to a tube containing specimen transport media (STM) that lyses the cells, releases target nucleic acid and protects them from degradation during storage.

Nucleic Acid Capture and Elution: Specimens are then first incubated in an alkaline reagent (FER-X) to enable cell lysis. The Internal Control (IC-X) is added to each test specimen and controls via the working Panther Fusion capture Reagent-X (wFCR-X). The IC-X monitors specimen processing, amplification and detection. Magnetic particles with covalently bound oligonucleotides, contained in Panther Fusion capture Reagent-X (FCR-X), mediate the nucleic acid capture by hybridizing to total nucleic acid in the test specimen. The capture nucleic acids are then separated from residual specimen matrix in a magnetic field by a series of wash steps with a mild detergent. The captured nucleic acid is then eluted from the magnetic particles with a reagent of low ionic strength (Panther Fusion Elution Buffer).

Elution transfer and PCR: During the elution transfer step, eluted nucleic acid is transferred to a Panther Fusion Reaction tube already containing oil and reconstituted mastermix. PCRbased target amplification subsequently occurs with target-specific forward and reverse primers, generating a fluorescence signal. The Panther Fusion GBS Software computes a cycle threshold result (Ct) to qualitatively determine the presence of the analyte targets and corresponding fluorescent channels used in the Panther Fusion GBS Assay are summarized in the Table 1 below.

AI/ML Overview

The document describes the Panther Fusion GBS Assay, an automated qualitative in vitro diagnostic test for the detection of Group B Streptococcus DNA. The acceptance criteria and the study proving the device meets these criteria are outlined in sections G, H, and I of the 510(k) summary.

Here's a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally implied by the performance metrics aimed for during the studies. While explicit "acceptance criteria" are not listed in a dedicated table, the studies aim to demonstrate high sensitivity and specificity as is standard for such diagnostic tests.

Performance MetricAcceptance Criteria (Implied/Standard for Dx tests)Reported Device Performance (Combined Lim & Carrot Broth)
Clinical SensitivityHigh (e.g., >95%)100% (95% CI: 98.1% - 100%)
Clinical SpecificityHigh (e.g., >95%)96.5% (95% CI: 94.9% - 97.6%)
Positive Predictive ValueAdequate for clinical use88.7% (95% CI: 83.9% - 92.1%)
Negative Predictive ValueHigh (e.g., >98%)100% (95% CI: 99.5% - 100%)
Analytical Sensitivity (LoD)Low CFU/mLRanges from 84.0 CFU/mL (Serotype IV) to 301.0 CFU/mL (Serotype IX)
Analytical Specificity (Interference)No impact on performanceAll tested substances and microorganisms found to have no impact.
Carryover/Cross-Contamination0% false positives (ideal)0.0%
Assay Precision (Agreement with Expected Results)High (e.g., >95%)100% for negative and moderate positive, ≥98.9% for low-positive panel members.

2. Sample Size Used for the Test Set and Data Provenance

  • Test Set Sample Size: A total of 947 clinical leftover samples.
  • Data Provenance: The study was conducted from January 2018 to March 2018 at three geographically distinct sites in the United States. The data was obtained from prospective collection of leftover enriched culture samples (Lim broth and Carrot broth) from vaginal/rectal specimens from antepartum women during routine GBS screening. This is considered prospective for the purpose of the study as the samples were collected and then tested by the investigational device and reference method.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

The document does not explicitly state the number of experts or their specific qualifications (e.g., "radiologist with 10 years of experience") used to establish the ground truth. However, the ground truth was established by the reference culture method following CDC recommendations. This implies that the laboratory personnel performing and interpreting these cultures are qualified, but specific details are not provided in this summary.

4. Adjudication Method for the Test Set

The document states that results obtained using the Panther Fusion GBS Assay were compared to those obtained with the reference method. It doesn't describe a specific adjudication method (e.g., 2+1, 3+1) if there were discrepancies between the investigational device and the reference method. For the 16 false positives in Lim Broth, it notes that 14 (87.5%) were positive on the Becton Dickinson BD MAX GBS Assay, suggesting some form of secondary verification for discordant results, but not a formal adjudication process involving multiple human readers as might be found in an imaging study.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, an MRMC comparative effectiveness study was not done. This type of study is typically performed for diagnostic imaging devices where human interpretation is a key component, comparing human reader performance with and without AI assistance. The Panther Fusion GBS Assay is an in vitro diagnostic (IVD) device, where the result is determined by the instrument/assay, not by human interpretation of complex images.

6. Standalone (Algorithm Only) Performance

Yes, this study essentially represents standalone performance of the Panther Fusion GBS Assay. The device is an automated qualitative in vitro diagnostic test. Its performance (sensitivity, specificity) is measured directly against the reference standard without human 'in-the-loop' assistance from the device output for diagnosis. The output (positive/negative) is the direct result of the algorithm.

7. Type of Ground Truth Used

The ground truth used was the reference culture method following CDC recommendations. This is a laboratory-based, established gold standard for GBS colonization status.

8. Sample Size for the Training Set

The document does not provide information on the sample size for the training set. This 510(k) summary focuses on the validation of the finished device (the "test set" in the context of typical AI/ML development), not the development or training process of the assay components. For molecular diagnostic assays, while there's an underlying 'algorithm' (primer design, probe chemistry, cutoff values), it's not typically an AI/ML algorithm that learns from a dataset in the way a deep learning model would. Therefore, a distinct "training set" in the AI/ML sense is not described.

9. How the Ground Truth for the Training Set Was Established

Since information about a dedicated "training set" in the AI/ML sense is not provided, the method for establishing its ground truth is also not described. For an IVD assay like this, the "training" involved designing and optimizing the molecular components (primers, probes) and establishing the cut-off values for detection based on analytical studies and perhaps smaller internal development studies. The ground truth for such optimization would similarly rely on controlled lab experiments and reference methods, but is not detailed here.

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July 27, 2018

Diagenode % Jinjie Hu Principle Consultant Axteria BioMed Consulting Inc. 8040 Cobble Creek Circle Potomac, Maryland 20854

Re: K181156

Trade/Device Name: Panther Fusion GBS Assay Regulation Number: 21 CFR 866.3740 Regulation Name: Streptococcus spp. serological reagents Regulatory Class: Class I Product Code: NJR, OOI Dated: May 1, 2018 Received: May 1, 2018

Dear Jinjie Hu:

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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

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

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requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.htm); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 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 comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Noel J. Gerald -S
For

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

Enclosure

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Indications for Use

510(k) Number (if known) K181156

Device Name Panther Fusion GBS Assay

Indications for Use (Describe)

The Panther Fusion GBS assay is an automated qualitative in vitro diagnostic test utilizing real-time PCR for detection of Group B Streptococcus DNA from either Lim or Carrot enrichment broth cultures of vaginal/rectal swabs from antepartum women following 18-24 hours incubation.

This test is performed on the Hologic Panther Fusion system and is intended to aid in determining the GBS colonization status of antepartum women. This assay does not diagnose or monitor treatment for GBS infections. The Panther Fusion GBS assay does not provide susceptibility results. Culture isolates are needed for performing susceptibility testing as recommended for penicillin-allergic women.

X Prescription Use (Part 21 CFR 801 Subpart D)

Over-The-Counter Use (21 CFR 801 Subpart C)

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510(K) SUMMARY

A. GENERAL INFORMATION

SUBMITTER

Diagenode SARue du Bois Saint-Jean, 34102 SeraingBelgium
Contact person:Jinjie Hu,Axteria BioMed Consulting Inc.8040 Cobble Creek CirclePotomac, MD 20854Tel: 1-(301)814-4985Email: jinjiehu@axteriabiomed.com
Date prepared:July 9, 2018
Purpose of Submission:To obtain a substantial equivalence for the PantheFusion GBS Assay

B. MEASURAND

SIP and Cfb genes of Streptococcus agalactiae (Group B Streptococcus, GBS)

C. DEVICE INFORMATION

Proprietary Name of the device:Panther Fusion GBS Assay
Classification name:Streptococcus spp. serological reagents and Real-time Nucleic Acid Amplification
Regulation number:21 CFR 866.3740 and 862.2570
Classification Name and Reference:Class 1 (Not exempt)
Device product CodeNJR and OOI
Panel:83, Microbiology

D. INTENDED USE/INDICATIONS FOR USE

The Panther Fusion GBS assay is an automated qualitative in vitro diagnostic test utilizing realtime PCR for detection of Group B Streptococcus DNA from either Lim or Carrot enrichment broth cultures of vaginal/rectal swabs from antepartum women following 18-24 hours incubation.

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This test is performed on the Hologic Panther Fusion system and is intended to aid in determining the GBS colonization status of antepartum women. This assay does not diagnose or monitor treatment for GBS infections. The Panther Fusion GBS assay does not provide susceptibility results. Culture isolates are needed for performing susceptibility testing as recommended for penicillin-allergic women.

E. DEVICE DESCRIPTION

The Panther Fusion GBS assay involves the following steps: Sample lysis, nucleic acid capture and elution, and multiplex RT-PCR where analytes (when present) are simultaneously amplified, detected and differentiated. Nucleic acid capture and elution takes place in a single tube on the Panther Fusion system. The eluate is transferred to the Panther Fusion system reaction tube containing the assay reagents. RT-PCR is then performed for the eluted nucleic acid on the Panther Fusion system.

Sample Collection and Enrichment: After collecting and transporting a swab sample to the laboratory, the swab is placed in Lim Broth or Carrot Broth for 18 to 24 hours of enrichment. Prior to testing on the Panther Fusion system, enriched specimens are then transferred to a tube containing specimen transport media (STM) that lyses the cells, releases target nucleic acid and protects them from degradation during storage.

Nucleic Acid Capture and Elution: Specimens are then first incubated in an alkaline reagent (FER-X) to enable cell lysis. The Internal Control (IC-X) is added to each test specimen and controls via the working Panther Fusion capture Reagent-X (wFCR-X). The IC-X monitors specimen processing, amplification and detection. Magnetic particles with covalently bound oligonucleotides, contained in Panther Fusion capture Reagent-X (FCR-X), mediate the nucleic acid capture by hybridizing to total nucleic acid in the test specimen. The capture nucleic acids are then separated from residual specimen matrix in a magnetic field by a series of wash steps with a mild detergent. The captured nucleic acid is then eluted from the magnetic particles with a reagent of low ionic strength (Panther Fusion Elution Buffer).

Elution transfer and PCR: During the elution transfer step, eluted nucleic acid is transferred to a Panther Fusion Reaction tube already containing oil and reconstituted mastermix. PCRbased target amplification subsequently occurs with target-specific forward and reverse primers, generating a fluorescence signal. The Panther Fusion GBS Software computes a cycle threshold result (Ct) to qualitatively determine the presence of the analyte targets and corresponding fluorescent channels used in the Panther Fusion GBS Assay are summarized in the Table 1 below.

AnalyteGene TargetedInstrument Channel
GBSSIP and CfbFAM
Internal ControlNot applicableRED677

Table 1: Analytes and Detection Channels

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Assay Components

The reagents required to perform the Panther Fusion GBS assay are packed together in the Panther Fusion GBS assay box. A description of the components that are required to perform the Panther Fusion GBS assay are detailed in Table 2.

BoxComponents
1Panther Fusion GBS Cartridges
2Panther Fusion Extraction Reagent-X
- Panther Fusion Capture Reagent-X
- Panther Fusion Enhancer Reagent-X
3Panther Fusion Internal Control-X
4Panther Fusion Elution Buffer
5Panther Fusion Reconstitution Buffer I
6Panther Fusion Oil
7Panther Fusion GBS Assay Controls
- Panther Fusion GBS Assay Positive Control
- Panther Fusion GBS Assay Negative Control

Table 2: Reagents Required to Perform the Panther Fusion GBS Assay

Instrumentation

The Panther Fusion GBS assay has been designated for and validated on the Panther Fusion system. The Panther Fusion system is an integrated hardware and software system that together with the Panther Fusion GBS assay automates all the steps necessary to perform the assay.

The Panther Fusion system integrates Hologic's commercialized Panther instrument system with an add-on sidecar, the Panther Fusion module, which extends the functionality of the Panther system by increasing the assay processing capabilities to include multiplex real-time RT-PCR. The Panther Fusion module includes instrument hardware and can be installed on existing Panther instruments or ordered with new Panther instruments.

The Panther Fusion system employs non-specific target capture (NSTC) for the purification of RNA and DNA from the sample, followed by nucleic acid amplification and real-time fluorescent detection. The process involves sample loading and preparation (i.e. nucleic acid extraction) on the Panther instrument using the same workflow and processing steps as for other commercialized Hologic Aptima Transcription Mediated Amplification (TMA) assays. The extracted nucleic acid for each sample is transferred to the Panther Fusion module where PCR amplification and detection occurs.

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SUBSTANTIAL EQUIVALENCE INFORMATION F.

Predicate device

Cepheid Xpert® GBS LB (K121539).

Comparison with Predicate

A comparison of the Panther Fusion GBS assay to the predicate is summarized in Table 3 (similarities) and Table 4 (differences).

Proposed Device:Panther Fusion GBS assayPredicate Device:Cepheid Xpert® GBS LB assay(K121539)
ClassificationClass ISame
Technology Principleof OperationFully automated Real Time nucleic acidamplification, detection and resultinterpretationSame
AnalyteGenomic DNASame
Organism DetectedGroup B StreptococcusSame
Patient PopulationAntepartum womenSame
Specimen TypesFrom 18-24 hour enriched-media culturesof vaginal/rectal swabSame
Intended UseThe Panther Fusion GBS assay is anautomated qualitative in vitro diagnostictest utilizing real-time PCR for detectionof Group B Streptococcus DNA fromeither Lim or Carrot enrichment brothcultures of vaginal/rectal swabs fromantepartum women following 18-24hours incubation.This test is performed on the HologicPanther Fusion system and is intended toaid in determining the GBS colonizationstatus of antepartum women. This assaydoes not diagnose or monitor treatmentfor GBS infections. The Panther FusionGBS assay does not providesusceptibility results.Culture isolates are needed forperforming susceptibility testing asrecommended for penicillin-allergicwomen.The Cepheid Xpert GBS LB Assay,performed on the GeneXpert®Instrument Systems, is a qualitative invitro diagnostic test designed to detectGroup B Streptococcus (GBS) DNAfrom enriched vaginal/rectal swabspecimens, using fully automated real-time polymerase chain reaction (PCR)with fluorogenic detection of theamplified DNA. Xpert GBS LB Assaytesting is indicated as an aid indetermining GBS colonization status inantepartum women.The Xpert GBS LB Assay is used forantepartum testing on enriched Lim brothcultures of vaginal/rectal swabs after 18-24 hours of incubation.The Xpert GBS LB assay does notprovide susceptibility results. Cultureisolates are needed for performingsusceptibility testing as recommendedfor penicillin allergic women.
UsersProfessional useSame
Proposed Device:Panther Fusion GBS assayPredicate Device:Cepheid Xpert® GBS LB assay(K121539)
PlatformPanther Fusion SystemGeneXpert® Dx System (Cepheid)GeneXpert® Infinity-48 System (Cepheid)GeneXpert ® Infinity-80 System (Cepheid)
Assay FormatExtraction: Hologic Non- SpecificTarget CaptureAmplification: Real-time PCRDetection: Fluorogenic target-specifichybridizationExtraction: Solid Phase CaptureAmplification: Real-time PCRDetection: Fluorogenic target-specifichybridization
DNA Target SequenceSIP and cfb genes3'untranslated region of the cfb gene
Specimen EnrichmentLim Broth and Carrot BrothLim Broth
Time to ObtainResults≤ 2.5 hours total after sample loadingon the Panther Fusion system≤ 55 minutes total after sample additionto the cartridge

Table 3 : Similarities between Panther Fusion GBS Assay and Predicate Device

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Table 4 : Differences between Panther Fusion GBS Assay and Predicate Device

G. PERFORMANCE CHARACTERISTICS DATA

The following performance data were provided to support the substantial equivalence determination.

Brief Description of Analytical (Non-Clinical) Studies

The following analytical studies (non-clinical) were conducted to support the clearance of the Panther Fusion GBS Assay on the Panther Fusion System.

Analytical Sensitivity and Limit of Detection (LoD) of GBS in Vaginal/Rectal Swab Specimens

The LoD of the Panther Fusion GBS assay was determined by testing serial dilutions of 11 GBS serotypes and one non-hemolytic (NH) isolate in Lim Broth clinical negative matrix. Thirty replicates were tested with each of the three reagent lots for a combined total of 90 replicates per dilution. Probit analysis was performed for each reagent lot with the reported 95% LoD based upon the worst estimate, as shown in Table 5. Serotype specific LoD predictions were verified by testing an additional 20 replicates with one reagent lot.

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GBS Serotype95% LoD in CFU/mL (95% CI)
Ia137.4 (103.7 – 209.7)
Ib140.5 (100.6 – 234.7)
Ic136.3 (99.2 – 220.5)
II179.0 (135.1 – 276.2)
III168.0 (125.2 – 261.5)
IV84.0 (63.0 – 130.4)
V122.3 (92.2 – 186.8)
VI282.0 (201.9 – 475.8)
VII250.8 (180.2 – 424.8)
VIII231.3 (167.3 – 380.9)
IX301.0 (202.0 – 567.7)
NH300.2 (212.0 – 523.0)

Table 5 : GBS Limit of Detection (LoD)

CFU= colony forming units, CI= confidence interval, NH= non-hemolytic

Interferences

Amniotic fluid, blood, urine, stool and other potentially interfering endogenous and exogenous substances that may be present in vaginal/rectal specimens were evaluated in the Panther Fusion GBS assay. Concentrations exceeding clinically relevant amounts of the potentially interfering substances were added to Lim Broth clinical negative matrix and tested un-spiked or spiked with GBS analyte at a 3X LoD concentration. The substances consisted of topical medications, lubricants, deodorants, laxatives and contraceptives as shown in Table 6.

All of the substances tested were found to have no impact on the performance of the Panther Fusion GBS assay, at the concentrations tested.

Table 6 : Potentially Interfering Substances

Substance NameIngredient(s)Concentration
Human Amniotic FluidN/A4% v/v
Human Whole Blood EDTAN/A4% v/v
Human Whole Blood Na CitrateN/A4% v/v
Human SerumN/A4% v/v
Human Urine SampleN/A4% v/v
Human Fecal SampleN/A4% v/v
Topical Hemorrhoid Ointment(Preparation H Cream)Mineral Oil, Petrolatum, PhenylephrineHCl3.4% w/v
Anti-Diarrheal Medication(Pepto Bismol)Bismuth subsalicylate4% v/v
Personal Lubricant(K-Y Jelly Personal Lubricant)Glycerine, Methylparaben,Propylparaben2.2% w/v
Substance NameIngredient(s)Concentration
Lubricating gel (Aquagel)N/A2.1% w/v
Vaginal Anti-itch Cream (OTC) (Vagisil)Benzocaine, Resorcinol3.9% w/v
Vaginal Anti-itch Cream (OTC)(Gyno-Daktarin)Miconazole nitrate3.8% w/v
Vaginal Antifungal Cream (OTC)(Monistat)Miconazole nitrate3.1% w/v
Vaginal Antifungal GelCandida albicans 27X HPUS, Candidaparapsilosis 27X HPUS, Pulsatilla 27XHPUS3.0% w/v
Anti-Diarrheal Caplet (Kaopectate)Bismuth subsalicylate1.1% w/v
Deodorant Powder (Vagisil)Zea Mays Starch, Magnesium Stearate,Sodium Bicarbonate, Aloe BarbadensisLeaf extract, Tocopheryl Acetate,Tricalcium Phosphate, Mineral Oil,1.1% w/v
Deodorant Suppositories(Norforms Suppositories)PEG-20, PEG-32, PEG-20 Stearate,Benzethonium Chloride,Methylparaben, Lactic Acid,Fragrance, Neutresse (Odor synthesis)2.1% w/v
Deodorant Spray(FDS)Isopropyl Myristate, Zea Mays Starch,Magnesium Stearate, Fragrance, ZincRicinoleate, Laureth-3, Benzyl alcohol,Mineral Oil (Paraffinum Liquidum,Huile Minérale), TetrahydroxypropylEthylenediamine, Sodium Bicarbonate,Citronellol, Linalool, PropyleneGlycol, Butylphenyl Methylpropional,Lanolin Alcohol, Anise Alcohol, OleylAlcohol, Benzyl Benzoate,Chamomilla Recutita, Flower extract,Tocopheryl Acetate, Aloe BarbadensisLeaf extract1.5% w/v
Body Powder (Gold Bond Powder)Menthol0.4% w/v
Body OilIsopropyl Myristate, sesame seed oil,PEG-40, Sorbitan Peroleate,Propylparaben, BHT, Fragrance4% v/v
Spermicidal FoamNonoxynol-92.1% w/v
Oral Laxative(Metamucil Fiber Supplement)Psyllium husk2.2% w/v
Grains de Vals (SennosideB)Sennocide B0.4% w/v
Oral Laxative(Phillips Milk of Magnesia)Magnesium hydroxide7.3% w/v
Stool SoftenerBisacodyl0.9% w/v
Astroglide Liquid personal lubricantGlycerin, Propylene Glycol,Polyquaternium 15, Methylparaben,Propylparaben2.7% w/v
Enema Solution(Fleet enema)Dinatriumhydrogenphosphat-Dodecahydrat /Natriumhydrogenphosphat-Dihydrat4% v/v

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Analytical Specificity and Microbial Interference

The analytical specificity of the Panther Fusion GBS assay was evaluated by testing a panel of 110 microorganisms (as listed in Table 7), consisting viral, bacterial, fungal, parasite, protozoan and yeast strains representing pathogens or flora commonly present in the vaginal/rectal tract or related to the GBS family. Bacteria and yeast were tested at 1 x106 CFU/mL, except where noted. Viruses, fungi, parasites and protozoan were tested at 1x 105 PFU/mL, except where noted. Organisms were tested both with and without GBS spiked at a concentration 3X the established LoD. All of the microorganisms tested were found to have no impact on the performance or analytical specificity of the Panther Fusion GBS assay.

PathogenConcentration*(CFU/mL orPFU/mL)PathogenConcentration*(CFU/mL orPFU/mL)
Bacillus cereus1x106Streptococcus anginosus1x106
Yersinia enterocolitica subsp.enterocolitica1x106Prevotella oralis1x106
Anaerococcus prevotii1x106Streptococcus canis1x106
Propionibacterium acnes1x106Lactobacillus delbrueckii subsp.lactis1x106
Clostridium difficile1x106Corynebacterium sp(genitalium)1x106
Fusobacterium nucleatum1x106Neisseria gonorrhoeae1x106
Bifidobacterium adolescentisReuter1x106Streptococcus pneumoniae (oralgroup)1x106
Candida albicans (NIH 3147)1x106Streptococcus mutans (oralgroup)1x106
Candida glabrata (CBS 138)1x106Corynebacterium urealyticum1x106
Candida tropicalis1x106Lactobacillus reuteri1x106
Cryptococcus neoformans1x105*Lactobacillus sp.1x106
Klebsiella pneumoniae1x106Lactobacillus casei1x106
Proteus mirabilis1x106Lactobacillus acidophilus1x106
Alcaligenes faecalis1x106Streptococcus gordonii (oralgroup)1x106
Enterobacter aerogenes1x106Bulkholderia cepacia1x106
Stenotrophomonas maltophilia1x106Aeromonas hydrophila1x106
Campylobacter jejuni1x106Moraxella atlantae1x106
Providencia stuartii1x106Prevotella bivia1x106
Micrococcus luteus1x106Pasteurella aerogenes1x106
Staphylococcus haemolyticus1x106Rhodococcus equi1x106
Enterococcus faecalis1x106Listeria monocytogenes1x106
Pseudomonas fluorescens1x106Lactobacillus gasseri1x106
Staphylococcus saprophyticus1x106Peptoniphilus asaccharolyticus1x106
Proteus vulgaris1x106Atopobium vaginae1x106
Toxoplasma gondii1x105*Bifidobacterium brevis1x106
Enterococcus faecium1x106Abiotropha defectiva1x106
Escherichia coli1x106Anaerococcus tetradius1x106

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PathogenConcentration*(CFU/mL orPFU/mL)PathogenConcentration*(CFU/mL orPFU/mL)
Enterobacter cloacae1x106Finegoldia magna1x106
Morganella morganii1x106Peptostreptococcus anaerobius1x106
Shigella flexneri1x106Anaerococcus lactolyticus1x106
Streptococcus pyogenes(group A)1x106Human herpesvirus 4 (EBV)1x105*
Streptococcus ratti1x106Bacteroides fragilis1x106
Staphylococcus lugdunensis1x106Bordetella pertussis1x106
Acinetobacter baumannii1x106Chlamydia trachomatis1x106
Staphylococcus aureus1x106Human herpesvirus 5 (CMV)1x105*
Staphylococcus epidermidis1x106Hafnia alvei1x106
Shigella sonnei1x106Trichomonas vaginalis1x105*
Citrobacter freundii1x106Human immuno-deficiencyvirus-1 (HIV-1)1x105*
Enterococcus gallinarum1x106Moraxella catarrhalis1x106
Acinetobacter lwoffii1x106Mycoplasma genitalium1x106
Pseudomonas aeruginosa1x106Prevotella melaninogenica1x106
Streptococcus criceti1x106Rubella Virus1x105*
Haemophilus influenzae1x106Serratia marcescens1x106
Klebsiella oxytoca1x106Streptococcus intermedius1x106
Streptococcus bovis (group D)1x106Human Papilloma Virus Type16 (HPV16)1x105*
Streptococcus parasanguinis1x106Hepatitis B Virus1x105*
Streptococcus equi subsp. equi(group D)1x106Hepatitis C Virus1x105*
Enterococcus durans1x106Herpes Simplex Virus-1 (HSV-1)1x105*
Lactobacillus plantarum1x106Herpes Simplex Virus-2 (HSV-2)1x105*
Streptococcus dysgalactiae1x106Human herpesvirus 3 (VZV)1x105*
Streptococcus constellatus1x106Arcanobacterium pyogenes1x106
Streptococcus oralis (oralgroup)1x106Mobiluncus curtisii subsp.curtisii1x106
Bacillus coagulans1x106Gardnerella vaginalis1x106
Streptococcus pseudoporcinus1x106Salmonella enterica subsp.enterica ser. dublin (group D)1x106
Streptococcus mitis(oral group)1x106Streptococcus acidominus1x106

*Microorganisms evaluated as extracted DNA were tested in Copies/mL

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Carryover/Cross-Contamination

The carryover/cross-contamination study was performed with Lim Broth clinical negative samples alternately placed between high positive samples and tested. High positive samples were prepared by spiking GBS at > 1x 106 CFU/mL (> 5,000X LoD). A total of ten separate runs with negative samples and positive samples placed in a checkerboard pattern were tested in addition to four runs of negative specimens over two different instruments a combined total of 300 positive and 420 negative samples. There were no false positive results observed for a carry-over rate of 0.0%.

Assay Precision

Panther Fusion GBS Assay precision was evaluated with a 7-member panel. The panel was tested by three operators on five separate runs per day, using three reagent lots on one Panther Fusion systems over 12 non-consecutive days. The panel members are described in Table 8 along with a summary of the agreement with expected results for each target.

Panel Member% Positive(Pos n/valid n)% Agreement(95% CI)
GBS III Low Positive (1-2X LoD)100% (180/180)100% (97.9-100)
GBS III Moderate Positive (3X LoD)100% (180/180)100% (97.9-100)
GBS V Low Positive (1-2X LoD)100% (180/180)100% (97.9-100)
GBS V Moderate Positive (3X LoD)100% (180/180)100% (97.9-100)
GBS NH Low Positive (1-2X LoD)100% (180/180)100% (97.9-100)
GBS NH Moderate Positive (3X LoD)100% (180/180)100% (97.9-100)
Negative0% (0/180)100% (97.9-100)

Table 8 : Percent Agreement to the Expected Result

CI= confidence interval, LoD= limit of detection, NH= non-hemolytic

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Table 9 presents the mean and variability analysis between reagent lots, between operators, between days, between runs and within runs, and overall (total) for Ct.

PanelMeanCtBetweenReagents LotsBetweenOperatorsBetween DaysBetween RunsWithin RunsTotal
MemberSDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)
GBS III1-2X LoD36.30.060.16%0.160.45%0.110.31%0.330.91%0.431.18%0.531.46%
GBS III3X LoD35.40.170.48%0.120.35%0.130.36%0.340.95%0.320.90%0.431.22%
GBS V1-2X LoD36.40.130.37%0.130.35%0.170.46%0.290.78%0.501.36%0.551.51%
GBS V3X LoD35.40.130.38%0.110.31%0.120.34%0.280.79%0.411.14%0.461.31%
GBS NH1-2X LoD35.70.230.65%0.120.35%0.140.39%0.310.86%0.381.06%0.461.28%
GBS NH3X LoD34.80.190.55%0.040.12%0.100.29%0.280.81%0.290.84%0.401.14%
Negative31.50.240.77%0.080.24%0.140.43%0.321.03%0.270.86%0.411.32%

Table 9 : Signal Variability

Ct= threshold cycle, CV= coefficient of variation, LoD= limit of detection, SD= standard deviation

Reproducibility

Panther Fusion GBS Assay reproducibility was evaluated at three US sites using a seven panel members. Testing was performed using one lot of assay reagents and six operators (two at each site). At each site, testing was performed two times per day during five non-consecutive days. Each run had three replicates of each panel member. A negative panel member was created using Lim Broth matrix. Positive panel members were created by spiking GBS at 1-2X LoD (low-positive) or 3X LoD (moderate-positive) concentrations of the target analyte into Lim Broth matrix. The agreement with expected results was 100% in the negative and moderate positive panel members and ≥98.9% in low-positive panel members for the three GBS strains evaluated (serotypes III, V and non-hemolytic isolate- NH), as shown in Table 10.

Table 10 : Agreement of Panther Fusion GBS Assay Results with Expected Results
PanelsExpectedResultAgreement with ExpectedResult
DescriptionCompositionConcentration(CFU/mL)GBSN% (95% CI)
GBS III Low Positive1-2X LoD262+90/90100% (95.9-100%)
GBS III Moderate Positive3X LoD504+90/90100% (95.9-100%)
GBS V Low Positive1-2X LoD188+89/9098.9% (94.0-99.8%)
GBS V Moderate Positive3X LoD367+90/90100% (95.9-100%)
GBS NH Low Positive1-2X LoD523+90/90100% (95.9-100%)
GBS NH ModeratePositive3X LoD900+90/90100% (95.9-100%)
Nec.NegativeN/A-90/90100% (95.9-100%)

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The total GBS signal variability measured as %CV ranged from 1.51% to 2.25% in low and moderate positive panel members. Across the sources of variation, excluding within run, %CV values were ≤ 1.33%, as shown in Table 11.

PanelDescriptionMeanBetweenSitesBetweenOperatorsBetweenDaysBetweenRunsWithinRunsTotal
NCtSDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)
GBS III Low Pos9037.10.491.33%0.471.26%0.180.48%0.140.37%0.551.47%0.772.09%
GBS III Mod Pos9036.20.451.24%0.411.12%0.150.41%0.050.14%0.421.15%0.661.81%
GBS V Low Pos9037.30.441.17%0.411.09%0.090.23%0.110.31%0.681.82%0.842.25%
GBS V Mod Pos9036.30.310.84%0.310.85%0.260.72%0.080.23%0.481.33%0.611.69%
GBS NH Low Pos9036.20.270.75%0.270.74%0.140.40%0.100.28%0.501.37%0.581.61%
GBS NH Mod Pos9035.40.200.57%0.200.55%0.160.45%0.030.08%0.461.31%0.531.51%
Negative (IC)9031.90.321.00%0.300.95%0.060.20%0.160.50%0.260.83%0.561.77%

Table 11 : Signal Variability of the Panther Fusion GBS Assay by Panel Member

The signal variability as measured as % CV was ≤1.35% between sites/operators, between days/runs, or overall for the Panther Fusion GBS assay positive control and negative control, as shown in Table 12.

Table 12 : Signal Variability of the Panther Fusion GBS Assay Controls

ControlNMean CtBetweenSites/OperatorsBetweenDays/ RunsTotal
SDCV (%)SDCV (%)SDCV (%)
Positive1531.90.170.53%0.100.32%0.220.70%
Negative1528.30.200.72%0.270.94%0.381.35%

Ct= threshold cycle, CV= coefficient of variation, SD= standard deviation

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H. COMPARISON STUDIES

Method Comparison

Not applicable.

Matrix Comparison

GBS strains (serotypes III and V and non-hemolytic) were serially diluted in each negative clinical matrix (Lim Broth and Carrot Broth) to their respective concentrations at ½2x, 2x, or 5x LoD. 30 replicates per strain per concentration and per broth were processed along with at least 5 replicates of negative clinical matrix for each type of broth. All positives and negative specimen were correctly identified by the Panther Fusion GBS Assay.

According to the acceptance criteria, the equivalence between Lim Broth and Carrot Broth was demonstrated at 2x and 5x LoD concentrations for the 3 tested GBS strains. Equivalence below the LoD level is not demonstrated for these enrichment broths. This concentration has been chosen as a most challenging scenario and is not clinically relevant considering that the Panther Fusion GBS Assay is intended to aid for GBS diagnosis after 24 hours enrichment. The concentration of GBS target in either broth is not expected to be below the LoD after enrichment.

I. CLINICAL STUDY

Prospective Clinical Study

This prospective study was performed at three sites using leftover enriched culture samples in Lim broth and Carrot broth from vaginal/rectal specimens collected from antepartum women during routine GBS screening. The leftover culture samples were selected according to the inclusion and exclusion criteria, patient information was de-identified and each specimen was given a unique ID number. All samples were tested with both the Panther Fusion GBS Assay and the reference culture method following CDC recommendations. Results obtained using the Panther Fusion GBS Assay were compared to those obtained with the reference method to calculate the clinical sensitivity and specificity of the Panther Fusion GBS Assay.

This study was performed from January 2018 to March 2018 at clinical evaluation at three geographically distinct sites in the United States in compliance with Good Clinical Practices (GCP). Among the three sites, two sites enrolled specimen enriched in Lim Broth and one site enrolled leftover specimen enriched in Carrot Broth. A total of 947 clinical leftover samples, meeting the inclusion criteria, were enrolled in the study with an average GBS prevalence of 24% (229 positive) in culture.

Results showed a clinical sensitivity of 100% in both matrices and a clinical specificity of 96.9% and 95.5% in Lim Broth and Carrot Broth respectively. Overall performance of the Panther Fusion Assay demonstrated a clinical sensitivity of 100% and a clinical specificity of 96.5%. Study results are summarized in Table 13, Table 14 and Table 15.

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Table 13 : Lim Broth Specimens

Reference Method
Lim BrothPositiveNegativeTotal
Panther Fusion GBS AssayPositive12016*136
Negative0507507
Total120523643
Sensitivity120/120 = 100% (95% CI: 96.9% - 100%)
Specificity507/523 = 96.9% (95% CI: 95.1% - 98.1%)
Positive Predictive Value120/136 = 88.2% (95% CI: 81.7% - 92.6%)
Negative Predictive Value507/507 = 100% (95% CI: 99.3% - 100%)
  • Of 16 False Positives, 14 (87.5%) were positive on the Becton Dickinson BD MAX GBS Assay

Table 14 : Carrot Broth Specimens

Carrot Broth: CarolinasReference Method
PositiveNegativeTotal
Panther Fusion GBSAssayPositive8310*93
Negative0211211
Total83221304
Sensitivity83/83 = 100% (95% CI: 95.6% - 100%)
Specificity211/221 = 95.5% (95% CI: 91.9% - 97.5%)
Positive Predictive Value83/93 = 89.3% (95% CI: 81.3% - 94.1%)
Negative Predictive Value211/211 = 100% (95% CI: 98.2% - 100%)

Table 15 : Combined Lim Broth and Carrot Broth Specimens

Lim & Carrot Broth CombinedReference Method
PositiveNegativeTotal
Panther Fusion GBS AssayPositive20326229
Negative0718718
Total203744947
Sensitivity203/203 = 100% (95% CI: 98.1% - 100%)
Specificity718/744 = 96.5% (95% CI: 94.9% - 97.6%)
Positive Predictive Value203/229 = 88.7% (95% CI: 83.9% -92.1%)
Negative Predictive Value718/718 = 100% (95% CI: 99.5% - 100%)

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Expected Values/Reference Range

The performance of the Panther Fusion GBS assay was evaluated in a prospective Clinical Study on clinical vaginal specimen from antepartum women conducted at three sites in the U.S. Overall, the prevalence of GBS colonization as determined by the Panther Fusion GBS Assay was 24.2% (229/947) whereas by conventional culture it was 21.4% (203/947) as shown in Table 16.

Culture MediumClinical SiteNPanther Fusion GBS AssayConventional Culture
N Positive% PrevalenceN Positive% Prevalence
Lim Broth13006521.7%6020.0%
Lim Broth23437120.7%6017.5%
Overall64313621.2%12018.7%
Carrot Broth33049330.6%8327.3%
CombinedOverall94722924.2%20321.4%

Table 16 : Panther Fusion GBS Assay and Culture Prevalence

J. CONCLUSIONS

The analytical and the clinical study results demonstrate that the Panther Fusion GBS assay on the Panther Fusion system performs comparably to the predicate device that is currently marketed for the same intended use. Hardware and software verification and validation demonstrate that the Panther Fusion GBS Assay on the Panther Fusion system will perform as intended. The submitted information in this premarket notification support a substantial equivalence decision.

§ 866.3740

Streptococcus spp. serological reagents.(a)
Identification. Streptococcus spp. serological reagents are devices that consist of antigens and antisera (excluding streptococcal exoenzyme reagents made from enzymes secreted by streptococci) used in serological tests to identifyStreptococcus spp. from cultured isolates derived from clinical specimens. The identification aids in the diagnosis of diseases caused by bacteria belonging to the genusStreptococcus and provides epidemiological information on these diseases. Pathogenic streptococci are associated with infections, such as sore throat, impetigo (an infection characterized by small pustules on the skin), urinary tract infections, rheumatic fever, and kidney disease.(b)
Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.