(111 days)
The BD MAX™ Enteric Bacterial Panel performed on the BD MAX™ System is an automated in vitro diagnostic test for the direct qualitative detection and differentiation of enteric bacterial pathogens. The BD MAX Enteric Bacterial Panel detects nucleic acids from:
- Salmonella spp. .
- Campylobacter spp. (jejuni and coli) .
- Shigella spp. / Enteroinvasive E. coli (EIEC) .
- Shiga toxin 1 (stx1) / Shiga toxin 2 (stx2) genes (found in Shiga toxin-producing . E. coli [STEC]) as well as Shigella dysenteriae, which can possess a Shiga toxin gene (stx) that is identical to the stx1 gene of STEC.
Testing is performed on unoreserved soft to diarrheal stool specimens or Cary-Blair preserved stool specimens from symptomatic patients with suspected acute gastroenteritis, enteritis or colitis. The test is performed directly on the specimen, utilizing real-time polymerase chain reaction (PCR) for the amplification of SpaO, a Campylobacter specific tuf gene sequence, ipaH and stx1/stx2. The test utilizes fluorogenic sequence-specific hybridization probes for detection of the amplified DNA.
This test is intended for use, in conjunction with clinical presentation, laboratory findings, and epidemiological information, as an aid in the differential diagnosis of Salmonella, Shigella/EIEC, Campylobacter and Shiga toxin-producing E. coli (STEC) infections. Results of this test should not be used as the sole basis for diagnosis, treatment, or other patient management decisions. Positive results do not rule out co-infection with other organisms that are not detected by this test, and may not be the sole or definitive cause of patient illness. Negative results in the setting of clinical illness compatible with gastroenteritis may be due to infection by pathogens that are not detected by this test or non-infectious causes such as ulcerative colitis, irritable bowel syndrome, or Crohn's disease.
The BD MAX™ System and the BD MAX™ Enteric Bacterial Panel are comprised of an instrument with associated hardware and accessories, disposable microfluidic cartridges. master mixes, unitized reagent strips, extraction reagents, and sample buffer tubes. The instrument automates sample preparation including target lysis, DNA extraction and concentration, reagent rehydration, and target nucleic acid amplification and detection using real-time PCR. The assay includes a Sample Processing Control (SPC) that is present in the Extraction Tube. The SPC monitors DNA extraction steps, thermal cycling steps, reagent integrity and the presence of inhibitory substances. The BD MAX™ System software automatically interprets test result may be called as POS. NEG or UNR for each of the assay's targets, based on the amplification status of the target and of the Sample Processing Control. IND (Indeterminate) or INC (Incomplete) results are due to BD MAX™ System failure.
Here's a breakdown of the acceptance criteria and study details for the BD MAX™ Enteric Bacterial Panel, based on the provided document:
Acceptance Criteria and Device Performance
The document describes various analytical and clinical performance studies, each with inherent acceptance criteria demonstrated by the reported results. The explicit acceptance criteria are outlined in the "Precision" section for analytical performance. For clinical performance, the acceptance is implied by the achieved PPA (Positive Percent Agreement) and NPA (Negative Percent Agreement) values with corresponding confidence intervals.
Table of Acceptance Criteria and Reported Device Performance
| Study Type | Target | Acceptance Criteria | Reported Device Performance (Summary) |
|---|---|---|---|
| Analytical Performance | |||
| Precision (Within-laboratory) | MP | Overall correct percentage of approximately 100% with 95% CI | Shiga toxins: 100.00% (72/72) Campylobacter: 98.61% (71/72) Shigella: 98.61% (71/72) Salmonella: 100.00% (72/72) |
| LP | Overall correct percentage of approximately 95% with 95% CI | Shiga toxins: 98.61% (71/72) Campylobacter: 100.00% (72/72) Shigella: 98.61% (71/72) Salmonella: 100.00% (72/72) | |
| TN | Overall correct percentage of approximately 100% with 95% CI | Shiga toxins: 100.00% (72/72) Campylobacter: 100.00% (72/72) Shigella: 100.00% (72/72) Salmonella: 100.00% (72/72) | |
| HN | Overall correct percentage between 20% and 80% | Shiga toxins: 27.78% (20/72) Campylobacter: 54.17% (39/72) Shigella: 30.56% (22/72) Salmonella: 25.00% (18/72) | |
| Reproducibility (Site-to-Site) | TN | 100% agreement (implied by categories) | All Targets: 100.0% |
| HN | Agreement range 41.1% to 77.8% (implied by categories) | Campylobacter: 77.8% Salmonella: 44.4% Shigella: 41.1% Shiga toxins: 50.0% | |
| LP | Agreement range 96.7% to 100% (implied by categories) | Campylobacter: 100.0% Salmonella: 96.7% Shigella: 97.8% Shiga toxins: 100.0% | |
| MP | Agreement range 98.9% to 100% (implied by categories) | Campylobacter: 100.0% Salmonella: 98.9% Shigella: 100.0% Shiga toxins: 98.9% | |
| Reproducibility (Lot-to-Lot) | TN | 100% agreement (implied by categories) | All Targets: 100.00% |
| HN | Agreement range 13.33% to 62.22% (implied by categories) | STEC: 30.00% Campy: 62.22% Shig: 16.67% Sal: 13.33% | |
| LP | Agreement range 95.56% to 100% (implied by categories) | STEC: 98.89% Campy: 100.00% Shig: 95.56% Sal: 98.89% | |
| MP | Agreement range 97.78% to 100% (implied by categories) | STEC: 100.00% Campy: 97.78% Shig: 98.89% Sal: 100.00% | |
| Clinical Performance | |||
| Clinical Accuracy (PPA, NPA) | Varies | High PPA and NPA with tight 95% CIs (implied by successful comparison to reference method) | Campylobacter: PPA (96.2%-100%), NPA (97.5%-100%) Salmonella: PPA (85%-100%), NPA (98.9%-100%) Shigella/EIEC: PPA (98%-100%), NPA (99.4%-100%) Shiga toxins: PPA (75%-100%), NPA (99%-100%) (Specific ranges depend on specimen type and origin, detailed in the tables 19-22 of the document) |
| Unresolved Rates (Initial) | All | Low unresolved rates (implied by successful operation and repeat testing) | Cary-Blair Preserved: Prospective 4.0%, Retrospective 2.2% Unpreserved: Prospective 7.8%, Retrospective 4.1% |
| Unresolved Rates (After Repeat) | All | Very low unresolved rates after repeat (implied by successful operation and repeat testing) | Cary-Blair Preserved: Prospective 0.1%, Retrospective 0.2% Unpreserved: Prospective 1.0%, Retrospective 0.6% |
| Indeterminate Rates (Initial) | All | Low indeterminate rates (implied by successful operation and repeat testing) | Cary-Blair Preserved: Prospective 1.7%, Retrospective 1.5% Unpreserved: Prospective 1.6%, Retrospective 1.9% |
| Indeterminate Rates (After Repeat) | All | Very low indeterminate rates after repeat (implied by successful operation and repeat testing) | Cary-Blair Preserved: Prospective 0.0%, Retrospective 0.0% Unpreserved: Prospective 0.2%, Retrospective 0.0% |
| Incomplete Rates (Initial) | All | Low incomplete rates (implied by successful operation) | Cary-Blair Preserved: Prospective 1.3%, Retrospective 1.3% Unpreserved: Prospective 2.0%, Retrospective 0.0% |
| Incomplete Rates (After Repeat) | All | Very low incomplete rates after repeat (implied by successful operation) | Cary-Blair Preserved: Prospective 0.0%, Retrospective 0.0% Unpreserved: Prospective 0.0%, Retrospective 0.0% |
Study Details
The provided document describes both Analytical Performance and Clinical Performance studies.
Analytical Performance Studies
These studies evaluate the device's technical capabilities in detecting the target pathogens.
- Sample Size Used for the Test Set and Data Provenance:
- Precision:
- Within-laboratory: For each of 4 different target types (Shiga toxins, Campylobacter, Shigella, Salmonella), 4 sample categories (TN, HN, LP, MP) were tested in triplicate over 12 days, with 2 runs per day. This results in 72 replicates per category per target.
- Site-to-Site Reproducibility: 3 clinical sites were provided with 10 panels, each with 12 tubes. Each site performed the study over 5 distinct days, with 2 panels tested per day by 2 technologists. This results in 90 replicates per category per target across all sites (though specific numbers vary slightly when looking at site-by-site data for positive/negative agreement).
- Lot-to-Lot Reproducibility: Data from 5 days of an accuracy and precision study, using 12 panel members per lot, with two users for each of two lots, was used. This equates to 90 replicates per category per target across the lots.
- Data Provenance: Not explicitly stated as real-world patient data. These appear to be spiked samples (engineered to be near LoD, etc.) into negative stool matrix. The origin of the negative stool matrix is stated as "from patients".
- Precision:
- Number of Experts and Qualifications for Ground Truth: Not applicable for analytical studies, as ground truth is established by spiked concentrations of known organisms.
- Adjudication Method: Not applicable for analytical studies.
- Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study: Not applicable. These are analytical studies of the device's performance, not comparative effectiveness of human readers with/without AI assistance.
- Standalone Performance: Yes, these studies evaluate the standalone performance of the BD MAX™ Enteric Bacterial Panel system.
- Type of Ground Truth Used: For precision and reproducibility, known concentrations of target strains were used (e.g., "5 CFU/mL" for HN, "≥1 and <2 x LoD" for LP, etc.) Spiked samples into negative stool matrix.
- Sample Size for Training Set: Not applicable. These are analytical validation studies, not machine learning model training.
- How Ground Truth for Training Set was Established: Not applicable.
Clinical Performance Studies
These studies evaluate the device's accuracy in a real-world clinical setting.
- Sample Size Used for the Test Set and Data Provenance:
- Prospective Specimens (Fresh): 3457 specimens were enrolled (2112 Cary-Blair preserved, 1345 unpreserved). The compliant dataset used for PPA and NPA calculations included a total of:
- Campylobacter: 3038 (48 positive, 2990 negative)
- Shigella: 3069 (41 positive, 3028 negative)
- Salmonella: 3067 (44 positive, 3023 negative)
- Shigatoxins: 2502 (10 positive, 2492 negative)
- Retrospective Specimens (Frozen): 785 specimens were enrolled (464 Cary-Blair preserved, 321 unpreserved). 104 retrospective specimens were excluded from performance calculations because historical results were not confirmed. The compliant dataset used for PPA and NPA calculations included a total of:
- Campylobacter: 507 (133 positive, 374 negative)
- Shigella: 543 (92 positive, 451 negative)
- Salmonella: 618 (167 positive, 451 negative)
- Shigatoxins: 156 (66 positive, 90 negative)
- Data Provenance:
- Country of Origin: Geographically diverse clinical centers (8 sites) and collection centers (unspecified number, but imply multiple locations in the US given FDA submission). The document states "United States, European Union, Canada, other geographical regions" for analytical inclusivity, suggesting a broad scope, but for clinical trials, it only refers to "geographically diverse clinical centers."
- Retrospective/Prospective: Both retrospective (collected March 2012 - August 2013, and archived June-Sept 2007, Oct-Dec 2011) and prospective (collected June-September 2013 on an "all-comers" basis) specimens were used.
- Prospective Specimens (Fresh): 3457 specimens were enrolled (2112 Cary-Blair preserved, 1345 unpreserved). The compliant dataset used for PPA and NPA calculations included a total of:
- Number of Experts and Qualifications for Ground Truth:
- The "reference method" involved historical culture results (for retrospective samples) which were confirmed by alternate PCR and bi-directional amplicon sequencing. For prospective samples, the reference method is also implied to be culture (not explicitly detailed, but standard for these pathogens).
- The document does not specify the number or qualifications of experts (e.g., microbiologists, lab technicians) involved in performing the reference methods or interpreting the sequencing results. It refers to "clinical centers utilizing methodologies that did not have a high degree of similarity sent specimens to a central laboratory for reference method testing," suggesting specialized labs for the reference methods.
- Adjudication Method: For discrepant prospective specimens (where the device result differed from the reference method), further investigation was conducted using an "alternate PCR assay followed by bi-directional sequencing." This acts as a form of "tie-breaker" or confirmatory adjudication.
- Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study: No, this study evaluates the standalone diagnostic accuracy of the device against a reference method, not the impact of AI on human reader performance.
- Standalone Performance: Yes, the clinical performance study evaluated the device in a standalone capacity (algorithm only, against a reference standard).
- Type of Ground Truth Used:
- Clinical Culture/Reference Method: For prospective samples, the reference method is indicated as clinical presentation, laboratory findings, and epidemiological information, along with culture.
- Composite Reference Method: For retrospective samples, the ground truth was established by historical culture results confirmed using an alternate PCR and bi-directional amplicon sequencing. Discrepant prospective specimens were also adjudicated using alternate PCR and bi-directional sequencing.
- Sample Size for the Training Set: Not applicable. These are clinical validation studies. The device itself (BD MAX™ Enteric Bacterial Panel) is a nucleic acid-based assay (PCR), not an AI algorithm that would typically require a separate training set of clinical images/data.
- How Ground Truth for the Training Set was Established: Not applicable.
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BD MAX™ Enteric Bacterial Panel
CONFIDENTIAL AND PROPRIETARY
510(k) Summary
MAY 0 6 2014
May 5, 2014
BD MAX™ Enteric Bacterial Panel
Regulatory Affairs Project Manager
Becton, Dickinson and Company Submitted by: 7 Loveton Circle Sparks, MD 21152 Phone: 410-316-4905 Fax: 410-316-4499
Contact:
Device:
510(k) Number: K140111
Trade Name: BD MAX™ Enteric Bacterial Panel
Common Name: Gastrointestinal pathogen panel multiplex nucleic acidbased assay system
Paul Swift, RAC
Classification: Class II
Regulation Number: 866.3990
Product Code: PCI, PCH, OOI
Microbiology (83) Panel:
Predicate Device: Gen-Probe Prodesse, Inc. ProGastro SSCS Assay
Predicate 510(k) Numbers: K123274
Intended Use
The BD MAX™ Enteric Bacterial Panel performed on the BD MAX™ System is an automated in vitro diagnostic test for the direct qualitative detection and differentiation of enteric bacterial pathogens. The BD MAX Enteric Bacterial Panel detects nucleic acids from:
- Salmonella spp. .
- Campylobacter spp. (jejuni and coli) .
- Shigella spp. / Enteroinvasive E. coli (EIEC) .
- Shiga toxin 1 (stx1) / Shiga toxin 2 (stx2) genes (found in Shiga toxin-producing . E. coli [STEC]) as well as Shigella dysenteriae, which can possess a Shiga toxin gene (stx) that is identical to the stx1 gene of STEC.
BD Diagnostic Systems Becton, Dickinson and Company
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Testing is performed on unoreserved soft to diarrheal stool specimens or Cary-Blair preserved stool specimens from symptomatic patients with suspected acute gastroenteritis, enteritis or colitis. The test is performed directly on the specimen, utilizing real-time polymerase chain reaction (PCR) for the amplification of SpaO, a Campylobacter specific tuf gene sequence, ipaH and stx1/stx2. The test utilizes fluorogenic sequence-specific hybridization probes for detection of the amplified DNA.
This test is intended for use, in conjunction with clinical presentation, laboratory findings, and epidemiological information, as an aid in the differential diagnosis of Salmonella, Shigella/EIEC, Campylobacter and Shiga toxin-producing E. coli (STEC) infections. Results of this test should not be used as the sole basis for diagnosis, treatment, or other patient management decisions. Positive results do not rule out co-infection with other organisms that are not detected by this test, and may not be the sole or definitive cause of patient illness. Negative results in the setting of clinical illness compatible with gastroenteritis may be due to infection by pathogens that are not detected by this test or non-infectious causes such as ulcerative colitis, irritable bowel syndrome, or Crohn's disease.
Special Conditions for Use Statement:
Special Instrument Requirements:
BD MAX™ System
For prescription use
Device Description
The BD MAX™ System and the BD MAX™ Enteric Bacterial Panel are comprised of an instrument with associated hardware and accessories, disposable microfluidic cartridges. master mixes, unitized reagent strips, extraction reagents, and sample buffer tubes. The instrument automates sample preparation including target lysis, DNA extraction and concentration, reagent rehydration, and target nucleic acid amplification and detection using real-time PCR. The assay includes a Sample Processing Control (SPC) that is present in the Extraction Tube. The SPC monitors DNA extraction steps, thermal cycling steps, reagent integrity and the presence of inhibitory substances. The BD MAX™ System software automatically interprets test result may be called as POS. NEG or UNR for each of the assay's targets, based on the amplification status of the target and of the Sample Processing Control. IND (Indeterminate) or INC (Incomplete) results are due to BD MAX™ System failure.
Test Principle
The BD MAX™ Enteric Bacterial Panel performed on the BD MAX™ System is an automated in vitro diagnostic test for the direct, qualitative detection of enteric bacterial pathogens responsible for gastreoenteritis due to Salmonella spp., Campylobacter spp. (jejuni and coli), Shigella spp. / Enteroinvasive E. coli (EIEC), and Shiga toxin-producing E. coli (STEC) as well as Shigella dysenteriae, which can possess a Shiga toxin gene (stx) that is identical to the stx1 gene of STEC. The BD MAX Enteric Bacterial Panel detects target DNA from unpreserved soft to diarrheal stool specimens or Cary-Blair preserved stool specimens from symptomatic patients with suspected acute gastroenteritis, enteritis or colitis.
A stool specimen is collected and transported to the laboratory in a dry, clean conta for unpreserved specimens) or in Cary-Blair transport media. The specimen is vortexed BD Diagnostic Systems Becton, Dickinson and Company
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for 15 seconds and then a 10 µL loop is used to inoculate a BD MAX™ Enteric Bacterial Panel Sample Buffer Tube. The Sample Buffer Tube is closed with a septum cap and vortexed. A worklist is created and the Sample Buffer Tube, the BD MAX™ Enteric Bacterial Panel unitized reagent strip (URS) and the BD MAX™ PCR Cartridge are loaded onto the BD MAX ™ System.
Following enzymatic cell lysis, the released nucleic acids are captured on magnetic beads. The beads, with the bound nucleic acids, are washed using Wash Buffer and the nucleic acids are eluted by heat in Elution Buffer. Eluted DNA is neutralized using Neutralization Buffer and transferred to a Master Mix to rehydrate PCR reagents, After reconstitution, the BD MAX™ System dispenses a fixed volume of PCR-ready solution containing extracted nucleic acids into the BD MAX™ PCR Cartridge. Microvalves in the BD MAX™ PCR Cartridge are sealed by the system prior to initiating PCR to contain the amplification mixture, thus preventing evaporation and contamination.
The amplified DNA targets are detected using hydrolysis (TagMan®) probes, labeled at one end with a fluorescent reporter dye (fluorophore) and at the other end with a quencher moiety. Probes labeled with different fluorophores are used to detect amplicons for enteric bacterial targets (Campylobacter specific tuf gene sequence variants, the SpaO gene for specific detection of Salmonella spp., the ipaH gene for specific detection of Shigella spp. / Enteroinvasive E. coli (EIEC), the stx1 & stx2 genes associated with production of Shiga toxins in STEC and S. dysenteriae) and the SPC in five different optical channels of the BD MAX System. When the probes are in their native state, the fluorescence of the fluorophore is guenched due to its proximity to the quencher. However, in the presence of target DNA, the probes hybridize to their complementary sequences and are hydrolyzed by the 5-3' exonuclease activity of the DNA polymerase as it synthesizes the nascent strand along the DNA template. As a result, the fluorophores are separated from the quencher molecules and fluorescence is emitted. The amount of fluorescence detected in the optical channels used for the BD MAX™ Enteric Bacterial Panel is directly proportional to the quantity of the corresponding probe that is hydrolyzed. The BD MAX™ System measures these signals at the end of each amplification cvcle, and interprets the data to provide a result.
Substantial Equivalence
Table 1 shows the similarities and differences between the BD MAX™ Enteric Bacterial Panel and the predicate device.
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| ITEM | BD MAX™ Enteric Bacterial Panel | Hologic® Prodesse®ProGastro™ SSCS (K123274) |
|---|---|---|
| Intended Use | The BD MAX™ Enteric Bacterial Panelperformed on the BD MAX™ System is anautomated in vitro diagnostic test for thedirect qualitative detection anddifferentiation of enteric bacterialpathogens. The BD MAX Enteric BacterialPanel detects nucleic acids from:Salmonella spp. Campylobacter spp. (jejuni and coli) Shigella spp. / Enteroinvasive E. coli (EIEC) Shiga toxin 1 (stx1) / Shiga toxin 2 (stx2) genes (found in Shiga toxin-producing E. coli (STEC)) as well as Shigella dysenteriae, whichcan possess a Shiga toxin gene (stx) that is identical to the stx1 gene of STEC.Testing is performed on unpreserved soft todiarrheal stool specimens or Cary-Blairpreserved stool specimens fromsymptomatic patients with suspected acutegastroenteritis, enteritis or colitis. The test isperformed directly on the specimen, utilizingreal-time polymerase chain reaction (PCR)for the amplification of SpaO , aCampylobacter specific tuf gene sequence,ipaH and stx1/stx2 . The test utilizesfluorogenic sequence-specific hybridizationprobes for detection of the amplified DNA.This test is intended for use, in conjunctionwith clinical presentation, laboratoryfindings, and epidemiological information,as an aid in the differential diagnosis ofSalmonella, Shigella/EIEC, Campylobacterand Shiga toxin-producing E. coli (STEC)infections. Results of this test should not be | The Prodesse® ProGastro SSCSAssay is a multiplex real time PCRin vitro diagnostic test for thequalitative detection anddifferentiation of Salmonella,Shigella , and Campylobacter (C.jejuni and C. coli only,undifferentiated) nucleic acids andShiga Toxin 1 ( stx1 ) and ShigaToxin 2 ( stx2 ) genes. Shiga toxinproducing E. coli (STEC) typicallyharbor one or both genes thatencode for Shiga Toxins 1 and 2.Nucleic acids are isolated andpurified from preserved stoolspecimens obtained fromsymptomatic patients exhibitingsigns and symptoms ofgastroenteritis. This test isintended for use, in conjunctionwith clinical presentation andepidemiological risk factors, as anaid in the differential diagnosis ofSalmonella, Shigella,Campylobacterjejuni/Campylobacter coli , andSTEC infections in humans.The results of this test should notbe used as the sole basis fordiagnosis, treatment, or otherpatient management decisions.Positive results do not rule out co-infection with other organisms thatare not detected by this test, andmay not be the sole or definitivecause of patient illness. NegativeProGastro SSCS Assay results inthe setting of clinical illnesscompatible with gastroenteritis maybe due to infection by pathogens |
| ITEM | BD MAX™ Enteric Bacterial Panel | Hologic® Prodesse®ProGastro™ SSCS (K123274) |
| used as the sole basis for diagnosis,treatment, or other patient managementdecisions. Positive results do not rule outco-infection with other organisms that arenot detected by this test, and may not bethe sole or definitive cause of patientillness. Negative results in the setting ofclinical illness compatible withgastroenteritis may be due to infection bypathogens that are not detected by this testor non-infectious causes such as ulcerativecolitis, irritable bowel syndrome, or Crohn'sdisease. | that are not detected by this test ornon-infectious causes such asulcerative colitis, irritable bowelsyndrome, or Crohn's disease. | |
| Specimen type | Unpreserved and Cary-Blair preservedstool. | Stool in Cary-Blair preserved orPara-Pak® C&S transport medium. |
| Assay Format | Amplification: PCRDetection: fluorogenic target-specifichybridization. | Same |
| Mode ofDetection forCampylobacter | Presence of tuf gene specific forCampylobacter. | Presence of glyA gene specific forCampylobacter jejuni and cadFgene specific for C. coli . |
| Mode ofDetection forSalmonella | Presence of SpaO gene specific forSalmonella. | Presence of orgC gene specific forSalmonella. |
| Mode ofDetection forShigella | Presence of ipaH gene specific forShigella/EIEC. | Presence of ipaH gene specific forShigella. |
| Mode ofDetection forShiga toxins | Presence of stx1 and stx2 genes specific toShiga toxin-producing organisms. | Presence of stx1 and stx2 genesspecific to Shiga toxin-producingorganisms. |
| Interpretation ofTest Results | Automated (BD MAX™ System diagnosticsoftware) | Automated (Cepheid SmartCycler® II) |
| AnalysisPlatform | BD MAX ™ System | Cepheid SmartCycler® II |
| PCR SamplePreparation | Automated by the BD MAX™ System | bioMérieux NucliSENS®easyMAG® |
| DetectionProbes | TaqMan® Probe | TaqMan® Probe |
| Assay Controls | Sample Processing Control (SPC) | Internal Control |
Table 1: Substantial Equivalence1 Information
1 The term "substantial equivalence" as used in this 510(k) notification is limited to the definition of substantial equivalence as found in the Federal Food, Drug and Cosmetic Act, as amended and as applied under 21 CFR 807, Subpart E under which a device can be marketed without pre-market approval or reclassification. A determination of substantial equivalency under this not intended to have any bearing whatsoever on the resolution of patent infringement suits or any other patent matters. No statements related to, or in support of substantial equivalence herein shall be construed as an admission against interest under the US Patent Laws or their application by the courts.
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Analytical Performance
Precision
Within-laboratory precision was evaluated for the BD MAX™ Enteric Bacterial Panel at one (1) site. The Precision panel consisted of 4 sample categories near the LoD. Each specimen contained negative stool matrix. Target strains were tested as follows:
- For moderate positives (MP): overall correct percentage of approximately 100% with . 95% Cl
- For low positives (LP): overall correct percentage of approximately 95% with 95% C1 .
- For true neqatives (TN): overall correct percentage of approximately 100% with 95% . Cl
- For high neqatives (HN): overall correct percentage between 20 and 80% .
Testing was performed in triplicate, over 12 days, with 2 runs per day, by 2 different technologists. Precision study results are summarized below in Table 2.
| Target | Level | Correct | Total | % Correct | ||
|---|---|---|---|---|---|---|
| TN' | 72 | 72 | 100.00% | |||
| Shiga toxins | HN, | 20 | 72 | 27.78% | ||
| Гр | 71 | 72 | 98.61% | |||
| MP | 72 | 72 | 100.00% | |||
| 1:N | 72 | 72 | 100.00% | |||
| Campylobacter | HN | 39 | 72 | 54.17% | ||
| lP | 72 | 72 | 100.00%5 | |||
| ﺔ ﺍﻟﺘﻲ ﺗﻌﻠﻴﻘﺎﺕ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪﺓ ﺍﻟﻤﺘﺤﺪ | MP | 71 | 72 | 98.61% | ||
| TN | 72 | 72 | 100.00% | |||
| Shigella | HN | 22 | 72 | 30.56% | ||
| LP | 7 1 | 72 | 98.61% | |||
| MP | 7 1 | 72 | 98.61% | |||
| TN | 72 | 72 | 100.00% | |||
| Salmonella | HN | 18 | 72 | 25.00% · | ||
| P | 72 | 72 | 100.00% | |||
| MP | 72 | 72 | 100.00% |
Table 2: Within-laboratory Precision Testing
For the True Negative (TN) and High Negative (HN) categories, the expected assay result was deemed to be negative. Therefore, percent agreement was calculated for negative results.
Reproducibility
For the Site-to-Site reproducibility study, three (3) clinical sites were provided with a fotal of ten (10) panels, each consisting of 12 tubes. The panels used were the same as described under the Precision heading, above. Each site was asked to perform the study on five (5) distinct days (consecutive or not), wherein each day, two (2) panels were tested, one (1) for each of two (2) technologists.
The overall Site-to-Site Reproducibility percent agreement was 100% for the TN category for all targets, and ranged from 41.1% to 77.8%, 96.7% to 100% and 98.9% to 100% for the HN, LP and MP categories, respectively (Table 3). The qualitative and
BD Diagnostic Systems Becton, Dickinson and Company
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quantitative reproducibility across sites and by target is presented below in Tables 4 through 10. Ct.Score is an internal criterion used to determine final assay results and was selected as an additional means of assay reproducibility. Overall mean Ct.Score values with variance components (SD and %CV) are shown in Tables 4, 6, 8 and 10.
| Category | Campylobacter( coli and jejuni )[n], (95% CI) | Salmonella spp.[n], (95% CI) | Shigella spp.[n], (95% CI) | Shiga toxins( stx1 and stx2 )[n], (95% CI) |
|---|---|---|---|---|
| TN* | 100.0%, [90/90],(95.9%, 100.0%) | 100.0%, [90/90], (95.9%,100.0%) | 100.0%, [90/90], (95.9%,100.0%) | 100.0%, [90/90], (95.9%,100.0%) |
| HN* | 77.8%, [70/90],(68.2%, 85.1%) | 44.4%, [40/90], (34.6%,54.7%) | 41.1%, [37/90], (31.5%,51.4%) | 50.0%, [45/90], (39.9%,60.1%) |
| LP | 100.0%, [90/90],(95.9%, 100.0%) | 96.7%, [87/90], (90.7%,98.9%) | 97.8%, [88/90], (92.3%,99.4%) | 100.0%, [90/90], (95.9%,100.0%) |
| MP | 100.0%, [90/90],(95.9%, 100.0%) | 98.9%, [89/90], (94.0%,99.8%) | 100.0%, [90/90], (95.9%,100.0%) | 98.9%, [89/90], (94.0%,99.8%) |
Table 3: Site-to-Site Reproducibility Study Results using one lot of the BD MAX Enteric Bacterial Panel
- For the True Negative (TN) and High Negative (HN) categories, the expected assay result was deemed to be negative. Therefore, percent was calculated for negative results
| Category | Concentration | SITE | Total | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2 | 3 | 5 | |||||||||||||||
| Correct | Incorrect | Correct | Incorrect | Correct | Incorrect | Correct | Incorrect | ||||||||||
| N | % | N | % | N | % | N | % | ||||||||||
| TN | Blank | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 90 | 100.0 | 0 | 0 |
| HN | 5 CFU/mL | 22 | 73.3 | 8 | 26.7 | 24 | 80.0 | 6 | 20.0 | 24 | 80.0 | 6 | 20.0 | 70 | 77.8 | 20 | 22.2 |
| LP | ≥1 and <2 x LoD | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 90 | 100.0 | 0 | 0 |
| MP | ≥2 and ≤5 x LoD | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 90 | 100.0 | 0 | 0 |
Table 4: Campylobacter Site-to-Site Qualitative Reproducibility across sites with pooled days, runs and replicates
BD Diagnostic Systems Becton, Dickinson and Company
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BD MAX™ Enteric Bacterial Panel
CONFIDENTIAL AND PROPRIETARY
| - Within Run# Within Day " Within Day | Between Run | - Day | BetweenWithin Site | 1Between Site | Total: | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Variable | Category | Mean | SD | %CV- I SD | i %CV . | -SD- %CV | SD | :%CV | SD | %CV | |||
| HN | 20 | 36.2 | 0.54 | 1.5% | 1.18 | 3.2% | 0.00 | 0.0% | 0.00 | 0.0% | 1.30 | 3.6% | |
| Ct.Score | LP | 90 | 32.7 | 0.49 | 1.5% | 0.28 | 0.9% | 0.00 | 0.0% | 0.00 | 0.0% | 0.57 | 1.7% |
| MP | 90 | 32.2 | 0.60 | 1.8% | 0.14 | 0.4% | 0.00 | 0.0% | 0.00 | 0.0% | 0.61 | 1.9% |
Table 5: Campylobacter Site-to-Site Quantitative Reproducibility across sites, days, runs and within run
Table 6: Salmonella Site-to-Site Qualitative Reproducibility across sites with pooled days, runs, and replicates
| Category | Concentration | SITE | Total | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2 | 3 | 5 | |||||||||||||||
| Correct | Incorrect | Correct | Incorrect | Correct | Incorrect | Correct | Incorrect | ||||||||||
| N | % | N | % | N | % | N | % | N | % | ||||||||
| TN | Blank | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 90 | 100.0 | 0 | 0 |
| HN | 75 CFU/mL | 10 | 33.3 | 20 | 66.7 | 16 | 53.3 | 14 | 46.7 | 14 | 46.7 | 16 | 53.3 | 40 | 44.4 | 50 | 55.6 |
| LP | ≥1 and <2 x LoD | 30 | 100.0 | 0 | 0 | 28 | 93.3 | 2 | 6.7 | 29 | 96.7 | 1 | 3.3 | 87 | 96.7 | 3 | 3.3 |
| MP | ≥2 and ≤5 x LoD | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 29 | 96.7 | 1 | 3.3 | 89 | 98.9 | 1 | 1.1 |
Table 7: Salmonella Site-to-Site Quantitative Reproducibility across sites, days, runs and within run
| Variable | Category | N | Mean | Within RunWithin DaySD | Within RunWithin Day%CV | Between RunWithin DaySD | Between RunWithin Day%CV | Between DayWithin SiteSD | Between DayWithin Site%CV | Between SiteSD | Between Site%CV | TotalSD | Total%CV |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Ct.Score | HN | 50 | 36.4 | 0.92 | 2.5% | 0.00 | 0.0% | 0.00 | 0.0% | 0.43 | 1.2% | 1.01 | 2.8% |
| Ct.Score | LP | 87 | 34.6 | 0.99 | 2.9% | 0.00 | 0.0% | 0.00 | 0.0% | 0.61 | 1.8% | 1.16 | 3.4% |
| Ct.Score | MP | 89 | 33.2 | 0.61 | 1.9% | 0.34 | 1.0% | 0.23 | 0.7% | 0.43 | 1.3% | 0.85 | 2.6% |
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| Category | Concentration | SITE | Total | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2 | 3 | 5 | |||||||||||||||
| Correct | Incorrect | Correct. | Incorrect | Correct | Incorrect | Correct | Incorrect | ||||||||||
| N | % | N | % | N | % | N | % | N | % | ||||||||
| TN | Blank | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 90 | 100.0 | 0 | 0 |
| HN | 9 CFU/mL | 12 | 40.0 | 18 | 60.0 | 13 | 43.3 | 17 | 56.7 | 12 | 40.0 | 18 | 60.0 | 37 | 41.1 | 53 | 58.9 |
| LP | ≥1 and <2 x LoD | 29 | 96.7 | 1 | 3.3 | 30 | 100.0 | 0 | 0 | 29 | 96.7 | 1 | 3.3 | 88 | 97.8 | 2 | 2.2 |
| MP | ≥2 and ≤5 x LoD | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 90 | 100.0 | 0 | 0 |
Table 8: Shigella Site-to-Site Qualitative Reproducibility across sites with pooled days, runs and replicates
| Table 9: Shigella Site-to-Site Quantitative Reproducibility |
|---|
| across sites, days, runs and within run |
| Variable | Category | N | Mean | Within RunWithin DaySD | Within RunWithin Day%CV | Between RunWithin DaySD | Between RunWithin Day%CV | Between DayWithin SiteSD | Between DayWithin Site%CV | Between SiteSD | Between Site%CV | TotalSD | Total%CV |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Ct.Score | HN | 53 | 34.8 | 0.99 | 2.8% | 0.57 | 1.6% | 0.52 | 1.5% | 0.29 | 0.8% | 1.29 | 3.7% |
| LP | 88 | 33.1 | 0.79 | 2.4% | 0.35 | 1.1% | 0.23 | 0.7% | 0.47 | 1.4% | 1.01 | 3.1% | |
| MP | 90 | 32.5 | 0.80 | 2.5% | 0.39 | 1.2% | 0.00 | 0.0% | 0.50 | 1.5% | 1.03 | 3.2% |
Table 10: Shiga toxin Site-to-Site Qualitative Reproducibility across sites with pooled days, runs and replicates
| Category | SITE | Total | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 2 | 3 | 5 | Correct | Incorrect | |||||||||||||
| Concentration | Correct | Incorrect | Correct | Incorrect | Correct | Incorrect | N | % | N | % | |||||||
| N | % | N | % | N | % | ||||||||||||
| TN | Blank | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 90 | 100.0 | 0 | 0 |
| HN | 100 CFU/mL | 16 | 53.3 | 14 | 46.7 | 15 | 50.0 | 15 | 50.0 | 14 | 46.7 | 16 | 53.3 | 45 | 50.0 | 45 | 50.0 |
| LP | ≥1 and <2x LoD | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 90 | 100.0 | 0 | 0 |
| MP | ≥2 and ≤5x LoD | 30 | 100.0 | 0 | 0 | 30 | 100.0 | 0 | 0 | 29 | 96.7 | 1 | 3.3 | 89 | 98.9 | 1 | 1.1 |
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| Within RunWithin Day | Between RunWithin Day | Between DayWithin Site | Between Site | Total | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Variable | Category | N | Mean | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| HN | 45 | 35.9 | 1.78 | 5.0% | 0.00 | 0.0% | 0.00 | 0.0% | 1.03 | 2.9% | 2.06 | 5.7% | |
| Ct.Score | LP | 90 | 31.8 | 0.65 | 2.0% | 0.00 | 0.0% | 0.00 | 0.0% | 0.36 | 1.1% | 0.74 | 2.3% |
| MP | 89 | 31.3 | 0.62 | 2.0% | 0.22 | 0.7% | 0.07 | 0.2% | 0.24 | 0.8% | 0.70 | 2.2% |
Table 11: Shiga toxin Site-to-Site Quantitative Reproducibility across sites, days, runs and within run
For the Lot-to-Lot reproducibility study, two users each completed a single run of 12 panel members on a single instrument for each of two lots of reagents over a 5-day period. The panels used were the same as described under the Precision heading, above. Results from 5 days of the accuracy and precision study were used to comprise data for one lot of reagents for the Lot-to-Lot study.
The overall Lot-to-Lot reproducibility percent agreement was 100% for the TN category for all targets, and ranged from 13.33% to 62.22%, 95.56% to 100% and 97.78% to 100% for the HN, LP and MP categories, respectively (Table 12).
| Target | Level | Correct | Total | % Correct | 95% CI | |
|---|---|---|---|---|---|---|
| STEC | TN* | 90 | 90 | 100.00% | LowerCl | UpperCl |
| STEC | HN* | 27 | 90 | 30.00% | 21.51% | 40.13% |
| STEC | LP | 89 | 90 | 98.89% | 93.97% | 99.80% |
| STEC | MP | 90 | 90 | 100.00% | 95.91% | 100.00% |
| Campy | TN | 90 | 90 | 100.00% | 95.91% | 100.00% |
| Campy | HN | 56 | 90 | 62.22% | 51.90% | 71.54% |
| Campy | LP | 90 | 90 | 100.00% | 95.91% | 100.00% |
| Campy | MP | 88 | 90 | 97.78% | 92.26% | 99.39% |
| Shig | TN | 90 | 90 | 100.00% | 95.91% | 100.00% |
| Shig | HN | 15 | 90 | 16.67% | 10.37% | 25.69% |
| Shig | LP | 86 | 90 | 95.56% | 89.12% | 98.26% |
| Shig | MP | 89 | 90 | 98.89% | 93.97% | 99.80% |
| Sal | TN | 90 | 90 | 100.00% | 95.91% | 100.00% |
| Sal | HN | 12 | 90 | 13.33% | 7.79% | 21.87% |
| Sal | LP | 89 | 90 | 98.89% | 93.97% | 99.80% |
| Sal | MP | 90 | 90 | 100.00% | 95.91% | 100.00% |
Table 12: Lot-to-Lot Reproducibility Study Results using three lots of the BD MAX Enteric Bacterial Panel
- For the True Negative (TN) and High Negative (HN) categories, the expected assay result was deemed to be negative. Therefore, percent agreement was calculated for negative results
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Sample Storage
Specimens can be stored at 2-25 °C for a maximum of 24 hours or at 2-8 °C for a maximum of 120 hours (5 days) before testing. In case of repeat testing from the Sample Buffer Tube, the following storage conditions apply:
- • within 48 hours of the steps covered in the Specimen Preparation section of the package insert, when stored at 2-25°C or
- up to 120h (5 days) after the end of the initial run when stored at 2-8°C.
Controls
External Control materials are not provided by BD: however, Quality Control strains and procedures are included in the package insert. Various types of External Controls are recommended to allow the user to select the most appropriate for their laboratory qualify control program:
- Commercially available positive control materials —
- Salmonella enterica subsp. enteric serovar Typhimurium (ATCC 14028) containing the SpaO gene target.
- Shigella sonnei (ATCC 9290) containing the ipaH gene target. l
- l E. coli, stx 1a (ATCC 43890) containing the stx 1a gene target.
- Campylobacter jejuni subsp. jejuni (ATCC 33291) containing the -Campylobacter specific tuf gene sequence variants.
External negative control --
- Express 10 µL of saline in the BD MAX™ Enteric Bacterial Panel SBT ເ
The assay includes a Specimen Processing Control (SPC) that is present in the Extraction Tube. The SPC monitors DNA extraction steps, thermal cycling steps, reagent integrity and the presence of inhibitory substances.
Analytical Sensitivity
The analytical sensitivity (Limit of Detection or LoD) for the BD MAX™ Enteric Bacterial Panel was determined using two distinct target mixes of organisms. A target mix was defined as a combination of 4 target organisms that represent one strain of a genus or variant of a gene coding for a shiga-like toxin. The BD MAX™ Enteric Bacterial Panel is not designed to discriminate between the stx1 and stx2 genes. A second round of LoD testing was performed only for the stx1 target. without a target mix. Cultures of the target organisms were prepared and used to prepare bacterial targets that were inoculated into the SBT along with negative, pooled stool matrix (both unpreserved and Cary-Blair preserved). The negative stool matrix pool was created from stool specimens obtained from patients that were characterized by the BD MAX™ Enteric Bacterial Pane. The LoD was determined for each organism tested with both unpreserved and Cary-Blair preserved target-negative stool matrix. The results from the LoD study can be found below in Table 13.
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| Unpreservednumber of positive results[95% Confidence Interval] | Cary-Blair preservednumber of positive results[95% Confidence Interval] | |
|---|---|---|
| Salmonella typhimurium | 296 [233 – 376] | 193 [142-263] |
| LoD (CFU/mL in stool)[95% confidence interval] | 44,400 [34,950 - 56,400] | 28,950 [21,300 – 39,450] |
| Shigella sonnei | ||
| LoD (CFU/mL in SBT)[95% confidence interval] | 84 [59-118] | 124 [67-229] |
| LoD (CFU/mL in stool)[95% confidence interval] | 12,600 [8,850 - 17,700] | 18,600 [10,050 - 34,350] |
| Campylobacter coli | ||
| LoD (CFU/mL in SBT)[95% confidence interval] | 95 [70-128] | 55 [41-76] |
| LoD (CFU/mL in stool)[95% confidence interval] | 14,250 [10,500 - 19,200] | 8,250 [6,150-11,400] |
| E. coli stx1 / stx2 | ||
| LoD (CFU/mL in SBT)[95% confidence interval] | 910 [550 - 1,505] | 653 [384-1111] |
| LoD (CFU/mL in stool)[95% confidence interval] | 136,500 [82,500 - 225,750] | 97,950 [57,600 - 166,650] |
| Salmonella enteriditis | ||
| LoD (CFU/mL in SBT)[95% confidence interval] | 620 [403-954] | 502 [345-729] |
| LoD (CFU/mL in stool)[95% confidence interval] | 93,000 [60,450 - 143,100] | 75,300 [51,750 - 109,350] |
| Shigella flexneri | ||
| LoD (CFU/mL in SBT)[95% confidence interval] | 374 [249-561] | 229 [151-347] |
| LoD (CFU/mL in stool)[95% confidence interval] | 56,100 [37,350 - 84,150] | 34,350 [22,650 - 52,050] |
| Campylobacter jejuni | ||
| LoD (CFU/mL in SBT)[95% confidence interval] | 42 [36-49] | 10 [9-10] |
| LoD (CFU/mL in stool)[95% confidence interval] | 6,300 [5,400 - 7,350] | 1,500 [1,350 - 1,500] |
| E. coli stx2 | ||
| LoD (CFU/mL in SBT)[95% confidence interval] | 722 [519-1006] | 599 [291-1231] |
| LoD (CFU/mL in stool)[95% confidence interval] | 108,300 [77,850 - 150,900] | 89,850 [43,650 – 184,650] |
| E. coli stx1 | ||
| LoD (CFU/mL in SBT)[95% confidence interval] | 255 [195-332] | 223 [167-299] |
| LoD (CFU/mL in stool)[95% confidence interval] | 38,202 [29,259 – 49,865] | 33,495 [25,026 - 44,817] |
Table 13: BD MAX™ Enteric Bacterial Panel Target Limits of Detection
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Analytical Inclusivity
The objective of this study was to demonstrate that the BD MAX™ Enteric Bacterial Panel is able to detect clinically relevant and geographically diverse serovars/strains/ subspecies for each of the BD MAX™ Enteric Bacterial Panel targets found in various geographical origins (e.g., United States, European Union, Canada, other geographical regions).
The study was designed to validate the functional performance of the BD MAX" Enteric Bacterial Panel by verifying the specificity of the assay's primers and probes for the targeted bacterial enteric analytes [Salmonella spp., Campylobacter spp. (jejuni and coli), Shigella spp. and Enteroinvasive E. coli (EIEC)) as well as Shiga toxinproducing organisms.
One-hundred twenty-one (121) enteric target organism strains, serovars, or subspecies Table 14) were included in the study at 1x the point estimate of the 95% LoD obtained in the BD MAX™ Enteric Bacterial Panel LoD study (Table 13). Organisms were prepared and tested as 'target mixes', consisting of one strain/serovar/ subspecies from each of the target organisms. Specimen target mixes were diluted and screened to the pre-determined, genus-specific LoD. The assay correctly identified 120 of the 121 strains tested at the LOD. One strain of Shigella sonnei (ENF 15987) demonstrated 79.17% positivity at a concentration of 56.1 CFU/mL. The isolate was further evaluated and vielded 100% positivity at a concentration of 405 CFU/mL. Seven (7) other strains of Shigella sonnei were evaluated during the analytical inclusivity study and met the study acceptance criteria at a concentration of 56.1 CFU/mL.
| Organism | Organism ID |
|---|---|
| C. jejuni subsp. doylei | ATCC 49349 |
| C. jejuni subsp. doylei | ATCC BAA-1458 |
| C. jejuni subsp. doylei | BD NH1 450 |
| C. jejuni subsp. doylei | BD NH 451 |
| C. jejuni subsp. doylei | BD NH 452 |
| C. jejuni subsp. jejuni | ATCC 33292 |
| C. jejuni subsp. jejuni | ATCC 33560 |
| C. jejuni subsp. jejuni | ATCC 35918 |
| C. jejuni subsp. jejuni | ATCC 29428 |
| C. jejuni subsp. jejuni | ATCC 43434 |
| C. jejuni subsp. jejuni | ATCC 43435 |
| C. jejuni subsp. jejuni | ATCC 43449 |
| C. jejuni subsp. jejuni | ATCC 43503 |
| C. jejuni subsp. jejuni | ATCC 6960 |
| C. jejuni subsp. jejuni | ATCC 700819 |
| Campylobacter coli | ATCC 43483 |
| Campylobacter coli | ATCC 43484 |
| Organism | Organism ID |
| Campylobacter coli | ATCC 43133 |
| Campylobacter coli | ATCC 43135 |
| Campylobacter coli | ATCC 43136 |
| Campylobacter coli | ATCC 43472 |
| Campylobacter coli | ATCC 43473 |
| Campylobacter coli | ATCC 43478 |
| Campylobacter coli | ATCC 43481 |
| Campylobacter coli | ATCC 43482 |
| Campylobacter coli | ATCC 43485 |
| Campylobacter coli | ATCC 49941 |
| Campylobacter coli | BD NH 422 |
| Campylobacter coli | BD NH 423 |
| Campylobacter coli | BD NH 424 |
| Escherichia coli (EIEC) | BD ENF² 15626 |
| Escherichia coli O103:H11 | ATCC BAA-2215 |
| Escherichia coli O103:H2 | BD ENF15805 |
| Escherichia coli O103:H2 | ATCC BAA-2210 |
| Escherichia coli O103:H25 | ATCC BAA-2213 |
| Escherichia coli O103:H8 | BD ENF 15804 |
| Escherichia coli O104:H21 | ATCC BAA 178 |
| Escherichia coli O111:H8 | ATCC BAA-184 |
| Escherichia coli O111:H8 | ATCC BAA-2217 |
| Escherichia coli O111:H8 | ATCC BAA-179 |
| Escherichia coli O111:NM | BD ENF15809 |
| Escherichia coli O113:H21 | ATCC BAA-177 |
| Escherichia coli O121:H19 | ATCC BAA-2219 |
| Escherichia coli O124:NM (EIEC) | ATCC 43893 |
| Escherichia coli O145:H25 | ATCC BAA-2211 |
| Escherichia coli O145:H28 | ATCC BAA-2129 |
| Escherichia coli O145:H48 | ATCC BAA-1652 |
| Escherichia coli O145:NM | BD ENF15811 |
| Escherichia coli O145:NM | ATCC BAA-2222 |
| Escherichia coli O145:NM | BD ENF15812 |
| Escherichia coli O157 | BD ENF13581 |
| Escherichia coli O157 | BD ENF 7582 |
| Escherichia coli O157 | BD ENF13568 |
| Escherichia coli O157 | BD ENF13604 |
| Escherichia coli O157:H7 | BD ENF13579 |
| Organism | Organism ID |
| Escherichia coli O157:H7 | ATCC 43894 |
| Escherichia coli O157:H7 | ATCC 35150 |
| Escherichia coli O157:NM | ATCC 700376 |
| Escherichia coli O157:NM | BD ENF10301 |
| Escherichia coli O29:NM (EIEC) | ATCC 43892 |
| Escherichia coli O91:H21 | ATCC 51435 |
| Escherichia coli O91:H21 | ATCC 51434 |
| Escherichia coli OX3:H21 | BD ENF 15816 |
| Salmonella agona | BD ENF 15960 |
| Salmonella anatum | BD ENF 15961 |
| Salmonella aareilly | ATCC 9115 |
| Salmonella bongori | ATCC 43975 |
| Salmonella bongori | BD ENF 16009 |
| Salmonella araenderup | BD ENF 15962 |
| Salmonella aholeraesuis | ATCC 7001 |
| Salmonella enterica subsp. arizonae | ATCC 13314 |
| Salmonella enterica subsp. diarizonae | ATCC 29226 |
| Salmonella enterica subsp. diarizonae | ATCC 43973 |
| Salmonella enterica subsp. houtenae | ATCC 15788 |
| Salmonella enterica subsp. houtenae | ATCC 43974 |
| Salmonella enterica subsp. indica | ATCC BAA-1576 |
| Salmonella enterica subsp. indica | ATCC 43976 |
| Salmonella enterica subsp. salamae | ATCC 43972 |
| Salmonella hadar | ATCC 51956 |
| Salmonella heidelberg | BD ENF15963 |
| Salmonella infantis | ATCC 51741 |
| Salmonella javiana | BD ENF13330 |
| Salmonella montevideo | BD ENF 15964 |
| Salmonella muenchen | BD ENF 8388 |
| Salmonella newport | BD ENF15965 |
| Salmonella oranienburg | BD ENF 7482 |
| Salmonella paratyphi A | ATCC 9150 |
| Salmonella paratyphi B | ATCC 51962 |
| Salmonella saintpaul | BD ENF 15967 |
| Salmonella schwarzengrund | BD ENF 7452 |
| Salmonella thompson | BD ENF 15968 |
| Salmonella typhi | ATCC 10749 |
| Salmonella virchow | ATCC 51955 |
| Organism | Organism ID |
| Shigella boydii | ATCC 12028 |
| Shigella boydii | ATCC 8700 |
| Shigella boydii | ATCC 9207 |
| Shigella boydii | BD ENF 15975 |
| Shigella boydii | BD ENF 15976 |
| Shigella dysenteriae | ATCC 11835 |
| Shigella dysenteriae | ATCC 13313 |
| Shigella dysenteriae | ATCC 9361 |
| Shigella dysenteriae | BD ENF 2932 |
| Shigella dysenteriae | BD ENF 15977 |
| Shigella flexneri | ATCC 29903 |
| Shigella flexneri | ATCC 33948 |
| Shigella flexneri | BD ENF 2900 |
| Shigella flexneri | BD ENF 7419 |
| Shigella flexneri | ATCC 12022 |
| Shigella flexneri | BD ENF 15983 |
| Shigella flexneri | BD ENF 15984 |
| Shigella flexneri | BD ENF 15985 |
| Shigella flexneri | BD ENF 15428 |
| Shigella flexneri | BD ENF 2903 |
| Shigella sonnei | ATCC 13096 |
| Shigella sonnei | ATCC 25931 |
| Shigella sonnei | BD ENF 5704 |
| Shigella sonnei | BD ENF 8063 |
| Shigella sonnei | BD ENF 15986 |
| Shigella sonnei | BD ENF 15987 |
| Shigella sonnei | BD ENF 15988 |
| Shigella sonnei | ATCC 29930 |
Table 14: Inclusivity Organisms
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TBD NH - BD internal strain designation
²BD ENF – BD internal strain designation
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Analytical Specificity
The BD MAX™ Enteric Bacterial Panel was performed on samples containing phylogenetically related species and other organisms (bacteria, viruses, parasites and veast) likely to be found in stool specimens.
- Nine (9) out of 9 Campylobacter strains (Campylobacter species other than C. iejuni or C. coli) with undetectable tuf gene sequences, tested at a concentration ≥ 1 x 10° CFU/mL per SBT, produced negative results with the BD MAX™ Enteric Bacterial Panel.
- Six (6) out of 6 E. coli strains other than Shiga toxin-producing strains, tested at a . concentration ≥ 1 x 10° CFU/mL of SBT. produced negative results with the BD MAX™ Enteric Bacterial Panel.
- . Ninety-eight (98) out of 99 other bacterial strains (including 53 species and subspecies). tested at a concentration ≥ 1 x 10° CFU/mL of SBT (or ~ 1 x 108 genomic DNA cp/mL or 1 x 10° elementary bodies/mL of SBT), produced negative results with the BD MAX™ Enteric Bacterial Panel. S. boydii (ATCC 12028) produced 1 replicate out of 3 as positive for the presence of stx.
- Fifteen (15) out of 15 viruses, tested at a concentration ≥ 1 x 104 PFU/mL of SBT, . produced negative results with the BD MAX™ Enteric Bacterial Panel.
- Three (3) out of 3 ova and parasites, tested at a concentration ≥ 1 x 105 cysts/mL . of SBT, produced negative results with the BD MAX™ Enteric Bacterial Panel.
- . Sixteen (16) Enteric organisms representing each target of the BD MAX™ Enteric Bacterial Panel were tested, with results as follows:
- o Three (3) of 3 Campylobacter spp.; one C. coli, one C. jejuni, subsp. doylei and one C. jejuni, subsp. jejuni bearing the tuf gene tested at a concentration ≥ 1 x 108 CFU/mL of SBT, produced positive results for Campylobacter and negative results for all other targets with the BD MAX™ Enteric Bacterial Panel.
- Four (4) of 4 E. coli: two O157 and two non-O157 strains bearing the stx gene tested at a concentration ≥ 1 x 10° CFU/mL of SBT, produced positive results for E. coli and negative results for all other targets with the BD MAX™ Enteric Bacterial Panel.
- Five (5) of 5 Salmonella spp. bearing the spaO gene tested at a o concentration≥ 1 x 108 CFU/mL of SBT, produced positive results for Salmonella and negative results for all other targets with the BD MAX™ Enteric Bacterial Panel.
- Three (3) of 4 Shigella spp.; one S. sonnei, one S. boydii, one S. flexneri and S. dysentariae bearing the ipaH gene tested at a concentration ≥ 1 x 10° CFU/mL of SBT, produced positive results for ipaH and negative results for all other targets with the BD MAX™ Enteric Bacterial Panel.
- Initial testing of S. boydii (ATCC 12028) produced 1 replicate out . of 3 as positive for the presence of stx. Subsequent testing of this strain produced positive results with 8 out of 20 replicates for the presence of stx.
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Interfering Substances
Nineteen (19) biological and chemical substances occasionally used or found in stool specimens were evaluated for potential interference with the BD MAX Enteric Bacterial Panel. Included in this study was an Antibiotics Mixture, which consisted of a combination of 8 different antibiotics, tested simultaneously, with each antibiotic at a concentration that may be excreted in a stool sample. Vagisil was identified as a potentially interfering substance at a concentration of 9.2% Vagisil in a stool sample or 0.92 mg/mL of SBT. Nystatin cream and spermicidal lubricant both demonstrated potential interference at a concentration of 50% (5.0 mg/mL of interferent in the SBT). The BD MAX Enteric Bacterial Panel demonstrated acceptable performance with nystatin cream at a concentration of 31% (3.1 mg/mL of nystatin cream in the SBT) and spermicidal lubricant at 34% (3.4 mg/mL of spermicidal lubricant in the SBT). Results demonstrated no reportable interference with any other substance tested (Table 15).
Table 15: Endogenous and Commercial Exogenous Substances tested with the BD MAX Enteric Bacterial Panel
| Brand Name orDescription | Result | Brand Name or Description | Result |
|---|---|---|---|
| Fecal Fat | NI | Spermicidal Lubricant | P |
| Human DNA | NI | Diaper Rash Cream | NI |
| Mucus | NI | Vagisil | 1 |
| Whole human blood | NI | Laxatives | NI |
| Hydrocortisone Cream | NI | Anti-Diarrheal (liquid) | NI |
| Antiseptic Towelettes | NI | Anti-Diarrheal (pill) | NI |
| Enema | NI | Antibiotics Mixture | NI |
| Hemorrhoidal Gel | NI | Antacids | NI |
| Nystatin Cream | P | Non-Steroidal Anti-Inflammatory(NSAID) | NI |
| Topical Antibiotic | NI |
1: Interference with the BD MAX Enteric Bacterial Panel,
P: Potential interference with the BD MAX Enteric Bacterial Panel at high concentrations
NI: No reportable interference with the BD MAX Enteric Bacterial Panel.
Carryover / Cross-Contamination
A study was conducted to investigate the potential for cross-contamination between high positive and negative specimens throughout the BD MAX™ Enteric Bacterial Panel workflow. Of one-hundred sixty-seven (167) valid results, one-hundred sixty-six (166) valid negative results were reported for all targets. Four (4) false positive results were reported overall, all from 1 sample tube. The overall contamination rate was 0.6% for all targets, and for the study as a whole.
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Mixed Infection/Competitive Interference
The mixed infection/competitive interference study was designed to evaluate the ability of the BD MAX Enteric Bacterial Panel to detect low positive results in the presence of other targets at high concentrations. Four (4) organisms (Salmonella typhimurium, Campylobacter coli, Shigella sonnei and E. coli O157:H7) were individually prepared at 1.5X their respective LoD to serve as a low target in the BD MAX Enteric Bacterial Panel SBT. A high target mix comprised of the organisms representative of the other three BD MAX Enteric Bacterial Panel analytes at a concentration of > 1x10 CFU/mL in the SBT was spiked into the SBT along with 10 uL of unpreserved stool and tested to simulate mixed infections. All four low target orqanisms were successfully detected by the BD MAX Enteric Bacterial Panel when combined with their respective simulated high target concentration mixed infection preparations.
Clinical Performance Studies
The Clinical Accuracy study was designed to assess the performance of the BD MAX™ Enteric Bacterial Panel for the identification of Campylobacter (ieiuni & coli), Salmonella spp. Shigella spp. and EIEC as well as shiga toxin-producing organisms , from unpreserved or Cary-Blair preserved soft to diarrheal stool specimens. This multicenter study evaluated results obtained with the BD MAX Enteric Bacterial Panel compared to those obtained with the reference method. Clinical centers were employed to collect and test patient specimens; whereas collection centers were employed to collect and test patient specimens using the reference method, with BD MAX™ Enteric Bacterial Panel testing being performed by a testing center.
The study involved a total of eight (8) geographically diverse clinical centers where specimens were collected as part of routine patient care, enrolled into the trial, and tested on the BD MAX™ Enteric Bacterial Panel. Only excess, de-identified palient specimens were used. Additionally, an internal site was involved as a clinical center to perform BD MAX™ testing on specimens supplied by other collection centers.
Clinical centers were selected for the clinical study based on a number of criteria, such as investigator and site personnel availability, number of specimens of interest tested for each target, prevalence, and familiarity with PCR methodology. The clinical centers were also selected according to the specimen types that they routinely collect. Collection centers were selected for their high level of similarity with clinical centers in the culture and identification methods used for the study targets. Clinical centers utilizing methodologies that did not have a high degree of similarity sent specimens to a central laboratory for reference method testing. Prospective (fresh) specimens collected at the collection centers consisted of a mix of Cary-Blair preserved and unpreserved specimens, and were not pre-selected but rather collected on an "all-comers" basis between June and September, 2013. Accordingly, the specimens were enrolled as prospective specimens.
Retrospective (frozen) specimens were collected from sites between March 2012 and August 2013. Further, one site enrolled unpreserved specimens collected and archived from June to September 2007 and from October to December 2011. Inclusion and exclusion criteria were identical to those as for prospective specimens. Retrospective specimens were stored frozen (-20 °C or lower) after collection and did not undergo
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freeze-thaw cycles. Specimens were thawed at the time of testing with the BD MAX™ Enteric Bacterial Panel.
For retrospective specimens, the historical culture results were recorded at the collection site and the specimens were not re-cultured. The historical culture results were confirmed using an alternate PCR and bi-directional amplicon sequencing as part of the composite reference method in order to confirm the presence of target DNA.
A total of 3457 prospective specimens (2112 Cary-Blair preserved and 1345 unpreserved) and 785 retrospective specimens (464 Cary-Blair preserved and 321 unpreserved) were enrolled. Table 16 below presents the number of prospective compliant specimens for which a reportable (positive or negative) result was obtained by the reference method and for which a reportable result was obtained by the BD MAX EBP (i.e., the total compliant dataset used for PPA and NPA calculations), by target and specimen type. A total of 104 retrospective specimens were not included in the performance calculations below as the historical results were not confirmed by an alternate PCR and bi-directional sequencing.
| Campylobacter | Shigella | Salmonella | Shigatoxins | |
|---|---|---|---|---|
| Positive | ||||
| Cary-Blair | 26 | 19 | 20 | 8 |
| Unpreserved | 22 | 22 | 24 | 2 |
| Sub-Total | 48 | 41 | 44 | 10 |
| Negative | ||||
| Cary-Blair | 1774 | 1809 | 1808 | 1781 |
| Unpreserved | 1216 | 1219 | 1215 | 711 |
| Sub-Total | 2990 | 3028 | 3023 | 2492 |
| Grand Total | 3038 | 3069 | 3067 | 2502 |
Table 16: Summary of Prospective Enrollment, by Target and Specimen Type
Table 17 describes the number of compliant specimens enrolled by patient age and specimen type. A total of 104 retrospective specimens were not included in the performance calculations below as the historical results were not confirmed by an alternate PCR and bi-directional sequencing. Tables 19 through 22 describe the performance characteristics of the BD MAX™ Enteric Bacterial Panel that were observed during the clinical trial.
Table 17: Compliant clinical trial enrollment summary by age group and specimen type
| Age Group | Cary-BlairPreserved | Unpreserved | Combined |
|---|---|---|---|
| < 1 | 110 | 43 | 153 |
| 1-4 | 302 | 128 | 430 |
| 5-12 | 270 | 209 | 479 |
| 13-18 | 271 | 168 | 439 |
| 19-65 | 1222 | 799 | 2021 |
| Over 65 | 388 | 249 | 637 |
| Unknown | 3 | 2 | 5 |
| Total | 2566 | 1598 | 4164 |
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Table 18 below presents the number of compliant specimens for which historical routine results were confirmed by the confirmatory method (i.e. alternate PCR and bi-directional amplicon sequencing) and for which a reportable result was obtained by the BD MAX EBP (i.e., the total compliant dataset used for PPA and NPA calculations), by target and specimen type.
| Campylobacter | Shigella | Salmonella | Shigatoxins | |
|---|---|---|---|---|
| Positive | ||||
| Cary-Blair | 66 | 51 | 106 | 41 |
| Unpreserved | 67 | 41 | 61 | 25 |
| Sub-Total | 133 | 92 | 167 | 66 |
| Negative | ||||
| Cary-Blair | 151 | 187 | 213 | 79 |
| Unpreserved | 223 | 264 | 238 | 11 |
| Sub-Total | 374 | 451 | 451 | 90 |
| Grand Total | 507 | 543 | 618 | 156 |
Table 18: Summary of Retrospective (Frozen) Enrollmen
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For the Cary-Blair preserved specimen type, the BD MAX Enteric Bacterial Panel identified 96.2% and 98.7% of the Campylobacter spp. prospective and negative specimens, respectively, and 97% and 100% of the retrospective and negative specimens, respectively. For the unpreserved specimen type, the BD MAX Enteric Bacterial Panel identified 100% and 97.5% of the Campylobacter spp. prospective positive and negative specimens, respectively, and 99.1% of the retrospective positive and negative specimens, respectively (Table 19).
| Specimen Type | Specimen Origin | BD MAX | RM | Total | |
|---|---|---|---|---|---|
| P | N | ||||
| Cary-Blair | Prospective(Fresh) | P | 25 | 232 | 48 |
| N | 11 | 1751 | 1752 | ||
| Total | 26 | 1774 | 1800 | ||
| PPA (95% CI): 96.2% (81.1%, 99.3%) | |||||
| NPA (95% CI): 98.7% (98.1%, 99.1%) | |||||
| Cary-Blair | Retrospective(Frozen) | P | 64 | 0 | 64 |
| N | 2 | 151 | 153 | ||
| Total | 66 | 151 | 217 | ||
| PPA (95% CI): 97% (89.6%, 99.2%) | |||||
| NPA (95% CI): 100% (97.5%, 100%) | |||||
| Unpreserved | Prospective(Fresh) | P | 22 | 313 | 53 |
| N | 0 | 1185 | 1185 | ||
| Total | 22 | 1216 | 1238 | ||
| PPA (95% CI): 100% (85.1%, 100%) | |||||
| NPA (95% CI): 97.5% (96.4%, 98.2%) | |||||
| Unpreserved | Retrospective(Frozen) | P | 65 | 2 | 67 |
| N | 2 | 221 | 223 | ||
| Total | 67 | 223 | 290 | ||
| PPA (95% CI): 97% (89.8%, 99.2%) | |||||
| NPA (95% CI): 99.1% (96.8%, 99.8%) |
Table 19: Campylobacter spp. - Overall Performance
් This specimen was also tested using an alternate PCR assay followed by bi-directional sequencing and gave a negative result.
These twenty-three (23) specimens were also tested using an alternate PCR assay followed by bi-
directional sequencing; ten (10) of twenty-three (23) gave a positive result.
3 These thirty-one (31) specimens were also tested using an alternate PCR assay followed by bi-directional sequencing; fourteen (14) of thirty-one (31) gave a positive result.
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For the Cary-Blair preserved specimen type, the BD MAX Enteric Bacterial Panel identified 85% and 99.1% of the Salmonella spp. prospective positive and negative specimens, respectively, and 99.1% and 100% of the retrospective positive and negative specimens, respectively. For the unpreserved specimen type, the BD MAX Enteric Bacterial Panel identified 91.7% and 98.9% of the Salmonella spp. prospective positive and negative specimens, respectively, and 100% and 99.6% of the retrospective positive and negative specimens, respectively (Table 20).
| Specimen Type | Specimen Origin | BD MAX | RM | Total | |
|---|---|---|---|---|---|
| P | N | ||||
| Cary-Blair | Prospective(Fresh) | P | 17 | 172 | 34 |
| N | 31 | 1791 | 1794 | ||
| Total | 20 | 1808 | 1828 | ||
| PPA (95% CI): 85% (64%, 94.8%) | |||||
| NPA (95% CI): 99.1% (98.5%, 99.4%) | |||||
| Cary-Blair | Retrospective(Frozen) | P | 105 | 0 | 105 |
| N | 1 | 213 | 214 | ||
| Total | 106 | 213 | 319 | ||
| PPA (95% CI): 99.1% (94.8%, 99.8%) | |||||
| NPA (95% CI): 100% (98.2%, 100%) | |||||
| Unpreserved | Prospective(Fresh) | P | 22 | 133 | 35 |
| N | 21 | 1202 | 1204 | ||
| Total | 24 | 1215 | 1239 | ||
| PPA (95% CI): 91.7% (74.2%, 97.7%) | |||||
| NPA (95% CI): 98.9% (98.2%, 99.4%) | |||||
| Unpreserved | Retrospective(Frozen) | P | 61 | 1 | 62 |
| N | 0 | 237 | 237 | ||
| Total | 61 | 238 | 299 | ||
| PPA (95% CI): 100% (94.1%, 100%) | |||||
| NPA (95% CI): 99.6% (97.7%, 99.9%) |
Table 20: Salmonella spp. – Overall Performance
1 These three (3) specimens were also tested using an alternate PCR assay followed by bi-directional
sequencing and gave a negative result.
4 These seventeen (17) specimens were also tested using an alternate PCR assay followed by bi-directional sequencing; eleven (11) of seventeen (17) gave a positive result.
3 These thirteen (13) specimens were also tested using an alternate PCR assay followed by bi-directional sequencing; eleven (11) of thirteen (13) gave a positive result.
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For the Cary-Blair preserved specimen type, the BD MAX Enteric Bacterial Panel identified 100% and 99.7% of the Shigella spp. / EIEC organisms prospective positive and negative specimens, respectively, and 98% and 100% of the retrospective positive and negative specimens, respectively. For the unpreserved specimen type, the BD MAX Enteric Bacterial Panel identified 100% and 99.4% of the Shigella spp. / EIEC organisms prospective positive and negative specimens, respectively, and 100% of the retrospective positive and negative specimens, respectively (Table 21).
| Specimen Type | Specimen Origin | BD MAX | RM | |||
|---|---|---|---|---|---|---|
| p | N | Total | ||||
| P | 19 | ട് ' | 24 | |||
| Cary-Blair | Prospective(Fresh) | N | O | 1804 | 1804 | |
| Total | 19 | 1809 | 1828 | |||
| PPA (95% CI): 100% (83.2%, 100%) | ||||||
| NPA (95% CI): 99.7% (99.4%, 99.9%) | ||||||
| P | 50 | O | 50 | |||
| Cary-Blair | Retrospective | N | 1 | 187 | 188 | |
| (Frozen) | Total | 51 | 187 | 238 | ||
| PPA (95% CI): 98% (89.7%, 99.7%) | ||||||
| NPA (95% CI): 100% (98%, 100%) | ||||||
| Prospective | 2 | 22 | 72 | 29 | ||
| Unpreserved | (Fresh) | N | O | 1212 | 1212 | |
| Total | 22 | 1219 | 1241 | |||
| PPA (95% CI): 100% (85.1%, 100%) | ||||||
| NPA (95% CI): 99.4% (98.8%, 99.7%) | ||||||
| Retrospective(Frozen) | P | 41 | O | 41 | ||
| Unpreserved | N | 0 | 264 | 264 | ||
| Total | 41 | 264 | 305 | |||
| PPA (95% Cl): 100% (91.4%, 100%) | ||||||
| NPA (95% CI): 100% (98.6%, 100%) |
Table 21: Shigella spp. / EIEC - Overall Performance
1 These five (5) specimens were also tested using an alternate PCR assay followed by bi-directional sequencing; all five (5) specimens gave a positive result.
² These seven (7) specimens were also tested using an alternate PCR assay followed by bi-directional
sequencing; six (6) of seven (7) gave a positive result.
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For the Cary-Blair preserved specimen type, the BD MAX Enteric Bacterial Panel identified 75% and 99.3% of the Shiga toxins (stx1/stx2) prospective positive and negative specimens, respectively, and 100% of the retrospective positive and negative specimens, respectively. For the unpreserved specimen type, the BD MAX Enteric Bacterial Panel identified 100% and 99% of the Shiga toxins (stx1 and/or stx2) prospective positive and negative specimens, respectively, and 100% and 100% of the retrospective positive and negative specimens, respectively (Table 22).
| Specimen Type | Specimen Origin | BD MAX | RM | Total | |
|---|---|---|---|---|---|
| P | N | ||||
| Cary-Blair | Prospective(Fresh) | P | 6 | 132 | 19 |
| N | 21 | 1768 | 1770 | ||
| Total | 8 | 1781 | 1789 | ||
| PPA (95% CI): 75% (40.9%, 92.9%) | |||||
| NPA (95% CI): 99.3% (98.8%, 99.6%) | |||||
| Cary-Blair | Retrospective(Frozen) | P | 41 | 0 | 41 |
| N | 0 | 79 | 79 | ||
| Total | 41 | 79 | 120 | ||
| PPA (95% CI): 100% (91.4%, 100%) | |||||
| NPA (95% CI): 100% (95.4%, 100%) | |||||
| Unpreserved | Prospective(Fresh) | P | 2 | 73 | 9 |
| N | 0 | 704 | 704 | ||
| Total | 2 | 711 | 713 | ||
| PPA (95% CI): 100% (34.2%, 100%) | |||||
| NPA (95% CI): 99% (98%, 99.5%) | |||||
| Unpreserved | Retrospective(Frozen) | P | 25 | 0 | 25 |
| N | 0 | 11 | 11 | ||
| Total | 25 | 11 | 36 | ||
| PPA (95% CI): 100% (86.7%, 100%) | |||||
| NPA (95% CI): 100% (74.1%, 100%) |
Table 22: Shiga toxins (stx1/stx2) - Overall Performance
1 These two (2) specimens were also tested using an alternate PCR assay followed by bi-directional sequencing and gave a negative result.
2 These thirteen (13) specimens were also tested using an alternate PCR assay followed by bi-directional sequencing: seven (7) of thirteen (13) gave a positive result.
3 These seven (7) specimens were also tested using an alternate PCR assay followed by bi-directional sequencing; three (3) of seven (7) gave a positive result.
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Performance of the BD MAX Enteric Bacterial Panel by species/toxin type as observed during the clinical trial is presented below in Tables 23 through 25. The species identification was obtained either from the culture and identification portion of the reference method testing or from sequencing performed for the confirmation of retrospective specimen historical results and on discrepant prospective specimens. While the BD MAX Enteric Bacterial Panel is designed to detect the species and toxin types described below, the panel does not report results to the species or toxin level.
| Campylobacter | PPA | |||
|---|---|---|---|---|
| SpecimenType | Specimen Origin | Species | Estimate | 95% CI |
| Cary-BlairPreserved | Prospective(Fresh) | jejuni | 95.8% (23/24) | (79.8%, 99.3%) |
| Retrospective(Frozen) | Untyped | 100.0% (2/2) | (34.2%, 100.0%) | |
| Retrospective(Frozen) | coli | 100.0% (2/2) | (34.2%, 100.0%) | |
| Prospective(Fresh) | jejuni | 96.9% (62/64) | (89.3%, 99.1%) | |
| Unpreserved | Prospective(Fresh) | jejuni | 100.0% (19/19) | (83.2%, 100.0%) |
| Retrospective(Frozen) | jejuni or coli | 100.0% (1/1) | (20.7%, 100.0%) | |
| Retrospective(Frozen) | Untyped | 100.0% (2/2) | (34.2%, 100.0%) | |
| Prospective(Fresh) | coli | 100.0% (5/5) | (56.6%, 100.0%) | |
| Prospective(Fresh) | jejuni | 96.8% (60/62) | (89.0%, 99.1%) |
Table 23: Campylobacter performance per species observed during the clinical trial
1 Of these specimens, one (1) prospective specimen was also tested using a validated PCR assay followed by bi-directional sequencing and gave a negative result.
| Shigella | PPA | |||
|---|---|---|---|---|
| SpecimenType | Specimen Origin | Species | Estimate | 95% CI |
| Cary-BlairPreserved | Prospective(Fresh) | flexneri | 100.0% (1/1) | (20.7%, 100.0%) |
| Prospective(Fresh) | sonnei | 100.0% (18/18) | (82.4%, 100.0%) | |
| Retrospective(Frozen) | sonnei | 98.0% (50/51) | (89.7%, 99.7%) | |
| Unpreserved | Prospective(Fresh) | flexneri | 100.0% (2/2) | (34.2%, 100.0%) |
| Prospective(Fresh) | sonnei | 100.0% (20/20) | (83.9%, 100.0%) | |
| Retrospective(Frozen) | flexneri | 100.0% (1/1) | (20.7%, 100.0%) | |
| Retrospective(Frozen) | sonnei | 100.0% (40/40) | (91.2%, 100.0%) |
Table 24: Shigella performance per species type observed during the clinical trial
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| Shiga toxins | PPA | |||
|---|---|---|---|---|
| SpecimenType | Specimen Origin | Toxin Type | Estimate | 95% CI |
| Cary-BlairPreserved | Prospective(Fresh) | stx1 | 100.0% (4/4) | (51.0%, 100.0%) |
| Prospective(Fresh) | stx2 | 100.0% (1/1) | (20.7%, 100.0%) | |
| Prospective(Fresh) | stx1 and stx2¹ | 33.3% (1/3) | (6.1%, 79.2%) | |
| Cary-BlairPreserved | Retrospective(Frozen) | stx1 | 100.0% (28/28) | (87.9%, 100.0%) |
| Retrospective(Frozen) | stx2 | 100.0% (6/6) | (61.0%, 100.0%) | |
| Retrospective(Frozen) | stx1 and stx2 | 100.0% (7/7) | (64.6%, 100.0%) | |
| Unpreserved | Prospective(Fresh) | stx1 | 100.0% (1/1) | (20.7%, 100.0%) |
| Prospective(Fresh) | stx1 and stx2 | 100.0% (1/1) | (20.7%, 100.0%) | |
| Unpreserved | Retrospective(Frozen) | stx1 | 100.0% (5/5) | (56.6%, 100.0%) |
| Retrospective(Frozen) | stx2 | 100.0% (6/6) | (61.0%, 100.0%) | |
| Retrospective(Frozen) | stx1 and stx2 | 100.0% (14/14) | (78.5%, 100.0%) |
Table 25: Shiga toxins performance per toxin type observed during the clinical trial
1 Two (2) prospective specimens were also tested using a validated PCR assay followed by bi-directional sequencing and gave a negative result.
Table 26 below shows the co-infections detected by the BD MAX Enteric Bacterial Panel during the prospective segment of the clinical trial. Note that there were no co-infections detected by the reference method during the prospective segment of the clinical trial.
Table 26: Co-infections observed during the BD MAX Enteric Bacterial Panel prospective clinical trial
| Distinct Co-infection CombinationsDetected by BD MAX Enteric BacterialAssay | Number ofDiscrepant Co-Infections | Discrepant Analyte(s)1 | |
|---|---|---|---|
| Analyte 1 | Analyte 2 | ||
| Shigella | stx | 1 | stx2 |
| stx | Campylobacter | 1 | stx3 |
| stx | Salmonella | 2 | stx (2) and Salmonella (1)4 |
| Campylobacter | Salmonella | 2 | Campylobacter (2), Salmonella (1)5 |
A discrepant co-infection or discrepant analyte was defined as one that was detected by the BD MAX assay but not detected by the reference method.
2 One (1) discrepant six was investigated using an alternate method; bi-directional sequence analysis identified the analyte in 0/1 cases.
3 One (1) discrepant stx was investigated using an alternate method; bi-directional sequence analysis identified the analyte in 1/1 cases.
4 Two (2) discrepant stx were investigated using an alternate method; bi-directional sequence analysis identified the analyte in 0/2 cases. One (1) discrepant Salmonella was investigated using an allernate method; bi-directional sequence analysis identified the analyte in 1/1 cases.
Two (2) discrepant Campylobacter were investigated using an allernate method; bi-directional sequence analysis identified the analyte in 0/2 cases. One (1) discrepant Salmonella was investigated using an alternate method; bi-directional sequence analysis identified the analyte in 0/1 cases.
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Of the 3183 prospective specimens initially evaluated with the BD MAX™ Enteric Bacterial Panel, 4.0% of the Carv-Blair preserved and 7.8% of the unpreserved specimens initially reported as Unresolved. Following a valid repeat test, 0.1% of the Cary-Blair preserved and 1.0% of the unpreserved specimens remained Unresolved. Of the 783 retrospective specimens initially evaluated with the BD MAX™ Enteric Bacterial Panel, 2.2% of the Cary-Blair preserved and 4.1% of the unpreserved specimens initially reported as Unresolved. Following a valid repeat test, 0.2% of the Cary-Blair preserved and 0.6% of the unpreserved specimens remained Unresolved (Table 27). The total numbers provided in Table 27 are based on compliant specimens and BD MAX™ Enteric Bacterial Panel results.
| Initial Unresolved Rates | Unresolved Rates AfterRepeat | ||||
|---|---|---|---|---|---|
| SpecimenType | SpecimenOrigin | Percent | 95% Cl | Percent | 95% Cl |
| Cary-Blair | Prospective(Fresh) | 4.0% (77/1905) | (3.2%, 5.0%) | 0.1% (2/1897) | (0.0%, 0.4%) |
| Retrospective(Frozen) | 2.2% (10/464) | (1.2%, 3.9%) | 0.2% (1/463) | (0.0%, 1.2%) | |
| Unpreserved | Prospective(Fresh) | 7.8%(100/1278) | (6.5%, 9.4%) | 1.0% (13/1251) | (0.6%, 1.8%) |
| Retrospective(Frozen) | 4.1% (13/319) | (2.4%, 6.8%) | 0.6% (2/317) | (0.2%, 2.3%) |
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BD MAX™ Enteric Bacterial Panel
Of the 3183 prospective specimens initially evaluated with the BD MAX™ Enteric Bacterial Panel, 1.7% of the Cary-Blair preserved and 1.6% of the unpreserved specimens initially reported as Indeterminate. Following a valid repeat test, 0% of the Cary-Blair preserved and 0.2% of the unpreserved specimens remained Indeterminate. Of the 783 retrospective specimens initially evaluated with the BD MAX™ Enteric Bacterial Panel, 1.5% of the Cary-Blair preserved and 1.9% of the unpreserved specimens initially reported as Indeterminate. Following a valid repeat test, 0% of the Cary-Blair preserved and 0% of the unpreserved specimens remained Indeterminate (Table 28). The total numbers provided in Table 28 are based on compliant specimens and BD MAX ™ Enteric Bacterial Panel results.
| Initial IndeterminateRates | Final Indeterminate Rates AfterRepeat | ||||
|---|---|---|---|---|---|
| SpecimenType | SpecimenOrigin | Percent | 95% Cl | Percent | 95% Cl |
| Cary-Blair | Prospective(Fresh) | 1.7%(33/1905) | (1.2%,2.4%) | 0.0% (0/1897) | (0.0%, 0.2%) |
| Retrospective(Frozen) | 1.5% (7/464) | (0.7%,3.1%) | 0.0% (0/463) | (0.0%, 0.8%) | |
| Unpreserved | Prospective(Fresh) | 1.6%(20/1278) | (1.0%,2.4%) | 0.2% (2/1251) | (0.0%, 0.6%) |
| Retrospective(Frozen) | 1.9% (6/319) | (0.9%,4.0%) | 0.0% (0/317) | (0.0%, 1.2%) |
Table 28: Indeterminate Rates
BD Diagnostic Systems Becton, Dickinson and Company
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Of the 3183 prospective specimens initially evaluated with the BD MAX™ Enterio Bacterial Panel. 1,3% of the Carv-Blair preserved and 2.0% of the unpreserved specimens initially reported as Incomplete. Following a valid repeat test, 0% of the Cary-Blair preserved and 0% of the unpreserved specimens remained Incomplete. Of the 783 retrospective specimens initially evaluated with the BD MAX™ Enteric Bacterial Panel, 1.3% of the Cary-Blair preserved and 0% of the unpreserved specimens initially reported as Unresolved. Following a valid repeat test, 0% of the Cary-Blair preserved specimens remained Incomplete (Table 29). The total numbers provided in Table 29 are based on remainou moomplete (Table 20). The tetail hambers provided in Panel results.
| Initial Incomplete Rates | Final Incomplete Rates AfterRepeat | ||||
|---|---|---|---|---|---|
| SpecimenType | SpecimenOrigin | Percent | 95% Cl | Percent | 95% Cl |
| Cary-Blair | Prospective(Fresh) | 1.3%(24/1905) | (0.8%,1.9%) | 0.0% (0/1897) | (0.0%, 0.2%) |
| Retrospective(Frozen) | 1.3% (6/464) | (0.6%,2.8%) | 0.0% (0/463) | (0.0%, 0.8%) | |
| Unpreserved | Prospective(Fresh) | 2.0%(26/1278) | (1.4%,3.0%) | 0.0% (0/1251) | (0.0%, 0.3%) |
| Retrospective(Frozen) | 0.0% (0/319) | (0.0%,1.2%) | 0.0% (0/317) | (0.0%, 1.2%) |
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Expected Values
In the BD MAX Enteric Bacterial Panel clinical study, reportable results from compliant specimens, were obtained from 8 geographically diverse sites and compared to the reference methods. The study population was grouped based on specimen type. The number and percentage of positive cases by target, as determined by the BD MAX Enteric Bacterial Panel during the prospective segment of the clinical trial, are presented below in Table 30.
| Prevalence | |||||
|---|---|---|---|---|---|
| Specimen Type | Site | Salmonella | Shigella/EIEC | Campylobacter | Shiga toxins |
| Cary-Blair Preserved | 1 | 0.0% (0/186) | 0.0% (0/186) | 1.1% (2/188) | 0.0% (0/185) |
| 2 | 0.8% (3/377) | 0.3% (1/377) | 1.6% (6/368) | 0.8% (3/391) | |
| 3 | 0.9% (5/548) | 0.2% (1/548) | 0.8% (4/528) | 0.2% (1/551) | |
| 4 | 3.9% (6/152) | 11.2% (17/152) | 2.0% (3/152) | 0.0% (0/135) | |
| 5 | 0.3% (1/339) | 0.0% (0/339) | 1.5% (5/340) | 0.3% (1/320) | |
| 6 | 1.4% (6/431) | 0.0% (0/431) | 1.9% (8/431) | 0.7% (3/411) | |
| Total | 1.0% (21/2033) | 0.9% (19/2033) | 1.4% (28/2007) | 0.4% (8/1993) | |
| Unpreserved | 1 | 1.6% (6/376) | 0.3% (1/376) | 0.8% (3/376) | 0.0% (0/176) |
| 7 | 1.6% (5/305) | 0.0% (0/305) | 2.0% (6/304) | 0.0% (0/229) | |
| 8 | 1.4% (4/284) | 0.0% (0/284) | 1.1% (3/284) | 0.4% (1/265) | |
| 4 | 2.9% (9/314) | 6.7% (21/314) | 3.5% (11/314) | 0.4% (1/266) | |
| Total | 1.9% (24/1279) | 1.7% (22/1279) | 1.8% (23/1278) | 0.2% (2/936) |
Table 30: Observed Prevalence by Target and Specimen Type
BD Diagnostic Systems Becton, Dickinson and Company
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DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Food und Drug Administra 10903 New Hampshire Aven Document Control Center - WO Silver Spring, MD 20993-0007
BECTON, DICK INSON AND COMPANY PAUL SWIFT REGULATORY AFFAIRS PROJECT MANAGER 7 LOVETON CIRCLE SPARKS MD 21152
May 06, 2014
Re: K140111
Trade/Device Name: BD MAX™ Enteric Bacterial Panel Regulation Number: 21 CFR 866.3990 Regulation Name: Gastrointestinal microorganism multiplex nucleic acid-based assay Regulatory Class: II Product Code: PCI, PCH, OOI Dated: April 25, 2014 Received: April 28, 2014
Dear Mr. Swift:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, 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 oublish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
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Page 2-Mr. Swift
If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to promarket notification" (21CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.
Sincerely yours,
John Hobson -S for
Sally Hojvat, M.Sc., PhD Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
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DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration
Indications for Use
Form Approved: OMB No. 0910-0120 Expiration Date: January 31, 2017 See PRA Statement on last page.
510(k) Number (if known)
K140111
Device Name
BD MAX™ Enteric Bacterial Panel
Indications for Use (Describe)
The BD MAX™ Enteric Bacterial Panel performed on the BD MAX™ System is an automated in vitro diagnostic test for the direct oualitative detection and differentiation of enterial pathogens. The BD MAX Enteric Bacterial Panel detects nucleic acids from:
- Salmonella spp. ●
- . Campylobacter spp. (jejuni and coli)
- Shigella spp. / Enteroinvasive E. coll (EIEC) .
- Shiga toxin 1 (stx1) / Shiga toxin 2 (stx2) genes (found in Shiga toxin-producing E. coli [STEC]) as well as Shigello . dysenterioe, which can possess a Shiga toxin gene (stx) that is identical to the stx1 gene of STEC.
Testing is performed on unpreserved soft to diarrheal stool specimens or Cary-Blair preserved stool specimens from symptomatic patients with suspected acute gastroenteritis, enteritis or colitis. The test is performed directly on the specimen, utilizing real-time polymerase chain reaction (PCR) for the amplification of SpoO, a Campylobocter specific tufgene sequence, ipoH and stx1/stx2. The test utilizes fluorogenic sequence-specific hybridization probes for detection of the amplified DNA.
This test is intended for use, in conjunction, with clinical presentation, laboratory findings, and epidemiological information, as an aid in the differential diagnosis of Salmonella, Shigella/EEC, Compylobacter and Shiga toxin-producing E. coll (STEC) infections. Results of this test should not be used as tor diagnosis, treatment, or other patient management decisions. Positive results do not rule out co-infection with other organisms that are not detected by this test, and may not be the sole or definitive cause of patient illness. Negative of cinical illness compatible with gastroenteritis may be due to infection by pathogens that are not detected by this test or non-infectious causes such as ulcerative colitis, irritable bowel syndrome, or Crohn's disease.
Type of Use (Select one or both, as applicable) 2 Prescription Use (Part 21 CFR 801 Subpart D) | Over-The-Counter Use (21 CFR 801 Subpart C)
- ☐ Over-the-Counter use (21 CFR 301) Sunpain C
PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON A SEPARATE PAGE IF NEEDED.
ੰ , ਹੁੰ , ਹੁੰ , ਕੁ , ਮੁ , ਮੁ FOR FDA USE ONLY :
Concurrence of Center for Devices and Radiological Health (CDRH) (Signature)
John Hobson-S
2014.05.06-11:33:07-04'00'
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§ 866.3990 Gastrointestinal microorganism multiplex nucleic acid-based assay.
(a)
Identification. A gastrointestinal microorganism multiplex nucleic acid-based assay is a qualitativein vitro diagnostic device intended to simultaneously detect and identify multiple gastrointestinal microbial nucleic acids extracted from human stool specimens. The device detects specific nucleic acid sequences for organism identification as well as for determining the presence of toxin genes. The detection and identification of a specific gastrointestinal microbial nucleic acid from individuals exhibiting signs and symptoms of gastrointestinal infection aids in the diagnosis of gastrointestinal infection when used in conjunction with clinical evaluation and other laboratory findings. A gastrointestinal microorganism multiplex nucleic acid-based assay also aids in the detection and identification of acute gastroenteritis in the context of outbreaks.(b)
Classification. Class II (special controls). The special controls are set forth in FDA's guideline document entitled: “Class II Special Controls Guideline: Gastrointestinal Microorganism Multiplex Nucleic Acid-Based Assays for Detection and Identification of Microorganisms and Toxin Genes from Human Stool Specimens.” For availability of the guideline document, see § 866.1(e).