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The eSensor® Respiratory Viral Panel (RVP) is a qualitative nucleic acid multiplex in vitro diagnostic test intended for use on the eSensor XT-8™ system for the simultaneous detection and identification of multiple respiratory viral nucleic acids in nasopharyngeal swabs (NPS) obtained from individuals exhibiting signs and symptoms of respiratory infection.

The following virus types and subtypes are identified using the eSensor RVP: Influenza A, Influenza A H1 Seasonal Subtype, Influenza A H3 Seasonal Subtype; Influenza A 2009 H1N1 subtype, Influenza B, Respiratory Syncytial Virus subtype A, Respiratory Syncytial Virus subtype B, Parainfluenza Virus 1, Parainfluenza Virus 2, Parainfluenza Virus 3, Human Metapneumovirus, Human Rhinovirus, Adenovirus species B/E, and Adenovirus species C.

The detection and identification of specific viral nucleic acids from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respiratory viral infection if used in conjunction with other clinical and epidemiological information.

Negative results do not preclude respiratory viral infection and should not be used as the sole basis for diagnosis, treatment or other patient management decisions. Positive results do not rule out bacterial infection, or co-infection with other viruses. The agent detected may not be the definite cause of disease. The use of additional laboratory testing (e.g. bacterial and viral culture, immunofluorescence and radiography) and clinical presentation must be taken into consideration in the final diagnosis of respiratory viral infection.

Performance characteristics for Influenza A were established during the 2010/2011 influenza season when Influenza A 2009 H1N1 and H3N2 were the predominant Influenza A viruses in circulation. When other Influenza A viruses emerge, performance characteristics may vary.

If infection with a novel Influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent influenza viruses and sent to state or local health departments for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.

For prescription use only.

The eSensor RVP is a multiplex microarray-based genotyping test system. It is based on the principles of competitive DNA hybridization using a sandwich assay format, wherein a singlestranded target binds concurrently to sequence-specific solution-phase signal probe and solidphase electrode-bound capture probe. The test employs reverse transcription polymerase chain reaction amplification, exonuclease digestion and hybridization of target DNA/RNA. In the process, the double-stranded PCR amplicons are digested with exonuclease to generate singlestranded DNA suitable for hybridization. Hybridization occurs in the eSensor XT-8 Cartridge (described below) where the single-stranded target DNA is mixed with a hybridization solution containing labeled signal probes.

During hybridization, the single-stranded target DNA binds to a complementary, single-stranded capture probe immobilized on the working electrode surface. Single-stranded signal probes (labeled with electrochemically active ferrocenes) bind to the target adjacent to the capture probe. When inserted into the eSensor XT-8 instrument (described below), simultaneous hybridization of target to signal probes and capture probe is detected by alternating current voltammetry (ACV). Each pair of working electrodes on the array contains a different capture probe, and sequential analysis of each electrode allows detection of multiple viral targets.

The eSensor XT-8 cartridge device consists of a printed circuit board (PCB) with a multi-layer laminate and a plastic cover that forms a hybridization chamber. The cartridge is fitted with a pump and check valves that circulate the hybridization when inserted into the eSensor XT-8 instrument. The PCB chip consists of an array of 72 gold-plated working electrodes, a silver reference electrode, and two gold-plated auxiliary electrodes. Each working electrode has a connector contact pad on the opposite side of the chip for electrical connection to the eSensor XT-8 instrument. Each electrode is modified with a multi-component; self-assembled monolayer that includes oligonucleotide capture probes specific for each polymorphic site on the test panel and insulator molecules. The cartridge also contains an electrically erasable programmable readonly memory component (EEPROM) that stores information related to the cartridge (e.g., assay identifier, cartridge lot number, and expiration date).

The eSensor XT-8 instrument was previously cleared for IVD use by the FDA under K073720 and K090901.

The eSensor XT-8 is a clinical multiplex instrument that has a modular design consisting of a base module and one, two, or three cartridge-processing towers containing 8, 16, or 24 cartridge slots, respectively. The cartridge slots operate independently of each other. Any number of cartridges can be loaded at one time, and the remaining slots are available for use while the instrument is running.

The base module controls each processing tower, provides power, and stores and analyzes data. The instrument is designed to be operated solely with the touch screen interface. Entering patient accession numbers and reagent lot numbers can be performed by the bar code scanner or the touch screen.

Each processing tower consists of eight cartridge modules, each containing a cartridge connector, a precision-controlled heater, an air pump, and electronics. The air pumps drive the pump and valve system in the cartridge, eliminating fluid contact between the instrument and the cartridge. The pneumatic pumping enables recirculation of the hybridization solution allowing the target DNA and the signal probes to hybridize with the complementary capture probes on the electrodes. The pump in the cartridge is connected to a pneumatic source from the eSensor XT-8 instrument and provides unidirectional pumping of the hybridization mixture through the channel during hybridization. Using this process to circulate the hybridization solution minimizes the unstirred boundary laver at the electrode surface and continuously replenishes the volume above the electrode that has been depleted of complementary targets and signal probes.

The XT-8 instrument provides electrochemical detection of bound signal probes by ACV and subsequent data analysis and test report generating functions. All hybridization, ACV scanning and analysis parameters are defined by a scanning protocol loaded into the XT-8 Software, and then specified for use by the EEPROM on each cartridge.

Principle of eSensor Technology: eSensor technology uses a solid-phase electrochemical method for determining the presence of one or more of a defined panel of virus target sequences. Purified DNA/RNA is isolated from the patient specimen according to defined laboratory procedures and the extracted nucleic acid is reverse transcribed and/or amplified using virus specific primers with an RT-PCR enzyme mix. The amplified DNA is converted to single-stranded DNA via exonuclease digestion and is then combined with a signal buffer containing ferrocenelabeled signal probes that are specific for the different viral targets. The mixture of amplified sample and signal buffer is loaded onto a cartridge containing single-stranded oligonucleotide capture probes bound to gold-plated electrodes. The cartridge is inserted into the XT-8 instrument where the single-stranded targets hybridize to the complementary sequences of the capture probes and signal probes, as shown in Figure 1. The presence of each target is determined by voltammetry, which generates specific electrical signals from the ferrocene-labeled signal probe.

The eSensor RVP provides a qualitative result based upon the presence (Positive) or absence (Target Not Detected) of the viruses contained in the panel along with the internal MS2 control. Positive and negative results are determined based on the electrical signals generated being either above or below specified signal boundaries, respectively.

I will provide a summary of the acceptance criteria and study information for the eSensor® Respiratory Viral Panel (RVP) based on the provided text.

eSensor® Respiratory Viral Panel (RVP) Acceptance Criteria and Study Details

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the eSensor RVP are embedded within the "Sensitivity" (Positive Percent Agreement - PPA) and "Specificity" (Negative Percent Agreement - NPA) results of the clinical performance study. The reported performance for each viral target is presented below, representing the device meeting these implicit criteria.

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

• Prospective Clinical Study:
  • Total Samples Collected: 1182 nasopharyngeal (NP) swab specimens.
  • Evaluable Samples: 1037 specimens. (145 excluded due to not tested within 5 days of collection, operator/easyMAG errors, or not retested/sequenced).
  • Data Provenance: Prospective collection from January 2011 during the 2010/2011 influenza season. Collected at three North American clinical laboratories (Cleveland, Ohio; Providence, RI; and Albuquerque, NM).
• Retrospective Clinical Study:
  • Total Samples Collected: 343 banked samples.
  • Evaluable Samples: 320 banked samples (for 5 viral targets: Influenza A H1, PIV1, PIV2, ADV B/E, ADV C).
  • Data Provenance: Frozen banked samples previously characterized as positive for certain analytes. Collected from various sites across the United States or from the Centers for Disease Control and Prevention (CDC).

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

The document does not explicitly state the number or specific qualifications (e.g., "radiologist with 10 years of experience") of experts involved in establishing the ground truth. However, it indicates the following methods were used:

• For most viral targets (Flu A, Flu B, RSV, PIV1, PIV2, PIV3, Adenovirus): "established gold standard reference method of viral culture followed by DFA identification testing."
• For subtyping (Influenza A H3, Influenza A 2009 H1N1, RSVA, RSVB, ADVB/E, ADVC): "independently developed qRT-PCR assay or qPCR assay followed by bidirectional sequencing."
• For HRV and hMPV: "two independently developed and validated qRT-PCR assays followed by bidirectional sequencing."
• For discrepancy resolution: Bidirectional sequencing was used to investigate discrepant results for many analytes (e.g., 35/47 RVP False Positive Influenza A samples were confirmed positive by sequencing, 22/25 RVP False Positive Influenza A H3 samples confirmed positive by sequencing, etc.). This implies expert interpretation of sequencing data.

While specific expert details are not provided, the ground truth relies on established laboratory "gold standard" methods and advanced molecular techniques (RT-PCR/qPCR and bidirectional sequencing), which are inherently performed and interpreted by trained laboratory professionals.

4. Adjudication Method (e.g., 2+1, 3+1, none) for the Test Set

The primary method for establishing ground truth was comparison to established reference methods (viral culture + DFA or multiple PCR/sequencing methods). For cases where the RVP result disagreed with the initial comparator method (often leading to "False Positive" or "False Negative" categories in the 2x2 tables), bidirectional sequencing was used as a tertiary method for "confirmation." This suggests a form of adjudication, where sequencing serves as a higher-level tie-breaker or confirmatory test rather than a simple 2+1 or 3+1 consensus among human readers.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. The study focuses on the standalone performance of the eSensor RVP diagnostic device compared to laboratory-based reference methods, not on how human readers improve with or without AI assistance. The device is a "qualitative nucleic acid multiplex in vitro diagnostic test," and its output is automated.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

Yes, a standalone performance study was conducted. The clinical performance data presented (sensitivity/PPA and specificity/NPA) are measures of the eSensor RVP as a standalone diagnostic device, comparing its automated qualitative results against reference laboratory methods. The device is described as having "Automated test interpretation and report generation."

7. The Type of Ground Truth Used

The ground truth for the test set was established using a combination of:

• Laboratory Reference Methods:
  • Viral Culture followed by DFA identification: For Influenza A, Influenza B, RSV, Parainfluenza Viruses (PIV1, PIV2, PIV3), and Adenovirus.
  • Composite (Multi-Test) Reference Method: For Human Metapneumovirus and Human Rhinovirus, consisting of "two independently developed and validated qRT-PCR assays followed by bidirectional sequencing."
  • qRT-PCR/qPCR followed by Bidirectional Sequencing: Used for subtyping Influenza A and RSV, and for determining subtypes of Adenovirus. Also used as a confirmatory method for resolving discrepancies identified between the eSensor RVP and initial reference methods.
• Publicly Available Databases: Bidirectional sequencing results were compared to sequences in the National Center for Biotechnology Information (NCBI) GenBank database.

8. The Sample Size for the Training Set

The document primarily describes validation studies and does not explicitly state the sample size of a distinct training set used for the development or initial optimization of the eSensor RVP itself. The clinical performance data are derived from independent test sets (prospective and retrospective clinical samples). Device development would involve internal validation and optimization, but specific training set sizes are not provided in this regulatory summary.

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

Since a specific "training set" with established ground truth is not detailed, the methods described for establishing ground truth for the test sets (viral culture, DFA, qRT-PCR/qPCR, bidirectional sequencing, and comparison to NCBI GenBank for sequence matching) would logically be the same types of methods implied for any internal development or training efforts during the device's creation.

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The eSensor® Cystic Fibrosis Carrier Detection (CFCD) System is a device for the detection of carrier status for cystic fibrosis for all adult couples contemplating pregnancy, regardless of ethnicity. It is a qualitative genotyping assay that simultaneously detects mutations currently recommended by the American College of Medical Genetics and American College of Obstetricians and Gynecologists (ACMG/ACOG). The eSensor® CFCD System is not indicated for prenatal screening or for diagnostic purposes, and is for Rx only professional use within the confines of a licensed laboratory, as defined by the Clinical Laboratory Improvement Amminents (CLIA) of 1988.

The eSensor® Cystic Fibrosis Carrier Detection System is an in vitro diagnostic test for the detection and genotyping of a selected panel of 24 cystic fibrosis mutations from DNA isolated from human whole blood.

The CFCD System is a clinical multiplex genetic test system which includes reagents for polymerase chain reaction amplification, exonuclease digestion and hybridization of target DNA, instrumentation and software. The CFCD System uses electrochemical detection to determine the carrier status of patient blood specimens for the ACOG/ACMG recommended panel of 24 cystic fibrosis mutations. Sample preparation for genotyping involves converting each blood specimentions: "Bunp genomic DNA (gDNA); then using multiplex PCR amplification followed by exonuclease digestion to convert the gDNA into a set of single-stranded targets. The genotyping reaction is set up with the combination of the single-stranded targets with appropriate buffers containing allele-specific signal probes differentially labeled with electrochemical signaling molecules, called ferrocenes. This mixture is then loaded into cartridges that contain single-stranded capture probes bound to an array of electrodes, with each electrode containing capture probess specific for a single mutation. Cartridges are inserted into the eSensor 4800 Instrument where the single-stranded targets hybridize to the complementary sequences of the carture probes and signal probes. Detection of the target/probe complexes is achieved using alternating current voltammetry that generates specific electrical signals from the hybridized signal probes. The eSensor® DNA Detection System Application Software then classifies the signals from each mutation and generates a report for each specimen that describes the carrier or non-carrier status of each of the cystic fibrosis panel mutations.

The requested information is detailed below, based on the provided text:

Acceptance Criteria and Device Performance for eSensor® Cystic Fibrosis Carrier Detection System

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria for the entire system's performance metrics (e.g., a target percentage for overall agreement). However, it reports the performance observed in the studies. Given the context of a 510(k) submission, the "performance characteristics" section details the metrics used to demonstrate substantial equivalence. I will present the reported performance as if they implicitly represent the achieved acceptance criteria based on the clearance.

2. Sample Size and Data Provenance for Test Set

• Sample Size for Test Set:
  • Method Comparison: 486 samples (freshly collected and banked) were used.
  • Reproducibility: Genomic DNA samples from one non-carrier cell line and 20 carrier cell lines (expressing all 23 panel mutations) were used. This set was tested repeatedly.
  • Input DNA Requirements: 96 tests were performed with 10 ng gDNA samples.
• Data Provenance: The document does not explicitly state the country of origin of the data. It refers to "freshly collected and banked samples" for the method comparison, implying a retrospective component to the data collection, potentially combined with prospectively collected samples.

3. Number and Qualifications of Experts for Ground Truth

The document does not mention the number or specific qualifications of experts used to establish the ground truth.

4. Adjudication Method for the Test Set

The document does not describe any specific adjudication method (e.g., 2+1, 3+1) for the test set.

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

No Multi-Reader Multi-Case (MRMC) comparative effectiveness study was mentioned in the provided text. The device is for laboratory use, not image interpretation by human readers.

6. Standalone Performance Study

Yes, a standalone performance study was conducted. The "Method Comparison" section directly compares the CFCD System's results to DNA sequencing, which serves as the reference standard, demonstrating the algorithm's performance without direct human-in-the-loop intervention during the genotyping output.

7. Type of Ground Truth Used

The primary type of ground truth used for performance evaluation was DNA sequencing. This is considered a highly reliable and definitive method for genetic mutation detection.

8. Sample Size for the Training Set

The document does not explicitly state the sample size used for the training set. The performance data focuses on validation and comparison.

9. How Ground Truth for the Training Set Was Established

The document does not describe how ground truth was established for a training set, as a specific training set size is not mentioned. It is common for such systems to be developed and optimized using a variety of known samples, but the specifics are not provided in this summary. The ground truth for the validation test set was established by DNA sequencing.

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