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The DiaSorin Molecular Simplexa™ HSV 1 & 2 Direct assay is intended for use on the LIAISON® MDX instrument for the qualitative detection and differentiation of herpes simplex virus (HSV-2) DNA present in mucocutaneous and cutaneous lesion swabs from patients with signs and symptoms of HSV-1 or HSV-2 infection. This test is an aid in the differential diagnosis of HSV-1 and HSV-2 infections.

The assay is not intended for use as a screening test for the presence of HSV-2 in blood or blood products. The assay is for professional use only.

Simplexa™ HSV 1 & 2 Positive Control Pack MOL2160

The Simplexa™ HSV 1 & 2 Positive Control Pack is intended to be used as a control with the Simplexa™HSV 1 & 2 Direct kit.

This control is not intended for use with other assays or systems.

The Simplexa™ HSV 1 & 2 Direct assay system is a real-time PCR that enables the direct amplification, detection and differentiation of HSV-1 and/or HSV-2 DNA from unprocessed cutaneous and mucocutaneous lesion swab specimens without nucleic acid extraction. The system consists of the Simplexa™ HSV 1 & 2 Direct assay, the LIAISON® MDX (with LIAISON® MDX Studio Software), the Direct Amplification Disc and associated accessories.

In the Simplexa™ HSV 1 & 2 Direct assay, bi-functional fluorescent probe-primers are used together with corresponding reverse primers to amplify HSV-1, HSV-2 and internal control targets. Well conserved regions of the HSV-1 and HSV-2 DNA polymerase genes are targeted to identify HSV-1 and HSV-2 DNA respectively in the specimen. An internal control is used to detect PCR failure and/or inhibition.

Here's a breakdown of the acceptance criteria and study information for the Simplexa™ HSV 1 & 2 Direct device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria (e.g., "PPA must be ≥ 95%"). Instead, it presents the "Clinical Agreement" results from validation studies and implies that these figures demonstrate acceptable performance for clearance. Therefore, the "acceptance criteria" listed below are inferred from the reported performance, representing the observed outcomes deemed sufficient for the device to be considered substantially equivalent.

Note on "Acceptance Criteria": The document provides the study results directly. For diagnostics, these agreement percentages are typically compared against pre-specified acceptance criteria. The absence of explicit acceptance criteria in the provided text implies that the reported performance was considered adequate for FDA clearance.

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

• Prospective Study 1 (K150962 data, re-used):
  • Original Collected: 718 samples
  • Evaluated: 696 samples (after removals for various reasons like not tested, invalid results, internal control failure, wrong sample type, insufficient volume, control issues, non-enrollable)
  • Data Provenance: From 6 geographically diverse locations, prospectively collected from May 28, 2014, through December 4, 2014.
• Prospective Study 2 (K173798 data):
  • Original Collected: 514 samples
  • Evaluated:
    • 511 samples for Simplexa™ HSV 1 & 2 Direct
    • 512 samples for culture method
    • 510 samples for bi-directional sequencing method (after removals for EC505 codes, insufficient volume, daily control issues, non-enrollable)
  • Data Provenance: From 4 geographically diverse sites, prospectively collected from July 24, 2017, through October 11, 2017.
• Retrospective Study:
  • Evaluated: 174 Cutaneous HSV-1 swabs, 174 Mucocutaneous HSV-2 swabs, and 17 samples from unknown locations.
  • Data Provenance: Retrospectively collected from June 6, 2011, to May 17, 2014, and February 21, 2017, through July 17, 2017.

All clinical samples were cutaneous and mucocutaneous lesion swabs from patients with signs and symptoms of HSV-1 or HSV-2 infection.

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

The document does not specify the number or qualifications of experts for establishing ground truth. The ground truth was established using a "composite comparator algorithm" rather than expert opinion alone.

4. Adjudication Method for the Test Set

The ground truth was established using a composite comparator algorithm based on a "2 out of 3 rule":

• Components: Culture, bi-directional sequencing, and an FDA-cleared NAAT (Nucleic Acid Amplification Test).
• Method: Any sample yielding a positive result by either sequencing or culture was then tested on an FDA-cleared NAAT. A "2 out of 3 rule" (implying agreement between at least two of the three methods) was used to determine the final composite results.
• Note: For culture, HSV-2 was tested first. If positive for HSV-2, no further culture testing was done (meaning dual positives could not be identified by culture alone).

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

No, an MRMC comparative effectiveness study was not explicitly done. The study focuses on evaluating the device's performance against a composite reference method, not on human reader performance with or without AI assistance. The device is a molecular diagnostic assay, not an AI-assisted diagnostic tool for human readers.

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

Yes, the studies presented are for the standalone performance of the Simplexa™ HSV 1 & 2 Direct assay, which is a real-time PCR system. This system performs direct amplification, detection, and differentiation of HSV-1 and HSV-2 DNA from unprocessed swab specimens, without requiring human interpretation of results beyond reading the instrument's output. The "algorithm" here refers to the PCR assay's mechanics and the LIAISON® MDX instrument's software for detection.

7. The Type of Ground Truth Used

The ground truth for the clinical studies was a composite comparator algorithm consisting of:

• Cell culture
• Bi-directional sequencing
• An FDA-cleared NAAT

This is considered a robust method for establishing ground truth in molecular diagnostics, combining phenotypic (culture) and genotypic (sequencing, NAAT) evidence.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning, as this is a molecular diagnostic assay cleared through substantial equivalence, not an AI/ML-based device requiring separate training and test sets in that sense. The analytical studies (reproducibility, LoD, cross-reactivity, interference) use contrived samples and defined panels. The "clinical agreement" uses the prospective and retrospective patient samples as the validation/test sets to demonstrate performance against the composite reference standard.

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

As stated above, no "training set" in the AI/ML context is described. For the analytical studies, the "ground truth" (e.g., presence/absence and concentration of a virus, presence of cross-reactants/interferents) was established by using:

• Quantified stocks of HSV-1 and HSV-2 (for Limit of Detection, Analytical Reactivity).
• Known concentrations of various microorganisms and substances (for Cross-Reactivity and Interference studies).
• Contrived sample pools with known viral loads (for Reproducibility and Competitive Interference).

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The Focus Diagnostics Simplexa™ HSV 1 & 2 Direct assay is intended for use on the 3M Integrated Cycler instrument for the qualitative detection and differentiation of herpes simples virus (HSV-1 and HSV-2) DNA present in genital lesion swabs samples from patients with signs and symptoms of HSV-1 or HSV-2 infection of the genitalia. This test is an aid in the differential diagnosis of HSV-1 and HSV-2 genital infections.

The assay is not intended for use as a screening test for the presence of HSV-1 and HSV-2 in blood or blood products. The assay is for professional use only.

Simplexa™ HSV 1 & 2 Positive Control Pack

The Simplexa™ HSV 1 & 2 Positive Control Pack is intended to be used as a control with the Simplexa™ HSV 1 & 2 Direct kit. This control is not intended for use with other assays or systems.

The Simplexa™ HSV 1 & 2 Direct assay system is a real-time PCR that enables the direct amplification, detection and differentiation of HSV-1 and/or HSV-2 DNA from unprocessed genital swab specimens without nucleic acid extraction. The system consists of the Simplexa™ HSV 1 & 2 Direct assay, the 3M Integrated Cycler (with 3M Integrated Cycler Studio Software), the Direct Amplification Disc and associated accessories.

In the Simplexa™ HSV 1 & 2 Direct assay, bi-functional fluorescent probe-primers are used together with corresponding reverse primers to amplify HSV-1, HSV-2 and internal control targets. Well conserved regions of the HSV-1 and HSV-2 DNA polymerase genes are targeted to identify HSV-1 and HSV-2 DNA respectively in the specimen. An internal control is used to detect PCR failure and/or inhibition.

The provided document describes the Simplexa™ HSV 1 & 2 Direct assay and its performance evaluation. Here's a breakdown of the acceptance criteria and study details:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as distinct "acceptance criteria" but can be inferred from the reported performance results and the common thresholds for such diagnostic tests (e.g., typically ≥ 95% agreement/sensitivity/specificity). The document presents the performance in terms of percent agreement with expected results for reproducibility and sensitivity/specificity for clinical agreement.

Reproducibility (Inter-site, Inter-day, Inter/Intra-assay)

Analytical Sensitivity/Limit of Detection (LoD)

Clinical Agreement (Prospective Study vs. Composite Comparator)

Clinical Agreement (Retrospective Study vs. Validated Bi-Directional Sequencing Assay)

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

• Reproducibility Study:

  • Test Set Size: For each of the six sample pools (HSV-1 Low Positive, HSV-1 Medium Positive, HSV-2 Low Positive, HSV-2 Medium Positive, High Negative, Positive Control), they were tested in triplicate on five different days by two operators at each of three sites. This amounts to: 6 samples * 3 replicates * 5 days * 2 operators * 3 sites = 540 data points (assuming complete datasets). The tables consolidate this, showing "Total Agreement" out of 539 samples for HSV-1, and 539 for HSV-2 and DNA IC across all categories (e.g., 531/539 for HSV-1 Total Agreement, 528/539 for HSV-2 Total Agreement, 539/539 for DNA IC Total Agreement).
  • Data Provenance: The study was conducted at "Three investigative sites," implying a multi-center study within the U.S. (typical for FDA submissions). It's a prospective design as samples were "contrived" (prepared specifically for the study) and tests were performed over different days.

• Clinical Agreement (Prospective Study):

  • Test Set Size:
    • Initially, 718 genital swab samples were prospectively collected.
    • 9 samples were removed (not tested or invalid results on 3 assays).
    • 13 samples were removed (not tested on comparator method sufficiently).
    • 696 samples were used for the primary analysis.
    • Further exclusions for specific analyses: 6 samples excluded from discordant analysis due to insufficient volume for FDA cleared NAAT; 2 samples excluded for HSV-1/HSV-2 discrepancy due to insufficient volume for FDA cleared NAAT.
    • Final analysis for HSV-1: 684 samples.
    • Final analysis for HSV-2: 688 samples.
  • Data Provenance: "Prospectively collected from patients with signs and symptoms of genital herpes simplex virus (HSV) infection from 6 geographically diverse locations." This indicates the data is from the U.S. and is prospective.

• Clinical Agreement (Retrospective Study):

  • Test Set Size: 28 genital swab samples (14 positive HSV-1 and 14 positive HSV-2).
  • Data Provenance: "Retrospectively collected from male patients with signs and symptoms of genital herpes simplex virus (HSV) infection." Specific country of origin is not stated but implies within the U.S. given the FDA submission.

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

• For the Reproducibility Study, the ground truth for contrived samples (low positive, medium positive, high negative, positive control) was established based on the known concentrations of HSV-1 and HSV-2 spiked into the matrix. This is an analytical study, not one requiring clinical experts for ground truth.

• For the Clinical Agreement Studies (Prospective and Retrospective), the ground truth was established by a "composite comparator algorithm" and "validated bi-directional sequencing assay." This ground truth relies on laboratory results rather than expert interpretation of clinical data or images. Therefore, the document does not specify human experts for establishing ground truth, but rather relies on the interpretative methods of the comparator assays. Those interpreting the culture results, sequencing data, and FDA-cleared NAAT results would typically be trained laboratory personnel or clinical laboratorians.

4. Adjudication Method for the Test Set

• Reproducibility Study: No explicit adjudication method is mentioned as the ground truth was "expected results" for contrived samples based on known concentrations. Adjudication wasn't necessary for these controlled samples.

• Clinical Agreement (Prospective Study): An adjudication method was used for discordant results in the composite comparator algorithm:

  • "A positive result for HSV-1 and/or HSV-2 was determined by a positive test result in either the culture or the bi-directional sequencing."
  • "If both the culture and the bi-directional sequencing yielded positive results but disagreed in the differentiation of HSV-1 versus HSV-2, the results of the FDA cleared NAAT were used and a 2 out of 3 rule was followed to determine the type of the virus (e.g. if two of the methods were positive for HSV-1, the final comparator result was HSV-1 positive)." This is a form of 2-out-of-3 or majority rule adjudication.

• Clinical Agreement (Retrospective Study): The ground truth was established by a "validated bi-directional sequencing assay." No specific adjudication process is described beyond the sequencing assay itself.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

• No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This study focuses on an in vitro diagnostic (IVD) PCR assay for the detection of viral DNA, not on image interpretation or other tasks typically performed by human readers that could be augmented by AI. Therefore, there's no mention of human readers or AI assistance.

6. If a Standalone (i.e. algorithm only without human-in-the loop performance) was done

• Yes, the performance presented for the Simplexa™ HSV 1 & 2 Direct assay is standalone performance. It describes the diagnostic accuracy of the assay itself (device only) against a comparator method. The device is an automated, real-time PCR system, and its output (qualitative detection and differentiation of HSV-1 and HSV-2 DNA) is directly compared. The assay operates without human "in-the-loop" interpretation for the final diagnostic call.

7. The Type of Ground Truth Used

• Reproducibility Study: Known concentrations of spiked viral material (contrived samples) were used as ground truth.
• Clinical Agreement (Prospective Study): A composite comparator algorithm was used as ground truth, consisting of:
  • Culture
  • Bi-directional sequencing
  • An FDA cleared NAAT (used for discordant resolution)
• Clinical Agreement (Retrospective Study): A validated bi-directional sequencing assay was used as ground truth.

8. The Sample Size for the Training Set

• The document describes performance evaluation studies (reproducibility and clinical agreement) for the Simplexa™ HSV 1 & 2 Direct assay. It does not explicitly mention a "training set" or "validation set" in the context of machine learning model development. This is typical for IVD assays which are developed and then verified/validated rather than 'trained'. The data presented is for validation of the a priori defined assay.

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

• As no "training set" in the machine learning sense is described, this question is not applicable based on the provided document. The ground truth for the validation and reproducibility sets is detailed in point 7.

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