(98 days)
The DiaSorin Molecular Simplexa™ VZV Direct assay is intended for use on the LIAISON® MDX instrument for the qualitative detection of varicella-zoster virus (VZV) DNA in cerebrospinal fluid (CSF) from patients signs and/or symptoms of meningitis and/or encephalitis. This test is intended as an aid in the diagnosis of VZV infections of the central nervous system (CNS).
Negative results do not preclude VZV infection and should not be used as the sole basis for treatment or other patient management decisions.
The assay is not intended for use as a donor screening test. The assay is for professional use only.
The Simplexa™ VZV Positive Control Pack is intended to be used as a control with the Simplexa™ VZV Direct kit.
This control is not intended for use with other assays or systems.
The Simplexa™ VZV Direct assay is a real-time polymerase chain reaction (PCR) system that enables the direct amplification and detection of VZV DNA from unprocessed cerebral spinal fluid (CSF) specimens without nucleic acid extraction. The system consists of the Simplexa™ VZV Direct assay, the LIAISON® MDX (with LIAISON® MDX Studio Software), the Direct Amplification Disc and associated accessories. In the Simplexa™ VZV Direct assay, fluorescent probes are used together with corresponding forward and reverse primers to amplify VZV and internal control targets. A well-conserved region of the VZV DNA polymerase gene is targeted to identify VZV DNA in the specimen. An internal control is used to detect PCR failure and/or inhibition.
Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided text:
Acceptance Criteria and Device Performance for Simplexa™ VZV Direct Assay
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly list "acceptance criteria" as a set of predefined thresholds. Instead, it presents performance metrics from various studies. Based on the provided clinical agreement study, the implicit acceptance criteria for clinical performance would likely be a high Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA). For analytical performance, the LoD is a key metric.
| Metric (Implicit Acceptance Criteria) | Reported Device Performance (Simplexa™ VZV Direct) |
|---|---|
| Clinical Performance | |
| Positive Percent Agreement (PPA) | 100.0% (12/12) (95% CI: 75.7% to 100.0%) |
| Negative Percent Agreement (NPA) | 99.7% (623/625) (95% CI: 98.8% to 99.9%) |
| PPA (Contrived Samples) | 100.0% (120/120) (95% CI: 96.9-100.0%) |
| Analytical Performance | |
| Limit of Detection (LoD) VZV Strain 9939 | 2.03 TCID50/mL (1,614 copies/mL) |
| Limit of Detection (LoD) VZV Strain Ellen | 0.001 TCID50/mL (1,505 copies/mL) |
| Analytical Reactivity (VZV strains) | 100.0% agreement for 5 additional VZV strains |
| Cross-Reactivity (159 microorganisms) | 0.0% detection (no cross-reactivity observed) |
| Reproducibility (VZV) %CV | 0.5-4.6% |
| Interference | No interference observed |
| Inhibition by other microorganisms | No inhibition observed |
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size (Clinical):
- Prospective Samples: 637 clinical samples.
- Contrived Samples: 240 contrived VZV positive samples.
- Data Provenance:
- Country of Origin: Not explicitly stated, but the submission is to the U.S. FDA by a company in Cypress, California, USA, and the testing was performed at "testing sites" and "DiaSorin Molecular, Cypress, CA", suggesting U.S.-based data.
- Retrospective or Prospective: The study included both:
- Prospective and prospectively banked collections from eight (8) collection sites (February 2018 to November 2018).
- Contrived samples were used to supplement low prevalence true positive clinical samples.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications
Not applicable. This device is an in vitro diagnostic (IVD) based on molecular detection. Ground truth for diagnostic assays like this is typically established by comparative methods rather than expert human interpretation of images or other subjective data. No human "experts" were used to establish the ground truth in the sense of clinical decision-making from images.
4. Adjudication Method for the Test Set
Not applicable in the sense of expert human review (e.g., 2+1, 3+1). The ground truth for the clinical samples was established using a composite reference method:
- Two (2) validated real-time PCR assays.
- Followed by confirmation of positive PCR amplification products with bi-directional sequencing.
- Decision Rule: Samples were characterized as positive if one (1) or both PCR assays were positive AND confirmed by bi-directional sequencing. Samples were characterized as negative if both PCR assays were negative.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, an MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) designed for laboratory use to detect VZV DNA. Its performance is evaluated against reference methods, not against human readers (e.g., radiologists, pathologists). Therefore, improvement for human readers with AI assistance is not applicable in this context.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance)
Yes, the primary performance studies presented focus on the standalone performance of the Simplexa™ VZV Direct assay. The "Clinical Agreement" section directly compares the Simplexa™ VZV Direct results to the composite reference method without explicit human intervention in the interpretation of the Simplexa™ VZV Direct results. The assay is an automated real-time PCR system.
7. Type of Ground Truth Used
The ground truth for the clinical agreement study was established using a composite reference method. This method involved:
- Two (2) validated real-time PCR assays.
- Confirmation of positive PCR amplification products with bi-directional sequencing.
8. Sample Size for the Training Set
The document does not explicitly mention a "training set" in the context of machine learning or AI models. This device is an in vitro diagnostic (IVD) based on real-time PCR technology, which relies on molecular biology principles (primers and probes) rather than machine learning models that require distinct training and test sets. The assay design and optimization would involve internal development and validation, but not typically a "training set" in the AI sense.
9. How the Ground Truth for the Training Set Was Established
Not applicable, as a "training set" for an AI model is not described or relevant for this type of molecular diagnostic device. The analytical characteristics and design of the PCR assay (e.g., primer and probe specificity) are established through various analytical studies (e.g., analytical sensitivity, specificity, cross-reactivity) rather than a ground-truthed training set for machine learning.
§ 866.3970 Device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid.
(a)
Identification. A device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid is a qualitative in vitro device intended for the detection and identification of microbial-associated nucleic acid sequences from patients suspected of meningitis or encephalitis. A device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid is intended to aid in the diagnosis of meningitis or encephalitis when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include detailed device description documentation, including the device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including primer/probe sequence, design, and rationale for sequence selection.
(2) Premarket notification submissions must include detailed documentation from the following analytical studies: Analytical sensitivity (limit of detection), inclusivity, reproducibility, interference, cross reactivity, and specimen stability.
(3) Premarket notification submissions must include detailed documentation from a clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from well-accepted comparator methods.
(4) Premarket notification submissions must include detailed documentation for device software, including, but not limited to, software applications and hardware-based devices that incorporate software.
(5) The Intended Use statement in the device labeling must include a statement that the device is intended to be used in conjunction with standard of care culture.
(6) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling.
(7) The device labeling must include a limitation stating that the negative results do not preclude the possibility of central nervous system infection.
(8) The device labeling must include a limitation stating that device results are not intended to be used as the sole basis for diagnosis, treatment, or other patient management decisions.
(9) The device labeling must include a limitation stating that positive results do not mean that the organism detected is infectious or is the causative agent for clinical symptoms.
(10) As part of the risk management activities performed as part of your 21 CFR 820.30 design controls, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.