(81 days)
The BD ProbeTec™ Herpes Simplex Viruses (HSV 1 & 2) Q* Amplified DNA Assays, when tested with the BD Viper™ System in Extracted Mode, use Strand Displacement Amplification technology for the direct, qualitative detection and differentiation of Herpes Simplex virus type 1 (HSV1) and Herpes Simplex virus type 2 (HSV2) DNA in clinician-collected external anogenital lesion specimens. The assays are indicated for use with symptomatic individuals to aid in the diagnosis of anogenital HSV1 and HSV2 infections.
Warning: The BD ProbeTec™ Herpes Simplex Viruses (HSV 1 & 2) Q* Amplified DNA Assays (HSV Q* Assays) are not FDA cleared for use with cerebrospinal fluid (CSF). The assays are not intended to be used for prenatal screening or for individuals under the age of 17 years.
The BD ProbeTec Herpes Simplex Viruses (HSV 1 & 2) Q* Amplified DNA Assays (HSV Q* Assays) are based on the simultaneous amplification and detection of target DNA using amplification primers and fluorescently-labeled detector probes. The reagents for SDA are dried in two separate disposable microwells for each HSV Q* Assay: the Priming Microwell contains the amplification primers, fluorescently-labeled detector probe, nucleotides and other reagents necessary for amplification, while the Amplification Microwell contains the two enzymes (a necessary for amplification, a restriction endonuclease) that are required for SDA. The BD Viper™ System pipettes a portion of the purified DNA solution from each Extraction Tube into a Priming Microwell to rehydrate the contents. After a brief incubation, the reaction mixture is transferred to a corresponding, pre-warmed Amplification Microwell which is then sealed to prevent contamination and incubated in one of the two thermally-controlled fluorescent readers. The presence or absence of Herpes Simplex virus type 1 (HSV1) or Herpes Simplex virus type 2 (HSV2) DNA is determined by calculating the peak fluorescence (Maximum Relative Fluorescent Units (MaxRFU)) over the course of the amplification process and by comparing this measurement to a predetermined threshold value.
In addition to the fluorescent probe used to detect amplified HSV1 or HSV2 target DNA, a second labeled oligonucleotide is incorporated in each reaction. The Extraction Control (EC) oligonucleotide is labeled with a different dye than that used for detection of the HSV 1 or HSV2 specific target and is used to confirm the validity of the extraction process. The EC is dried in the Extraction Tubes and is rehydrated upon addition of the specimen and extraction reagents. At the end of the extraction process, the EC fluorescence is monitored by the BD Viper System and an automated algorithm is applied to both the EC and target-specific signals to report results as positive, negative, or EC failure.
Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided text:
BD ProbeTec™ Herpes Simplex Viruses (HSV1 & 2) Q* Amplified DNA Assays
The provided document describes the BD ProbeTec™ Herpes Simplex Viruses (HSV1 & 2) Q Amplified DNA Assays*, which are intended for the direct, qualitative detection and differentiation of HSV1 and HSV2 DNA in clinician-collected external anogenital lesion specimens from symptomatic individuals.
1. Acceptance Criteria and Reported Device Performance
The document does not explicitly present a table of predefined acceptance criteria in the format of a requirement with a corresponding target performance. Instead, it reports the device's performance characteristics, particularly diagnostic sensitivity and specificity, against a reference method (viral culture and PCR for discrepants). The performance of the predicate device is not provided, making a direct comparison to explicit acceptance criteria difficult. However, the study aims to demonstrate substantial equivalence.
Based on the clinical performance section, the key performance metrics reported are:
| Performance Metric | Acceptance Criteria (Implied) | Reported Device Performance (HSV1 Q* Assay) | Reported Device Performance (HSV2 Q* Assay) |
|---|---|---|---|
| Sensitivity (UVT_Qx Swab Diluent) | Sufficient for diagnostic aid | 96.8% (60/62) | 98.4% (186/189) |
| Specificity (UVT_Qx Swab Diluent) | Sufficient for diagnostic aid | 97.6% (244/250) | 83.7% (261/312) |
| Sensitivity (Qx Swab Diluent) | Sufficient for diagnostic aid | 96.7% (59/61) | 98.4% (186/189) |
| Specificity (Qx Swab Diluent) | Sufficient for diagnostic aid | 95.1% (235/247) | 80.6% (249/309) |
| Analytical Sensitivity (LOD) HSV1 | To detect low viral loads | 23 vp/mL (Q Swab Diluent), 85 vp/mL (UVT) | N/A (HSV1 assay) |
| Analytical Sensitivity (LOD) HSV2 | To detect low viral loads | N/A (HSV2 assay) | 84 vp/mL (Q Swab Diluent), 635 vp/mL (UVT) |
| Analytical Specificity | No cross-reactivity with common organisms | No interference observed with 57 organisms (Table 1) | No interference observed with 57 organisms (Table 1) |
| Interfering Substances | No significant interference from common substances | No interference observed with listed substances (Table 2) | No interference observed with listed substances (Table 2) |
| Reproducibility | Consistent results across sites/runs | High agreement with expected results (Tables 7 & 8) | High agreement with expected results (Tables 7 & 8) |
Note: The document states "The analytical and clinical study results ... support the determination of substantial equivalence in accordance with the intended use as stated in the product labeling." This implies that the reported performance metrics met the FDA's criteria for substantial equivalence to a predicate device, even if explicit quantitative targets for each metric are not listed as "acceptance criteria."
2. Sample Size and Data Provenance for the Test Set
- Sample Size (Clinical Performance Study - Test Set):
- Initial Subjects: 564 subjects
- Final Compliant Subjects for Analysis: 508 subjects
- HSV1 Analysis: 501 samples for viral culture typing reference method evaluation.
- UVT in Qx Swab Diluent: n=312 for positive/negative comparison to viral culture.
- Qx Swab Diluent: n=308 for positive/negative comparison to viral culture.
- HSV2 Analysis: 501 total samples for viral culture typing reference method evaluation for UVT in Qx Swab Diluent, and 498 for Qx Swab Diluent.
- Data Provenance: The clinical samples were collected prospectively from nine geographically diverse clinical sites in North America.
3. Number and Qualifications of Experts for Ground Truth (Test Set)
The document does not specify the number or qualifications of experts used to establish the "ground truth" for the test set.
4. Adjudication Method for the Test Set
The primary reference method for the clinical performance study was a commercially available viral culture and typing procedure.
For discrepant results between the ProbeTec HSV Q* Amplified DNA Assays and the reference culture and typing method, a PCR method was used for analysis. The document states, for example, regarding HSV2 specificity that "46 of the 51 HSV2 UVT in Q* Swab Diluent positive and viral culture negative were positive for HSV2 by PCR," indicating that PCR served as a secondary adjudicator for discrepant cases to determine the true positive or negative status when culture results conflicted with the new assay.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No Multi-Reader Multi-Case (MRMC) comparative effectiveness study was done. This device is a diagnostic assay (DNA amplification) and not an imaging or diagnostic support tool for human readers. Therefore, the concept of human readers improving with AI vs. without AI assistance is not applicable.
6. Standalone Performance Study (Algorithm Only)
Yes, a standalone performance study was done. The entire document describes the performance of the BD ProbeTec™ Herpes Simplex Viruses (HSV1 & 2) Q Amplified DNA Assays* as a standalone diagnostic device. The assay determines results (positive, negative, or Extraction Control failure) using an automated algorithm applied to the fluorescent signals.
7. Type of Ground Truth Used
The type of ground truth used for the clinical performance evaluation was:
- Viral Culture and Typing Procedure: This was the primary reference method.
- PCR Testing: Used as an adjudicator for discrepant results between the viral culture and the BD ProbeTec assays.
8. Sample Size for the Training Set
The document does not explicitly define or report a "training set" sample size in the context of machine learning. The study focuses on evaluating the performance of the already developed assay. The analytical performance characteristics (Limit of Detection, Analytical Specificity, Interfering Substances) and reproducibility studies involve controlled experiments with known viral strains and substances, which could be considered part of the assay's development and internal validation, but not a "training set" in the typical ML sense.
9. How the Ground Truth for the Training Set Was Established
As there is no distinct "training set" described in the context of an AI/ML algorithm development, the method for establishing ground truth for such a set is not applicable or detailed in this submission. The assay's "algorithm" described is likely based on fixed thresholds and logic for interpreting fluorescent signals, rather than a machine learning model requiring a training phase with labeled data. The established ground truth for analytical studies involved controlled spiking of known quantities of viral particles and other organisms or substances.
§ 866.3305 Herpes simplex virus serological assays.
(a)
Identification. Herpes simplex virus serological assays are devices that consist of antigens and antisera used in various serological tests to identify antibodies to herpes simplex virus in serum. Additionally, some of the assays consist of herpes simplex virus antisera conjugated with a fluorescent dye (immunofluorescent assays) used to identify herpes simplex virus directly from clinical specimens or tissue culture isolates derived from clinical specimens. The identification aids in the diagnosis of diseases caused by herpes simplex viruses and provides epidemiological information on these diseases. Herpes simplex viral infections range from common and mild lesions of the skin and mucous membranes to a severe form of encephalitis (inflammation of the brain). Neonatal herpes virus infections range from a mild infection to a severe generalized disease with a fatal outcome.(b)
Classification. Class II (special controls). The device is classified as class II (special controls). The special control for the device is FDA's revised guidance document entitled “Class II Special Controls Guidance Document: Herpes Simplex Virus Types 1 and 2 Serological Assays.” For availability of the guidance revised document, see § 866.1(e).