(217 days)
The Alinity m HSV 1 & 2 / VZV assay is an in vitro real-time polymerase chain reaction (PCR) assay for the qualitative detection and differentiation of Herpes Simplex Virus 1 (HSV-1), Herpes Simplex Virus 2 (HSV-2) and Varicella Zoster Virus (VZV) DNA from clinician-collected cutaneous or mucocutaneous lesion swab specimens from symptomatic patients suspected of active herpes simplex virus 2 and/or varicella-zoster infection. The Alinity m HSV 1 & 2 / VZV assay is intended to aid in the diagnosis of herpes simplex virus 1, herpes simplex virus 2 and/or varicella-zoster active cutaneous or mucocutaneous infections. Negative results do not preclude herpes virus type 1, herpes simplex virus type 2 or varicella-zoster virus infections and should not be used as the sole basis for diagnosis, treatment or other management decisions.
The Alinity m HSV 1 & 2 / VZV assay is not intended for use with cerebrospinal fluid (CSF) or to aid in the diagnosis of HSV or VZV infections of the central nervous system (CNS). The Alinity m HSV 1 & 2 / VZV assay is not intended for use in prenatal screening.
The Alinity m HSV 1 & 2 / VZV assay is an in vitro real-time polymerase chain reaction (PCR) assay for the qualitative detection and differentiation of Herpes Simplex Virus 1 (HSV-1), Herpes Simplex Virus 2 (HSV-2) and Varicella Zoster Virus (VZV) DNA from clinician--collected cutaneous or mucocutaneous lesion swab specimens from symptomatic patients suspected of active herpes simplex virus 1, herpes simplex virus 2 and/or varicella-zoster infection. This assay is intended for use with the automated Alinity m System.
The steps of the Alinity m HSV 1 & 2 / VZV assay consist of sample preparation, PCR assembly, amplification/detection, and result calculation and reporting. The steps involved in all stages of the Alinity m HSV 1 & 2 / VZV assay procedure are executed automatically by the Alinity m System. No intermediate processing or transfer steps are performed by the user. The Alinity m System is designed to be a random access analyzer that can perform the Alinity m HSV 1 & 2 / VZV assay in parallel with other Alinity assays on the same instrument.
The Alinity m HSV 1 & 2 / VZV assay requires two separate assay specific kits as follows:
- The Alinity m HSV 1 & 2 / VZV AMP Kit (List No. 09N61-095) is comprised of 2 types of multi-well trays:
TRAY 1: Alinity m HSV 1 & 2 / VZV AMP TRAY 1 TRAY 2: Alinity m HSV 1 & 2 / VZV ACT TRAY 2.
TRAY 1 - Alinity m HSV 1 & 2 / VZV AMP is individually packed in a foil pouch and contains 48 unit-dose liquid amplification reagent wells and 48 unitdose liquid IC wells. One well of each is used per test.
· Amplification reagent wells consist of synthetic oligonucleotides, DNA Polymerase, dNTPs, and 0.15% ProClin® 950 in a buffered solution with a reference dye. IC wells consist of plasmid DNA with unrelated IC sequences and poly dA:dT in a TE buffer containing 0.15% ProClin 950 as a preservative.
TRAY 2 - Alinity m HSV 1 & 2 / VZV ACT is individually packed in a foil pouch and contains 48 unit-dose liquid activation reagent wells. One reagent well is used per test.
· Activation reagent wells consist of magnesium chloride, potassium chloride, and tetramethylammonium chloride. Preservative: 0.15% ProClin 950.
- The Alinity m HSV 1 & 2 / VZV CTRL Kit (09N61-085) consists of negative controls and positive controls, each supplied as liquid in single-use tubes.
Alinity m HSV 1 & 2 / VZV Negative CTRL (List No. 9N61Z) consists of Negative Diluent / TE buffer (containing 0.085% Sodium Azide and 0.087% ProClin 950).
Alinity m HSV 1 & 2 / VZV Positive CTRL (List No. 9N61W) consists of linearized plasmid DNA containing HSV-1, HSV-2 and VZV DNA sequences in Negative Diluent / TE buffer (containing 0.085% Sodium Azide and 0.087% ProClin 950).
The Alinity m HSV 1 & 2 / VZV assay is to be run on the Alinity m System which is a fully integrated, sample to result automated system that performs real-time PCR test using the Alinity m HSV 1 & 2 / VZV AMP Kit along with the Alinity m HSV 1 & 2 / VZV CTRL Kit.
The provided text describes the performance of the "Alinity m HSV 1 & 2 / VZV" assay, which is an in vitro real-time PCR assay for detecting and differentiating Herpes Simplex Virus 1 (HSV-1), Herpes Simplex Virus 2 (HSV-2), and Varicella Zoster Virus (VZV) DNA.
Here's an analysis of the acceptance criteria and study proving the device meets them:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are implicitly defined by the clinical agreement and analytical performance values demonstrated to establish substantial equivalence to a predicate device. For clinical agreement, the performance is measured by Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) compared to a commercially available NAAT comparator method.
| Acceptance Criteria Category | Specific Metric | Target (Implicit) | Reported Device Performance (Table 9 - Prospective Study) | Reported Device Performance (Table 11 - Retrospective Study) |
|---|---|---|---|---|
| Clinical Agreement (Total) | HSV-1 PPA | High (e.g., >95%) | 97.6% (123/126) (95% CI: 93.2, 99.2) | 100.0% (72/72) (95% CI: 94.9, 100.0) |
| HSV-1 NPA | High (e.g., >95%) | 98.9% (1119/1131) (95% CI: 98.2, 99.4) | 96.2% (325/338) (95% CI: 93.5, 97.7) | |
| HSV-2 PPA | High (e.g., >95%) | 99.2% (122/123) (95% CI: 95.5, 99.9) | 98.7% (74/75) (95% CI: 92.8, 99.8) | |
| HSV-2 NPA | High (e.g., >95%) | 99.2% (1125/1134) (95% CI: 98.5, 99.6) | 95.8% (321/335) (95% CI: 93.1, 97.5) | |
| VZV PPA | High (e.g., >95%) | 97.7% (43/44) (95% CI: 88.2, 99.6) | 97.8% (44/45) (95% CI: 88.4, 99.6) | |
| VZV NPA | High (e.g., >95%) | 99.8% (1211/1213) (95% CI: 99.4, 100.0) | 98.4% (360/366) (95% CI: 96.5, 99.2) | |
| Analytical Sensitivity | LoD (HSV-1) | Low (e.g., as defined) | 5.90 TCID50/mL | N/A (Analytical study) |
| LoD (HSV-2) | Low (e.g., as defined) | 2.07 TCID50/mL | N/A (Analytical study) | |
| LoD (VZV) | Low (e.g., as defined) | 0.055 TCID50/mL | N/A (Analytical study) | |
| Analytical Specificity | Cross-Reactivity | No cross-reactivity | No cross-reactivity observed with 55 microorganisms | N/A (Analytical study) |
| Interference | No interference | No interference observed with 55 microorganisms at 3X LoD | N/A (Analytical study) | |
| Precision | Detection Rate (3X LoD / 5X LoD) | 100% | 100% for all analytes at 3X LoD (Table 6) | 100% for all analytes at 5X LoD (Table 7) |
| Carryover Contamination | 0% | 0.0% (0/360) (95% CI: 0.0%, 1.1%) | N/A (Analytical study) |
The acceptance criteria typically would be pre-defined statistical thresholds for PPA and NPA (e.g., PPA ≥ 95% and NPA ≥ 95%). Based on the reported results, the device successfully meets high performance metrics, suggesting that the implicit acceptance criteria were met for substantial equivalence.
2. Sample Size Used for the Test Set and Data Provenance
- Prospective Study Test Set:
- Sample Size: 1,258 results (1,257 for HSV-1, 1,257 for HSV-2, and 1,257 for VZV) from unique specimens.
- Data Provenance: Multicenter, prospective clinical study conducted in the United States. Specimens were clinician-collected from symptomatic individuals.
- Retrospective Study Test Set:
- Sample Size: 411 specimens (410 for HSV-1, 410 for HSV-2, and 411 for VZV).
- Data Provenance: Retrospective study using archived, leftover lesion swab specimens from routine clinical testing. The location is not explicitly stated, but given it follows a prospective US study and is for US FDA clearance, it is highly likely to be from the US.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
- The document does not specify the number or qualifications of experts used to establish the ground truth.
- The ground truth was established by comparison to a "commercially available NAAT comparator method (NAAT 1)". For discordant results, a "second commercially available RT-PCR comparator method (NAAT 2)" was used for informational purposes only (not for the primary analysis of device performance). This means the ground truth is essentially defined by the predicate/comparator device(s).
4. Adjudication Method for the Test Set
- The primary ground truth was established by a single comparator method (NAAT 1).
- For specimens with discordant results between the Alinity m assay and NAAT 1, a second NAAT method (NAAT 2) was used. However, the results of this second test were "not included in the analysis of device performance and are considered for information purposes only." This implies that the primary PPA/NPA calculations are based solely on the agreement with NAAT 1, and there was no formal 2+1 or 3+1 adjudication to establish a "resolved" ground truth for discordant cases that would then be used in the performance calculations.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, and what was the effect size of how much human readers improve with AI vs without AI assistance
- This is not applicable as the device is an in vitro diagnostic (IVD) assay detecting viral DNA, not an AI-assisted diagnostic imaging device requiring human reader interpretation. There are no "human readers" in the context of this device.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done
- Yes, this is a standalone device performance study. The Alinity m HSV 1 & 2 / VZV assay is an automated system described as "fully integrated, sample to result." The performance data presented (clinical agreement, analytical sensitivity, specificity, precision, reproducibility, carryover) represent the performance of the algorithm/assay system without direct human interpretation of raw data being a variable. The "results are calculated and reported" automatically by the Alinity m System.
7. The Type of Ground Truth Used
- The ground truth was established by comparison to a "commercially available NAAT comparator method (NAAT 1)." For discordant cases, a second NAAT (NAAT 2) was used, but its results were for informational purposes only. This is a form of clinical surrogate ground truth, relying on an established and legally marketed diagnostic method. It is not pathology, expert consensus (in the traditional sense of multiple human interpretations), or outcomes data.
8. The Sample Size for the Training Set
- The document does not provide information regarding a specific training set size or how the device's algorithms (if any, beyond PCR signal processing) were trained. Regulatory submissions for IVD assays primarily focus on analytical and clinical validation of the final, locked-down device performance, rather than algorithm development specifics. The device seems to be a PCR assay, where the "training" would be more akin to assay design and optimization, not machine learning model training on large datasets in the way an AI imaging model is.
9. How the Ground Truth for the Training Set was Established
- As the document does not mention a training set in the context of machine learning, there is no information on how a ground truth for such a set would have been established. For a PCR assay, the development process involves extensive analytical characterization, optimization, and verification using characterized samples (e.g., known positive/negative samples, spiked samples, reference strains) to establish assay parameters and thresholds. This is distinct from establishing ground truth for a machine learning training dataset.
§ 866.3309 Herpes virus nucleic acid-based cutaneous and mucocutaneous lesion panel.
(a)
Identification. A herpes virus nucleic acid-based cutaneous and mucocutaneous lesion panel is a qualitative in vitro diagnostic device intended for the simultaneous detection and differentiation of different herpes viruses in cutaneous and mucocutaneous lesion samples from symptomatic patients suspected of Herpetic infections. Negative results do not preclude infection and should not be used as the sole basis for treatment or other patient management decisions. The assay is not intended for use in cerebrospinal fluid samples.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include detailed documentation for the device description, including the device components, ancillary reagents required but not provided, and a detailed explanation of the methodology including primer design and selection.
(2) Premarket notification submissions must include detailed documentation from the following analytical and clinical performance studies: Analytical sensitivity (Limit of Detection), reactivity, inclusivity, precision, reproducibility, interference, cross reactivity, carry-over, and cross contamination.
(3) Premarket notification submissions must include detailed documentation of a clinical study using lesion samples in which Herpes Simplex Virus 1, Herpes Simplex Virus 2, or Varicella Zoster Virus DNA detection was requested. The study must compare the device performance to an appropriate well established reference method.
(4) 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.
(5) The device labeling must include a limitation statement that reads: “The device is not intended for use with cerebrospinal fluid or to aid in the diagnosis of HSV or VZV infections of the central nervous system (CNS).”
(6) Premarket notification submissions must include quality assurance protocols and a detailed documentation for device software, including, but not limited to, standalone software applications and hardware-based devices that incorporate software.
(7) The risk management activities performed as part of the manufacturer's 21 CFR 820.30 design controls must document an appropriate end user device training program that will be offered as part of efforts to mitigate the risk of failure to correctly operate the instrument.