(231 days)
The HemosIL dRVVT Screen and HemosIL dRVVT Confirm assays are qualitative in-vitro diagnostic products to aid in the detection of lupus anticoagulants in human citrated plasma by the diluted Russell's Viper Venom method, on the ACL TOP® Family. The HemosIL dRVVT Screen and HemosIL dRVVT Confirm assays are intended to evaluate patients who have unexplained prolonged APTT test results The HemosIL dRVVT Screen and HemosIL dRVVT Confirm assays should be used in parallel as an integrated test for Lupus Anticoagulant detection.
DRVVT Screen and dRVVT Confirm are improved dRVVT reagents, intended to simplify and standardize the detection of Lupus Anticoagulant (LA) disorder in clinical chemistry evaluations. DRVVT Screen is poor in phospholipid, making it sensitive to LA. The additional amount of phospholipid in dRVVT Confirm neutralizes LA to give shorter clotting times. Russell's viper venom, in the presence of calcium, directly activates factor X (in a test sample). DRVVT Screen and dRVVT Confirm are therefore unaffected by contact factor abnormalities, factor VII, VIII and IX deficiencies, or inhibitors. As a result, dRVVT Screen and dRVVT Confirm are more specific tests for the evaluation of LA than APTT.
Acceptance Criteria and Device Performance Study for HemosIL® dRVVT Screen and Confirm Assays
1. Table of Acceptance Criteria and Reported Device Performance
The device (HemosIL® dRVVT Screen and HemosIL® dRVVT Confirm assays) is a qualitative in-vitro diagnostic product. Instead of traditional sensitivity/specificity acceptance criteria for quantitative devices, the performance is demonstrated through comparison with a predicate device and via inter-laboratory validation studies using established cut-offs.
| Performance Metric | Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|---|
| Analytical Performance | ||
| Precision (Total %CV) | Within acceptable ranges for coagulation assays (not explicitly stated, but industry standard for diagnostic tests). | LA Negative Control: Lot 1: 2.3%, Lot 2: 3.4%, Lot 3: 2.1% |
| Weakly LA Positive Control: Lot 1: 3.0%, Lot 2: 2.6%, Lot 3: 2.2% | ||
| LA Positive Control: Lot 1: 5.0%, Lot 2: 3.5%, Lot 3: 3.0% (across three lots and three instruments) | ||
| Interferent Tolerance | Maximum tolerated concentrations of common interferents should not significantly affect results (defined as base clotting time ± 15%). | UFH: ≤ 1.0 IU/mL |
| LMWH: ≤ 1.0 IU/m | ||
| Hemoglobin: ≤ 200 mg/dL | ||
| Bilirubin: ≤ 10 mg/dL | ||
| Triglyceride: ≤ 500 mg/dL (at any LA level tested) | ||
| Assay Cut-off Determination | Normal healthy individual samples should be used to establish a cut-off (Mean + 3SD). | Normalized Ratio cut-off determined using 40 normal healthy individuals. |
| ACL TOP: >1.2 | ||
| ACL TOP 500CTS: >1.2 (Note: Each lab should establish its own cut-off). | ||
| Comparison to Predicate Device | High Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) with the predicate device (HemosIL LAC Screen & LAC Confirm). | In-house (115 samples): |
- ACL TOP & ACL TOP 500 CTS: PPA 100.0% (35/35), NPA 100.0% (80/80), Overall 100% (115/115) (CI 95% provided)
3 US Field Sites (100+ samples each): - Site 1: PPA 92.7% (38/41), NPA 98.9% (91/92), Overall 97% (129/133)
- Site 2: PPA 90.2% (46/51), NPA 98.9% (91/92), Overall 95.8% (137/143)
- Site 3: PPA 98.1% (52/53), NPA 100.0% (80/80), Overall 99.2% (132/133) (CI 95% provided for all sites) |
| Matrix Comparison (Citrate Type) | Normalized Ratio should not be significantly affected by 3.8% versus 3.2% sodium citrate sample tubes, demonstrating high PPA and NPA. | ACL TOP: PPA 100% (19/19), NPA 92% (24/26) (CI 95% provided). Results showed the dRVVT NR is not affected by citrate tube type. |
| Matrix Comparison (Fresh vs. Frozen) | Normalized Ratio should not be significantly affected by fresh versus frozen and once-thawed samples, demonstrating high PPA and NPA. | ACL TOP: PPA 100% (28/28), NPA 100% (26/26) (CI 95% provided). The method comparison demonstrated the dRVVT NR is not affected by fresh or frozen use. |
| Specificity to LA | The assay should detect LA specifically and not be significantly affected by other conditions like oral anticoagulants, LMWH, UFH, DIC, or Factor Deficiency. | Known LA Positive: 100% (35/35)
Oral Anticoagulants: 40% (2/5)
LMWH: 0% (0/5)
UFH: 20% (1/5)
DIC: 0% (0/5)
Factor Deficiency: 0% (0/6) (Performance on both ACL TOP and ACL TOP 500CTS were similar). |
| Reference Range | A normal range study should be performed with a sufficient number of normal healthy individuals to establish reference intervals for the Normalized Ratio (NR). | A normal range study (n=120) established reference intervals for dRVVT Screen/Confirm Normalized Ratio:
ACL TOP: Lower Limit 0.92 (0.91-0.93), Upper Limit 1.11 (1.10-1.15)
ACL TOP 500 CTS: Lower Limit 0.91 (0.89-0.92), Upper Limit 1.13 (1.11-1.16) |
2. Sample Size Used for the Test Set and Data Provenance
- Precision/Reproducibility Study Test Set:
- Sample Size: N=80 per instrument per lot (Total: 3 lots x 2 instruments x 80 = 480 individual measurements for each control level). Specifically, 20 days, 2 runs/day, 2 replicates/run for each sample level (Negative, Weakly Positive, Positive controls).
- Data Provenance: Not explicitly stated, but implied to be in-house laboratory testing as part of the manufacturer's analytical performance assessment.
- Interference Studies Test Set:
- Sample Size: Not explicitly stated, but different concentrations of interferent were spiked into pooled normal plasma, weak LA positive plasma, and high LA positive plasma. The number of samples for each interferent type is not given.
- Data Provenance: Not explicitly stated, but implied to be in-house laboratory testing.
- Assay Cut-off Determination Test Set:
- Sample Size: 40 normal healthy individual samples.
- Data Provenance: Not explicitly stated, but likely from a healthy donor pool.
- "Clinical Sample" Testing (LA Positive, Oral Anticoagulants, etc.) Test Set:
- Sample Size: Known LA Positive (35 samples), Oral Anticoagulants (5 samples), LMWH (5 samples), UFH (5 samples), DIC (5 samples), Factor Deficiency (6 samples).
- Data Provenance: Not explicitly stated, but these are patient samples with specific conditions.
- Comparison Studies (Primary In-house) Test Set:
- Sample Size: 115 samples (80 Normal / 35 known LA Positive).
- Data Provenance: Not explicitly stated, but implied to be in-house, possibly from a reference laboratory.
- Comparison Studies (US Field Sites) Test Set:
- Sample Size: Site 1: 133 samples (41 LA positive + 92 normal); Site 2: 143 samples (51 LA positive + 92 normal); Site 3: 133 samples (53 LA positive + 80 normal). Over 100 samples per site.
- Data Provenance: US field sites (presumably clinical laboratories in the US).
- Matrix Comparison (Citrate Type) Test Set:
- Sample Size: Plasma from 26 donors. Artificial LA-Positive samples were prepared by spiking this pool.
- Data Provenance: Not explicitly stated, but implied healthy donors.
- Matrix Comparison (Fresh vs. Frozen) Test Set:
- Sample Size: Blood samples from 26 normal healthy donors. LA-Positive samples were prepared by spiking this pool.
- Data Provenance: Not explicitly stated, but implied healthy donors.
- Expected Values/Reference Range Study Test Set:
- Sample Size: 120 normal healthy individuals.
- Data Provenance: Not explicitly stated, but implied healthy donors.
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 of experts or their qualifications used to establish the ground truth for the test sets.
- For the "Known LA Positive" samples and samples from patients with specific conditions (Oral Anticoagulants, LMWH, UFH, DIC, Factor Deficiency), the ground truth is implied to be based on established clinical diagnosis and/or previous laboratory results for those conditions. The method of determining if a sample was "Known LA Positive" (e.g., diagnosis by a hematologist, positive by multiple other LA tests) is not detailed.
- For the "Normal" samples, ground truth is based on samples from supposedly healthy individuals.
4. Adjudication Method for the Test Set
No explicit adjudication method is described for conflicting results in the test set.
- For the comparison studies, the device's results (dRVVVT NR) were compared against the predicate device's results (LAC NR) which served as the reference/ground truth for in-house validation.
- For the field site validations, "LAC Screen/Confirm" is listed as the reference, suggesting comparison against the predicate device or a combination of standard diagnostic practices at those sites.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done
No, an MRMC comparative effectiveness study was not done. This device is a diagnostic reagent for automated analyzers, not an imaging device requiring human reader interpretation. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not applicable. The study focuses on comparing the new reagent's performance against a predicate device and assessing analytical validity.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was Done
Yes, the studies presented are essentially "standalone" performance studies for the reagent and instrument combination. The device (reagent) and the automated analyzer (ACL TOP Family) generate the results without human interpretive input for the final Normalized Ratio. Human involvement is in sample collection, running the assay on the instrument, and interpreting the final numerical ratio against the established cut-off, but the diagnostic determination of the ratio itself is automated.
7. The Type of Ground Truth Used
The ground truth used depends on the specific study:
- Comparison Studies: The predicate device (HemosIL LAC Screen & LAC Confirm) served as the reference/ground truth.
- Specificity Studies (LA Positive, Oral Anticoagulants, etc.): Ground truth was based on the "known" status of the plasma samples (e.g., "Known LA Positive," "Oral Anticoagulants"). How these "known" statuses were originally established (e.g., clinical diagnosis, other laboratory methods) is not detailed.
- Assay Cut-off and Reference Range Studies: Ground truth was based on plasma samples from "normal healthy individuals."
8. The Sample Size for the Training Set
The concept of a "training set" in the context of an AI/machine learning algorithm does not directly apply here, as this is a chemical reagent-based diagnostic assay. Therefore, there is no explicit training set in the AI sense.
However, if "training set" is interpreted as data used to establish device parameters or optimize its performance before formal validation, the following might be considered:
- The development process of the improved dRVVT reagents (HemosIL dRVVT Screen and dRVVT Confirm) would have involved extensive R&D and internal testing to optimize their composition and function. This internal optimization data is not detailed in the 510(k) summary.
- The "Assay cut-off" was determined using 40 normal healthy individual samples, which could be seen as an "internal" reference set for parameter setting.
- The normal range study used 120 normal healthy individuals to establish reference intervals.
9. How the Ground Truth for the Training Set Was Established
As noted in point 8, a formal "training set" as understood in AI/ML is not applicable. For the data used to establish parameters like the assay cut-off or reference ranges, the ground truth was established by using plasma samples from normal healthy individuals, indicating they were free from the condition the test aims to detect (lupus anticoagulants). The method for confirming their "normal healthy" status (e.g., physical examination, medical history review, other lab tests) is not specified.
§ 864.8950 Russell viper venom reagent.
(a)
Identification. Russell viper venom reagent is a device used to determine the cause of an increase in the prothrombin time.(b)
Classification. Class I (general controls).