(240 days)
CRYOcheck Chromogenic Factor VIII is for clinical laboratory use in the quantitative determination of factor VIII activity in 3.2% citrated human plasma. It is intended to be used in identifying factor VIII deficiency and as an aid in the management of hemophilia A in individuals aged 2 years and older. For in vitro diagnostic use.
CRYOcheck Chromogenic Factor VIII is used for determination of FVIII activity and contains the following four components, packaged in glass vials and provided frozen to preserve the integrity of the components:
Reagent 1: Bovine FX and a fibrin polymerization inhibitor, with activators and stabilizers.
Reagent 2: Human FIIa, human FIXa, calcium chloride and phospholipids.
Reagent 3: FXa substrate containing EDTA and a thrombin inhibitor.
Diluent Buffer: Tris buffer solution containing 1% BSA and a heparin antagonist.
The CRYOcheck Chromogenic Factor VIII device is intended for the quantitative determination of Factor VIII (FVIII) activity in human plasma to identify FVIII deficiency and aid in Hemophilia A management.
Here's an analysis based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are generally implied by the successful outcomes of various studies, aligning with CLSI guidelines and demonstrating performance comparable to the predicate device. Specific numerical acceptance criteria were not explicitly stated as pass/fail thresholds in the document, but the reported performance values are presented as the fulfillment of these criteria.
| Performance Characteristic | Acceptance Criteria (Implied by Study Design & Comparator Performance) | Reported Device Performance (CRYOcheck Chromogenic Factor VIII) |
|---|---|---|
| Precision | CV 1%; SD $\leq$ 0.1% for very low FVIII | Pooled precision: 1%; $\leq$0.1% SD for very low FVIII plasma (Table in document) |
| Reproducibility | CV 1%; SD $\leq$ 0.1% for very low FVIII | Pooled reproducibility: 1%; $\leq$0.1% SD for very low FVIII plasma (Table in document) |
| Linearity Range | Clinically relevant range (e.g., 0-200% FVIII activity) | 0 to 200% FVIII activity |
| Reference Interval | Established from healthy population | 43.2-159.3% FVIII activity (95% CI) |
| Shelf-Life Stability | At least 12 months at recommended storage conditions | At least 12 months at $\leq$-70°C (study completed up to 13 months) |
| In-Use Stability | Defined operational stability durations | 8 hours on-board instrument; 5 days at 2-8°C; 1 month refrozen storage at $\leq$-70°C (if refrozen within 4 hours of initial thaw) |
| Limit of Detection (LoD) | Clinically relevant low detection limit | 0.5% FVIII activity |
| Limit of Blank (LoB) | Clinically relevant lower blank limit | 0.4% FVIII activity |
| Limit of Quantitation (LoQ) | Clinically relevant low quantitation limit | 0.5% FVIII activity |
| Interferences | No significant interference from common substances | No interference from tested: Hemoglobin $\leq$ 500 mg/dL, Intralipid $\leq$ 500 mg/dL, Bilirubin (unconjugated) $\leq$ 29 mg/dL, vWF $\leq$ 20 µg/mL, Unfractionated heparin $\leq$ 2 IU/mL, Low molecular weight heparin $\leq$ 2 IU/mL, Fondaparinux $\leq$ 1.25 mg/L, Lupus Anticoagulant $\leq$ 1.8 dRVVT ratio. Interference from Rivaroxaban and Dabigatran noted. |
| Method Comparison | Equivalent performance to predicate device | Passing-Bablok regression: Slope ~1, Intercept ~0, Pearson Correlation Coefficient > 0.99 (Overall: Slope 1.038, Intercept 0.473, r=0.994) |
| Sample Integrity | Defined sample stability durations | 2 hours at room temperature; 3 months at $\leq$-70°C (including up to two freeze-thaw cycles) |
2. Sample Sizes Used for the Test Set and Data Provenance
- Precision Study: One normal and two abnormal reference controls, and five patient plasma samples (representing very low, mid, normal, and high FVIII activity). Each sample was measured in duplicate, twice a day for 20 days (total 80 replicates per sample per lot) with 3 lots of the device. Data provenance is internal (as it's an internal study).
- Reproducibility Study: One normal and two abnormal reference controls, and three patient plasma samples (representing very low, normal, and high FVIII activity). Each sample was measured in triplicate, twice a day for 5 days at each of 3 sites with 3 lots of the device. Data provenance includes one internal and two external sites, but specific countries are not mentioned beyond "Canada" for the submitter. This appears to be prospective data collection for the study.
- Linearity/Assay Reportable Range Study: Fifteen sample dilutions created by combining high FVIII plasma (260%) with congenital FVIII deficient plasma (0%). Each level was tested in quadruplicate. Data provenance is internal (as it implies an internal study).
- Reference Interval Study: One hundred and twenty ostensibly healthy individuals $\geq$ 18 years. Data provenance is not specified beyond "citrated plasma samples collected from". This appears to be prospective data collection.
- Shelf-Life Stability Study: Six plasma samples representing low to normal FVIII activity levels. Three lots of the device were tested at various time points up to 37 months (13 months completed). Data provenance is internal.
- In-Use Stability Study: Six plasma samples representing low to normal FVIII activity levels. Three lots of the device were tested at various time points. Data provenance is internal.
- Detection Limit (LoB/LoD/LoQ) Studies:
- LoB: Four blank plasma samples from individuals with severe congenital hemophilia A.
- LoD: Four plasma samples with low FVIII activity from congenital hemophilia A donors.
- LoQ: Aliquots of four plasma samples with low FVIII activity from congenital hemophilia A donors.
All samples for LoB/LoD were measured in triplicate over five days using three lots of the device. For LoQ, samples were tested in triplicate on five different days at an external laboratory. Data provenance for LoB/LoD/LoQ samples is from individuals with hemophilia A.
- Interference Studies: Plasma samples spiked with possible interferents. Ten replicates of each spiked sample and 10 replicates of corresponding blank matrix control were tested. Data provenance is internal.
- Method Comparison Studies: Three hundred and eighteen human plasma samples from normal individuals, patients with congenital or acquired hemophilia A, and various types of von Willebrand disease. Samples were distributed across three sites. Data provenance spans "normal ostensibly healthy individuals and from patients". This appears to be prospective data collection.
- Sample Integrity Study: Forty-six plasma samples. Data provenance is not further specified. This appears to be prospective data collection at two external sites.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
For this in vitro diagnostic device, "ground truth" is typically established by reference methods or accepted clinical classifications rather than expert consensus on individual images or cases.
- For studies like Precision, Reproducibility, Linearity, Stability, and Detection Limits, the "ground truth" for the FVIII activity levels in controls and calibrators would be established by the manufacturer's internal characterization methods, traceable to international standards if applicable (though not explicitly stated as such for FVIII activity). The expertise would lie in clinical chemistry, hematology, and laboratory medicine for the development and validation of these reference materials and methods. No specific number or qualification of experts is mentioned for these.
- For the Reference Interval Study, the ground truth is derived from the statistical distribution of FVIII activity in a population of ostensibly healthy individuals. This doesn't involve individual expert ground-truthing but rather statistical analysis.
- For the Method Comparison Study, the ground truth for FVIII activity was established by a comparator device, Coatest SP FVIII (K042576), used at a central reference laboratory. The "experts" in this context are the trained laboratory personnel performing the reference method.
- For sample selection in studies involving "congenital hemophilia A donors" or "patients with congenital or acquired hemophilia A and various types of von Willebrand disease," the diagnosis (which forms part of the "ground truth" for classifying these samples) would have been made by medical professionals (e.g., hematologists) based on standard clinical and laboratory diagnostic criteria. No specific number or qualifications are given.
4. Adjudication Method for the Test Set
Adjudication methods like "2+1" or "3+1" are typically used for subjective diagnostic tasks, often involving image interpretation or clinical reviews. Since the CRYOcheck Chromogenic Factor VIII is a quantitative assay for FVIII activity, the "adjudication method" is the quantitative measurement itself, often with replicates and statistical analysis, as detailed in the study designs (e.g., "in duplicate," "in triplicate"). No expert adjudication in the traditional sense is described or expected for this type of device.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size
No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. MRMC studies are primarily for evaluating the impact of a new diagnostic tool on the diagnostic performance of human readers, typically with subjective assessments. This device is a quantitative in vitro diagnostic, not a tool for human reading in the conventional sense.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, the device operates as a standalone algorithm (assay) measuring FVIII activity. The performance studies described (Precision, Reproducibility, Linearity, Reference Interval, Stability, Detection Limits, Interferences, Method Comparison, Sample Integrity) all represent the performance of the device itself, without human-in-the-loop diagnostic interpretation as part of its core function, other than trained laboratory personnel operating the instrument and interpreting numerical output.
7. The Type of Ground Truth Used
The ground truth used for these studies varies by the specific test:
- Reference materials and controls: For precision, linearity, and detection limit studies, the ground truth for FVIII activity levels is based on established values of these materials, likely traceable to international standards or well-characterized internal standards.
- Healthy population data: For the reference interval, the ground truth for "normal" FVIII activity is derived from a statistically representative healthy population.
- Comparator device: For the method comparison study, the ground truth was established by the predicate device, Coatest SP FVIII (K042576).
- Clinical diagnosis: For studies involving patient samples (e.g., hemophilia A, von Willebrand disease), the ground truth for their disease status would be based on clinical diagnosis by medical professionals.
8. The Sample Size for the Training Set
The document describes performance studies (validation tests) for the device. It does not provide information on a "training set" in the context of machine learning. This is because the device is a chemical assay, not an AI/ML-based diagnostic system that would require a training set to develop its model.
9. How the Ground Truth for the Training Set Was Established
As no training set is mentioned or applicable for this type of chemical assay device, this question is not relevant based on the provided information.
§ 864.7290 Factor deficiency test.
(a)
Identification. A factor deficiency test is a device used to diagnose specific coagulation defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene).(b)
Classification. Class II (performance standards).