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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 stabilizer.
• Reagent 2: Human FIIa, bovine 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.

In the first stage of the chromogenic assay, test plasma (containing an unknown amount of functional FVIII) is added to a reaction mixture comprised of calcium, phospholipids, human purified thrombin and FIXa, and bovine FX (Reagent 1 and Reagent 2). This mixture swiftly activates FVIII to FVIIIa, which works in concert with FIXa to activate FX. When the reaction is stopped, FXa production is assumed to be proportional to the amount of functional FVIII present in the sample. The second stage of the assay is to measure FXa through cleavage of a FXa-specific peptide nitroanilide substrate (FXa Substrate). P-nitroaniline is produced, giving a color that can be measured spectrophotometrically by absorbance at 405 nm.

Based on the provided FDA 510(k) Clearance Letter, the device in question is the CRYOcheck Chromogenic Factor VIII. This document details the clearance of a modified version of an existing device, emphasizing the differences from the previous version regarding interference claims and recovery of Factor VIII replacement therapies.

Here's an analysis of the acceptance criteria and study proving the device meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" for each performance claim in a quantified manner (e.g., "Interference must be less than X%"). Instead, it reports the limits of non-interference found in their studies, implying these served as the de facto acceptance criteria. For the Factor VIII replacement therapy recovery, the acceptance criterion appears to be "accurate evaluation" across a range of concentrations, with specific over/under recovery noted.

2. Sample Sizes Used for the Test Set and Data Provenance

• Interference Studies: Plasma samples were "spiked with possible interferents," and "10 replicates were tested alongside 10 replicates of the corresponding blank matrix control." The total number of individual patient samples from which this plasma was derived is not specified, nor is the country of origin. The study design implies a prospective spiking experiment in a laboratory setting.
• Recovery of Factor VIII Replacement Therapy: "Congenital FVIII deficient plasma was spiked with 14 FVIII replacement therapies at seven concentrations." The number of individual patient plasma units or lots of deficient plasma used is not specified. The study design implies a prospective spiking experiment in a laboratory setting.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications

N/A. This is an in vitro diagnostic device for quantitative determination of factor VIII activity, not an AI/imaging device requiring expert human readers for ground truth generation. The ground truth for these studies is established by the known concentrations of spiked interferents or FVIII replacement therapies, and the intrinsic properties of the FVIII deficient plasma.

4. Adjudication Method for the Test Set

N/A. As this is a quantitative in vitro diagnostic device, an adjudication method in the context of human expert review of imaging or clinical data is not applicable. The results are measured spectrophotometrically.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done

No, an MRMC study was not done. This type of study is relevant for AI imaging devices where human readers interpret medical images with and without AI assistance. This document describes an in vitro diagnostic device.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) was Done

Yes, this entire submission describes the standalone performance of the CRYOcheck Chromogenic Factor VIII assay. The device itself performs the quantitative determination of FVIII activity, entirely without a "human-in-the-loop" once the sample is loaded and the assay run according to protocol.

7. The Type of Ground Truth Used

• Interference Studies: The ground truth was the known concentration of the spiked interferent (e.g., Hemoglobin, Intralipid, Bilirubin, etc.) added to plasma samples, and the corresponding blank matrix control.
• Recovery of Factor VIII Replacement Therapy: The ground truth was the known concentration of the spiked FVIII replacement therapy added to congenital FVIII deficient plasma at various concentrations.

8. The Sample Size for the Training Set

N/A. This document describes an in vitro diagnostic assay based on chromogenic principles, not an AI/ML algorithm that requires a "training set" in the computational sense. The device's components (reagents, diluent buffer) and their interaction define the assay, which is then validated through performance studies.

9. How the Ground Truth for the Training Set was Established

N/A. See point 8. The "ground truth" for developing and optimizing such a chromogenic assay would stem from extensive biochemical research, characterization of reagents, and titrations against known standards, which is inherent in the development of any diagnostic assay, but not referred to as a "training set" or "ground truth establishment" in the AI/ML context.

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CRYOcheck Factor VIII Deficient Plasma with VWF is for clinical laboratory use as a deficient substrate in the quantitative determination of Factor VIII activity in 3.2% citrated human plasma based on the activated partial thromboplastin time (APTT) assay. 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 Factor VIII Deficient Plasma with VWF is normal human citrated plasma which has been immunodepleted of factor VIII and to which an exogenous source of human von Willebrand Factor (vWF) has been added and buffered with HEPES. Factor VIII has been assayed at less than 1% of normal activity levels and vWF antigen and activity are >50%. It will be provided to users frozen in small-volume aliquots (25 vials of 1.0 mL, and 25 vials of 1.5 mL). Vials will be packaged into boxes; these will be frozen during the manufacturing process and will be shipped and stored frozen until use to preserve the integrity of the components

The provided FDA 510(k) summary for the "CRYOcheck Factor VIII Deficient Plasma with VWF" describes various performance studies and their results. Based on the document, here's a structured breakdown of the acceptance criteria and the study details:

1. A table of acceptance criteria and the reported device performance

The document does not explicitly present a table of pre-defined acceptance criteria for each performance characteristic in a pass/fail format. Instead, it presents the results of various studies and implies that these results met internal or regulatory expectations for substantial equivalence to the predicate device. However, we can infer performance targets based on the documented results and common regulatory expectations for in vitro diagnostic devices.

Here's a table summarizing the reported device performance, with inferred acceptance "criteria" based on the conclusions drawn in the report:

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CRYOcheck Chromogenic Factor IX is for clinical laboratory use in the quantitative determination of factor IX activity in 3.2% citrated human plasma. It is intended to be used in identifying factor IX deficiency and as an aid in the management of hemophilia B in individuals aged 2 years and older. For in vitro diagnostic use.

CRYOcheck Chromogenic Factor IX is used for determination of FIX activity and contains the following four components, packaged in vials, and provided frozen to preserve the integrity of the components:
Reagent 1: Human FVIII, human FX, bovine FV and a fibrin polymerization inhibitor.
Reagent 2: Human FXIa, human FII, 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 provided text describes the performance of the CRYOcheck Chromogenic Factor IX device. Here's a breakdown of the acceptance criteria and the study that proves the device meets these criteria, based on the information provided:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria with pass/fail thresholds for each performance characteristic. Instead, it presents study results and concludes that the device performed effectively and demonstrates substantial equivalence. However, we can infer some criteria from the performance data presented.

2. Sample Size Used for the Test Set and Data Provenance

• Multi-Reagent Lot Precision: 6 samples (1 normal reference control, 2 abnormal reference controls, 3 patient plasma samples).
• Multi-Reagent Lot Site to Site Reproducibility: 6 samples (1 normal reference control, 2 abnormal reference controls, 3 patient plasma samples).
• Linearity/Assay Reportable Range: 14 sample dilutions.
• Reference Interval: 128 normal, ostensibly healthy individuals.
• Shelf-Life Stability: Not specified, but likely involved multiple reference controls and patient plasma samples at each time point.
• In-Use Stability: Not specified, but involved multiple reference controls and patient plasma samples.
• Detection Limit (LoB): 4 blank plasma samples from individuals with severe congenital hemophilia B.
• Detection Limit (LoD): 4 plasma samples with low FIX activity from congenital hemophilia B donors.
• Detection Limit (LoQ): 4 plasma samples with low FIX activity from congenital hemophilia B donors.
• Interferences: Not specified, but likely involved spiked plasma samples.
• Recovery of FIX Replacements: Congenital FIX deficient plasma spiked with 7 FIX replacement therapies at 7 concentrations.
• Method Comparison Studies: 368 human plasma samples. These samples were from normal ostensibly healthy individuals, patients with von Willebrand disease, patients with congenital and acquired hemophilia A and B, and patients on recombinant factor IX treatments.
• Sample Integrity: 65 plasma samples.

Data Provenance: The document does not explicitly state the country of origin for the patient or donor samples. The studies involve both internal and external sites for reproducibility and method comparison. The mention of "congenital hemophilia B donors" and "patients with von Willebrand disease, and congenital and acquired hemophilia A and B" suggests the use of patient samples, implying a clinical or diagnostic context. The studies are retrospective in nature as they involve testing existing plasma samples.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

For the studies described, the "ground truth" for Factor IX activity is established by:

• Reference controls: These are quality control materials with known or assigned values for FIX activity.
• Patient plasma samples: Their FIX activity is determined either by the device itself (for precision and reproducibility) or by a "comparator method" or "validated laboratory developed chromogenic factor IX assay" (for method comparison and LoQ studies).
• Spiked samples: For linearity, interference, and recovery studies, known amounts of FIX or interfering substances are added to samples to create a controlled "ground truth."
• Congenital FIX deficient plasma: For LoB, LoD, and recovery studies, plasma from individuals with a known severe deficiency serves as a baseline.

The document does not mention specific "experts" in the context of radiologists or similar roles establishing ground truth through consensus. Instead, the ground truth is based on:

• Established assay methods: The comparator method and the validated laboratory developed chromogenic factor IX assay are implicitly considered accurate for determining FIX activity. The qualifications of the personnel running these assays are not individually listed but are assumed to be trained laboratory professionals.
• Reference materials: Reference controls have assigned values.

4. Adjudication Method for the Test Set

The concept of an "adjudication method" (like 2+1 or 3+1) is typically relevant for studies where human expert interpretation is compared, e.g., in medical image analysis. In this context of an in vitro diagnostic device for quantitative determination in plasma, such an adjudication method is not described or applicable. The "ground truth" is based on the results of the reference methods, reference materials, and defined sample preparations.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This type of study is not relevant for an in vitro diagnostic device like the CRYOcheck Chromogenic Factor IX, which directly measures a biomarker rather than assisting human readers in interpreting complex data like medical images. The device itself is the "reader" providing a quantitative result.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

Yes, the studies presented are all standalone (algorithm only) performance assessments for the CRYOcheck Chromogenic Factor IX device. The device itself performs the quantitative determination of factor IX activity. The results are generated by the instrument (IL ACL TOP Series or TOP 50 Series Instruments) based on the reagents and the plasma sample, without human interpretative input in the output. Human operators are involved in running the tests, but not in interpreting the quantitative output in a way that typical human-in-the-loop AI studies would assess.

7. The Type of Ground Truth Used

The ground truth used in these studies includes:

• Assigned values of reference controls: For precision and reproducibility.
• Results from a "comparator device" or "validated laboratory developed chromogenic factor IX assay": For method comparison and limit of quantitation. These are considered gold standards for FIX activity measurement.
• Known concentrations in spiked samples: For linearity, interference, and recovery studies.
• Known characteristics of congenital FIX deficient plasma: For detection limits and recovery studies.
• Plasma samples from "normal, ostensibly healthy individuals": For establishing reference intervals.

This primarily falls under the category of established assay methods and reference materials.

8. The Sample Size for the Training Set

The document does not mention a "training set" in the context of machine learning or AI. The CRYOcheck Chromogenic Factor IX is an in vitro diagnostic assay, not an AI/ML algorithm that requires training data. Its performance is based on chemical and enzymatic reactions, and its parameters are established through conventional analytical validation studies like those described.

9. How the Ground Truth for the Training Set Was Established

As there is no "training set" in the AI/ML sense for this device, this question is not applicable. The device's operational parameters and performance are intrinsically defined by its design, chemical components, and the analytical validation tests presented.

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CRYOcheck Hex LA is for clinical laboratory use as a qualitative test kit intended to aid in the detection of lupus anticoagulants (LA) in 3.2% citrated human plasma by the application of hexagonal phase phospholipids. CRYOcheck Hex LA should be used as an integrated test for lupus anticoagulant detection. For in vitro diagnostic use. The performance of this device has not been established in neonate and pediatric patient populations.

CRYOcheck Hex LA is comprised of three reagents supplied in a frozen format as follows:

LA Start: Pooled normal plasma with buffer and a heparin neutralizer.

LA Correct: Pooled normal plasma with buffer, a heparin neutralizer, and inverted hexagonal phase phospholipid.

LA APTT: Silica-based lupus sensitive APTT reagent with stabilizer.

1. Acceptance Criteria and Device Performance:

2. Sample Sizes and Data Provenance:

• Precision Study:
  • 3 control plasmas and 5 plasmas with varying LA positivity.
  • Tested in duplicate, twice a day for 20 days per lot of reagent (3 lots used).
• Reproducibility Study:
  • 3 control plasmas and 5 plasmas with varying LA positivity.
  • Each sample tested in triplicate, twice a day for 5 days for each of the 3 lots of reagent.
• Normal Range and Assay Cut-off Study:
  • Normal samples: 137 on Analyzer A, 126 on Analyzer B.
  • Each sample tested using 3 lots of CRYOcheck Hex LA.
• Shelf Life Stability Study:
  • 3 lots of CRYOcheck Hex LA.
  • 10 replicates of 3 controls tested at time = 0 and regular intervals up to 37 months.
  • One additional plasma sample close to the cut-off for one lot.
• In-Use Stability Study:
  • 3 lots of CRYOcheck Hex LA.
  • 5 replicates of 3 control plasmas and 4 test plasmas with varying levels of LA.
  • Tested at 0, 2, 4, 6, 7, 8, and 9 hours.
• Interference Studies:
  • Patient plasma samples spiked with possible interferents.
  • 20 replicates of spiked samples tested alongside 20 replicates of corresponding blank matrix control.
  • Single lot of CRYOcheck Hex LA used.
• Method Comparison Studies (Test Set):
  • Total samples: 446
    • 124 known (previously characterized) LA positive samples.
    • 75 normal (presumed LA negative) samples from individuals with other medical conditions including autoimmune disorders.
    • 220 LA target screening population samples.
  • Data Provenance: The document does not explicitly state the country of origin for the patient samples. The study involved one internal site and three external sites, suggesting a multi-center study. It is a retrospective study since samples were "known (previously characterized) LA positive" or "presumed LA negative."
• Sample Integrity Study:
  • 64 samples.

3. Number of Experts and Qualifications for Ground Truth:

• This device is an in vitro diagnostic (IVD) test, not an AI/imaging device requiring expert interpretation for ground truth.
• The ground truth for the method comparison study was established by comparing the CRYOcheck Hex LA results against a legally marketed predicate device, Staclot® LA (K923731).
• The determination of "known (previously characterized)" LA positive samples and "presumed LA negative" samples would implicitly rely on established clinical or laboratory diagnostic procedures, which are performed by qualified laboratory personnel, not typically "experts" in the sense of a radiology reader study.

4. Adjudication Method for the Test Set:

• Not applicable as this is a comparison study against a predicate device's results, not a human reader study needing adjudication. The "ground truth" for the test set was the result obtained from the predicate device (Staclot® LA).

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:

• No, an MRMC comparative effectiveness study was not done. This is an IVD device measuring a biomarker, not an imaging AI device assisting human readers. Therefore, the concept of "effect size" of how human readers improve with AI vs. without AI assistance is not relevant here.

6. Standalone Performance:

• Yes, the performance data presented (Precision, Reproducibility, Normal Range, Stability, Interferences) are essentially standalone (algorithm-only) performance characteristics of the CRYOcheck Hex LA device in a laboratory setting.
• The method comparison study also evaluated the device's performance independently against a predicate, effectively demonstrating its standalone performance in identifying LA status.

7. Type of Ground Truth Used:

• For the method comparison study (test set), the ground truth was comparison to a legally marketed predicate device (Staclot® LA).
• For the known LA positive/negative samples, the ground truth was "previously characterized" LA status, likely established through a combination of clinical diagnosis and existing laboratory methods.

8. Sample Size for the Training Set:

• This document describes a 510(k) submission for an in vitro diagnostic (IVD) device, not an AI/machine learning device that typically involves a "training set" in the same computational sense.
• The development and optimization of such an IVD assay would involve internal development samples and studies, but these are not referred to as "training sets" in the context of this regulatory filing. The provided information focuses on analytical and clinical performance validation.

9. How the Ground Truth for the Training Set Was Established:

• Not applicable due to the nature of the device as explained in point 8. The device's "training" or development would involve laboratory optimization and calibration using reference materials and characterized samples, but not "ground truth" in the AI sense for a dedicated "training set."

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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.

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.

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The CRYOcheck FVIII Inhibitor Kit is for clinical laboratory use in conjunction with a Factor VIII activity assay to enable the performance of a modified Nijmegen-Bethesda assay using 3.2% citrated human plasma. It enables the determination of a functional FVIII inhibitor titer to aid in the clinical management of congenital hemophilia A in individuals aged 2 years or older. For in vitro diagnostic use.

The FVIII Inhibitor Kit is used in the CDC modification of the Nijmegen-Bethesda assay and contains the following components:
Imidazole Buffered Pooled Normal Plasma (IB-PNP): Pooled normal plasma from a minimum of twenty donors with a factor VIII activity value of 95-113% and buffered with imidazole to a pH of 7.3 – 7.5.
Imidazole Buffered Bovine Serum Albumin (IB-BSA): A 4% BSA solution buffered with imidazole to a pH of 7.3-7.5.
Negative Factor VIII Inhibitor Control: Pooled normal plasma from a minimum of five donors buffered with HERES to a pH of 6.2-8.2
Positive Factor VIII Inhibitor Control: HEPES buffered (pH 6.2-8.2) immunodepleted FVIII deficient plasma to which anti-human FVIII antibodies have been added.

The document provided describes the performance characteristics and studies for the CRYOcheck FVIII Inhibitor Kit, rather than an AI/ML-driven medical device. Therefore, a direct mapping to all the requested criteria for AI/ML device acceptance (such as MRMC studies, number of experts for ground truth, adjudication methods, and training set details) is not possible.

However, I can extract and present the information relevant to the device's performance and the studies conducted to demonstrate its effectiveness, aligning with the spirit of the acceptance criteria for a diagnostic kit.

Device: CRYOcheck™ FVIII Inhibitor Kit

Intended Use: For clinical laboratory use in conjunction with a Factor VIII activity assay to enable the performance of a modified Nijmegen-Bethesda assay using 3.2% citrated human plasma. It enables the determination of a functional FVIII inhibitor titer to aid in the clinical management of congenital hemophilia A in individuals aged 2 years or older. For in vitro diagnostic use.

Acceptance Criteria and Reported Device Performance

Since this is an in-vitro diagnostic kit and not an AI/ML device, the "acceptance criteria" are related to standard analytical performance characteristics. The table below summarizes the key performance metrics and the reported results.

• Negative Plasma Sample: SD 0.1 BU/mL (29.0% CV)
• Low Plasma Sample: 8.2% CV
• Mid Plasma Sample: 8.3% CV
• High Plasma Sample: 8.4% CV |
  | Reproducibility (Multi-Reagent Lot Site to Site) | - Kit Negative Control: SD 0.1 BU/mL (422.7% CV) - Kit Positive Control: 16.0% CV - Negative Plasma Sample: SD 0.1 BU/mL (28.4% CV) - Low Plasma Sample: 10.6% CV - Mid Plasma Sample: 8.3% CV - High Plasma Sample: 13.2% CV
  (Pooled 3-Site Data) The results demonstrated a pooled reproducibility of ≤16% CV for the positive samples and 0.1 BU/mL SD for the negative plasma sample. |
  | Linearity/Assay Reportable Range | Linearity Range: 0.2 to 1402.9 BU/mL. |
  | Shelf-Life Stability | Supported a 12-month shelf-life stability claim when stored at

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cryocheck Clot APCR is a clotting assay intended to screen for resistance to activated protein C in citrated human plasma from individuals with the factor V Leiden mutation.

cryocheck Clot APCR consists of:

• 5 x 2.0 mL Activator Reagent (APC-AR) .
• 5 x 4.0 mL Russell's Viper Venom Reagent (APC-RV)

Here's a breakdown of the acceptance criteria and study information for the cryocheck™ Clot APCR™ device, based on the provided 510(k) summary:

1. Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria in terms of numerical thresholds for sensitivity, specificity, or correlation. Instead, it frames the acceptance criteria implicitly as "comparable precision," "identical results when challenged with interfering substances and factor deficiencies," and "identical sensitivity and specificity" when compared to the predicate device. The primary performance metric reported is a correlation coefficient.

2. Sample Size and Data Provenance

• Sample Size for Test Set: 207 clinical samples.
• Data Provenance: The document states that clinical tests were performed "at Precision BioLogic and a US university hospital-based clinical coagulation laboratory." This indicates the data is prospective clinical data collected from human subjects (patients). The clinical samples were from "the target population for the assay."

3. Number of Experts and Their Qualifications for Ground Truth

The document does not specify the number of experts used to establish ground truth or their qualifications. The comparison is made against a predicate device, implies that the predicate device's results are considered the reference standard, rather than independently established expert ground truth.

4. Adjudication Method for the Test Set

The document does not describe any specific adjudication method for the test set. The comparison appears to be a direct one-to-one comparison of results between the new device and the predicate device for each sample.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, an MRMC comparative effectiveness study was not done. The study focuses on comparing the new device's performance to a predicate device, not on assessing human reader performance with or without AI assistance.

6. Standalone (Algorithm Only) Performance Study

Yes, the study is a standalone performance study. The device itself is an in vitro diagnostic (IVD) assay that provides a result (clotting time ratio). The "performance" being evaluated is the accuracy and reliability of this assay in classifying samples compared to the predicate device. There is no human-in-the-loop component described for the operation of this specific device or its interpretation in the context of the study.

7. Type of Ground Truth Used

The "ground truth" for the test set was essentially the results obtained from the predicate device (GradiLeiden V). The study compared the cryocheck Clot APCR's performance to the GradiLeiden V results across the 207 clinical samples.

8. Sample Size for the Training Set

The document does not explicitly mention a "training set" or its size. Since this is an in vitro diagnostic assay rather than an AI/machine learning algorithm, the concept of a distinct training set in the typical machine learning sense does not apply. The development of the assay would involve R&D and validation, but not a "training set" in the computational context.

9. How Ground Truth for Training Set Was Established

As noted above, the concept of a training set as it applies to AI/ML is not relevant here. The "ground truth" for the development and validation of such an assay would typically be established through robust laboratory methods, perhaps using known Factor V Leiden positive and negative samples, and comparison to established clinical diagnostic methods, but specific details of this process for assay development are not provided in the 510(k) summary.

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cryocheck™ Clot S™ is a clot-based assay intended for the quantitative determination of protein S activity in citrated human plasma.

cryocheck™ Clot S™ is used to diagnose protein S deficiency (congenital or acquired) which is indicative of an increased risk of thromboembolism. A deficiency in protein S may produce recurrent thrombotic episodes.

Congenital deficiencies of protein S are classified as three types:

• type I deficiencies correspond to reduced antigen levels of both total and free protein S .
• type II deficiencies are characterized by a reduced protein S activity but with normal . antigen levels of both total and free protein S
• type III deficiencies are defined by a reduced antigen level and activity of free protein S . but the antigen level of total protein S remains normal

Acquired protein S deficiencies are associated with several clinical states:

• oral anticoagulant therapy ●
• liver disease .
• disseminated intravascular coagulation .
• . oral contraceptives
• oestrogen therapy .
• acute phase inflammatory responses .
• pregnancy .
• newborns

CRYOcheck™ Clot S™ consists of:
• Protein S Deficient Plasma - contains citrated pooled normal
human plasma that has been depleted of protein S by
immunoadsorption, buffers and stabilizers.
• Clot S Activator - contains activated protein C, Russell's viper
venom, heparin neutralizing agents, buffers and stabilizers.
• Precision BioLogic Clot C & S Diluent (available separately from
Precision BioLogic).

Here's an analysis of the provided information regarding the acceptance criteria and study for the CRYOcheck™ Clot S™ device:

1. Table of Acceptance Criteria and Reported Device Performance

The FDA 510(k) summary primarily focuses on demonstrating substantial equivalence to a predicate device rather than explicitly stating acceptance criteria for the new device's performance in isolation. Instead, the "performance" presented is the correlation to the predicate.

2. Sample Size Used for the Test Set and Data Provenance

• Sample Size: 115 clinical samples.
• Data Provenance: The samples were "clinical samples from the target population for the assay." The document does not specify the country of origin, whether they were retrospective or prospective, or other explicit demographic details.

3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications of those Experts

Not applicable. The "ground truth" in this context is established by the predicate device (STA® - Staclot® Protein S) rather than human experts interpreting results. The comparison is between the new device's measurements and the predicate device's measurements on the same samples.

4. Adjudication Method for the Test Set

Not applicable. There was no human adjudication as the comparison was made against a predicate device's quantitative outputs.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done, and the Effect Size of how much Human Readers Improve with AI vs. without AI Assistance

Not applicable. This is a medical device for quantitative laboratory analysis, not an AI-based diagnostic tool requiring human reader interpretation in an MRMC study.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was Done

Not explicitly stated as a "standalone" study in the AI sense, but the device performance itself, i.e., the quantitative measurement of protein S activity, is a standalone function. The "study" presented here is the comparison of this standalone function's output to that of a predicate device. The 0.880 correlation is a standalone performance metric relative to the predicate.

7. The Type of Ground Truth Used

The "ground truth" for the comparison study was the measurements obtained from the predicate device (STA® - Staclot® Protein S).

8. The Sample Size for the Training Set

Not applicable. This device is a biochemical assay, not a machine learning algorithm that requires a training set.

9. How the Ground Truth for the Training Set Was Established

Not applicable, as there is no training set for this type of device.

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CryoCheck Clot C is a clot-based assay intended for the quantitative determination of protein C activity in citrated human plasma.

CryoCheck Clot C consists of: Protein C Deficient Plasma - contains citrated pooled normal human plasma that has been depleted of protein C by immunoadsorption. Clot C Activator - Contains protein isolated from the venom of Agkistrodon contortrix capable of activating protein C in human plasma, Russell's viper venom, phospholipids, heparin neutralizing agents, buffers and stabilizers. CS Diluent (provided separately by Precision BioLogic).

Here's a breakdown of the acceptance criteria and study information for the CryoCheck Clot C device, extracted from the provided text:

1. Acceptance Criteria and Reported Device Performance:

Note: The document primarily focuses on demonstrating substantial equivalence to a predicate device rather than defining explicit acceptance criteria with numerical performance thresholds. The "acceptance criteria" are therefore inferred from the comparison study's objective to show equivalence.

2. Sample Size Used for the Test Set and Data Provenance:

• Sample Size: 119 clinical samples.
• Data Provenance: The document states "clinical samples," implying human patient samples, but does not specify the country of origin or whether they were retrospective (previously collected) or prospective (collected specifically for the study).

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:

• The document does not mention the use of experts to establish ground truth for the test set. The comparison is made against a predicate device, implying the predicate device's results serve as the reference or "ground truth" for correlation.

4. Adjudication Method for the Test Set:

• Not applicable. The study is a direct comparison to a predicate device, not an expert-driven adjudication process.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done, If so, What Was the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance:

• Not applicable. This device is a clot-based assay (an in-vitro diagnostic test measuring a protein in plasma), not an AI-powered imaging or diagnostic tool requiring human reader interpretation. Therefore, an MRMC study or AI assistance is not relevant to this type of device.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done:

• Not applicable. This is an assay performed in a laboratory, not an algorithm. The "standalone" performance is effectively the performance of the assay itself as described in the correlation study.

7. The Type of Ground Truth Used:

• The ground truth for the comparison study was the results obtained from the STA - Staclot Protein C (K861079) predicate device. The study correlated the CryoCheck Clot C results with those of the predicate device using clinical samples.

8. The Sample Size for the Training Set:

• Not applicable. This is an in-vitro diagnostic assay, not a machine learning algorithm that requires a training set.

9. How the Ground Truth for the Training Set Was Established:

• Not applicable. No training set was used.

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CryoCheck Weak Lupus Positive Control is prepared from human source plasma and is recommended for use as a positive control in assays for lupus anticoagulant.

CryoCheck Weak Lupus Positive Control contains citrated human plasma collected from donors that have tested positive in accordance with the revised criteria of the SSC Subcommittee for the Standardization of Lupus Anticoagulants. Source plasmas are processed in a manner that yields platelet-poor plasmas. Plasma is then buffered, aliquoted and rapidly frozen.

The provided text describes a 510(k) premarket notification for a medical device called "CryoCheck Weak Lupus Positive Control." The document focuses on demonstrating substantial equivalence to a predicate device rather than presenting a study with specific acceptance criteria and performance data for the new device. Therefore, many of the requested sections regarding a study cannot be directly extracted as such a study with detailed performance metrics is not included.

Here's an analysis based on the available information:

1. A table of acceptance criteria and the reported device performance

This information is not explicitly provided in the document. The document's purpose is to establish substantial equivalence, not to demonstrate performance against specific quantitative acceptance criteria for the new device itself. The "performance" described is in terms of its characteristics being similar to the predicate device.

2. Sample size used for the test set and the data provenance (e.g., country of origin of the data, retrospective or prospective)

This information is not provided. The document does not describe a clinical study or a test set in the traditional sense for evaluating the new device's performance. It states that the device "contains citrated human plasma collected from donors that have tested positive in accordance with the revised criteria of the SSC Subcommittee for the Standardization of Lupus Anticoagulants." This indicates the source material, but not a separate "test set" for performance evaluation, nor its provenance details.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience)

This information is not provided. As there's no described "test set" for performance evaluation, there's no mention of experts establishing ground truth for such a set. The "ground truth" for the source plasma is implicitly the results of the tests performed on the donors to determine their lupus anticoagulant status, following the SSC Subcommittee's criteria.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set

This information is not provided. There is no described test set or adjudication method.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

This information is not applicable/not provided. The device is a "Lupus Positive Control" (a biological reagent), not an AI-powered diagnostic tool for human readers. Therefore, an MRMC study or AI assistance is not relevant to this device.

6. If a standalone (i.e., algorithm only without human-in-the loop performance) was done

This information is not applicable/not provided. The device is a biological control, not an algorithm.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The ground truth for the source plasma used in the device is based on "donors that have tested positive in accordance with the revised criteria of the SSC Subcommittee for the Standardization of Lupus Anticoagulants." This implies a set of established laboratory test results and clinical criteria for diagnosing lupus anticoagulant status.

8. The sample size for the training set

This information is not provided. The concept of a "training set" as understood in machine learning/AI is not applicable to this biological control device.

9. How the ground truth for the training set was established

This information is not provided. As above, the concept of a training set is not applicable. The "ground truth" for the source material refers to the diagnostic criteria for lupus anticoagulants used to select the plasma donors.

Summary of Device and Substantial Equivalence Claim:

The "CryoCheck Weak Lupus Positive Control" is a biological control designed for use in assays for lupus anticoagulant. It is composed of citrated human plasma from donors who have tested positive for lupus anticoagulant according to specific scientific guidelines (SSC Subcommittee criteria). The manufacturer, Precision BioLogic Inc., is seeking 510(k) clearance by demonstrating substantial equivalence to their previously cleared device, the "CryoCheck Lupus Positive Control (K952623)."

The claim of substantial equivalence is based on the following similarities:

• Intended Use: Both devices are recommended as positive controls in assays for lupus anticoagulant.
• Matrix: Both consist of citrated human plasma from donors testing positive for lupus anticoagulant based on the same SSC Subcommittee criteria.
• Format: Both are provided in a frozen format.
• Volume: Both are available in 0.5 mL and 1.0 mL vial sizes.

The FDA reviewed these similarities and concluded that the new device is substantially equivalent to the predicate device. This means that the new device does not require new efficacy or performance studies to prove its safety and effectiveness, as its characteristics are considered sufficiently similar to an already approved device. The regulatory approval is for the device itself as a control material, not for a diagnostic test utilizing the control, nor an AI algorithm.

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