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The B.R.A.H.M.S PCT sensitive KRYPTOR® is designed for automated detection of PCT (procalcitonin) in human serum or plasma (EDTA, heparin) samples by the immunofluorescent B·R·A·H·M·S PCT sensitive KRYPTOR® assay.

The B·R·A·H·M·S PCT sensitive KRYPTOR® is intended for use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.

The B-R-A-H-M-S PCT sensitive KRYPTOR® assay is a homogeneous sandwich immunoassay for detection of PCT in human serum or plasma. The BrR.A.H.M.S KRYPTOR® analyzer is a fully automated system. The B·R·A·H·M·S KRYPTOR® analyzer is a closed system and can only operate utilizing special reagents provided by B.R.A.H.M.S Aktiengesellschaft. The measuring principle is based on Time-Resolved Amplified Cryptate Emission (TRACE®) technology, which measures the signal that is emitted from an immunocomplex with time delay.

The basis of the TRACE® technology is a non-radiative energy transfer from a donor [a cage-like structure with a europium ion in the center (cryptate)] to an acceptor (XL 665). The proximity of donor (cryptate) and acceptor (XL 665) in a formed immunocomplex and the spectral overlap between donor emission and acceptor absorption spectra on the one hand intensifies the fluorescent signal and on the other hand extends the life span of the acceptor signal, allowing for the measurement of temporally delayed fluorescence.

After the sample to be measured has been excited with a nitrogen laser at 337 nm, the donor (cryptate) emits a long-life fluorescent signal in the milli-second range at 620 nm, while the acceptor (XL 665) generates a short-life signal in the range of nanoseconds at 665 nm. When both components are bound in an immunocomplex, both the signal amplification and the prolonged life span of the acceptor signal occur at 665 nm, and the life is in the microsecond range. This delayed acceptor signal is proportional to the concentration of the analyte to be measured.

The specific fluorescence which is proportional to the antigen concentration is obtained through a double selection: spectral (separation depending on wave-length) and temporal (time resolved measurement). This enables an exclusive measurement of the signal emitted by the immunological complex and the ratio between the two wave-lengths (665/620) allows a real-time correction of the variations in optic transmission from the medium.

Here's a summary of the acceptance criteria and the study details for the B·R·A·H·M·S PCT sensitive KRYPTOR® Test System, based on the provided 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

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

• Sample Size (Method Comparison): 184 samples.
• Data Provenance: The samples were collected from three (3) sites. The country of origin is not specified, but the applicant is based in Germany with a US contact. The mention of "patients" and "clinical situations" suggests these were clinical samples. The study involved a comparison between a new device and a marketed predicate, indicating it was likely a retrospective analysis of previously collected samples or prospectively collected samples analyzed by both methods.

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

• Not Applicable / Not Provided: For this type of in vitro diagnostic device (immunoassay), the "ground truth" for the test set (method comparison) is the measurement result from the predicate device (B·R·A·H·M·S PCT LIA). Clinical "ground truth" for disease progression to severe sepsis/septic shock is based on consensus criteria (American College of Chest Physicians/Society of Critical Care Medicine), not individual expert adjudication of assay results. The device itself provides a quantitative measurement.

4. Adjudication Method for the Test Set

• Not Applicable: As this is an in vitro diagnostic device providing quantitative measurements, there is no direct expert adjudication method applied to the test results in the way it would be for image analysis or subjective clinical assessments. The comparison is between two quantitative assays.

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

• No: This is an in vitro diagnostic assay, not a medical imaging device or a diagnostic requiring human interpretation of complex data (beyond reading a number). Therefore, an MRMC study is not relevant or performed. The device provides a standalone quantitative result.

6. Standalone Performance Study (Algorithm only without human-in-the-loop performance)

• Yes, this is a standalone performance study. The B·R·A·H·M·S PCT sensitive KRYPTOR® is a fully automated system that measures PCT concentrations in human serum or plasma. Its performance for analytical sensitivity, functional assay sensitivity, precision, high dose hook effect, interference, and method comparison are all intrinsic to the device and assay reagents themselves, without human intervention in the measurement process. The "Interpretation of Results" section provides guidance on how clinicians should use the standalone PCT results in conjunction with other laboratory findings and clinical assessments.

7. Type of Ground Truth Used

• Method Comparison: The "ground truth" for the method comparison study was the measurements obtained from the legally marketed predicate device, the B·R·A·H·M·S PCT LIA assay. This is a comparative "truth" to an established method.
• Clinical Relevance: The interpretation of results (e.g., PCT > 2 ng/ml indicates high risk) implicitly relies on established clinical consensus criteria for severe sepsis and septic shock (American College of Chest Physicians/Society of Critical Care Medicine) as the clinical ground truth against which the PCT values are correlated to assess risk.

8. Sample Size for the Training Set

• Not explicitly provided/applicable in the same way: For in vitro diagnostic assays, especially those based on established immunofluorescence technology like TRACE®, the concept of a "training set" for an algorithm in the machine learning sense is not directly applicable. The assay formulation, antibody selection, and calibration are developed through R&D, not typically "trained" on a large dataset in the way an AI algorithm would be. The document describes the device's components and underlying technology rather than a data-driven training process.

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

• Not explicitly provided/applicable: As mentioned above, the assay's development isn't described in terms of a "training set" and "ground truth" in an AI/machine learning context. The "ground truth" in assay development is typically established through rigorous analytical verification and validation against known standards, spiked samples, and comparison with reference methods or clinically characterized samples during the research and development phases of the assay itself. The given document focuses on the validation of the finalized device.

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VIDAS® BRAHMS PCT is an automated test for use on the VIDAS instruments for the determination of human procalcitonin in human serum or plasma (lithium heparin) using the ELFA (Enzyme-Linked Fluorescent Assay) technique. The VIDAS BRAHMS PCT assay is intended for use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of ICU admission, for progression to severe sepsis and septic shock.

The VIDAS BRAHMS PCT Assay is an enzyme-linked fluorescent immunoassay (ELFA) performed in an automated VIDAS® instrument. The assay principle combines a one-step immunoassay sandwich method with a final fluorescent detection (ELFA). The Solid Phase Receptacle (SPR), serves as the solid phase as well as the pipetting device for the assay. Reagents for the assay are ready-to-use and pre-dispensed in the sealed reagent strips. All of the assay steps are performed automatically by the instrument. The sample is transferred into the wells containing anti-procalcitorin antibodies labeled with alkaline phosphatase (conjugate). The sample/conjugate mixture is cycled in and out of the SPR several times. This operation enables the antigen to bind with the immunoglobulins fixed to the interior wall of the SPR and the conjugate to form a sandwich. Unbound compounds are eliminated during washing steps. Two detection steps are performed successively. During each step, the substrate (4-Methylumbellifery| phosphate) is cycled in and out of the SPR. The conjugate enzyme catalyzes the hydrolysis of this substrate into a fluorescent product (4-Methyl-umbelliferone) the fluorescence of which is measured at 450 nm. The intensity of the fluorescence is proportional to the concentration of antigen present in the sample. At the end of the assay, results are automatically calculated by the instrument in relation to two calibration curves corresponding to the two revelation steps and stored in memory, and then printed out.

The provided document describes the VIDAS® B-R.A.H.M.S PCT Assay, an enzyme-linked fluorescent immunoassay (ELFA) for determining human procalcitonin in serum or plasma. It is intended for critically ill patients on their first day of ICU admission to aid in the risk assessment for progression to severe sepsis and septic shock.

The study presented focuses on establishing substantial equivalence to a predicate device, the BRAHMS PCT LIA Assay, rather than proving the device meets specific acceptance criteria via a standalone study with pre-defined metrics. Therefore, a table of acceptance criteria and reported device performance as typically understood for a novel device demonstrating efficacy against disease outcomes is not explicitly provided. Instead, the document compares analytical and clinical performance between the new device and the predicate.

Here's an analysis based on the provided information, framed to address your questions as much as possible, interpreting "acceptance criteria" as meeting or exceeding the performance of the predicate device.

1. Table of "Acceptance Criteria" and Reported Device Performance

As mentioned, explicit "acceptance criteria" for clinical performance are not stated in terms of specific sensitivity, specificity, PPV, or NPV targets for predicting severe sepsis/septic shock against a definitive ground truth. Instead, the comparison is against the predicate device's performance. The analytical performance comparisons can be seen as meeting "acceptance criteria" if they are comparable to or better than the predicate's.

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

• Clinical Sensitivity/Specificity Study:
  • Device (VIDAS BRAHMS PCT): 232 patients (US and Europe, likely retrospective or mixed, not explicitly stated but common for such studies).
  • Predicate (BRAHMS PCT LIA): 179 patients (Europe).
• Clinical Specificity Study on Healthy Subjects:
  • Device (VIDAS BRAHMS PCT): 200 healthy subjects (US).
  • Predicate (BRAHMS PCT LIA): 144 healthy subjects (US).
• Non-clinical (Analytical) Precision Study: 6 samples over 20 days for the device, 14 samples over 20 days for the predicate (no specific provenance mentioned for these samples, but assumed to be laboratory-prepared or pooled clinical samples).

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 "severe sepsis or septic shock." The studies are comparing the PCT assay results between the device and the predicate, and how those results correlate with the clinical diagnosis of severe sepsis or septic shock. The diagnostic criteria for severe sepsis/septic shock are assumed to be standard clinical practice at the study sites.

4. Adjudication Method for the Test Set

No multi-reader adjudication method (e.g., 2+1, 3+1) is described for establishing the clinical ground truth. It is implied that the clinical diagnoses of severe sepsis or septic shock were based on standard clinical assessments by treating physicians at the study sites.

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

No MRMC comparative effectiveness study involving human readers and AI assistance is described. This device is an in-vitro diagnostic (IVD) assay, not an AI-powered diagnostic imaging or decision support system that would typically involve human-in-the-loop performance evaluation.

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

Yes, the performance data presented (analytical and clinical comparison) reflects the standalone performance of the VIDAS® B-R.A.H.M.S PCT Assay in determining procalcitonin levels. The assay itself is the algorithm/device being evaluated. Its intended use is "in conjunction with other laboratory findings and clinical assessments," meaning it's a tool for clinicians, not a complete standalone diagnostic for severe sepsis/septic shock.

7. The Type of Ground Truth Used

The ground truth for the clinical studies appears to be the clinical diagnosis of "severe sepsis or septic shock" in critically ill patients, and the classification of subjects as "healthy." For the healthy subjects, the ground truth is simply their healthy status. For the critically ill patients, the ground truth is the outcome or diagnosis of severe sepsis/septic shock, which would be based on established medical criteria (e.g., Sepsis-3 definitions, though the document is from 2007 so older criteria like SIRS/Sepsis/Severe Sepsis/Septic Shock definitions would apply).

8. The Sample Size for the Training Set

The document does not explicitly mention a separate "training set" for the device, as it is an immunoassay, not a machine learning algorithm that typically requires a large training dataset. The development and optimization of the assay would have involved various internal studies, but these are not specified as a "training set" in the context of clinical validation data.

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

Given that this is an immunoassay, the concept of "ground truth for a training set" as it applies to machine learning is not directly applicable. Assay development would involve optimizing parameters against known concentration controls and spiked samples, and eventually validating against clinical samples with known diagnoses (as described in the clinical studies).

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The B.R.A.H.M.S.PCT LIA is an immunoluminometric assay (ILMA) used to determine the concentration of PCT (procalcitonin) in human serum and plasma.

The B.R.A.H.M.S PCT LIA is intended for use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.

B-R A-H-S PCT LIA is an immunoluminometric assay (ILMA) used to determine the concentration of Procalcitonin (PCT) in human serum and plasma. Two antigen-specific monoclonal antibodies that bind PCT (the antigen) at two different binding sites (the calcitonin and katacalcin segments) are added in excess. One of these antibodies is luminescence labeled (the tracer), and the other is fixed to the inner walls of the tube (coated tube system). During the course of incubation, both antibodies react with PCT molecules in the sample to form "sandwich complexes". As result the luminescence labeled antibody is bound to the inner surface of the tube. Once the reaction is completed, the excess tracer is completely removed from the tube and discarded. Then, the amount of residual tracer on the test-tube wall is quantified by measuring the luminescence signal using a suitable luminometer and the B·R·A·H·M·S Basiskit LIA reagents. The intensity of the luminescence signal (RLU) is directly proportional to the PCT concentration in the sample. After a standard curve has been established using standards with known antigen concentrations (calibrated against recombinant intact human PCT), the unknown PCT concentrations in patient serum or plasma samples can then be quantitated by comparison of test values with the curve.

Here's a breakdown of the acceptance criteria and the study details for the B·R·A·H·M·S PCT LIA device, based on the provided 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" in a codified format with target values. Instead, it presents performance characteristics and clinical study results that demonstrate the device's utility for its intended use. I will present the performance characteristics provided as "reported device performance."

2. Sample Size for the Test Set and Data Provenance

The "test set" in this context refers to the clinical study populations.

• Study 1:
  • Sample Size: 101 consecutive critically ill patients.
  • Data Provenance: Medical ICU in Switzerland. Retrospective or prospective is not explicitly stated in the summary itself, but the reference "Müller B. et al., Crit. Care Med. 2000; 28(4): 977-983" suggests it's a published, likely prospective, clinical study. The summary explicitly states "controlled prospective studies."
• Study 2:
  • Sample Size: 78 consecutive critically ill patients.
  • Data Provenance: Medical and surgical ICU in Switzerland. Prospective.

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

The document does not provide details on the number or qualifications of experts used to establish the "ground truth" for the clinical classifications (SIRS/Sepsis, Severe Sepsis, Septic Shock). The classification of patients into these categories would typically be based on established clinical criteria and diagnosis by attending physicians or critical care specialists. The referenced studies (Müller et al. and Harbarth et al.) would have detailed their methodology for patient classification.

4. Adjudication Method for the Test Set

The document does not describe a formal "adjudication method" for the clinical classifications. Patient classification into SIRS/Sepsis, Severe Sepsis, or Septic Shock was presumably done according to standard clinical diagnostic criteria at the time of the studies, likely by the clinicians managing the patients.

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

No. This was not an MRMC comparative effectiveness study. This device is an in vitro diagnostic assay that provides a quantitative measurement (PCT concentration). The studies evaluated the diagnostic utility of this quantitative measurement in aiding risk assessment, not the performance improvement of human readers with or without AI assistance.

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

Yes, in essence. The B·R·A·H·M·S PCT LIA is a standalone diagnostic assay. Its performance output is the PCT concentration, which is then interpreted by clinicians based on established thresholds and along with other clinical findings. The studies presented demonstrate the performance of the assay results in correlation with clinical outcomes (progression to severe sepsis/septic shock).

7. The Type of Ground Truth Used

The ground truth used for the clinical studies was clinical diagnosis and patient outcomes as defined by:

• SIRS (Systemic Inflammatory Response Syndrome), Sepsis, Severe Sepsis, and Septic Shock based on established clinical criteria at the time of the studies.
• Progression to severe sepsis and septic shock as observed in the critically ill patient populations.

8. The Sample Size for the Training Set

The document does not specify a separate "training set" for the clinical performance evaluation. The two studies (Study 1 with 101 patients and Study 2 with 78 patients) are presented as the clinical validation for the device's intended use.

For the assay's technical performance (e.g., sensitivity, precision, interference), these types of studies typically involve a series of laboratory experiments using controlled samples (e.g., spiked samples, known concentrations), rather than a "training set" in the machine learning sense. The "standards" (S1-S6) and "controls" (K1, K2) mentioned in the reagents section are used for calibrating and quality control of the assay itself.

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

As there is no distinct "training set" identified for clinical performance in the machine learning sense, this question is not fully applicable. For the technical performance aspects (e.g., calibration, linearity, precision), the ground truth is established through:

• Known concentrations of PCT (recombinant PCT used for standards S1-S6).
• Controlled spiking of interfering substances at defined concentrations.
• NCCLS testing guidelines for analytical and functional sensitivity, and precision, which involve standardized procedures and reference materials.

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