Search Results

For the qualitative determination of total (IgG and IgM) antibodies to Treponema pallidum (TP) specific antigens in human serum and plasma using the VITROS 5600 Integrated System.

The presence of antibodies to Treponema pallidum (TP) specific antigens, in conjunction with non-treponemal laboratory tests and clinical findings may aid in the diagnosis of syphilis infection.

The VITROS Syphilis test is not intended for blood and tissue donor screening.

The VITROS Immunodiagnostic Products Syphilis test is performed using the VITROS Immunodiagnostic Products Syphilis Reagent Pack and VITROS Immunodiagnostic Products Syphilis Calibrator on the VITROS 5600 Integrated System.

An immunometric technique is used; this involves a two-stage reaction. In the first stage antibodies to Syphilis TP specific antigens present in the sample bind with biotinylated recombinant Syphilis TP antigens immobilized on streptavidin coated wells. Unbound sample is removed by washing. In the second stage conjugate reagent containing horseradish peroxidase (HRP)-labeled recombinant Syphilis TP antigens is added. The conjugate binds specifically to any antibody to Syphilis TP specific antigens captured on the well in the first stage. Unbound conjugate is removed by washing.

The bound HRP conjugate is measured by a luminescent reaction. A reagent containing luminogenic substrates (a luminol derivative and a peracid salt) and an electron transfer agent is added to the wells. The HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent (a substituted acetanilide) increases the level of light produced and prolongs its emission. The light signals are read by the system.

Here's a detailed breakdown of the acceptance criteria and the study proving the device meets these criteria, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the clinical performance results meeting high percentage agreements. While explicit numeric acceptance criteria (e.g., "PPA must be >X%") are not directly stated in a dedicated section, the sponsor presents the results and concludes substantial equivalence, indicating that these results were considered acceptable.

2. Sample size used for the test set and the data provenance

• Test Set Sample Size:
  • Prospective Specimens: 924 total specimens.
    • 615 subjects for routine syphilis testing (from 6 sites in the United States).
    • 47 pregnant women.
    • 262 HIV positive subjects.
  • Retrospective Specimens: 547 total specimens.
    • 243 samples from pregnant women.
    • 152 HIV positive samples.
    • 152 pre-selected positive samples.
  • Medically Diagnosed Individuals: 151 samples.
  • Apparently Healthy Individuals: 201 prospective specimens (from 3 sites in the United States).
  • Total Clinical Samples: 924 (prospective) + 547 (retrospective) + 201 (apparently healthy) = 1672 specimens for primary clinical evaluation. The medically diagnosed group is a subset likely included within the prospective/retrospective groups or as additional targeted samples.
• Data Provenance:
  • Country of Origin: United States (for prospective and apparently healthy specimens). Retrospective samples are "purchased," implying they may originate from various sources but were tested at sites.
  • Retrospective or Prospective: Both retrospective and prospective clinical studies were conducted.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

The document does not specify the number of experts or their qualifications for establishing the ground truth. Instead, the ground truth was established using a "composite testing algorithm."

4. Adjudication method for the test set

The adjudication method relied on a composite testing algorithm using:

• A treponemal electrochemiluminescence immunoassay (TP-ECLIA)
• A Rapid Plasma Reagin (RPR) non-treponemal assay
• A Treponema pallidum Particle Agglutination (TP-PA) Treponema-specific assay

Cases were categorized as "Positive for Syphilis" or "Negative for Syphilis" based on the results of these FDA-cleared comparator assays. The document describes specific combinations of results from these three assays that led to a final comparator result. For example, "Non-reactive TP-ECLIA + Non-reactive RPR" was deemed "Negative," while "Reactive TP-ECLIA + Reactive RPR (and N/A TP-PA)" was "Positive." Discordant results with the final comparator were further analyzed (e.g., 14 discordant prospective samples were found reactive by another FDA-cleared TP antibody test).

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

No, an MRMC comparative effectiveness study involving human readers and AI assistance was not conducted or reported. This device is an in vitro diagnostic test (IVD) for laboratory use, not an AI-powered image analysis or diagnostic aid for human readers.

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

Yes, the studies presented are standalone performance evaluations of the VITROS Immunodiagnostic Products Syphilis test (an algorithm-driven instrument/reagent system) without human-in-the-loop performance being a variable in the reported clinical accuracy. The assay itself performs the determination.

7. The type of ground truth used

The ground truth used was a composite testing algorithm based on multiple FDA-cleared comparator assays (TP-ECLIA, RPR, and TP-PA). This is a form of clinical surrogate ground truth derived from established diagnostic tests, rather than direct pathology, biopsy, or long-term outcomes data, which are typically used for definitive diagnosis in some other medical fields.

8. The sample size for the training set

The document does not provide information on the sample size for a training set. This is because the device described is an immunoassay, a biochemical test, not a machine learning or AI algorithm that typically requires a separate training set. The reported studies evaluate the locked-down analytical and clinical performance of the manufactured diagnostic kit.

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

Since there is no training set mentioned for an AI/machine learning algorithm, the concept of establishing ground truth for a training set is not applicable here. The assay's internal calibration and optimization would have been performed during product development, but this is distinct from "training" an AI model in the context of imaging or predictive analytics.

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For in vitro diagnostic use only.

For the quantitative measurement of human chorionic gonadotropin (hCG) and its ß-subunit in human serum and plasma (heparin and EDTA) using the VITROS 5600 Integrated System to aid in the early detection of pregnancy.

The VITROS Immunodiagnostic Products Total ß-hCG II Reagent Pack (test) is performed using the VITROS Immunodiagnostic Products Total β-hCG II Reagent Pack and VITROS Immunodiagnostic Products Total B-hCG II Calibrators on the VITROS 5600 Integrated System.

An immunometric immunoassay technique is used, which involves the reaction of human chorionic gonadotropin (hCG) present in the sample with a microwell coated with biotinylated Antibody (mouse monoclonal anti-ß-hCG) bound to streptavidin, and a Horseradish Peroxidase (HRP)-labelled antibody conjugate (mouse monoclonal anti-ß-hCG). Unbound materials are removed by washing.

The bound HRP conjugate is measured by a luminescent reaction. A reagent containing luminogenic substrates (a luminol derivative and a peracid salt) and an electron transfer agent, is added to the wells. The HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent (a substituted acetanilide) increases the level of light produced and prolongs its emission. The light signals are read by the system. The amount of HRP conjugate bound is directly proportional to the concentration of hCG present in the sample.

VITROS Immunodiagnostic Products Total ß-hCG II Reagent Pack contains:
1 reagent pack containing:

• 100 coated wells (antibody, mouse monoclonal anti-ß-hCG, binds >600 mIU hCG/well)
• 14.4 mL assay reagent (buffer containing mouse serum, bovine serum albumin, bovine gamma globulin and . antimicrobial agent)
• 19.2 mL conjugate reagent (HRP-mouse monoclonal anti-β-hCG, binds ≥4005 mIU hCG/mL) in buffer with ● bovine serum albumin and antimicrobial agent.

VITROS Total ß-hCG II Calibrators contains:

• 3 sets of VITROS Total ß-hCG II Calibrators 1, 2 and 3, (freeze-dried, recombinant hCG in human plasma with antimicrobial agent, reconstitution volume 1.0 mL), nominal values 0; 3,000; 14,000 mIUmL (U/L)
• 24 calibrator bar code labels (8 for each calibrator)

Here's an analysis of the acceptance criteria and study information based on the provided text, structured according to your request:

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

The document does not explicitly present a dedicated "acceptance criteria" table for all non-clinical tests. Instead, it describes each test (e.g., Precision, Detection Capability, Linearity) and then presents the results, implying that the results met internal acceptance criteria for substantial equivalence to the predicate device. Therefore, I will derive the "acceptance criteria" from the stated goals or industry guidelines mentioned for each test and then present the reported performance.

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

• Stability Studies:
  • Long-term: 3 Lots evaluated.
  • On-board: 3 Lots evaluated.
• Precision:
  • Single Lot Precision: 6 precision fluids. 2 replicates per run, 2 runs per day for 20 days. Total of 80 data points per fluid.
  • Additional Precision Analysis Summary: 6 samples (PP1-6).
  • Multiple System (Reproducibility) Study: 6 precision fluids (RP1-6). 5 replicates per run, 1 run per day for 5 days. Tested on 3 VITROS 5600 integrated systems.
• Detection Capability (LoB): 4 serums containing no measurable hCG. Study design: 2 replicates per run, 2 runs per day over 5 test days (20 reps per test fluid x 4 fluids = 80 replicates) x 3 lots = 240 total replicates.
• Detection Capability (LoD & LoQ): 5 LoD samples targeted at 1 to 5 times LoB. 4 LoQ fluids for Total Error method. All samples run using 3 reagent lots on one VITROS 5600 System. 6 replicates per run, 2 runs per day over 5 test days (60 reps per fluid x 5 fluids = 300 replicates) x 3 lots = 900 total replicates.
• Linearity: Two series: one across entire range (pools 1a to 10a) and one in lower range (pools 1b to 10b). 10 replicates of pools 1a/10 and 10a/10b, and 5 replicates of pools 2a/2b to 9a/9b. Run on one VITROS 5600 Integrated System.
• Matrix Comparison: 41 samples each for Lithium-Heparin Plasma and K2-EDTA Plasma.
• Analytical Specificity (Known Interferents): Not specifically quantified, but refers to "compounds tested" at three hCG concentrations.
• Analytical Specificity (Cross-Reactivity): hCG negative samples and hCG pools at approximately 25 mIU/mL were used for spiking test substances (FSH, LH, TSH).
• Expected Values (Adult Reference Interval):
  • Original Claim (from predicate): 290 total samples (98 normal male, 123 normal female, 69 post-menopausal).
  • Updated Pack Validation: 180 normal healthy non-pregnant blood donors (60 Normal Male, 60 Normal Female, 60 Post-Menopausal).
• Method Comparison: 135 human serum samples.

Data Provenance:

• The document states that human serum samples for method comparison were "obtained from certified vendors."
• Precision fluids mentioned as "pooling female serum samples."
• "Normal healthy non-pregnant blood donors" for expected values.
• "Neat serum samples containing low levels of endogenous hCG" for LoD samples.
• The overall context is non-clinical laboratory testing. No specific country of origin or retrospective/prospective status is explicitly stated for the patient samples used, though the tests themselves were conducted in a laboratory setting per CLSI guidelines. The stability studies and many precision studies seem to be prospective evaluations of the manufactured product. Patient samples, however, are often retrospectively collected from vendors in such studies unless specified.

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 device is an in-vitro diagnostic (IVD) test for quantitative measurement of hCG. The "ground truth" for such devices is established through reference methods, traceability to international standards, and comparison with legally marketed predicate devices, rather than expert human interpretation of images or clinical outcomes.

• Traceability: The device's calibration is traceable to "in-house reference calibrators, which have been value-assigned with reference to the 4th International Standard (NIBSC 75/589)." This international standard serves as the "ground truth" for the quantitative measurement.
• Method Comparison: The predicate device (VITROS Immunodiagnostic Products Total β-hCG II, K063720) serves as the comparative "ground truth" for assessing equivalence of performance with patient samples.

Therefore, there were no human "experts" (like radiologists) establishing ground truth in the way described for image-based diagnostic AI. The "ground truth" is defined by established metrological standards and comparative testing against a cleared predicate.

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

Not applicable. This is an IVD device for quantitative measurement based on chemical reactions and instrumental readings. There is no human interpretation or subjective assessment of results that would require an adjudication method among experts.

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 is an IVD device, not an AI-assisted diagnostic tool that aids human readers in image interpretation or clinical decision-making. No MRMC study was conducted.

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

This device itself is a "standalone" analytical system in the context of laboratory testing. The VITROS Immunodiagnostic Products Total ß-hCG II Reagent Pack, used on the VITROS 5600 Integrated System, performs the quantitative measurement of hCG without immediate human intervention in the assay process itself. The "performance" sections (Precision, Detection Capability, Linearity, etc.) describe its standalone analytical performance.

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

The ground truth for this IVD device is primarily:

• International Reference Standards: Specifically, the 4th International Standard (NIBSC 75/589) for hCG, to which the device's calibration is traceable.
• Comparison to a Legally Marketed Predicate Device: The performance of the new device is compared to the predicate device (VITROS Immunodiagnostic Products Total β-hCG II Reagent Pack, K063720), which established its own accuracy and reliability.
• CLSI Guidelines: Various CLSI (Clinical and Laboratory Standards Institute) documents (e.g., EP05-A3 for Precision, EP17-A2 for Detection Capability, EP06 for Linearity, EP07/EP37 for Interferents, EP28-A3c for Reference Intervals, EP09c for Method Comparison) define the acceptable methodologies for establishing truth and performance in laboratory diagnostics.

8. The sample size for the training set

This document describes a non-AI IVD device. There is no "training set" in the machine learning sense. The device is a chemical reagent pack used on an analyzer. Its "training" equivalent relies on the design, manufacturing tolerances, and calibration traceable to international standards.

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

Not applicable, as there is no "training set" in the context of an AI/ML algorithm. The "ground truth" for the device's fundamental function (accurate hCG measurement) is established through its traceability to international reference materials and validation against the predicate device, as detailed in point 7.

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VITROS Immunodiagnostic Products Intact PTH II Reagent Pack quantitatively measures intact parathyroid hormone (iPTH) in human serum and plasma (K2-EDTA, lithium heparin) using the automated VITROS 3600 Immunodiagnostic System.

Intact PTH is indicated to aid in the diagnosis of hyperparathyroidism, differential diagnosis of hypocalcemia or hypercalcemia and for intraoperative measurement of iPTH levels.

The VITROS Immunodiagnostic Products Intact PTH II assay is performed using the VITROS Intact PTH II Reagent Pack and the VITROS Intact PTH II Calibrators on the VITROS 3600 Immunodiagnostic System.

VITROS Intact PTH II Reagent Pack contains:

1 reagent pack containing:

• 100 coated wells (biotinylated anti-PTH antibody, 2ug/ml). ●
• 7.4 mL assay reagent as buffer with bovine gamma globulin, bovine serum albumin, and antimicrobial agent.
• 7.4 mL conjugate reagent (HRP-mouse monoclonal anti-PTH, 6 ug/mL) in buffer with bovine serum albumin and antimicrobial agent).

The provided text is a 510(k) premarket notification for Ortho-Clinical Diagnostics' VITROS Immunodiagnostic Products Intact PTH II Reagent Pack, a device for quantitatively measuring intact parathyroid hormone (iPTH). While it details various performance characteristics, it does not describe an AI/ML-based device and therefore does not contain information on acceptance criteria for such a device, nor an AI/ML specific study.

The document focuses on the analytical and clinical performance of an in vitro diagnostic (IVD) assay, comparing it to a predicate device (Roche Elecsys PTH assay). The studies described are typical for IVD assays: precision, linearity, detection limits, analytical specificity (interference and cross-reactivity), and method comparison against a commercially available PTH assay and a clinical study for intra-operative use.

Therefore, I cannot extract the requested information regarding AI/ML device acceptance criteria and study details from the provided text. The questions below are specifically tailored for AI/ML device evaluations.

However, I can provide the available information relevant to the IVD device's performance studies:

Based on the provided document, here is the information available for the VITROS Immunodiagnostic Products Intact PTH II Reagent Pack, noting that it is an IVD assay, not an AI/ML device:

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

The document does not formally present a table of "acceptance criteria" against which performance is measured in the same way an AI/ML device would demonstrate specified accuracy metrics. Instead, it presents various performance characteristics and states that results "met the acceptance criteria" for certain comparisons without detailing those criteria explicitly in a table.

However, key performance parameters and their reported values are listed below:

2. Sample size used for the test set and the data provenance

• Precision/Reproducibility: Patient pools tested with 80 observations (measurements) over 20 days for each concentration level. Data provenance not specified (country of origin, retrospective/prospective implied as prospective measurement in lab).
• Method Comparison: 206 patient (serum) samples. Data provenance not specified.
• Intra-operative Clinical Study: 32 subjects (sets of specimens) qualified for primary endpoints. Data provenance not specified (likely prospective for the study measurements, but subjects were undergoing surgery, so possibly a mix of retrospective patient selection and prospective sample collection).

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

• This device is an IVD assay, not an imaging/AI device requiring expert interpretation for ground truth. Ground truth for an IVD is established by standardized reference methods or the performance of a predicate device/comparator assay.
• For the intra-operative clinical study, the "success" criterion for surgery (50% or greater drop in PTH level) is based on the result from the comparator assay (hospital's assay) and the investigational device, rather than expert judgment on the device's output.

4. Adjudication method for the test set

• Not applicable as this is an IVD assay measuring a biomarker concentration, not an AI/ML device relying on human interpretation or adjudication of output.

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 as this is an IVD assay, not an AI/ML imaging device.

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

• The device is a standalone IVD assay. Its performance (precision, linearity, detection limits, analytical specificity, method comparison) is evaluated directly, without human interpretation of its output in the sense of an AI/ML diagnosis. The intra-operative study compares its quantitative results to another quantitative assay.

7. The type of ground truth used

• Analytical Performance (Precision, Linearity, Detection Limits): Established through laboratory testing using controlled samples (e.g., patient pools, dilutions, blanks) according to CLSI (Clinical and Laboratory Standards Institute) protocols (EP05, EP06, EP17). The "ground truth" here is the expected value of the controlled sample or the known characteristics of the samples used.
• Analytical Specificity (Interference, Cross-Reactivity): Known concentrations of interferents or cross-reactants added to samples with known PTH concentrations. Ground truth is the unbiased PTH value.
• Method Comparison: Comparison against a "commercially available PTH assay" (presumably the predicate device, although it's not explicitly named as such in this section, it's implied by "comparative method") as the reference.
• Intra-operative Clinical Study: The "success" criterion (50% or greater drop in PTH) was determined by comparing the device's results to the results from the hospital's (comparator) assay for the same patient samples. The "ground truth" for surgical success was defined by this 50% drop as measured by the comparator, and the study assessed concordance.

8. The sample size for the training set

• Not applicable. This is an IVD assay, not an AI/ML algorithm that requires a "training set." The system is a reagent pack and instrument system, not a learned model.

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

• Not applicable (no training set for an IVD assay).

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For In Vitro Diagnostic Use Only

For the quantitative measurement of carcinoembryonic antigen (CEA) concentration in human serum and plasma (EDTA or heparin) using the VITROS 5600 Integrated System, to aid in the prognosis and management of cancer patients in whom changing concentrations of CEA are observed.

The VITROS Immunodiagnostic Products CEA Reagent Pack (test) is performed using the VITROS CEA Reagent Pack and VITROS CEA Calibrators on the VITROS 5600 System.

An immunometric immunoassay technique is used, which involves the reaction of CEA present in the sample with a microwell coated with biotinylated Antibody (Mouse monoclonal anti-CEA) bound to Streptavidin, and a Horseradish Peroxidase (HRP)-labelled antibody conjugate (Mouse monoclonal anti- CEA). Unbound (HRP)-labeled anti-CEA antibody conjugate is removed by washing.

The bound HRP conjugate is measured by a luminescent reaction. A reagent containing luminogenic substrates (a luminol derivative and a peracid salt) and an electron transfer agent, is added to the wells. The HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent (a substituted acetanilide) increases the level of light produced and prolongs its emission. The light signals are read by the system. The amount of HRP conjugate bound is directly proportional to the concentration of CEA present in the sample.

VITROS CEA Reagent Pack contains:
1 reagent pack containing:

• 100 coated wells (antibody, mouse monoclonal anti-CEA, binds ≥8ng CEA/well); ●
• 9.7 mL assay reagent (buffer containing bovine serum albumin, bovine gamma globulin and . antimicrobial agent).
• 9.7 mL conjugate reagent (HRP-mouse monoclonal anti-CEA, binds ≥123ng CEA/mL). ●

VITROS CEA Calibrator contains:

• 1 set of VITROS CEA Calibrators 1 and 2 (human CEA in bovine serum with ● antimicrobial agent, 2 mL); nominal values 3 and 250 ng/mL (us/L)
• 16 calibrator bar code labels (8 for each calibrator) ●

The provided document describes the safety and effectiveness information for the VITROS Immunodiagnostic Products CEA Reagent Pack (K231517), which is intended for the quantitative measurement of carcinoembryonic antigen (CEA) in human serum and plasma to aid in the prognosis and management of cancer patients. The document primarily focuses on nonclinical performance studies to demonstrate substantial equivalence to a predicate device.

Here's a breakdown of the requested information based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" in a singular table alongside performance for all aspects. However, it implicitly defines acceptance by stating that certain studies were performed "consistent with CLSI document" guidelines and that "all results were acceptable" or "met the acceptance criteria." For linearity, it specifies "Allowable nonlinearity." For matrix comparison, it states "The results met the acceptance criteria."

Here's an attempt to synthesize the acceptance criteria and performance from the text for key analytical characteristics:

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

• Precision:
  • 5600 System (Table 1): 4 precision fluids. 2 replicates per fluid, 2 occasions per day, for 20 days. Total 80 data points per fluid.
  • Additional Precision Analysis (Table 2): 4 precision fluids (PP1-PP4). 240 observations per sample (likely 2 replicates per run, multiple runs, over multiple days/lots as per CLSI guideline EP05-A3).
• Detection Capability (LoB): 4 endogenous fluids. 2 replicates per run, 2 runs per day, over 5 test days. Total 20 replicates per test fluid x 4 fluids = 80 replicates total for LoB. Tested on 3 lots, so 240 total replicates.
• Detection Capability (LoD & LoQ): 5 samples. 6 replicates per run, 2 runs per day, over 5 test days. Total 60 replicates per fluid x 5 fluids = 300 replicates total for LoD/LoQ. Tested on 3 lots, so 900 total replicates.
• Linearity: 13 levels, five replicates for each level.
• Matrix Comparison: Not specified precisely, but samples were "spanning the expected measuring interval."
• Analytical Specificity (Interferents): Not specified (e.g., number of replicates or distinct samples).
• High Dose Hook: Panel of ten fluids. Tested in singleton.
• Method Comparison (Accuracy): 110 human serum samples. Tested in singleton.

Data Provenance:
The document consistently refers to "human serum" or "patient samples." For the method comparison, it states "Human serum samples were obtained from certified vendors." For detection capability, it mentions "endogenous fluids" and "admixtures of serum samples containing endogenous CEA combined with CEA affinity stripped serum." For expected values, it refers to "healthy non-smokers (n=68)" and "healthy smokers (n=72)."
The country of origin is not specified but the submitter is Ortho-Clinical Diagnostics Inc. from the UK. The studies are nonclinical performance studies, often conducted in-house or by contract research organizations. These studies are prospective in nature, as they are designed experiments to evaluate specific performance characteristics.

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

Ground truth for these studies is analytically derived, not expert consensus interpretation. For in vitro diagnostic devices like the CEA assay, the "ground truth" for test sets in nonclinical studies typically refers to:

• Reference values assigned by highly accurate reference methods or known concentrations of analytes (e.g., spiked samples) for linearity, detection, and accuracy studies.
• The known physiological state of samples (e.g., healthy non-smokers, healthy smokers) for reference intervals.
• The known presence/absence and concentration of interferents for specificity studies.

Therefore, the concept of "experts establishing ground truth" in the sense of clinical interpretation (like radiologists for imaging) is not applicable here. The ground truth is established by the design of the analytical experiment and the reference materials/methods used.

4. Adjudication Method for the Test Set

Adjudication methods (like 2+1, 3+1) are typically used in clinical studies where human interpretation of data (e.g., images) forms the ground truth, and discrepancies need to be resolved. This is not relevant for the analytical performance studies of a laboratory immunoassay described in this document.

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

No. An MRMC study is relevant for devices involving human interpretation (e.g., medical imaging) to assess how the device impacts human reader performance. This document describes the analytical performance of an in vitro diagnostic immunoassay.

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

Yes, this entire submission describes the standalone performance of the VITROS Immunodiagnostic Products CEA Reagent Pack and the VITROS 5600 Integrated System. The data presented are purely analytical measurements performed by the device, without human interpretive input or assistance being part of its core function.

7. The Type of Ground Truth Used

• Stability: Time points with known age of reagents/calibrators/samples.
• Precision: Control materials or patient samples where inherent variability is being measured. No "ground truth" in the sense of an absolute true value is typically assigned for precision, but rather the repeatability and reproducibility of the measurements around a mean.
• Detection Capability: Samples confirmed to contain no measurable CEA (for LoB) or samples with targeted, known low concentrations of CEA (for LoD and LoQ), often prepared by spiking.
• Linearity: Samples covering a wide range of concentrations, often prepared by dilution of a high-concentration sample with known low-concentration diluent, such that the "expected value" is calculable.
• Matrix Comparison: Patient samples (serum vs. various plasma types) where a comparison between matrices is the objective, not an absolute ground truth value.
• Analytical Specificity: Samples spiked with known concentrations of potential interfering substances, with the expectation that the CEA measurement should not be significantly biased.
• High Dose Hook: Samples with extremely high, known CEA concentrations to ensure the device correctly reports high values and doesn't "hook" and report falsely low.
• Method Comparison (Accuracy): Patient samples compared against a legally marketed predicate device (VITROS CEA assay K041322) on the same system. The predicate device's results serve as the comparative measure, assumed to be accurate for the purpose of demonstrating equivalence.
• Expected Values: Clinically healthy subjects (non-smokers and smokers) categorized by their CEA levels.

In summary, the ground truth is primarily based on analytical reference materials, known spiked concentrations, and comparative measurements against a predicate device, all within the domain of quantitative laboratory measurements.

8. The Sample Size for the Training Set

This document describes nonclinical performance testing for an in vitro diagnostic device, not a machine learning or AI algorithm in the typical sense that would involve a "training set." The device is a chemical reagent pack used on an automated immunoassay system. While there were certainly development and validation phases during the device's creation (which might involve analogous processes to "training"), the document provided does not detail a "training set" in the context of an AI/ML algorithm. The studies described are validation studies of the finalized product.

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

As noted in point 8, the concept of a "training set" with established ground truth as typically understood for AI/ML is not applicable to this kind of device and its regulatory submission. The document focuses on demonstrating the analytical performance of a developed immunoassay kit.

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For in vitro diagnostic use only.

For the quantitative measurement of 1116-NS-19-9 defined antigen in human serum and plasma (EDTA or heparin), using the VITROS 5600 Integrated System. The VITROS CA 19-9 test is to be used to aid in the management of patients diagnosed with cancers of the exocrine pancreas. The VITROS CA 19-9 test can be used to monitor the disease status in patients with confirmed pancreatic cancer who show measurable CA 19-9 values over the course of their disease. Serial CA 19-9 test results should be used in conjunction with all other available clinical and laboratory data before a medical decision is determined.

The VITROS Immunodiagnostic Products CA 19-9 assay (test) is performed using the VITROS Immunodiagnostic Products CA 19-9TM Reagent Pack and VITROS CA 19-9 Calibrators on the VITROS 5600 System.

An immunometric immunoassay technique is used, which involves the simultaneous reaction of 1116-NS-19-9 defined antigen present in the sample with a microwell coated with biotinylated Antibody (Mouse monoclonal anti-1116-NS-19-9 defined antigen) bound to Streptavidin. In a second incubation a Horseradish Peroxidase (HRP)- labelled antibody conjugate (Mouse monoclonal anti-1116-NS-19-9 defined antigen) binds to the immobilized 1116-NS-19-9 defined antigen. Unbound materials are removed by washing.

The bound HRP conjugate is measured by a luminescent reaction. A reagent containing luminogenic substrates (a luminol derivative and a peracid salt) and an electron transfer agent, is added to the wells. The HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent (a substituted acetanilide) increases the level of light produced and prolongs its emission. The light signals are read by the system. The amount of conjugate bound is directly proportional to the concentration of 1116-NS-19-9 defined antigen present in the sample.

VITROS Immunodiagnostic Products CA 19-9™ Reagent Pack contains:
1 reagent pack containing:

• 100 coated wells (antibody, mouse monoclonal anti-1116-NS-19-9 defined antigen, binds >49 U 1116-NS-19-9 defined antigen/well)
• 13.4 mL assay reagent (buffer containing bovine gamma globulin and antimicrobial agent)
• 20.0 mL conjugate reagent (HRP-mouse monoclonal anti-1116-NS-19-9 defined antigen, binds ≥326 U 1116-NS-19-9 defined antigen/mL) in buffer with bovine serum albumin, bovine gamma globulin and antimicrobial agent.

VITROS CA 19-9 Calibrator contains:

• 1, 2, and 3 (OC 1116-NS-19-9 defined antigen in buffer with bovine serum albumin and antimicrobial agent, 1.75 mL); nominal values 15; 60 and 700 U 1116-NS-19-9 defined antigen/mL
• 24 calibrator bar code labels (8 for each calibrator)

This document describes the non-clinical performance studies conducted for the VITROS CA 19-9 assay to demonstrate its safety and effectiveness. The information focuses on analytical performance characteristics rather than clinical diagnostic accuracy studies involving human experts for ground truth, which are typically found in studies for AI/ML-based medical devices or imaging diagnostics.

Since this device is an in-vitro diagnostic (IVD) assay for measuring a tumor-associated antigen (CA 19-9) in human serum and plasma, the "acceptance criteria" and "study that proves the device meets the acceptance criteria" are primarily based on established analytical performance parameters, not on human-expert-validated diagnostic accuracy. Therefore, several points from your request (e.g., number of experts, adjudication methods, MRMC studies, human-in-the-loop performance) are not directly applicable or reported in this type of submission.

Here's the breakdown of the acceptance criteria and study information provided:

1. Table of Acceptance Criteria and Reported Device Performance

The document presents validation studies against established guidelines (e.g., CLSI documents) and compares the modified device's performance to its predicate. The nature of these acceptance criteria is based on quantitative analytical performance characteristics.

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

The "test set" here refers to the samples used in the analytical validation studies. These are not human-interpreted images or clinical datasets in the AI/ML sense but rather biological samples.

• Stability Studies: Four runs on each of 3 lots at monthly intervals for long-term; 3 lots up to 12 weeks for on-board stability. Number of samples not explicitly stated but implies sufficient runs to validate stability claims.
• Precision: 6 precision fluids; 2 replicates, 2 runs/day for 20 days (total 80 data points per fluid).
• Detection Capability (LoB): 4 endogenous fluids with no CA19-9; 2 replicates, 2 runs/day for 5 test days (20 reps/fluid) x 4 fluids = 80 replicates x 3 lots = 240 total replicates.
• Detection Capability (LoD/LoQ): 5 samples; 6 replicates, 2 runs/day for 5 test days (60 reps/fluid) x 5 fluids = 300 replicates x 3 lots = 900 total replicates.
• Linearity: 16 levels in the test panel; 5 replicates of each level run on 3 reagent lots over 2 days.
• Matrix Comparison: 41 specimens for Li-Hep vs. Serum and 41 specimens for EDTA vs. Serum.
• Analytical Specificity (Interferences): Tested at CA 19-9 concentrations of ~5.0 U/mL and ~50.0 U/mL. Specific sample numbers for this testing are not given but are implied to be within CLSI guidelines.
• Expected Values (Reference Interval): 60 normal blood donors.
• Method Comparison: 118 patient serum samples.

Data Provenance: The document does not explicitly state the country of origin for the samples or if they were retrospectively or prospectively collected. The studies appear to be laboratory-based analytical validation studies.

3. Number of Experts Used to Establish Ground Truth and Qualifications

This concept is not applicable to this type of IVD analytical device validation. The "ground truth" for the performance of a CA 19-9 assay is established by the known concentration of the analyte in control samples, reference materials, or by comparison to a well-validated predicate method, not by human expert interpretation of images or clinical outcomes.

4. Adjudication Method for the Test Set

This concept is not applicable to this type of IVD analytical device validation. Adjudication is typically used for reconciling disagreements among human experts in diagnostic imaging interpretation or clinical decision-making.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, and its effect size

An MRMC study is not applicable to this device. This type of study assesses how human readers' diagnostic accuracy changes with or without AI assistance, which is for AI/ML-based diagnostic devices (e.g., imaging AI). This device is a quantitative immunoassay.

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

This concept is not applicable in the context of an IVD assay. The "algorithm" is the biochemical reaction and the instrument's measurement system. The device's "standalone" performance is what these non-clinical analytical studies demonstrate. The results are quantitative measurements of the CA 19-9 antigen, not classifications or detections that would then be presented to a human for interpretation.

7. The Type of Ground Truth Used

• Analyte Concentration: For precision, detection capability, linearity, known interferences, and dilution, the "ground truth" is based on the known or reference concentrations of CA 19-9 in control materials, spiked samples, or reference standards.
• Comparative Method: For method comparison, the "ground truth" is established by the results from the legally marketed predicate device (VITROS CA 19-9 assay, K052889).
• Normal Population Reference: For expected values, the "truth" is established by determining the range of values observed in a healthy, "normal" population.

8. The Sample Size for the Training Set

This document does not describe a "training set" in the context of machine learning. For an IVD assay, the development process involves reagent formulation, instrument calibration, and optimization using iterative testing and refinement, not a distinct "training set" of data in the AI/ML sense. The studies described are validation activities for the final device.

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

As there is no "training set" in the AI/ML sense for this IVD, this question is not applicable. The "ground truth" for developing and calibrating an IVD like this would be established through highly controlled laboratory preparations of samples with known concentrations of the target analyte, often traceable to international standards if available. Calibration itself establishes the relationship between the measured signal and the concentration of the analyte.

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For the quantitative measurement of OC 125 defined antigen concentration in human serum and plasma (EDTA or heparin) using the VITROS 5600 Integrated System. The VITROS CA 125 II assay is to be used as an aid in monitoring response to therapy for patients with epithelial ovarian cancer. Serial testing for patient CA 125 assay concentrations should be used in conjunction with other clinical methods used for monitoring ovarian cancer.

The VITROS Immunodiagnostic Products CA 125 II Reagent Pack (test) is performed using the VITROS CA 125 II Reagent Pack and VITROS CA 125 II Calibrators on the VITROS 5600 System. An immunometric immunoassay technique is used, which involves the reaction of OC 125 present in the sample with a microwell coated with biotinylated Antibody (Mouse monoclonal anti-OC 125) bound to Streptavidin, and a Horseradish Peroxidase (HRP)-labelled antibody conjugate (Mouse monoclonal anti- OC 125). Unbound (HRP)-labeled anti-OC 125 antibody conjugate is removed by washing. The bound HRP conjugate is measured by a luminescent reaction. A reagent containing luminogenic substrates (a luminol derivative and a peracid salt) and an electron transfer agent, is added to the wells. The HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent (a substituted acetanilide) increases the level of light produced and prolongs its emission. The light signals are read by the system. The amount of conjugate bound is directly proportional to the concentration of OC 125 present in the sample.

Here's an analysis of the provided text, outlining the acceptance criteria and study details for the VITROS Immunodiagnostic Products CA 125 II Reagent Pack:

This document is a 510(k) summary for a medical device ([K221355](https://510k.innolitics.com/search/K221355)) and primarily focuses on demonstrating substantial equivalence to a predicate device. As such, it reports on various analytical performance studies rather than user studies or comparative effectiveness studies involving human readers or AI.

Acceptance Criteria and Reported Device Performance

Study Details

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

   • Precision: Not explicitly stated for the "test set" in the context of device approval but uses multiple runs, days, and lots for calculation. Each sample shown in the precision table represents multiple determinations over different runs, days, and reagent lots.
   • Detection Capability: Not explicitly stated, but consistent with CLSI EP17-A2.
   • Linearity: 4 replicates from each level of a linearity panel (2 through 15 levels) were collected using three reagent lots. Data for one lot (9991) is presented.
   • Matrix Comparison: n=49 for both Li-Hep and EDTA comparisons.
   • Analytical Specificity: Not explicitly stated, but tested at two CA 125 concentrations (10.0 U/mL and 50.0 U/mL) with various interferent concentrations.
   • Expected Values (Reference Interval): 60 healthy female and male blood donors.
   • Method Comparison: n=146 patient serum samples.
   • Data Provenance: Not explicitly stated, but typical for such studies performed by manufacturers. Generally, such studies are prospective, and data would be collected from various clinical sites. No country of origin is specified.

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

   • This device is an in-vitro diagnostic (IVD) assay measuring a quantitative biomarker (CA 125 II antigen concentration). The "ground truth" for these types of devices is based on well-defined analytical methods, reference materials, and established predicate devices. No human experts or consensus panels are typically used to establish ground truth for this type of quantitative IVD device. The "ground truth" here is the actual concentration of the analyte, often determined by a reference method or assigned value of a calibrator.

3. Adjudication Method for the Test Set:

   • Not applicable as this is an analytical performance study for a quantitative IVD, not a diagnostic imaging or clinical decision-making study that would involve expert interpretation requiring adjudication.

4. 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:

   • No, an MRMC comparative effectiveness study was not done. This device is a lab-based immunoassay, not an AI-powered diagnostic imaging tool or a system involving human readers in its direct use.

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

   • Yes, the entire submission describes standalone performance. This is an automated immunoassay system (VITROS 5600 Integrated System) that produces a quantitative result. Its performance is entirely "algorithm only" or "device only" in the sense that once a sample is loaded, the measurement is automated without human interpretation of the direct signal to derive the CA 125 concentration. Human interpretation comes into play when a clinician uses the result in conjunction with other clinical findings.

6. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.):

   • The ground truth for the analytical performance studies (precision, linearity, detection, etc.) is the known concentration of the analyte in control materials, calibrators, or spiked samples, or comparison to a legally marketed predicate device (for method comparison).
   • For the method comparison study, the "ground truth" is established by the predicate device's measurement (VITROS CA 125 II (GEM.1125A)).

7. The Sample Size for the Training Set:

   • Not applicable in the context of an immunoassay using a specific reagent pack and established analytical reactions. This is not a machine learning or AI model that requires a "training set" in the conventional sense. The "training" of the device is its initial calibration and quality control setup based on manufacturer-defined calibrators and controls.

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

   • Not applicable. The "ground truth" for the device's operational setup (calibration) is established by in-house reference calibrators that have been value-assigned to correlate to another commercially available test. These calibrators have known, assigned concentrations of the OC 125 defined antigen.

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For the quantitative measurement of alpha-fetoprotein (AFP) concentrations in human serum using the VITROS 5600 Integrated system to aid in the management of patients with non-seminomatous testicular cancer.

The VITROS Immunodiagnostic Products AFP Reagent Pack is performed using the VITROS Immunodiagnostic Products AFP Reagent Pack and the VITROS AFP Calibrators on the VITROS 5600 System. VITROS Immunodiagnostic Products AFP Reagent Pack contains: 1 reagent pack containing: 100 coated wells (antibody, sheep anti-AFP, binds>25 IU AFP/well); 20.6 mL conjugate reagent (HRP-mouse monoclonal anti-AFP, binds ≥156 IU AFP/ mL) in buffer with bovine serum and antimicrobial agent; 15.8 mL assay reagent (buffer containing bovine serum albumin and antimicrobial agent). VITROS Immunodiagnostic Products AFP Calibrator contains: 1 set of VITROS AFP Calibrators 1, 2 and 3 (human cord serum/plasma derived AFP in human plasma with antimicrobial agent, 2 mL); nominal values 2; 22 and 220 IU/mL (1st International Reference Preparation 72/225) (2.42; 26.6 and 266 ng/mL); Lot calibration card; Protocol card; 24 calibrator bar code labels (8 for each calibrator).

Here's a breakdown of the acceptance criteria and the study proving the device meets them, based on the provided FDA 510(k) summary for the VITROS Immunodiagnostic Products AFP Reagent Pack:

Device Name: VITROS® Immunodiagnostic Products AFP Reagent Pack
Intended Use: For the quantitative measurement of alpha-fetoprotein (AFP) concentrations in human serum using the VITROS 5600 Integrated system to aid in the management of patients with non-seminomatous testicular cancer.

1. Acceptance Criteria and Reported Device Performance

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

• Precision/Reproducibility: Patient pools were used.
  • For each mean AFP concentration value, 80 observations were made over 20 days.
  • Provenance: Not explicitly stated (e.g., country of origin). The use of "patient pools" implies human samples, likely retrospective, created by combining individual patient samples.
• Linearity: Not specified as a separate "test set" with a specific sample size, but established using the CLSI protocol EP06, which involves creating dilution series.
• Detection Limits (LoB, LoD, LoQ): Not specified as a distinct "test set" sample size. Determined consistent with CLSI document EP17.
• Analytical Specificity/Known Interferences: Not specified as a distinct "test set" sample size. Tested at two AFP concentrations (4.80 IU/mL and 19.2 IU/mL) with various interfering substances.
• Cross-Reactivity: Not specified as a distinct "test set" sample size. Evaluated by adding specific substances to an AFP-free sample.
• Method Comparison with Predicate Device:
  • Sample Size: 150 patient serum samples.
  • Provenance: Not explicitly stated (e.g., country of origin, retrospective or prospective). The samples were "patient (serum) samples."

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

This device is an in vitro diagnostic (IVD) immunoassay for quantitative measurement of alpha-fetoprotein. The "ground truth" for such devices is typically established through reference methods and certified reference materials traceable to international standards, rather than expert consensus on individual cases.

• Traceability: Calibration is traceable to in-house reference calibrators, which are calibrated against the First International Reference Preparation 72/225. This indicates a high-level, international standard for AFP measurement, providing the "ground truth" reference for the assays.
• There were no experts used in the sense of clinical specialists establishing a diagnosis or outcome for the test data, as the study focuses on the analytical performance of the assay.

4. Adjudication Method for the Test Set

Not applicable. As an IVD device measuring a biomarker concentration, the "judgement" is determined by the analytical results against established reference materials and comparison to a predicate device, not by multi-expert review of clinical cases.

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

No, an MRMC comparative effectiveness study was not done. This type of study is typically relevant for interpretative diagnostic devices (e.g., imaging AI) where human readers make a diagnosis or assessment, and the AI assists or replaces that human interpretation. For a quantitative immunoassay like this AFP reagent pack, the performance is assessed analytically and by method comparison, not by reader performance.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

Yes, the studies presented are standalone performance evaluations of the VITROS Immunodiagnostic Products AFP Reagent Pack and the VITROS 5600 Integrated system. The reported precision, linearity, detection limits, analytical specificity, cross-reactivity, and method comparison are all characteristics of the assay system itself, without human intervention in the result generation or interpretation beyond the standard operation of the instrument.

7. Type of Ground Truth Used

The ground truth for the analytical performance of this immunoassay is based on:

• Reference Materials and International Standards: Calibration is traceable to the First International Reference Preparation 72/225. This is a highly characterized and internationally recognized standard for AFP.
• Predicate Device Comparison: For accuracy, the device's performance was compared against a legally marketed predicate device (VITROS Immunodiagnostic Products AFP Reagent Pack K983031), which itself would have been validated against reference standards.

8. Sample Size for the Training Set

The document does not specify a "training set" in the context of a machine learning or AI algorithm. This device is a traditional immunoassay, not an AI/ML-based diagnostic. Therefore, the concept of a "training set" for an algorithm is not applicable here. Performance characteristics are established through analytical validation studies using various types of samples (patient pools, spiked samples, etc.).

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

As noted in point 8, the concept of a "training set" is not applicable for this traditional immunoassay device. The analytical "ground truth" is established using traceable reference materials and comparison to a predicate device, as described in point 7.

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Rx ONLY

For in vitro diagnostic use only.

For the quantitative measurement of CK-MB in human serum and plasma (EDTA or heparin) using the VITROS 3600 Immunodiagnostic System.

Measurements of creatine phosphokinase and its isoenzymes are used in the diagnosis and treatment of myocardial infarction and muscle diseases such as progressive, Duchenne-type muscular dystrophy.

The VITROS Immunodiagnostic Products CK-MB assay is performed using the VITROS CK-MB Reagent Pack and the VITROS CK-MB Calibrators on the VITROS Systems.

The current VITROS Immunodiagnostic Products CK-MB assay is susceptible to interference from biotin. Ortho has made a modification to the manufacturing process to allow the biotinylated antibody capture conjugate to be pre-bound to the well, thus mitigating the risk of biotin interference.
The modified product utilizes all the same antibodies and raw materials with the exception of the addition of 0.7% Tween 20 and an increase in EDTA concentration from 0.001M to 0.030M, both of these modifications are to improve serum/plasma agreement which required a conversion factor in the previously cleared product.

An immunometric immunoassay technique is used, which involves the reaction of CK-MB present in the sample with a microwell coated with biotinylated Antibody (Mouse monoclonal anti-CK-BB bound to Streptavidin), and a Horseradish Peroxidase (HRP)-labeled antibody conjugate (Mouse monoclonal anti-CK-MB). Unbound (HRP)-labeled anti-CK-MB antibody conjugate is removed by washing.

The bound HRP conjugate is measured by a luminescent reaction. A reagent containing luminogenic substrates (a luminol derivative and a peracid salt) and an electron transfer agent, is added to the wells. The HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent (a substituted acetanilide) increases the level of light produced and prolongs its emission. The light signals are read by the system. The amount of CK-MB conjugate bound is directly proportional to the concentration of CK-MB present in the sample.

The provided document describes the 510(k) premarket notification for the VITROS Immunodiagnostic Products CK-MB Reagent Pack. This is an in vitro diagnostic device, not an AI/ML-based medical device. Therefore, many of the requested criteria related to AI/ML device testing (e.g., number of experts for ground truth, adjudication methods, MRMC studies, sample sizes for training sets) are not applicable to this document.

The document focuses on demonstrating the substantial equivalence of a modified CK-MB assay to a legally marketed predicate device, primarily through non-clinical performance studies.

Here's an analysis based on the provided text, addressing the applicable criteria for an in vitro diagnostic device:

1. Table of Acceptance Criteria and Reported Device Performance

For an in vitro diagnostic device like this, acceptance criteria typically revolve around analytical performance characteristics such as precision, linearity, detection limits, and method comparison to a predicate. The document doesn't explicitly state "acceptance criteria" as a pass/fail threshold, but rather presents the results of various validation studies.

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

• Precision:
  • Sample Size: 80 observations (likely meaning replicates across runs and days, as per CLSI EP05 methodology) for each of 4 patient pools.
  • Data Provenance: Not explicitly stated, but typically from internal lab testing.
• Limit of Detection/Quantitation: Not explicitly stated, but derived from experiments consistent with CLSI document EP17.
• Analytical Specificity (Interference) & Cross-Reactivity: Not explicitly stated, but involves testing at specific concentrations of CK-MB and interferents.
• Method Comparison to Predicate Device:
  • Sample Size: 149 patient (serum) samples.
  • Data Provenance: Not explicitly stated regarding country of origin, but described as "patient (serum) samples," implying collected clinical samples. The study is an analytical/non-clinical study, not a clinical trial, so it's prospective in the sense of testing the new device on these samples.

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

• Not Applicable. This is an in vitro diagnostic device measuring a biomarker concentration. The "ground truth" for method comparison is the measurement obtained by the predicate device and the analytical properties of the reference materials. Expertise is in laboratory medicine and analytical chemistry, not interpretation of images for diagnosis by human experts.

4. Adjudication Method for the Test Set

• Not Applicable. As above, no human expert adjudication is involved in establishing the "ground truth" for quantitative assay validation.

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 is not an AI/ML device, nor does it involve human readers interpreting images.

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

• Not Applicable. While the device operates standalone (human performs the test, the system provides a result), the concept of an "algorithm only" performance study typically refers to AI/ML models. For an IVD, the "standalone performance" is exactly what is described in the precision, linearity, and detection limit sections.

7. The Type of Ground Truth Used

• For precision, linearity, and detection limits: Analyte concentrations of reference materials or patient pools. The "truth" is established by highly controlled laboratory methods.
• For method comparison: Results obtained from the legally marketed predicate device (VITROS Immunodiagnostic CK-MB Reagent Pack, K993068). The predicate serves as the "true" or gold standard against which the modified device is compared. This is a common "ground truth" for demonstrating substantial equivalence for IVDs. While not explicitly stated, these predicate measurements would have been established through a similar robust validation process.

8. The Sample Size for the Training Set

• Not Applicable. This is not an AI/ML device, so there is no "training set" in the sense of machine learning. The device's performance characteristics are inherent to its chemical and biological components and manufacturing process, validated through the non-clinical studies detailed.

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

• Not Applicable. As there is no training set for an AI/ML model, this question is not relevant. The device development involved standard IVD R&D and manufacturing, not machine learning training.

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For in vitro diagnostic use only.

For the quantitative measurement of N-terminal pro Brain Natriuretic Peptide (NT-proBNP) in human serum and plasma (K2 EDTA or Lithium Heparin) using the VITROS 3600 Immunodiagnostic System to aid in the diagnosis of heart failure. The test can also be used in the assessment of heart failure severity in patients diagnosed with heart failure.

The VITROS NT-proBNP II test is performed using the VITROS VITROS NT-proBNP II Reagent Pack and the VITROS NT-proBNP II Calibrators on the VITROS Systems.

The VITROS NT-proBNP II test utilizes a one-step immunometric bridging assay design. A well is pushed from the pack and patient sample is dispensed into the antibody coated well. The assay reagent and the conjugate reagent are then dispensed into the well with the patient sample. NT-proBNP present in the sample binds with horseradish peroxidase (HRP)-labeled antibody conjugate which is captured by biotinylated anti-NT-proBNP capture antibody which is bound to Streptavidin coated microwells. The well is incubated for 8 minutes, before unbound materials are removed by washing.

The bound HRP conjugate is measured by a luminescent reaction. A reagent containing luminogenic substrate (a luminol derivative and a peracid salt) and an electron transfer agent, is added to the wells. The HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent (a substituted acetanilide) increases the level of light produced and prolongs its emission. The light signals are read by the System. The amount of HRP conjugate bound is directly proportional to the concentration of NT-proBNP present.

The provided document describes the analytical and clinical performance of the VITROS Immunodiagnostic Products NT-proBNP II Reagent Pack, an in vitro diagnostic device used to aid in the diagnosis and assessment of heart failure.

Here's an analysis of the acceptance criteria and the study proving the device meets them:

1. Table of acceptance criteria and the reported device performance

The document does not explicitly present a "table of acceptance criteria" in terms of pre-defined thresholds for performance metrics that the device must meet for clearance. Instead, it describes the design goals and then reports the observed performance. For clarity, I will create a table summarizing the reported performance, which implicitly indicates the criteria were met or exceeded for FDA clearance.

2. Sample size used for the test set and the data provenance

• ED Setting (Diagnosis of Heart Failure):
  • Sample Size: 2200 subjects.
  • Data Provenance: Multi-center prospective study, 20 collection sites across the United States.
• Outpatient Setting (Diagnosis of Heart Failure):
  • Sample Size: 777 subjects.
  • Data Provenance: Multi-center prospective study, 10 collection sites across the United States.
• Correlation with NYHA Functional Classification:
  • Sample Size: 1143 subjects with heart failure.
  • Data Provenance: Not explicitly stated if this was a separate collection or a subset of the ED/outpatient studies, but given it's "subjects with heart failure," it likely derives from similar clinical populations.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

• For both the ED and Outpatient settings: The final clinical diagnosis (ground truth) was adjudicated by independent cardiologists or ED physicians experienced in diagnosing HF.
• Number of Experts: Not specified. The document only mentions "independent cardiologists or ED physicians," implying more than one, but not a precise number.
• Qualifications: "Experienced in diagnosing HF." No specific number of years of experience or board certifications are mentioned.

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

• The document states that the final clinical diagnosis was "adjudicated by independent cardiologists or ED physicians experienced in diagnosing HF." It does not specify a quantitative adjudication method like "2+1" or "3+1." This suggests that the adjudication process was qualitative and relied on the clinical expertise of the adjudicators to reach a consensus diagnosis for each patient, rather than a fixed number of readers and a tie-breaking rule.

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

• No, a MRMC comparative effectiveness study was not done. This document describes the performance validation of an in vitro diagnostic (IVD) immunoassay kit (VITROS NT-proBNP II Reagent Pack), which measures blood biomarkers. This is not an AI/imaging device where human readers would typically be assisted by AI. The product is a laboratory test, and its performance is evaluated based on its accuracy in measuring the biomarker and its diagnostic utility compared to clinical truth.

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

• Yes, this is effectively a standalone performance study. The VITROS NT-proBNP II Reagent Pack provides a quantitative measurement of NT-proBNP. Its performance is assessed purely on the analytical accuracy of the measurement and its direct correlation with clinical outcomes (diagnosis of HF, NYHA classification) as determined by the expert adjudicators, without human interpretation of the device's numerical output for diagnosis (i.e., it's a direct measurement, not an interpretative AI). The output values are then interpreted against established cutoffs to aid in diagnosis, but the device itself does not involve a human-in-the-loop for its direct performance.

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

• The primary ground truth for heart failure diagnosis was expert clinical judgment/adjudication. For the diagnostic studies, "The final clinical diagnosis was adjudicated by independent cardiologists or ED physicians experienced in diagnosing HF."
• For the assessment of heart failure severity, the ground truth was New York Heart Association (NYHA) Functional Classification, which is a clinical classification based on patient symptoms and physical activity levels.

8. The sample size for the training set

• This document describes the validation of an in vitro diagnostic device (a reagent pack and system) for measuring a biomarker, not a machine learning or AI algorithm in the typical sense that would involve a "training set" for model development. The assays (immunoassays) are based on chemical reactions rather than statistical models trained on large datasets.
• The "training" of such a device primarily involves rigorous analytical development and characterization, ensuring the chemical processes are precise and accurate. Therefore, the concept of a separate "training set" with ground truth data, as used in AI/ML, is not directly applicable here. The document focuses on the performance validation of the developed assay.

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

• As noted above, the concept of a "training set" with ground truth for an AI/ML algorithm doesn't directly apply to this type of IVD immunoassay. The analytical methods and performance characteristics (precision, linearity, LoD, LoQ, analytical specificity, etc.) are established through laboratory experiments and characterization studies, not by training on a clinical dataset with ground truth in the AI/ML sense. Clinical performance is then validated against independently established clinical diagnoses (expert adjudication).

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For in-vitro diagnostic use only.

For the quantitative measurement of procalcitonin (PCT) in human serum and plasma (lithium heparin and EDTA) using the VITROS 3600 Immunodiagnostic System.

Used in conjunction with other laboratory findings and clinical assessments, the VITROS B R A PA - M S PCT test is intended for use as follows:

· 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,

· to aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using a change in PCT level over time,

· to aid in decision making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) - in an inpatient setting or an emergency department,

· to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

The VITROS B·R·A·H·M·S PCT test is performed using the VITROS B·R·A·H·M·S PCT Reagent Pack and the VITROS B·R·A·H·M·S PCT Calibrators on the VITROS Systems.

Reagent Pack Contents
1 reagent pack containing:

• 100 coated wells (rat monoclonal anti-procalcitonin antibody, 1.0 µg/mL) ●
• 10.20 mL assay reagent (buffer containing bovine gamma globulin, bovine serum ● albumin and antimicrobial agent)
• . 13.10 mL conjugate reagent (HRP-conjugated mouse monoclonal procalcitonin antibody. 1.65 ug/mL in buffer with bovine serum albumin and antimicrobial agent)

Calibrator Contents

• . 3 sets of VITROS B•R•A•H•M•S PCT Calibrators 1 and 2, 1.0 mL, procalcitonin in buffer with antimicrobial agent, nominal values 0.080 and 75.0 ng/mL (ug/L)
• . Lot calibration card
• Protocol card ●
  • 16 calibrator bar code labels (8 for each calibrator) ●

The provided text is a 510(k) Summary for the VITROS B·R·A·H·M·S PCT Reagent Pack and Calibrators, intended for quantitative measurement of procalcitonin (PCT). This document describes the device's performance characteristics and clinical studies to establish substantial equivalence to a predicate device.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

Since this is a 510(k) summary for an in vitro diagnostic device, the "acceptance criteria" are implied by the comparison to the predicate device and established analytical performance metrics. The key criterion is demonstrating substantial equivalence to the predicate device, B·R·A·H·M·S PCT sensitive KRYPTOR (K171338), especially at critical clinical decision points.

2. Sample Sizes and Data Provenance

• Test Set (Method Comparison with Predicate):

  • Sample Size: 266 patient samples were used for the regression analysis comparing the VITROS B·R·A·H·M·S PCT test to the B·R·A·H·M·S PCT sensitive KRYPTOR assay. 246 samples were within the measuring range.
  • Data Provenance: Not explicitly stated for analytical studies, but for the clinical performance study, samples were "retrospective samples from a study of 858 adult patients diagnosed with severe sepsis or septic shock recruited across 13 investigational sites in the United States." The original MOSES Study (DEN150009) collected samples from patients admitted to ICU from emergency departments, other wards, or directly from out of the hospital. EDTA samples were used.

• Test Set (Clinical Concordance):

  • Sample Size: 2168 samples (evaluating concordance at various PCT decision points).
  • Data Provenance: "serial sample sets obtained from the Multicenter Procalcitonin MOnitoring SEpsis (MOSES) Study collection, a well-characterized sample collection in 13 sites across the United States." This indicates a prospective collection used retrospectively for this specific device's evaluation.

• Test Set (28-Day Mortality Prediction):

  • Sample Size: 858 adult patients in the study, with an analysis population of 598 subjects.
  • Data Provenance: Retrospective samples from the Multicenter Procalcitonin MOnitoring SEpsis (MOSES) Study collection in 13 sites across the United States.

3. Number of Experts and Qualifications for Ground Truth

• For an in vitro diagnostic device measuring an analyte (procalcitonin), the "ground truth" for analytical studies is typically established by reference methods or gravimetric preparation with known concentrations. Experts are not typically involved in establishing ground truth for analytical performance like precision, linearity, LoD/LoQ, and interference.
• For clinical studies (concordance and mortality prediction), the primary "ground truth" for the device's performance against clinical decision points is the predicate device's measurement (B.R.A.H.M.S PCT sensitive KRYPTOR assay). Physician discretion and clinical assessments were used for patient diagnosis and mortality outcomes in the MOSES study, which provided the samples. While physicians made clinical diagnoses, they were not experts establishing a "ground truth score" for the device; rather, clinical outcomes (mortality, diagnosis of sepsis/septic shock) were endpoints. No individual "experts" were formally used to establish a ground truth for the test set, but rather the clinical outcomes and the predicate device's results served as the reference.

4. Adjudication Method

• Not applicable in the context of this 510(k) summary for an in vitro diagnostic device assessing an analyte level. Adjudication methods like 2+1 or 3+1 are typically used for subjective evaluations (e.g., imaging interpretation) where expert consensus is needed to determine the correct ground truth for a given case. Here, the ground truth for analytical performance is quantitative, and for clinical performance, it is the predicate device's measurement and observed clinical outcomes (e.g., 28-day mortality).

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

• No, an MRMC comparative effectiveness study was not performed. This device is an in vitro diagnostic assay, not an AI-assisted diagnostic tool for human readers. Therefore, the concept of "how much human readers improve with AI vs without AI assistance" does not apply.

6. Standalone Performance Study

• Yes, the performance described is a standalone performance study of the VITROS B·R·A·H·M·S PCT Reagent Pack and Calibrators. The "algorithm only" in this context refers to the assay's ability to quantitatively measure PCT levels. All analytical performance studies (precision, linearity, detection limits, analytical specificity, matrix comparison, high-dose hook, sample auto-dilution, carry-over) were conducted to demonstrate the standalone performance of the VITROS B·R·A·H·M·S PCT test. The clinical concordance with the predicate device also serves as a standalone performance benchmark.

7. Type of Ground Truth Used

• Analytical Ground Truth: For analytical performance studies (precision, linearity, LoD/LoQ, interference, matrix equivalence, high dose hook, carry over), the ground truth was established by:
  • Reference calibrators: Traceable to in-house reference calibrators, which were value-assigned to correlate to B·R·A·H·M·S PCT sensitive KRYPTOR.
  • Known concentrations: Prepared by gravimetric spiking with recombinant PCT.
  • Validated analytical methods: Following CLSI guidelines (e.g., EP05-A3 for precision, EP17-A2 for detection limits, EP06-A for linearity, EP07-A3 for interference).
• Clinical Ground Truth:
  • Predicate device results: For clinical concordance, the measurements from the B·R·A·H·M·S PCT sensitive KRYPTOR assay were considered the reference for comparison.
  • Outcomes data: For the 28-day mortality prediction claim, the vital status (mortality) of patients at Day 28 was the ground truth. This outcome data was collected during the original MOSES study.

8. Sample Size for the Training Set

• This 510(k) document describes a traditional in vitro diagnostic device clearance, not an AI/ML software submission that often explicitly details "training sets."
• However, the device's calibration is "traceable to in-house reference calibrators, which have been value-assigned to correlate to B·R·A·H·M·S PCT sensitive KRYPTOR." The development of these in-house reference calibrators and the assay itself would have involved some form of "training" or optimization using an internal dataset, but its size and specific characteristics are not provided in this regulatory summary.
• The clinical study samples from the MOSES study were used for validation (evaluation) of the device's clinical performance, not as a training set for the assay's underlying methodology.

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

• As noted above, a formal "training set" in the AI/ML sense is not described. The ground truth for the development of the assay (e.g., for calibrator assignment) would have been established through a combination of:
  • Reference materials: Highly characterized procalcitonin standards.
  • Defined analytical methods: Using established laboratory practices and potentially comparing to existing, well-regarded PCT assays during the R&D phase to create the "in-house reference calibrators."
  • Value assignment: A process where the concentration of an analyte in a calibrator is accurately determined. This often involves multiple measurements using reference methods or by gravimetric preparation.

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