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Immunoassay for the in vitro quantitative determination of c1-fetoprotein in human serum and in the management of patients with non-seminomatous germ cell tumors.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on the cobas e immunoassay analyzers.

Immunoassay for the in vitro quantitative determination of αι-fetoprotein in human serum and plasma to aid in the management of patients with non-seminomatous germ cell tumors.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

Elecsys AFP utilizes a sandwich test principle and has a total test duration of 18 minutes.

• 1st incubation: 10 uL of sample, a biotinylated monoclonal AFP specific antibody, and . a monoclonal AFP specific antibody labeled with a ruthenium complex® react to form a sandwich complex.
• 2nd incubation: After addition of streptavidin-coated microparticles, the complex . becomes bound to the solid phase via interaction of biotin and streptavidin.
• The reaction mixture is aspirated into the measuring cell where the microparticles are . magnetically captured onto the surface of the electrode. Unbound substances are then removed with ProCell/ProCell M. Application of a voltage to the electrode then induces chemiluminescent emission which is measured by a photomultiplier.
• Results are determined via a calibration curve which is instrument-specifically . generated by 2 point calibration and a master curve provided via the reagent barcode or e barcode.
• a) Tris(2,2'-bipyridyl)ruthenium(II)-complex (Ru(bpy) )

The reagent rackpack (M, R1, R2) is labeled as AFP:

• M: Streptavidin-coated microparticles (transparent cap), 1 bottle. 12 mL: Streptavidin-. coated microparticles 0.72 mg/mL; preservative.
• R1: Anti-AFP-Ab~biotin (gray cap), 1 bottle, 17 mL: Biotinylated monoclonal anti-. AFP antibodies (mouse) 4.5 mg/L; phosphate buffer 100 mmol/L, pH 6.0; preservative.
• R2: Anti-AFP-Ab~Ru(bpy) (black cap), 1 bottle, 17 mL: Monoclonal anti-AFP . antibodies (mouse) labeled with ruthenium complex 12.0 mg/L; phosphate buffer 100 mmol/L, pH 6.0; preservative.

The provided text describes a 510(k) premarket notification for the Elecsys AFP immunoassay. While it details numerous non-clinical tests conducted to prove the device's performance, it does not describe a study involving a "human-in-the-loop" or "algorithm-only" performance study in the context of an AI/ML device. The device described is an "immunological test system" and its performance is evaluated based on quantitative analytical metrics rather than the type of diagnostic performance (e.g., sensitivity, specificity, accuracy) typically associated with AI/ML devices interpreting medical images or complex data for diagnostic purposes.

Therefore, many of the requested items (e.g., number of experts, adjudication methods, MRMC studies, effect size of human reader improvement with AI) are not applicable or cannot be extracted from the provided text for this specific device.

However, I can extract information related to the acceptance criteria and performance of the described immunoassay device based on the non-clinical tests performed.

Here's a breakdown of the available information based on your request, focusing on what can be extracted and noting what cannot (due to the nature of the device and the provided document):

Device: Elecsys AFP Immunoassay (K220176)

Purpose of the study (as described in the document): To demonstrate substantial equivalence of the updated Elecsys AFP assay to a predicate device (K981282) by improving biotin tolerance and reducing streptavidin interference. The studies are non-clinical evaluations of the analytical performance of the immunoassay.

1. Table of Acceptance Criteria and Reported Device Performance

The document states that "All predefined acceptance criteria was met" for the various tests. While the specific numerical acceptance criteria (e.g., acceptable range for precision, linearity, interference limits) are not fully detailed, the reported performance is often given or implied by the "met" statement and the claimed range/limits.

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

• Precision (Repeatability, Intermediate Precision): Not explicitly stated, but CLSI EP05-A3 typically involves multiple runs over several days with specific sample replicates.
• Lot-to-lot Reproducibility: Used "three reagent lots."
• Limit of Blank/Detection/Quantitation: Not explicitly stated, but CLSI EP17-A2 involves specific sample types and replicates.
• Linearity: Evaluated on "one cobas e 601 analyzer" using samples spanning the linearity range, but the number of distinct samples or replicates is not specified beyond "0.58 IU/mL - 1129 IU/mL".
• High-Dose Hook Effect: Assessed on "one cobas e 601 analyzer" in "two-fold determination" for "both samples."
• Interference (Endogenous): "Seven endogenous substances were evaluated."
• Interference (Exogenous): "17 commonly used and ten specially used pharmaceutical compounds" were evaluated.
• Method Comparison: "A total of 181 serum sample concentrations were between 1.58 and 966 IU/mL."
• Anticoagulant Effect: "native, single-donor samples drawn into serum, Li-Heparin, K2-EDTA, and K3-EDTA plasma primary tubes." (Number of samples or donors not specified).
• Data Provenance: The document does not specify the country of origin for the samples/data or if they were retrospective or prospective. Given the nature of analytical validation studies for IVD devices, they are typically prospective studies performed in a controlled laboratory setting.

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

• Not Applicable. This is an immunoassay, not an AI/ML device relying on expert interpretation for ground truth. The "ground truth" for these analytical studies is derived from established laboratory methods, reference materials, and defined analytical ranges.

4. Adjudication Method for the Test Set:

• Not Applicable. No human adjudication process as typically seen in AI/ML diagnostic studies.

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

• No. This is not an AI/ML device; therefore, an MRMC study comparing human readers with and without AI assistance is not relevant or was not performed.

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

• Not Applicable (in the context of AI/ML). The device itself is an automated immunoassay. Its performance is inherently "standalone" in that it produces a quantitative result without human "interpretation" of a complex output, but this is a very different concept than an AI algorithm's standalone diagnostic performance. The document describes the analytical performance of the automated assay system.

7. The Type of Ground Truth Used:

• The "ground truth" for these types of analytical studies is based on:
  • Reference Methods/Materials: For linearity, analytical range, LoB/LoD/LoQ determinations, often using diluted/spiked samples with known concentrations.
  • Comparative Analysis: The "method comparison" compares the new assay's results against the existing (predicate) assay.
  • Defined Limits/Spiked Samples: For interference studies, known amounts of interferents are added to samples.
  • Established CLSI Guidelines: The studies explicitly state adherence to CLSI (Clinical and Laboratory Standards Institute) guidelines (e.g., EP05-A3, EP17-A2, EP06-A) for methodology, which dictate how "truth" is assessed for analytical performance.

8. The Sample Size for the Training Set:

• Not Applicable. This is not an AI/ML device that requires a "training set" in the computational sense. The device's performance is based on its chemical and technological design, and its validation involves analytical testing rather than machine learning on a dataset.

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

• Not Applicable. As above, no "training set" in the AI/ML context.

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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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The AFP method is an in vitro diagnostic test for the quantitative measurement of alphafetoprotein in human serum and lithium heparinized plasma on the Dimension Vista® System. Measurements of alpha-fetoprotein are used as an aid in managing nonseminomatous testicular cancer when used in conjunction with physical examination, histology/pathology, and other clinical evaluation procedures.

The Dimension Vista® AFP method is a homogeneous, sandwich chemiluminescent immunoassay based on LOCI® technology. The LOCI® reagents include two synthetic bead reagents and a biotinylated anti-AFP monoclonal antibody fragment. The first bead reagent (Chemibeads) is coated with an anti-AFP monoclonal antibody and contains chemiluminescent dye. The second bead reagent (Sensibeads) is coated with streptavidin and contains a photosensitizer dye. Sample is incubated with biotinylated antibody and Chemibeads to form bead-AFP-biotinylated antibody sandwiches. Sensibeads are added and bind to the biotin to form bead-pair immunocomplexes. Illumination of the complex at 680 nm generates singlet oxygen from Sensibeads which diffuses into the Chemibeads, triggering a chemiluminescent reaction. The resulting signal is measured at 612 mm and is a direct function of the AFP concentration in the sample.

Here's a breakdown of the acceptance criteria and study details for the Siemens Healthcare Diagnostics Inc. Dimension Vista® AFP Flex® reagent cartridge, based on the provided 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance:

The primary objective of this submission is to add lithium heparinized plasma as an approved sample type. Therefore, the "acceptance criteria" are implied by the comparison to the existing, approved serum sample type. The study demonstrates analytical and clinical agreement between serum and lithium heparinized plasma samples.

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

• Sample Size for Test Set: 70
• Data Provenance: The document states "human serum versus lithium heparinized plasma samples," implying human-derived samples. There is no information regarding the country of origin of the data or whether it was retrospective or prospective.

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

This submission does not involve clinical experts establishing a ground truth for diagnostic accuracy in the traditional sense (e.g., radiologists interpreting images). Instead, it's a comparative analytical study assessing the equivalence of different sample types for the same assay. The ground truth for AFP levels would be the measurement obtained from the predicate device using serum samples. Therefore, this section is not directly applicable.

4. Adjudication Method for the Test Set:

Not applicable. This was an analytical comparison study between two sample types using instrument measurements, not a diagnostic interpretation study requiring adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size:

No, an MRMC comparative effectiveness study was not done. This is an in vitro diagnostic device for quantitative measurement, not an imaging or interpretation device that would typically involve human readers.

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

Yes, a standalone performance assessment was conducted in the sense that the device (Dimension Vista® AFP Flex® reagent cartridge) was used to measure AFP levels in both serum and lithium heparin plasma samples. The reported performance refers to the analytical agreement of these measurements, without human intervention in the result generation itself.

7. The Type of Ground Truth Used:

The "ground truth" in this context is the analytical measurement obtained from the predicate Dimension Vista® AFP method using serum samples. The study aims to demonstrate that lithium heparin plasma samples provide equivalent measurements to these established serum values.

8. The Sample Size for the Training Set:

The document does not explicitly mention a "training set" in the context of an algorithm or machine learning model. This is an update to a reagent cartridge for an established immunoassay. The method itself (LOCI® technology) is a well-defined chemical reaction, not a machine learning algorithm that requires a separate training set for model development.

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

Not applicable, as explained in point 8.

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The Olympus AFP assay is a paramagnetic particle (Dynabeads®), chemiluminescent immunoassay for the quantitative determination of alpha-fetoprotein levels in human serum and lithium heparin plasma using the Olympus AU3000i Immunoassay System. The Olympus AFP assay is intended for use as an aid in the management of patients with non-seminomatous germ cell tumors.

For in vitro diagnostic use only.

The Olympus AFP Calibrator is for calibrating the quantitative Olympus AFP assay on the Olympus AU3000i Immunoassay System.

The Olympus AFP Control is used for quality control of the Olympus AFP assay on the Olympus AU3000i Immunoassay System.

The Olympus Alpha-fetoprotein (AFP) Test System is a paramagnetic particle (Dynabeads®), chemiluminescent immunoassay for the quantitative determination of alpha-fetoprotein levels in human serum and lithium heparin plasma using the Olympus AU3000i Immunoassay System.

The provided text is a 510(k) premarket notification acceptance letter for the Olympus AFP Test System. It does not contain information about acceptance criteria or a study proving the device meets those criteria. The letter acknowledges that the device is substantially equivalent to a legally marketed predicate device but does not detail the performance metrics or study design.

Therefore, I cannot provide the requested information based on the provided input.

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VIDAS® AFP is an automated quantitative test for use on the VIDAS instruments for the quantitative measurement of alpha-fetoprotein (AFP) in human serum using the ELFA technique (Enzyme Linked Fluorescent Assay). The VIDAS AFP assay is indicated for the quantitative measurement of Alpha-Fetoprotein (AFP) in serum to aid in the management of patients with nonseminomatous testicular carcinoma.

The assay principle combines a one-step immunoassay sandwich method with a final fluorescent detection (ELFA). The Solid Phase Receptacle (SPR), a pipette tip-like device, serves as the solid phase as well as the pipetting device for the assay. The assay reagents are ready-to-use and pre-dispensed in the sealed reagent strips (STRs). All of the assay steps are performed automatically by the VIDAS instrument. The sample is transferred into the well containing AFP antibody (conjugate) labeled with alkaline phosphatase. 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 to 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-Methylumbeliferyl 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 VIDAS instrument in relation to two calibration curves corresponding to the two detection steps stored in memory, and then printed out.

Here's a breakdown of the acceptance criteria and study information for the VIDAS® AFP Assay, based on the provided text:

Acceptance Criteria and Device Performance

Study Information:

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

   • Clinical Trial Test Set: 257 samples were tested to compare the VIDAS® AFP and the TOSOH ST AIA-PACK AFP assays. 253 samples were used for the Passing and Bablok regression analysis.
   • Data Provenance: Not explicitly stated. The nature of the samples for the clinical trial (e.g., patient samples) suggests retrospective or prospective testing, but the specific origin (e.g., country) is not mentioned.

2. 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)

   • Not Applicable. For this in-vitro diagnostic device, ground truth for the clinical trial was established by comparison to a legally marketed predicate device (TOSOH ST AIA-PACK AFP assay), which itself serves as the reference standard in this context. There were no human expert readers establishing ground truth in the traditional sense for image interpretation or similar applications.

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

   • Not Applicable. As the ground truth was established by comparison to a predicate device's quantitative measurement, adjudication by multiple human experts is not relevant to this type of study.

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. This was not a MRMC comparative effectiveness study involving human readers and AI assistance. It is an in-vitro diagnostic device measuring a biomarker.

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

   • Yes, in essence. The VIDAS® AFP assay is an automated quantitative test. Its performance characteristics (precision, limits of detection, linearity, interference, hook effect) are evaluated as a standalone system. The "clinical trial" section compares its performance directly to another automated in-vitro diagnostic device (the predicate), essentially evaluating the algorithm/device's output without direct human interpretation influencing the final quantified result.

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

   • For the clinical trial, the ground truth was established by comparison to a legally marketed predicate device (TOSOH ST AIA-PACK AFP assay). The predicate device's measurements served as the reference standard for evaluating the new device's quantitative agreement.
   • For the precision, limits of detection, linearity, interference, and hook effect studies, the ground truth was based on the inherent characteristics of the samples used (e.g., known concentrations of AFP, spike/recovery studies), measured against the expected analytical performance.

7. The sample size for the training set

   • Not Applicable/Not provided. This submission describes an in-vitro diagnostic assay rather than a machine learning algorithm that typically undergoes distinct "training" with a labeled dataset. The device's calibration curves are "stored in memory," and for each kit lot and calibrator lot, there's a "master curve." This suggests a calibration process, not a machine learning training phase in the conventional sense.

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

   • Not Applicable/Not provided. Similar to the above, there isn't a "training set" with ground truth in the context of a machine learning algorithm. The assay uses two calibration curves related to two detection steps, which are stored in memory. It also mentions a "Master curve for each kit lot and each calibrator lot are traceable to 1st IS 72/225 International Reference Preparation (IRP)". This traceability to an International Reference Preparation is how the assay's quantitative accuracy is established and maintained.

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The AFP method is an in vitro diagnostic test for the quantitative measurement of alpha-fetoprotein in human serum on the Dimension Vista® system. Measurements of alpha-fetoprotein are used as an aid in managing non-seminomatous testicular cancer when used in conjunction with physical examination, histology/pathology, and other clinical evaluation procedures.

For the calibration of the Alpha-Fetoprotein (AFP) method on the Dimension Vista® System.

Method: The AFP method is a homogeneous, sandwich chemiluminescent immunoassay based on LOCI™ technology. The LOCT™ reagents include two synthetic bead reagents and a biotinylated anti-AFP monoclonal antibody fragment. The first bead reagent (Chemibeads) is coated with an anti-AFP monoclonal antibody and contains chemiluminescent dye. The second bead reagent (Sensibeads) is coated with streptavidin and contains a photosensitizer dve. Sample is incubated with biotinylated antibody and Chemibeads to form bead-AFP-biotinylated antibody sandwiches. Sensibeads are added and bind to the biotin to form bead-pair immunocomplexes. Illumination of the complex at 680 nm generates singlet oxygen from Sensibeads which diffuses into the Chemibeads, triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is a direct function of the AFP concentration in the sample.

Calibrator: The LOCI 5 Calibrator is a liquid multi-analyte product containing AFP from human cord serum. An additional analyte (CEA from human tissue culture) is contained in the product and will be included in the submission to FDA with its respective method. The kit consists of ten vials, two each of five levels containing 2 mL per vial. Description of the manufacturing, value assignment and stability testing processes are provided.

For the Siemens Healthcare Diagnostics Inc. Dimension Vista® AFP reagent cartridge and LOCI 5 calibrator (K071597):

1. Table of Acceptance Criteria and Reported Device Performance

   The document does not explicitly state acceptance criteria in a quantitative format (e.g., a specific threshold for correlation coefficient or slope). Instead, it presents performance data and concludes "good analytical and clinical agreement." The substantial equivalence claim is based on this agreement with the predicate device.

   Performance Metric (Device: Dade Behring Dimension Vista® AFP Method)	Reported Device Performance (vs. Predicate Abbott AxSYM® AFP Method)
   Slope (Passing-Bablok linear regression)	0.93
   Intercept (ng/mL)	0.1
   Correlation Coefficient	0.995

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

   • Sample Size for Test Set: 317 patient samples.
   • Data Provenance: Not specifically mentioned, but the study is a "split sample method comparison," implying prospective collection of human serum samples for comparison against a predicate device. The country of origin is not specified.

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

   This study describes a method comparison for an in vitro diagnostic test measuring AFP levels in serum. The "ground truth" in this context is the quantitative result provided by the predicate device (Abbott AxSYM® AFP method). This is not a study requiring expert readers to establish ground truth from images or clinical assessments.

4. Adjudication Method for the Test Set

   Not applicable. This is a quantitative method comparison study against a predicate device, not a study involving expert adjudication of interpretations.

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

   No. This document describes a method comparison study for an in vitro diagnostic device, not a comparative effectiveness study involving human readers and AI assistance for interpretation.

6. Standalone (i.e., algorithm only without human-in-the-loop performance) Study

   Yes, in essence. The study evaluates the performance of the Dimension Vista® AFP method (the "algorithm/device") by directly comparing its quantitative results to those of a predicate device using patient samples. This is a standalone performance evaluation of the assay itself.

7. Type of Ground Truth Used

   The "ground truth" for this method comparison study is the quantitative Alpha-Fetoprotein (AFP) concentration obtained from the predicate device (Abbott AxSYM® AFP method) for each human serum sample.

8. Sample Size for the Training Set

   The document does not provide information about a separate "training set" for the Dimension Vista® AFP method itself. This is a performance validation of a finished assay and calibrator. The development and internal validation of the assay (e.g., defining reagent concentrations, detection parameters) likely involved numerous experiments and historical data, but these are not disclosed as a distinct "training set" in a machine learning sense. Clinical validation studies for IVDs typically focus on demonstrating performance against established methods or clinical outcomes.

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

   As noted in point 8, a "training set" in the context of a machine learning algorithm is not explicitly described. For the development of the assay, the "ground truth" for calibrating and establishing the assay's performance characteristics would involve using certified reference materials (e.g., traceable to WHO Reference preparation for human AFP (72/225)) and well-characterized human samples. The document states that the device is "Traceable to the World Health Organization (WHO) Reference preparation for human AFP (72/225)," indicating the standard used for establishing accuracy and calibration.

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ST AIA-PACK AFP is designed for IN VITRO DIAGNOSTIC USE ONLY for the quantitative measurement of Alpha-Fetoprotein (AFP) in serum to aid in the management of patients with nonseminomatous testicular carcinoma.

The ST AIA-PACK AFP is a two-site immunoenzymometric assay which is performed entirely in the AIA-PACK. AFP present in the test sample is bound with monoclonal antibody immobilized on a magnetic solid phase and enzyme-labeled monoclonal antibody in the AIA-PACK. The magnetic beads are washed to remove unbound enzyme-labeled monoclonal antibody and are then incubated with a fluorogenic substrate, 4-methylumbelliferyl phosphate (4MUP). The amount of enzyme-labeled monoclonal antibody that binds to the beads is directly proportional to the AFP concentration in the test sample. A standard curve is constructed, and unknown sample concentrations are calculated using this curve.

The provided text is a 510(k) summary for the ST AIA-PACK AFP device, which is an in vitro diagnostic for measuring Alpha-Fetoprotein (AFP) in human serum. This submission is a "Special 510(k)" for a modification to an already cleared device (P910006).

Based on the information provided in the document, here's an analysis of the acceptance criteria and the study that proves the device meets them:

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

The document states: "This Special 510(k) is for a modification in the packaging, incubation period and certain components of the conjugate diluent of the AIA-PACK AFP, which was previously cleared as P910006 on December 18, 1992. The intended use, assay principles, antibody type, analyte detected, and performance characteristics of both assays are equivalent."

This statement implies that the acceptance criteria for the modified device are the same as those established for the original P910006 device and that the modified device's performance is equivalent to the predicate. However, the document does not explicitly list the acceptance criteria (e.g., specific thresholds for accuracy, precision, linearity, etc.) or detailed reported performance data for the ST AIA-PACK AFP itself. Instead, it relies on the predicate device's established performance.

To construct a table, we would need the original 510(k) (P910006) which is not provided, but based on the text, the performance "acceptance criteria" are implicitly met if the performance is "equivalent" to the predicate.

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

The document does not provide details on a specific "test set" and its sample size for the modified device. The submission relies on the concept of "substantial equivalence" to the predicate device P910006. The modifications are in "packaging, incubation period and certain components of the conjugate diluent." The implication is that these changes were not substantial enough to require a new, comprehensive clinical performance study to establish new performance criteria. Therefore, no specific sample size for a new test set is mentioned.

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 section is not applicable to the provided document. The device is an in vitro diagnostic for quantitative measurement of AFP in serum, not one that requires expert interpretation of images or other subjective data for ground truth establishment. The ground truth for such devices is typically established through reference methods or highly characterized calibrators, not human expert consensus, especially for a 510(k) modification where performance is asserted to be equivalent to a predicate.

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

This is not applicable for the same reasons as point 3. Adjudication methods like 2+1 or 3+1 are typically used in studies involving subjective human interpretation (e.g., radiology reads) where discrepancies between readers need resolution. For an in vitro diagnostic, performance is usually measured quantitatively against a reference, not through multi-reader adjudication.

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

This is not applicable. The device is an in vitro diagnostic for measuring AFP, not an AI-assisted diagnostic tool that aids human readers. Therefore, an MRMC study or assessment of AI assistance is irrelevant to this submission.

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

The device itself is a standalone immunoassay kit used on a specific analyzer (TOSOH AIA System analyzers). It operates as an "algorithm only" in the sense that the instrument performs the assay and calculates results without human intervention in the result determination phase. However, the document does not detail specific "standalone performance studies" beyond stating equivalence to the predicate. The "performance characteristics of both assays are equivalent" implies that the standalone performance metrics (e.g., precision, accuracy, sensitivity, specificity, linearity, etc.) were demonstrated to be similar to the predicate device, but these specific studies or their results are not presented in this summary.

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

For an in vitro diagnostic assay like this, the "ground truth" for validation studies (which led to the original P910006 clearance) would typically be established using:

• Reference materials/calibrators: Samples with known, accurately determined concentrations of AFP.
• Reference laboratory methods: Comparison with established, validated methods for AFP measurement.
• Clinical correlation: While not a direct "ground truth" for analytical performance, clinical utility is supported by correlation with disease status (e.g., in patients with nonseminomatous testicular carcinoma), often confirmed by pathology or clinical follow-up.

However, for this specific 510(k) modification, the document does not describe new ground truth establishment. It relies on the previously established ground truth for the predicate device, asserting that the modifications do not change the fundamental performance.

8. The sample size for the training set

This is not applicable. Immunoassays like the ST AIA-PACK AFP are not "trained" in the machine learning sense. Their performance is inherent in their biochemical design (antibodies, reagents, protocol). Therefore, there is no "training set" as understood in AI/ML contexts.

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

This is not applicable for the same reasons as point 8.

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The Bayer ADVIA® IMS™ AFP assay is an in vitro diagnostic device intended to quantitatively measure afetoprotein (AFP) in human serum on the Bayer ADVIA IMS system as an aid in the management of nonseminomatous testicular cancer. AFP values obtained using the Bayer ADVIA IMS assay method must be interpreted in conjunction with all other available clinical and laboratory data before a medical decision is determined. AFP testing is not recommended as a screening procedure to detect cancer in the general population.

The Bayer ADVIA® IMS™ AFP assay is an in vitro diagnostic device intended to quantitatively measure afetoprotein (AFP) in human serum on the Bayer ADVIA IMS system.

Acceptance Criteria and Study for Bayer ADVIA® IMS™ AFP Assay

This document summarizes the acceptance criteria and the study conducted to demonstrate the safety and effectiveness of the Bayer ADVIA® IMS™ AFP Assay.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the ADVIA IMS AFP Assay are primarily established by demonstrating substantial equivalence to the predicate device, Immuno 1 AFP Assay, across various performance metrics. The specific quantitative acceptance criteria are implicitly defined by the reported performance metrics of the predicate device and the observed performance of the new device.

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For the quantitative determination of alpha-fetoprotein (AFP) in the following: human serum, as an aid in managing non-seminomatous testicular cancer when used in conjunction with physical examination, histology/pathology, and other clinical evaluation procedures, using the Bayer Diagnostics ACS:180 Automated Chemiluminescence System or the ADVIA Centaur System.

The Bayer Diagnostics ACS:180 & ADVIA Centaur AFP immunoassay is a two-site immunoassay using direct chemiluminometric technology, which uses constant amounts of two antibodies. The first antibody, in the Lite Reagent, is a purified polyclonal rabbit anti-AFP antibody labeled with acridinium ester. The second antibody, in the Solid Phase, is a monoclonal mouse anti-AFP antibody covalently coupled to paramagnetic particles. A direct relationship exists between the amount of AFP present in the patient sample and the amount of relative light units (RLU's) detected by the system.

The provided text describes the performance data for the ACS:180 & ADVIA Centaur AFP Immunoassay. Here's an analysis based on your request:

1. Table of Acceptance Criteria and Reported Device Performance

• Measures AFP up to 1000 ng/mL.
• Minimum detectable concentration: 1.3 ng/mL.
  ACS:180:
• Measures AFP up to 1000 ng/mL.
• Minimum detectable concentration: 0.19 ng/mL. |
  | Accuracy | High correlation with predicate/alternate methods (e.g., r > 0.95). | ADVIA Centaur vs. ACS:180 (N=498):
• Equation: ADVIA Centaur AFP = 1.05 (ACS:180 AFP) - 0.3 ng/mL
• Correlation coefficient (r) = 0.99
  ACS:180 vs. Alternate Methods:
• Abbott IMX (N=504): ACS:180 = 0.94(Abbott IMX) + 4.6
• Kallestd AFP/Ob (N=1575): ACS:180 = 0.92(Kallestd AFP/Ob) + 6.2
• Abbott mEIA (N=183): ACS:180 = 0.97(Abbott mEIA) - 1.0
• Kallestd AFP/Ob (N=477): ACS:180 = 1.10(Kallestd AFP/Ob) + 1.0 |

Note on Acceptance Criteria: The document does not explicitly state specific numerical acceptance criteria for correlation coefficients or minimum detectable limits. Instead, it presents the performance data in comparison to a predicate device (ACS:180 for ADVIA Centaur) and other established methods. The "acceptance criteria" are implied by the excellent correlation values (r=0.99 for ADVIA Centaur vs. ACS:180) which are typically considered a strong indicator of agreement in such assays.

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

• ADVIA Centaur Accuracy Test Set: 498 serum samples.
• ACS:180 Accuracy Test Set (vs. alternate methods):
  • vs. Abbott IMX: 504 samples
  • vs. Kallestd AFP/Ob (first test): 1575 samples
  • vs. Abbott mEIA: 183 samples
  • vs. Kallestd AFP/Ob (second test): 477 samples
• Data Provenance: Not explicitly stated. The document describes clinical performance data but does not specify the country of origin of the data or whether it was retrospective or prospective.

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

• This information is not provided in the document. The study compares the device's measurements to existing established methods (predicate device and alternate AFP methods), not to a ground truth established by human experts in the traditional sense of image or pathology review.

4. Adjudication Method for the Test Set

• Not applicable. The "ground truth" for these tests are the results from the established existing immunoassay methods. There is no mention of human adjudication as would be relevant for subjective assessments.

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

• No. This type of study is typically done for diagnostic imaging devices where human interpretation is a key component. The ACS:180 & ADVIA Centaur AFP Immunoassay is an in vitro diagnostic (IVD) immunoassay that provides quantitative results. Therefore, an MRMC study is not relevant for this device.

6. Standalone Performance Study

• Yes, standalone performance was assessed. The "Performance Data" section details the sensitivity (minimum detectable concentration) and accuracy (correlation with predicate and other immunoassay methods) of the devices themselves, without direct human intervention in the result generation. The device outputs a quantitative value for AFP concentration based on its internal processes.

7. Type of Ground Truth Used

• The "ground truth" in this context is the results obtained from legally marketed and established predicate/alternate AFP immunoassay methods. The study aims to demonstrate that the new devices produce results that are highly correlated and comparable to these existing, accepted methods.

8. Sample Size for the Training Set

• This information is not provided in the document. Immunoassays typically involve calibration and validation rather than a "training set" in the machine learning sense. The document describes performance data, likely from validation studies, rather than development or training phases.

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

• Not applicable / Information not provided. As mentioned above, the concept of a "training set" and "ground truth" for it, as typically used in machine learning, does not align with the description of this immunoassay. The document focuses on demonstrating performance against established methods.

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The DSL 10-8400 AFP ELISA assay is intended for the quantitative determination of AFP in human serum. It is intended for in vitro diagnostic use to aid in the management of patients with nonseminomatous testicular cancer.

The DSL-10-8400 ACTIVE™ AFP ELISA is an enzymatically amplified "two-step" sandwichtype immunoassay. In the assay, Standards, Controls and unknown serum samples are incubated in microtitration wells which have been coated with anti-AFP antibody. After incubation and washing, the wells are treated with another anti-AFP detection antibody labelled with the enzyme horseradish peroxidase (HRP). After a second incubation and washing step, the wells are incubated with the substrate tetramethylbenzidine (TMB). An acidic stopping solution is then added and the degree of enzymatic turnover of the substrate is determined by dual wavelength absorbance measurement at 450 and 620 nm.

The absorbance measured is directly proportional to the concentration of AFP present. A set of AFP Standards is used to plot a standard curve of absorbance versus AFP concentration from which the AFP concentrations in the unknowns can be calculated.

Here's an analysis of the DSL 10-8400 ACTIVE™ AFP ELISA Kit's acceptance criteria and the studies performed, based on the provided document.

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state acceptance criteria in a pass/fail format for each performance characteristic. Instead, it presents the results of various performance studies. For the purpose of this response, I infer "acceptance criteria" from the reported performance, implying that the reported values were deemed acceptable for the device's intended use and for demonstrating substantial equivalence to the predicate device.

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

• Substantial Equivalence Study (Method Comparison):
  • Sample Size: 73 male human serum samples.
  • Data Provenance: Not explicitly stated, but "human serum samples" implies clinical samples. Whether they were retrospective or prospective is not specified. The country of origin is not specified, but the submitter is based in Webster, Texas, USA.
• Performance Characteristics (Analytical Studies - Precision, Recovery, Linearity, Specificity, Sensitivity): These studies typically use a controlled set of samples (e.g., pooled human serum, spiked samples, diluted samples).
  • Sample Size:
    • Sensitivity: 22 replicates of 0 ng/mL AFP Standard.
    • Intra-assay Precision: 14 replicates for each of 3 male human serum samples.
    • Inter-assay Precision: 4 replicates for each of 3 human serum samples, done in 2 separate runs each day for 20 days.
    • Recovery: 3 male human serum samples, each spiked with 3 different AFP amounts.
    • Linearity: 3 male human serum samples, each diluted at multiple factors.
  • Data Provenance: "Male human serum samples" is stated for some. These are laboratory-based analytical studies, not clinical patient data. The origin isn't specified beyond "human serum."
• Expected Values (Normal Population):
  • Sample Size: 199 healthy adult males, 72 healthy adult females.
  • Data Provenance: Not explicitly stated, but "a study conducted with apparently normal healthy adults" implies prospective collection for assay validation. Country of origin not specified.
• Longitudinal Study (Clinical Utility):
  • Sample Size: 3 patients with diagnosed nonseminomatous testicular cancer were serially monitored. Additionally, 15 male patients with nonseminomatous testicular cancer had their AFP levels determined.
  • Data Provenance: Clinical patient data. Retrospective or prospective is not explicitly stated for the 15 patients; for the 3 longitudinal patients, it implies prospective monitoring or use of stored serial samples. Country of origin not specified.

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

There is no mention of "experts" being used to establish ground truth in the context of this device's analytical or clinical performance evaluation.

• For the Substantial Equivalence study: The "ground truth" was based on the measurement by the predicate device (Abbott IMx AFP Immunoassay).
• For analytical performance (Precision, Recovery, Linearity, Sensitivity): The "ground truth" or true value is based on the known concentrations of standards, spiked amounts, or calculated values from dilutions. These are intrinsic to the assay's design and laboratory experimentation.
• For Expected Values and Longitudinal Studies: The "ground truth" for patient diagnosis (nonseminomatous testicular cancer) would have been established by standard clinical diagnostic procedures (e.g., histology, imaging, clinical presentation), which would implicitly involve expert medical practitioners, but the document does not detail this. The AFP values themselves are the direct measurements from the device in these studies.

4. Adjudication Method (for the test set)

No adjudication method is described. For most in vitro diagnostic (IVD) assays, particularly quantitative ones like ELISA, adjudication by experts for ground truth is not typically part of the analytical validation or method comparison. The measured values from the device or the predicate device are directly compared or analyzed. Clinical outcomes (disease diagnosis, response to treatment) form the "ground truth" for clinical utility, which is established through standard medical practice rather than an active adjudication process for the purpose of validating the assay.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This type of study is typically performed for diagnostic imaging devices where human readers interpret images with and without AI assistance. The DSL 10-8400 ACTIVE™ AFP ELISA Kit is an in vitro diagnostic assay that provides a quantitative numerical result, and therefore, an MRMC study is not applicable.

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

Yes, the studies presented are primarily standalone performance assessments of the DSL 10-8400 ACTIVE™ AFP ELISA Kit. The device provides a quantitative measurement of AFP; it doesn't involve a "human-in-the-loop" for interpretation in the same way an imaging AI might. The clinical utility studies demonstrate how the results from the device aid in patient management, but the performance characteristics (sensitivity, precision, recovery, etc.) are evaluating the device itself, separate from human interpretation or modification of its direct output.

7. The Type of Ground Truth Used

• Substantial Equivalence Study: The predicate device's (Abbott IMx AFP Immunoassay) results served as the reference or "ground truth" for comparison.
• Analytical Performance Studies (Sensitivity, Precision, Recovery, Linearity, Specificity): The "ground truth" was based on known concentrations of standards, known amounts of spiked AFP, or expected values from dilutions.
• Expected Values Study: The "ground truth" for these samples was based on the clinical status of the individuals (apparently normal healthy adults).
• Longitudinal / Clinical Utility Studies: The "ground truth" for these patients was established through clinical diagnosis of nonseminomatous testicular cancer and monitoring of their clinical course and response to treatment, presumably via established medical diagnostic and monitoring protocols (e.g., biopsy/histology, imaging, other markers).

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning or AI. This is an ELISA kit, which is a biochemical assay. The "training" of such a device would involve optimizing the assay reagents and protocols during development. The various performance studies mentioned serve as validation of the developed assay.

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

As this is not an AI/machine learning device, the concept of a "training set" and its "ground truth" in the AI sense does not apply. The development of the assay (akin to "training" in a broader sense) would involve extensive experimentation with known AFP concentrations in various matrices to establish optimal antibody concentrations, incubation times, substrate reactions, and standard curve parameters. The "ground truth" for such development would be the precisely known concentrations of AFP standards and controls.

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