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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.

• 5.33 mIU/mL: 0.095 (1.80%)
• 15.46 mIU/mL: 0.181 (1.20%)
• 45.67 mIU/mL: 0.666 (1.50%)
• 297.34 mIU/mL: 4.970 (1.70%)
• 4708.50 mIU/mL: 82.29 (1.70%)
• 9651.00 mIU/mL: 286.71 (3.00%) |
  | Precision (Within Lab) | Evaluation consistent with CLSI document EP05-A3. (Specific %CV or SD targets not explicitly stated in this section, but implied by acceptable performance.) | Within Lab (SD/%CV):
• 5.33 mIU/mL: 0.281 (5.30%)
• 15.46 mIU/mL: 0.706 (4.60%)
• 45.67 mIU/mL: 1.560 (3.40%)
• 297.34 mIU/mL: 8.640 (2.90%)
• 4708.50 mIU/mL: 151.22 (3.20%)
• 9651.00 mIU/mL: 464.48 (4.80%)
  Further breakdown including Between Lot shows Total %CV up to 6.4% |
  | Detection Capability (LoB) | Evaluation consistent with CLSI document EP17-A2. Supporting the claimed LoB of 0.05 mIU/mL. | Representative LoB is 0.00 mIU/mL (IU/L), which supports the claimed LOB of 0.05 mIU/mL. |
  | Detection Capability (LoD) | Evaluation consistent with CLSI document EP17-A2. Supporting the claimed LoD of 0.70 mIU/mL. | Representative Limit of Detection (LoD) is 0.21 mIU/mL (IU/L), which supports the claimed LoD of 0.70 mIU/mL (IU/L). |
  | Detection Capability (LoQ) | Designed to be less than or equal to the claimed low end of the measuring range (2.39 mIU/mL) at 20% CV. Consistent with CLSI document EP17 (Total Error approach). | Representative LoQ using the Total Error approach was 2.32 mIU/mL (IU/L). Claimed LoQ verified at 2.39 mIU/mL (IU/L). |
  | Linearity | Established in accordance with CLSI guideline EP06 2nd edition. Results support linearity across the specified range. | Supported linearity from 1.51 mIU/mL (IU/L) to 15695 mIU/mL (IU/L). For Lot 2643, Slope was 0.991 (38.6 to 15695) and 1.025 (1.51 to 51.18); R2 was 0.996 and 0.999 respectively; % Recovery ranged from 92.2% to 112.7%. |
  | Measuring Range | The device is expected to have a measuring range on the VITROS 5600 system. | 2.39*-15,000 mIU/mL (IU/L). |
  | Matrix Comparison | Serum and plasma (Lithium-Heparin and K2-EDTA) specimen matrices determined to be equivalent. Results met acceptance criteria for comparison between serum and plasma spanning the expected measuring interval. | Weighted Deming Regression: Li-Hep Plasma (Slope 0.978, Corr. Coef r 0.999), K2-EDTA Plasma (Slope 0.978, Corr. Coef r 0.999). Serum and plasma (Li-Heparin and K2-EDTA) found suitable matrices. |
  | Analytical Specificity (Known Interferents) | Evaluated following CLSI EP07 and EP37. None found to cause a bias of >10% at specified hCG concentrations. | Over 30 common substances (e.g., Acetaminophen, Bilirubin, Biotin, Hemoglobin, Triglycerides) tested at high concentrations (e.g., Acetaminophen 15.6 mg/dL, Hemoglobin 1000 mg/dL, Triglycerides 1500 mg/dL) showed no bias >10% at hCG concentrations of 5.00, 50.00, and 10,000 mIU/mL. |
  | Analytical Specificity (Cross-Reactivity) | Evaluation for cross-reactivity with FSH, LH, and TSH in hCG negative samples and samples with ~25 mIU/mL hCG. | In hCG negative samples, FSH, LH, and TSH (at 400 mIU/mL and 200 mIU/mL respectively) were Not Detectable (ND). With a pool at ~25 mIU/mL hCG, % Cross Reactivity was: FSH (0.6%), LH (-0.3%), TSH (0.4%). |
  | Expected Values (Adult Reference Interval) | Validated following CLSI document EP28-A3c. Distribution of hCG values from normal healthy non-pregnant blood donors shows equivalency to the predicate device's expected values claim. | Original Claim: Total 290 samples, Mean 0.56, Min 0.00, Max 6.66, 2.5th Percentile 0.00, 97.5th Percentile 4.83.
  Updated Pack: Total 180 samples, Mean 0.47, Min 0.00, Max 5.61, 2.5th Percentile 0.00, 97.5th Percentile 3.73. Demonstrated equivalency. |
  | Method Comparison (Accuracy) | Evaluated consistent with CLSI guideline EP09c. Comparison with predicate device (VITROS Immunodiagnostic Products Total β-hCG II reagent pack, K063720). | n=135 samples. Slope 0.99 (95% CI: 0.977 to 0.995). Correlation Coefficient 0.998. Intercept -0.0215 (95% CI: -0.160 to 0.117). (Comparing VITROS Total ß-hCG II (GEM.1076A) against predicate VITROS Total B-hCG (GEM.1076)). Consistent with graphs indicating strong agreement. |

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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