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This in vitro diagnostic procedure is intended to quantitatively measure human chorionic gonadotropin (hCG) in human serum on the Technicon Immuno 1º system. Measurements of human chorionic gonadotropin are used for the detection of pregnancy. This method is an adaptation of an existing Technicon Immuno 1 hCG method and has an extended range from 800 mIU/mL to 100,000 mIU/mL. This diagnostic method is not intended for use on any other system.

Device Description

This method is a double antibody immunoassay. hCG Antibody Conjugate 1 (R1) and hCG Antibody Conjugate 2 (R2) are reacted with patient sample (or calibrator containing hCG) and incubated on the Technicon Immuno 1 system at 37℃. The mIMP Reagent (monoclonal ImmunoMagnetic Particle) is added and a second incubation occurs during which the antibody complex is bound. The mIMP/antibody complex is then washed and the pNPP (para nitrophenylphosphate) substrate is added. The alkaline phosphatase (ALP) in the antibody conjugate reacts with the pNPP to form para-nitrophenoxide and phosphate. Increasing absorbance, due to the formation of para-nitrophenoxide, is monitored at 405 nm and 450 nm. A sample having no hCG will have the minimum label bound, while samples containing high hCG concentrations will have maximum label bound. Thus the dose/response curve is directly proportional to the hCG in the sample.

The hCG ER method is an adaptation of the existing Technicon Immuno 1 hCG method. They both use the identical hCG Reagent, Part No. T01-2966-51. The hCG ER Calibrators, Part No. T03-3668-01, are identical in formulation to the Technicon SET point Reproductive Calibrators, Part No. T03-3148-01, which are used for the standard hCG method. There are no changes in either reagent or callbrator formulation. The hCG ER method differs from the standard hCG method in three ways:

1. The hCG ER calibrators, are reconstituted in 1.0 mL of Reproductive Calibrator Diluent while the Reproductive Calibrators are reconstituted in 2.0mL of Reproductive Calibrator Diluent. This doubles the concentrations of hCG in the calibrator from 0 -1000 mIU/mL to 0 - 2000 mIU/mL.
1. 65uL of calibrator are reacted with reagent, while 1.3uL of any other sample, serum or control, are reacted. 65uL of the highest calibrator, 2000 mIU/mL, corresponds to 130 total mIU of hCG. A corresponding serum sample with 130 total mIU of hCG, at 1.3uL volume, would have 100,000 mIU/mL concentration. Thus a serum sample at 100,000 mIU/mL reacts the same total quantity of hCG, and produces the same amount of p-nitrophenoxide, as does calibrator at 2,000 mIU/mL.
1. The concentrations of all samples other than calibrator are automatically multiplied by a factor of 50, which is the difference in volume between 65uL and 1.3uL.

AI/ML Overview

Here's an analysis of the provided text, focusing on acceptance criteria and supporting study details:

Acceptance Criteria and Device Performance for hCG Extended Range (hCG ER) Method

1. Table of Acceptance Criteria and Reported Device Performance

Performance Metric	Acceptance Criteria (Implied)	Reported Device Performance (hCG ER Method)	Notes
Reference Range	Quantitative measurement of hCG in human serum in an extended range from 800 mIU/mL to 100,000 mIU/mL.	800 - 100,000 mIU/mL	The primary intended use and key differentiation from the standard hCG method.
Precision (Within-run %CV)	Acceptable precision for quantitative diagnostic assay (implied to be similar to standard hCG method's 2.1-2.4% for lower concentrations).	3.2% - 3.8%	While slightly higher than the lower range of the standard method, these values are for significantly higher hCG concentrations, where larger absolute variations may be acceptable. The clinical significance of these CVs at higher concentrations would be evaluated by experts.
Precision (Total %CV)	Acceptable overall precision for quantitative diagnostic assay (implied to be similar to standard hCG method's 3.7-4.0% for lower concentrations).	4.8% - 6.8%	Similar to within-run precision, the values are slightly higher, but for a much higher concentration range.
Correlation with Standard Method (r)	High correlation (implied: >0.95 or similar to demonstrate equivalent performance with the extended range)	0.998 (for 104 sera, range 840-88,500 mIU/mL)	This is an excellent correlation, indicating strong agreement between the hCG ER method and the standard hCG method.
Linearity (Recovery)	Recoveries consistently falling within a defined range (e.g., 90-110% of expected)	99% - 107% of expected	Excellent linearity, demonstrating accurate measurements across the extended range.
Parallelism (Recovery after Dilution)	Mean observed values within a defined range of expected (e.g., 90-110% of expected)	95% - 107% of expected	Good parallelism, indicating that dilution of high samples yields proportional and accurate results. This is critical for assays with an extended range requiring dilution.
Interfering Substances/Specificity	Expected to be the same as the standard hCG method.	Expected to be the same as the standard hCG method due to reduced sample volume.	The claim is based on the reduced sample volume, which theoretically reduces the amount of interfering substances. No new experimental data for specificity is presented for the hCG ER method itself, but relies on the established performance of the standard method.
Expected Values	Same as the standard hCG method.	Same as the standard hCG method.	Confirms that the extended range doesn't alter the clinical interpretation of hCG levels, only the measurable range.
Reagent and Calibrator Stability	Reagent stability for the existing hCG reagent is established. Calibrators stable for 30 days after reconstitution.	Reagent: No additional studies needed. Calibrators: Serum pool recoveries within a target range (implied by "Fresh Recon, Week 0 Calibration, and Weekly Calibration, as well as a -2SD Range line" showing agreement).	Based on the identical formulation to existing products, indicating prior establishment of stability. The calibrator stability study explicitly confirms the 30-day stability of the reconstituted calibrators.
Minimal Detectable Concentration	Lowest reportable result is 800 mIU/mL.	800 mIU/mL (lowest reportable result)	This is a statement of the method's lower limit, not an acceptance criterion to be met by a specific test, but rather a characteristic of the assay design. Minimal detectable dose was not determined, with emphasis on the lowest reportable result for the defined extended range.

2. Sample Sizes and Data Provenance

Test Set for Precision:
- Within-run & Total Precision: n = 130 over 20 days for Controls 1, 2 and Serum Pools 1, 2, 3.
- Data Provenance: Not explicitly stated (e.g., retrospective/prospective, country of origin). It seems to be prospective internal testing by Bayer Corporation as data is "on file at Bayer Corporation".
Test Set for Correlation:
- n = 104 serum samples.
- Data Provenance: Not explicitly stated (e.g., retrospective/prospective, country of origin). Appears to be internal testing.
Test Set for Parallelism:
- 3 unique serum samples.
- Data Provenance: Not explicitly stated.
Test Set for Linearity:
- 3 unique pairs of high and low hCG serum samples.
- Data Provenance: Not explicitly stated.
Test Set for Calibrator Stability:
- 3 sets of calibrators (reconstituted weekly over 5 weeks).
- Data Provenance: Not explicitly stated.

3. Number of Experts and Qualifications for Ground Truth

This submission describes an in vitro diagnostic assay for quantitative measurement of a biomarker (hCG). The ground truth for such assays is typically established by the reference method or established analytical techniques, not by human experts in the sense of image interpretation or clinical diagnosis.
In the correlation study, the "ground truth" (or comparative method) was the standard Technicon Immuno 1 hCG method. This method itself would have been validated against a traceable reference method or gold standard.
For precision, linearity, and parallelism, the "ground truth" is derived from expected values based on the known concentrations of controls/pools or theoretical dilutions, rather than expert consensus on individual samples.

4. Adjudication Method for the Test Set

For an in vitro diagnostic assay evaluating analytical performance like precision, linearity, and correlation, adjudication by multiple human readers (like in imaging studies) is not applicable.
The correlation study involved two researchers separately diluting samples "to minimize individual biases in dilution," which is a form of quality control to reduce measurement error, but not an adjudication of a judgment call.

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

No MRMC comparative effectiveness study was done. This type of study is more relevant for diagnostic aids where human interpretation is involved (e.g., radiology AI). This submission focuses on the analytical performance of an automated in vitro diagnostic device.

6. Standalone Performance Study

Yes, this entire submission details the standalone performance of the hCG ER method. It describes the algorithm's (the Immuno 1 system's) ability to quantitatively measure hCG without human interpretation in the loop. The results (precision, correlation, linearity) are direct measurements of the device's output.

7. Type of Ground Truth Used

Reference Method Comparison: For the correlation study, the ground truth was the standard Technicon Immuno 1 hCG method.
Known Concentrations/Expected Values: For precision, linearity, parallelism, and calibrator stability, the ground truth was based on known concentrations in control materials, serum pools, or mathematically derived expected values from dilutions.

8. Sample Size for the Training Set

The document primarily describes the validation or performance verification of the hCG ER method, which is an adaptation of an existing method. It does not explicitly mention a "training set" in the context of machine learning.
The "training" of the system would broadly refer to the calibration of the instrument using a set of calibrators. The document mentions the concentrations of the calibrators: 0, 20, 80, 200, 1000, 2000 mIU/mL (for the hCG ER calibrators). The dose-response curve (page 3) shows these points.

9. How Ground Truth for the Training Set Was Established

The "ground truth" for the calibrators (the "training set" in a broader sense for an IVD) would be established by traceability to a recognized reference standard for hCG, often an International Reference Preparation (IRP) or World Health Organization (WHO) standard. The calibrators are prepared at precisely known concentrations, which are verified against these reference materials. The document states that the hCG ER Calibrators are "identical in formulation" to the Technicon SET point Reproductive Calibrators, suggesting their ground truth is rooted in the same established traceability as the standard method.

Summary

Regulation Number and Section

§ 862.1155 Human chorionic gonadotropin (HCG) test system.

(a)
Human chorionic gonadotropin (HCG) test system intended for the early detection of pregnancy —(1)Identification. A human chorionic gonadotropin (HCG) test system is a device intended for the early detection of pregnancy is intended to measure HCG, a placental hormone, in plasma or urine.(2)
Classification. Class II.(b)
Human chorionic gonadotropin (HCG) test system intended for any uses other than early detection of pregnancy —(1)Identification. A human chorionic goadotropin (HCG) test system is a device intended for any uses other than early detection of pregnancy (such as an aid in the diagnosis, prognosis, and management of treatment of persons with certain tumors or carcinomas) is intended to measure HCG, a placental hormone, in plasma or urine.(2)
Classification. Class III.(3)
Date PMA or notice of completion of a PDP is required. As of the enactment date of the amendments, May 28, 1976, an approval under section 515 of the act is required before the device described in paragraph (b)(1) may be commercially distributed. See § 862.3.