(28 days)
For in vitro diagnostic use only. VITROS® Chemistry Products Calibrator Kit 3 is used to calibrate VITROS® 250/350/5,1 FS and 4600 Chemistry Systems and the VITROS 5600 Integrated System for the quantitative measurement of ALT, ALKP, AMYL, AST, CK, GGT, LDH and LIPA.
VITROS® Calibrator Kit 3 contains three levels of calibrators: Calibrator 1, 2, and 3. The calibrators are lyophilized, multi-analyte products prepared from processed bovine serum to which enzymes, electrolytes, stabilizers, and preservatives have been added. VITROS Chemistry Products Calibrator Kit 3 contains four vials each of lyophilized calibrator 1, 2, and 3 and four vials each of calibrator diluent 1, 2, and 3.
This document describes the VITROS Chemistry Products Calibrator Kit 3, a multi-analyte calibrator. The submission focuses on modifications to the calibrator kit, specifically the addition of nominal values and traceability information for Lactate Dehydrogenase (LDH) to the IFCC/L->P method, and the removal of value-assignment information for Acid Phosphatase (ACP).
Here's the breakdown of the acceptance criteria and study information:
1. Acceptance Criteria and Reported Device Performance
The core of this submission is demonstrating substantial equivalence to a predicate device (VITROS Chemistry Products Calibrator Kit 3, K001679). Unlike a diagnostic or screening algorithm with specific performance metrics like sensitivity and specificity, this device is a calibrator, meaning its performance is tied to its ability to accurately assign values and maintain stability for subsequent diagnostic tests.
The document does not present a single table of "acceptance criteria" and "reported device performance" in the typical sense of a diagnostic assay's accuracy metrics. Instead, the acceptance is based on establishing Substantial Equivalence to the predicate device and meeting stability and traceability requirements.
Implicit Acceptance Criteria and Reported Performance:
| Acceptance Criteria Category | Specific Criteria (Implicit) | Reported Device Performance (as described in the document) |
|---|---|---|
| Device Intent/Functionality | New device must have the same intended use as the predicate. | Intended Use: "For in vitro diagnostic use only. VITROS® Chemistry Products Calibrator Kit 3 is used to calibrate VITROS® 250/350/5,1 FS and 4600 Chemistry Systems and the VITROS 5600 Integrated System for the quantitative measurement of ALT, ALKP, AMYL, AST, CK, GGT, LDH and LIPA." (Matches predicate, except for ACP removal) |
| Measured Analytes (Value Assigned) | Must measure the same analytes as the predicate (with intended modifications). | Measured Analytes: ALT, ALKP, AMYL, AST, CK, GGT, LDH, LIPA. (Matches predicate, ACP removed as stated in modifications) |
| Form and Source | Form of the calibrator and source of analytes should be consistent with the predicate. | Form: Lyophilized. Analyte Source: ALT: Porcine Heart, ALKP: Porcine Kidney, AMYL: Porcine Pancreas, AST: Porcine Heart, CK: Porcine Heart, GGT: Porcine Kidney, LDH: Chicken Heart, LIPA: Porcine Pancreas. (Matches predicate) |
| Number of Levels | Number of calibrator levels should be consistent. | Number of Levels: Three. (Matches predicate) |
| Target Concentrations (for shared analytes) | Target concentrations for analytes (excluding LDH due to change) should be consistent with the predicate. | Target Concentrations (U/L): ALT: 20, 250, 900; ALKP: 20, 150, 1450; AMYL: 35, 360, 1000; AST: 11, 243, 775; CK: 40, 700, 1650; GGT: 25, 125, 1360; LIPA: 30, 200, 1950. (Matches predicate for these analytes) |
| Stability | The device must meet established stability criteria for shelf-life and reconstituted product. | Stability: "Real-time stability studies for shelf-life and open-vial claims have been conducted and acceptance criteria were met. VITROS Chemistry Products Calibrator Kit 3 is to be stored frozen at less than or equal to -18℃ for 24 months or until the expiration date printed on each carton. Real-time stability studies for shelf-life are on-going. The final shelf life claims will be based on the completed real-time study results. Reconstituted products should be used immediately or stored refrigerated at 2-8°C for less than or equal to 24 hours." (Acceptance criteria met, ongoing study for final claims) |
| Traceability (LDH specific) | The modified device's LDH values must be traceable to the specified reference method. | Traceability (LDH): "Values assigned to the VITROS Chemistry Products Calibrator Kit 3 for lactate dehydrogenase LDHI Slides are traceable to the IFCC recommended reference method as described in IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 C. Part 3. Reference procedure for the measurement of catalytic concentration of lactate dehydrogenase." (Traceability to IFCC/L->P/37 °C established) |
| Nominal Calibrator Values (LDH specific) | New nominal values for LDH, corresponding to the new traceability, must be provided and validated. | Nominal Calibrator Value LDH (U/L): Calibrator Vial 1: 90; Calibrator Vial 2: 320; Calibrator Vial 3: 800. (New values provided and implicit to be accurate based on traceability) |
| Overall Substantial Equivalence | The modified device must be substantially equivalent to the predicate device, demonstrating that the changes do not raise new questions of safety or effectiveness. | Conclusion: "Based on the testing and the comparisons with the predicate device, the VITROS Calibrator Kit 3 (Modified) is substantially equivalent to the VITROS Calibrator Kit 3 cleared under K001679." (Overall acceptance criterion met) |
Summary of Differences from Predicate (and how they meet criteria):
- Target Concentrations (U/L) for LDH: New Device (LDH: 90, 320, 800) vs. Predicate Device (LDH: 225, 800, 2000). This change is justified by the updated traceability method.
- Traceability for LDH: New Device (Buhl method and IFCC method) vs. Predicate Device (Buhl method). The addition of IFCC method traceability is an improvement and aligns the calibrator with a recognized standard.
2. Sample Size Used for the Test Set and Data Provenance
The document does not explicitly state a "test set" and its sample size in a manner typical for diagnostic device validation (e.g., a cohort of patient samples). The studies performed for this calibrator focus on stability testing and traceability/value assignment.
- Stability Studies: "Real-time stability studies for shelf-life and open-vial claims have been conducted..." No specific sample size (number of calibrator kits or vials) is given, nor is the data provenance by country. These are generally prospective studies done in-house by the manufacturer.
- Traceability and Value Assignment: "...using a panel of human samples as an intermediate Working Calibrator."
- Sample Size for "panel of human samples": Not specified.
- Data Provenance: The "panel of human samples" implies human-derived samples, but specific country of origin or whether they were retrospective/prospective is not mentioned. This is typically internal validation data.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications
N/A. This is a calibrator, not a diagnostic device that interprets clinical output requiring expert review for ground truth.
For the traceability and value assignment, the reference methods (e.g., IFCC recommended reference method) are the "ground truth" for the calibrator values themselves, rather than clinical experts establishing a ground truth for a test set. This process relies on scientific and metrological standards for enzyme activity measurement.
4. Adjudication Method for the Test Set
N/A. Not applicable for a calibrator device.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
N/A. This is a calibrator, not a diagnostic device involving human readers or interpretation of cases.
6. Standalone Performance Study (Algorithm Only)
N/A. This is a physical calibrator product, not a software algorithm. Its "performance" is its ability to accurately transfer values and maintain stability. The "algorithm" for value assignment is described as analogous to the Broughton and Eldjarn method, which is a statistical and analytical process for value transfer.
7. Type of Ground Truth Used
- For Calibrator Values: The ground truth for the assigned values of the analytes, particularly LDH, is established by internationally recognized reference methods/procedures. For LDH, it is the "IFCC recommended reference method as described in IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 C. Part 3. Reference procedure for the measurement of catalytic concentration of lactate dehydrogenase." Other analytes also have their traceability linked to established reference methods (e.g., IFCC, PG5, NCCLS, pH Stat).
- For Stability: The ground truth is experimental measurement against predefined stability specifications/acceptance criteria.
8. Sample Size for the Training Set
N/A. This is a calibrator, not an AI/ML algorithm that is "trained" on data. The "training" for a calibrator (if an analogy must be made) is the process of its manufacturing and initial value assignment according to established scientific methods.
9. How the Ground Truth for the Training Set Was Established
N/A, for the reasons mentioned above. However, the document does describe how the values are assigned:
"The process by which Supplementary Assigned Values (SAV) are assigned to VITROS Chemistry Products Calibrator Kit 3 is analogous to the value transfer process described by Broughton and Eldjarn... The major difference is that instead of transferring values from one serum pool to another, reference method values are transferred to product calibrator fluids, using a panel of human samples as an intermediate Working Calibrator."
This implies a multi-step process involving:
- Reference method measurement (the ultimate ground truth).
- Transferring these values to human samples (the "panel of human samples").
- Using these human samples as an "intermediate Working Calibrator" to assign values to the final product calibrator fluids.
§ 862.1150 Calibrator.
(a)
Identification. A calibrator is a device intended for medical purposes for use in a test system to establish points of reference that are used in the determination of values in the measurement of substances in human specimens. (See also § 862.2 in this part.)(b)
Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9.