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510(k) Data Aggregation
Binding assay for the in vitro quantitation of vitamin B12 in human serum and plasma. Measurements obtained by this device are used in the diagnosis and treatment of gastrointestinal malabsorption. The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.
Vitamin B12 II CalSet is used for calibrating the quantitative Elecsys Vitamin B12 II assay on the Elecsys and cobas e immunoassay analyzers.
The Elecsys Vitamin B12 II assay employs a competitive test principle using intrinsic factor specific for vitamin B12. Vitamin B12 in the sample competes with the added vitamin B12 labeled with biotin for the binding sites on the ruthenium-labeled intrinsic factor complex.
Results are determined via a calibration curve which is instrument specifically generated by 2-point calibration and a master curve provided via reagent barcode.
The reagent working solutions include:
- the rackpack (kit placed on instrument) .
- Streptavidin coated microparticles, .
- Reagent 1 (ruthenium labeled intrinsic factor) and .
- Reagent 2 (vitamin B12 labeled biotin). .
- Pretreatment 1 (Dithiothreitol) .
- Pretreatment 2 (sodium hydroxide, sodium cyanide) .
The Vitamin B12 II CalSet is a lyophilized human serum matrix with added vitamin B12 in two concentration ranges.
The CalSet includes:
- Cal 1 (approximately 250 pg/mL vitamin B12 in a Human serum matrix) .
- Cal 2 (approximately 1500 pg/mL vitamin B12 in a Human serum matrix) .
The document describes the Elecsys Vitamin B12 II Assay and Elecsys Vitamin B12 II CalSet, which are used for in vitro quantitative determination of Vitamin B12 in human serum and plasma. The device is intended for use in the diagnosis and treatment of anemias of gastrointestinal malabsorption.
Here's a breakdown of the requested information:
1. A table of acceptance criteria and the reported device performance
| Test Category | Acceptance Criteria | Reported Device Performance and Remarks |
|---|---|---|
| Precision | Elecsys Vitamin B12 II Assay (Candidate Device) | |
| Within-run (Repeatability) | ≤ 200 pg/mL: SD ≤ 14 pg/mL > 200 pg/mL: CV ≤ 7 % | Cobas e 411: |
| HS 1 (176 pg/mL): 8.86 SD (5.0% CV) | ||
| HS 2 (405 pg/mL): 13 SD (3.2% CV) | ||
| HS 3 (960 pg/mL): 19.7 SD (2.1% CV) | ||
| HS 4 (1230 pg/mL): 27.4 SD (2.2% CV) | ||
| HS 5 (1940 pg/mL): 40.9 SD (2.1% CV) | ||
| PCV0 (229 pg/mL): 8.96 SD (3.9% CV) | ||
| PCV1 (447 pg/mL): 12.2 SD (2.7% CV) | ||
| PCV2 (934 pg/mL): 20.2 SD (2.2% CV) | ||
| All results met the acceptance criteria. | ||
| Intermediate Precision | ≤ 200 pg/mL: SD ≤ 24 pg/mL > 200 pg/mL: CV ≤ 12 % | Cobas e 411: |
| HS 1 (176 pg/mL): 12.7 SD (7.2% CV) | ||
| HS 2 (405 pg/mL): 17.5 SD (4.3% CV) | ||
| HS 3 (960 pg/mL): 31.0 SD (3.2% CV) | ||
| HS 4 (1230 pg/mL): 46.4 SD (3.8% CV) | ||
| HS 5 (1940 pg/mL): 72.6 SD (3.7% CV) | ||
| PCV0 (229 pg/mL): 12.4 SD (5.4% CV) | ||
| PCV1 (447 pg/mL): 18.6 SD (4.2% CV) | ||
| PCV2 (934 pg/mL): 38.4 SD (4.1% CV) | ||
| All results met the acceptance criteria. | ||
| Limit of Blank (LoB) | LoB ≤ 50 pg/mL | Achieved. (Specific value not reported in the summary, but stated as meeting criterion.) |
| Limit of Detection (LoD) | LoD ≤ 100 pg/mL | Achieved. (Specific value not reported in the summary, but stated as meeting criterion.) |
| Limit of Quantitation (LoQ) | LoQ (Imprecision) ≤ 20 % at 150 pg/mL | Achieved. (Specific value not reported in the summary, but stated as meeting criterion.) |
| Linearity | ≤ 200 pg/mL: ± 20 pg/mL > 200 pg/mL: ± 10 % (for deviation to higher order polynomial regression) Significant level for deviation to higher order polynomial: 5% | Reported that "All results met the predefined acceptance criteria for linearity." and "The linearity results support a claimed measuring range." |
| Endogenous Interferences | 200 pg/mL: ± 10% of unspiked reference value | Reported that "Predefined acceptance criterion was met." Claims included in the method sheet were set to the concentration without observed interference. |
| Exogenous Interferences - Drugs | ± 10% of the reference value (unspiked sample) | Reported that "No interference with the assay was found." for 16 commonly used pharmaceuticals. |
| Exogenous Interferences - Anticoagulants | Slope (Passing/Bablok): 0.9 – 1.1 Intercept (Passing/Bablok): 0.95 Intercept (Passing/Bablok): 200 pg/mL: ± 14 % | Study 1, 2, and 3: Recovery was calculated as percent of the reference value. (Implied to be met as no issues stated). |
| Calibrator Reconstitution (Signal Recovery) | 90 to 110 % signal recovery of the reference material value | Achieved. (Specific values not reported in summary, but stated as meeting criterion.) |
| Calibrator Stability (-20°C, 2-8°C, Onboard) (Signal Recovery) | 90 to 110 % signal recovery of the reference material value | Achieved. (Specific values not reported in summary, but stated as meeting criterion.) |
2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)
- Precision: Not explicitly stated as a separate "test set" sample size but evaluated using "human serum samples" (HS 1-5) and "PreciControl Varia" (PCV0-2). The protocol involved testing 2 replicates per run, 2 runs per day for 21 days for precision.
- Limit of Blank (LoB): n = 60 LoB measurements (5 replicates, 2 runs per day on 2 instruments over 3 days) using a buffered human serum albumin matrix.
- Limit of Detection (LoD): n = 60 LoD measurements (5 samples, 2 runs per day on 2 instruments over 3 days) using 5 low-level human serum samples.
- Limit of Quantitation (LoQ): Minimum of seven human serum samples, analyzed in replicates of 5, one run per day over 5 days.
- Linearity: Serum samples.
- Analytical Specificity: Two human serum samples (single donors, native) spiked with potential cross-reactant compounds.
- Endogenous Interferences: Three human serum samples (single donors, native as well as spiked) for each interfering substance.
- Exogenous Interferences - Drugs: Two human serum samples (single donors, native) spiked with 16 pharmaceutical compounds.
- Exogenous Interferences - Anticoagulants: Minimum of 90 serum/plasma pairs per sample material (single donors, native as well as spiked).
- Method Comparison: 120 human serum samples (all single donors, native as well as spiked) covering the entire measuring range.
- Reference Range Study: 120 apparently healthy male & female subjects. Data provenance: USA for sample collection, evaluation done at one site in Germany. Samples were native human serum samples.
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 is an in-vitro diagnostic (IVD) device for quantitative measurement of a biomarker (Vitamin B12). The "ground truth" for such devices is typically established through analytical methods and highly controlled reference materials, not through expert consensus on qualitative interpretation of images or clinical findings. The document does not describe the use of human experts to establish ground truth for this type of test.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set
Not applicable. As an IVD device, the performance is assessed through analytical validation studies (precision, linearity, accuracy against reference methods/materials) rather than human expert adjudication of results.
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 in-vitro diagnostic device for measuring Vitamin B12, not an imaging device or AI-assisted diagnostic tool that relies on human readers/interpreters.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
The device is a standalone in-vitro diagnostic assay (Elecsys Vitamin B12 II assay) intended to quantitatively measure Vitamin B12. Its performance is evaluated analytically, separate from human interpretation of the results for direct diagnostic decision-making, though the results contribute to a physician's overall diagnosis and treatment plan. The studies described (precision, linearity, LoB/LoD/LoQ, interference, method comparison) are all "standalone" evaluations of the device's analytical performance.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)
The ground truth for the analytical and method comparison studies is established based on:
- Reference methods/materials (e.g., specific calibrators, spiked samples with known concentrations, comparison to the legally marketed predicate device).
- Defined analytical standards and statistical methods (e.g., CLSI guidelines).
- The "value assignment" for calibrators is a key part of establishing the reference for the assay.
8. The sample size for the training set
This document does not describe a "training set" in the context of machine learning. The studies described are validation and verification studies for an analytical assay. The "Elecsys Vitamin B12 II CalSet" serves as a calibrator for the assay, analogous to the concept of a "calibration set" for an analytical instrument, but not a training set for an AI/ML algorithm.
9. How the ground truth for the training set was established
Not applicable as there is no "training set" in the machine learning sense. However, for the calibrator (Elecsys Vitamin B12 II CalSet), its "target values" are assigned to obtain the best fit with the Master Calibration Curve, using multiple analyzers (at least 3 cobas e 411 and at least 3 cobas e 601/MODULAR ANALYTICS E170 analyzers) and multiple reagent lots. The assigned value for each calibrator is the mean value obtained over at least six runs on at least three analyzers. PreciControl Varia is also used to monitor accuracy and precision of analytes, and acceptance criteria for these controls must be met to release the assigned values for the CalSet. This process establishes the "ground truth" for the calibrators.
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The ARCHITECT B12 assay is a chemiluminescent microparticle Intrinsic Factor assay for the quantitative determination of vitamin B12 in human serum on the ARCHITECT i System. Measurements obtained by this device are used in the diagnosis and treatment of anemias of gastrointestinal malabsorption.
The ARCHITECT B12 Controls are used for the estimation of test precision and the detection of systematic analytical deviations of the ARCHITECT i System when used for the quantitative determination of vitamin B12 in human serum when using the ARCHITECT B12 Reagent Kit.
The ARCHITECT B12 Calibrators are used to calibrate the ARCHITECT i System when the system is used for the quantitative determination of vitamin B12 in human serum using the ARCHITECT B12 Reagent Kit.
The ARCHITECT B12 assay is a two-step assay with an automated sample pretreatment, for determining the presence of B12 in human serum using chemiluminescent microparticle immunoassay (CMIA) technology with flexible assay protocols, referred to as Chemiflex.
Sample and Pre-Treatment Reagent 1, Pre-Treatment Reagent 2, and Pre-Treatment Reagent 3 are combined. An aliquot of the pre-treated sample is aspirated and transferred into a new reactions vessel (RV). The pre-treated sample, assay diluent, and intrinsic factor coated paramagnetic microparticles are combined. B12 present in the sample binds to the intrinsic factor coated microparticles. After washing, B12 acridinium-labeled conjugate is added in the second step. Pre-Trigger and Trigger Solutions are then added to the reaction mixture; the resulting chemiluminescent reaction is measured as relative light units (RLUs). An inverse relationship exists between the amount of B12 in the sample and the RLUs' detected by the ARCHITECT i System optics.
Acceptance Criteria and Device Performance Study for ARCHITECT B12 Assay
This document describes the acceptance criteria and the study conducted to demonstrate the substantial equivalence of the ARCHITECT B12 assay to a legally marketed predicate device.
1. Table of Acceptance Criteria and Reported Device Performance
The provided 510(k) summary does not explicitly state pre-defined acceptance criteria in terms of specific performance metrics (e.g., target accuracy, precision thresholds) that the ARCHITECT B12 assay needed to meet. Instead, the study aimed to demonstrate substantial equivalence to a predicate device. The performance was assessed through a comparison study.
| Performance Metric (Implied) | Reported Device Performance |
|---|---|
| Agreement with Predicate Device (Correlation) | Equivalence demonstrated using current commercially available Roche Elecsys E170 Vitamin B12 reagents with 172 patient samples covering the range of 83 pg/mL to 2000 pg/mL. |
Note: The 510(k) summary focuses on demonstrating equivalence rather than meeting specific numerical acceptance criteria for a new device type. The key acceptance was the FDA's determination of "substantial equivalence."
2. Sample Size and Data Provenance for the Test Set
- Sample Size: 172 patient samples.
- Data Provenance: Not explicitly stated, but based on the context of a medical device submission, these would typically be human serum samples. The geographical origin (e.g., country) is not specified. The study is implicitly retrospective as it involves testing archived patient samples against an existing predicate device.
3. Number of Experts and Qualifications for Ground Truth
- Number of Experts: Not applicable. The ground truth for this type of assay comparison is established by the results of the legally marketed predicate device, not by expert interpretation.
- Qualifications of Experts: Not applicable.
4. Adjudication Method for the Test Set
- Adjudication Method: Not applicable. The comparison is objective, based on quantitative measurements from two different assay systems, rather than subjective interpretation requiring adjudication.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- MRMC Study: No, an MRMC comparative effectiveness study was not done. This type of study is typically used for diagnostic imaging devices where human readers interpret images. The ARCHITECT B12 assay is a quantitative in-vitro diagnostic test.
- Effect Size of Human Reader Improvement with AI: Not applicable, as no MRMC study was performed.
6. Standalone (Algorithm Only) Performance Study
- Standalone Study: Yes, the study described is a standalone performance study in the context of an in-vitro diagnostic device. The ARCHITECT B12 assay's performance was evaluated independently by comparing its results to a predicate device, without direct human-in-the-loop interpretation of the assay results themselves. The "algorithm" here refers to the entire assay system and its methodology.
7. Type of Ground Truth Used
- Type of Ground Truth: The ground truth was established by the results obtained from the legally marketed predicate device, the Roche Elecsys E170 Vitamin B12 assay (K060755). This is considered the "gold standard" for comparison in demonstrating substantial equivalence for an in-vitro diagnostic device.
8. Sample Size for the Training Set
- Sample Size: The 510(k) summary does not provide specific details about a "training set" for the ARCHITECT B12 assay in the context of machine learning or AI. In the development of an in-vitro diagnostic, calibration and validation samples are used during the development and manufacturing process, but these are distinct from a "training set" in an AI/ML context. The information provided focuses on the pivotal study for regulatory submission.
9. How Ground Truth for the Training Set Was Established
- How Ground Truth Was Established (Training Set): As no specific training set in the AI/ML sense is described, the method for establishing its ground truth is not applicable in this document portion. For the overall assay, calibration materials are used, and their values are typically traceable to reference methods or primary standards, but this is a different concept than ground truth for a machine learning model.
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