(270 days)
The Elecsys Toxo IgM immunoassay is for the in vitro qualitative detection of IgM antibodies to Toxoplasma gondii in human serum and plasma. This assay may be used as an aid in the diagnosis of an acute or recent Toxoplasma gondii infection in suspected patients and pregnant women. Patient testing must be performed in conjunction with an anti-Toxoplasma gondii IgG antibody assay. The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immuno-assay analyzers. This assay has not been cleared by the FDA for blood/plasma donor screening.
PreciControl Toxo IgM is used for quality control of the Elecsys Toxo IgM immunoassay on the Elecsys and cobas e immunoassay analyzers.
The Elecsys Toxo IgM is a two-step sandwich immunoassay with streptavidin microparticles and electrochemiluminescence detection. In the first incubation 10 uL of sample are automatically prediluted 1:20 with Elecsys Diluent Universal and T. gondii-specific recombinant antigen labeled with a ruthenium complex is added. Anti-Toxo IgM antibodies present in the sample react with the ruthenium-labeled T. gondii-specific recombinant antigen. Then biotinylated monoclonal human-IgM- specific antibodies and streptavidin-coated microparticles are added. The complex becomes bound to the solid phase via interaction of biotin and streptayidin. 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. Application of a voltage to the electrode then induces chemiluminescent emission which is measured by a photomultiplier. Results are determined automatically by the Elecsys software by comparing the electrochemiluminescence signal obtained from the reaction product of the sample with the signal of the cutoff value previously obtained by Toxo IgM calibration.
The provided document describes the Elecsys Toxo IgM Immunoassay, an in vitro qualitative test for the detection of IgM antibodies to Toxoplasma gondii. It details the performance evaluation supporting its substantial equivalence to a predicate device.
Here's an analysis of the acceptance criteria and study proving the device meets them:
1. Acceptance Criteria and Reported Device Performance
The acceptance criteria for substantial equivalence are not explicitly listed in a table format with numerical targets, as might be seen for a novel device. Instead, the document presents performance metrics and compares them to a predicate device and established CLSI protocols. The implicit acceptance criterion is that the Elecsys Toxo IgM assay demonstrates comparable performance (precision, reproducibility, and agreement with a predicate method for clinical samples) to the legally marketed predicate device, VIDAS TOXO IgM Test System (K923166), for its stated indications for use.
Below is a table summarizing the reported device performance:
| Performance Metric | Reported Device Performance (Elecsys Toxo IgM) |
|---|---|
| Precision | Repeatability (within-run): CV (%) range from 2.3% to 4.9% (Serum Pool 1 to 3). |
| Intermediate Precision (within-lab): CV (%) range from 3.2% to 5.2% (PC Toxo IgM 1 to Serum Pool 3). | |
| Reproducibility | Repeatability (within-site): CV (%) range from 1.9% to 4.0% (Serum Pool 1 to 3). |
| Intermediate Precision (within-lab): CV (%) range from 3.6% to 4.6% (Serum Pool 2 to 3). | |
| Between Site: CV (%) range from 3.3% to 13.0% (Serum Pool 2 to 1). | |
| Total Precision: CV (%) range from 4.9% to 13.6% (Serum Pool 2 to 1). | |
| Cross-reactivity | Tested 218 potentially cross-reacting samples. Most showed 0% cross-reactivity. Some observed cross-reactivity (Ama: 6.7%, EBV: 10%, HBV: 4.8%, Malaria: 8%, Rubella: 10%). Note: "Equivocal samples are counted as positive." |
| Matrix Equivalency | Evaluated serum/gel separation tubes, lithium heparin plasma, K2-EDTA plasma, and sodium citrate plasma. "All results met the acceptance criteria." (Specific criteria not detailed, but imply acceptable recovery compared to serum). |
| Hook Effect | "High-dose Hook effect does not lead to false-negative results." Demonstrated by diluting high-positive samples; results remained above the cutoff where expected. |
| Clinical Performance (Agreement with Predicate) | Study 1 (US Prospective, n=440): |
- Positive agreement: 66.7% (2/3)
- Negative agreement: 98.6% (431/437)
Study 2 (US Retrospective, n=60): - Positive agreement: NA (0/0)
- Negative agreement: 98.3% (59/60)
Study 3 (EU Prospective, General Population, n=101): - Positive agreement: 94.2% (81/86)
- Negative agreement: 50.0% (7/14)
Study 3 (EU Prospective, Pregnant Women, n=87): - Positive agreement: 93.2% (68/73)
- Negative agreement: 53.9% (7/13) |
| Interference | Unaffected by high concentrations of Bilirubin, Hemoglobin, Intralipid, and Biotin (within specified limits). No interference from rheumatoid factors (up to 3720 IU/mL) or 18 common pharmaceuticals. Noted potential interference from unspecific IgM and, in rare cases, high titers of antibodies to immunological components, streptavidin or ruthenium. |
2. Sample Sizes Used for the Test Set and Data Provenance
The "test set" in this context refers to the clinical samples used for performance evaluation against the predicate device.
- Study 1: 440 prospective specimens from a US reference laboratory.
- Study 2: 60 retrospective samples from a US commercial sample vendor.
- Study 3: 101 prospective samples from the general population in Europe. (87 of these were pregnant women).
Data Provenance:
- Country of Origin: US (Study 1 & 2), Europe (Study 3).
- Retrospective/Prospective: Mix of prospective (Studies 1 & 3) and retrospective (Study 2) samples.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document does not specify the number or qualifications of experts used to establish the ground truth. The "ground truth" for the clinical performance studies (Studies 1, 2, and 3) was established by comparison with a "FDA cleared method," specifically the VIDAS TOXO IgM Test System (K923166), which served as the reference method. This indicates that the predicate device's results were considered the de-facto ground truth for the comparison.
4. Adjudication Method for the Test Set
The document does not describe an explicit adjudication method beyond comparing the Elecsys Toxo IgM results to those of the predicate device. It notes that "Equivocals are counted as discrepant results against the Elecsys." in the agreement calculations, implying a direct comparison without a multi-reader or independent adjudication process for discordant 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
This is an in vitro diagnostic (IVD) assay, not an AI-assisted diagnostic imaging device or a decision support system for human readers. Therefore, an MRMC comparative effectiveness study involving human readers with and without AI assistance is not applicable to this type of device. The study evaluates the performance of the assay itself.
6. If a Standalone (i.e. algorithm only without human-in-the loop performance) Was Done
Yes, the studies presented are essentially standalone performance evaluations of the Elecsys Toxo IgM immunoassay. It's an automated test run on Elecsys and cobas e immunoassay analyzers, with results determined automatically by its software. The performance data (precision, reproducibility, cross-reactivity, matrix equivalency, hook effect, and agreement with the predicate) are purely those of the assay system without human interpretation as part of the primary diagnostic step. Human involvement would be in sample collection and loading onto the analyzer, and clinical interpretation of the final report.
7. The Type of Ground Truth Used
The ground truth for the clinical performance evaluation was established by a predicate device/reference method: the VIDAS TOXO IgM Test System (K923166). In the context of IVD assays, this is a common and accepted form of "ground truth" for demonstrating substantial equivalence. It's not pathology, outcomes data, or expert consensus in the typical sense of a human panel reviewing images, but rather the result from another validated, cleared assay.
8. The Sample Size for the Training Set
The document does not provide information on a separate "training set" or its size for the Elecsys Toxo IgM immunoassay. For IVD assays like this, the "training" (or development/optimization) phase involves extensive analytical studies (e.g., reagent formulation, calibration curve development, cutoff determination, specificity, sensitivity studies during R&D) rather than machine learning on a distinct training dataset. The established "Assay Cut-off" was likely derived from a large set of characterized samples during the development phase.
9. How the Ground Truth for the Training Set Was Established
Since there isn't an explicit "training set" described in the context of machine learning, the concept of establishing ground truth for it doesn't directly apply. However, the document states:
"The cut-off for the Elecsys Toxo IgM immunoassay was established by the use of sample collectives characterized with commercially available assays."
This indicates that the cutoff was determined based on a large collection of samples whose Toxoplasma gondii IgM status was characterized using other commercially available (presumably well-established reference or predicate) assays. This process is analogous to establishing ground truth for a development or training phase in IVD contexts. Specific details on the number of samples or the exact methodology of "characterization" are not provided but it implies a reference method was used.
§ 866.3780
Toxoplasma gondii serological reagents.(a)
Identification. Toxoplasma gondii serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies toToxoplasma gondii in serum. Additionally, some of these reagents consist of antisera conjugated with a fluorescent dye (immunofluorescent reagents) used to identifyToxoplasma gondii from clinical specimens. The identification aids in the diagnosis of toxoplasmosis caused by the parasitic protozoanToxoplasma gondii and provides epidemiological information on this disease. Congenital toxoplasmosis is characterized by lesions of the central nervous system, which if undetected and untreated may lead to brain defects, blindness, and death of an unborn fetus. The disease is characterized in children by inflammation of the brain and spinal cord.(b)
Classification. Class II (performance standards).