(263 days)
An enzyme linked immunoassay (ELISA) for the qualitative or semi-quantitative detection of anti-RNA POL III IgG antibodies in human serum as an aid in diagnosis of systemic scleroderma) in conjunction with other laboratory and clinical findings.
An enzyme linked immunoassay (ELISA) for the qualitative or semi-quantitative detection of anti-RNA POL III IgG antibodies in human serum as an aid in diagnosis (scleroderma) in conjunction with other laboratory and clinical findings. This test is performed as a solid phase immunoassay. Microwells are coated with recombinant RNA POLIII antigen. Controls, calibrators and patient sera are incubated in the antigen coated wells to allow specific antibodies present in the RNA POL III antigen. Bound antibodies are detected by adding an enzyme labeled anti-human IgG conjugate. Specific enzyme substrate (TMB) is then added and the presence of antibodies is detected by a spectrophotometer at 450 nm. Results are expressed in ELISA units per milliliter (EU/ml) and reported as positive or negative.
Here's an analysis of the provided text to extract the acceptance criteria and study details:
1. Table of Acceptance Criteria and Reported Device Performance:
The document doesn't explicitly state "acceptance criteria" in a formal table format with target performance values. Instead, it presents various performance characteristics and their corresponding results. I will infer the acceptance criteria from the reported performance, implying that these results met the manufacturer's internal criteria for substantial equivalence.
| Performance Characteristic | Acceptance Criterion (Inferred) | Reported Device Performance |
|---|---|---|
| Method Comparison (Qualitative - Borderline considered positive) | Sufficient agreement with predicate device (INOVA QUANTA Lite™ RNA POL III ELISA) for Positive, Negative, and Overall. | Positive Percent Agreement: 96.2% (95% Cl 85.7% - 99.3%) |
| Negative Percent Agreement: 99.4% (95% CI 97.8% - 99.9%) | ||
| Overall Agreement: 99.0% (95% Cl 97.8% - 99.7%) | ||
| Method Comparison (Qualitative - Borderline considered negative) | Sufficient agreement with predicate device (INOVA QUANTA Lite™ RNA POL III ELISA) for Positive, Negative, and Overall. | Positive Percent Agreement: 78.8% (95% Cl 64.9% - 88.4%) |
| Negative Percent Agreement: 99.7% (95% Cl 98.2% - 100.0%) | ||
| Overall Agreement: 97.1% (95% Cl 95.0% - 98.3%) | ||
| Cross-Reactivity (Specificity) | Low positivity rate in various autoimmune and infectious disease control populations and cancer patients. Minimal reactivity outside of Systemic Sclerosis (SSc). | Percent Positive for various control populations detailed in the "Cross Reactivity" table (e.g., SLE: 0.0%, Sjögren's: 0.0%, HSV-1: 0.0%, etc.). |
| Some minor reactivity noted (e.g., Myositis: 2.5%, Rheumatoid arthritis: 2.5%, Hepatitis C: 5.0%, Breast Cancer: 14.3%, Psoriasis: 11.1%). | ||
| Precision (Total Imprecision CV%) | Acceptable variability (CV%) across different concentrations. | Ranged from 4.4% to 7.8% (for EU/ml values from 10.0 to 159.0) |
| Reproducibility (Qualitative Agreement) | High qualitative agreement, especially for samples not near the cutoff. | Cutoff specimen: 60% agreement |
| ~20% above cutoff: 98% agreement | ||
| All other specimens: 100% agreement | ||
| Limit of Detection (LoD) | Low enough to detect relevant low levels of analyte. | 3.2 EU/ml |
| Linearity and Recovery | Demonstrated linearity and acceptable recovery across the assay's reportable range. | Test Range 2.5 to 33.5: Slope 1.02, R^2 0.9943, Recovery 96% to 117% |
| Test Range 8.0 to 66.1: Slope 0.98, R^2 0.9987, Recovery 97% to 109% | ||
| Test Range 31.8 to 169.5: Slope 0.99, R^2 0.9890, Recovery 91% to 103% | ||
| Interference | No significant interference from common substances at specified levels. | No significant interference demonstrated for a list of 16 substances. |
| Clinical Sensitivity (Systemic Sclerosis) | Clinically relevant sensitivity for Systemic Sclerosis. | 23.1% (95% C.I. 18.4-28.6%) |
| Clinical Specificity (Systemic Sclerosis) | High clinical specificity for Systemic Sclerosis. | 98.2% (95% C.I. 96.6-99.1%) |
2. Sample sizes used for the test set and the data provenance:
- Method Comparison Test Set: 413 samples (52 positive, 361 negative, based on the predicate device).
- Data Provenance: "well-characterized systemic sclerosis subjects and disease controls." The country of origin is not specified but implicitly North America (given the US FDA submission). Retrospective, as these were "well-characterized" samples.
- Cross-Reactivity Test Set:
- Systemic Sclerosis (SSc): 281 samples
- Diffuse cutaneous SSc (dcSSc): 105 samples
- Limited cutaneous SSc (lcSSc): 176 samples
- Various autoimmune and infectious disease controls, and cancer patients: 549 samples in total across 22 different categories (sample sizes per category detailed in the table, e.g., SLE: 40, Sjögren's: 41, etc.).
- Data Provenance: Clinical samples. Country of origin not specified. Retrospective, as they were "sets of clinical samples" collected and tested.
- Clinical Study Test Set:
- 281 systemic sclerosis samples
- 549 autoimmune and infectious disease controls (the same breakdown as the Cross-Reactivity section).
- Data Provenance: Clinical samples. Country of origin not specified. Retrospective.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
The document does not specify the number of experts or their qualifications for establishing the ground truth for any of the test sets. For the "Method Comparison," it refers to "well-characterized systemic sclerosis subjects and disease controls," implying a clinical diagnosis as the ground truth, likely established by medical professionals. For "Cross Reactivity" and "Clinical Study," it refers to "clinical samples" and "autoimmune and infectious disease controls," which implicitly means ground truth was based on established clinical diagnoses.
4. Adjudication method for the test set:
Not explicitly stated. Given that the ground truth for method comparison relied on a predicate device and for cross-reactivity/clinical study on "clinical samples" and "disease controls," it's highly probable that the ground truth was established by clinical diagnosis, which often involves a consensus among treating physicians or established diagnostic criteria rather than a dedicated adjudication process for the purpose of this study.
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 device is an in-vitro diagnostic (IVD) ELISA test, not an AI-powered image analysis or diagnostic support tool for human readers. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance is not applicable to this type of device and was not performed or reported.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
This device is a standalone in-vitro diagnostic test. Its performance metrics (sensitivity, specificity, agreement with predicate, precision, etc.) are all based on its own intrinsic performance, without any human-in-the-loop interpretation impacting these reported analytical and clinical performance characteristics. So, yes, a standalone performance was done for the device itself.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- Method Comparison Test Set: The ground truth was based on the performance of a legally marketed predicate device, the INOVA QUANTA Lite™ RNA POL III ELISA, and "well-characterized systemic sclerosis subjects and disease controls," implying clinical diagnosis.
- Cross-Reactivity and Clinical Study Test Sets: The ground truth was based on the clinical diagnosis of the patients from whom the samples were obtained ("Systemic sclerosis," "Systemic lupus erythematosus," "Sjögren's syndrome," etc.), and the characterization of "autoimmune and infectious disease controls." This points to clinical diagnosis (and possibly expert medical consensus) as the ground truth.
8. The sample size for the training set:
The document does not explicitly mention a "training set" in the context of device development. Given that this is an ELISA kit, which is a chemical assay, it does not typically involve machine learning algorithms that require distinct training and test sets in the same way an AI-driven device would. The development samples and internal validation studies would likely fall under what could be considered "training" or optimization, but a specific "training set" size is not reported as it would be for an AI model.
9. How the ground truth for the training set was established:
As mentioned above, a formal "training set" as understood in AI/ML contexts is not directly applicable here. The development and optimization of the ELISA assay would typically involve extensive testing with known positive and negative controls, and clinical samples previously characterized by established diagnostic methods (e.g., other validated tests, clinical diagnosis) to refine the assay parameters (e.g., antibody concentrations, incubation times, cutoff values). This characterization would rely on standard clinical diagnostic practices and existing reference methods.
§ 866.5100 Antinuclear antibody immunological test system.
(a)
Identification. An antinuclear antibody immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the autoimmune antibodies in serum, other body fluids, and tissues that react with cellular nuclear constituents (molecules present in the nucleus of a cell, such as ribonucleic acid, deoxyribonucleic acid, or nuclear proteins). The measurements aid in the diagnosis of systemic lupus erythematosus (a multisystem autoimmune disease in which antibodies attack the victim's own tissues), hepatitis (a liver disease), rheumatoid arthritis, Sjögren's syndrome (arthritis with inflammation of the eye, eyelid, and salivary glands), and systemic sclerosis (chronic hardening and shrinking of many body tissues).(b)
Classification. Class II (performance standards).