(65 days)
The KRONUS Zinc Transporter 8 Autoantibody (ZnT8Ab) ELISA Assay is for the semi-quantitative determination of autoantibodies to Zinc Transporter 8 (ZnT8) in human serum. The KRONUS Zinc Transporter 8 Autoantibody (ZnT8Ab) ELISA Assay may be useful as an aid in the diagnosis of Type 1 diabetes mellitus (autoimmune mediated diabetes). The ZnT8Ab assay is not to be used alone and is to be used in conjunction with other clinical and laboratory findings.
The KRONUS Zinc Transporter 8 Autoantibody (ZnT8Ab) ELISA Assay contains the following: strip wells coated with ZnT8 (96 wells in total) and supplied as 12 strips of 8 wells in a frame and sealed in a foil bag with desiccant; ready-to-use 4 levels of calibrators (10, 20, 75, and 500 U/mL, 5x0.7 mL each); one each ready-to-use positive I, positive II and negative control serum (1x0.7 mL); Zinc T8 Biotin (lyophilized) 3x5.5 mL (reconstituted); ready-to-use reconstitution buffer for Zinc T8 Biotin 2x15 mL (colored red); Streptavidin Peroxidase (SA-POD dilute before use) 1x0.7 mL; ready-to-use diluent for SA-POD 1x15 mL; ready-to-use peroxidase substrate (TMB) 1x15 mL; concentrated wash solution (dilute with deionized water before use) 1x125 mL and ready-to-use stop solution 1x12 mL.
Here's a summary of the acceptance criteria and the study that proves the device meets them, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance:
The document doesn't explicitly state "acceptance criteria" as a separate, pre-defined set of thresholds that the device must meet. Instead, it describes performance characteristics that were evaluated and determined to be acceptable for classification. The "clinical validation results must demonstrate clinical sensitivity and clinical specificity for the test values based on the presence or absence of Type 1 diabetes mellitus." The benefits and risks section effectively summarizes what was found and deemed acceptable.
Therefore, the table below reflects the presented clinical performance data which, given the overall conclusion, can be interpreted as the device meeting the implied acceptance criteria.
| Performance Characteristic | Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|---|
| Clinical Sensitivity | Sufficiently high to aid in diagnosis, especially when other autoantibodies are negative. | 68% (95% CI: 63-73%) |
| Clinical Specificity | Sufficiently high to minimize false positives. | 98% (95% CI: 95-99%) |
| Overall Agreement | - | 81% (95% CI: 76-85%) |
| False Negative Risk | Mitigated by companion use. | 32% |
| False Positive Risk | Low | 2% |
| Intra-assay %CV | Low | 1.7-5.6% |
| Inter-assay %CV | Low | 2.9-17.7% |
| Lot-to-lot %CV | Low | 7.6-9.2% |
| Linearity Range | Appropriate for clinical use | 7.0 to 485 U/mL |
| Limit of Blank (LoB) | Low | 2.1 U/mL |
| Limit of Detection (LoD) | Low | 5.6 U/mL |
| Cut-off | Established based on healthy population. | >= 15 U/mL (positive) |
2. Sample Size Used for the Test Set and Data Provenance:
- Test Set Sample Size: 569 clinically defined patient samples.
- 323 patients with Type 1 diabetes mellitus (T1D).
- 246 patients from non-target disease groups (60 Type 2 diabetes mellitus, and 186 other autoimmune/medical conditions).
- Data Provenance: Not explicitly stated regarding country of origin. The study appears to be retrospective, as the patients were "clinically defined" with existing diagnoses.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Their Qualifications:
The document does not specify the number of experts or their qualifications for establishing the ground truth for the clinical sample diagnoses. It simply states that the "diagnosis of Type 1 diabetes mellitus must be based on clinical history, physical examination, and laboratory tests, such as one or more pancreatic or insulin autoantibody test." Similarly, "Diseases for the differential groups must be based on established diagnostic criteria and clinical evaluation."
4. Adjudication Method for the Test Set:
The document does not describe an adjudication method for establishing the ground truth diagnoses for the clinical test set. It refers to diagnoses being "clinically defined" or based on "established diagnostic criteria and clinical evaluation."
5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done:
No, an MRMC comparative effectiveness study was not done. This study assesses the standalone performance of the KRONUS Zinc Transporter 8 Autoantibody ELISA Assay. The device is intended to be used "in conjunction with other clinical and laboratory findings," but its performance is evaluated in isolation against clinical diagnoses.
6. If a Standalone Performance Study Was Done:
Yes, a standalone study was done. The performance characteristics (sensitivity, specificity) presented for the KRONUS ZnT8Ab ELISA Assay are based on the device's output alone compared to the clinical diagnoses of the 569 patient samples.
7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.):
The ground truth for the test set was clinical diagnosis, based on:
- "clinical history, physical examination, and laboratory tests, such as one or more pancreatic or insulin autoantibody test" for Type 1 diabetes mellitus.
- "established diagnostic criteria and clinical evaluation" for the differential diagnosis groups.
This can be categorized as a form of clinical diagnosis/expert assessment, although the involvement of specific "experts" is not detailed.
8. The Sample Size for the Training Set:
The document does not explicitly mention a separate "training set" for the development of the assay's core diagnostic algorithm (e.g., how the assay generates its U/mL values). The closest approximation to a "training" or "development" process is the determination of the assay cut-off.
- Assay Cut-off Determination: The cut-off of 15 U/mL was determined by testing 397 US healthy blood donors. This can be considered the dataset used to establish the "normal" range and thus define the threshold for a positive result.
9. How the Ground Truth for the Training Set Was Established:
For the assay cut-off determination:
- Ground Truth: The 397 individuals were identified as "healthy blood donors." This implies their healthy status was the ground truth against which the assay results were compared to set the cut-off.
- Method: 99% (394/397) of these healthy individuals were negative for ZnT8Ab. The mean and SD of results from these donors were used to establish the cut-off, with the goal of identifying 99th percentile or similar for negatives.
§ 866.5670 Zinc transporter 8 autoantibody immunological test system.
(a)
Identification. A zinc transporter 8 autoantibody immunological test system is a device that consists of reagents used to measure, by immunochemical techniques, the autoantibodies in human serum samples that react with Zinc Transporter 8 (ZnT8). The measurements aid in the diagnosis of Type 1 diabetes mellitus (autoimmune mediated diabetes) in conjunction with other clinical and laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include the following information:
(i) A detailed description of the device that includes:
(A) A detailed description of all components in the test system, including a description of the assay components in the kit and all required ancillary reagents;
(B) A detailed description of instrumentation and equipment, and illustrations or photographs of non-standard equipment or methods if applicable;
(C) Detailed documentation of the device software, including, but not limited to, standalone software applications and hardware-based devices that incorporate software where applicable;
(D) A detailed description of appropriate internal and external quality controls that are recommended or provided. The description must identify those control elements that are incorporated into the recommended testing procedures;
(E) Detailed specifications for sample collection, processing, and storage;
(F) A detailed description of methodology and assay procedure; and
(G) Detailed specification of the criteria for test results interpretation and reporting.
(ii) Information that demonstrates the performance characteristics of the device, including:
(A) Device precision/reproducibility data generated from within-run, between-run, between-day, between-lot, between-operator, between-instruments, between-site, and total precision for multiple nonconsecutive days as applicable. A well characterized panel of patient samples or pools from the intended use population that covers the device measuring range must be used;
(B) Device linearity data generated from patient samples covering the assay measuring range if applicable;
(C) Information on traceability to a reference material and description of value assignment of calibrators and controls if applicable;
(D) Device analytical sensitivity data, including limit of blank, limit of detection and limit of quantitation if applicable;
(E) Device analytical specificity data, including interference by endogenous and exogenous substances, as well as cross-reactivity with samples derived from patients with other autoimmune diseases or conditions;
(F) Device instrument carryover data when applicable;
(G) Device stability data including real-time stability under various storage times and temperatures;
(H) Specimen stability data, including stability under various storage times, temperatures, freeze-thaw, and transport conditions where appropriate;
(I) Method comparison data generated by comparison of the results obtained with the device to those obtained with a legally marketed predicate device with similar indication of use. Patient samples from the intended use population covering the device measuring range must be used;
(J) Specimen matrix comparison data if more than one specimen type or anticoagulant can be tested with the device. Samples used for comparison must be from patient samples covering the device measuring range;
(K) A description of how the assay cut-off (the medical decision point between positive and negative) was established and validated as well as supporting data;
(L) Clinical performance must be established by comparing data generated by testing samples from the intended use population and the differential diagnosis groups with the device to the clinical diagnostic standard. The diagnosis of Type 1 diabetes mellitus must be based on clinical history, physical examination, and laboratory tests, such as one or more pancreatic or insulin autoantibody test. Because the intended use population for Type 1 diabetes mellitus includes subjects less than 18 years old, samples from representative numbers of these subjects must be included. Representative numbers of samples from all age strata must also be included. The differential diagnosis groups must include, but not be limited to the following: Type 2 diabetes mellitus; metabolic syndrome; latent autoimmune diabetes in adults; other autoimmune diseases such as celiac disease (without a concomitant diagnosis of Type 1 diabetes mellitus), systemic lupus erythematosus, rheumatoid arthritis, and Hashimoto's thyroiditis; infection; renal disease; and testicular cancer. Diseases for the differential groups must be based on established diagnostic criteria and clinical evaluation. For all samples, the diagnostic clinical criteria and the demographic information must be collected and provided. The clinical validation results must demonstrate clinical sensitivity and clinical specificity for the test values based on the presence or absence of Type 1 diabetes mellitus. The data must be summarized in tabular format comparing the interpretation of results to the disease status; and
(M) Expected/reference values generated by testing an adequate number of samples from apparently healthy normal individuals.
(iii) Identification of risk mitigation elements used by the device, including description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing.
(2) Your 21 CFR 809.10(a) compliant label and 21 CFR 809.10(b) compliant labeling must include warnings relevant to the assay including:
(i) A warning statement that reads, “The device is for use by laboratory professionals in a clinical laboratory setting”;
(ii) A warning statement that reads, “The test is not a stand-alone test but an adjunct to other clinical information. A diagnosis of Type 1 diabetes mellitus should not be made on a single test result. The clinical symptoms, results on physical examination, and laboratory tests (
e.g., serological tests), when appropriate, should always be taken into account when considering the diagnosis of Type 1 diabetes mellitus and Type 2 diabetes mellitus”;(iii) A warning statement that reads, “Absence of Zinc T8 autoantibody does not rule out a diagnosis of Type 1 diabetes mellitus”; and
(iv) A warning statement that reads, “The assay has not been demonstrated to be effective for monitoring the stage of disease or its response to treatment.”
(3) Your 21 CFR 809.10(b) compliant labeling must include a description of the protocol and performance studies performed in accordance with paragraph (b)(1)(ii) of this section and a summary of the results.