(a) Identification. An anti-phospholipase A2 receptor immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the autoantibodies in human blood samples that react with phospholipase A2 receptor. The measurements aid in the diagnosis of primary membranous glomerulonephritis (pMGN), in conjunction with other laboratory and clinical findings.

(b) Classification. Class II (special controls). The special controls for this device are:

(1) Design verification and validation must include:

(i) A detailed description of the device that includes:

(A) A detailed description of all parts of the test system, including a description of the assay parts 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 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) A clinical performance assessment established by comparing data generated by testing samples from the intended use population and differential diagnosis groups with the device to the clinical diagnostic standard. Diagnosis of pMGN must be based primarily on clinical history, physical examination, laboratory tests (including urinalysis), and renal biopsy. Membranous glomerulonephritis is considered to be idiopathic/primary when no secondary cause can be elucidated on the basis of clinical and laboratory criteria. The differential diagnosis groups must include secondary membranous glomerulonephritis, membranoproliferative glomerulonephritis, lupus nephritis, focal segmental glomerulosclerosis, IgA nephritis, diabetic nephropathy, systemic lupus erythematosus, systemic sclerosis, and Goodpasture syndrome. Diagnosis of autoimmune and immune-mediated diseases that are associated with membranous glomerulonephritis must be based on established diagnostic criteria and clinical evaluation. For all samples, clinical criteria, including demographic information, must be considered in the differentiation between pMGN and secondary membranous glomerulonephritis. The clinical validation results must demonstrate correlation clinical sensitivity and clinical specificity between the test values and the presence or absence of pMGN. 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 a description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing.

(2) The label required under § 809.10(a) and labeling required under § 809.10(b) of this chapter must include warnings relevant to the assay including:

(i) A warning statement that explains: The device is for use by laboratory professionals in a clinical laboratory setting;

(ii) A warning statement that explains: The test is not a standalone test but an adjunct to other clinical information. A diagnosis of pMGN or secondary MGN should not be made based 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 primary versus secondary MGN;

(iii) A warning statement that explains: Absence of circulating PLA2R autoantibody does not rule out a diagnosis of pMGN; and

(iv) A warning statement that explains: The assay has not been demonstrated to be effective for monitoring the stage of disease or its response to treatment.

(3) The labeling required under § 809.10(b) of this chapter 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.