Editorial Note on Part 866
Editorial Note: Nomenclature changes to part 866 appear at 73 FR 35341, June 23, 2008.

§ 866.5665 Aquaporin-4 autoantibody immunological test system. ( a ) *Identification.* An Aquaporin-4 autoantibody immunological test system is a device that consists of reagents used to measure by immunochemical techniques autoantibodies in human serum samples that react with Aquaporin-4 (AQP4Ab). The measurements aid in the diagnosis of neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorders (NMOSD) in conjunction with other clinical, laboratory, and radiological (*e.g.,* magnetic resonance imaging) 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 device description including: ( A ) A detailed description of all components including all required ancillary reagents in the test;
( B ) If applicable, a detailed description of instrumentation and equipment, including illustrations or photographs of non-standard equipment or manuals;
( C ) If applicable, detailed documentation of the device software, including, but not limited to, standalone software applications and hardware-based devices that incorporate software;
( 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 specified testing procedures;
( E ) Detailed specifications for sample collection, processing, and storage;
( F ) A detailed description of methodology and assay procedure;
( G ) A description of how the assay cutoff (the medical decision point between positive and negative) was established and validated as well as supporting data; and
( H ) Detailed specification of the criteria for test results interpretation and reporting.
( ii ) Detailed information demonstrating the performance characteristics of the device, including: ( A ) Device precision/reproducibility data generated from within-run, between-run, between-day, between-lot, between-site, and total precision for multiple nonconsecutive days, as applicable. A well characterized panel of patient samples or pools from the indicated population that covers the device measuring range must be used.
( B ) Device linearity data generated from samples covering the device 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 indications of use. A well-characterized panel of patient samples from the indicated 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 well-characterized patient samples covering the device measuring range.
( K ) Clinical performance must be established by comparing data generated by testing samples from the indicated population and the differential diagnosis or non-target disease groups with the device to the clinical diagnostic standard. ( 1 ) The diagnosis of NMO and NMOSD must be based on clinical findings, laboratory tests (*e.g.,* serological tests), and radiological tests (*e.g.,* magnetic resonance imaging).
( 2 ) The differential diagnosis or non-target disease group must include the applicable diseases or conditions, including but not be limited to the following: Multiple sclerosis, stroke, Lyme disease, shingles, syphilis, human immunodeficiency virus, hepatitis B, tuberculosis, Srgen's syndrome, systemic lupus erythematous, systemic vasculitis, sarcoidosis, Graves' disease, Hashimoto's disease, Type I diabetes, rheumatoid arthritis, Addison's disease, and myasthenia gravis.
( 3 ) Diagnosis of diseases or conditions for the differential or non-target disease groups must be based on established diagnostic criteria and clinical evaluation.
( 4 ) For all samples, the diagnostic clinical criteria and the demographic information must be collected and provided.
( 5 ) The clinical validation results must demonstrate clinical sensitivity and clinical specificity for the test values based on the presence or absence of NMO and NMOSD.
( 6 ) The data must be summarized in tabular format comparing the interpretation of results to the disease status.
( L ) 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 ) The device's 21 CFR 809.10(b) compliant labeling must include warnings relevant to the device including: ( i ) A warning statement that reads “The device is for use by laboratory professionals in a clinical laboratory setting”; and
( ii ) A warning statement that reads “The device is not to be used as a stand-alone device but as an adjunct to other clinical information. A diagnosis of Neuromyelitis Optica (NMO) and Neuromyelitis Optica Spectrum Disorders (NMOSD) should not be made on a single test result. The clinical symptoms, results from physical examination, laboratory tests (*e.g.,* serological tests), and radiological tests (*e.g.* Magnetic Resonance Imaging), when appropriate, should always be taken into account when considering the diagnosis of NMO and NMOSD.”
( 3 ) The device's 21 CFR 809.10(b) compliant labeling must include a detailed description of the protocol and performance studies performed in accordance with paragraph (b)(1)(ii) of this section and a summary of the results.
[82 FR 50076, Oct. 30, 2017]