§ 866.3983 — SARS-CoV-2 serology test.

§ 866.3983 SARS-CoV-2 serology test.

(a) Identification. A SARS-CoV-2 serology test is a prescription in vitro diagnostic device for the detection of specific binding antibodies to SARS-CoV-2 in clinical specimens. The detection of SARS-CoV-2 antibodies is intended to aid in identifying individuals with an adaptive immune response to SARS-CoV-2. The test is not intended for the diagnosis of acute SARS-CoV-2 infection, nor screening blood, plasma, cells, or tissue donors.

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

(1) The intended use in the labeling required under § 809.10 of this chapter must include a description of the following: Analytes the device detects, the specimen types tested, the results provided to the end user, the clinical indications for which the test is to be used, the specific intended population(s), the intended use locations including testing location(s) where the device is to be used (if applicable), and other conditions of use, as appropriate.

(2) If sample collection devices are used, any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of specimen types claimed by this device; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.

(3) The labeling required under § 809.10(b) of this chapter must include:

(i) A detailed device description, including reagents, instruments, ancillary materials, all control elements, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens;

(ii) Detailed descriptions of the performance characteristics of the device for each specimen type claimed in the intended use based on analytical studies, including the following, as applicable: Assay cutoff or limit of detection expressed in international standard units, inclusivity, cross-reactivity, interfering substances, competitive inhibition, carryover and cross contamination, matrix equivalency, hook effect, specimen stability, precision, reproducibility, and clinical studies, including the time period in which the clinical performance was established and the variant(s) prevalent in the United States at the time of performance validation;

(iii) Detailed descriptions of the test procedure(s), the interpretation of test results for clinical specimens, and acceptance criteria for any quality control testing;

(iv) When applicable, performance results of the analytical study testing of a standardized reference material that FDA has determined is appropriate;

(v) Limiting statements that indicate:

(A) A negative test result does not preclude the possibility of infection;

(B) A negative result can occur if the quantity of the anti-SARS-CoV-2 antibodies present in the specimen is below the detection limits of the assay, or the antibodies that are detected are not present during the stage of disease in which a sample is collected;

(C) There is a risk of erroneous results (i.e., negative results) due to the presence of novel emerging viral variants circulating in the intended use population;

(D) The performance characteristics for that analyte were established when [insert predominant strain, subtype, or variant] was prevalent and that due to the propensity of the virus to mutate, new strains emerge over time which may affect the performance of this device and have serious public health implications;

(E) The test results should be interpreted in conjunction with other clinical and laboratory data available to the healthcare provider (as applicable);

(F) Positive and negative predictive values are highly dependent on prevalence;

(G) Accurate results are dependent on adequate specimen collection, transport, storage, and processing (as applicable). Failure to observe proper procedures in any one of these steps can lead to incorrect results;

(H) The test is not intended for donor screening; and

(I) The test is not intended to diagnose acute SARS-CoV-2 infection. An assay that directly detects the virus should be used to evaluate individuals for acute COVID-19, particularly those who have been in contact with the virus.

(vi) For devices intended for the quantitative detection of SARS-CoV-2 antibodies, labeling must include a prominent statement that includes the following: the test calibrators' traceability to a standardized reference material that FDA has determined is appropriate and the limit of blank, limit of detection, and limit of quantitation, with the defined analytical measuring interval.

(4) Design verification and validation must include:

(i) Detailed documentation of performance from a multisite clinical study with an appropriate number of clinical samples (i.e., be appropriately statistically powered) from individuals with recent or prior SARS CoV-2 infection in which the results are compared to results obtained from a comparator that FDA has determined to be appropriate. This study must be conducted in the appropriate laboratory setting to demonstrate clinical performance. For any SARS-CoV-2 serology test intended for use in near-patient settings, a separate clinical study must be conducted in near-patient settings. Documentation from these studies must include study reports with study description, testing results, and all statistical analyses, including an appropriate justification describing how the sample set is representative of the intended use population. These studies must compare the device performance to results obtained from a comparator that FDA has determined to be appropriate. These clinical studies must include testing of unique prospective samples from subjects that are representative of the intended use populations and may, when determined to be acceptable by FDA, include additional characterized clinical samples; or, as an alternative, when determined to be acceptable by FDA, an equivalent sample set;

(ii) For any SARS-CoV-2 antibody test intended for use in near-patient settings, detailed documentation that demonstrates the effectiveness of risk control measures and device robustness, including flex studies, and performance with weakly-reactive samples when used by the intended operators;

(iii) Risk analysis and documentation demonstrating how risk control measures are implemented to address device system hazards, such as failure modes effects analysis and hazard analysis. This documentation must include a detailed description of a protocol (including all procedures and methods) for the continuous monitoring, identification, and handling of genetic mutations and/or novel respiratory pathogen isolates or strains (e.g., regular review of published literature and periodic in silico analysis of target amino acid sequence(s) to detect possible mismatches) that may affect detection of antibody. All results of this protocol, including any findings, must be documented and must include any additional data analysis that is requested by FDA in response to any performance concerns identified under this section or identified by FDA during routine evaluation. Additionally, if requested by FDA, these evaluations must be submitted to FDA within 48 hours of the request for FDA review, and any results that are reasonably interpreted to support the conclusion that novel respiratory pathogen strains or isolates impact the stated expected performance of the device must be sent to FDA immediately to the email address provided in FDA's request;

(iv) Documentation of the specific amino acid sequence of the SARS-CoV-2 target protein(s) that the device utilizes to detect specific antibodies to SARS-CoV-2;

(v) A detailed device description, including device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including protein sequence target(s) for each analyte, design of target detection reagents, internal and external controls, and computational path from collected raw data to reported result (e.g., how collected raw signals are converted into a reported signal and result), as applicable to the detection method and device design;

(vi) For devices with associated software or instrumentation, documentation must include a detailed description of device software, including software applications and hardware-based devices that incorporate software. The detailed description must include documentation of verification, validation, and hazard analysis and risk assessment activities, including an assessment of the impact of threats and vulnerabilities on device functionality and end users and patients as part of cybersecurity review;

(vii) For devices intended for the detection of SARS-CoV-2 antibodies for which a standardized reference material (that FDA has determined is appropriate) is available, the performance results of an analytical study testing this standardized reference material. Detailed documentation of that study and its results must be provided, including the study protocol, study report, testing results, and all statistical analyses;

(viii) Detailed documentation of analytical studies conducted as appropriate to the technology, specimen types tested, and intended use of the device, including precision, endogenous interferences, cross reactivity, carryover, matrix equivalency, class specificity, hook effect, and sample and reagent stability. Samples selected for use in analytical studies or used to prepare contrived samples for use in analytical studies must be from subjects with clinically relevant circulating antibodies to SARS-CoV-2 in the United States. Cross-reactivity studies must include samples from SARS-CoV-2 antibody negative subjects with antibodies to viruses, high prevalence disease agents, and normal or pathogenic flora. Endogenous interference studies must include SARS-CoV-2 antibody negative and low positive samples with endogenous interference substances, including antibodies present in autoimmune diseases that are reasonably likely to be encountered in clinical specimens under actual use conditions. In addition, for devices intended for the quantitative detection of SARS-CoV-2 antibodies, the information provided must also include the metrological calibration traceability hierarchy to a standardized reference material that FDA has determined is appropriate. As appropriate to the technology and specimen types tested, the information provided to support quantitative tests must also include studies to support the analytical measuring interval, including a limit of blank study, a limit of detection study, an upper and lower limits of quantitation study, a precision study, and a linearity study using clinical samples, and, using a standardized reference material that FDA has determined is appropriate, an accuracy study;

(ix) Detailed documentation of data and protocols, including acceptance criteria, from a real-time reagent stability study must include testing of samples with adequately challenging analyte concentrations and must include shelf-life stability and shipping stability, and, as applicable, in-use and open-kit stability and freeze-thaw stability. The shelf-life stability assessment must include a minimum of three lots;

(x) Detailed documentation of a multisite reproducibility study with testing conducted at a minimum of three sites;

(xi) Final release criteria to be used for manufactured test lots with appropriate evidence that lots released at the extremes of the specifications will meet the claimed analytical and clinical performance characteristics as well as the stability claims; and

(xii) Lot-to-lot precision studies, as appropriate.

(5) For any SARS-CoV-2 antibody test intended for use in near-patient settings, labeling must also include a brief reference sheet (quick reference instructions) for the intended user(s) that includes, at a minimum, the name and intended use of the test, easy to follow step-by-step instructions of all control and sample testing procedures for the claimed sample types, including graphic illustrations targeted towards lay users (as applicable), the result(s) interpretation guidance, warnings and limitation statements, toxicology information and safety considerations for any hazardous materials, information for troubleshooting (e.g., frequently asked questions), and technical assistance with the device (e.g., helpline contact information).

(6) If one of the actions listed in section 564(b)(1)(A) through (D) of the Federal Food, Drug, and Cosmetic Act occurs with respect to one or more of the analytes claimed in the intended use, or if the Secretary of Health and Human Services determines, under section 319(a) of the Public Health Service Act, that a disease or disorder presents a public health emergency, or that a public health emergency otherwise exists, with respect to one or more of the analytes claimed in the intended use:

(i) Within 30 days from the date that FDA notifies manufacturers that characterized samples are available for test evaluation, the manufacturer must have testing performed on the device with those samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate; and

(ii) Within 60 days from the date that FDA notifies manufacturers that characterized samples are available for test evaluation and continuing until 3 years from that date, the results of the emergency analytical reactivity testing, including the detailed information for the samples tested as described in the certificate of authentication, must be included as part of the device's labeling in a tabular format.

[91 FR 38500, June 26, 2026]