(a) Identification. Human immunodeficiency virus (HIV) serological diagnostic and supplemental tests are prescription devices for the qualitative detection of HIV antigen(s) and/or detection of antibodies against HIV in human body fluids or tissues. The tests are intended for use as an aid in the diagnosis of infection with HIV and are for professional use only. The test results are intended to be interpreted in conjunction with other relevant clinical and laboratory findings. These tests are not intended to be used for monitoring patient status, or for screening donors of blood or blood products, or human cells, tissues, and cellular and tissue-based products (HCT/Ps).

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

(1) For all HIV serological diagnostic and supplemental tests

(i) The labeling must include:

(A) An intended use that states that the device is not intended for use for screening donors of blood or blood products or HCT/Ps.

(B) A detailed explanation of the principles of operation and procedures used for performing the assay.

(C) A detailed explanation of the interpretation of results and recommended actions to take based on results.

(D) Limitations, which must be updated to reflect current clinical practice and disease presentation and management. The limitations must include, but are not limited to, statements that indicate:

(1) The matrices with which the device has been cleared, and that use of this test kit with specimen types other than those specifically cleared for this device may result in inaccurate test results.

(2) The test is not intended to be used to monitor individuals who are undergoing treatment for HIV infection.

(3) A specimen with a reactive result should be investigated further following current guidelines.

(4) All test results should be interpreted in conjunction with the individual's clinical presentation, history, and other laboratory results.

(5) A test result that is nonreactive does not exclude the possibility of exposure to or infection with HIV. Nonreactive results in this assay may be due to analyte levels that are below the limit of detection of this assay.

(ii) Device verification and validation must include:

(A) Detailed device description, including the device components, ancillary reagents required but not provided, and an explanation of the methodology. Additional information appropriate to the technology must be included, such as the amino acid sequence of antigen(s) and design of capture antibodies.

(B) For devices with assay calibrators, the design of all primary, secondary, and subsequent quantitation standards used for calibration as well as their traceability to a reference material. In addition, analytical testing must be performed following the release of a new lot of the standard material that was used for device clearance, or when there is a transition to a new calibration standard.

(C) Detailed documentation of analytical performance studies conducted as appropriate to the technology, specimen types tested, and intended use of the device, including, but not limited to, limit of blank, limit of detection, cutoff determination, precision, endogenous and exogenous interferences, cross reactivity, carryover, quality control, matrix equivalency, and sample and reagent stability. Samples selected for use in analytical studies or used to prepare samples for use in analytical studies must be from subjects with clinically relevant circulating genotypes in the United States.

(D) Multisite reproducibility study that includes the testing of three independent production lots.

(E) Analytical sensitivity of the test must be the same as or better than that of other cleared or approved tests. Samples tested must include appropriate numbers and types of samples, including real clinical samples near the lower limit of detection. Analytical specificity of the test must be the same as or better than that of other cleared or approved tests. Samples must include appropriate numbers and types of samples from patients with different underlying illnesses or infections and from patients with potential endogenous interfering substances.

(F) Detailed documentation of performance from a multisite clinical study. Performance must be analyzed relative to an FDA-cleared or approved comparator. This study must be conducted using patient samples, with an appropriate number of HIV positive and HIV negative samples in applicable risk categories. Additional subgroups or types must be validated using appropriate numbers and types of samples. The samples may be a combination of fresh and repository samples, sourced from within and outside the United States, as appropriate. The study designs, including number of samples tested, must be sufficient to meet the following criteria:

(1) Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 99 percent.

(2) Clinical specificity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 99 percent.

(G) Strategies for detection of new strains, types, subtypes, genotypes, and genetic mutations as they emerge.

(H) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on test performance.

(I) 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.

(J) All stability protocols, including acceptance criteria.

(K) Appropriate and acceptable procedure(s) for evaluating customer complaints and other device information that determines when to submit a medical device report.

(L) Premarket notification submissions must include the information contained in paragraph (b)(1)(ii)(A) through (K) of this section.

(iii) Manufacturers must submit a log of all complaints. The log must include the following information regarding each complaint if available: The type of event (e.g., false negative/false nonreactive or false positive/false reactive), lot, date, population, and whether or not the complaint was reported under part 803 of this chapter (Medical Device Reporting). The log must be submitted annually on the anniversary of clearance for 5 years following clearance of a traditional premarket notification.

(2) If the test is intended for Point of Care (PoC) use, the following special controls, in addition to those listed in paragraph (b)(1) of this section apply:

(i) The PoC labeling must include a statement that the test is intended for PoC use.

(ii) The PoC labeling must include the following information near the statement of the intended use:

(A) That the test is for distribution to clinical laboratories that have an adequate quality assurance program, including planned systematic activities that provide adequate confidence that requirements for quality will be met and where there is assurance that operators will receive and use the instructional materials.

(B) That the test is for use only by an agent of a clinical laboratory.

(C) Instructions for individuals to receive the “Subject Information Notice” prior to specimen collection and appropriate information when test results are provided.

(iii) PoC labeling must include instructions to follow current guidelines for informing the individual of the test result and its interpretation.

(iv) The instructions in the labeling must state that reactive results are considered preliminary and should be confirmed following current guidelines.

(v) Device verification and validation for PoC use must include:

(A) Detailed documentation of performance from a multisite clinical study conducted at appropriate PoC sites. Performance must be analyzed relative to an FDA cleared or approved comparator. This study must be conducted using patient samples, with appropriate numbers of HIV positive and HIV negative samples in applicable risk categories. Additional subgroup or type claims must be validated using appropriate numbers and types of samples. The samples may be a combination of fresh and repository samples, sourced from within and outside the United States, as appropriate. If the test is intended solely for PoC use, the test must meet only the performance criteria in paragraphs (b)(2)(v)(A)(1) and (2) of this section and not the criteria in paragraph (b)(1)(ii)(F) of this section:

(1) Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 98 percent.

(2) Clinical specificity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 98 percent.

(B) Premarket notification submissions must include the information contained in paragraph (b)(2)(v)(A) of this section.

(3) If the test is intended for supplemental use in addition to use as an aid in initial diagnosis, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, as appropriate, apply:

(i) The labeling must include a statement that the test is intended for use as an additional test to confirm the presence of HIV antibodies or antigens in specimens found to be repeatedly reactive by a diagnostic screening test.

(ii) Device validation and verification for supplemental use must include a clinical study, including samples that were initially reactive and repeatedly reactive on a diagnostic test but were negative or indeterminate on a different confirmatory test. Premarket notification submissions must include this information.

(4) If the test is intended solely as a supplemental test, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, except those in paragraphs (b)(1)(ii)(F) and (b)(2)(v)(A) of this section, as appropriate, apply:

(i) The labeling must include a statement that the test is intended for use as an additional test to confirm the presence of HIV antibodies or antigens in specimens found to be repeatedly reactive by a diagnostic screening test.

(ii) The labeling must clearly state that the test is not for use for initial diagnosis or is not intended as a first-line test.

(iii) Device validation and verification must include a clinical study including samples that were initially reactive and repeatedly reactive on a diagnostic test but were negative or indeterminate on a confirmatory test. Premarket notification submissions must include this information.

(5) If the test is intended to differentiate different HIV types, the following special controls, in addition to those listed in paragraphs (b)(1) through (4) of this section, as appropriate, apply:

(i) The labeling must include the statement that the test is intended for the confirmation of initial results from a diagnostic test and differentiation of different HIV types.

(ii) The results interpretation in the labeling must include instructions for the user on how to interpret the results, including un-typeable and co-infection results.

(iii) Device validation and verification must include evaluation of analytical and clinical sensitivity and specificity for each of the HIV types, strains, and subtypes of HIV intended to be differentiated. Premarket notification submissions must include this information.

[87 FR 29665, May 16, 2022]