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66172

Federal Register / Vol. 86, No. 222 / Monday, November 22, 2021 / Rules and Regulations
available at https www.fda.gov/
downloads/AdvisoryCommittees/
CommitteesMeetingMaterials/
BloodVaccinesandOtherBiologics/
BloodProductsAdvisoryCommittee/
UCM630139.pdf.

List of Subjects in 21 CFR Part 866
Biologics, Laboratories, Medical devices.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under authority delegated to the Commissioner of Food and Drugs, 21 CFR part 866 is amended as follows:
PART 866IMMUNOLOGY AND
MICROBIOLOGY DEVICES
1. The authority citation for part 866
continues to read as follows:

Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.

2. Add 866.3170 to subpart D to read as follows:

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866.3170 Nucleic acid-based hepatitis C
virus ribonucleic acid tests.

a Identification. A nucleic acidbased hepatitis C virus HCV
ribonucleic acid RNA test is identified as an in vitro diagnostic device intended for prescription use as an aid in the diagnosis of HCV infection in specified populations, and/or as an aid in the management of HCV-infected patients including guiding the selection of genotype-specific treatment in individuals with chronic HCV infection.
The test is intended for use with human serum or plasma. The test is not intended for use as a donor screening test for the presence of HCV antibodies in blood, blood products, or tissue donors.
b Classification. Class II special controls. The special controls for this device are:
1 For all nucleic acid-based HCV
RNA tests, the labeling required under 809.10b of this chapter must include:
i A prominent statement that the test is not intended for use as a donor screening test for the presence of HCV
RNA from human cells, tissues, and cellular and tissue-based products.
ii A detailed explanation of the principles of operation and procedures for performing the assay.
iii A detailed explanation of the interpretation of results.
iv Limitations, which must be updated to reflect current clinical practice and disease presentation and management. These limitations must include, but are not limited to, statements that indicate:
A The specimen types for which the device has been cleared and that use of
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this test kit with specimen types other than those specifically cleared for this device may result in inaccurate test results.
B When applicable, that assay performance characteristics have not been established in populations of immunocompromised or immunosuppressed patients or, other populations where test performance may be affected.
C Test results are to be interpreted by qualified licensed healthcare professionals in conjunction with the individuals clinical presentation, history, and other laboratory results.
2 For all nucleic acid-based HCV
RNA tests, the design verification and validation must include:
i Detailed device description, including the device components, ancillary reagents required but not provided, and an explanation of the device methodology. Additional information appropriate to the technology must be included such as design of primers and probes, rationale for the selected gene targets, specifications for amplicon size, and degree of nucleic acid sequence conservation.
ii For devices with assay calibrators, the design and nature of all primary, secondary, and subsequent quantitation standards used for calibration as well as their traceability to a standardized reference material that FDA has determined is appropriate e.g., a recognized consensus standard. 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 approval, or when there is a transition to a new calibration standard.
iii Documentation and characterization e.g., determination of the identity, supplier, purity, and stability of all critical reagents including nucleic acid sequences for primers and probes and protocols for maintaining product integrity.
iv 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 detection LoD, upper and lower limits of quantitation ULoQ and LLoQ, respectively, linearity, precision, endogenous and exogenous interferences, cross reactivity, carryover, 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
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in the United States. Cross-reactivity studies must include samples from HCV
RNA negative subjects with other causes of liver disease, including autoimmune hepatitis, alcoholic liver disease, chronic hepatitis B virus, primary biliary cirrhosis, and nonalcoholic steatohepatitis, when applicable. The effect of each claimed nucleic-acid isolation and purification procedure on detection must be evaluated.
v 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.
vi 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.
vii Multisite reproducibility study that includes the testing of three independent production lots.
viii All stability protocols, including acceptance criteria.
ix Final release test results for each lot used in clinical studies.
x Analytical sensitivity and specificity of the test must be the same or better than that of other cleared or approved tests.
xi Lot-to-lot precision studies, as appropriate.
3 For devices intended for the qualitative detection of HCV RNA, in addition to the special controls listed in paragraphs b1 and 2 of this section, the design verification and validation must include detailed documentation of performance from a multisite clinical study. Performance must be analyzed relative to an FDA cleared or approved qualitative HCV RNA test, or a comparator that FDA has determined is appropriate. This study must be conducted using appropriate patient samples, with appropriate numbers of HCV positive and negative samples in applicable risk categories. Additional genotypes 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:
i Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 95 percent.
ii Clinical specificity of the test must have a lower bound of the 95 percent
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