(a) Identification. A human leukocyte antigen (HLA) typing companion diagnostic (CDx) test is a prescription genotyping or phenotyping in vitro diagnostic product intended for use as an aid in identifying patients who have specific HLA allele(s) or express specific HLA antigen(s) and may benefit from treatment with a corresponding therapeutic product or are likely to be at increased risk for serious adverse reactions as a result of treatment with a corresponding therapeutic product.

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

(1) The intended use of the device must specify the target HLA allele(s) or antigen(s), the patient population(s), and the corresponding therapeutic product(s).

(2) Design verification and validation must include:

(i) Detailed documentation of an analytical accuracy study that uses well-characterized samples including clinical samples from intended use population(s) focusing on the target allele(s) needed for patient selection;

(ii) Detailed documentation of precision studies (repeatability, reproducibility) that evaluate possible sources of variation that may affect test results;

(iii) Detailed documentation of a study determining range of input sample concentrations that meet performance specifications;

(iv) Detailed description of the ambiguity resolution method, if applicable;

(v) For a sequencing-based assay, documentation of coverage and predefined coverage threshold of target genomic regions, pertinent variant types, and sequence contexts;

(vi) For multiplex assays, documentation of a risk assessment and design specifications that are in place to prevent incorrect reactivity assignment;

(vii) Description of a plan on how to ensure the performance of the device does not change when new HLA alleles are identified, and/or when reactivity assignments are changed; and

(viii) Detailed description of device software including standalone software, or software and bioinformatics analysis pipeline, if applicable, incorporated in the instruments, and documentation of software including the level of concern and associated risks, software requirement specifications, software design specifications (e.g., algorithms, alarms and device limitations), hazard analysis, traceability matrix, verification and validation testing, unresolved anomalies, hardware requirements, and effective cybersecurity management.

(3) Clinical validity data (which may include summary reports from clinical trials, comparison studies using clinical samples, or through an alternative approach determined to be appropriate by FDA), demonstrating the following, as applicable:

(i) Which patients identified by the HLA CDx test are most likely to benefit from the corresponding therapeutic product; and

(ii) Which patients identified by the HLA CDx test are likely to be at increased risk for serious adverse reactions as a result of treatment with the corresponding therapeutic product.

(4) If the HLA test used in the clinical trials is different from the HLA CDx test in the premarket notification submission, the submission must include results of a bridging study, or an alternative approach determined to be appropriate by FDA.

[87 FR 79252, Dec. 27, 2022]