§ 862.2265 High throughput genomic sequence analyzer for clinical use.

(a) Identification. A high throughput genomic sequence analyzer for clinical use is an analytical instrument system intended to generate, measure and sort signals in order to analyze nucleic acid sequences in a clinical sample. The device may include a signal reader unit; reagent handling, dedicated instrument control, and other hardware components; raw data storage mechanisms; data acquisition software; and software to process detected signals.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9. The special controls for this device are:

(1) The labeling for the instrument system must reference legally marketed pre-analytical and analytical reagents to be used with the instrument system and include or reference legally marketed analytical software that includes sequence alignment and variant calling functions, to be used with the instrument system.

(2) The labeling for the instrument system must include a description of the following information:

(i) The specimen type(s) validated as an appropriate source of nucleic acid for this instrument.

(ii) The type(s) of nucleic acids (e.g., germline DNA, tumor DNA) validated with this instrument.

(iii) The type(s) of sequence variations (e.g. single nucleotide variants, insertions, deletions) validated with this instrument.

(iv) The type(s) of sequencing (e.g., targeted sequencing) validated with this instrument.

(v) The appropriate read depth for the sensitivity claimed and validation information supporting those claims.

(vi) The nucleic acid extraction method(s) validated for use with the instrument system.

(vii) Limitations must specify the types of sequence variations that the instrument cannot detect with the claimed accuracy and precision (e.g., insertions or deletions larger than a certain size, translocations).

(viii) Performance characteristics of the instrument system must include:

(A) Reproducibility data generated using multiple instruments and multiple operators, and at multiple sites. Samples tested must include all claimed specimen types, nucleic acid types, sequence variation types, and types of sequencing. Variants queried shall be located in varying sequence context (e.g., different chromosomes, GC-rich regions). Device results shall be compared to reference sequence data with high confidence.

(B) Accuracy data for all claimed specimen types and nucleic acid types generated by testing a panel of well characterized samples to query all claimed sequence variation types, types of sequencing, and sequences located in varying sequence context (e.g., different chromosomes, GC-rich regions). The well-characterized sample panel shall include samples from at least two sources that have highly confident sequence based on well-validated sequencing methods. At least one reference source shall have sequence generated independently of the manufacturer with respect to technology and analysis. Percent agreement and percent disagreement with the reference sequences must be described for all regions queried by the instrument.

(C) If applicable, data describing endogenous or exogenous substances that may interfere with the instrument system.

(D) If applicable, data demonstrating the ability of the system to consistently generate an accurate result for a given sample across different indexing primer combinations.

(ix) The upper and lower limit of input nucleic acid that will achieve the claimed accuracy and reproducibility. Data supporting such claims must also be summarized.

[82 FR 13552, Mar. 14, 2017, as amended at 84 FR 71797, Dec. 30, 2019]