(a) Identification. A setmelanotide eligibility gene variant detection system is a qualitative in vitro diagnostic device intended to detect germline variants within genes isolated from human specimens for the purpose of identifying patients with obesity who may benefit from treatment with setmelanotide in accordance with the approved therapeutic product labeling.
(b) Classification. Class II (special controls). The special controls for this device are:
(1) Design verification and validation must include:
(i) Detailed documentation of studies that provide data bridging the efficacy of setmelanotide in the clinical trial patient population identified by the clinical trial assay(s) to the efficacy of setmelanotide in the device intended use population identified by the device using the clinical trial samples, or through an alternative approach determined to be appropriate by FDA.
(ii) Detailed documentation of studies that provide data demonstrating the accuracy of the device using clinical specimens representing the intended use specimen type(s) and intended use variant type(s) from the intended use population, including the clinical trial samples, or through an alternative approach determined to be appropriate by FDA. Accuracy of the device must be evaluated at the variant level and sample level, through evaluation of variant and non-variant sequences at the nucleotide level as well as variant interpretation, by comparison to validated bidirectional Sanger sequencing methods or through other methods determined to be appropriate by FDA. If the device will be used at more than one site, the data must demonstrate accuracy across multiple intended use sites.
(iii) Detailed documentation of studies that provide data demonstrating the precision of the device for the intended use specimen type(s) and intended use variant type(s) from the intended use population. Precision must be evaluated at the variant level and sample level, through evaluation of variant and non-variant sequences at the nucleotide level as well as variant interpretation, using multiple reagent lots, operators, and instruments over multiple days, or through an alternative precision study design determined to be appropriate by FDA. If the device will be used at more than one site, data must demonstrate adequate, as determined by FDA, reproducibility across multiple intended use sites.
(iv) Detailed documentation of studies that provide data demonstrating the analytical specificity of the device for the intended use specimen type(s), including an evaluation of cross-reactivity and cross contamination.
(A) Cross-reactivity ( e.g., from homologous regions, paralogs, pseudogenes, repeated sequences, high GC (Guanine and Cytosine) content regions, segmental duplications, and other types of cross-reactive sequences) must be evaluated to assess the detection of unintended alleles or incorrect calls in the target regions covered by the device; and
(B) Cross-contamination must be evaluated to detect carryover and co-mingling of input specimens throughout the process ( e.g., from sample collection and library preparation to variant interpretation).
(v) Detailed documentation of studies that provide data demonstrating adequate, as determined by FDA, stability of the specimens used in the design validation studies in paragraphs (b)(1)(i) through (iv) of this section, as applicable.
(vi) Detailed documentation of information demonstrating adequate, as determined by FDA, analytical quality metrics and thresholds.
(vii) Detailed documentation of information demonstrating adequate, as determined by FDA, procedures that will be performed for variant interpretation and classification, including the procedures that will be performed for variant interpretation and classification changes that may occur as new scientific information becomes available. The information must indicate how the personnel performing such interpretation and classification are trained.
(2) The labeling required under § 809.10(b) of this chapter and any test report generated must include:
(i) Limiting statements that:
(A) Explain that the classification and interpretation of variants identified reflects the current state of scientific understanding at the time the results are issued.
(B) Explain variants could change classification as new scientific information becomes available, which may impact patient eligibility for therapeutic treatment; and
(C) If applicable, explain sufficient scientific information is not available to assign pathogenicity to variants of uncertain significance (VUS).
(ii) A detailed summary of the performance testing, including results, required under paragraphs (b)(1)(i) through (iv) of this section.
