(a) Identification. A postnatal chromosomal copy number variation detection system is a qualitative assay intended for the detection of copy number variations (CNVs) in genomic DNA obtained from whole blood in patients referred for chromosomal testing based on clinical presentation. It is intended for the detection of CNVs associated with developmental delay, intellectual disability, congenital anomalies, or dysmorphic features. Assay results are intended to be used in conjunction with other clinical and diagnostic findings, consistent with professional standards of practice, including confirmation by alternative methods, parental evaluation, clinical genetic evaluation, and counseling, as appropriate. Interpretation of assay results is intended to be performed by qualified healthcare professionals such as clinical cytogeneticists or molecular geneticists. This device is not intended to be used for standalone diagnostic purposes, pre-implantation or prenatal testing or screening, population screening, or for the detection of, or screening for, acquired or somatic genetic aberrations.

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

(1) Design verification and validation must include the following information:

(i) A detailed description of all components in the test system that includes:

(A) A description of the assay components, array composition and layout, all required reagents, instrumentation, and equipment, including illustrations or photographs of non-standard equipment or methods;

(B) A description of the design of the array in terms of chromosomal coverage and probe density for different regions;

(C) An identification of the number of probes and size of the CNVs reported at the lower range of the assay;

(D) Detailed documentation of the device software, including standalone software applications and hardware-based devices that incorporate software;

(E) Methodology and protocols for detecting copy number and visualizing results;

(F) A description of the result outputs along with sample reports, and a description of any links to external databases provided by the device to the user or accessed by the device;

(G) Specifications for the methods to be used in specimen collection, extraction (including DNA criteria for DNA quality and quantity to perform the assay), and storage; and

(H) A description of appropriate internal and external controls that are recommended or provided. The description must identify those control elements that are incorporated into the testing procedure.

(ii) Information that demonstrates the performance characteristics of the system, including:

(A) Device reproducibility data generated, at a minimum, using three sites, with two operators at each site, for three non-consecutive days using at least three instruments. A well-characterized panel of samples that provide a wide range of CNVs (i.e., gains, losses, adequate size coverage across the range of sizes claimed by the device, adequate chromosomal coverage, challenging regions in the genome, CNVs reported at the lower range of the assay, interstitial, subtelomeric, and pericentromeric rearrangements, aneuploidy, unbalanced translocations, mosaicism, and known syndromic regions) must be used. The results must be itemized for all CNVs detected in each sample across all replicates and summarized in a tabular format stratified by size range and range of probe numbers for gains and losses separately and calculated for overall. The results must be analyzed using pairwise replicate agreement, and summarized as overall pairwise replicate agreement as well as pairwise replicate agreement conditional on replicates having a positive copy number state call (gains or losses), call rate, CNV size variation, and endpoint agreement;

(B) Device accuracy data using cell lines and clinical samples representing a variety of CNVs and syndromes. In this analytical study, accuracy must be determined for every CNV detected in a particular sample. The accuracy data provided must include the copy number state determination and endpoint accuracy. The accuracy samples must cover different genomic variations across the genome (i.e., gains, losses, adequate CNV size coverage across the range of sizes claimed by the device, adequate chromosomal coverage, challenging regions in the genome, CNVs reported at the lower range of the assay, interstitial, subtelomeric, and pericentromeric rearrangements, aneuploidy, unbalanced translocations, mosaicism, and known syndromic regions). CNVs identified by the device must be compared to comparator method(s). Agreement between the CNVs detected by the array and the comparator must be summarized in a tabular format that includes the positive percent agreement and false positive rate stratified by size range and range of probe numbers for gains and losses separately and calculated for overall;

(C) Assay performance data for CNVs reported at the lower range of the assay for both gains and losses;

(D) Device analytical sensitivity data, including DNA input and limit of detection for mosaicism, if applicable;

(E) Device analytical specificity data, including interference, carryover, and cross-contamination data;

(F) Device stability data, including real-time stability under various storage times, temperatures, and freeze-thaw conditions;

(G) Specimen matrix comparison data if more than one specimen type or anticoagulant can be tested with the device;

(H) Data that demonstrates the clinical validity, including diagnostic yield, of the device using a minimum of 800 retrospective clinical samples that were collected prospectively and obtained from three or more clinical laboratories, with results interpretation equally divided between two or more qualified healthcare professionals (e.g., cytogeneticists). Patients must be representative of the intended use population and not limited to common syndromes. Diagnostic yield data must be summarized in tabular format and stratified by the comparison methodologies. Data must also be summarized comparing interpretation of results, with description of reasons for variability in calls between the device and the standard of care methods. Data to support the accuracy of calls for known syndromes must be included; and

(I) Data that demonstrates device results when a minimum of 100 apparently healthy, phenotypically normal individuals are tested and interpreted by one or more cytogeneticists blinded to the patient status.

(iii) Identification of risk mitigation elements used by the device, including a description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing.

(2) The labeling required under § 809.10 of this chapter must include:

(i) A warning statement that the device is not intended to be used for standalone diagnostic purposes, pre-implantation or prenatal testing or screening, population screening, or for the detection of, or screening for, acquired or somatic genetic aberrations;

(ii) Limitations regarding the assay's performance with respect to validated CNVs reported at the lower range of the assay, stratified by size range and range of probe numbers for gains and losses separately; and limitations regarding problematic (hypervariable) regions, loss of heterozygosity, mosaicism, and inability to detect balanced translocations, as appropriate;

(iii) A warning statement that interpretation of assay results is intended to be performed by qualified healthcare professionals such as clinical cytogeneticists or molecular geneticists; and,

(iv) A description of the performance studies performed in accordance with paragraph (b)(1)(ii) of this section and a summary of the results.