Postnatal Chromosome Test Device Classification Rules

Summary

The Food and Drug Administration (FDA, the Agency, or we) is classifying the postnatal chromosomal copy number variation detection system into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the postnatal chromosomal copy number variation detection system's classification. We are taking this action because we have determined that classifying the device into class II will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens.

Compliance Requirements

1. #1

   Design verification and validation must include 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.; Design verification and validation must include 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 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; (B) Device accuracy data using cell lines and clinical samples representing a variety of CNVs and syndromes. Accuracy must be determined for every CNV detected in a particular sample; (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; 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.; Design verification and validation must include 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.; 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.; This device is subject to premarket notification requirements under section 510(k) of the FD&C Act.; For a device to fall within this classification, and thus avoid automatic classification in class III, it would have to comply with the special controls named in this final order.

Market Impacts

• Reclassification from class III to class II with special controls reduces regulatory burden and enables market access through 510(k) pathway instead of premarket approval (PMA); Device can serve as predicate for future substantially equivalent devices under section 513(f)(2)(B)(i) of FD&C Act; Device is not intended for use in pre-implantation or prenatal testing, population screening, or standalone diagnostic purposes; Device subject to premarket notification requirements under section 510(k) of FD&C Act for market entry

Validated Company Impacts