(a) Identification. A cervical intraepithelial neoplasia (CIN) test system is a device used to detect a biomarker associated with CIN in human tissues. The device is indicated as an adjunct test and not to be used as a stand-alone device. The test results must be interpreted in the context of the patient's clinical history including, but not limited to, prior and current cervical biopsy results, Papanicolaou (Pap) test results, human papillomavirus (HPV) test results, and morphology on hematoxylin and eosin (H&E) stained sections. This device is not intended to detect the presence of HPV.

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

(1) Premarket notification submissions must include the following information:

(i) The indications for use must specify the biomarker that is intended to be identified and its adjunct use (e.g., adjunct to examination of H&E stained slides) to improve consistency in the diagnosis of CIN.

(ii) Summary of professional society recommendations, as applicable.

(iii) A detailed device description including:

(A) A detailed description of all test components, including all provided reagents and required, but not provided, ancillary reagents.

(B) A detailed description of instrumentation and equipment, including illustrations or photographs of non-standard equipment or manuals.

(C) If applicable, detailed documentation of the device software, including, but not limited to, stand-alone software applications and hardware-based devices that incorporate software.

(D) A detailed description of appropriate positive and negative controls that are recommended or provided.

(E) Detailed specifications for sample collection, processing, and storage.

(F) A detailed description of methodology and assay procedure.

(G) A description of the assay cutoff (the medical decision point between positive and negative) or other relevant criteria that distinguishes positive and negative results, including the rationale for the chosen cutoff or other relevant criteria and results supporting validation of the cutoff.

(H) Detailed specification of the criteria for test results interpretation and reporting.

(iv) Detailed information demonstrating the performance characteristics of the device, including:

(A) Analytical specificity studies such as, but not limited to, antibody characterization (e.g., Western Blot, peptide inhibition analysis), studies conducted on panels of normal tissues and neoplastic tissues, interference by endogenous and exogenous substances as well as cross-reactivity, as applicable.

(B) Device analytical sensitivity data generated by testing an adequate number of samples from individuals with the target condition including limit of blank, limit of detection, and limit of quantification, as applicable.

(C) Device precision/reproducibility data to evaluate within-run, between-run, between-day, between-lot, between-site, between-reader, within-reader and total precision, as applicable, using a panel of samples covering the device measuring range and/or the relevant disease categories (e.g. No CIN, CIN1, CIN2, CIN3, cervical cancer) and testing in replicates across multiple, nonconsecutive days.

(D) Device robustness/guardbanding studies to assess the tolerance ranges for various critical test and specimen parameters.

(E) Device stability data, including real-time stability and shipping stability under various storage times, temperatures, and freeze-thaw conditions.

(F) Data from a clinical study demonstrating clinical validity using well-characterized prospectively or retrospectively obtained clinical specimens, as appropriate, representative of the intended use population. The study must evaluate the consistency of the diagnosis of CIN, for example, by comparing the levels of agreements of diagnoses rendered by community pathologists to those rendered by a panel of expert pathologists. Agreement for each CIN diagnostic category (e.g., No CIN, CIN1, CIN2, CIN3, cancer) and for alternate diagnostic categories (e.g., No CIN, low grade squamous intraepithelial lesion (LSIL)-histology, high grade squamous intraepithelial lesion (HSIL)-histology, cancer) between reference diagnosis by expert pathologist and community pathologist must be evaluated, as applicable. In addition, agreements for CIN binary categories as ≥CIN2 (i.e., CIN2 or CIN3 or cancer) and ≤CIN1 (i.e., No CIN or CIN1) between reference diagnosis by expert pathologist with H&E staining and community pathologist with H&E staining and agreements for alternate CIN binary categories as ≥HSIL-histology (i.e., HSIL-histology or cancer) and ≤LSIL-histology (i.e., No CIN or LSIL-histology) between reference diagnosis by an expert pathologist with H&E + [biomarker specified in paragraph (b)(1)(i) of this section] and a community pathologist with H&E + [biomarker specified in paragraph (b)(1)(i) of this section] must be evaluated and compared, as applicable.

(G) The staining performance of the device as determined by the community pathologists during review of the study slides must be evaluated. The staining performance criteria assessed must include overall staining acceptability, background staining acceptability, and morphology acceptability, as applicable.

(H) Appropriate training requirements for users, including interpretation manual, as applicable.

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

(2) The device's 21 CFR 809.10(b) compliant labeling must include a detailed description of the protocol, including the information described in paragraph (b)(1)(ii) of this section, as applicable, and a detailed description of the performance studies performed and the summary of the results, including those that relate to paragraph (b)(1)(ii) of this section, as applicable.

[83 FR 234, Jan. 3, 2018]