(a) Identification. A fluorescence in situ hybridization (FISH)-based detection of chromosomal abnormalities from patients with hematologic malignancies is used to detect chromosomal abnormalities in human specimens from patients with hematologic malignancies. The test is indicated for the clinical management of patients consistent with internationally accepted guidelines (e.g., World Health Organization guidelines for Classification of Tumours of Haematopoietic and Lymphoid Tissues) and in conjunction with other clinical and clinicopathological criteria. The results are to be interpreted by a pathologist or equivalent professional.

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

(1) Design verification and validation must include:

(i) A detailed description of all probes included in the kit;

(ii) Purpose of each probe;

(iii) Probe molecular specificity;

(iv) Probe specificity;

(v) Probe limits;

(vi) Probe sensitivity;

(vii) Specification of required ancillary reagents, instrumentation, and equipment;

(viii) Specification of the specimen collection, processing, storage and slide preparation methods;

(ix) Specification of the assay procedure;

(x) Specification of control elements that are incorporated into the recommended testing procedures;

(xi) Specification of the criteria for test result interpretation and reporting;

(xii) Documentation demonstrating analytical validation that includes:

(A) Device analytical sensitivity data with a minimum of 25 specimens from karyotypically normal males.

(B) Device analytical specificity data with a minimum of five specimens from karyotypically normal males.

(C) Description of how the clinical threshold was assigned and verification of the assigned clinical threshold.

(D) Device precision/reproducibility data with a minimum of six clinical specimens including two negative specimens, two positive specimens near the clinical decision threshold (cut-off) and two positive specimens. The data must include results obtained from three sites (as applicable), with two operators at each site, with the assay run for a minimum of 3-5 non-consecutive days and each specimen run in duplicate for a minimum of 30 replicates.

(E) Between-reagent lot reproducibility using three reagent lots and three clinical specimens representing negative, near cut-off/low positive, and positive.

(F) Device stability data to include:

(1) Real-time stability,

(2) Freeze-thaw stability,

(3) Transport and temperature stability, as applicable,

(4) Post-hybridization signal stability, and

(5) Photostability of probe.

(xiii) Documentation demonstrating the clinical validity of the device that includes:

(A) A summary of the prevalence and clinical thresholds reported in three peer-reviewed published literature references for the intended use population of the device and device performance data demonstrating conformance with the published prevalence as reported in peer-reviewed published literature references based on testing clinical specimens, selected without bias (e.g., consecutively selected) from the intended use population using the specific device seeking marketing clearance. A minimum number of clinical specimens must be tested to ensure sufficient positives are evaluated by the device, or alternatively, in the absence of a sufficient number of positives, an additional comparison of results obtained with the device to clinical truth (e.g., confirmed clinical diagnosis and/or G-banded karyotyping) with an independent specimen set must be conducted.

(B) Documentation for peer-reviewed published literature references must include the following elements:

(1) Whether the specific device was used in the literature reference;

(2) Number and type of specimens;

(3) Target population studied;

(4) Upper reference limit; and

(5) Prevalence range estimated based on the number of positive probe results.

(C) In the absence of clinical data obtained from paragraphs (b)(1)(xiii)(A) and (B) of this section, clinical data obtained from a method comparison to the predicate with positives and negative clinical specimens.

(2) The intended use required on the label under § 809.10(a)(4) of this chapter and on the labeling required under § 809.10(b)(5)(ii) of this chapter must include a statement that “The test is not intended for use as a stand-alone diagnostic, disease screening, or as a companion diagnostic.”

(3) The labeling required under § 809.10(b) of this chapter must include information that demonstrates the performance characteristics of the test, including a detailed summary of the performance studies conducted and their results, as described in paragraphs (b)(1)(iv) through (xiii) of this section. The labeling required under § 809.10(b) of this chapter must include the pre-specified acceptance criteria for these performance studies, justification for the pre-specified acceptance criteria, and whether the pre-specified acceptance criteria were met.

(4) The labeling required under § 809.10(b) of this chapter must include the following limiting statements:

(i) “Reporting and interpretation of FISH results should be consistent with professional standards of practice and should take into consideration other clinical and diagnostic information. This kit is intended as an adjunct to other diagnostic laboratory tests and therapeutic action should not be initiated on the basis of the FISH result alone. Failure to adhere to the protocol may affect the performance and lead to false results.”

(ii) “Each lab is responsible for establishing their own cut-off values. Each laboratory should test sufficiently large number of samples to establish normal population distribution of the signal levels and to assign a cut-off value. The product is for professional use only and is intended to be interpreted by a qualified pathologist or cytogeneticist.”