(a) Identification. A flow cytometric test for hematopoietic neoplasms is a device that consists of reagents for immunophenotyping of human cells in relation to the level of expression, antigen density, and distribution of specific cellular markers. These reagents are used as an aid in the differential diagnosis or monitoring of hematologically abnormal patients having or suspected of having hematopoietic neoplasms. The results should be interpreted by a pathologist or equivalent professional in conjunction with other clinical and laboratory findings.

(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 indicate the clinical hematopoietic neoplasms for which the assay was designed and validated, for example, chronic leukemia or lymphoma.

(ii) A detailed device description including the following:

(A) A detailed description of all test components, all required reagents, and all instrumentation and equipment, including illustrations or photographs of nonstandard equipment or methods.

(B) Detailed documentation of the device software including, but not limited to, standalone software applications and hardware-based devices that incorporate software.

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

(D) A description of appropriate internal and external quality control materials that are recommended or provided. The description must identify those control elements that are incorporated into the testing procedure, if applicable.

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

(F) Detailed specification of the criteria for test results interpretation and reporting including pre-established templates.

(G) If applicable, based on the output of the results, a description of the specific number of events to collect, result outputs, and analytical sensitivity of the assay that will be reported.

(iii) Information that demonstrates the performance characteristics of the test, including:

(A) Device performance data from either a method comparison study comparing the specific lymphocyte cell markers to a predicate device or data collected through a clinical study demonstrating clinical validity using well-characterized clinical specimens. Samples must be representative of the intended use population of the device including hematologic neoplasms and the specific sample types for which the test is indicated for use.

(B) If applicable, device performance data from a clinical study demonstrating clinical validity for parameters not established in a predicate device of this generic type using well-characterized prospectively obtained clinical specimens including all hematologic neoplasms and the specific sample types for which the device is indicated for use.

(C) Device precision data using clinical samples to evaluate the within-lot, between-lot, within-run, between run, site-to-site and total variation using a minimum of three sites, of which at least two sites must be external sites. Results shall be reported as the standard deviation and percentage coefficient of variation for each level tested.

(D) Reproducibility data generated using a minimum of three lots of reagents to evaluate mean fluorescence intensity and variability of the recovery of the different markers and/or cell populations.

(E) Data from specimen and reagent carryover testing performed using well-established methods (e.g., CLSI H26-A2).

(F) Specimen and prepared sample stability data established for each specimen matrix in the anticoagulant combinations and storage/use conditions that will be indicated.

(G) A study testing anticoagulant equivalency in all claimed specimen type/anticoagulant combinations using clinical specimens that are representative of the intended use population of the device.

(H) Analytic sensitivity data using a dilution panel created from clinical samples.

(I) Analytical specificity data, including interference and cross-contamination.

(J) Device stability data, including real-time stability of reagents under various storage times and temperatures.

(K) For devices that include polyclonal antibodies, Fluorescence Minus One (FMO) studies to evaluate non-specific binding for all polyclonal antibodies. Each FMO tube is compared to reagent reference to demonstrate that no additional population appears when one marker is absent. Pre-specified acceptance criteria must be provided and followed.

(L) For devices indicated for use as a semi-quantitative test, linearity data using a dilution panel created from clinical samples.

(M) For devices indicated for use as a semi-quantitative test, clinically relevant analytical sensitivity data, including limit of blank, limit of detection, and limit of quantification.

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

(2) The 21 CFR 809.10 compliant labeling must include the following:

(i) The intended use statement in the 21 CFR 809.10(a)(2) and (b)(2) compliant labeling must include a statement that the results should be interpreted by a pathologist or equivalent professional in conjunction with other clinical and laboratory findings. The intended use statement must also include information on what the device detects and measures, whether the device is qualitative, semi-quantitative, and/or quantitative, the clinical indications for which the device is to be used, and the specific population(s) for which the device is intended.

(ii) A detailed description of the performance studies conducted to comply with paragraph (b)(1)(iii) of this section and a summary of the results.

(3) As part of the risk management activities performed under 21 CFR 820.30 design controls, product labeling and instruction manuals must include clear examples of all expected phenotypic patterns and gating strategies using well-defined clinical samples representative of both abnormal and normal cellular populations. These samples must be selected based upon the indications described in paragraph (b)(1)(i) of this section.

[82 FR 61165, Dec. 27, 2017]