Monday, February 23, 2015

The FDA and its Classification of Clinical Laboratory Diagnostic Tests.

Like CLIA, the FDA has a fairly dated-appearing classification system for diagnostic tests.

FDA regulations are found at CFR 21.

Subpart H is devices is found at 21 CFR 800-898 (radiology follows with mammography at 900.X and other radiology health at 10XX.).  

Within devices, 862 is clinical chemistry, 864 is hematology and pathology, and 866 is immunology and microbiology.

Most entries are specific.  for example, 862.110 is a direct bilirubin test system.  866.5210 is a ceruloplasmin immunology test system.   Tucked in alphabetic order between Biocarbonate Test System (866.1160) and Catecholamines (866.1165) is "Cardiac allograft gene expression profiling test system," e.g. Allomap (866.1163).

However, some categories are quite broad.  864.1850 is "dye and chemical solution stains" which may be "synthetic or natural dyes" and are "exempt" as Class I devices.   864.1860 is "immunohistochemistry" which may be Class I, II or III depending on indication.

  • Class I IHC - "IHC's that provide the pathologist with adjunctive diagnostic information that may be incorporated into the pathologist's report, but that is not ordinarily reported to the clinician as an independent finding...used after the primary diagnosis of a tumor has been subclassify tumors, such as keratin."
  • Class II IHC - " provdie prognostic or predictive data that are not directly confirmed by routine histopathologic control specimens...ordinarily reported as independent diagnostic information to the ordering clinician and the claims asasociated with these data are widely accepted and supported by valid scientific evidence...such as hormone receptors in breast cancer."
  • Class III IHC - "Intended for any use not described above."
EGFR FISH has its own category, however, at 864.1870:

§864.1870   Early growth response 1 (EGR1) gene fluorescence in-situ hybridization (FISH) test system for specimen characterization.
(a) Identification. An early growth response 1 (EGR1) gene fluorescence in-situ hybridization (FISH) test system for specimen characterization is a device intended to detect the EGR1 probe target on chromosome 5q in bone marrow specimens from patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). The assay results are intended to be interpreted only by a qualified pathologist or cytogeneticist. These devices do not include automated systems that directly report results without review and interpretation by a qualified pathologist or cytogeneticist. These devices also do not include any device intended for use to select patient therapy, predict patient response to therapy, or to screen for disease as well as any device with a claim for a particular diagnosis, prognosis, monitoring, or risk assessment.
(b) Classification. Class II (special controls). The special controls for this device are:
(1) Premarket notification submissions must also include the following information:
(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 risk mitigation elements: Description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing;
(xii) Specification of the criteria for test result interpretation and reporting;
(xiii) Device analytical sensitivity data;
(xiv) Device analytical specificity data;
(xv) Device reference limit data;
(xvi) Device precision/reproducibility data;
(xvii) Device stability data to include:
(A) Real-time stability,
(B) Freeze-thaw stability,
(C) Transport and temperature stability,
(D) Post-hybridization signal stability,
(E) Photostability of probe, and
(xviii) Documentation that demonstrates the clinical validity of the device. The documentation must include data from clinical studies, a minimum of two peer-reviewed published literature references using the specific device seeking marketing clearance, or both. Documentation for the clinical studies and peer-reviewed published literature references cited must include the following elements:
(A) Documentation that the sponsor's probe was used in the literature reference,
(B) Number and type of specimens,
(C) Target population studied,
(D) Upper reference limit, and
(E) Range of positive probe results.
(2) Your §809.10(b)(12) of this chapter compliant labeling must include a statement summarizing the data identified in paragraphs (b)(1)(xiii) through (xviii) of this section and a description of the studies supporting the information, including 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.
(3) Your §809.10 of this chapter compliant labeling must include:
(i) A warning that reads “The assay results are intended to be interpreted only by a qualified pathologist or cytogeneticist.”
(ii) A warning that reads “This device is not for high-risk uses such as selecting therapy, predicting therapeutic response or disease screening.”
(iii) A warning that reads “The use of this device for diagnosis, monitoring or risk assessment has not been established.”
[79 FR 52196, Sept. 3, 2014]


As noted earlier, the 866 category contains dozens and dozens of immunologic test names (tryptase system, thyroid autoantibody system, transferrin system, etc).  
Then sudden appears 866.5900, the Illumina CFTR genetic sequencing tes category (here).  
The 23andMe genetic screening tests will be in a generic, genetic test carrier screening category to appear next in series, at 866.5940.

Tumor associated antigens have their own category, at 866.6010.  
Class II (special controls). Tumor markers must comply with the following special controls: (1) A guidance document entitled “Guidance Document for the Submission of Tumor Associated Antigen Premarket Notifications (510(k)s) to FDA,” and (2) voluntary assay performance standards issued by the National Committee on Clinical Laboratory Standards.
Note that you "must comply with" the "voluntary standards" of the NCCLS.   

This tumor-associated immunology test system category is where CMS has also placed gene expression tests for breast cancer prognosis (e.g. Mammaprint, Prosigna) at 866.6040 and the Ova1 and ROMA ovarian mass tests, at 866.6050.  

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