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U.S. Department of Health and Human Services

CFR - Code of Federal Regulations Title 21

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The information on this page is current as of April 1 2020.

For the most up-to-date version of CFR Title 21, go to the Electronic Code of Federal Regulations (eCFR).

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Help | More About 21CFR
[Code of Federal Regulations]
[Title 21, Volume 8]
[Revised as of April 1, 2020]
[CITE: 21CFR864]





TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION
DEPARTMENT OF HEALTH AND HUMAN SERVICES
SUBCHAPTER H - MEDICAL DEVICES
 
PART 864HEMATOLOGY AND PATHOLOGY DEVICES
 

Subpart B - Biological Stains

Sec. 864.1850 Dye and chemical solution stains.

(a) Identification. Dye and chemical solution stains for medical purposes are mixtures of synthetic or natural dyes or nondye chemicals in solutions used in staining cells and tissues for diagnostic histopathology, cytopathology, or hematology.

(b) Classification. Class I (general controls). These devices are exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9. These devices are also exempt from the current good manufacturing practice requirements of the quality system regulation in part 820 of this chapter, with the exception of § 820.180, with respect to general requirements concerning records, and § 820.198, with respect to complaint files.

[45 FR 60583, Sept. 12, 1980, as amended at 54 FR 25044, June 12, 1989; 66 FR 38789, July 25, 2001]

Sec. 864.1860 Immunohistochemistry reagents and kits.

(a) Identification. Immunohistochemistry test systems (IHC's) are in vitro diagnostic devices consisting of polyclonal or monoclonal antibodies labeled with directions for use and performance claims, which may be packaged with ancillary reagents in kits. Their intended use is to identify, by immunological techniques, antigens in tissues or cytologic specimens. Similar devices intended for use with flow cytometry devices are not considered IHC's.

(b) Classification of immunohistochemistry devices. (1) Class I (general controls). Except as described in paragraphs (b)(2) and (b)(3) of this section, these devices are exempt from the premarket notification requirements in part 807, subpart E of this chapter. This exemption applies to 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. These IHC's are used after the primary diagnosis of tumor (neoplasm) has been made by conventional histopathology using nonimmunologic histochemical stains, such as hematoxylin and eosin. Examples of class I IHC's are differentiation markers that are used as adjunctive tests to subclassify tumors, such as keratin.

(2) Class II (special control, guidance document: "FDA Guidance for Submission of Immunohistochemistry Applications to the FDA," Center for Devices and Radiologic Health, 1998). These IHC's are intended for the detection and/or measurement of certain target analytes in order to provide prognostic or predictive data that are not directly confirmed by routine histopathologic internal and external control specimens. These IHC's provide the pathologist with information that is ordinarily reported as independent diagnostic information to the ordering clinician, and the claims associated with these data are widely accepted and supported by valid scientific evidence. Examples of class II IHC's are those intended for semiquantitative measurement of an analyte, such as hormone receptors in breast cancer.

(3) Class III (premarket approval). IHC's intended for any use not described in paragraphs (b)(1) or (b)(2) of this section.

(c) Date of PMA or notice of completion of a PDP is required. As of May 28, 1976, an approval under section 515 of the Federal Food, Drug, and Cosmetic Act is required for any device described in paragraph (b)(3) of this section before this device may be commercially distributed. See § 864.3.

[63 FR 30142, June 3, 1998]

Sec. 864.1865 Cervical intraepithelial neoplasia (CIN) test system.

(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 â?¥CIN2 (i.e., CIN2 or CIN3 or cancer) and â?¤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 â?¥HSIL-histology (i.e., HSIL-histology or cancer) and â?¤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]

Sec. 864.1866 Lynch syndrome test systems.

(a) Identification. Lynch syndrome test systems are in vitro diagnostic tests for use with tumor tissue to identify previously diagnosed cancer patients at risk for having Lynch syndrome.

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

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

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

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

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

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

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

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

(vii) A description of the assay cut-off (i.e., the medical decision point between positive and negative results) or other relevant criteria that distinguishes positive and negative results, or ordinal classes of marker expression, including the rationale for the chosen cut-off or other relevant criteria and results supporting validation of the cut-off.

(viii) Detailed specification of the criteria for test result interpretation and reporting.

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

(A) Data from an appropriate study demonstrating clinical accuracy using well-characterized clinical specimens representative of the intended use population (i.e., concordance to Deoxyribonucleic Acid (DNA) sequencing results of the Lynch syndrome associated genes or method comparison to the predicate device using samples with known alterations in genes representative of Lynch syndrome). Pre-specified acceptance criteria must be provided and followed.

(B) Appropriate device reproducibility data investigating all sources of variance (e.g., for distributed tests, data generated using a minimum of three sites, of which at least two sites must be external sites). Each site must perform testing over a minimum of 5 nonconsecutive days evaluating a sample panel that spans the claimed measuring range, and includes the clinical threshold. Pre-specified acceptance criteria must be provided and followed.

(C) Data demonstrating reader reproducibility, both within-reader and between-reader, assessed by three readers over 3 nonconsecutive days at each site, including a 2 week washout period between reads, as appropriate.

(D) Device precision data using clinical samples spanning the measuring range and controls to evaluate the within-lot, between-lot, within-run, between run, and total variation.

(E) Analytical specificity studies including as appropriate, western blots, peptide inhibition, testing in normal tissues and neoplastic tissues, interference by endogenous and exogenous substances, and cross-reactivity and cross contamination testing.

(F) Device analytical sensitivity data generated by testing an adequate number of samples from individuals with the target condition such that prevalence of the biomarker in the target population is established.

(G) Device stability data, including real-time stability and in-use stability, and stability evaluating various storage times, temperatures, and freeze-thaw conditions, as appropriate.

(H) The staining performance criteria assessed must include overall staining acceptability, background staining acceptability, and morphology acceptability, as appropriate.

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

(J) 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 § 809.10(b) of this chapter compliant labeling must include a detailed description of the protocol, including the information described in paragraphs (b)(1)(i) through (viii) of this section, as appropriate, and a detailed description of the performance studies performed and the summary of the results, including those that relate to paragraph (b)(1)(ix) of this section, as appropriate.

[83 FR 8357, Feb. 27, 2018]

Sec. 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]

Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.

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