(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]

(a) Identification. An adenosine triphosphate release assay is a device that measures the release of adenosine triphosphate (ATP) from platelets following aggregation. This measurement is made on platelet-rich plasma using a photometer and a luminescent firefly extract. Simultaneous measurements of platelet aggregation and ATP release are used to evaluate platelet function disorders.

(b) Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

[45 FR 60609, Sept. 12, 1980, as amended at 84 FR 71799, Dec. 30, 2019]

(a) Identification. An antithrombin III assay is a device that is used to determine the plasma level of antithrombin III (a substance which acts with the anticoagulant heparin to prevent coagulation). This determination is used to monitor the administration of heparin in the treatment of thrombosis. The determination may also be used in the diagnosis of thrombophilia (a congenital deficiency of antithrombin III).

(b) Classification. Class II (performance standards).

[45 FR 60609, Sept. 12, 1980]

(a) Identification. Red blood cell enzyme assay is a device used to measure the activity in red blood cells of clinically important enzymatic reactions and their products, such as pyruvate kinase or 2,3-diphosphoglycerate. A red blood cell enzyme assay is used to determine the enzyme defects responsible for a patient's hereditary hemolytic anemia.

(b) Classification. Class II (performance standards).

[45 FR 60610, Sept. 12, 1980]

(a) Identification. An activated whole blood clotting time tests is a device, used to monitor heparin therapy for the treatment of venous thrombosis or pulmonary embolism by measuring the coagulation time of whole blood.

(b) Classification. Class II (performance standards).

[45 FR 60611, Sept. 12, 1980]

(a) Identification. A erythropoietin assay is a device that measures the concentration of erythropoietin (an enzyme that regulates the production of red blood cells) in serum or urine. This assay provides diagnostic information for the evaluation of erythrocytosis (increased total red cell mass) and anemia.

(b) Classification. Class II. The special control for this device is FDA's “Document for Special Controls for Erythropoietin Assay Premarket Notification (510(k)s).”

[45 FR 60612, Sept. 12, 1980, as amended at 52 FR 17733, May 11, 1987; 65 FR 17144, Mar. 31, 2000]

(a) Identification. A euglobulin lysis time test is a device that measures the length of time required for the lysis (dissolution) of a clot formed from fibrinogen in the euglobulin fraction (that fraction of the plasma responsible for the formation of plasmin, a clot lysing enzyme). This test evaluates natural fibrinolysis (destruction of a blood clot after bleeding has been arrested). The test also will detect accelerated fibrinolysis.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

[45 FR 60612, Sept. 12, 1980, as amended at 84 FR 71799, Dec. 30, 2019]

(a) Identification. Factor V Leiden deoxyribonucleic acid (DNA) mutation detection systems are devices that consist of different reagents and instruments which include polymerase chain reaction (PCR) primers, hybridization matrices, thermal cyclers, imagers, and software packages. The detection of the Factor V Leiden mutation aids in the diagnosis of patients with suspected thrombophilia.

(b) Classification. Class II (special controls). The special control is FDA's guidance entitled “Class II Special Controls Guidance Document: Factor V Leiden DNA Mutation Detection Systems.” (See § 864.1(d) for the availability of this guidance document.)

[69 FR 12273, Mar. 16, 2004]

(a) Identification. A factor deficiency test is a device used to diagnose specific coagulation defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene).

(b) Classification. Class II (performance standards).

[45 FR 60613, Sept. 12, 1980]

(a) Identification. A heparin and direct oral factor Xa inhibitor drug test system is intended for the detection of heparin and direct oral factor Xa inhibitors in human specimens collected from patients taking heparin or direct oral factor Xa inhibitors. This device is intended to aid in the management of therapy in conjunction with other clinical and laboratory findings.

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

(1) Design verification and validation must include the following:

(i) Detailed documentation of analytical device performance studies and results demonstrating acceptable analytical performance with a sufficient number of specimens tested in order to obtain unbiased estimates of analytical performance. This documentation shall include the following as appropriate to the technology, specimen types tested, and intended use of the device:

(A) Studies and results for that demonstrate device precision including repeatability and reproducibility, using quality controls and clinical samples, when appropriate. Precision studies must assess specimens for each indicated drug at concentrations throughout the measuring range of the device including near clinically relevant levels, as appropriate. The study must evaluate different sources of variability including, as appropriate, between-run, between-operator, between-lot, between-instrument, between-day, and between-site;

(B) Studies and results that demonstrate that the device is free from clinically significant interference, from endogenous and exogenous interferents associated with the target population(s), and interferents that are specific for, or related to, the technology or methodology of the device;

(C) Data to demonstrate appropriate specimen stability for the intended sample matrices under the intended conditions for specimen collection, handling, and storage described in the device labeling;

(D) Studies and results that demonstrate the linear range, limit of blank (LoB), limit of detection (LoD), and limit of quantitation (LoQ), as applicable to the technology of the device; and

(E) For any devices intended for use for near patient testing, studies and results that demonstrate the robustness of the device in the hands of the intended user, including the entire testing procedure, pre-analytical specimen processing steps, and results interpretation.

(ii) Detailed documentation of clinical performance testing in which the performance is analyzed relative to a comparator that FDA has determined is appropriate. Specimens must be representative of the intended use population(s) and must cover the full range of the device output and any clinically relevant decision points as appropriate.

(2) The labeling required under § 809.10(b) of this chapter must include:

(i) Identification of any known interferents, including all endogenous, exogenous, technology-specific, and patient population-specific interferents, specific to the test outputs. The information must include the concentration(s) or level(s) of the interferent at which clinically significant interference was found to occur, and the concentration range or levels at which interference was not found to occur;

(ii) A prominent statement that the device is not intended for use in monitoring patients taking heparin or direct oral factor Xa inhibitors; and

(iii) Limiting statements indicating, as applicable:

(A) That the device should only be used in conjunction with information available from clinical evaluations and other diagnostic procedures; and

(B) That the device is not specific to the direct oral factor Xa inhibitor that has been evaluated and may detect the presence of other direct factor Xa inhibitors that have not been evaluated.

[89 FR 72317, Sept. 5, 2024]

(a) Identification. A fibrin monomer paracoagulation test is a device used to detect fibrin monomer in the diagnosis of disseminated intravascular coagulation (nonlocalized clotting within a blood vessel) or in the differential diagnosis between disseminated intravascular coagulation and primary fibrinolysis (dissolution of the fibrin in a blood clot).

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9. The special control for this device is FDA's “In Vitro Diagnostic Fibrin Monomer Paracoagulation Test.” See § 864.1(d) for information on obtaining this document.

[45 FR 60614, Sept. 12, 1980, as amended at 52 FR 17733, May 11, 1987; 65 FR 17144, Mar. 31, 2000, 84 FR 71799, Dec. 30, 2019]

(a) Identification. A fibrinogen/fibrin degradation products assay is a device used to detect and measure fibrinogen degradation products and fibrin degradation products (protein fragments produced by the enzymatic action of plasmin on fibrinogen and fibrin) as an aid in detecting the presence and degree of intravascular coagulation and fibrinolysis (the dissolution of the fibrin in a blood clot) and in monitoring therapy for disseminated intravascular coagulation (nonlocalized clotting in the blood vessels).

(b) Classification. Class II (performance standards).

[45 FR 60615, Sept. 12, 1980]

(a) Identification. A fibrinogen determination system is a device that consists of the instruments, reagents, standards, and controls used to determine the fibrinogen levels in disseminated intravascular coagulation (nonlocalized clotting within the blood vessels) and primary fibrinolysis (the dissolution of fibrin in a blood clot).

(b) Classification. Class II (special controls). A control or fibrinogen standard intended for use with a fibrinogen determination system is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

[45 FR 60615, Sept. 12, 1980, as amended at 84 FR 71799, Dec. 30, 2019]

(a) Identification. An erythrocytic glucose-6-phosphate dehydrogenase assay is a device used to measure the activity of the enzyme glucose-6-phosphate dehydrogenase or of glucose-6-phosphate dehydrogenase isoenzymes. The results of this assay are used in the diagnosis and treatment of nonspherocytic congenital hemolytic anemia or drug-induced hemolytic anemia associated with a glucose-6-phosphate dehydrogenase deficiency. This generic device includes assays based on fluorescence, electrophoresis, methemoglobin reduction, catalase inhibition, and ultraviolet kinetics.

(b) Classification. Class II (performance standards).

[45 FR 60616, Sept. 12, 1980]

(a) Identification. A glutathione reductase assay is a device used to determine the activity of the enzyme glutathione reductase in serum, plasma, or erythrocytes by such techniques as fluorescence and photometry. The results of this assay are used in the diagnosis of liver disease, glutathione reductase deficiency, or riboflavin deficiency.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

[45 FR 60616, Sept. 12, 1980, as amended at 84 FR 71799, Dec. 30, 2019]

(a) Identification. A hemoglobin A2 assay is a device used to determine the hemoglobin A2 content of human blood. The measurement of hemoglobin A2 is used in the diagnosis of the thalassemias (hereditary hemolytic anemias characterized by decreased synthesis of one or more types of hemoglobin polypeptide chains).

(b) Classification. Class II (performance standards).

[45 FR 60617, Sept. 12, 1980]

(a) Identification. An abnormal hemoglobin assay is a device consisting of the reagents, apparatus, instrumentation, and controls necessary to isolate and identify abnormal genetically determined hemoglobin types.

(b) Classification. Class II (special controls). A control intended for use with an abnormal hemoglobin assay is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

[45 FR 60618, Sept. 12, 1980, as amended at 84 FR 71799, Dec. 30, 2019]

(a) Identification. A carboxyhemoglobin assay is a device used to determine the carboxyhemoglobin (the compound formed when hemoglobin is exposed to carbon monoxide) content of human blood as an aid in the diagnosis of carbon monoxide poisoning. This measurement may be made using methods such as spectroscopy, colorimetry, spectrophotometry, and gasometry.

(b) Classification. Class II (performance standards).

[45 FR 60619, Sept. 12, 1980]

(a) Identification. An electrophoretic hemoglobin analysis system is a device that electrophoretically separates and identifies normal and abnormal hemoglobin types as an aid in the diagnosis of anemia or erythrocytosis (increased total red cell mass) due to a hemoglobin abnormality.

(b) Classification. Class II (performance standards).

[45 FR 60620, Sept. 12, 1980]

(a) Identification. A fetal hemoglobin assay is a device that is used to determine the presence and distribution of fetal hemoglobin (hemoglobin F) in red cells or to measure the amount of fetal hemoglobin present. The assay may be used to detect fetal red cells in the maternal circulation or to detect the elevated levels of fetal hemoglobin exhibited in cases of hemoglobin abnormalities such as thalassemia (a hereditary hemolytic anemia characterized by a decreased synthesis of one or more types of hemoglobin polypeptide chains). The hemoglobin determination may be made by methods such as electrophoresis, alkali denaturation, column chromatography, or radial immunodiffusion.

(b) Classification. Class II (special controls). A fetal hemoglobin stain intended for use with a fetal hemoglobin assay is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

[45 FR 60620, Sept. 12, 1980, as amended at 84 FR 71799, Dec. 30, 2019]

(a) Identification. A glycosylated hemoglobin assay is a device used to measure the glycosylated hemoglobins (A1a, A1b, and A1c) in a patient's blood by a column chromatographic procedure. Measurement of glycosylated hemoglobin is used to assess the level of control of a patient's diabetes and to determine the proper insulin dosage for a patient. Elevated levels of glycosylated hemoglobin indicate uncontrolled diabetes in a patient.

(b) Classification. Class II (performance standards).

[45 FR 60621, Sept. 12, 1980]

(a) Identification. A sulfhemoglobin assay is a device consisting of the reagents, calibrators, controls, and instrumentation used to determine the sulfhemoglobin (a compound of sulfur and hemoglobin) content of human blood as an aid in the diagnosis of sulfhemoglobinemia (presence of sulfhemoglobin in the blood due to drug administration or exposure to a poison). This measurement may be made using methods such as spectroscopy, colorimetry, spectrophotometry, or gasometry.

(b) Classification. Class II (performance standards).

[45 FR 60621, Sept. 12, 1980]

(a) Identification. A whole blood hemoglobin assay is a device consisting or reagents, calibrators, controls, or photometric or spectrophotometric instrumentation used to measure the hemoglobin content of whole blood for the detection of anemia. This generic device category does not include automated hemoglobin systems.

(b) Classification. Class II (special controls). An acid hematin intended for use with whole blood hemoglobin assays is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

[45 FR 60622, Sept. 12, 1980, as amended at 84 FR 71799, Dec. 30, 2019]

(a) Identification. A heparin assay is a device used to determine the level of the anticoagulant heparin in the patient's circulation. These assays are quantitative clotting time procedures using the effect of heparin on activated coagulation factor X (Stuart factor) or procedures based on the neutralization of heparin by protamine sulfate (a protein that neutralizes heparin).

(b) Classification. Class II (performance standards).

[45 FR 60623, Sept. 12, 1980]

(a) Identification. A leukocyte alkaline phosphatase test is a device used to identify the enzyme leukocyte alkaline phosphatase in neutrophilic granulocytes (granular leukocytes stainable by neutral dyes). The cytochemical identification of alkaline phosphatase depends on the formation of blue granules in cells containing alkaline phosphatase. The results of this test are used to differentiate chronic granulocytic leukemia (a malignant disease characterized by excessive overgrowth of granulocytes in the bone marrow) and reactions that resemble true leukemia, such as those occuring in severe infections and polycythemia (increased total red cell mass).

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

[45 FR 60623, Sept. 12, 1980, as amended at 59 FR 63007, Dec. 7, 1994; 66 FR 38790, July 25, 2001]

(a) Identification. A leukocyte peroxidase test is a device used to distinguish certain myeloid cells derived from the bone marrow, i.e., neutrophils, eosinophils, and monocytes, from lymphoid cells of the lymphatic system and erythroid cells of the red blood cell series on the basis of their peroxidase activity as evidenced by staining. The results of this test are used in the differential diagnosis of the leukemias.

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

[45 FR 60624, Sept. 12, 1980, as amended at 59 FR 63007, Dec. 7, 1994; 66 FR 38790, July 25, 2001]

(a) Identification. A platelet factor 4 radioimmunoassay is a device used to measure the level of platelet factor 4, a protein released during platelet activation by radioimmunoassay. This device measures platelet activiation, which may indicate a coagulation disorder, such as myocardial infarction or coronary artery disease.

(b) Classification. Class II (performance standards).

[45 FR 60625, Sept. 12, 1980; 46 FR 14890, Mar. 3, 1981]

(a) Identification. A prothrombin consumption tests is a device that measures the patient's capacity to generate thromboplastin in the coagulation process. The test also is an indirect indicator of qualitative or quantitative platelet abnormalities. It is a screening test for thrombocytopenia (decreased number of blood platelets) and hemophilia A and B.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

[45 FR 60625, Sept. 12, 1980, as amended at 84 FR 71800, Dec. 30, 2019]

(a) Identification. The prothrombin-proconvertin test and thrombotest are devices used in the regulation of coumarin therapy (administration of a coumarin anticoagulant such as sodium warfarin in the treatment of venous thrombosis and pulmonary embolism) and as a diagnostic test in conjunction with, or in place of, the Quick prothrombin time test to detect coagulation disorders.

(b) Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

[45 FR 60626, Sept. 12, 1980, as amended at 84 FR 71800, Dec. 30, 2019]

(a) Identification. A prothrombin time test is a device used as a general screening procedure for the detection of possible clotting factor deficiencies in the extrinsic coagulation pathway, which involves the reaction between coagulation factors III and VII, and to monitor patients receiving coumarin therapy (the administration of one of the coumarin anticoagulants in the treatment of venous thrombosis or pulmonary embolism).

(b) Classification. Class II (performance standards).

[45 FR 60626, Sept. 12, 1980]

(a) Identification. A sickle cell test is a device used to determine the sickle cell hemoglobin content of human blood to detect sickle cell trait or sickle cell diseases.

(b) Classification. Class II (performance standards).

[45 FR 60627, Sept. 12, 1980]

(a) Identification. A thrombin time test is a device used to measure fibrinogen concentration and detect fibrin or fibrinogen split products for the evaluation of bleeding disorders.

(b) Classification. Class II (performance standards).

[45 FR 60628, Sept. 12, 1980]

(a) Identification. A thromboplastin generation test is a device used to detect and identify coagulation factor deficiencies and coagulation inhibitors.

(b) Classification. Class I (general controls). This device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 864.9.

[45 FR 60628, Sept. 12, 1980, as amended at 59 FR 63007, Dec. 7, 1994; 66 FR 38790, July 25, 2001]

(a) Identification. A partial thromboplastin time test is a device used for primary screening for coagulation abnormalities, for evaluation of the effect of therapy on procoagulant disorders, and as an assay for coagulation factor deficiencies of the intrinsic coagulation pathway.

(b) Classification. Class II (performance standards).

[45 FR 60629, Sept. 12, 1980]