Immunological Test Systems

Immunological Test Systems

Albumin immunological test system.

§866.5040
Albumin immunological test system.
Identification. An albumin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the albumin (a plasma protein) in serum and other body fluids. Measurement of albumin aids in the diagnosis of kidney and intestinal diseases.
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 866.9.

Prealbumin immunological test system.

§866.5060
Prealbumin immunological test system.
Identification. A prealbumin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the prealbumin (a plasma protein) in serum and other body fluids. Measurement of prealbumin levels in serum may aid in the assessment of the patient's nutritional status.
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 866.9.

Human allotypic marker immunological test system.

§866.5065
Human allotypic marker immunological test system.
Identification. A human allotypic marker immunological test system is a device that consists of the reagents used to identify by immunochemical techniques the inherited human protein allotypic markers (such as nGm, nA2 m, and Km allotypes) in serum and other body fluids. The identification may be used while studying population genetics.
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 866.9.

Alpha-1-antichymotrypsin immunological test system.

§866.5080
Alpha-1-antichymotrypsin immunological test system.
Identification. An alpha-1-antichymotrypsin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques alpha-1-antichymotrypsin (a protein) in serum, other body fluids, and tissues. Alpha-1-antichymotrypsin helps protect tissues against proteolytic (protein-splitting) enzymes released during infection.
Classification. Class II (performance standards).

Antimitochondrial antibody immunological test system.

§866.5090
Antimitochondrial antibody immunological test system.
Identification. An antimitochondrial antibody immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the antimitochondrial antibodies in human serum. The measurements aid in the diagnosis of diseases that produce a spectrum of autoantibodies (antibodies produced against the body's own tissue), such as primary biliary cirrhosis (degeneration of liver tissue) and chronic active hepatitis (inflammation of the liver).
Classification. Class II (performance standards).

Antinuclear antibody immunological test system.

§866.5100
Antinuclear antibody immunological test system.
Identification. An antinuclear antibody immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the autoimmune antibodies in serum, other body fluids, and tissues that react with cellular nuclear constituents (molecules present in the nucleus of a cell, such as ribonucleic acid, deoxyribonucleic acid, or nuclear proteins). The measurements aid in the diagnosis of systemic lupus erythematosus (a multisystem autoimmune disease in which antibodies attack the victim's own tissues), hepatitis (a liver disease), rheumatoid arthritis, Sjgren's syndrome (arthritis with inflammation of the eye, eyelid, and salivary glands), and systemic sclerosis (chronic hardening and shrinking of many body tissues).
Classification. Class II (performance standards).

Antiparietal antibody immunological test system.

§866.5110
Antiparietal antibody immunological test system.
Identification. An antiparietal antibody immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the specific antibody for gastric parietal cells in serum and other body fluids. Gastric parietal cells are those cells located in the stomach that produce a protein that enables vitamin B12 to be absorbed by the body. The measurements aid in the diagnosis of vitamin B12 deficiency (or pernicious anemia), atrophic gastritis (inflammation of the stomach), and autoimmune connective tissue diseases (diseases resulting when the body produces antibodies against its own tissues).
Classification. Class II (performance standards).

Antismooth muscle antibody immunological test system.

§866.5120
Antismooth muscle antibody immunological test system.
Identification. An antismooth muscle antibody immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the antismooth muscle antibodies (antibodies to nonstriated, involuntary muscle) in serum. The measurements aid in the diagnosis of chronic hepatitis (inflammation of the liver) and autoimmune connective tissue diseases (diseases resulting from antibodies produced against the body's own tissues).
Classification Class II (performance standards).

Alpha-1-antitrypsin immunological test system.

§866.5130
Alpha-1-antitrypsin immunological test system.
Identification. An alpha-1-antitrypsin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the alpha-1-antitrypsin (a plasma protein) in serum, other body fluids, and tissues. The measurements aid in the diagnosis of several conditions including juvenile and adult cirrhosis of the liver. In addition, alpha-1-antitrypsin deficiency has been associated with pulmonary emphysema.
Classification. Class II (performance standards).

Bence-Jones proteins immunological test system.

§866.5150
Bence-Jones proteins immunological test system.
Identification. A Bence-Jones proteins immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the Bence-Jones proteins in urine and plasma. Immunoglobulin molecules normally consist of pairs of polypeptide chains (subunits) of unequal size (light chains and heavy chains) bound together by several disulfide bridges. In some cancerous conditions, there is a proliferation of one plasma cell (antibody-producing cell) with excess production of light chains of one specific kind (monoclonal light chains). These free homogeneous light chains not associated with an immunoglobulin molecule can be found in urine and plasma, and have been called Bence-Jones proteins. Measurement of Bence-Jones proteins and determination that they are monoclonal aid in the diagnosis of multiple myeloma (malignant proliferation of plasma cells), Waldenstrom's macroglobulinemia (increased production of large immunoglobulins by spleen and bone marrow cells), leukemia (cancer of the blood-forming organs), and lymphoma (cancer of the lymphoid tissue).
Classification. Class II (performance standards).

Beta-globulin immunological test system.

§866.5160
Beta-globulin immunological test system.
Identification. A beta-globulin immunological test system is a device that consists of reagents used to measure by immunochemical techniques beta globulins (serum protein) in serum and other body fluids. Beta-globulin proteins include beta-lipoprotein, transferrin, glycoproteins, and complement, and are rarely associated with specific pathologic disorders.
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 866.9.

Breast milk immunological test system.

§866.5170
Breast milk immunological test system.
Identification. A breast milk immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the breast milk proteins.
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 866.9.

Fecal calprotectin immunological test system.

§866.5180
Fecal calprotectin immunological test system.
Identification. A fecal calprotectin immunological test system is an in vitro diagnostic device that consists of reagents used to quantitatively measure, by immunochemical techniques, fecal calprotectin in human stool specimens. The device is intended forin vitro diagnostic use as an aid in the diagnosis of inflammatory bowel diseases (IBD), specifically Crohn's disease and ulcerative colitis, and as an aid in differentiation of IBD from irritable bowel syndrome.
Classification. Class II (special controls). The special control for these devices is FDA's guidance document entitled Class II Special Controls Guidance Document: Fecal Calprotectin Immunological Test Systems. For the availability of this guidance document, see 866.1(e).

Carbonic anhydrase B and C immunological test system.

§866.5200
Carbonic anhydrase B and C immunological test system.
Identification. A carbonic anhydrase B and C immunological test system is a device that consists of the reagents used to measure by immunochemical techniques specific carbonic anhydrase protein molecules in serum and other body fluids. Measurements of carbonic anhydrase B and C aid in the diagnosis of abnormal hemoglobin metabolism.
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 866.9.

Ceruloplasmin immunological test system.

§866.5210
Ceruloplasmin immunological test system.
Identification. A ceruloplasmin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the ceruloplasmin (copper-transporting serum protein) in serum, other body fluids, or tissues. Measurements of ceruloplasmin aid in the diagnosis of copper metabolism disorders.
Classification. Class II (performance standards).

Cohn fraction II immunological test system.

§866.5220
Cohn fraction II immunological test system.
Identification. A Cohn fraction II immunological test system is a device that consists of the reagents that contain or are used to measure that fraction of plasma containing protein gamma globulins, predominantly of the IgG class. The device may be used as a coprecipitant in radioimmunoassay methods, as raw material for the purification of IgG subclasses, and to reduce nonspecific adsorption of plasma proteins in immunoassay techniques. Measurement of these proteins aids in the diagnosis of any disease concerned with abnormal levels of IgG gamma globulins such as agammaglobulinemia or multiple myeloma.
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 866.9.

Colostrum immunological test system.

§866.5230
Colostrum immunological test system.
Identification. A colostrum immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the specific proteins in colostrum. Colostrum is a substance excreted by the mammary glands during pregnancy and until production of breast milk begins 1 to 5 days after childbirth.
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 866.9.

Complement components immunological test system.

§866.5240
Complement components immunological test system.
Identification. A complement components immunological test system is a device that consists of the reagents used to measure by immunochemical techniques complement components C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, and C9, in serum, other body fluids, and tissues. Complement is a group of serum proteins which destroy infectious agents. Measurements of these proteins aids in the diagnosis of immunologic disorders, especially those associated with deficiencies of complement components.
Classification. Class II (performance standards).

Complement C2 inhibitor (inactivator) immunological test system.

§866.5250
Complement C2 inhibitor (inactivator) immunological test system.
Identification. A complement C1 inhibitor (inactivator) immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the complement C1 inhibitor (a plasma protein) in serum. Complement C1 inhibitor occurs normally in plasma and blocks the action of the C1 component of complement (a group of serum proteins which destroy infectious agents). Measurement of complement C1 inhibitor aids in the diagnosis of hereditary angioneurotic edema (increased blood vessel permeability causing swelling of tissues) and a rare form of angioedema associated with lymphoma (lymph node cancer).
Classification. Class II (performance standards).

Complement C3b inactivator immunological test system.

§866.5260
Complement C3b inactivator immunological test system.
Identification. A complement C3b inactivator immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the complement C3b inactivator (a plasma protein) in serum. Complement is a group of serum proteins that destroy infectious agents. Measurement of complement C3b inactivator aids in the diagnosis of inherited antibody dysfunction.
Classification. Class II (performance standards).

C-reactive protein immunological test system.

§866.5270
C-reactive protein immunological test system.
Identification. A C-reactive protein immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the C-reactive protein in serum and other body fluids. Measurement of C-reactive protein aids in evaluation of the amount of injury to body tissues.
Classification. Class II (performance standards).

Properdin factor B immunological test system.

§866.5320
Properdin factor B immunological test system.
Identification. A properdin factor B immunological test system is a device that consists of the reagents used to measure by immunochemical techniques properdin factor B in serum and other body fluids. The deposition of properdin factor B in body tissues or a corresponding depression in the amount of properdin factor B in serum and other body fluids is evidence of the involvement of the alternative to the classical pathway of activation of complement (a group of plasma proteins which cause the destruction of cells which are foreign to the body). Measurement of properdin factor B aids in the diagnosis of several kidney diseases, e.g., chronic glomerulonephritis (inflammation of the glomeruli of the kidney), lupus nephritis (kidney disease associated with a multisystem autoimmune disease, systemic lupus erythematosus), as well as several skin diseases, e.g., dermititis herpetiformis (presence of vesicles on the skin that burn and itch), and pemphigus vulgaris (large vesicles on the skin). Other diseases in which the alternate pathway of complement activation has been implicated include rheumatoid arthritis, sickle cell anemia, and gram-negative bacteremia.
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 866.9.

Factor XIII, A, S, immunological test system.

§866.5330
Factor XIII, A, S, immunological test system.
Identification. A factor XIII, A, S, immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the factor XIII (a bloodclotting factor), in platelets (A) or serum (S). Measurements of factor XIII, A, S, aid in the diagnosis and treatment of certain bleeding disorders resulting from a deficiency of this factor.
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 866.9. This exemption does not apply to factor deficiency tests classified under 864.7290 of this chapter.

Ferritin immunological test system.

§866.5340
Ferritin immunological test system.
Identification. A ferritin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the ferritin (an iron-storing protein) in serum and other body fluids. Measurements of ferritin aid in the diagnosis of diseases affecting iron metabolism, such as hemochromatosis (iron overload) and iron deficiency amemia.
Classification. Class II (performance standards).

Fibrinopeptide A immunological test system.

§866.5350
Fibrinopeptide A immunological test system.
Identification. A fibrinopeptide A immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the fibrinopeptide A (a blood-clotting factor) in plasma and other body fluids. Measurement of fibrinopeptide A may aid in the diagnosis and treatment of certain blood-clotting disorders.
Classification. Class II (performance standards).

Cohn fraction IV immunological test system.

§866.5360
Cohn fraction IV immunological test system.
Identification. A Cohn fraction IV immunological test system is a device that consists of or measures that fraction of plasma proteins, predominantly alpha- and beta- globulins, used as a raw material for the production of pure alpha- or beta- globulins. Measurement of specific alpha- or beta- globulins aids in the diagnosis of many diseases, such as Wilson's disease (an inherited disease affecting the liver and brain), Tangier's disease (absence of alpha-1-lipoprotein), malnutrition, iron deficiency anemia, red blood cell disorders, and kidney disease.
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 866.9.

Cohn fraction V immunological test system.

§866.5370
Cohn fraction V immunological test system.
Identification. A Cohn fraction V immunological test system is a device that consists of or measures that fraction of plasma containing predominantly albumin (a plasma protein). This test aids in the diagnosis of diseases where albumin levels may be depressed, e.g., nephrosis (disease of the kidney), proteinuria (protein in the urine), gastroenteropathy (disease of the stomach and small intestine), rheumatoid arthritis, and viral hepatitis.
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 866.9.

Free secretory component immunological test system.

§866.5380
Free secretory component immunological test system.
Identification. A free secretory component immunological test system is a device that consists of the reagents used to measure by immunochemical techniques free secretory component (normally a portion of the secretory IgA antibody molecule) in body fluids. Measurement of free secretory component (protein molecules) aids in the diagnosis or repetitive lung infections and other hypogammaglobulinemic conditions (low antibody levels).
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 866.9.

Alpha-globulin immunological test system.

§866.5400
Alpha-globulin immunological test system.
Identification. An alpha-globulin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the alpha-globulin (a serum protein) in serum and other body fluids. Measurement of alpha-globulin may aid in the diagnosis of inflammatory lesions, infections, severe burns, and a variety of other conditions.
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 866.9.

Alpha-1-glycoproteins immunological test system.

§866.5420
Alpha-1-glycoproteins immunological test system.
Identification. An alpha-1-glycoproteins immunological test system is a device that consists of the reagents used to measure by immunochemical techniques alpha-1-glycoproteins (a group of plasma proteins found in the alpha-1 group when subjected to electrophoresis) in serum and other body fluids. Measurement of specific alpha-1-glycoproteins may aid in the diagnosis of collagen (connective tissue) disorders, tuberculosis, infections, extensive malignancy, and diabetes.
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 866.9.

Alpha-2-glycoproteins immunological test system.

§866.5425
Alpha-2-glycoproteins immunological test system.
Identification. An alpha-2-glycoproteins immunolgical test system is a device that consists of the reagents used to measure by immunochemical techniques the alpha-2-glycoproteins (a group of plasma proteins found in the alpha-2 group when subjected to electrophoresis) in serum and other body fluids. Measurement of alpha-2-glycoproteins aids in the diagnosis of some cancers and genetically inherited deficiencies of these plasma proteins.
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 866.9.

Beta-2-glycoprotein I immunological test system.

§866.5430
Beta-2-glycoprotein I immunological test system.
Identification. A beta-2-glycoprotein I immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the beta-2-glycoprotein I (a serum protein) in serum and other body fluids. Measurement of beta-2-glycoprotein I aids in the diagnosis of an inherited deficiency of this serum protein.
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 866.9.

Beta-2-glycoprotein III immunological test system.

§866.5440
Beta-2-glycoprotein III immunological test system.
Identification. A beta-2-glycoprotein III immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the beta-2-glycoprotein III (a serum protein) in serum and other body fluids. Measurement of beta-2-glycoprotein III aids in the diagnosis of an inherited deficiency of this serum protein and a variety of other conditions.
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 866.9.

Haptoglobin immunological test system.

§866.5460
Haptoglobin immunological test system.
Identification. A haptoglobin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the haptoglobin (a protein that binds hemoglobin, the oxygen-carrying pigment in red blood cells) in serum. Measurement of haptoglobin may aid in the diagnosis of hemolytic diseases (diseases in which the red blood cells rupture and release hemoglobin) related to the formation of hemoglobin-haptoglobin complexes and certain kidney diseases.
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 866.9.

Hemoglobin immunological test system.

§866.5470
Hemoglobin immunological test system.
Identification. A hemoglobin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the different types of free hemoglobin (the oxygen-carrying pigment in red blood cells) in blood, urine, plasma, or other body fluids. Measurements of free hemoglobin aid in the diagnosis of various hematologic disorders, such as sickle cell anemia, Fanconi's anemia (a rare inherited disease), aplastic anemia (bone marrow does not produce enough blood cells), and leukemia (cancer of the blood-forming organs).
Classification. Class II (performance standards).

Hemopexin immunological test system.

§866.5490
Hemopexin immunological test system.
Indentification. A hemopexin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the hemopexin (a serum protein that binds heme, a component of hemoglobin) in serum. Measurement of hemopexin aids in the diagnosis of various hematologic disorders, such as hemolytic anemia (anemia due to shortened in vivo survival of mature red blood cells and inability of the bone marrow to compensate for their decreased life span) and sickle cell anemia.
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 866.9.

Hypersensitivity pneumonitis immunological test system.

§866.5500
Hypersensitivity pneumonitis immunological test system.
Identification. A hypersensitivity pneumonitis immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the immunoglobulin antibodies in serum which react specifically with organic dust derived from fungal or animal protein sources. When these antibodies react with such dusts in the lung, immune complexes precipitate and trigger an inflammatory reaction (hypersensitivity pneumonitis). Measurement of these immunoglobulin G antibodies aids in the diagnosis of hypersensitivity pneumonitis and other allergic respiratory disorders.
Classification. Class II (performance standards).

Immunoglobulins A, G, M, D, and E immunological test system.

§866.5510
Immunoglobulins A, G, M, D, and E immunological test system.
Identification. An immunoglobulins A, G, M, D, and E immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the immunoglobulins A, G, M, D, an E (serum antibodies) in serum. Measurement of these immunoglobulins aids in the diagnosis of abnormal protein metabolism and the body's lack of ability to resist infectious agents.
Classification. Class II (performance standards).

Immunoglobulin G (Fab fragment specific) immunological test system.

§866.5520
Immunoglobulin G (Fab fragment specific) immunological test system.
Identification. An immunoglobulin G (Fab fragment specific) immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the Fab antigen-binding fragment resulting from breakdown of immunoglobulin G antibodies in urine, serum, and other body fluids. Measurement of Fab fragments of immunoglobulin G aids in the diagnosis of lymphoproliferative disorders, such as multiple myeloma (tumor of bone marrow cells), Waldenstrom's macroglobulinemia (increased immunoglobulin production by the spleen and bone marrow cells), and lymphoma (tumor of the lymphoid tissues).
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 866.9.

Immunoglobulin G (Fc fragment specific) immunological test system.

§866.5530
Immunoglobulin G (Fc fragment specific) immunological test system.
Identification. An immunoglobulin G (Fc fragment specific) immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the Fc (carbohydrate containing) fragment of immunoglobulin G (resulting from breakdown of immunoglobulin G antibodies) in urine, serum, and other body fluids. Measurement of immunoglobulin G Fc fragments aids in the diagnosis of plasma cell antibody-forming abnormalities, e.g., gamma heavy chain disease.
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 866.9.

Immunoglobulin G (Fd fragment specific) immunological test system.

§866.5540
Immunoglobulin G (Fd fragment specific) immunological test system.
Identification. An immunoglobulin G (Fd fragment specific) immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the amino terminal (antigen-binding) end (Fd fragment) of the heavy chain (a subunit) of the immunoglobulin antibody molecule in serum. Measurement of immunoglobulin G Fd fragments aids in the diagnosis of plasma antibody-forming cell abnormalities.
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 866.9.

Immunoglobulin (light chain specific) immunological test system.

§866.5550
Immunoglobulin (light chain specific) immunological test system.
Identification. An immunoglobulin (light chain specific) immunological test system is a device that consists of the reagents used to measure by immunochemical techniques both kappa and lambda types of light chain portions of immunoglobulin molecules in serum, other body fluids, and tissues. In some disease states, an excess of light chains are produced by the antibody-forming cells. These free light chains, unassociated with gamma globulin molecules, can be found in a patient's body fluids and tissues. Measurement of the various amounts of the different types of light chains aids in the diagnosis of multiple myeloma (cancer of antibody-forming cells), lymphocytic neoplasms (cancer of lymphoid tissue), Waldenstrom's macroglobulinemia (increased production of large immunoglobulins), and connective tissue diseases such as rheumatoid arthritis or systemic lupus erythematosus.
Classification. Class II (performance standards).

Lactic dehydrogenase immunological test system.

§866.5560
Lactic dehydrogenase immunological test system.
Identification. A lactic dehydrogenase immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the activity of the lactic dehydrogenase enzyme in serum. Increased levels of lactic dehydrogenase are found in a variety of conditions, including megaloblastic anemia (decrease in the number of mature red blood cells), myocardial infarction (heart disease), and some forms of leukemia (cancer of the blood-forming organs). However, the diagnostic usefulness of this device is limited because of the many conditions known to cause increased lactic dehydrogenase levels.
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 866.9.

Lactoferrin immunological test system.

§866.5570
Lactoferrin immunological test system.
Identification. A lactoferrin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the lactoferrin (an iron-binding protein with the ability to inhibit the growth of bacteria) in serum, breast milk, other body fluids, and tissues. Measurement of lactoferrin may aid in the diagnosis of an inherited deficiency of this protein.
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 866.9.

Alpha-1-lipoprotein immunological test system.

§866.5580
Alpha-1-lipoprotein immunological test system.
Identification. An alpha-1-lipoprotein immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the alpha-1-lipoprotein (high-density lipoprotein) in serum and plasma. Measurement of alpha-1-lipoprotein may aid in the diagnosis of Tangier disease (a hereditary disorder of fat metabolism).
Classification. Class II (performance standards).

Lipoprotein X immunological test system.

§866.5590
Lipoprotein X immunological test system.
Identification. A lipoprotein X immunological test system is a device that consists of the reagents used to measure by immunochemical techniques lipoprotein X (a high-density lipoprotein) in serum and other body fluids. Measurement of lipoprotein X aids in the diagnosis of obstructive liver disease.
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 866.9.

Low-density lipoprotein immunological test system.

§866.5600
Low-density lipoprotein immunological test system.
Identification. A low-density lipoprotein immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the low-density lipoprotein in serum and other body fluids. Measurement of low-density lipoprotein in serum may aid in the diagnosis of disorders of lipid (fat) metabolism and help to identify young persons at risk from cardiovascular diseases.
Classification. Class II (performance standards).

Alpha-2-macroglobulin immunological test system.

§866.5620
Alpha-2-macroglobulin immunological test system.
Identification. An alpha-2-macroglobulin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the alpha-2-macroglobulin (a serum protein) in plasma. Measurement of alpha-2-macroglobulin may aid in the diagnosis of blood-clotting or clot lysis disorders.
Classification. Class II (performance standards).

Beta-2-microglobulin immunological test system.

§866.5630
Beta-2-microglobulin immunological test system.
Identification. A beta-2-microglobulin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques beta-2-microglobulin (a protein molecule) in serum, urine, and other body fluids. Measurement of beta-2-microglobulin aids in the diagnosis of active rheumatoid arthritis and kidney disease.
Classification. Class II (performance standards).

Infectious mononucleosis immunological test system.

§866.5640
Infectious mononucleosis immunological test system.
Identification. An infectious mononucleosis immunological test system is a device that consists of the reagents used to measure by immunochemical techniques heterophile antibodies frequently associated with infectious mononucleosis in serum, plasma, and other body fluids. Measurements of these antibodies aid in the diagnosis of infectious mononucleosis.
Classification. Class II (performance standards).

Multiple autoantibodies immunological test system.

§866.5660
Multiple autoantibodies immunological test system.
Identification. A multiple autoantibodies immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the autoantibodies (antibodies produced against the body's own tissues) in serum and other body fluids. Measurement of multiple autoantibodies aids in the diagnosis of autoimmune disorders (disease produced when the body's own tissues are injured by autoantibodies).
Classification. Class II (performance standards).

Aquaporin-4 autoantibody immunological test system.

§866.5665
Aquaporin-4 autoantibody immunological test system.
Identification. An Aquaporin-4 autoantibody immunological test system is a device that consists of reagents used to measure by immunochemical techniques autoantibodies in human serum samples that react with Aquaporin-4 (AQP4Ab). The measurements aid in the diagnosis of neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorders (NMOSD) in conjunction with other clinical, laboratory, and radiological (e.g., magnetic resonance imaging) findings.
Classification. Class II (special controls). The special controls for this device are: (1) Premarket notification submissions must include the following information: (i) A detailed device description including: (A) A detailed description of all components including all required ancillary reagents in the test; (B) If applicable, 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, standalone software applications and hardware-based devices that incorporate software; (D) A detailed description of appropriate internal and external quality controls that are recommended or provided. The description must identify those control elements that are incorporated into the specified testing procedures; (E) Detailed specifications for sample collection, processing, and storage; (F) A detailed description of methodology and assay procedure (G) A description of how the assay cutoff (the medical decision point between positive and negative) was established and validated as well as supporting data; and (H) Detailed specification of the criteria for test results interpretation and reporting. (ii) Detailed information demonstrating the performance characteristics of the device, including: (A) Device precision/reproducibility data generated from within-run, between-run, between-day, between-lot, between-site, and total precision for multiple nonconsecutive days, as applicable. A well characterized panel of patient samples or pools from the indicated population that covers the device measuring range must be used. (B) Device linearity data generated from samples covering the device measuring range, if applicable. (C) Information on traceability to a reference material and description of value assignment of calibrators and controls, if applicable. (D) Device analytical sensitivity data, including limit of blank, limit of detection, and limit of quantitation, if applicable. (E) Device analytical specificity data, including interference by endogenous and exogenous substances, as well as cross-reactivity with samples derived from patients with other autoimmune diseases or conditions. (F) Device instrument carryover data, when applicable. (G) Device stability data, including real-time stability under various storage times and temperatures. (H) Specimen stability data, including stability under various storage times, temperatures, freeze-thaw, and transport conditions, where appropriate. (I) Method comparison data generated by comparison of the results obtained with the device to those obtained with a legally marketed predicate device with similar indications of use. A well-characterized panel of patient samples from the indicated population covering the device measuring range must be used. (J) Specimen matrix comparison data, if more than one specimen type or anticoagulant can be tested with the device. Samples used for comparison must be from well-characterized patient samples covering the device measuring range. (K) Clinical performance must be established by comparing data generated by testing samples from the indicated population and the differential diagnosis or non-target disease groups with the device to the clinical diagnostic standard. (1) The diagnosis of NMO and NMOSD must be based on clinical findings, laboratory tests (e.g., serological tests), and radiological tests (e.g., magnetic resonance imaging). (2) The differential diagnosis or non-target disease group must include the applicable diseases or conditions, including but not be limited to the following: Multiple sclerosis, stroke, Lyme disease, shingles, syphilis, human immunodeficiency virus, hepatitis B, tuberculosis, Srgen's syndrome, systemic lupus erythematous, systemic vasculitis, sarcoidosis, Graves' disease, Hashimoto's disease, Type I diabetes, rheumatoid arthritis, Addison's disease, and myasthenia gravis. (3) Diagnosis of diseases or conditions for the differential or non-target disease groups must be based on established diagnostic criteria and clinical evaluation. (4) For all samples, the diagnostic clinical criteria and the demographic information must be collected and provided. (5) The clinical validation results must demonstrate clinical sensitivity and clinical specificity for the test values based on the presence or absence of NMO and NMOSD. (6) The data must be summarized in tabular format comparing the interpretation of results to the disease status. (L) Expected/reference values generated by testing an adequate number of samples from apparently healthy normal individuals. (iii) Identification of risk mitigation elements used by the device, including description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing. (2) The device's 21 CFR 809.10(b) compliant labeling must include warnings relevant to the device including: (i) A warning statement that reads The device is for use by laboratory professionals in a clinical laboratory setting; and (ii) A warning statement that reads The device is not to be used as a stand-alone device but as an adjunct to other clinical information. A diagnosis of Neuromyelitis Optica (NMO) and Neuromyelitis Optica Spectrum Disorders (NMOSD) should not be made on a single test result. The clinical symptoms, results from physical examination, laboratory tests (e.g., serological tests), and radiological tests (e.g. Magnetic Resonance Imaging), when appropriate, should always be taken into account when considering the diagnosis of NMO and NMOSD. (3) The device's 21 CFR 809.10(b) compliant labeling must include a detailed description of the protocol and performance studies performed in accordance with paragraph (b)(1)(ii) of this section and a summary of the results.

Zinc transporter 8 autoantibody immunological test system.

§866.5670
Zinc transporter 8 autoantibody immunological test system.
Identification. A zinc transporter 8 autoantibody immunological test system is a device that consists of reagents used to measure, by immunochemical techniques, the autoantibodies in human serum samples that react with Zinc Transporter 8 (ZnT8). The measurements aid in the diagnosis of Type 1 diabetes mellitus (autoimmune mediated diabetes) in conjunction with other clinical and laboratory findings.
Classification. Class II (special controls). The special controls for this device are: (1) Premarket notification submissions must include the following information: (i) A detailed description of the device that includes: (A) A detailed description of all components in the test system, including a description of the assay components in the kit and all required ancillary reagents; (B) A detailed description of instrumentation and equipment, and illustrations or photographs of non-standard equipment or methods if applicable; (C) Detailed documentation of the device software, including, but not limited to, standalone software applications and hardware-based devices that incorporate software where applicable; (D) A detailed description of appropriate internal and external quality controls that are recommended or provided. The description must identify those control elements that are incorporated into the recommended testing procedures; (E) Detailed specifications for sample collection, processing, and storage; (F) A detailed description of methodology and assay procedure; and (G) Detailed specification of the criteria for test results interpretation and reporting. (ii) Information that demonstrates the performance characteristics of the device, including: (A) Device precision/reproducibility data generated from within-run, between-run, between-day, between-lot, between-operator, between-instruments, between-site, and total precision for multiple nonconsecutive days as applicable. A well characterized panel of patient samples or pools from the intended use population that covers the device measuring range must be used; (B) Device linearity data generated from patient samples covering the assay measuring range if applicable; (C) Information on traceability to a reference material and description of value assignment of calibrators and controls if applicable; (D) Device analytical sensitivity data, including limit of blank, limit of detection and limit of quantitation if applicable; (E) Device analytical specificity data, including interference by endogenous and exogenous substances, as well as cross-reactivity with samples derived from patients with other autoimmune diseases or conditions; (F) Device instrument carryover data when applicable; (G) Device stability data including real-time stability under various storage times and temperatures; (H) Specimen stability data, including stability under various storage times, temperatures, freeze-thaw, and transport conditions where appropriate; (I) Method comparison data generated by comparison of the results obtained with the device to those obtained with a legally marketed predicate device with similar indication of use. Patient samples from the intended use population covering the device measuring range must be used (J) Specimen matrix comparison data if more than one specimen type or anticoagulant can be tested with the device. Samples used for comparison must be from patient samples covering the device measuring range; (K) A description of how the assay cut-off (the medical decision point between positive and negative) was established and validated as well as supporting data; (L) Clinical performance must be established by comparing data generated by testing samples from the intended use population and the differential diagnosis groups with the device to the clinical diagnostic standard. The diagnosis of Type 1 diabetes mellitus must be based on clinical history, physical examination, and laboratory tests, such as one or more pancreatic or insulin autoantibody test. Because the intended use population for Type 1 diabetes mellitus includes subjects less than 18 years old, samples from representative numbers of these subjects must be included. Representative numbers of samples from all age strata must also be included. The differential diagnosis groups must include, but not be limited to the following: Type 2 diabetes mellitus; metabolic syndrome; latent autoimmune diabetes in adults; other autoimmune diseases such as celiac disease (without a concomitant diagnosis of Type 1 diabetes mellitus), systemic lupus erythematosus, rheumatoid arthritis, and Hashimoto's thyroiditis; infection; renal disease; and testicular cancer. Diseases for the differential groups must be based on established diagnostic criteria and clinical evaluation. For all samples, the diagnostic clinical criteria and the demographic information must be collected and provided. The clinical validation results must demonstrate clinical sensitivity and clinical specificity for the test values based on the presence or absence of Type 1 diabetes mellitus. The data must be summarized in tabular format comparing the interpretation of results to the disease status; and (M) Expected/reference values generated by testing an adequate number of samples from apparently healthy normal individuals. (iii) Identification of risk mitigation elements used by the device, including description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing. (2) Your 21 CFR 809.10(a) compliant label and 21 CFR 809.10(b) compliant labeling must include warnings relevant to the assay including: (i) A warning statement that reads, The device is for use by laboratory professionals in a clinical laboratory setting; (ii) A warning statement that reads, The test is not a stand-alone test but an adjunct to other clinical information. A diagnosis of Type 1 diabetes mellitus should not be made on a single test result. The clinical symptoms, results on physical examination, and laboratory tests (e.g., serological tests), when appropriate, should always be taken into account when considering the diagnosis of Type 1 diabetes mellitus and Type 2 diabetes mellitus; (iii) A warning statement that reads, Absence of Zinc T8 autoantibody does not rule out a diagnosis of Type 1 diabetes mellitus; and (iv) A warning statement that reads, The assay has not been demonstrated to be effective for monitoring the stage of disease or its response to treatment. (3) Your 21 CFR 809.10(b) compliant labeling must include a description of the protocol and performance studies performed in accordance with paragraph (b)(1)(ii) of this section and a summary of the results.

Myoglobin immunological test system.

§866.5680
Myoglobin immunological test system.
Identification. A myoglobin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the myoglobin (an oxygen storage protein found in muscle) in serum and other body fluids. Measurement of myoglobin aids in the rapid diagnosis of heart or renal disease.
Classification. Class II (performance standards).

Whole human plasma or serum immunological test system.

§866.5700
Whole human plasma or serum immunological test system.
Identification. A whole human plasma or serum immunological test system is a device that consists of reagents used to measure by immunochemical techniques the proteins in plasma or serum. Measurements of proteins in plasma or serum aid in the diagnosis of any disease concerned with abnormal levels of plasma or serum proteins, e.g., agammaglobulinemia, allergies, multiple myeloma, rheumatoid vasculitis, or hereditary angioneurotic edema.
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 866.9.

Plasminogen immunological test system.

§866.5715
Plasminogen immunological test system.
Identification. A plasminogen immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the plasminogen (an inactive substance from which plasmin, a blood-clotting factor, is formed) in serum, other body fluids, and tissues. Measurement of plasminogen levels may aid in the diagnosis of fibrinolytic (blood-clotting) disorders.
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 866.9.

Prothrombin immunological test system.

§866.5735
Prothrombin immunological test system.
Identification. A prothrombin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the prothrombin (clotting factor II) in serum. Measurements of the amount of antigenically competent (ability to react with protein antibodies) prothrombin aid in the diagnosis of blood-clotting disorders.
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 866.9. This exemption does not apply to multipurpose systems for in vitro coagulation studies classified under 864.5425 of this chapter or prothrombin time tests classified under 864.7750 of this chapter.

Radioallergosorbent (RAST) immunological test system.

§866.5750
Radioallergosorbent (RAST) immunological test system.
Identification. A radioallergosorbent immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the allergen antibodies (antibodies which cause an allergic reaction) specific for a given allergen. Measurement of specific allergen antibodies may aid in the diagnosis of asthma, allergies, and other pulmonary disorders.
Classification. Class II (performance standards).

Tryptase test system.

§866.5760
Tryptase test system.
Identification. A tryptase test system is a device that aids in the diagnosis of systemic mastocytosis. It is intended for in vitro diagnostic use as an aid in the clinical diagnosis of patients with a suspicion of systemic mastocytosis in conjunction with other clinical and laboratory findings.
Classification. Class II (special controls). The special control is FDA's guideline entitled Class II Special Controls Guideline: Tryptase Test System as an Aid in the Diagnosis of Systemic Mastocytosis. For availability of the document, see 866.1(e).

Retinol-binding protein immunological test system.

§866.5765
Retinol-binding protein immunological test system.
Identification. A retinol-binding protein immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the retinol-binding protein that binds and transports vitamin A in serum and urine. Measurement of this protein may aid in the diagnosis of kidney disease and in monitoring patients with kidney transplants.
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 866.9.

Rheumatoid factor immunological test system.

§866.5775
Rheumatoid factor immunological test system.
Identification. A rheumatoid factor immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the rheumatoid factor (antibodies to immunoglobulins) in serum, other body fluids, and tissues. Measurement of rheumatoid factor may aid in the diagnosis of rheumatoid arthritis.
Classification. Class II (performance standards).

Anti-Saccharomyces cerevisiae (S. cerevisiae) antibody (ASCA) test systems.

§866.5785
Anti-Saccharomyces cerevisiae (S. cerevisiae) antibody (ASCA) test systems.
Identification. The Anti-Saccharomyces cerevisiae (S. cerevisiae) antibody (ASCA) test system is an in vitro diagnostic device that consists of the reagents used to measure, by immunochemical techniques, antibodies to S. cerevisiae (baker's or brewer's yeast) in human serum or plasma. Detection of S. cerevisiae antibodies may aid in the diagnosis of Crohn's disease.
Classification. Class II (special controls). The special control is FDA's Guidance for Industry and FDA Reviewers: Class II Special Control Guidance Document for Anti-Saccharomyces cerevisiae (S. cerevisiae) Antibody (ASCA) Premarket Notifications.

Seminal fluid (sperm) immunological test system.

§866.5800
Seminal fluid (sperm) immunological test system.
Identification. A seminal fluid (sperm) immunological test system is a device that consists of the reagents used for legal purposes to identify and differentiate animal and human semen. The test results may be used as court evidence in alleged instances of rape and other sex-related crimes.
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 866.9.

Systemic lupus erythematosus immunological test system.

§866.5820
Systemic lupus erythematosus immunological test system.
Identification. A systemic lupus erythematosus (SLE) immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the autoimmune antibodies in serum and other body fluids that react with cellular nuclear double-stranded deoxyribonucleic acid (DNA) or other nuclear constituents that are specifically diagnostic of SLE. Measurement of nuclear double-stranded DNA antibodies aids in the diagnosis of SLE (a multisystem autoimmune disease in which tissues are attacked by the person's own antibodies).
Classification. Class II (performance standards).

Total spinal fluid immunological test system.

§866.5860
Total spinal fluid immunological test system.
Identification. A total spinal fluid immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the total protein in cerebrospinal fluid. Measurement of spinal fluid proteins may aid in the diagnosis of multiple sclerosis and other diseases of the nervous system.
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 866.9.

Thyroid autoantibody immunological test system.

§866.5870
Thyroid autoantibody immunological test system.
Identification. A thyroid autoantibody immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the thyroid autoantibodies (antibodies produced against the body's own tissues). Measurement of thyroid autoantibodies may aid in the diagnosis of certain thyroid disorders, such as Hashimoto's disease (chronic lymphocytic thyroiditis), nontoxic goiter (enlargement of thyroid gland), Grave's disease (enlargement of the thyroid gland with protrusion of the eyeballs), and cancer of the thyroid.
Classification. Class II (performance standards).

Transferrin immunological test system.

§866.5880
Transferrin immunological test system.
Identification. A transferrin immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the transferrin (an iron-binding and transporting serum protein) in serum, plasma, and other body fluids. Measurement of transferrin levels aids in the diagnosis of malnutrition, acute inflammation, infection, and red blood cell disorders, such as iron deficiency anemia.
Classification. Class II (performance standards).

Inter-alpha trypsin inhibitor immunological test system.

§866.5890
Inter-alpha trypsin inhibitor immunological test system.
Identification. An inter-alpha trypsin inhibitor immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the inter-alpha trypsin inhibitor (a protein) in serum and other body fluids. Measurement of inter-alpha trypsin inhibitor may aid in the diagnosis of acute bacterial infection and inflammation.
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 866.9.

Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation detection system.

§866.5900
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation detection system.
Identification. The CFTR gene mutation detection system is a device used to simultaneously detect and identify a panel of mutations and variants in the CFTR gene. It is intended as an aid in confirmatory diagnostic testing of individuals with suspected cystic fibrosis (CF), carrier identification, and newborn screening. This device is not intended for stand-alone diagnostic purposes, prenatal diagnostic, pre-implantation, or population screening.
Classification. Class II (special controls). The special control is FDA's guidance document entitled Class II Special Controls Guidance Document: CFTR Gene Mutation Detection System. See 866.1(e) for the availability of this guidance document.

Quality control material for cystic fibrosis nucleic acid assays.

§866.5910
Quality control material for cystic fibrosis nucleic acid assays.
Identification. Quality control material for cystic fibrosis nucleic acid assays. A quality control material for cystic fibrosis nucleic acid assays is a device intended to help monitor reliability of a test system by detecting analytical deviations such as those that may arise from reagent or instrument variation in genetic testing. This type of device includes recombinant, synthetic, and cell line-based DNA controls.
Classification. Class II (special controls). The special control is FDA's guidance document entitled Class II Special Controls Guidance Document: Quality Control Material for Cystic Fibrosis Nucleic Acid Assays. See 866.1(e) for the availability of this guidance document.

Newborn screening test for severe combined immunodeficiency disorder (SCID).

§866.5930
Newborn screening test for severe combined immunodeficiency disorder (SCID).
Identification. A newborn screening test for SCID is a prescription device intended to measure T-cell receptor excision circle (TREC) DNA obtained from dried blood spot specimens on filter paper using a polymerase chain reaction based test as an aid in screening newborns for SCID. Presumptive positive results must be followed up by diagnostic confirmatory testing. This test is not intended for use as a diagnostic test, or for screening of SCID-like syndromes, such as DiGeorge syndrome or Omenn syndrome. It is also not intended to screen for less acute SCID syndromes, such as leaky SCID or variant SCID.
Classification. Class II (special controls). The special controls for this device are: (1) Premarket notification submissions must include the following information: (i) The intended use must indicate: (A) The test is not intended for diagnostic use, or for screening of SCID-like syndromes, such as DiGeorge syndrome or Omenn syndrome; and (B) The test is not intended to screen for less acute SCID syndromes, such as leaky SCID or variant SCID. (ii) A detailed description of all components in the test that includes: (A) A detailed description of the test components, all required reagents, 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) Specifications for the filter paper, which must be appropriately labeled for in vitro diagnostic use, to be used in specimen collection and how it will be used in specimen collection validation. These specifications must include: descriptive characteristics of the filter paper, instructions on how a lab should choose the appropriate filter paper, chemical properties of the filter paper, interference concerns associated with the chemicals in the filter paper, absorption properties of the filter paper, punch size, absorption capacity, testing for homogeneity of punches, diameter of the circle for the dried blood spot aliquot, absorption time, physical composition, and number and size of punches to be tested; (D) Methodology and protocols for detection of T-cell receptor excision circles and methods for determination of results. The cutoff must be selected before conducting clinical and analytical studies; (E) A description of the result outputs along with sample reports. Sample reports must include the scale used in reporting of results (e.g., TREC copies/L) and the range of values that will be reported out; and (F) A description of appropriate internal and external controls that are recommended or provided. The description must identify those control elements that are incorporated into the testing procedure. (iii) Information that demonstrates the performance characteristics of the test, including: (A) Data that demonstrates the clinical validity of the device, using well characterized prospectively or retrospectively obtained clinical specimens representative of the intended use population. A minimum of 10 to 15 confirmed positive specimens must be obtained from more than 1 site, including relevant annotation, and, at 1 year or beyond, a SCID diagnosis by flow cytometry or clinically meaningful information regarding the status of the subject must be obtained. Additional specimens should have been obtained that are characterized by other disorders that can be found by screening specimens that have low or absent TREC (e.g., other T-cell lymphopenic disorders) to supplement the range of results. The clinical validation study must have a pre-specified clinical decision point (i.e., cutoff to distinguish positive and negative results). Results must be summarized in tabular format comparing interpretation of results to the reference method. Point estimates together with two-sided 95 percent confidence intervals must be provided for the positive percent agreement, negative percent agreement, and overall percent agreement. Data must include the retest rate, the false positive rate before retest, the final false positive rate, and the false negative rate; (B) Device reproducibility data generated, using a minimum of three sites of which at least two must be external sites, with two operators at each site. Each site must conduct a minimum of five runs per operator over five nonconsecutive days evaluating a minimum of six different relevant TREC concentrations that span and are well distributed over the measuring range and include the clinical cutoff. Specimens must include cord blood and cord blood diluted with ABO matched adult blood specimens. Identical specimens from the same sample panel must be tested at each site. Each specimen must be run in triplicate and include controls run in triplicate. Results must be reported as the standard deviation and percentage coefficient of variation for each level tested. Results must also be displayed as a dichotomous variable around the cutoff. Total variation must be partitioned into the sum of within-lab and between-lab variations with pre-specified acceptance criteria and 95 percent confidence intervals for all data. Pre-specified acceptance criteria must be provided and followed; (C) Device precision data using clinical samples to evaluate the within-lot, between-lot, within-run, between run, and total variation. A range of TREC levels of the specimen must include samples within the measuring range, samples above and below the measuring range, as well as with samples very near above and below the cutoff value. At least three replicates of each specimen must be tested with controls and calibrator(s) according to the device instructions for use. The precision study must use well characterized samples using different lots, instruments, and operators. Results must be summarized in tabular format. Pre-specified acceptance criteria must be provided and followed; (D) Linearity of the test must be demonstrated using a dilution panel from clinical samples. The range of dilution samples must include samples within the measuring range, samples above and below the measuring range, as well as with samples very near above and below the cutoff value. Results of the regression analysis must be summarized in tabular format and fitted into a linear regression model with the individual measurement results against the dilution factors. Pre-specified acceptance criteria must be provided and followed; (E) Device analytic sensitivity data, including limit of blank, limit of detection, and limit of quantification; (F) Device specificity data, including interference, carryover, cross-contamination, and in silico analysis of potential off-target genomic sequences; (G) Device stability data, including real-time stability of samples under various storage times, temperatures, and freeze-thaw conditions. A separate shipping stability study must be performed; (H) Lot-to-lot reproducibility study of each filter paper that will be validated with the test. The lot-to-lot study must include a minimum of three lots of each blood spot card that will be validated with the test and be conducted over five nonconsecutive days. The sample panel must consist of specimens with a range of TREC levels and include samples within the measuring range, samples above and below the measuring range, and samples very near above and below the cutoff value. Multiple punches must be obtained from each card for demonstration of homogeneity of the analyte across the dried blood spot. Comparability of the test performance for each filter paper must be demonstrated. Stability and storage of TREC DNA on each blood spot card must be demonstrated. Results of the lot-to-lot study must be summarized providing the mean, standard deviation, and percentage coefficient of variation in a tabular format. Data must be calculated for within-run, between-run, within-lot, and between-lot. Data demonstrating the concordance between results across different filter papers must be provided. Study acceptance criteria must be provided and followed; and (I) If applicable, a thermocycler reproducibility study must be performed using thermocyclers from three independent thermocyler manufacturers. The sample panel must consist of specimens with a range of TREC levels and must include samples within the measuring range, samples above and below the measuring range, and samples very near above and below the cutoff value. The study must be done using three filter paper lots and conducted over five nonconsecutive days. Results of the thermocycler reproducibility study must be summarized providing the mean, standard deviation, and percentage coefficient of variance in a tabular format. Data must be calculated for the within-run, between-run, within-lot, between-lot, and between thermocycler manufacturer study results. Study acceptance criteria must be provided and followed. (iv) Identification of risk mitigation elements used by your device, including a description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing. (2) Your 809.10 compliant labeling must include: (i) A warning statement that reads This test is not intended for diagnostic use, preimplantation or prenatal testing, or for screening of SCID-like syndromes, such as DiGeorge syndrome or Omenn syndrome. It is also not intended to screen for less acute SCID syndromes, such as leaky SCID or variant SCID.; (ii) A warning statement that reads Test results are intended to be used in conjunction with other clinical and diagnostic findings, consistent with professional standards of practice, including confirmation by alternative methods and clinical evaluation, as appropriate.; (iii) A description of the performance studies listed in paragraph (b)(1)(iii) and a summary of the results; and (iv) A description of the filter paper specifications required for the test.

Autosomal recessive carrier screening gene mutation detection system.

§866.5940
Autosomal recessive carrier screening gene mutation detection system.
Identification. Autosomal recessive carrier screening gene mutation detection system is a qualitative in vitro molecular diagnostic system used for genotyping of clinically relevant variants in genomic DNA isolated from human specimens intended for prescription use or over-the-counter use. The device is intended for autosomal recessive disease carrier screening in adults of reproductive age. The device is not intended for copy number variation, cytogenetic, or biochemical testing.
Classification. Class II (special controls). Autosomal recessive carrier screening gene mutation detection system must comply with the following special controls: (1) If the device is offered over-the-counter, the device manufacturer must provide information to a potential purchaser or actual test report recipient about how to obtain access to a board-certified clinical molecular geneticist or equivalent to assist in pre- and post-test counseling. (2) The device must use a collection device that is FDA cleared, approved, or classified as 510(k) exempt, with an indication for in vitro diagnostic use in DNA testing. (3) The device's labeling must include a prominent hyperlink to the manufacturer's public Web site where the manufacturer shall make the information identified in this section publicly available. The manufacturer's home page, as well as the primary part of the manufacturer's Web site that discusses the device, must provide a prominently placed hyperlink to the Web page containing this information and must allow unrestricted viewing access. If the device can be purchased from the Web site or testing using the device can be ordered from the Web site, the same information must be found on the Web page for ordering the device or provided in a prominently placed and publicly accessible hyperlink on the Web page for ordering the device. Any changes to the device that could significantly affect safety or effectiveness would require new data or information in support of such changes, which would also have to be posted on the manufacturer's Web site. The information must include: (i) A detailed device description including: (A) Gene (or list of the genes if more than one) and variants the test detects (using standardized nomenclature, Human Genome Organization (HUGO) nomenclature, and coordinates). (B) Scientifically established clinical validity of each variant detected and reported by the test, which must be well-established in peer-reviewed journal articles, authoritative summaries of the literature such as Genetics Home Reference (http://ghr.nlm.nih.gov/), GeneReviews (http://www.ncbi.nlm.nih.gov/books/NBK1116/), or similar summaries of valid scientific evidence, and/or professional society recommendations, including: (1) Genotype-phenotype information for the reported mutations. (2) Relevant American College of Medical Genetics (ACMG) or American Congress of Obstetricians and Gynecologists (ACOG) guideline recommending testing of the specific gene(s) and variants the test detects and recommended populations, if available. If not available, a statement stating that professional guidelines currently do not recommend testing for this specific gene(s) and variants. (3) Table of expected prevalence of carrier status in major ethnic and racial populations and the general population. (C) The specimen type (e.g., saliva, whole blood), matrix, and volume. (D) Assay steps and technology used. (E) Specification of required ancillary reagents, instrumentation, and equipment. (F) Specification of the specimen collection, processing, storage, and preparation methods. (G) Specification of risk mitigation elements and description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing. (H) Information pertaining to the probability of test failure (e.g., failed quality control) based on data from clinical samples, description of scenarios in which a test can fail (i.e., low sample volume, low DNA concentration, etc.), how customers will be notified, and followup actions to be taken. (I) Specification of the criteria for test result interpretation and reporting. (ii) Information that demonstrates the performance characteristics of the device, including: (A) Accuracy (method comparison) of study results for each claimed specimen type. (1) Accuracy of the device shall be evaluated with fresh clinical specimens collected and processed in a manner consistent with the device's instructions for use. If this is impractical, fresh clinical samples may be substituted or supplemented with archived clinical samples. Archived samples shall have been collected previously in accordance with the device's instructions for use, stored appropriately, and randomly selected. In some instances, use of contrived samples or human cell line samples may also be appropriate; the contrived or human cell line samples shall mimic clinical specimens as much as is feasible and provide an unbiased evaluation of the device's accuracy. (2) Accuracy must be evaluated as compared to bidirectional sequencing or other methods identified as appropriate by FDA. Performance criteria for both the comparator method and device must be predefined and appropriate to the test's intended use. Detailed appropriate study protocols must be provided. (3) Information provided shall include the number and type of specimens, broken down by clinically relevant variants, that were compared to bidirectional sequencing or other methods identified as appropriate by FDA. The accuracy, defined as positive percent agreement (PPA) and negative percent agreement (NPA), must be measured; accuracy point estimates must be greater than 99 percent (both per reported variant and overall) and uncertainty of the point estimate must be presented using the 95 percent confidence interval. Clinical specimens must include both homozygous wild type and heterozygous genotypes. The number of clinical specimens for each variant reported that must be included in the accuracy study must be based on the variant prevalence. Common variants (greater than 0.1 percent allele frequency in ethnically relevant population) must have at least 20 unique heterozygous clinical specimens tested. Rare variants (less than or equal to 0.1 percent allele frequency in ethnically relevant population) shall have at least three unique mutant heterozygous specimens tested. Any no calls (i.e., absence of a result) or invalid calls (e.g., failed quality control) in the study must be included in accuracy study results and reported separately. Variants that have a point estimate for PPA or NPA of less than 99 percent (incorrect test results as compared to bidirectional sequencing or other methods identified as appropriate by FDA) must not be incorporated into test claims and reports. Accuracy measures generated from clinical specimens versus contrived samples or cell lines must be presented separately. Results must be summarized and presented in tabular format, by sample and by genotype. Point estimate of PPA should be calculated as the number of positive results divided by the number of specimens known to harbor variants (mutations) without no calls or invalid calls. The point estimate of NPA should be calculated as the number of negative results divided by the number of wild type specimens tested without no calls or invalid calls, for each variant that is being reported. Point estimates should be calculated along with 95 percent two-sided confidence intervals. (4) Information shall be reported on the clinical positive predictive value (PPV) and negative predictive value (NPV) for carrier status (and where possible, for each variant) in each population. Specifically, to calculate PPV and NPV, estimate test coverage (TC) and the percent of persons with variant(s) included in the device among all carriers: PPV = (PPA * TC * )/(PPA * TC * + (1 NPA) * (1 )) and NPV = (NPA * (1 ))/(NPA *(1 ) + (1 PPA*TC) * ) where PPA and NPA described either in paragraph (b)(3)(ii)(A)(4)(i) or in paragraph (b)(3)(ii)(A)(4)(ii) of this section and is prevalence of carriers in the population (pre-test risk to be a carrier for the disease). (i) For the point estimates of PPA and NPA less than 100 percent, use the calculated estimates in the PPV and NPV calculations. (ii) Point estimates of 100 percent may have high uncertainty. If these variants are measured using highly multiplexed technology, calculate the random error rate for the overall device and incorporate that rate in the estimation of the PPA and NPA as calculated previously. Then use these calculated estimates in the PPV and NPV calculations. This type of accuracy study is helpful in determining that there is no systematic error in such devices. (B) Precision (reproducibility): Precision data must be generated using multiple instruments and multiple operators, on multiple non-consecutive days, and using multiple reagent lots. The sample panel must include specimens with claimed sample type (e.g. saliva samples) representing different genotypes (i.e., wild type, heterozygous). Performance criteria must be predefined. A detailed study protocol must be created in advance of the study and then followed. The failed quality control rate must be indicated. It must be clearly documented whether results were generated from clinical specimens, contrived samples, or cell lines. The study results shall state, in a tabular format, the variants tested in the study and the number of replicates for each variant, and what testing conditions were studied (i.e., number of runs, days, instruments, reagent lots, operators, specimens/type, etc). The study must include all nucleic acid extraction steps from the claimed specimen type or matrix, unless a separate extraction study for the claimed sample type is performed. If the device is to be used at more than one laboratory, different laboratories must be included in the precision study (and reproducibility must be evaluated). The percentage of no calls or invalid calls, if any, in the study must be provided as a part of the precision (reproducibility) study results. (C) Analytical specificity data: Data must be generated evaluating the effect on test performance of potential endogenous and exogenous interfering substances relevant to the specimen type, evaluation of cross-reactivity of known cross-reactive alleles and pseudogenes, and assessment of cross-contamination. (D) Analytical sensitivity data: Data must be generated demonstrating the minimum amount of DNA that will enable the test to perform accurately in 95 percent of runs. (E) Device stability data: The manufacturer must establish upper and lower limits of input nucleic acid and sample stability that will achieve the claimed accuracy and reproducibility. Data supporting such claims must be described. (F) Specimen type and matrix comparison data: Specimen type and matrix comparison data must be generated if more than one specimen type or anticoagulant can be tested with the device, including failure rates for the different specimen types. (iii) If the device is offered over-the-counter, including cases in which the test results are provided direct-to-consumer, the manufacturer must conduct a study that assesses user comprehension of the device's labeling and test process and provide a concise summary of the results of the study. The following items must be included in the user study: (A) The test manufacturer must perform pre- and post-test user comprehension studies to assess user ability to understand the possible results of a carrier test and their clinical meaning. The comprehension test questions must directly evaluate the material being presented to the user in the test reports. (B) The test manufacturer must provide a carrier testing education module to potential and actual test report recipients. The module must define terms that are used in the test reports and explain the significance of carrier status. (C) The user study must meet the following criteria: (1) The study participants must be comprised of a statistically justified and demographically diverse population (determined using methods such as quota-based sampling) that is representative of the intended user population. Furthermore, the users must be comprised of a diverse range of age and educational levels that have no prior experience with the test or its manufacturer. These factors shall be well-defined in the inclusion and exclusion criteria. (2) All sources of bias (e.g., non-responders) must be predefined and accounted for in the study results with regard to both responders and non-responders. (3) The testing must follow a format where users have limited time to complete the studies (such as an onsite survey format and a one-time visit with a cap on the maximum amount of time that a participant has to complete the tests). (4) Users must be randomly assigned to study arms. Test reports given to users must: Define the condition being tested and related symptoms; explain the intended use and limitations of the test; explain the relevant ethnicities regarding the variant tested; explain carrier status and relevance to the user's ethnicity; and provide links to additional information pertaining to situations where the user is concerned about their test results or would like followup information as indicated in test labeling. The study shall assess participants' ability to understand the following comprehension concepts: The test's limitations, purpose, and results. (5) Study participants must be untrained, naive to the test subject of the study, and be provided only the materials that will be available to them when the test is marketed. (6) The user comprehension study must meet the predefined primary endpoint criteria, including a minimum of a 90 percent or greater overall comprehension rate (i.e. selection of the correct answer) for each comprehension concept to demonstrate that the education module and test reports are adequate for over-the-counter use. (D) A summary of the user comprehension study must be provided and include the following: (1) Results regarding reports that are provided for each gene/variant/ethnicity tested. (2) Statistical methods used to analyze all data sets. (3) Completion rate, non-responder rate, and reasons for non-response/data exclusion, as well as a summary table of comprehension rates regarding comprehension concepts (purpose of test, test results, test limitations, ethnicity relevance for the test results, etc.) for each study report. (4) Your 21 CFR 809.10 compliant labeling and any test report generated must include the following warning and limitation statements, as applicable: (i) A warning that reads The test is intended only for autosomal recessive carrier screening in adults of reproductive age. (ii) A statement accurately disclosing the genetic coverage of the test in lay terms, including, as applicable, information on variants not queried by the test, and the proportion of incident disease that is not related to the gene(s) tested. For example, where applicable, the statement would have to include a warning that the test does not or may not detect all genetic variants related to the genetic disease, and that the absence of a variant tested does not rule out the presence of other genetic variants that may be disease-related. Or, where applicable, the statement would have to include a warning that the basis for the disease for which the genetic carrier status is being tested is unknown or believed to be non-heritable in a substantial number of people who have the disease, and that a negative test result cannot rule out the possibility that any offspring may be affected with the disease. The statement would have to include any other warnings needed to accurately convey to consumers the degree to which the test is informative for carrier status. (iii) For prescription use tests, the following warnings that read: (A) The results of this test are intended to be interpreted by a board-certified clinical molecular geneticist or equivalent and should be used in conjunction with other available laboratory and clinical information. (B) This device is not intended for disease diagnosis, prenatal testing of fetuses, risk assessment, prognosis or pre-symptomatic testing, susceptibility testing, or newborn screening. (iv) For over-the-counter tests, a statement that reads This test is not intended to diagnose a disease, or tell you anything about your risk for developing a disease in the future. On its own, this test is also not intended to tell you anything about the health of your fetus, or your newborn child's risk of developing a particular disease later on in life. (v) For over-the-counter tests, the following warnings that read: A) This test is not a substitute for visits to a healthcare provider. It is recommended that you consult with a healthcare provider if you have any questions or concerns about your results. (B) The test does not diagnose any health conditions. Results should be used along with other clinical information for any medical purposes. (C) The laboratory may not be able to process your sample. The probability that the laboratory cannot process your saliva sample can be up to [actual probability percentage]. (D) Your ethnicity may affect how your genetic health results are interpreted. (vi) For a positive result in an over-the-counter test when the positive predictive value for a specific population is less than 50 percent and more than 5 percent, a warning that reads The positive result you obtained may falsely identify you as a carrier. Consider genetic counseling and followup testing. (vii) For a positive result in an over-the-counter test when the positive predictive value for a specific population is less than 5 percent, a warning that reads The positive result you obtained is very likely to be incorrect due to the rarity of this variant. Consider genetic counseling and followup testing. (5) The testing done to comply with paragraph (b)(3) of this section must show the device meets or exceeds each of the following performance specifications: (i) The accuracy must be shown to be equal to or greater than 99 percent for both PPA and NPA. Variants that have a point estimate for PPA or NPA of less than 99 percent (incorrect test results as compared to bidirectional sequencing or other methods identified as appropriate by FDA) must not be incorporated into test claims and reports. (ii) Precision (reproducibility) performance must meet or exceed 99 percent for both positive and negative results. (iii) The user comprehension study must obtain values of 90 percent or greater user comprehension for each comprehension concept. (6) The distribution of this device, excluding the collection device described in paragraph (b)(2) of this section, shall be limited to the manufacturer, the manufacturer's subsidiaries, and laboratories regulated under the Clinical Laboratory Improvement Amendments.