Title 21—Food and Drugs--Volume 1
PART 866—IMMUNOLOGY AND MICROBIOLOGY DEVICES
§ 866.3956   Human immunodeficiency virus (HIV) serological diagnostic and/or supplemental test.
(a) Identification. Human immunodeficiency virus (HIV) serological diagnostic and supplemental tests are prescription devices for the qualitative detection of HIV antigen(s) and/or detection of antibodies against HIV in human body fluids or tissues. The tests are intended for use as an aid in the diagnosis of infection with HIV and are for professional use only. The test results are intended to be interpreted in conjunction with other relevant clinical and laboratory findings. These tests are not intended to be used for monitoring patient status, or for screening donors of blood or blood products, or human cells, tissues, and cellular and tissue-based products (HCT/Ps).
(b) Classification. Class II (special controls). The special controls for this device are:
(1) For all HIV serological diagnostic and supplemental tests
(i) The labeling must include:
(A) An intended use that states that the device is not intended for use for screening donors of blood or blood products or HCT/Ps.
(B) A detailed explanation of the principles of operation and procedures used for performing the assay.
(C) A detailed explanation of the interpretation of results and recommended actions to take based on results.
(D) Limitations, which must be updated to reflect current clinical practice and disease presentation and management. The limitations must include, but are not limited to, statements that indicate:
( 1 ) The matrices with which the device has been cleared, and that use of this test kit with specimen types other than those specifically cleared for this device may result in inaccurate test results.
( 2 ) The test is not intended to be used to monitor individuals who are undergoing treatment for HIV infection.
( 3 ) A specimen with a reactive result should be investigated further following current guidelines.
( 4 ) All test results should be interpreted in conjunction with the individual's clinical presentation, history, and other laboratory results.
( 5 ) A test result that is nonreactive does not exclude the possibility of exposure to or infection with HIV. Nonreactive results in this assay may be due to analyte levels that are below the limit of detection of this assay.
(ii) Device verification and validation must include:
(A) Detailed device description, including the device components, ancillary reagents required but not provided, and an explanation of the methodology. Additional information appropriate to the technology must be included, such as the amino acid sequence of antigen(s) and design of capture antibodies.
(B) For devices with assay calibrators, the design of all primary, secondary, and subsequent quantitation standards used for calibration as well as their traceability to a reference material. In addition, analytical testing must be performed following the release of a new lot of the standard material that was used for device clearance, or when there is a transition to a new calibration standard.
(C) Detailed documentation of analytical performance studies conducted as appropriate to the technology, specimen types tested, and intended use of the device, including, but not limited to, limit of blank, limit of detection, cutoff determination, precision, endogenous and exogenous interferences, cross reactivity, carryover, quality control, matrix equivalency, and sample and reagent stability. Samples selected for use in analytical studies or used to prepare samples for use in analytical studies must be from subjects with clinically relevant circulating genotypes in the United States.
(D) Multisite reproducibility study that includes the testing of three independent production lots.
(E) Analytical sensitivity of the test must be the same as or better than that of other cleared or approved tests. Samples tested must include appropriate numbers and types of samples, including real clinical samples near the lower limit of detection. Analytical specificity of the test must be the same as or better than that of other cleared or approved tests. Samples must include appropriate numbers and types of samples from patients with different underlying illnesses or infections and from patients with potential endogenous interfering substances.
(F) Detailed documentation of performance from a multisite clinical study. Performance must be analyzed relative to an FDA-cleared or approved comparator. This study must be conducted using patient samples, with an appropriate number of HIV positive and HIV negative samples in applicable risk categories. Additional subgroups or types must be validated using appropriate numbers and types of samples. The samples may be a combination of fresh and repository samples, sourced from within and outside the United States, as appropriate. The study designs, including number of samples tested, must be sufficient to meet the following criteria:
( 1 ) Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 99 percent.
( 2 ) Clinical specificity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 99 percent.
(G) Strategies for detection of new strains, types, subtypes, genotypes, and genetic mutations as they emerge.
(H) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on test performance.
(I) Final release criteria to be used for manufactured test lots with appropriate evidence that lots released at the extremes of the specifications will meet the claimed analytical and clinical performance characteristics as well as the stability claims.
(J) All stability protocols, including acceptance criteria.
(K) Appropriate and acceptable procedure(s) for evaluating customer complaints and other device information that determines when to submit a medical device report.
(L) Premarket notification submissions must include the information contained in paragraph (b)(1)(ii)(A) through (K) of this section.
(iii) Manufacturers must submit a log of all complaints. The log must include the following information regarding each complaint if available: The type of event ( e.g., false negative/false nonreactive or false positive/false reactive), lot, date, population, and whether or not the complaint was reported under part 803 of this chapter (Medical Device Reporting). The log must be submitted annually on the anniversary of clearance for 5 years following clearance of a traditional premarket notification.
(2) If the test is intended for Point of Care (PoC) use, the following special controls, in addition to those listed in paragraph (b)(1) of this section apply:
(i) The PoC labeling must include a statement that the test is intended for PoC use.
(ii) The PoC labeling must include the following information near the statement of the intended use:
(A) That the test is for distribution to clinical laboratories that have an adequate quality assurance program, including planned systematic activities that provide adequate confidence that requirements for quality will be met and where there is assurance that operators will receive and use the instructional materials.
(B) That the test is for use only by an agent of a clinical laboratory.
(C) Instructions for individuals to receive the “Subject Information Notice” prior to specimen collection and appropriate information when test results are provided.
(iii) PoC labeling must include instructions to follow current guidelines for informing the individual of the test result and its interpretation.
(iv) The instructions in the labeling must state that reactive results are considered preliminary and should be confirmed following current guidelines.
(v) Device verification and validation for PoC use must include:
(A) Detailed documentation of performance from a multisite clinical study conducted at appropriate PoC sites. Performance must be analyzed relative to an FDA cleared or approved comparator. This study must be conducted using patient samples, with appropriate numbers of HIV positive and HIV negative samples in applicable risk categories. Additional subgroup or type claims must be validated using appropriate numbers and types of samples. The samples may be a combination of fresh and repository samples, sourced from within and outside the United States, as appropriate. If the test is intended solely for PoC use, the test must meet only the performance criteria in paragraphs (b)(2)(v)(A)( 1 ) and ( 2 ) of this section and not the criteria in paragraph (b)(1)(ii)(F) of this section:
( 1 ) Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 98 percent.
( 2 ) Clinical specificity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 98 percent.
(B) Premarket notification submissions must include the information contained in paragraph (b)(2)(v)(A) of this section.
(3) If the test is intended for supplemental use in addition to use as an aid in initial diagnosis, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, as appropriate, apply:
(i) The labeling must include a statement that the test is intended for use as an additional test to confirm the presence of HIV antibodies or antigens in specimens found to be repeatedly reactive by a diagnostic screening test.
(ii) Device validation and verification for supplemental use must include a clinical study, including samples that were initially reactive and repeatedly reactive on a diagnostic test but were negative or indeterminate on a different confirmatory test. Premarket notification submissions must include this information.
(4) If the test is intended solely as a supplemental test, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, except those in paragraphs (b)(1)(ii)(F) and (b)(2)(v)(A) of this section, as appropriate, apply:
(i) The labeling must include a statement that the test is intended for use as an additional test to confirm the presence of HIV antibodies or antigens in specimens found to be repeatedly reactive by a diagnostic screening test.
(ii) The labeling must clearly state that the test is not for use for initial diagnosis or is not intended as a first-line test.
(iii) Device validation and verification must include a clinical study including samples that were initially reactive and repeatedly reactive on a diagnostic test but were negative or indeterminate on a confirmatory test. Premarket notification submissions must include this information.
(5) If the test is intended to differentiate different HIV types, the following special controls, in addition to those listed in paragraphs (b)(1) through (4) of this section, as appropriate, apply:
(i) The labeling must include the statement that the test is intended for the confirmation of initial results from a diagnostic test and differentiation of different HIV types.
(ii) The results interpretation in the labeling must include instructions for the user on how to interpret the results, including un-typeable and co-infection results.
(iii) Device validation and verification must include evaluation of analytical and clinical sensitivity and specificity for each of the HIV types, strains, and subtypes of HIV intended to be differentiated. Premarket notification submissions must include this information.
§ 866.3957   Human immunodeficiency virus (HIV) nucleic acid (NAT) diagnostic and/or supplemental test.
(a) Identification. Human immunodeficiency virus (HIV) nucleic acid (NAT) diagnostic and supplemental tests are prescription devices for the qualitative detection of HIV nucleic acid in human body fluids or tissues. The tests are intended for use as an aid in the diagnosis of infection with HIV and are for professional use only. The test results are intended to be interpreted in conjunction with other relevant clinical and laboratory findings. These tests are not intended to be used for monitoring patient status, or for screening donors of blood or blood products, or human cells, tissues, or cellular or tissue-based products (HCT/Ps).
(b) Classification. Class II (special controls). The special controls for this device are:
(1) For all HIV NAT diagnostic and/or supplemental tests
(i) The labeling must include:
(A) An intended use that states that the device is not intended for use for screening donors of blood or blood products, or HCT/Ps.
(B) A detailed explanation of the principles of operation and procedures used for performing the assay.
(C) A detailed explanation of the interpretation of results and recommended actions to take based on results.
(D) Limitations, which must be updated to reflect current clinical practice and disease presentation and management. The limitations must include, but are not limited to, statements that indicate:
( 1 ) The matrices with which the device has been cleared, and that use of this test kit with specimen types other than those specifically cleared for this device may result in inaccurate test results.
( 2 ) The test is not intended to be used to monitor individuals who are undergoing treatment for HIV infection.
( 3 ) A specimen with a reactive result should be investigated further following current guidelines.
( 4 ) All test results should be interpreted in conjunction with the individual's clinical presentation, history, and other laboratory results.
( 5 ) A test result that is nonreactive does not exclude the possibility of exposure to or infection with HIV. Nonreactive results in this assay may be due to analyte levels that are below the limit of detection of this assay.
(ii) Device verification and validation must include:
(A) Detailed device description, including the device components, ancillary reagents required but not provided, and an explanation of the methodology. Additional information appropriate to the technology must be included, such as design of primers and probes.
(B) For devices with assay calibrators, the design and nature of all primary, secondary, and subsequent quantitation standards used for calibration as well as their traceability to a reference material. In addition, analytical testing must be performed following the release of a new lot of the standard material that was used for device clearance, or when there is a transition to a new calibration standard.
(C) Detailed documentation of analytical performance studies conducted as appropriate to the technology, specimen types tested, and intended use of the device, including, but not limited to, limit of blank, limit of detection, cutoff determination, precision, endogenous and exogenous interferences, cross reactivity, carryover, quality control, matrix equivalency, and sample and reagent stability. Samples selected for use in analytical studies or used to prepare samples for use in analytical studies must be from subjects with clinically relevant circulating genotypes in the United States. The effect of each claimed nucleic-acid isolation and purification procedure on detection must be evaluated.
(D) Multisite reproducibility study that includes the testing of three independent production lots.
(E) Analytical sensitivity of the test must be the same as or better than that of other cleared or approved tests. Samples tested must include appropriate numbers and types of samples, including real clinical samples near the lower limit of detection. Analytical specificity of the test must be as the same as or better than that of other cleared or approved tests. Samples must include appropriate numbers and types of samples from patients with different underlying illnesses or infections and from patients with potential endogenous interfering substances.
(F) Detailed documentation of performance from a multisite clinical study. Performance must be analyzed relative to an FDA cleared or approved comparator. This study must be conducted using appropriate patient samples, with appropriate numbers of HIV positive and negative samples in applicable risk categories. Additional subtype, strain, or types must be validated using appropriate numbers and types of samples. The samples may be a combination of fresh and repository samples, sourced from within and outside the United States, as appropriate. The study designs, including number of samples tested, must be sufficient to meet the following criteria:
( 1 ) Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 99 percent.
( 2 ) Clinical specificity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 99 percent.
(G) Strategies for detection of new strains, types, subtypes, genotypes, and genetic mutations as they emerge.
(H) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on test performance.
(I) Final release criteria to be used for manufactured test lots with appropriate evidence that lots released at the extremes of the specifications will meet the claimed analytical and clinical performance characteristics as well as the stability claims.
(J) All stability protocols, including acceptance criteria.
(K) Appropriate and acceptable procedure(s) for evaluating customer complaints and other device information that determine when to submit a medical device report.
(L) Premarket notification submissions must include the information contained in paragraph (b)(1)(ii)(A) through (K) of this section.
(iii) Manufacturers must submit a log of all complaints. The log must include the following information regarding each complaint, if available: The type of event ( e.g., false negative/false nonreactive or false positive/false reactive), lot, date, population, and whether or not the complaint was reported under part 803 of this chapter (Medical Device Reporting). The log must be submitted annually on the anniversary of clearance for 5 years following clearance of a traditional premarket notification.
(2) If the test is intended for Point of Care (PoC) use, the following special controls, in addition to those listed in paragraph (b)(1) of this section, apply:
(i) The PoC labeling must include a statement that the test is intended for PoC use.
(ii) The PoC labeling must include the following information near the statement of the intended use:
(A) That the test is for distribution to clinical laboratories that have an adequate quality assurance program, including planned systematic activities that provide adequate confidence that requirements for quality will be met and where there is assurance that operators will receive and use the instructional materials.
(B) That the test is for use only by an agent of a clinical laboratory.
(C) Instructions for individuals to receive the “Subject Information Notice” prior to specimen collection and appropriate information when test results are provided.
(iii) PoC labeling must include instructions to follow current guidelines for informing the individual of the test result and its interpretation.
(iv) The instructions in the labeling must state that reactive results are considered preliminary and should be confirmed following current guidelines.
(v) Device verification and validation for PoC use must include:
(A) Detailed documentation from a well-conducted multisite clinical study conducted at appropriate PoC sites. Performance must be analyzed relative to an FDA cleared or approved comparator. This study must be conducted using patient samples, with appropriate numbers of HIV positive and HIV negative samples in applicable risk categories. Additional subgroup or type claims must be validated using appropriate numbers and types of samples. The samples may be a combination of fresh and repository samples, sourced from within and outside the United States, as appropriate. If the test is intended solely for PoC use, the test must meet only the performance criteria in paragraphs (b)(2)(v)(A)( 1 ) and ( 2 ) of this section and not the criteria in paragraph (b)(1)(ii)(F) of this section:
( 1 ) Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 98 percent.
( 2 ) Clinical specificity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 98 percent.
(B) Premarket notification submissions must include the information contained in paragraph (b)(2)(v)(A) of this section.
(3) If the test is intended for supplemental use in addition to use as an aid in initial diagnosis, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, as appropriate, apply:
(i) The labeling must include a statement that the test is intended for use as an additional test to confirm the presence of HIV viral nucleic acid in specimens found to be repeatedly reactive by a diagnostic screening test.
(ii) Device validation and verification for supplemental use must include a clinical study, including samples that were initially reactive and repeatedly reactive on a diagnostic test but were negative or indeterminate on a confirmatory test. Premarket notification submissions must include this information.
(4) If the test is intended solely as a supplemental test, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, except those in paragraphs (b)(1)(ii)(F) and (b)(2)(v)(A) of this section, as appropriate, apply:
(i) The labeling must include a statement that the test is intended for use as an additional test to confirm the presence of HIV viral nucleic acid in specimens found to be repeatedly reactive by a diagnostic screening test.
(ii) The labeling must clearly state that the test is not for use for initial diagnosis or is not intended as a first-line test.
(iii) Device validation and verification must include a clinical study including samples that were initially reactive and repeatedly reactive on a diagnostic test but were negative or indeterminate on a confirmatory test. Premarket notification submissions must include this information.
(5) If the test is intended to differentiate different HIV types, the following special controls, in addition to those listed in paragraphs (b)(1) through (4) of this section, as appropriate, apply:
(i) The labeling must include the statement that the test is intended for the confirmation of initial results and differentiation of different HIV types.
(ii) The results interpretation in the labeling must include instructions for the user on how to interpret the results, including un-typeable and co-infection results.
(iii) Device validation and verification must include evaluation of analytical and clinical sensitivity and specificity for each of the types, strains, and subtypes of HIV intended to be differentiated. Premarket notification submissions must include this information.
§ 866.3958   Human immunodeficiency virus (HIV) viral load monitoring test.
(a) Identification. A human immunodeficiency virus (HIV) viral load monitoring test is an in vitro diagnostic prescription device for the quantitation of the amount of HIV ribonucleic acid (RNA) in human body fluids. The test is intended for use in the clinical management of individuals living with HIV and is for professional use only. The test results are intended to be interpreted in conjunction with other relevant clinical and laboratory findings. The test is not intended to be used as an aid in diagnosis or for screening donors of blood or blood products or human cells, tissues, or cellular and tissue-based products (HCT/Ps).
(b) Classification. Class II (special controls). The special controls for this device are:
(1) The labeling must include:
(i) An intended use that states that the device is not intended for use as an aid in diagnosis or for use in screening donors of blood or blood products, or HCT/Ps.
(ii) A detailed explanation of the principles of operation and procedures used for assay performance.
(iii) A detailed explanation of the interpretation of results and that recommended actions should be based on current clinical guidelines.
(iv) Limitations, which must be updated to reflect current clinical practice and patient management. The limitations must include, but are not limited to, statements that indicate:
(A) The matrices and sample types with which the device has been cleared and that use of this test with specimen types other than those specifically cleared for this device may cause inaccurate test results.
(B) Mutations in highly conserved regions may affect binding of primers and/or probes resulting in the under-quantitation of virus or failure to detect the presence of virus.
(C) All test results should be interpreted in conjunction with the individual's clinical presentation, history, and other laboratory results.
(2) Device verification and validation must include:
(i) Detailed device description, including the device components, ancillary reagents required but not provided, and an explanation of the device methodology. Additional information appropriate to the technology must be included, such as detailed information on the design of primers and probes.
(ii) For devices with assay calibrators, the design and nature of all primary, secondary, and subsequent quantitation standards used for calibration as well as their traceability to a reference material. In addition, analytical testing must be performed following the release of a new lot of the standard material that was used for device clearance, or when there is a transition to a new calibration standard.
(iii) Detailed documentation of analytical performance studies conducted as appropriate to the technology, specimen types tested, and intended use of the device, including but not limited to, limit of blank, limit of detection, limit of quantitation, cutoff determination, precision, linearity, endogenous and exogenous interferences, cross-reactivity, carry-over, quality control, matrix equivalency, sample and reagent stability. Samples selected for use in analytical studies or used to prepare samples for use in analytical studies must be from subjects with clinically relevant genotypes circulating in the United States.
(iv) Multisite reproducibility study that includes the testing of three independent production lots.
(v) Analytical sensitivity of the device must demonstrate acceptable performance at current clinically relevant medical decision points. Samples tested to demonstrate analytical sensitivity must include appropriate numbers and types of samples, including real clinical samples near the lower limit of quantitation and any clinically relevant medical decision points. Analytical specificity of the device must demonstrate acceptable performance. Samples tested to demonstrate analytical specificity must include appropriate numbers and types of samples from patients with different underlying illnesses and infection and from patients with potential interfering substances.
(vi) Detailed documentation of performance from a multisite clinical study or a multisite analytical method comparison study.
(A) For devices evaluated in a multisite clinical study, the study must use specimens from individuals living with HIV being monitored for changes in viral load, and the test results must be compared to the clinical status of the patients.
(B) For tests evaluated in a multisite analytical method comparison study, the performance of the test must be compared to an FDA-cleared or approved comparator. The multisite method comparison study must include appropriate numbers and types of samples with analyte concentrations across the measuring range of the assay, representing clinically relevant genotypes. The multisite method comparison study design, including number of samples tested, must be sufficient to meet the following criteria:
( 1 ) Agreement between the two tests across the measuring range of the assays must have an r2 of greater than or equal to 0.95.
( 2 ) The bias between the test and comparator assay, as determined by difference plots, must be less than or equal to 0.5 log copies/mL.
(vii) Detailed documentation of a single-site analytical method comparison study between the device and an FDA-cleared or approved comparator if a multisite clinical study is performed under paragraph(b)(2)(vi) of this section. The analytical method comparison study must use appropriate numbers and types of samples with analyte concentrations across the measuring range of the assay, representing clinically relevant genotypes. The results must meet the criteria in paragraphs (b)(2)(vi)(B)( 1 ) and ( 2 ) of this section.
(viii) Strategies for detection of new strains, types, subtypes, genotypes, and genetic mutations as they emerge.
(ix) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on test performance.
(x) Final release criteria to be used for manufactured device lots with an appropriate justification that lots released at the extremes of the specifications will meet the claimed analytical and clinical performance characteristics as well as the stability claims.
(xi) All stability protocols, including acceptance criteria.
(xii) Appropriate and acceptable procedure(s) for addressing complaints and other device information that determines when to submit a medical device report.
(xiii) Premarket notification submissions must include the information contained in paragraphs (b)(2)(i) through (xii) of this section.
§ 866.3960   Nucleic acid-based device for the amplification, detection, and identification of microbial pathogens directly from whole blood specimens.
(a) Identification. A nucleic acid-based device for the amplification, detection, and identification of microbial pathogens directly from whole blood specimens is a qualitative in vitro device intended for the amplification, detection, and identification of microbial-associated nucleic acid sequences from patients with suspected bloodstream infections. This device is intended to aid in the diagnosis of bloodstream infection when used in conjunction with clinical signs and symptoms and other laboratory findings.
(b) Classification. Class II (special controls). The special controls for this device are:
(1) Premarket notification submissions must include detailed device description documentation, including the device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including primer/probe sequence, design, and rationale for sequence selection.
(2) Premarket notification submissions must include detailed documentation from the following analytical and clinical performance studies: Analytical sensitivity (limit of detection), reactivity, inclusivity, precision, reproducibility, interference, cross reactivity, carryover, and cross contamination.
(3) Premarket notification submissions must include detailed documentation from a clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from well-accepted reference methods.
(4) Premarket notification submissions must include detailed documentation for device software, including, but not limited to, software applications and hardware-based devices that incorporate software.
(5) The device labeling must include limitations regarding the need for culture confirmation of negative specimens, as appropriate.
(6) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling.
(7) Premarket notification submissions must include details on an end user device training program that will be offered while marketing the device, as appropriate.
(8) As part of the risk management activities performed as part of your 21 CFR 820.30 design controls, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.
§ 866.3966   Device to detect and identify selected microbial agents that cause acute febrile illness.
(a) Identification. A device to detect and identify selected microbial agents that cause acute febrile illness is identified as an in vitro device intended for the detection and identification of microbial agents in human clinical specimens from patients with signs and symptoms of acute febrile illness who are at risk for exposure or who may have been exposed to these agents. It is intended to aid in the diagnosis of acute febrile illness in conjunction with other clinical, epidemiologic, and laboratory data, including patient travel, pathogen endemicity, or other risk factors.
(b) Classification. Class II (special controls). The special controls for this device are:
(1) Any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of specimen types claimed by this device; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.
(2) The labeling required under § 809.10(b) of this chapter must include:
(i) An intended use that includes a detailed description of targets the device detects and measures, the results provided to the user, the clinical indications appropriate for test use, and the specific population(s) for which the device is intended.
(ii) Limiting statements indicating:
(A) Not all pathogens that cause febrile illness are detected by this test and negative results do not rule out the presence of other infections;
(B) Evaluation of more common causes of acute febrile illness should be considered prior to evaluation with this test;
(C) Test results are to be interpreted in conjunction with other clinical, epidemiologic, and laboratory data available to the clinician; and
(D) When using this test, consider patient travel history and exposure risk, as some pathogens are more common in certain geographical locations.
(iii) A detailed device description, including reagents, instruments, ancillary materials, all control elements, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens.
(iv) Detailed discussion of the performance characteristics of the device for all claimed specimen types as shown by the analytical and clinical studies required under paragraphs (b)(3)(ii) and (iii) of this section, except specimen stability performance characteristics.
(v) A statement that nationally notifiable results are to be reported to public health authorities in accordance with local, state, and federal law.
(3) Design verification and validation must include:
(i) A detailed device description ( e.g., all device parts, control elements incorporated into the test procedure, reagents required but not provided, the principle of device operation and test methodology), and the computational path from collected raw data to reported result ( e.g., how collected raw signals are converted into a reported result).
(ii) Detailed documentation of analytical studies, including those demonstrating Limit of Detection (LoD), inclusivity, cross-reactivity, microbial interference, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, within lab precision, and reproducibility, as appropriate.
(iii) Detailed documentation and performance results from a clinical study that includes prospective (sequentially collected) samples for each claimed specimen type and, when determined to be appropriate by FDA, additional characterized clinical samples. The study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained from FDA-accepted comparator methods. Documentation from the clinical studies must include the clinical study protocol (including a predefined statistical analysis plan), study report, testing results, and results of all statistical analyses.
(iv) A detailed description of the impact of any software, including software applications and hardware-based devices that incorporate software, on the device's functions.
§ 866.3970   Device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid.
(a) Identification. A device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid is a qualitative in vitro device intended for the detection and identification of microbial-associated nucleic acid sequences from patients suspected of meningitis or encephalitis. A device to detect and identify microbial pathogen nucleic acids in cerebrospinal fluid is intended to aid in the diagnosis of meningitis or encephalitis when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.
(b) Classification. Class II (special controls). The special controls for this device are:
(1) Premarket notification submissions must include detailed device description documentation, including the device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including primer/probe sequence, design, and rationale for sequence selection.
(2) Premarket notification submissions must include detailed documentation from the following analytical studies: Analytical sensitivity (limit of detection), inclusivity, reproducibility, interference, cross reactivity, and specimen stability.
(3) Premarket notification submissions must include detailed documentation from a clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from well-accepted comparator methods.
(4) Premarket notification submissions must include detailed documentation for device software, including, but not limited to, software applications and hardware-based devices that incorporate software.
(5) The Intended Use statement in the device labeling must include a statement that the device is intended to be used in conjunction with standard of care culture.
(6) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling.
(7) The device labeling must include a limitation stating that the negative results do not preclude the possibility of central nervous system infection.
(8) The device labeling must include a limitation stating that device results are not intended to be used as the sole basis for diagnosis, treatment, or other patient management decisions.
(9) The device labeling must include a limitation stating that positive results do not mean that the organism detected is infectious or is the causative agent for clinical symptoms.
(10) As part of the risk management activities performed as part of your 21 CFR 820.30 design controls, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.
§ 866.3980   Respiratory viral panel multiplex nucleic acid assay.
(a) Identification. A respiratory viral panel multiplex nucleic acid assay is a qualitative in vitro diagnostic device intended to simultaneously detect and identify multiple viral nucleic acids extracted from human respiratory specimens or viral culture. The detection and identification of a specific viral nucleic acid from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respiratory viral infection when used in conjunction with other clinical and laboratory findings. The device is intended for detection and identification of a combination of the following viruses:
(1) Influenza A and Influenza B;
(2) Influenza A subtype H1 and Influenza A subtype H3;
(3) Respiratory Syncytial Virus subtype A and Respiratory Syncytial Virus subtype B;
(4) Parainfluenza 1, Parainfluenza 2, and Parainfluenza 3 virus;
(5) Human Metapneumovirus;
(6) Rhinovirus; and
(7) Adenovirus.
(b) Classification. Class II (special controls). The special controls are:
(1) FDA's guidance document entitled “Class II Special Controls Guidance Document: Respiratory Viral Panel Multiplex Nucleic Acid Assay;”
(2) For a device that detects and identifies Human Metapneumovirus, FDA's guidance document entitled “Class II Special Controls Guidance Document: Testing for Human Metapneumovirus (hMPV) Using Nucleic Acid Assays;” and
(3) For a device that detects and differentiates Influenza A subtype H1 and subtype H3, FDA's guidance document entitled “Class II Special Controls Guidance Document: Testing for Detection and Differentiation of Influenza A Virus Subtypes Using Multiplex Nucleic Acid Assays.” See § 866.1(e) for the availability of these guidance documents.
§ 866.3981   Device to detect and identify nucleic acid targets in respiratory specimens from microbial agents that cause the SARS-CoV-2 respiratory infection and other microbial agents when in a multi-target test.
(a) Identification. A device to detect and identify nucleic acid targets in respiratory specimens from microbial agents that cause the SARS-CoV-2 respiratory infection and other microbial agents when in a multi-target test is an in vitro diagnostic device intended for the detection and identification of SARS-CoV-2 and other microbial agents when in a multi-target test in human clinical respiratory specimens from patients suspected of respiratory infection who are at risk for exposure or who may have been exposed to these agents. The device is intended to aid in the diagnosis of respiratory infection in conjunction with other clinical, epidemiologic, and laboratory data or other risk factors.
(b) Classification. Class II (special controls). The special controls for this device are:
(1) The intended use in the labeling required under § 809.10 of this chapter must include a description of the following: Analytes and targets the device detects and identifies, the specimen types tested, the results provided to the user, the clinical indications for which the test is to be used, the specific intended population(s), the intended use locations including testing location(s) where the device is to be used (if applicable), and other conditions of use as appropriate.
(2) Any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of specimen types claimed by this device; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.
(3) The labeling required under § 809.10(b) of this chapter must include:
(i) A detailed device description, including reagents, instruments, ancillary materials, all control elements, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens;
(ii) Detailed descriptions of the performance characteristics of the device for each specimen type claimed in the intended use based on analytical studies including the following, as applicable: Limit of Detection, inclusivity, cross-reactivity, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, precision, reproducibility, and clinical studies;
(iii) Detailed descriptions of the test procedure(s), the interpretation of test results for clinical specimens, and acceptance criteria for any quality control testing;
(iv) A warning statement that viral culture should not be attempted in cases of positive results for SARS-CoV-2 and/or any similar microbial agents unless a facility with an appropriate level of laboratory biosafety ( e.g., BSL 3 and BSL 3+, etc.) is available to receive and culture specimens; and
(v) A prominent statement that device performance has not been established for specimens collected from individuals not identified in the intended use population ( e.g., when applicable, that device performance has not been established in individuals without signs or symptoms of respiratory infection).
(vi) Limiting statements that indicate that:
(A) A negative test result does not preclude the possibility of infection;
(B) The test results should be interpreted in conjunction with other clinical and laboratory data available to the clinician;
(C) There is a risk of incorrect results due to the presence of nucleic acid sequence variants in the targeted pathogens;
(D) That positive and negative predictive values are highly dependent on prevalence;
(E) Accurate results are dependent on adequate specimen collection, transport, storage, and processing. Failure to observe proper procedures in any one of these steps can lead to incorrect results; and
(F) When applicable ( e.g., recommended by the Centers for Disease Control and Prevention, by current well-accepted clinical guidelines, or by published peer-reviewed literature), that the clinical performance may be affected by testing a specific clinical subpopulation or for a specific claimed specimen type.
(4) Design verification and validation must include:
(i) Detailed documentation, including performance results, from a clinical study that includes prospective (sequential) samples for each claimed specimen type and, as appropriate, additional characterized clinical samples. The clinical study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained using a comparator that FDA has determined is appropriate. Detailed documentation must include the clinical study protocol (including a predefined statistical analysis plan), study report, testing results, and results of all statistical analyses.
(ii) Risk analysis and documentation demonstrating how risk control measures are implemented to address device system hazards, such as Failure Modes Effects Analysis and/or Hazard Analysis. This documentation must include a detailed description of a protocol (including all procedures and methods) for the continuous monitoring, identification, and handling of genetic mutations and/or novel respiratory pathogen isolates or strains ( e.g., regular review of published literature and periodic in silico analysis of target sequences to detect possible mismatches). All results of this protocol, including any findings, must be documented and must include any additional data analysis that is requested by FDA in response to any performance concerns identified under this section or identified by FDA during routine evaluation. Additionally, if requested by FDA, these evaluations must be submitted to FDA for FDA review within 48 hours of the request. Results that are reasonably interpreted to support the conclusion that novel respiratory pathogen strains or isolates impact the stated expected performance of the device must be sent to FDA immediately.
(iii) A detailed description of the identity, phylogenetic relationship, and other recognized characterization of the respiratory pathogen(s) that the device is designed to detect. In addition, detailed documentation describing how to interpret the device results and other measures that might be needed for a laboratory diagnosis of respiratory infection.
(iv) A detailed device description, including device components, ancillary reagents required but not provided, and a detailed explanation of the methodology, including molecular target(s) for each analyte, design of target detection reagents, rationale for target selection, limiting factors of the device ( e.g., saturation level of hybridization and maximum amplification and detection cycle number, etc.), internal and external controls, and computational path from collected raw data to reported result ( e.g., how collected raw signals are converted into a reported signal and result), as applicable.
(v) A detailed description of device software, including software applications and hardware-based devices that incorporate software. The detailed description must include documentation of verification, validation, and hazard analysis and risk assessment activities, including an assessment of the impact of threats and vulnerabilities on device functionality and end users/patients as part of cybersecurity review.
(vi) For devices intended for the detection and identification of microbial agents for which an FDA recommended reference panel is available, design verification and validation must include the performance results of an analytical study testing the FDA recommended reference panel of characterized samples. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.
(vii) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiation between the Influenza A virus subtypes in human clinical specimens, the design verification and validation must include a detailed description of the identity, phylogenetic relationship, or other recognized characterization of the Influenza A and B viruses that the device is designed to detect, a description of how the device results might be used in a diagnostic algorithm and other measures that might be needed for a laboratory identification of Influenza A or B virus and of specific Influenza A virus subtypes, and a description of the clinical and epidemiological parameters that are relevant to a patient case diagnosis of Influenza A or B and of specific Influenza A virus subtypes. An evaluation of the device compared to a currently appropriate and FDA accepted comparator method. Detailed documentation must be kept of that study and its results, including the study protocol, study report for the proposed intended use, testing results, and results of all statistical analyses.
(5) When applicable, performance results of the analytical study testing the FDA recommended reference panel described in paragraph (b)(4)(vi) of this section must be included in the device's labeling under § 809.10(b) of this chapter.
(6) For devices with an intended use that includes detection of Influenza A and Influenza B viruses and/or detection and differentiation between the Influenza A virus subtypes in human clinical specimens in addition to detection of SARS-CoV-2 and similar microbial agents, the required labeling under § 809.10(b) of this chapter must include the following:
(i) Where applicable, a limiting statement that performance characteristics for Influenza A were established when Influenza A/H3 and A/H1-2009 (or other pertinent Influenza A subtypes) were the predominant Influenza A viruses in circulation.
(ii) Where applicable, a warning statement that reads if infection with a novel Influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent influenza viruses and sent to State or local health departments for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.
(iii) Where the device results interpretation involves combining the outputs of several targets to get the final results, such as a device that both detects Influenza A and differentiates all known Influenza A subtypes that are currently circulating, the device's labeling must include a clear interpretation instruction for all valid and invalid output combinations, and recommendations for any required followup actions or retesting in the case of an unusual or unexpected device result.
(iv) A limiting statement that if a specimen yields a positive result for Influenza A, but produces negative test results for all specific influenza A subtypes intended to be differentiated ( i.e., H1-2009 and H3), this result requires notification of appropriate local, State, or Federal public health authorities to determine necessary measures for verification and to further determine whether the specimen represents a novel strain of Influenza A.
(7) If one of the actions listed at section 564(b)(1)(A) through (D) of the Federal Food, Drug, and Cosmetic Act occurs with respect to an influenza viral strain, or if the Secretary of Health and Human Services determines, under section 319(a) of the Public Health Service Act, that a disease or disorder presents a public health emergency, or that a public health emergency otherwise exists, with respect to an influenza viral strain:
(i) Within 30 days from the date that FDA notifies manufacturers that characterized viral samples are available for test evaluation, the manufacturer must have testing performed on the device with those influenza viral samples in accordance with a standardized protocol considered and determined by FDA to be acceptable and appropriate.
(ii) Within 60 days from the date that FDA notifies manufacturers that characterized influenza viral samples are available for test evaluation and continuing until 3 years from that date, the results of the influenza emergency analytical reactivity testing, including the detailed information for the virus tested as described in the certificate of authentication, must be included as part of the device's labeling in a tabular format, either by:
(A) Placing the results directly in the device's labeling required under § 809.10(b) of this chapter that accompanies the device in a separate section of the labeling where analytical reactivity testing data can be found, but separate from the annual analytical reactivity testing results; or
(B) In a section of the device's label or in other labeling that accompanies the device, prominently providing a hyperlink to the manufacturer's public website where the analytical reactivity testing data can be found. The manufacturer's website, as well as the primary part of the manufacturer's website that discusses the device, must provide a prominently placed hyperlink to the website containing this information and must allow unrestricted viewing access.
§ 866.3985   Device to detect and identify microorganisms and associated resistance marker nucleic acids directly in respiratory specimens.
(a) Identification. A device to detect and identify microorganisms and associated resistance marker nucleic acids directly from respiratory specimens is an in vitro diagnostic device intended for the detection and identification of microorganisms and associated resistance markers in respiratory specimens collected from patients with signs or symptoms of respiratory infection. The device is intended to aid in the diagnosis of respiratory infection in conjunction with clinical signs and symptoms and other laboratory findings. These devices do not provide confirmation of antibiotic susceptibility since mechanisms of resistance may exist other than those detected by the device.
(b) Classification. Class II (special controls). The special controls for this device are:
(1) The intended use for the 21 CFR 809.10 labeling must include a detailed description of what the device detects, the type of results provided to the user, the clinical indications appropriate for test use, and the specific population(s) for which the device is intended.
(2) The 21 CFR 809.10(b) labeling must include:
(i) A detailed device description, including all device components, control elements incorporated into the test procedure, instrument requirements, ancillary reagents required but not provided, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens.
(ii) Performance characteristics from analytical studies, including, but not limited to, limit of detection, inclusivity, reproducibility, cross reactivity, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, and linearity, as applicable.
(iii) A limiting statement that the device is intended to be used in conjunction with clinical history, signs and symptoms, and results of other diagnostic tests, including culture and antimicrobial susceptibility testing.
(iv) A detailed explanation of the interpretation of test results for clinical specimens and acceptance criteria for any quality control testing.
(v) A limiting statement that negative results for microorganisms do not preclude the possibility of infection, and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.
(vi) If applicable, a limiting statement that detected microorganisms may not be the cause of lower respiratory tract infection and may be indicative of colonizing or normal respiratory flora.
(vii) If applicable, a limiting statement that detection of resistance markers cannot be definitively linked to specific microorganisms and that the source of a detected resistance marker may be an organism not detected by the assay, including colonizing flora.
(viii) If applicable, a limiting statement that detection of antibiotic resistance markers may not correlate with phenotypic gene expression.
(3) The 21 CFR 809.10(b) labeling and any test report generated by the device must include a limiting statement that negative results for resistance markers do not indicate susceptibility of detected microorganisms.
(4) Design verification and validation must include:
(i) Performance characteristics from clinical studies that include prospective (sequential) samples and, if appropriate, additional characterized samples. The study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained from an FDA accepted reference method and/or FDA accepted comparator method, as appropriate. Results from the clinical studies must include the clinical study protocol (including predefined statistical analysis plan, if applicable), clinical study report, and results of all statistical analyses.
(ii) A detailed device description including the following:
(A) Thorough description of the assay methodology including, but not limited to, primer/probe sequences, primer/probe design, and rationale for target sequence selection, as applicable.
(B) Algorithm used to generate a final result from raw data (e.g., how raw signals are converted into a reported result).
(iii) A detailed description of device software, including, but not limited to, validation activities and outcomes.
(iv) As part of the risk management activities, an appropriate end user device training program must be offered as an effort to mitigate the risk of failure from user error.
§ 866.3990   Gastrointestinal microorganism multiplex nucleic acid-based assay.
(a) Identification. A gastrointestinal microorganism multiplex nucleic acid-based assay is a qualitative in vitro diagnostic device intended to simultaneously detect and identify multiple gastrointestinal microbial nucleic acids extracted from human stool specimens. The device detects specific nucleic acid sequences for organism identification as well as for determining the presence of toxin genes. The detection and identification of a specific gastrointestinal microbial nucleic acid from individuals exhibiting signs and symptoms of gastrointestinal infection aids in the diagnosis of gastrointestinal infection when used in conjunction with clinical evaluation and other laboratory findings. A gastrointestinal microorganism multiplex nucleic acid-based assay also aids in the detection and identification of acute gastroenteritis in the context of outbreaks.
(b) Classification. Class II (special controls). The special controls are set forth in FDA's guideline document entitled: “Class II Special Controls Guideline: Gastrointestinal Microorganism Multiplex Nucleic Acid-Based Assays for Detection and Identification of Microorganisms and Toxin Genes from Human Stool Specimens.” For availability of the guideline document, see § 866.1(e).
§ 866.4070   RNA Preanalytical Systems.
(a) Identification. RNA Preanalytical Systems are devices intended to collect, store, and transport patient specimens, and stabilize intracellular RNA from the specimens, for subsequent isolation and purification of the intracellular RNA for RT-PCR used in in vitro molecular diagnostic testing.
(b) Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: RNA Preanalytical Systems (RNA Collection, Stabilization and Purification System for RT-PCR Used in Molecular Diagnostic Testing).” See § 866.1(e) for the availability of this guidance document.
§ 866.4100   Complement reagent.
(a) Identification. A complement reagent is a device that consists of complement, a naturally occurring serum protein from any warm-blooded animal such as guinea pigs, that may be included as a component part of serological test kits used in the diagnosis of disease.
(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 § 866.9.
§ 866.4500   Immunoelectrophoresis equipment.
(a) Identification. Immunoelectrophoresis equipment for clinical use with its electrical power supply is a device used for separating protein molecules. Immunoelectrophoresis is a procedure in which a complex protein mixture is placed in an agar gel and the various proteins are separated on the basis of their relative mobilities under the influence of an electric current. The separated proteins are then permitted to diffuse through the agar toward a multispecific antiserum, allowing precipitation and visualization of the separate complexes.
(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 § 866.9.
§ 866.4520   Immunofluorometer equipment.
(a) Identification. Immunofluorometer equipment for clinical use with its electrical power supply is a device used to measure the fluorescence of fluorochrome-labeled antigen-antibody complexes. The concentration of these complexes may be measured by means of reflected light. A beam of light is passed through a solution in which a fluorochrome has been selectively attached to serum protein antibody molecules in suspension. The amount of light emitted by the fluorochrome label is detected by a photodetector, which converts light energy into electrical energy. The amount of electrical energy registers on a readout system such as a digital voltmeter or a recording chart. This electrical readout is called the fluorescence value and is used to measure the concentration of antigen-antibody complexes.
(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 § 866.9.
§ 866.4540   Immunonephelometer equipment.
(a) Identification. Immunonephelometer equipment for clinical use with its electrical power supply is a device that measures light scattering from antigen-antibody complexes. The concentration of these complexes may be measured by means of reflected light. A beam of light passed through a solution is scattered by the particles in suspension. The amount of light is detected by a photodetector, which converts light energy into electrical energy. The amount of electrical energy registers on a readout system such as a digital voltmeter or a recording chart. This electrical readout is called the light-scattering value and is used to measure the concentration of antigen-antibody complexes. This generic type of device includes devices with various kinds of light sources, such as laser equipment.
(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 § 866.9.
§ 866.4600   Ouchterlony agar plate.
(a) Identification. An ouchterlony agar plate for clinical use is a device containing an agar gel used to examine antigen-antibody reactions. In immunodiffusion, antibodies and antigens migrate toward each other through gel which originally contained neither of these reagents. As the reagents come in contact with each other, they combine to form a precipitate that is trapped in the gel matrix and is immobilized.
(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 § 866.9.
§ 866.4700   Automated fluorescencein situhybridization (FISH) enumeration systems.
(a) Identification. An automated FISH enumeration system is a device that consists of an automated scanning microscope, image analysis system, and customized software applications for FISH assays. This device is intended for in vitro diagnostic use with FISH assays as an aid in the detection, counting and classification of cells based on recognition of cellular color, size, and shape, and in the detection and enumeration of FISH signals in interphase nuclei of formalin-fixed, paraffin-embedded human tissue specimens.
(b) Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Automated Fluorescence in situ Hybridization (FISH) Enumeration Systems.” See § 866.1(e) for the availability of this guidance document.
§ 866.4750   Automated indirect immunofluorescence microscope and software-assisted system.
(a) Identification. An automated indirect immunofluorescence microscope and software assisted system is a device that acquires, analyzes, stores, and displays digital images of indirect immunofluorescent slides. It is intended to be used as an aid in the determination of antibody status in clinical samples. The device may include a fluorescence microscope with light source, a motorized microscope stage, dedicated instrument controls, a camera, a computer, a sample processor, or other hardware components. The device may use fluorescent signal acquisition and processing software, data storage and transferring mechanisms, or assay specific algorithms to suggest results. A trained operator must confirm results generated with the device.
(b) Classification. Class II (special controls). The special controls for this device are:
(1) The labeling for the device must reference legally marketed assays intended for use with the device.
(2) Premarket notification submissions must include the following information:
(i) A detailed description of the device that includes:
(A) A detailed description of instrumentation and equipment, and illustrations or photographs of non-standard equipment or methods, if applicable;
(B) Detailed documentation of the software, including, but not limited to, stand-alone software applications and hardware-based devices that incorporate software, if applicable;
(C) 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;
(D) Detailed description and specifications for sample preparation, processing, and storage, if applicable;
(E) Methodology and protocols for detecting fluorescence and visualizing results; and
(F) Detailed specification of the criteria for test results interpretation and reporting.
(ii) Data demonstrating the performance characteristics of the device, which must include:
(A) A comparison study of the results obtained with the conventional manual method ( i.e., reference standard), the device, and the reading of the digital image without aid of the software, using the same set of patient samples for each. The study must use a legally marketed assay intended for use with the device. Patient samples must be from the assay-specific intended use population and differential diagnosis population. Samples must also cover the assay measuring range, if applicable;
(B) Device clinical performance established by comparing device results at multiple U.S. sites to the clinical diagnostic standard used in the United States, using patient samples from the assay-specific intended use population and the differential diagnosis population. For all samples, the diagnostic clinical criteria and the demographic information must be collected and provided. Clinical validation must be based on the determination of clinical sensitivity and clinical specificity using the test results ( e.g., antibody status based on fluorescence to include pattern and titer, if applicable) compared to the clinical diagnosis of the subject from whom the clinical sample was obtained. The data must be summarized in tabular format comparing the result generated by automated, manual, and digital only interpretation to the disease status;
(C) 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) using multiple operators, multiple instruments and at multiple sites. A well-characterized panel of patient samples or pools from the associated assay specific intended use population must be used;
(D) Device linearity data generated from patient samples covering the assay measuring range, if applicable;
(E) Device analytical sensitivity data, including limit of blank, limit of detection, and limit of quantitation, if applicable;
(F) Device assay specific cutoff, if applicable;
(G) Device analytical specificity data, including interference by endogenous and exogenous substances, if applicable;
(H) Device instrument carryover data, if applicable;
(I) Device stability data including real-time stability under various storage times and temperatures, if applicable; and
(J) Information on traceability to a reference material and description of value assignment of calibrators and controls, if applicable.
(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.
(3) Your 21 CFR 809.10 compliant labeling must include:
(i) A warning statement that reads “The device is for use by a trained operator in a clinical laboratory setting”;
(ii) A warning statement that reads “All software-aided results must be confirmed by the trained operator”;
(iii) A warning statement that reads “This device is only for use with reagents that are indicated for use with the device”; and
(iv) A description of the protocol and performance studies performed in accordance with paragraph (b)(2)(ii) of this section and a summary of the results, if applicable.
§ 866.4800   Radial immunodiffusion plate.
(a) Identification. A radial immunodiffusion plate for clinical use is a device that consists of a plastic plate to which agar gel containing antiserum is added. In radial immunodiffusion, antigens migrate through gel which originally contains specific antibodies. As the reagents come in contact with each other, they combine to form a precipitate that is trapped in the gel matrix and immobilized.
(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 § 866.9.
§ 866.4830   Rocket immunoelectrophoresis equipment.
(a) Identification. Rocket immunoelectrophoresis equipment for clinical use is a device used to perform a specific test on proteins by using a procedure called rocket immunoelectrophoresis. In this procedure, an electric current causes the protein in solution to migrate through agar gel containing specific antisera. The protein precipitates with the antisera in a rocket-shaped pattern, giving the name to the device. The height of the peak (or the area under the peak) is proportional to the concentration of the protein.
(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 § 866.9.
§ 866.4900   Support gel.
(a) Identification. A support gel for clinical use is a device that consists of an agar or agarose preparation that is used while measuring various kinds of, or parts of, protein molecules by various immunochemical techniques, such as immunoelectrophoresis, immunodiffusion, or chromatography.
(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 § 866.9.
§ 866.5040   Albumin immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5060   Prealbumin immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5065   Human allotypic marker immunological test system.
(a) 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, nA 2 m, and Km allotypes) in serum and other body fluids. The identification may be used while studying population genetics.
(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 § 866.9.
§ 866.5080Alpha-1-antichymotrypsin immunological test system.
(a) 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.
(b) Classification. Class II (performance standards).
§ 866.5090   Antimitochondrial antibody immunological test system.
(a) 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).
(b) Classification. Class II (performance standards).
§ 866.5100   Antinuclear antibody immunological test system.
(a) 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, Sjögren's syndrome (arthritis with inflammation of the eye, eyelid, and salivary glands), and systemic sclerosis (chronic hardening and shrinking of many body tissues).
(b) Classification. Class II (performance standards).
§ 866.5110   Antiparietal antibody immunological test system.
(a) 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 B 12 to be absorbed by the body. The measurements aid in the diagnosis of vitamin B 12 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).
(b) Classification. Class II (performance standards).
§ 866.5120   Antismooth muscle antibody immunological test system.
(a) 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).
(b) Classification Class II (performance standards).
§ 866.5130Alpha-1-antitrypsin immunological test system.
(a) 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.
(b) Classification. Class II (performance standards).
§ 866.5150   Bence-Jones proteins immunological test system.
(a) 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).
(b) Classification. Class II (performance standards).
§ 866.5160Beta-globulin immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5170   Breast milk immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5180   Fecal calprotectin immunological test system.
(a) 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 for in 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.
(b) 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).
§ 866.5200   Carbonic anhydrase B and C immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5210   Ceruloplasmin immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5220   Cohn fraction II immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5230   Colostrum immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5240   Complement components immunological test system.
(a) Identification. A complement components immunological test system is a device that consists of the reagents used to measure by immunochemical techniques complement components C 1q , C 1r , C 1s , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , and C 9 , 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.
(b) Classification. Class II (performance standards).
§ 866.5250   Complement C1inhibitor (inactivator) immunological test system.
(a) Identification. A complement C 1 inhibitor (inactivator) immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the complement C 1 inhibitor (a plasma protein) in serum. Complement C 1 inhibitor occurs normally in plasma and blocks the action of the C 1 component of complement (a group of serum proteins which destroy infectious agents). Measurement of complement C 1 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).
(b) Classification. Class II (performance standards).
§ 866.5260   Complement C3binactivator immunological test system.
(a) Identification. A complement C 3b inactivator immunological test system is a device that consists of the reagents used to measure by immunochemical techniques the complement C 3b inactivator (a plasma protein) in serum. Complement is a group of serum proteins that destroy infectious agents. Measurement of complement C 3b inactivator aids in the diagnosis of inherited antibody dysfunction.
(b) Classification. Class II (performance standards).
§ 866.5270   C-reactive protein immunological test system.
(a) 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.
(b) Classification. Class II (performance standards).
§ 866.5320   Properdin factor B immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5330   Factor XIII, A, S, immunological test system.
(a) 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.
(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 § 866.9. This exemption does not apply to factor deficiency tests classified under § 864.7290 of this chapter.
§ 866.5340   Ferritin immunological test system.
(a) 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.
(b) Classification. Class II (performance standards).
§ 866.5350   Fibrinopeptide A immunological test system.
(a) 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.
(b) Classification. Class II (performance standards).
§ 866.5360   Cohn fraction IV immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5370   Cohn fraction V immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5380   Free secretory component immunological test system.
(a) 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).
(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 § 866.9.
§ 866.5400Alpha-globulin immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5420Alpha-1-glycoproteins immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5425Alpha-2-glycoproteins immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5430Beta-2-glycoprotein I immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5440Beta-2-glycoprotein III immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5460   Haptoglobin immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5470   Hemoglobin immunological test system.
(a) Indentification. 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).
(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 § 866.9.
§ 866.5490   Hemopexin immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5500   Hypersensitivity pneumonitis immunological test system.
(a) 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.
(b) Classification. Class II (performance standards).
§ 866.5510   Immunoglobulins A, G, M, D, and E immunological test system.
(a) 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.
(b) Classification. Class II (performance standards).
§ 866.5520   Immunoglobulin G (Fab fragment specific) immunological test system.
(a) 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).
(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 § 866.9.
§ 866.5530   Immunoglobulin G (Fc fragment specific) immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5540   Immunoglobulin G (Fd fragment specific) immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5550   Immunoglobulin (light chain specific) immunological test system.
(a) 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.
(b) Classification. Class II (performance standards).
§ 866.5560   Lactic dehydrogenase immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5570   Lactoferrin immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5580Alpha-1-lipoprotein immunological test system.
(a) 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).
(b) Classification. Class II (performance standards).
§ 866.5590   Lipoprotein X immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5600   Low-density lipoprotein immunological test system.
(a) 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.
(b) Classification. Class II (performance standards).
§ 866.5620Alpha-2-macroglobulin immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5630Beta-2-microglobulin immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5640   Infectious mononucleosis immunological test system.
(a) 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.
(b) Classification. Class II (performance standards).
§ 866.5660   Multiple autoantibodies immunological test system.
(a) 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).
(b) Classification. Class II (performance standards).
§ 866.5665   Aquaporin-4 autoantibody immunological test system.
(a) 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.
(b) 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.
§ 866.5670   Zinc transporter 8 autoantibody immunological test system.
(a) 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.
(b) 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.
§ 866.5680   Myoglobin immunological test system.
(a) 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.
(b) Classification. Class II (performance standards).
§ 866.5700   Whole human plasma or serum immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5715   Plasminogen immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5735   Prothrombin immunological test system.
(a) 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.
(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 § 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.
§ 866.5750   Radioallergosorbent (RAST) immunological test system.
(a) 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.
(b) Classification. Class II (special controls). The device, when intended to detect any of the allergens included in Table 1 in this paragraph, is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9.
Table 1—Class II Exempt Allergens Under § 866.5750—Radioallergosorbent (RAST) Immunological Test Systems
§ 866.5760   Tryptase test system.
(a) 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.
(b) 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).
§ 866.5765   Retinol-binding protein immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5775   Rheumatoid factor immunological test system.
(a) 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.
(b) Classification. Class II (performance standards).
§ 866.5785   Anti-Saccharomyces cerevisiae(S. cerevisiae) antibody (ASCA) test systems.
(a) 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.
(b) 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.”
§ 866.5800   Seminal fluid (sperm) immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5820   Systemic lupus erythematosus immunological test system.
(a) 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).
(b) Classification. Class II (performance standards).
§ 866.5830   Brain trauma assessment test.
(a) Identification. A brain trauma assessment test is a device that consists of reagents used to detect and measure brain injury biomarkers in human specimens. The measurements aid in the evaluation of patients with suspected mild traumatic brain injury in conjunction with other clinical information to assist in determining the need for head imaging per current standard of care.
(b) Classification. Class II (special controls). The special controls for this device are:
(1) The 21 CFR 809.10(b) compliant labeling must include detailed descriptions of and results from performance testing conducted to evaluate precision, accuracy, linearity, analytical sensitivity, interference, and cross-reactivity. This information must include the following:
(i) Performance testing of device precision must, at minimum, use one unmodified clinical specimen from the intended use population with concentration of the brain injury biomarker(s) near the medical decision point. Contrived specimens that have been generated from pooling of multiple samples or spiking of purified analyte to cover the measuring range may be used, but the contrived samples must be prepared to mimic clinical specimens as closely as possible. This testing must evaluate repeatability and reproducibility using a protocol from an FDA-recognized standard.
(ii) Device performance data must be demonstrated through a clinical study and must include the following:
(A) Data demonstrating clinical validity including the clinical sensitivity and specificity, and positive and negative predictive value of the test in the intended use population of patients with suspected mild traumatic brain injury ( i.e., Glasgow Coma Score (GCS) of 13-15), or equivalent standard of care for determination of severity of traumatic brain injury (TBI).
(B) Study must be performed using the operators and in settings that are representative of the types of operators and settings for which the device is intended to be used.
(C) All eligible subjects must meet the well-defined study inclusion and exclusion criteria that define the intended use population. The prevalence of diseased or injured subjects in the study population must reflect the prevalence of the device's intended use population, or alternatively, statistical measures must be used to account for any bias due to enrichment of subpopulations of the intended use population.
(D) All eligible subjects must have undergone a head computerized tomography (CT) scan or other appropriate clinical diagnostic standard used to determine the presence of an intracranial lesion as part of standard of care and must also be evaluated by the subject device. All clinical diagnostic standards used in the clinical study must follow standard clinical practice in the United States.
(E) Relevant demographic variables and baseline characteristics including medical history and neurological history. In addition, head injury characteristics, neurological assessments, and physical evidence of trauma must be provided for each subject. This information includes but is not limited to the following: Time since head injury, time from head injury to CT scan, time from head injury to blood draw, GCS score or equivalent, experience of loss of consciousness, presence of confusion, episodes of vomiting, post-traumatic amnesia characteristics, presence of post-traumatic seizures, drug or alcohol intoxication, mechanism of injury, acute intracranial lesion type, neurosurgical lesion, and cranial fracture.
(F) Each CT scan or other imaging result must be independently evaluated in a blinded manner by at least two board-certified radiologists to determine whether it is positive or negative as defined by the presence or absence of acute intracranial lesions. This independent review must be conducted without access to test results of the device. Prior to conducting the review, the criteria and procedures to be followed for scoring the images must be established, including the mechanism for determining consensus.
(G) All the clinical samples must be tested with the subject device blinded to the TBI status and the neurological-lesion-status of the subject.
(H) Details on how missing values in data are handled must be provided.
(I) For banked clinical samples, details on storage conditions and storage period must be provided. In addition, a specimen stability study must be conducted for the duration of storage to demonstrate integrity of archived clinical samples. The samples evaluated in the assay test development must not be used to establish the clinical validity of the assays.
(iii) Performance testing of device analytical specificity must include the most commonly reported concomitant medications present in specimens from the intended use population. Additionally, potential cross-reacting endogenous analytes must be evaluated at the highest concentration reported in specimens from the intended use population.
(iv) Expected/reference values generated by testing a statistically appropriate number of samples from apparently healthy normal individuals.
(2) The 21 CFR 809.10(a) and (b) compliant labeling must include the following limitations:
(i) A limiting statement that this device is not intended to be used a stand-alone device but as an adjunct to other clinical information to aid in the evaluation of patients who are being considered for standard of care neuroimaging.
(ii) A limiting statement that reads “A negative result is generally associated with the absence of acute intracranial lesions. An appropriate neuroimaging method is required for diagnosis of acute intracranial lesions.”
(iii) As applicable, a limiting statement that reads “This device is for use by laboratory professionals in a clinical laboratory setting.”
§ 866.5860   Total spinal fluid immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5870   Thyroid autoantibody immunological test system.
(a) 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.
(b) Classification. Class II (performance standards).
§ 866.5880   Transferrin immunological test system.
(a) 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.
(b) Classification. Class II (performance standards).
§ 866.5890   Inter-alphatrypsin inhibitor immunological test system.
(a) 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.
(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 § 866.9.
§ 866.5900   Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation detection system.
(a) 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.
(b) 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.
§ 866.5910   Quality control material for cystic fibrosis nucleic acid assays.
(a) 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.
(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 § 866.9. 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.
§ 866.5930   Newborn screening test for severe combined immunodeficiency disorder (SCID).
(a) 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.
(b) 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/µL) 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.
§ 866.5940   Autosomal recessive carrier screening gene mutation detection system.
(a) 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.
(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 § 866.9, except § 866.9(c)(2). 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 * π)/(PPA * TC * π + (1 − NPA) * (1 − π)) and NPV = (NPA * (1 − π))/(NPA *(1 − π) + (1 − PPA*TC) * π) 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 π 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.
§ 866.5950   Genetic health risk assessment system.
(a) Identification. A genetic health risk assessment system is a qualitative in vitro molecular diagnostic system used for detecting variants in genomic deoxyribonucleic acid (DNA) isolated from human specimens that will provide information to users about their genetic risk of developing a disease to inform lifestyle choices and/or conversations with a health care professional. This assessment system is for over-the-counter use. This device does not determine the person's overall risk of developing a disease.
(b) Classification. Class II (special controls). The genetic health risk assessment system device, when it has previously received a first-time FDA marketing authorization ( e.g., 510(k) clearance) for the genetic health risk assessment system (a “one-time FDA reviewed genetic health risk assessment system”), is exempt from the premarket notification procedures in part 807, subpart E, of this chapter subject to the limitations in § 866.9. The device must comply with the following special controls:
(1) The 21 CFR 809.10 compliant labeling and any prepurchase page and test report generated, unless otherwise specified, must include:
(i) A section addressed to users with the following information:
(A) The limiting statement explaining that this test provides genetic risk information based on assessment of specific genetic variants but does not report on a user's entire genetic profile. This test [does not/may not, as appropriate] detect all genetic variants related to a given disease, and the absence of a variant tested does not rule out the presence of other genetic variants that may be related to the disease.
(B) The limiting statement explaining that other companies offering a genetic risk test may be detecting different genetic variants for the same disease, so the user may get different results using a test from a different company.
(C) The limiting statement explaining that other factors such as environmental and lifestyle risk factors may affect the risk of developing a given disease.
(D) The limiting statement explaining that some people may feel anxious about getting genetic test health results. This is normal. If the potential user feels very anxious, such user should speak to his or her doctor or other health care professional prior to collection of a sample for testing. This test is not a substitute for visits to a doctor or other health care professional. Users should consult with their doctor or other health care professional if they have any questions or concerns about the results of their test or their current state of health.
(E) Information about how to obtain access to a genetic counselor, board-certified clinical molecular geneticist, or equivalent health care professional about the results of a user's test.
(F) The limiting statement explaining that this test is not intended to diagnose a disease, tell you anything about your current state of health, or be used to make medical decisions, including whether or not you should take a medication or how much of a medication you should take.
(G) A limiting statement explaining that the laboratory may not be able to process a sample, and a description of the next steps to be taken by the manufacturer and/or the customer, as applicable.
(ii) A section in your 21 CFR 809.10 labeling and any test report generated that is for health care professionals who may receive the test results from their patients with the following information:
(A) The limiting statement explaining that this test is not intended to diagnose a disease, determine medical treatment, or tell the user anything about their current state of health.
(B) The limiting statement explaining that this test is intended to provide users with their genetic information to inform lifestyle decisions and conversations with their doctor or other health care professional.
(C) The limiting statement explaining that any diagnostic or treatment decisions should be based on testing and/or other information that you determine to be appropriate for your patient.
(2) The genetic test must use a sample collection device that is FDA-cleared, -approved, or -classified as 510(k) exempt, with an indication for in vitro diagnostic use in over-the-counter DNA testing.
(3) The device's labeling must include a hyperlink to the manufacturer's public Web site where the manufacturer shall make the information identified in paragraph (b)(3) of 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 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 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) An index of the material being provided to meet the requirements in paragraph (b)(3) of this section and its location.
(ii) A section that highlights summary information that allows the user to understand how the test works and how to interpret the results of the test. This section must, at a minimum, be written in plain language understandable to a lay user and include:
(A) Consistent explanations of the risk of disease associated with all variants included in the test. If there are different categories of risk, the manufacturer must provide literature references that support the different risk categories. If there will be multiple test reports and multiple variants, the risk categories must be defined similarly among them. For example, “increased risk” must be defined similarly between different test reports and different variant combinations.
(B) Clear context for the user to understand the context in which the cited clinical performance data support the risk reported. This includes, but is not limited to, any risks that are influenced by ethnicity, age, gender, environment, and lifestyle choices.
(C) Materials that explain the main concepts and terminology used in the test that include:
( 1 ) Definitions: Scientific terms that are used in the test reports.
( 2 ) Prepurchase page: This page must contain information that informs the user about what information the test will provide. This includes, but is not limited to, variant information, the condition or disease associated with the variant(s), professional guideline recommendations for general genetic risk testing, the limitations associated with the test ( e.g., test does not detect all variants related to the disease) and any precautionary information about the test the user should be aware of before purchase. When the test reports the risk of a life-threatening or irreversibly debilitating disease or condition for which there are few or no options to prevent, treat, or cure the disease, a user opt-in section must be provided. This opt-in page must be provided for each disease that falls into this category and must provide specific information relevant to each test result. The opt-in page must include:
( i ) An option to accept or decline to receive this specific test result;
( ii ) Specification of the risk involved if the user is found to have the specific genetic test result;
( iii ) Professional guidelines that recommend when genetic testing for the associated target condition is or is not recommended; and
( iv ) A recommendation to speak with a health care professional, genetic counselor, or equivalent professional before getting the results of the test.
( 3 ) Frequently asked questions (FAQ) page: This page must provide information that is specific for each variant/disease pair that is reported. Information provided in this section must be scientifically valid and supported by corresponding publications. The FAQ page must explain the health condition/disease being tested, the purpose of the test, the information the test will and will not provide, the relevance of race and ethnicity to the test results, information about the population to which the variants in the test is most applicable, the meaning of the result(s), other risk factors that contribute to disease, appropriate followup procedures, how the results of the test may affect the user's family, including children, and links to resources that provide additional information.
(iii) A technical information section containing the following information:
(A) Gene(s) and variant(s) the test detects using standardized nomenclature, Human Genome Organization nomenclature and coordinates as well as Single Nucleotide Polymorphism Database (dbSNP) reference SNP numbers (rs#).
(B) Scientifically established disease-risk association of each variant detected and reported by the test. This risk association information must include:
( 1 ) Genotype-phenotype information for the reported variants.
( 2 ) Table of expected frequency and risks of developing the disease in relevant ethnic populations and the general population.
( 3 ) A statement about the current professional guidelines for testing these specific gene(s) and variant(s).
( i ) If professional guidelines are available, provide the recommendations in the professional guideline for the gene, variant, and disease, for when genetic testing should or should not be performed, and cautionary information that should be communicated when a particular gene and variant is detected.
( ii ) If professional guidelines are not available, provide a statement that the professional guidelines are not available for these specific gene(s) and variant(s).
(C) The specimen type ( e.g., saliva, capillary whole blood).
(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 ( i.e., percentage of tests that failed quality control) based on data from clinical samples, a description of scenarios in which a test can fail ( i.e., low sample volume, low DNA concentration, etc.), how users will be notified of a test failure, and the nature of followup actions on a failed test to be taken by the user and the manufacturer.
(I) Specification of the criteria for test result interpretation and reporting.
(J) Information that demonstrates the performance characteristics of the test, including:
( 1 ) Accuracy of study results for each claimed specimen type.
( i ) Accuracy of the test shall be evaluated with fresh clinical specimens collected and processed in a manner consistent with the test'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 instructions for use, stored appropriately, and randomly selected. In some limited circumstances, use of contrived samples or human cell line samples may also be appropriate and used as an acceptable alternative. The contrived or human cell line samples shall mimic clinical specimens as much as is feasible and provide an unbiased evaluation of the device accuracy.
( ii ) Accuracy must be evaluated by comparison to bidirectional Sanger sequencing or other methods identified as appropriate by FDA. Performance criteria for both the comparator method and the device must be predefined and appropriate to the device's intended use. Detailed study protocols must be provided.
( iii ) Test specimens must include all genotypes that will be included in the tests and reports. The number of samples tested in the accuracy study for each variant reported must be based on the variant frequency using either the minimum numbers of samples identified in this paragraph or, when determined appropriate and identified by FDA, a minimum number of samples determined using an alternative method. When appropriate, the same samples may be used in testing to demonstrate the accuracy of testing for multiple genotypes by generating sequence information at multiple relevant genetic locations. At least 20 unique samples representing the wild-type genotype must be tested. To test samples that are heterozygous for the reported variant(s), common variants (>0.1 percent variant frequency in the relevant population) must be tested with at least 20 unique samples. Rare variants (≤0.1 percent variant frequency in the relevant population) must be tested with at least three unique samples. To test samples that are homozygous for the reported variant(s), variants with ≥2 percent variant frequency in a relevant population must be tested with at least 20 unique samples. Variants with a frequency in the relevant population <2 percent and ≥0.5 percent must be tested with at least 10 unique samples. Variants with a frequency in the relevant population <0.5 percent must be tested with at least three unique samples. If variants with a frequency of <0.5 percent are not found within the relevant population and homozygous samples are not tested, then the test results for this homozygous rare variant must not be reported to the user.
( iv ) Information about the accuracy study shall include the number and type of samples that were compared to bidirectional Sanger sequencing or other methods identified as appropriate by FDA. This information must either be reported in tabular format and arranged by clinically relevant variants or reported using another method identified as appropriate by FDA. As an example, for samples with different genotypes DD, Dd, and dd, the following table represents data from the accuracy study presented in tabular format:
( v ) The accuracy represents the degrees of agreement between the device results and the comparator results. The accuracy must be evaluated by measuring different percent agreements (PA) of device results with the comparator results and percent of `no calls' or `invalid calls.' Calculate the rate of `no calls' and `invalid calls' for each comparator output as %Inv(DD) = A 4 /N DD, %Inv(Dd) = B 4 /N Dd , %Inv(dd) = C 4 /N dd . If `no calls' or `invalid calls' are required to be retested according to the device instructions for use, the percent of final `no calls' or `invalid calls' must be provided. In the table presenting the results of the accuracy study, use only the final results ( i.e., after retesting the initial `no calls' or `invalid calls', if required according to the instructions for use). Samples that resulted in a `no call' or `invalid call' after retesting must not be included in the final calculations of agreement. If the percentages of `no calls' or `invalid calls' for each comparator output are similar, combine these estimates as (A 4 + B 4 + C 4 )/(N DD + N Dd + N dd ) and provide a 95 percent two-sided confidence interval. The percent of final `no calls' or `invalid calls' must be clinically acceptable.
( vi ) Point estimates of percent agreement for each genotype must be calculated as the number of correct calls for that genotype divided by the number of samples known to contain that genotype excluding `no calls' or `invalid calls'. The calculations must be performed as follows:
( vii ) For percent agreements for DD, Dd and dd (PA(DD|DD), PA(Dd|Dd) and PA(dd|dd)) as described in paragraph (b)(3)(iii)(J)( 1 )( vi ) of this section, the 95 percent two-sided confidence intervals must be provided. The accuracy point estimates for percent agreements for DD, Dd and dd must be ≥99 percent per reported variant and overall. Any variants that have a point estimate for either PA(DD|DD), PA(Dd|Dd), or PA(dd|dd) of <99 percent compared to bidirectional sequencing or other methods identified as appropriate by FDA must not be incorporated into test claims and reports. Accuracy results 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 type and by genotype or must be reported using another method identified as appropriate by FDA (see paragraph (b)(3)(iii)(J)( 1 )( iv ) of this section).
( viii ) Information must be reported on the Technical Positive Predictive Value (TPPV) related to the analytical (technical) performance of the device for genotypes in each relevant subpopulation ( e.g., ethnicity, gender, age, geographical location, etc.). TPPV is the percentage of individuals with the genotype truly present among individuals whose test reports indicate that this genotype is present. The TPPV depends on the accuracy measures of percent agreements and on the frequency of the genotypes in the subpopulation being studied. The f(DD) is the frequency of DD and f(Dd) is the frequency of Dd in the subpopulation being studied; TPPV must be calculated as described in paragraphs (b)(3)(iii)(J)( 1 )( ix ) through ( xi ) of this section.
( ix ) For variants where the point estimates of PA(DD|DD), PA(Dd|Dd) and PA(dd|dd) are less than 100 percent, use these point estimates in TPPV calculations.
( x ) Point estimates of 100 percent in the accuracy study may have high uncertainty about performance of the test in the population. If these variants are measured using highly multiplexed technology, calculate the random error rate for the overall device. The accuracy study described in paragraph (b)(3)(iii)(J) of this section in those cases is more to determine that there is no systematic error in such devices. In those cases, incorporate that rate in the estimation of the percent agreements as calculated in paragraph (b)(3)(iii)(J)( 1 )( vi ) of this section and include it in TPPV calculations.
( xi ) The TPPV for subpopulations with genotype frequencies of f(dd), f(Dd) and f(DD) = 1−f(dd)−f(Dd) in the subpopulation is calculated as:
( 2 ) Precision and reproducibility data must be provided using multiple instruments and multiple operators, on multiple non-consecutive days, and using multiple reagent lots. The sample panel must either include specimens from the claimed sample type ( e.g., saliva) representing all genotypes for each variant ( e.g., wild type, heterozygous, and homozygous) or, if an alternative panel composition of specimens is identified by FDA as appropriate, a panel composed of those specimens FDA identified as appropriate. A detailed study protocol must be created in advance of the study and must include predetermined acceptance criteria for performance results. The percentage of samples that failed quality control must be indicated ( i.e., the total number of sample replicates for which a sequence variant cannot be called (no calls) or that fail sequencing quality control criteria divided by the total number of replicates tested). It must be clearly documented whether results were generated from clinical specimens, contrived samples, or cell lines. The study results shall report the variants tested in the study and the number of replicates for each variant, and what conditions were tested ( i.e., number of runs, days, instruments, reagent lots, operators, specimens/type, etc.). Results must be evaluated and presented in tabular format and stratified by study parameter ( e.g., by site, instrument(s), reagent lot, operator, and sample variant). The study must include all extraction steps from the claimed specimen type or matrix, unless a separate extraction reproducibility 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 reproducibility study and reproducibility across sites must be evaluated. Any no calls or invalid calls in the study must be listed as a part of the precision and reproducibility study results.
( 3 ) Analytical specificity data: Data must be provided that evaluates the effect of potential endogenous and exogenous interferents on test performance, including specimen extraction and variant detection. Interferents tested must include those reasonably likely to be potentially relevant to the sample type used for the device.
( 4 ) Interfering variant data: Nucleotide mutations that can interfere with the technology must be cited and evaluated. Data must be provided to demonstrate the effect of the interfering variant(s) on the performance of the correct calls. Alternatively, for each suspected interfering mutation for which data is not provided demonstrating the effect of the interfering variant, the manufacturer must identify the suspected interfering variants in the labeling and indicate that the impact that the interfering variants may have on the assay's performance has not been studied by providing a statement that reads “It is possible that the presence of [insert clearly identifying information for the suspected interfering variant] in a sample may interfere with the performance of this test. However, its effect on the performance of this test has not been studied.”
( 5 ) Analytical sensitivity data: Data must be provided demonstrating the minimum amount of DNA that will enable the test to perform correctly in 95 percent of runs.
( 6 ) Reagent stability: The manufacturer must evaluate reagent stability using wild-type, heterozygous, and homozygous samples. Reagent stability data must demonstrate that the reagents maintain the claimed accuracy and reproducibility. Data supporting such claims must be provided.
( 7 ) Specimen type and matrix comparison data: Specimen type and matrix comparison data must be generated if more than one specimen type can be tested with this device, including failure rates for the different specimens.
(K) Clinical performance summary.
( 1 ) Information to support the clinical performance of each variant reported by the test must be provided.
( 2 ) Manufacturers must organize information by the specific variant combination as appropriate ( e.g., wild type, heterozygous, homozygous, compound heterozygous, hemizygous genotypes). For each variant combination, information must be provided in the clinical performance section to support clinical performance for the risk category ( e.g., not at risk, increased risk). For each variant combination, a summary of key results must be provided in tabular format or using another method identified as appropriate by FDA to include the appropriate information regarding variant type, data source, definition of the target condition ( e.g., disease), clinical criteria for determining whether the target disease is present or absent, description of subjects with the target disease present and target disease absent (exclusion or inclusion criteria), and technical method for genotyping. When available, information on the effect of the variant on risk must be provided as the risk of a disease (lifetime risk or lifetime incidences) for an individual compared with the general population risk.
( i ) If odds ratios are available, using information about the genotype distribution either among individuals with the target disease absent, or in the general population, or information about the risk variant frequency and odds ratios, the likelihood ratios for the corresponding device results along with 95 percent confidence intervals must be calculated. Using information about pretest risk (π), an estimate of likelihood ratio (LR), and a relationship between post-test risk R as R/(1−R) = LR·π/(1−π), the post-test risk R must be calculated.
( ii ) When available, likelihood ratios (LR) for different test results must be presented in a tabular format along with references to the source data or using another method identified as appropriate by FDA as stated in paragraph (b)(3)(iii)(K)(2) of this section. When these values are not directly available in published literature, likelihood ratios can be separately calculated along with the 95 percent confidence interval with references to the source data. Note that a minimum requirement for the presence of the variant's effect on the risk is that a corresponding LR is statistically higher than 1 (a lower bound of 95 percent two-sided confidence interval is larger than 1). It means that the post-test risk is statistically higher than the pretest risk (an observed value of the difference between the post-test and pretest risks).
(L) Materials that explain the main concepts and terminology used in the test that includes, but is not limited to:
( 1 ) Definitions: Scientific terms that are used in the test reports.
( 2 ) Prepurchase page: This page must contain information that informs the user about what the test will provide. This includes, but is not limited to, variant information, the condition or disease associated with the variant(s), professional guideline recommendations for general genetic risk testing, the limitations associated with the test ( e.g., test does not detect all variants related to the disease) and any precautionary information about the test the user should be aware of before purchase. When the test reports the risk of a life-threatening or irreversibly debilitating disease or condition for which there are few or no options to prevent, treat, or cure the disease, a user opt-in section must be provided. This opt-in page must be provided for each disease that falls into this category and must provide specific information relevant to each test result. The opt-in page must include:
( i ) An option to accept or decline to receive this specific test result;
( ii ) Specification of the risk involved if the user is found to have the specific genetic test result;
( iii ) Professional guidelines that recommend when genetic testing for the associated target condition is or is not recommended; and
( iv ) A recommendation to speak with a health care professional, genetic counselor, or equivalent professional before getting the results of the test.
( 3 ) Frequently asked questions (FAQ) page: This page must provide information that is specific for each variant/disease pair that is reported. Information provided in this section must be scientifically valid and supported by corresponding publications. The FAQ page must explain the health condition/disease being tested, the purpose of the test, the information the test will and will not provide, the relevance of race and ethnicity on the test results, information about the population to which the variants in the test is most applicable, the meaning of the result(s), other risks factors that contribute to disease, appropriate followup procedures, how the results of the test may affect the user's family, including children, and links to resources that provide additional information.
(M) User comprehension study: Information on a study that assesses comprehension of the test process and results by potential users of the test must be provided.
( 1 ) The test manufacturer must provide a genetic risk education module to naïve user comprehension study participants prior to their participation in the user comprehension study. The module must define terms that are used in the test reports and explain the significance of genetic risk reports.
( 2 ) The test manufacturer must perform pre- and post-test user comprehension studies. The comprehension test questions must include directly evaluating a representative sample of the material being presented to the user as described in paragraph (b)(3)(ii) of this section.
( 3 ) The manufacturer must provide a justification from a physician and/or genetic counselor that identifies the appropriate general and variant-specific concepts contained within the material being tested in the user comprehension study to ensure that all relevant concepts are incorporated in the study.
( 4 ) The user study must meet the following criteria:
( i ) The study participants must comprise a statistically sufficient sample size and demographically diverse population (determined using methods such as quota-based sampling) that is representative of the intended user population. Furthermore, the study participants must comprise a diverse range of age and educational levels and have no prior experience with the test or its manufacturer. These factors shall be well defined in the inclusion and exclusion criteria.
( ii ) All sources of bias must be predefined and accounted for in the study results with regard to both responders and non-responders.
( iii ) 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).
( iv ) Users must be randomly assigned to study arms. Test reports in the user comprehension study given to users must define the target condition being tested and related symptoms, explain the intended use and limitations of the test, explain the relevant ethnicities in regard to the variant tested, explain genetic health risks and relevance to the user's ethnicity, and assess participants' ability to understand the following comprehension concepts: The test's limitations, purpose, appropriate action, test results, and other factors that may have an impact on the test results.
( v ) Study participants must be untrained, be naïve to the test subject of the study, and be provided the labeling prior to the start of the user comprehension study.
( vi ) 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. Other acceptance criteria may be acceptable depending on the concept being tested. Meeting or exceeding this overall comprehension rate demonstrates that the materials presented to the user are adequate for over-the-counter use.
( vii ) The analysis of the user comprehension results must include results regarding reports that are provided for each gene/variant/ethnicity tested, statistical methods used to analyze all data sets, and completion rate, non-responder rate, and reasons for nonresponse/data exclusion. A summary table of comprehension rates regarding comprehension concepts ( e.g., purpose of test, test results, test limitations, ethnicity relevance for the test results, etc.) for each study report must be included.
(4) The intended use of the device must not include the following indications for use:
(i) Prenatal testing;
(ii) Determining predisposition for cancer where the result of the test may lead to prophylactic screening, confirmatory procedures, or treatments that may incur morbidity or mortality to the patient;
(iii) Assessing the presence of genetic variants that impact the metabolism, exposure, response, risk of adverse events, dosing, or mechanisms of prescription or over-the-counter medications; or
(iv) Assessing the presence of deterministic autosomal dominant variants.