[Federal Register Volume 80, Number 207 (Tuesday, October 27, 2015)]
[Rules and Regulations]
[Pages 65626-65632]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-27197]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2015-N-3472]


Medical Devices; Immunology and Microbiology Devices; 
Classification of Autosomal Recessive Carrier Screening Gene Mutation 
Detection System

AGENCY: Food and Drug Administration, HHS.

ACTION: Final order.

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SUMMARY: The Food and Drug Administration (FDA) has classified an 
autosomal recessive carrier screening gene mutation detection system 
into class II (special controls). The special controls that apply to 
this device are identified in this order and will be part of the 
codified language for the autosomal recessive carrier screening gene 
mutation detection system classification. The Agency has classified the 
device into class II (special controls) in order to provide a 
reasonable assurance of safety and effectiveness of the device.

DATES: This order is effective October 27, 2015. The classification was 
applicable February 19, 2015.

FOR FURTHER INFORMATION CONTACT: Sunita Shukla, Center for Devices and 
Radiological Health, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 66, Rm. 4647, Silver Spring, MD 20993-0002, 301-796-6406.

SUPPLEMENTARY INFORMATION: 

I. Background

    In accordance with section 513(f)(1) of the Federal Food, Drug, and 
Cosmetic Act (the FD&C Act) (21 U.S.C. 360c(f)(1)), devices that were 
not in commercial distribution before May 28, 1976 (the date of 
enactment of the Medical Device Amendments of 1976), generally referred 
to as postamendments devices, are classified automatically by statute 
into class III without any FDA rulemaking process. These devices remain 
in class III and require premarket approval, unless and until the 
device is classified or reclassified into class I or II, or FDA issues 
an order finding the device to be substantially equivalent, in 
accordance with section 513(i) of the FD&C Act, to a predicate device 
that does not require premarket approval. The Agency determines whether 
new devices are substantially equivalent to predicate devices by means 
of premarket notification procedures in section 510(k) of the FD&C Act 
(21 U.S.C. 360(k)) and part 807 (21 CFR part 807) of the regulations.
    Section 513(f)(2) of the FD&C Act, as amended by section 607 of the 
Food and Drug Administration Safety and Innovation Act (Pub. L. 112-
144), provides two procedures by which a person may request FDA to 
classify a device under the criteria set forth in section 513(a)(1). 
Under the first procedure, the person submits a premarket notification 
under section 510(k) of the FD&C Act for a device that has not 
previously been classified and, after receiving an order classifying 
the device into class III under section 513(f)(1) of the FD&C Act, the 
person requests a classification under section 513(f)(2). Under the 
second procedure, rather than first submitting a premarket notification 
under section 510(k) of the FD&C Act and then a request for 
classification under the first procedure, the person determines that 
there is no legally marketed device upon which to base a determination 
of substantial equivalence and requests a classification under section 
513(f)(2) of the FD&C Act. If the person submits a request to classify 
the device under this second procedure, FDA may decline to undertake 
the classification request if FDA identifies a legally marketed device 
that could provide a reasonable basis for review of substantial 
equivalence with the device or if FDA determines that the device 
submitted is not of ``low-moderate risk'' or that general controls 
would be inadequate to control the risks and special controls to 
mitigate the risks cannot be developed.
    In response to a request to classify a device under either 
procedure provided by section 513(f)(2) of the FD&C Act, FDA will 
classify the device by written order within 120 days. This 
classification will be the initial classification of the device.
    23andMe, Inc., submitted a direct de novo request for 
classification of the 23andMe PGS Carrier Screening Test for Bloom 
Syndrome under section 513(f)(2)(A)(ii) of the FD&C Act, based on a 
determination that there is no legally marketed device on which to base 
a determination of substantial equivalence.
    In accordance with section 513(f)(2) of the FD&C Act, FDA reviewed 
the request in order to classify the device under the criteria for 
classification set forth in section 513(a)(1) of the FD&C Act. After 
review of the information submitted in the de novo request, FDA 
classified the device into class II because general controls by 
themselves are insufficient to provide reasonable assurance of safety 
and effectiveness, and there is sufficient information to establish 
special controls to provide reasonable assurance of the safety and 
effectiveness of the device for its intended use.
    Therefore, on February 19, 2015, FDA issued an order to the 
requestor classifying the device into class II. The classification of 
the device will be codified at 21 CFR 866.5940.
    The device is assigned the generic name autosomal recessive carrier 
screening gene mutation detection system, and it is identified as 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.

[[Page 65627]]

    A gene mutation detection system indicated for the determination of 
carrier status by detection of clinically relevant gene mutations 
associated with cystic fibrosis is separately classified under 21 CFR 
866.5900--Cystic fibrosis transmembrane conductance regulator (CFTR) 
gene mutation detection system (class II, special controls), and is 
thus not included in the de novo classification.
    FDA has identified the following risks to health associated with 
this type of device and the measures required to mitigate these risks 
in table 1.

           Table 1--Identified Risks and Required Mitigations
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             Identified risks                   Required mitigations
------------------------------------------------------------------------
Incorrect understanding of the device and   Special controls 1 and 4.
 test system.
Incorrect test results....................  Special controls 2, 3, 5,
                                             and 6.
Incorrect interpretation of test results..  Special controls 1, 3, 4,
                                             and 5.
------------------------------------------------------------------------

    FDA believes that the following special controls, in addition to 
the general controls, address these risks to health and provide 
reasonable assurance of safety and effectiveness:
    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 subsection 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:
    a. A detailed device description including:
    i. 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);
    ii. 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:
    A. Genotype-phenotype information for the reported mutations.
    B. 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.
    C. Table of expected prevalence of carrier status in major ethnic 
and racial populations and the general population.
    iii. The specimen type (e.g., saliva, whole blood), matrix, and 
volume;
    iv. Assay steps and technology used;
    v. Specification of required ancillary reagents, instrumentation, 
and equipment;
    vi. Specification of the specimen collection, processing, storage, 
and preparation methods;
    vii. 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;
    viii. 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; and
    ix. Specification of the criteria for test result interpretation 
and reporting.
    b. Information that demonstrates the performance characteristics of 
the device, including:
    i. Accuracy (method comparison) of study results for each claimed 
specimen type.
    A. 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.
    B. 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.
    C. 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

[[Page 65628]]

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.
    D. 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 * [pi])/(PPA*TC*[pi] + (1 - NPA) * (1 - [pi])) 
and NPV = (NPA*(1 - [pi]))/(NPA*(1 - [pi]) + (1 - PPA*TC) * [pi]) where 
PPA and NPA described either in paragraph (3)(b)(i)(D)(1) or in 
(3)(b)(i)(D)(2) that follow and [pi] is prevalence of carriers in the 
population (pre-test risk to be a carrier for the disease).
    1. For the point estimates of PPA and NPA less than 100 percent, 
use the calculated estimates in the PPV and NPV calculations.
    2. 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.
    ii. 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.
    iii. 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.
    iv. 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.
    v. 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.
    vi. 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.
    c. 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:
    i. 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.
    ii. 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.
    iii. The user study must meet the following criteria:
    A. 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.
    B. 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.
    C. 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).
    D. Users must be randomly assigned to study arms. Test reports 
given to users must: (1) Define the condition being tested and related 
symptoms, (2) explain the intended use and limitations of the test, (3) 
explain the relevant ethnicities regarding the variant tested, (4) 
explain carrier status and relevance to the user's ethnicity, (5) 
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.
    E. 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.
    F. 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.
    iv. A summary of the user comprehension study must be provided and 
include the following:

[[Page 65629]]

    A. Results regarding reports that are provided for each gene/
variant/ethnicity tested.
    B. Statistical methods used to analyze all data sets.
    C. 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:
    a. A warning that reads ``The test is intended only for autosomal 
recessive carrier screening in adults of reproductive age.''
    b. 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.
    c. For prescription use tests, the following warnings that read:
    i. ``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.''
    ii. ``This device is not intended for disease diagnosis, prenatal 
testing of fetuses, risk assessment, prognosis or pre-symptomatic 
testing, susceptibility testing, or newborn screening.''
    d. 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.''
    e. For over-the-counter tests, the following warnings that read:
    i. ``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.''
    ii. ``The test does not diagnose any health conditions. Results 
should be used along with other clinical information for any medical 
purposes.''
    iii. ``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].''
    iv. ``Your ethnicity may affect how your genetic health results are 
interpreted.''
    f. 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.''
    g. 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 3 must show the device 
meets or exceeds each of the following performance specifications:
    a. 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.
    b. Precision (reproducibility) performance must meet or exceed 99 
percent for both positive and negative results.
    c. 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 2, shall be limited to the manufacturer, the 
manufacturer's subsidiaries, and laboratories regulated under the 
Clinical Laboratory Improvement Amendments.
    Section 510(m) of the FD&C Act provides that FDA may exempt a class 
II device from the premarket notification requirements under section 
510(k) of the FD&C Act if FDA determines that premarket notification is 
not necessary to provide reasonable assurance of the safety and 
effectiveness of the device. For this type of device, FDA believes 
premarket notification is not necessary to provide reasonable assurance 
of the safety and effectiveness of the device type and, therefore, is 
planning to exempt the device from the premarket notification 
requirements of the FD&C Act. Elsewhere in this issue of the Federal 
Register, FDA is publishing a notice of intent to exempt an autosomal 
recessive carrier screening gene mutation detection system under 
section 510(m) of the FD&C Act. If there are questions about 510(k) 
submission prior to finalization of the 510(k) exemption, you should 
contact FDA at the number provided in this Final order. Once finalized, 
persons who intend to market this device type need not submit a 510(k) 
premarket notification containing information on the autosomal 
recessive carrier screening gene mutation detection system prior to 
marketing the device.

II. Environmental Impact

    The Agency has determined under 21 CFR 25.34(b) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

III. Paperwork Reduction Act of 1995

    This final administrative order establishes special controls that 
refer to previously approved collections of information found in other 
FDA regulations. These collections of information are subject to review 
by the Office of Management and Budget (OMB) under the Paperwork 
Reduction Act of 1995 (44 U.S.C. 3501-3520). The collections of 
information in part 807, subpart E, regarding premarket notification 
submissions have been approved under OMB control number 0910-0120, and 
the collections of information in 21 CFR parts 801 and 809 regarding 
labeling have been approved under OMB control number 0910-0485.

List of Subjects in 21 CFR Part 866

    Biologics, Laboratories, Medical devices.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner

[[Page 65630]]

of Food and Drugs, 21 CFR part 866 is amended as follows:

PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES

0
1. The authority citation for 21 CFR part 866 continues to read as 
follows:

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


0
2. Add Sec.  866.5940 to subpart F to read as follows:


Sec.  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). 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

[[Page 65631]]

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 * [pi])/(PPA * TC * [pi] + (1 - NPA) * (1 - 
[pi])) and NPV = (NPA * (1 - [pi]))/(NPA *(1 - [pi]) + (1 - PPA*TC) * 
[pi]) 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 [pi] 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.

[[Page 65632]]

    (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.

    Dated: October 20, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-27197 Filed 10-26-15; 8:45 am]
BILLING CODE 4164-01-P