Document ID: FDA-2017-N-4341-0001
Agency: fda
Document Type: Rule
Title: Medical Devices; Immunology and Microbiology Devices; Classification of the Genetic Health Risk Assessment System
Posted Date: 2017-11-07T05:00Z

[Federal Register Volume 82, Number 214 (Tuesday, November 7, 2017)]
[Rules and Regulations]
[Pages 51560-51567]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-24159]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2017-N-4341]

Medical Devices; Immunology and Microbiology Devices; 
Classification of the Genetic Health Risk Assessment System

AGENCY: Food and Drug Administration, HHS.

ACTION: Final order.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
classifying the genetic health risk assessment system into class II 
(special controls). The special controls that apply to the device type 
are identified in this order and will be part of the codified language 
for the genetic health risk assessment system's classification. We are 
taking this action because we have determined that classifying the 
device into class II (special controls) will provide a reasonable 
assurance of safety and effectiveness of the device. We believe this 
action will also enhance patients' access to beneficial innovative 
devices, in part by reducing regulatory burdens.

DATES: This order is effective November 7, 2017. The classification was 
applicable on April 6, 2017.

FOR FURTHER INFORMATION CONTACT: Steven Tjoe, Center for Devices and 
Radiological Health, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 66, Rm. 4550, Silver Spring, MD 20993-0002, 301-796-5866, 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    Upon request, FDA has classified the genetic health risk assessment 
system as class II (special controls), which we have determined will 
provide a reasonable assurance of safety and effectiveness. In 
addition, we believe this action will enhance patients' access to 
beneficial innovation, in part by reducing regulatory burdens by 
placing the device into a lower device class than the automatic class 
III assignment.
    The automatic assignment of class III occurs by operation of law 
and without any action by FDA, regardless of the level of risk posed by 
the new device. Any device that was not in commercial distribution 
before May 28, 1976, is automatically classified as, and remains 
within, class III and requires premarket approval unless and until FDA 
takes an action to classify or reclassify the device (see section 
513(f)(1) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) 
(21 U.S.C. 360c(f)(1))). We refer to these devices as ``postamendments 
devices'' because they were not in commercial distribution prior to the 
date of enactment of the Medical Device Amendments of 1976, which 
amended the FD&C Act.
    FDA may take a variety of actions in appropriate circumstances to 
classify or reclassify a device into class I or II. We may issue an 
order finding a new device to be substantially equivalent under section 
513(i) of the FD&C Act to a predicate device that does not require 
premarket approval. We determine whether a new device is substantially 
equivalent to a predicate by means of the procedures for premarket 
notification under section 510(k) of the FD&C Act and part 807 (21 
U.S.C. 360(k) and 21 CFR part 807, respectively).
    FDA may also classify a device through ``De Novo'' classification, 
a common name for the process authorized under section 513(f)(2) of the 
FD&C Act. Section 207 of the Food and Drug Administration Modernization 
Act of 1997 established the first procedure for De Novo classification 
(Pub. L. 105-115). Section 607 of the Food and Drug Administration 
Safety and Innovation Act modified the De Novo application process by 
adding a second procedure (Pub. L. 112-144). A device sponsor may 
utilize either procedure for De Novo classification.
    Under the first procedure, the person submits a 510(k) for a device 
that has not previously been classified. After receiving an order from 
FDA classifying the device into class III under section 513(f)(1) of 
the FD&C Act, the person then requests a classification under section 
513(f)(2).
    Under the second procedure, rather than first submitting a 510(k) 
and then a request for classification, if the person determines that 
there is no legally marketed device upon which to base a determination 
of substantial equivalence, that person requests a classification under 
section 513(f)(2) of the FD&C Act.
    Under either procedure for De Novo classification, FDA is required 
to classify the device by written order within 120 days. The 
classification will be according to the criteria under section 
513(a)(1) of the FD&C Act. Although the device was automatically within 
class III, the De Novo classification is considered to be the initial 
classification of the device.
    We believe this De Novo classification will enhance patients' 
access to beneficial innovation, in part by reducing regulatory 
burdens. When FDA classifies a device into class I or II via the De 
Novo process, the device can serve as a predicate for future devices of 
that type, including for 510(k)s (see 21 U.S.C. 360c(f)(2)(B)(i)). As a 
result, other device sponsors do not have to submit a De Novo request 
or PMA in order to market a substantially equivalent device (see 21 
U.S.C. 360c(i), defining ``substantial equivalence''). Instead, 
sponsors can use the less-burdensome 510(k) process, when necessary, to 
market their device.

II. De Novo Classification

    On June 28, 2016, 23andMe, Inc. submitted a request for De Novo 
classification of the 23andMe Personal Genome Service (PGS) Test. 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.
    We classify devices into class II if general controls by themselves 
are insufficient to provide reasonable assurance of safety and 
effectiveness, but there is sufficient information to establish special 
controls that, in combination with the general controls, provide 
reasonable assurance of the safety and effectiveness of the device for 
its intended use (see 21 U.S.C. 360c(a)(1)(B)). After review of the 
information submitted in the request, we determined that the device can 
be classified into class II with the establishment of special controls. 
FDA has determined that these special controls, in addition to the 
general controls, will provide reasonable assurance of the safety and 
effectiveness of the device.

[[Page 51561]]

    Therefore, on April 6, 2017, FDA issued an order to the requester 
classifying the device into class II. FDA is codifying the 
classification of the device by adding 21 CFR 866.5950. We have named 
the generic type of device genetic health risk assessment system, and 
it is identified as 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.
    FDA has identified the following risks to health associated 
specifically with this type of device and the measures required to 
mitigate these risks in table 1.

   Table 1--Genetic Health Risk Assessment System Risks and Mitigation
                                Measures
------------------------------------------------------------------------
            Identified risk                    Mitigation measures
------------------------------------------------------------------------
Incorrect understanding of the device    General controls, Special
 and test system.                         control (1) (21 CFR
                                          866.5950(b)(1)), Special
                                          control (3) (21 CFR
                                          866.5950(b)(3)), and Special
                                          control (4) (21 CFR 866.5950
                                          (b)(4)).
Incorrect test results (false            General controls, Special
 positives, false negatives).             control (2) (21 CFR
                                          866.5950(b)(2)), and Special
                                          control (3) (21 CFR
                                          866.5950(b)(3)).
Incorrect interpretation of test         General controls, Special
 results.                                 control (1) (21 CFR
                                          866.5950(b)(1)), Special
                                          control (3) (21 CFR
                                          866.5950(b)(3)), and Special
                                          control (4) (21 CFR
                                          866.5950(b)(4)).
------------------------------------------------------------------------

    FDA has determined that special controls, in combination with the 
general controls, address these risks to health and provide reasonable 
assurance of safety and effectiveness. In order for a device to fall 
within this classification, and thus avoid automatic classification in 
class III, it would have to comply with the special controls named in 
this final order. The necessary special controls appear in the 
regulation codified by this order. This device is subject to premarket 
notification requirements under section 510(k) of the FD&C Act.
    Section 510(m)(2) of the FD&C Act provides that FDA may exempt a 
class II device from the premarket notification requirements under 
section 510(k) if, after notice of our intent to exempt and 
consideration of comments, we determine by order that premarket 
notification is not necessary to provide reasonable assurance of safety 
and effectiveness of the device. We believe this may be such a device. 
The notice of intent to exempt the device from premarket notification 
requirements is published elsewhere in this issue of the Federal 
Register.

III. Analysis of 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.

IV. Paperwork Reduction Act of 1995

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

PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES

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

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

0
2. Add Sec.  866.5950 to subpart F to read as follows:

Sec.  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 special 
controls for this device are:
    (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

[[Page 51562]]

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).

[[Page 51563]]

    (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:

[[Page 51564]]

[GRAPHIC] [TIFF OMITTED] TR07NO17.001

    (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) = A4/NDD, 
%Inv(Dd) = B4/NDd, %Inv(dd) = C4/
Ndd. 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 (A4 + B4 + 
C4)/(NDD + NDd + Ndd) 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:
[GRAPHIC] [TIFF OMITTED] TR07NO17.002

[[Page 51565]]

    (vii) For percent agreements for DD, Dd and dd (PA(DD[bond]DD), 
PA(Dd[bond]Dd) and PA(dd[bond]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[bond]DD), PA(Dd[bond]Dd), or PA(dd[bond]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[bond]DD), 
PA(Dd[bond]Dd) and PA(dd[bond]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:
[GRAPHIC] [TIFF OMITTED] TR07NO17.003

    (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

[[Page 51566]]

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 ([pi]), an 
estimate of likelihood ratio (LR), and a relationship between post-test 
risk R as R/(1-R) = LR[middot][pi]/(1-[pi]), 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 na[iuml]ve 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

[[Page 51567]]

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 na[iuml]ve 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.

    Dated: November 1, 2017.
Lauren Silvis,
Chief of Staff.
[FR Doc. 2017-24159 Filed 11-6-17; 8:45 am]
BILLING CODE 4164-01-P