[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
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Identified risk Mitigation measures
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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