Rule2025-16035
Medical Devices; Immunology and Microbiology Devices; Classification of the Cancer Predisposition Risk Assessment System
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
August 21, 2025
Effective
August 21, 2025
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA, the Agency, or we) is classifying the cancer predisposition 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 classification of the cancer predisposition risk assessment system. We are taking this action because we have determined that classifying the device into class II 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.
Full Text
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<title>Federal Register, Volume 90 Issue 160 (Thursday, August 21, 2025)</title>
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[Federal Register Volume 90, Number 160 (Thursday, August 21, 2025)]
[Rules and Regulations]
[Pages 40716-40721]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2025-16035]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2025-N-2425]
Medical Devices; Immunology and Microbiology Devices;
Classification of the Cancer Predisposition Risk Assessment System
AGENCY: Food and Drug Administration, HHS.
ACTION: Final amendment; final order.
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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
classifying the cancer predisposition 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 classification of the cancer predisposition risk
assessment system. We are taking this action because we have determined
that classifying the device into class II 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 August 21, 2025. The classification was
applicable on March 6, 2018.
FOR FURTHER INFORMATION CONTACT: Dina Jerebitski, Center for Devices
and Radiological Health, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 66, Rm. 3574, Silver Spring, MD 20993-0002, 301-
796-2411, <a href="/cdn-cgi/l/email-protection#d591bcbbb4fb9fb0a7b0b7bca1a6bebc95b3b1b4fbbdbda6fbb2baa3"><span class="__cf_email__" data-cfemail="7e3a17101f50341b0c1b1c170a0d15173e181a1f5016160d50191108">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Background
Upon request, FDA has classified the cancer predisposition 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
[[Page 40717]]
action to classify or reclassify the device (see 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 Federal Food,
Drug, and Cosmetic Act (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 (21 U.S.C. 360c(i)) to a predicate device that
does not require premarket approval. We determine whether a new device
is substantially equivalent to a predicate device by means of the
procedures for premarket notification under section 510(k) of the FD&C
Act (21 U.S.C. 360(k)) and part 807 (21 CFR part 807).
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 (see also part 860, subpart D (21 CFR part 860, subpart D)).
Section 207 of the Food and Drug Administration Modernization Act of
1997 (Pub. L. 105-115) established the first procedure for De Novo
classification. Section 607 of the Food and Drug Administration Safety
and Innovation Act (Pub. L. 112-144) modified the De Novo application
process by adding a second procedure. 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 placed
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 section 513(f)(2)(B)(i) of the
FD&C Act). As a result, other device sponsors do not have to submit a
De Novo request or premarket approval application to market a
substantially equivalent device (see section 513(i) of the FD&C Act,
defining ``substantial equivalence''). Instead, sponsors can use the
less burdensome 510(k) process, when necessary, to market their device.
II. De Novo Classification
On September 5, 2017, FDA received 23andMe, Inc.'s request for De
Novo classification of the 23andMe PGS Genetic Health Risk Report for
BRCA1/BRCA2 (Selected Variants). 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 section 513(a)(1)(B) of the FD&C Act). 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.
Therefore, on March 6, 2018, FDA issued an order to the requester
classifying the device into class II.\1\ In this final order, FDA is
codifying the classification of the device by adding 21 CFR
866.6090.\2\ We have named the generic type of device ``cancer
predisposition risk assessment system,'' and it is identified as a
qualitative in vitro molecular diagnostic system used for 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. The test could help to
inform conversations with a healthcare professional. This assessment
system is for over-the-counter use. This device does not determine the
person's overall risk of developing any types of cancer. This test is
not a substitute for visits to a healthcare provider for recommended
screenings or appropriate follow-up and should not be used to determine
any treatments.
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\1\ FDA issued a correction of this order to the requestor in a
letter dated January 17, 2019.
\2\ FDA notes that the ``ACTION'' caption for this final order
is styled as ``Final amendment; final order,'' rather than ``Final
order.'' Beginning in December 2019, this editorial change was made
to indicate that the document ``amends'' the Code of Federal
Regulations. The change was made in accordance with the Office of
Federal Register's (OFR) interpretations of the Federal Register Act
(44 U.S.C. chapter 15), its implementing regulations (1 CFR 5.9 and
parts 21 and 22), and the Document Drafting Handbook.
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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--Cancer Predisposition Risk Assessment System Risks and
Mitigation Measures
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Identified risks to health Mitigation measures
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Incorrect understanding of the device Special controls (1), (3), and
and test system. (4).
Incorrect test results (false Special controls (1), (2), (3),
positives, false negatives). and (4).
Incorrect interpretation of test Special controls (1), (3), and
results. (4).
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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. 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 final order. This device is subject to
[[Page 40718]]
premarket notification requirements under section 510(k) of the FD&C
Act.
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 and guidance. 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. 3501-3521). The collections
of information in part 860, subpart D, regarding De Novo classification
have been approved under OMB control number 0910-0844; the collections
of information in 21 CFR part 814, subparts A through E, regarding
premarket approval have been approved under OMB control number 0910-
0231; the collections of information in part 807, subpart E, regarding
premarket notification submissions have been approved under OMB control
number 0910-0120; the collections of information in 21 CFR part 820
regarding quality system regulation have been approved under OMB
control number 0910-0073; 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. 866.6090 to subpart G to read as follows:
Sec. 866.6090 Cancer predisposition risk assessment system.
(a) Identification. A cancer predisposition risk assessment system
is a qualitative in vitro molecular diagnostic system used for
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. The test could
help to inform conversations with a healthcare professional. This
assessment system is for over-the-counter use. This device does not
determine the person's overall risk of developing any types of cancer.
This test is not a substitute for visits to a healthcare provider for
recommended screenings or appropriate follow-up and should not be used
to determine any treatments.
(b) Classification. Class II (special controls). The special
controls for this device are:
(1) The labeling required under Sec. 809.10 of this chapter and
any pre-purchase page and test report generated, unless otherwise
specified, must include:
(i) An intended use that specifies in the indications for use the
genetic variants detected by the test. The specific variants must be
appropriately validated as described in paragraphs (b)(4)(xii) and
(b)(4)(xiii) of this section.
(ii) A section addressed to users with the following information:
(A) A warning statement accurately disclosing the genetic coverage
of the test in lay terms, including information on variants not queried
by the test, and the proportion of pathogenic variants in the genes
that the assay detects in a specific population as identified in
paragraph (b)(1)(i) of this section. The warning statement must
indicate that the test [does not/may not, as appropriate] 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 impact cancer risk. The warning statement must also
include the relevant population for which the variants reported by the
test are most relevant.
(B) A 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 healthcare professional prior to collection of a
sample for testing. This test is not a substitute for visits to a
doctor or other healthcare professional. Users should consult with
their doctor or other healthcare professional if they have any
questions or concerns about the results of their test or their current
state of health.
(C) A limiting statement that a user's ethnicity may affect whether
the test is relevant for them and may also affect how their genetic
health results are interpreted.
(D) A warning statement that the test is not a substitute for
visits to a healthcare professional for recommended screenings, and
should not be used to determine any treatments or medical
interventions.
(E) A warning statement that the test does not diagnose cancer or
any other health conditions and should not be used to make medical
decisions. The warning statement must indicate that the results should
be confirmed in a clinical setting before taking any medical action.
(F) A 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.
(G) If applicable, a limiting statement that states the test does
not test for variants in other genes linked to hereditary cancer.
(H) A limiting statement explaining that this test does not account
for non-genetic factors and that other factors such as environmental
and lifestyle risk factors may affect the risk of developing a given
disease.
(I) 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.
(J) A limiting statement explaining that this test is not intended
to 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.
(K) 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.
(iii) A section in the labeling required under Sec. 809.10 of this
chapter and any test report generated that is for healthcare
professionals who may receive the test results from their patients with
the following information:
(A) A limiting statement explaining that this test is not intended
to diagnose a disease, determine medical treatment or other medical
intervention, or tell the user anything about their current state of
health.
(B) A limiting statement explaining that this test is intended to
provide users with their genetic information to inform health-related
lifestyle decisions
[[Page 40719]]
and conversations with their doctor or other healthcare professional.
(C) A limiting statement explaining that any diagnostic or
treatment decisions should be based on confirmatory prescription
testing and/or other information that is determined to be appropriate
for the patient (e.g., additional clinical testing and other risk
factors that may affect individual risk and health care).
(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 website where the manufacturer must 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 website 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
website or testing using the device can be ordered from the website,
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 must also be posted on
the manufacturer's website. 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) Technical information about the device, as specified in
paragraph (b)(4) of this section.
(iii) 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, variants not included in the test,
and specific considerations by ethnicity. If there are different
categories of risk, the manufacturer must provide literature references
and/or data 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 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) Pre-purchase page: this page must contain information that
informs the user about what information the test will provide. This
includes variant information, the condition(s) or disease(s) 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), relevance of
race/ethnicity, 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 page must be provided. This opt-in page must be
provided for each disease type 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) Summary of professional guidelines that recommend when
genetic testing for the associated target condition is or is not
recommended;
(iv) A recommendation to speak with a healthcare professional,
genetic counselor, or equivalent professional before getting the
results of the test;
(v) The implications of receiving a no variants detected result;
and
(vi) The statement that the test does not diagnose cancer or any
other health conditions and should not be used to make medical
decisions. Results should be confirmed in a clinical setting before
taking any medical action. Users should consult with a healthcare
professional before taking any medical action.
(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 peer-reviewed 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 follow-up procedures, how the
results of the test may affect the user's family, including children,
and links to resources that provide additional information.
(4) The device labeling must include a technical information
section containing the following information:
(i) Gene(s) and variant(s) the test detects using standardized
nomenclature, Human Genome Organization (HUGO) nomenclature and
coordinates, as well as Single Nucleotide Polymorphism Database (dbSNP)
reference SNP numbers (rs#).
(ii) A statement indicating that more than 1,000 variants in the
BRCA1 and BRCA2 genes are known to increase cancer risk, as applicable.
(iii) Scientifically established disease-risk association of each
variant detected and reported by the test. This risk association
information must include:
(A) Genotype-phenotype information for the reported variants.
(B) When available, a table of expected frequency in the general
population and different ethnicities, and risks of developing the
disease in relevant ethnic populations and the general population.
(C) Information such as peer-reviewed published literature and/or
professional guidelines used to determine what types and levels of
evidence will distinguish whether the selected variants are reported as
``are associated with increased risk'' versus ``may be associated with
increased risk'' of developing other cancers. All selected variants
must be appropriately validated as required under paragraph (b)(1)(i)
of this section. For selected variants reported as ``are associated
with increased risk,'' the clinical evidence must be demonstrated with
sufficient information (e.g., professional guidelines and consistent
associations in peer-reviewed published literature). For the selected
variants reported as ``may be associated with increased risk,'' the
clinical evidence must be reported in professional guidelines, but
peer-reviewed published literature may not be consistent.
(D) A statement about the current professional guidelines for
testing these
[[Page 40720]]
specific gene(s) and variant(s) for the specified disease(s).
(1) If professional guidelines are available, provide the
recommendations in the professional guideline(s) 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.
(2) If professional guidelines are not available, provide a
statement that the professional guidelines are not available for these
specific gene(s) and variant(s).
(iv) The specimen type (e.g., saliva, whole blood).
(v) Assay steps and technology used.
(vi) Specification of required ancillary reagents, instrumentation,
and equipment.
(vii) Specification of the specimen collection, processing,
storage, and preparation methods.
(viii) 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.
(ix) Information pertaining to the probability of test failure
(e.g., percentage of tests that failed quality control) based on data
from clinical samples, a description of scenarios in which a test can
fail (e.g., low sample volume, low DNA concentration), how users will
be notified of a test failure, and the nature of follow-up actions on a
failed test to be taken by the user and the manufacturer.
(x) When available, information specifying the probability of a
false negative and false positive analytical result and any additional
considerations by ethnicity.
(xi) Specification of the criteria for test result interpretation
and reporting, including any distinctions between risk categories
(i.e., increased risk and greatly increased risk; are associated and
may be associated).
(xii) Information that demonstrates the performance characteristics
of the test including:
(A) Accuracy of study results for each claimed specimen type.
(1) Accuracy of the test must 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 must 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
must mimic clinical specimens as much as is feasible and provide an
unbiased evaluation of the test's accuracy.
(2) 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 test must
be pre-defined and appropriate to the test's intended use. Detailed
study protocols must be provided.
(3) Information provided must include the number and type of
specimens, broken down by clinically relevant variants for each
indicated report that were compared to bidirectional sequencing or
other methods identified as appropriate by FDA. The accuracy as
positive percent agreement (PPA) and negative percent agreement (NPA)
must be measured, and accuracy point estimates must be >99 percent
(both per reported variant and overall). Uncertainty of the point
estimate must be within an acceptable range, as identified by FDA, and
must be presented using the 95 percent confidence interval.
(4) Sufficient specimens must be tested per genotype and 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.
(5) 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. The percent of final
`no calls' or `invalid calls' must be clinically acceptable. Variants
that have a point estimate for PPA or NPA of <99 percent (incorrect
test results compared to bidirectional sequencing or other methods
identified as appropriate by FDA) must not be incorporated into test
claims and reports. Accuracy measures generated from clinical specimens
versus contrived samples or cell lines must be presented separately.
Results must be summarized and presented in tabular format, by sample
and by genotype.
(6) Point estimate of PPA 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. The point estimate of NPA for
each genotype must be calculated as the number of correct calls that do
not contain that genotype divided by the number of samples known to not
contain that genotype. `No calls' must not be included in these
calculations. Point estimates must be calculated along with 95 percent
two-sided confidence intervals.
(B) 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 include specimens from the claimed sample type (e.g., saliva)
representing all genotypes for each variant (e.g., wild type,
heterozygous, and homozygous). 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 (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 must
state, in a tabular format, the variants tested in the study and the
number of replicates for each variant, and what conditions were tested
(e.g., number of runs, days, instruments, reagent lots, operators,
specimens/type). The study must include all 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 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.
(C) Analytical specificity data: data must be provided evaluating
the test performance (e.g., specimen extraction and variant detection)
effect of potential endogenous and exogenous interferents relevant to
the specimen type, and assessment of cross-contamination.
Alternatively, for each suspected interfering mutation for which data
is not provided demonstrating the effect of the interfering variant,
the manufacturer must clearly identify the suspected interfering
variants in the labeling to user test reports, and indicate that the
impact the interfering variants may have on the test's performance has
not been studied by providing a statement that reads, ``It is possible
that the presence of [insert identifying information for the suspected
interfering variant] in a sample may interfere with the performance of
this test. However, its
[[Page 40721]]
effect on the performance of this test has not been studied.''
(D) 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.
(E) Device stability data: the manufacturer must establish upper
and lower limits of input nucleic acid, sample, and reagent stability
that will achieve the test's claimed accuracy and reproducibility. The
manufacturer must evaluate stability using wild-type, heterozygous, and
homozygous samples. Data supporting such claims must be provided.
(F) 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.
(xiii) Clinical Performance Summary.
(A) Information to support the clinical performance of each variant
in the specific condition which is labeled as ``are associated with
increased risk'' and reported by the test must be provided, as
identified in paragraph (b)(4)(iii)(C) of this section.
(B) 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.
(xiv) 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, including the following, as
appropriate:
(A) The test manufacturer must provide a genetic health 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.
(B) The test manufacturer must perform pre- and post-test user
comprehension studies. The comprehension test questions must directly
evaluate the material being presented to the user as described in
paragraph (b)(3)(ii) of this section.
(C) 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.
(D) The user comprehension study must meet the following criteria:
(1) The study participants must comprise a statistically sufficient
sample size and demographically diverse population (determined using
methods such as quota-based sampling) that is representative of the
intended user population. Furthermore, the study participants must
comprise a diverse range of age and educational levels and have no
prior experience with the test or its manufacturer. These factors must
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 on-site 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 in
the user comprehension study given to users must define the target
condition being tested and related symptoms, explain the intended use
and limitations (including warnings) for 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.
(5) 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.
(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. 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.
(7) The analysis of the user comprehension results must include:
(i) Results regarding reports that are provided for each gene/
variant/ethnicity tested;
(ii) Statistical methods used to analyze all data sets; and
(iii) 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, appropriate
actions following receipt of results) for each study report must be
included.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2025-16035 Filed 8-20-25; 8:45 am]
BILLING CODE 4164-01-P
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