DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Food and Drug Administration

10903 New Hampshire Avenue
Document Control Center WO66-G609
Silver Spring, MD 20993-0002

23andMe, Inc.
C/O Kathy Hibbs
Chief Legal and Regulatory Officer
1390 Shorebird Way
Mountain View, CA 94043
Re:

February 19, 2015

DEN140044
23andMe Personal Genome Service (PGS) Carrier Screening Test for Bloom Syndrome
Evaluation of Automatic Class III Designation De Novo Request
Regulation Number: 21 CFR 866.5940
Regulation Name: Autosomal recessive carrier screening gene mutation diagnostic system
Regulatory Classification: Class II
Product Code: PKB
Dated: May 27, 2014
Received: May 29, 2014

Dear Ms. Hibbs:

The Center for Devices and Radiological Health (CDRH) of the Food and Drug Administration
(FDA) has completed its review of your de novo request for classification of the 23andMe Personal
Genome Service (PGS) Carrier Screening Test for Bloom Syndrome, an over-the-counter device.
The 23andMe PGS Carrier Screening Test for Bloom Syndrome is indicated for
The 23andMe PGS Carrier Screening Test for Bloom Syndrome is indicated for the detection
of the BLMAsh variant in the BLM gene. This test can be used to determine carrier status for
Bloom syndrome, but cannot determine if a person has two copies of the BLMAsh variant.
The test is most relevant for people of Ashkenazi Jewish descent.
FDA concludes that this device, and substantially equivalent devices of this generic type, should be
classified into class II. This order, therefore, classifies the 23andMe PGS Carrier Screening Test for
Bloom Syndrome, and substantially equivalent devices of this generic type, into class II under the
generic name, Autosomal recessive carrier screening gene mutation diagnostic system.
FDA identifies this generic type of device as: Autosomal recessive carrier screening gene mutation
diagnostic system.
Autosomal recessive carrier screening gene mutation detection system is a qualitative in vitro
molecular diagnostic system used for genotyping of clinically relevant variants in genomic
DNA isolated from human specimens intended for prescription use or over-the-counter use.
The device is intended for autosomal recessive disease carrier screening in adults of

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reproductive age. The device is not intended for copy number variation, cytogenetic, or
biochemical testing.
Section 513(f)(2) of the Food, Drug & Cosmetic Act (FD&C Act) was amended by section 607 of
the Food and Drug Administration Safety and Innovation Act (FDASIA) on July 9, 2012. This
section of the FD&C Act now provides two options for de novo classification. First, any person who
receives a "not substantially equivalent" (NSE) determination in response to a 510(k) for a device
that has not been previously classified under the FD&C Act may, within 30 days of receiving notice
of the NSE determination, request FDA to make a risk-based classification of the device under
section 513(a)(1) of the FD&C Act. Alternatively, any person who determines that there is no
legally marketed device upon which to base a determination of substantial equivalence may request
FDA to make a risk-based classification of the device under section 513(a)(1) of the FD&C Act
without first submitting a 510(k). FDA shall, within 120 days of receiving such a request, classify
the device. This classification shall be the initial classification of the device. Within 30 days after
the issuance of an order classifying the device, FDA must publish a notice in the Federal Register
classifying the device type.
Your request is a direct de novo request submitted under section 513(f)(2)(A)(ii) of the FD&C Act,
based on a determination that there is no legally marketed device on which to base a determination
of substantial equivalence. In order to classify the 23andMe PGS Carrier Screening Test for Bloom
Syndrome into class I or II, it is necessary that the class have sufficient regulatory controls to
provide reasonable assurance of the safety and effectiveness of the device for its intended use.
After review of the information submitted in the de novo request, FDA has determined that the
23andMe PGS Carrier Screening Test for Bloom Syndrome indicated for
The 23andMe PGS Carrier Screening Test for Bloom Syndrome is indicated for the detection
of the BLMAsh variant in the BLM gene. This test can be used to determine carrier status for
Bloom syndrome, but cannot determine if a person has two copies of the BLMAsh variant.
The test is most relevant for people of Ashkenazi Jewish descent.
can be classified in class II with the establishment of special controls for this type of device. FDA
believes that the class II special controls identified later in this order, along with the applicable
general controls, provide reasonable assurance of the safety and effectiveness of the device type.
Table Identified Risks and Required Mitigations
Identified Risks

Required Mitigations

Incorrect understanding of the device and

test system

Special Controls (1) and (4)

Incorrect test results

Special Controls (2), (3), (5) and (6)

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Incorrect interpretation of test results

Special Controls (1), (3), (4), and (5)

In combination with the general controls of the FD&C Act, the autosomal recessive carrier screening
gene mutation diagnostic system is subject to the following special controls:
(1) If the device is offered over-the-counter, the device manufacturer must provide
information to a potential purchaser or actual test report recipient about how to obtain
access to a board-certified clinical molecular geneticist or equivalent to assist in pre and
post-test counseling.
(2) The device must use a collection device that is FDA cleared, approved, or classified as
510(k) exempt, with an indication for in vitro diagnostic use in DNA testing.
(3) The devices labeling must include a prominent hyperlink to the manufacturers public
Web site where the manufacturer shall make the information identified in this subsection
publicly available. The manufacturers home page, as well as the primary part of the
manufacturers website that discusses the device, must provide a prominently-placed
hyperlink to the Web page containing this information and must allow unrestricted
viewing access. If the device can be purchased from the 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 prominently-placed and publicly accessible
hyperlink on the Web page for ordering the device. The information must include:
(i)
A detailed device description including:
(A) Gene (or list of the genes if more than one) and variants the test detects
(using standardized nomenclature, Human Genome Organization (HUGO)
nomenclature and coordinates).
(B) Scientifically established clinical validity of each variant detected and
reported by the test, which may be supported by peer-reviewed journal
articles, professional society recommendations, or both, including:
(1) Genotype-phenotype information for the reported mutations.
(2) Relevant American College of Medical Genetics (ACMG) or
American Congress of Obstetricians and Gynecologists (ACOG)
guideline recommending testing of the specific gene(s) and
variants the test detects and recommended populations, if
available. If not available, a statement stating that professional
guidelines currently do not recommend testing for this specific
gene(s) and variants.
(3) Table of expected prevalence of carrier status in major ethnic and
racial populations and the general population.
(C) The specimen type (e.g., saliva, whole blood), matrix and volume.
(D) Assay steps and technology used.
(E) Specification of required ancillary reagents, instrumentation and
equipment

Page 4 Kathy Hibbs

(ii)

(F) Specification of the specimen collection, processing, storage and

preparation methods.
(G) Specification of risk mitigation elements and description of all additional
procedures, methods, and practices incorporated into the directions for use
that mitigate risks associated with testing.
(H) Information pertaining to the probability of test failure (e.g., failed quality
control) based on data from clinical samples, description of scenarios in
which a test can fail (i.e., low sample volume, low DNA concentration,
etc), how customers will be notified and follow-up actions to be taken.
(I) Specification of the criteria for test result interpretation and reporting.
Information that demonstrates the performance characteristics of the device,
including:
(A) Accuracy (method comparison) of study results for each claimed specimen
type.
(1) Accuracy of the device shall be evaluated with fresh clinical
specimens collected and processed in a manner consistent with the
devices 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 devices instructions for use, stored
appropriately and randomly selected. In some instances, use of
contrived samples or human cell line samples may also be
appropriate; the contrived or human cell line samples shall mimic
clinical specimens as much as is feasible and provide an unbiased
evaluation of the devices accuracy.
(2) Accuracy must be evaluated as compared to bidirectional
sequencing or other methods identified as appropriate by FDA.
Performance criteria for both the comparator method and device
must be pre-defined and appropriate to the tests intended use.
Detailed appropriate study protocols must be provided.
(3) Information provided shall include the number and type of
specimens, broken down by clinically relevant variants, that were
compared to bidirectional sequencing or other methods identified
as appropriate by FDA. The accuracy, defined as positive percent
agreement (PPA) and negative percent agreement (NPA), must be
measured, and, accuracy point estimates must be > 99% (both per
reported variant and overall), and uncertainty of the point estimate
must be presented using the 95% confidence interval. Clinical
specimens must include both homozygous wild type and
heterozygous genotypes. The number of clinical specimens for
each variant reported that must be included in the accuracy study
must be based on the variant prevalence. Common variants (>
0.1% allele frequency in ethnically relevant population) must have
at least 20 unique heterozygous clinical specimens tested. Rare
variants ( 0.1% allele frequency in ethnically relevant population)
shall have at least 3 unique mutant heterozygous specimens tested.

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Any no calls (i.e., absence of a result) or invalid calls (e.g., failed
quality control) in the study must be included in accuracy study
results and reported separately. Variants that have a point estimate
for PPA or NPA of < 99% (incorrect test results as compared to
bidirectional sequencing or other methods identified as appropriate
by FDA) must not be incorporated into test claims and reports.
Accuracy measures generated from clinical specimens versus
contrived samples or cell lines must be presented separately.
Results must be summarized and presented in tabular format, by
sample and by genotype. Point estimate of PPA should be
calculated as the number of positive results divided by the number
of specimens known to harbor variants (mutations) without no
calls or invalid calls and the point estimate of NPA should be
calculated as the number of negative results divided by the number
of wild type specimens tested, for each variant that is being
reported. Point estimates should be calculated along with 95%
two-sided confidence intervals.
(4) Information shall be reported on the clinical positive predictive
value (PPV) and the negative predictive value (NPV) for carrier
status (and where possible, for each variant) in each population.
(i) For the point estimates of PPA and NPA less than 100%,
use these point estimates in PPV and NPV calculations.
(ii) Point estimates of 100% may have high uncertainty. If
these variants are measured using highly multiplexed
technology, calculate the random error rate for the overall
device. The accuracy study described above 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 PPA and NPA as calculated above and
include in PPV and NPV calculations.
Specifically, to calculate PPV and NPV, estimate test coverage,
(TC) percent of persons with variant(s) included in the device
among all carriers.
PPV = (PPA*TC * ) / (PPA*TC* + (1- NPA) * (1-))
NPV = (NPA*(1- )) / (NPA*(1-) + (1- PPA*TC) * )
where PPA and NPA described either in i) or in ii) above and is
prevalence of carriers in the population (pre-test risk to be a carrier
for the disease)
(B) Precision (reproducibility) data must be generated using multiple
instruments and multiple operators, on multiple non-consecutive days, and
using multiple reagent lots. The sample panel must include specimens
with claimed sample type (e.g. saliva samples) representing different
genotypes (i.e., wild type, heterozygous). Performance criteria must be
pre-defined. A detailed study protocol must be created in advance of the
study and then followed. The failed quality control rate must be indicated.
It must be clearly documented whether results were generated from

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(iii)

clinical specimens, contrived samples, or cell lines. The study results

shall state, in a tabular format, the variants tested in the study and the
number of replicates for each variant, and what conditions were tested
(i.e., number of runs, days, instruments, reagent lots, operators,
specimens/type, etc). 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 must be evaluated). Any no calls or invalid calls
in the study must be listed as a part of the precision (reproducibility) study
results.
(C) Analytical specificity data: Data must be generated evaluating the test
performance effect of potential endogenous and exogenous interferents
relevant to the specimen type, evaluation of cross-reactivity of known
cross-reactive alleles and pseudogenes, and assessment of crosscontamination.
(D) Analytical sensitivity data: Data must be generated demonstrating the
minimum amount of DNA that will enable the test to perform correctly in
95% of runs.
(E) Device stability data: The manufacturer must establish upper and lower
limits of input nucleic acid and sample stability that will achieve the
claimed accuracy and reproducibility. Data supporting such claims must
be described.
(F) Specimen type and matrix comparison data must be generated if more than
one specimen type or anticoagulant can be tested with the device,
including failure rates for the different specimen types.
If the device is offered over-the-counter, including cases in which the test results
are provided direct-to-consumer, a study that assesses labeling comprehension
and test process by potential users of the test must be performed and a concise
summary of the results of the study provided in the labeling, including the
following:
(A) 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 in the test reports.
(B) The test manufacturer must provide a carrier testing education module to
potential and actual test report recipients. The module must define terms
that are used in the test reports and explain the significance of carrier
status.
(C) The user study must meet the following criteria:
(1) The study participants must be comprised of a statistically justified
and demographically diverse population (determined using
methods such as quota-based sampling) that is representative of the
intended user population. Furthermore, the users must be
comprised of a diverse range of age and educational levels that
have no prior experience with the test or its manufacturer. These
factors shall be well-defined in the inclusion and exclusion criteria.

Page 7 Kathy Hibbs

(2) All sources of bias (e.g., non-responders) must be pre-defined 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 onetime visit with a cap on the maximum amount of time that a
participant has to complete the tests).
(4) Users must be randomly assigned to study arms. Test reports
given to users must: a) define the condition being tested and
related symptoms; b) explain the intended use and limitations of
the test; c) explain the relevant ethnicities regarding the variant
tested; d) explain carrier status and relevance to the users
ethnicity; e) provide links to additional information pertaining to
situations where the user is concerned about their test results or
would like follow-up information as indicated in test labeling).
The study shall assess participants ability to understand the
following comprehension concepts: the tests limitations, purpose,
and results.
(5) Study participants must be untrained, nave to the test subject of
the study and be provided only the materials that will be available
to them when the test is marketed.
(6) The user comprehension study must meet the predefined primary
endpoint criteria, including a minimum of a 90% or greater overall
comprehension rate (i.e. selection of the correct answer) for each
comprehension concept to demonstrate that the education module
and test reports are adequate for over-the-counter use.
(D) The analysis of the user comprehension results must include:
(1) Results regarding reports that are provided for each
gene/variant/ethnicity tested.
(2) Statistical methods used to analyze all data sets.
(3) Completion rate, non-responder rate and reasons for nonresponse/data exclusion. A summary table of comprehension rates
regarding comprehension concepts (purpose of test, test results,
test limitations, ethnicity relevance for the test results, etc) for each
study report must be included.
(4) Your 21 CFR 809.10 compliant labeling and any test report generated must include the
following warning and limitation statements, as applicable:
(i)
A warning that reads The test is intended only for autosomal recessive carrier
screening in adults of reproductive age.
(ii)
A warning that reads This test [does not/may not (as appropriate)] detect all
genetic variants related to [genetic disease]. The absence of a variant tested does
not rule out the presence of other genetic variants that may be disease related.
(iii)
For prescription use tests, the following warnings that read:

Page 8 Kathy Hibbs

(iv)

(v)

(vi)

(vii)

(A) The results of this test are intended to be interpreted by a board-certified

clinical molecular geneticist or equivalent and should be used in
conjunction with other available laboratory and clinical information.
(B) This device is not intended for disease diagnosis, prenatal testing of
fetuses, risk assessment, prognosis or pre-symptomatic testing,
susceptibility testing, or newborn screening.
For over-the-counter tests, a statement that reads This test is not intended to
diagnose a disease, or tell you anything about your risk for developing a disease
in the future. On its own, this test is also not intended to tell you anything about
the health of your fetus, or your newborn childs risk of developing a particular
disease later on in life.
For over-the-counter tests, the following warnings that read:
(A) This test is not a substitute for visits to a healthcare provider. It is
recommended that you consult with a healthcare provider if you have any
questions or concerns about your results.
(B) The test does not diagnose any health conditions. Results should be used
along with other clinical information for any medical purposes
(C) The laboratory may not be able to process your sample. The probability
that the laboratory cannot process your saliva sample can be up to [actual
probability percentage].
(D) Your ethnicity may affect how your genetic health results are
interpreted.
For a positive result in an over-the-counter test when the positive predictive value
for a specific population is less than 50% and more than 5%, a warning that reads
The positive result you obtained may falsely identify you as a carrier. Consider
genetic counseling and follow-up testing.
For a positive result in an over-the-counter test when the positive predictive value
for a specific population is less than 5%, a warning that reads The positive result
you obtained is very likely to be incorrect due to the rarity of this variant.
Consider genetic counseling and follow-up testing.

(5) The testing done to meet section (3) must show the device meets or exceeds each of the
following performance specifications:
(i)
The accuracy must be shown to be equal to or greater than 99 percent for both
positive percent agreement (PPA) and negative percent agreement (NPA).
Variants that have a point estimate for PPA or NPA of <99% (incorrect test
results as compared to bidirectional sequencing or other methods identified as
appropriate by FDA) must not be incorporated into test claims and reports.
(ii)
Precision (reproducibility) performance must meet or exceed 99% for both
positive and negative results.
(iii)
The user comprehension study must obtain values of 90% or greater user
comprehension for each comprehension concept.
(6) The distribution of this device, excluding the collection device described in section (2),
shall be limited to the manufacturer, the manufacturers subsidiaries, and laboratories
regulated under the Clinical Laboratory Improvement Amendments.

Page 9 Kathy Hibbs

Section 510(m) of the FD&C Act provides that FDA may exempt a class II device from the
premarket notification requirements under section 510(k) of the FD&C Act if FDA determines that
premarket notification is not necessary to provide reasonable assurance of the safety and
effectiveness of the device type. FDA believes premarket notification is not necessary to provide
reasonable assurance of the safety and effectiveness of the device type and, therefore, is planning to
exempt the device from the premarket notification requirements of the FD&C Act. Accordingly,
FDA intends to issue a notice of intent to exempt an autosomal recessive carrier screening gene
mutation diagnostic system under Section 510(m) of the FD&C Act. If there are questions about
510(k) submission prior to finalization of the 510(k) exemption, you should contact FDA at the
number provided below. Once finalized, persons who intend to market this device type need not
submit a 510(k) premarket notification containing information on the autosomal recessive carrier
screening gene mutation diagnostic system prior to marketing the device.
Please be advised that FDAs decision to grant this de novo request does not mean that FDA has
made a determination that your device complies with other requirements of the FD&C Act or any
Federal statutes and regulations administered by other Federal agencies. You must comply with all
the FD&C Acts requirements, including, but not limited to: registration and listing (21 CFR Part
807); labeling (21 CFR Part 801 and 809); medical device reporting (reporting of medical devicerelated adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the
quality systems (QS) regulation (21 CFR Part 820); and, if applicable, the electronic product
radiation control provisions (Sections 531-542 of the FD&C Act); 21 CFR 1000-1050.
A notice announcing this classification order will be published in the Federal Register. A copy of
this order and supporting documentation are on file in the Dockets Management Branch (HFA-305),
Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852 and are
available for inspection between 9 a.m. and 4 p.m., Monday through Friday.
As a result of this order, you may immediately market your device as described in the de novo
request, subject to the general control provisions of the FD&C Act and the special controls identified
in this order.

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If you have any questions concerning this classification order, please contact Sunita Shukla at 301796-6406.
Sincerely yours,

Katherine Serrano -A
For: Courtney H. Lias, Ph.D.
Director
Division of Chemistry and Toxicology Devices
Office of In Vitro Diagnostics and
Radiological Health
Center for Devices and
Radiological Health